[Anatomical description of a natural perforation present in the human lumbar pia mater].
The pia mater has always been considered more permeable than other meningeal membranes. Natural pia mater perforations found in some animals at-test to this membrane's permeability. Such perforations, however, have never been demonstrated in human tissue. Our objective was to study human pia mater from the dorsal lumbar region, looking for perforations that facilitate the diffusion of substances to the spinal cord following subarachnoid administration. The specimens were removed from four human cadavers aged 70, 72, 77 and 78 years between 8 and 12 hours after death. The specimens were fixed in a phosphate glutaraldehyde buffer solution, followed by desiccation in acetone and critical point elimination of acetone, treatment with carbon and metallization with gold. The pia mater was composed of a smooth surfaced, thin layer of cells and underlying connective tissue formed mainly of collagen fibers and fundamental amorphous matter. The collagen fibers were oriented in various directions. Throughout the surface of the pia mater, natural circular, elliptical and ovoid perforations were distributed irregularly. Size varied. Most measured over 10 to 15 micrometers in diameter or less than 5 to 8 micrometers. Inside the openings, fibers similar to collagen fibers could be seen at the point where they would normally be found beneath the cell layer. The total thickness of the pia mater varies in different zones of the spine, as a result of variations in the thickness of the cell layer and in the underlying extracellular layer. The existence of natural fenestrations in all the analyzed specimens of human dorsal lumbar pia mater accounts for the high permeability of this membrane, which permits substances administered in spinal fluid to reach the spinal cord. These natural fenestrations are areas where the cell surface in absent, with underlying collagen fibers usually visible. The pia mater is generally believed to be composed of a complete cell layer that forms a barrier between the central nervous system and the subarachnoid space; however, the presence of fenestrations would indicate that such a barrier does not exist, the base membrane being placed under the connective fibers, the only intact structure prior to medullary glial cells.


Cystatin C and renal function in pediatric kidney transplant recipients.
In clinical practice, the glomerular filtration rate (GFR) is often determined with serum creatinine. However, studies have shown cystatin C to be a better parameter for the diagnosis of impaired renal function. We compared GFR estimated by plasma cystatin C with GFR estimated by serum creatinine in a sample of 50 pediatric renal transplant recipients and 24 healthy children. The correlation between GFR estimated by serum creatinine and by cystatin C was significant (r = 0.75; P < 0.001, Person's correlation); however, in pediatric kidney transplant recipients, the GFR was 6.7 mL/min lower when determined using cystatin C rather than serum creatinine. Moreover, using GFR estimated by cystatin C we found that 42% of the pediatric kidney transplant recipients had an estimated GFR <60 mL.min-1.1.73 (m(2))-1, whereas when GFR was estimated by the serum creatinine formula only 16% of the children had values below this cutoff point indicative of chronic kidney disease (P < 0.001). We conclude that, in pediatric kidney transplant recipients, estimation of GFR yields lower values when cystatin C is used rather than serum creatinine.


Asteraceae Paradox: Chemical and Mechanical Protection of Taraxacum Pollen.
Excessive pollen harvesting by bees can compromise the reproductive success of plants. Plants have therefore evolved different morphological structures and floral cues to narrow the spectrum of pollen feeding visitors. Among "filtering" mechanisms, the chemical and mechanical protection of pollen might shape bee-flower interactions and restrict pollen exploitation to a specific suite of visitors such as observed in Asteraceae. Asteraceae pollen is indeed only occasionally exploited by generalist bee species but plentifully foraged by specialist ones (i.e., Asteraceae paradox). During our bioassays, we observed that micro-colonies of generalist bumblebee (Bombus terrestris L.) feeding on Taraxacum pollen (Asteraceae) reduced their pollen collection and offspring production. Bees also experienced physiological effects of possible defenses in the form of digestive damage. Overall, our results suggest the existence of an effective chemical defense in Asteraceae pollen, while the hypothesis of a mechanical defense appeared more unlikely. Pre- and post-ingestive effects of such chemical defenses (i.e., nutrient deficit or presence of toxic compounds), as well as their role in the shaping of bee-flower interactions, are discussed. Our results strongly suggest that pollen chemical traits may act as drivers of plant selection by bees and partly explain why Asteraceae pollen is rare in generalist bee diets.


Migraine pathogenesis: the neural hypothesis reexamined.
The hypothesis that migraine is a primary neurological disturbance with secondary vascular manifestations is tested by analysing the five phases of migraine attacks and the eight groups of recognised precipitating factors. Accessory evidence from cerebral blood flow and EEG recordings taken during attacks is also considered. The evidence supports the concept that the sensory cortex and hypothalamus could be initiating sites for migraine attacks, and indicates that a neurological mechanism, suggested by Liveing and Gowers 100 years ago, remains viable and needs to be considered in future research.


Bridging the Gap: The Predictive Roles of Emotion Dysregulation and Stalking-related Attitudes on Offline and Online Stalking and Intrusive Harassment.
Stalking and intrusive harassment (SIH) are prevalent and serious public health issues associated with significant psychological, social, and economic consequences. Further exacerbating this problem is the growing use of technology and the internet, which has facilitated the perpetration of SIH behaviors via electronic means. Given its prevalence and negative impact, it is imperative to identify precursors of cyber and offline SIH to better predict and mitigate its detrimental effects. Thus, the current study examined whether overall emotion dysregulation and stalking-related attitudes are predictive factors of SIH perpetration. In addition, it was determined whether specific difficulties with emotion regulation and stalking supportive attitudes were differentially associated with online and offline SIH perpetration. Participants consisted of 874 university students who completed an online survey comprised of a battery of self-report measures, including the Difficulties with Emotion Regulation Scale, Stalking-related Attitudes Questionnaire, Obsessive-Relational Intrusion Pursuit Short Form, and the Cyber-Obsessional Pursuit scale. Logistic regression analyses revealed that overall emotion dysregulation and greater endorsement of stalking supportive attitudes predicted SIH perpetration. Moreover, emotion regulation difficulties distinguished the domain(s) in which an individual was more likely to perpetrate SIH behaviors. Specifically, those who reported more problems with emotion regulation, particularly a lack of emotional awareness, were more likely to engage in both offline and online SIH behaviors concurrently than to perpetrate purely offline or purely online. These findings have significant implications for stalking risk assessment and prevention efforts. In particular, understanding the predictive roles of emotion dysregulation and stalking-related attitudes on online and offline SIH perpetration can inform the development and improvement of evidence-based prevention and intervention programs, as well as stalking risk assessment instruments.


The radial sensory nerve. An anatomic study.
The superficial branch of the radial nerve was dissected using loupe magnification in 20 cadaver forearms. The nerve was found to arise between the tendons of the branchioradialis and extensor carpi radialis longus 8.6 cm proximal to the radial styloid, piercing the forearm fascia 6.0 cm from the radial styloid. An average of 5.8 branches crossed the wrist joint. Innervation to the dorsum of the digits was variable, with 45% of specimens innervating the radial 2 1/2 digits and 30% innervating the radial 3 1/2 digits. Sixteen specimens had branches directly overlying the typical transverse incision for De Quervain's release and 12 specimens had branches directly overlying the 3-4 wrist arthroscopy portal. An appreciation for the location of the superficial radial nerve in the forearm, the variation of its digital innervation, and the proximity of branches to commonly used surgical incisions is important when performing surgical procedures over the dorsum of the hand and wrist.


X-linked juvenile retinoschisis.
X-linked juvenile retinoschisis is an infrequently occurring inherited disease affecting males. Female carriers are phenotypically normal. A stellate or wheel-spoke macular cystic appearance is considered by some to be pathognomonic for the disease in early stages. One half of the cases also have peripheral retinal and vitreal defects. We review the fundus changes, histologic characteristics, visual course and electrophysiologic findings of the disease, and describe an illustrative case and its low vision management.


Serum paraoxonase and arylesterase activities and oxidative stress levels in patients with SSRI intoxication.
Oxidative stress is a critical route of damage in various psychological stress-induced disorders, such as depression. Paraoxonase-1 (PON1) plays an important role as an endogenous free-radical scavenging molecule. The aim of this study was to evaluate the influence of serum PON1 activity and oxidative stress in patients with selective serotonin reuptake inhibitor (SSRI) intoxication. A total of 11 patients with SSRI intoxication and 20 healthy controls were enrolled. The serum total antioxidant capacity (TAC) and malondialdehyde (MDA) levels, as well as the paraoxonase and arylesterase activities, were measured spectrophotometrically. The serum TAC levels and the paraoxonase and arylesterase activities were significantly lower (for all, p < 0.001), whereas the serum MDA levels were significantly higher in the patients with SSRI intoxication than in the controls (p < 0.001). These results indicated that decreased PON1 activity and increased oxidative stress represent alternative mechanisms in SSRI toxicity. More studies are needed to elucidate the role of PON1 activity in the etiology of SSRI intoxication.


Fluorides and dental fluorosis.
This paper attempts to review present knowledge on the ingestion and metabolism of fluoride in relation to the occurrence of endemic dental fluorosis, a condition caused by an excessive intake of fluoride during tooth formation. The clinical appearance of dental fluorosis is characterized by lustreless opaque white patches in the enamel which may become striated, mottled and/or pitted. The opaque areas may become stained yellow to dark brown. The affected teeth may show a pronounced accentuation of the perikymata and, in more severe cases, multiple pits and larger areas of hypoplasia of the enamel appear so that the normal morphology of the tooth is lost. Due to the universal presence of fluoride in water, soil and the atmosphere it is not surprising that humans are exposed to various levels of fluoride intake , not only through food and water, but in industrial and pharmaceutical products and other sources. Water-borne fluoride, however, has been said to represent the largest single component of this element's daily intake, except where unusual dietary patterns exist. The daily amount of fluoride intake through water varies with climate (maximum daily temperature) and age. It has been postulated that significant changes in patterns of food and beverage ingestion, because of changes in available products and the ways in which they are marketed as well as many foods and beverages being processed in fluoridated communities, may have caused a change in the prevalence and severity of dental fluorosis over the past 30 years. Since fluoride remains pre-eminent among the measures available for increasing the resistance of teeth to caries attack, continued and renewed research on the ingestion and metabolism still has high priority.


[Prevalence of anti-CCP antibodies in systemic sclerosis].
Joint involvement in systemic sclerosis (SSc) commonly occurs as arthralgias, while a true arthritis is less frequent. The most common arthritis developing in SSc is rheumatoid arthritis (RA) and its diagnosis may be misled by concomitant joint contracture or tendon sheath involvement due to SSc. Anti-citrullinated cyclic peptide (CCP) antibodies are an emerging tool to diagnose RA and have shown to be more specific than rheumatoid factor. We assessed the prevalence of anti-CCP antibodies in SSc patients and evaluated their sensitivity and specificity for associated RA. Searching for RF and anti-CCP antibodies and joint examination were carried out in sixty consecutive SSc patients. Hands and feet standard x-rays were performed in patients complaining with arthralgia and/or arthritis. Six out of sixty (10%) SSc patients had RA according to 1987 ARA revised criteria. Anti-CCP were detected in 5 patients (sensitivity 83%) and RF was present in all RA patients (sensitivity 100%). However, anti-CCP antibodies had a much higher specificity (94%) than RF (41%) for RA. Our study suggests that anti-CCP antibodies are a useful test to identify patients with SSc having also RA. This is crucial in the management of SSc because may allow an adequate therapy of RA and prevent further joint damage in patients who already have a poor quality of life.


Effects of interferon on vesicular stomatitis virus transcription and translation.
The effect of interferon on the synthesis of the RNA species and proteins of vesicular stomatitis virus has been studied in two cell types. Virus protein synthesis is inhibited by interferon despite the apparent presence of near normal amounts of virus RNA with sedimentation values characteristic of virus messenger RNA. The synthesis of those virus RNA species which are completely dependent on virus protein synthesis is preferentially inhibited in interferon-treated cells. These results are most consistent with a model of interferon action postulating a primary effect on translation of virus messenger RNA.


Polymers for Biomedical Applications: The Importance of Hydrophobicity in Directing Biological Interactions and Application Efficacy.
The past decades have seen significant research effort in the field of polymers for a range of biomedical applications, driven by the promising prospect of these materials for realizing next generation therapeutics in the clinic. In this regard, it is widely accepted that polymer properties such as chemistry, charge, and block composition, as well as properties of their self-assemblies including size, shape, surface chemistry, and biodegradation, all influence and direct their interactions with cells and biological membranes. In particular, polymer hydrophobicity is a property of interest, with growing evidence demonstrating the significant impact that hydrophobic interactions with lipid membranes and proteins can have on biomaterial application efficacy within the body. However, to date, this phenomenon has been relatively underexplored, and therefore there exists no clear universal understanding to direct polymer design. In this Perspective, we highlight important contributions to this field, focusing on seminal studies which investigate experimentally and theoretically how incorporation of hydrophobic moieties within polymer systems can influence their ultimate properties when used in biomedical applications. In this way, we aim to signify future directions in the design of highly performing polymers for biomedicine, making a case for the importance of standardized computational modeling to achieve widely applicable conclusions and facilitate future translational efforts.


Value of different methods for the characterisation of Aspergillus terreus strains.
To evaluate different methods for strain differentiation, 10 isolates of Aspergillus terreus from Germany and two epidemiologically unrelated strains were investigated. The sources of the isolates were patients with cystic fibrosis (4), immunosuppression (2), otitis externa (2), sinusitis (1) and endocarditis (1). Environmental isolates were obtained from a contaminated cell culture and from soil. The isolates did not differ in their macroscopic and microscopic morphology, in their protein patterns analysed by SDS-PAGE and in their susceptibility to amphotericin B and itraconazole. The RFLP analysis of total genomic DNA digested by EcoRI resulted in patterns that were too faint for interpretation. However, after hybridisation of the digested DNA with a short DNA probe of repetitive sequence, six different patterns were found. Based on the patterns of the randomly amplified polymorphic DNA (RAPD) with three primers, nine different genotypes were discriminate. RAPD patterns discriminated the epidemiologically unrelated reference strains (endocarditis isolate from Thailand, soil isolate from the USA) and the isolates from Germany. It is concluded that, in contrast to the phenotypic methods, the analysis of RAPD patterns is useful for strain differentiation of A. terreus.


In vivo antinociceptive activity of anti-rat mGluR1 and mGluR5 antibodies in rats.
To examine the specific roles of group I metabotropic glutamate receptors (mGluRs) in nociceptive processing, we examined the effects of intrathecal (i.t.) treatment with antibodies raised against the C-terminals of mGluR1 and mGluR5 in various rat pain models. The effects of anti-mGluR1 IgG and anti-mGluR5 IgG were assessed in a model of persistent pain induced by intrathecal administration of the mGluR1/5 agonist DHPG, as well as in models of heat pain (plantar test), chemical pain (formalin test) and neuropathic pain. DHPG-induced spontaneous nociceptive behaviours (SNB) were significantly attenuated by i.t. treatment with either anti-mGluR1 IgG (30 microg) or anti-mGluR5 IgG (10 and 30 microg). Neither anti-mGluR1 IgG (30 microg) nor anti-mGluR5 IgG (30 microg) significantly increased response latencies to noxious heat in the plantar test, compared with anti-rat IgG (control IgG). Moreover, neither antibody (30 microg) significantly reduced formalin pain scores as compared to control IgG. However, i.t. treatment with anti-mGluR1 IgG (30 microg) or anti-mGluR5 IgG (30 microg) significantly reduced cold hypersensitivity exhibited 8 days after constriction injury of the sciatic nerve, supporting the contention that group I mGluRs play a role in the development of neuropathic pain. Because these antibodies were effective against neuropathic pain, and not acute heat or chemical noxious stimuli, these results suggest that mGluRs are involved in nociceptive processing in chronic pain states rather than signaling acute noxious stimuli, and that DHPG-induced pain may be mediated by similar mechanisms as neuropathic pain.


Hepatoprotective effect of fullerenol/doxorubicin nanocomposite in acute treatment of healthy rats.
In our recent studies we have designed fullerenol/doxorubicin nanocomposite (FNP/DOX) as the new drug nanocarrier. This research has demonstrated that this novel nanocomposite has had better implications on the liver tissue in vivo (Wistar rats treated intraperitoneally), than treatment based only on DOX. FNP/DOX has been characterised by DLS, TEM and AFM measurements which have shown that DOX loaded onto FNP did not influence fullerenol nanoparticle's size. FNP/DOX affected oxidative status in blood causing a significant decrease of catalase and SOD activity in comparison to DOX, implicating the reduction in oxidative stress. qRT-PCR results on the mRNA level of antioxidative enzymes (catalase and MnSOD) revealed that the effect of oxidative stress is significantly reduced by the treatment with FNP/DOX (p < .05). The ultrastructural analysis of the liver tissue has revealed that FNP/DOX nanocomposite generated considerably less damage in the liver tissue, than DOX applied at the same dose. Hence, our results have indicated that FNP, within FNP/DOX nanocomposite, exhibits protective effects to the liver tissue of the healthy rats.


Educational and Health Outcomes of Children Treated for Type 1 Diabetes: Scotland-Wide Record Linkage Study of 766,047 Children.
This study was conducted to determine the association between childhood type 1 diabetes and educational and health outcomes. Record linkage of nine Scotland-wide databases (diabetes register, dispensed prescriptions, maternity records, hospital admissions, death certificates, annual pupil census, school absences/exclusions, school examinations, and unemployment) produced a cohort of 766,047 singleton children born in Scotland who attended Scottish schools between 2009 and 2013. We compared the health and education outcomes of schoolchildren receiving insulin with their peers, adjusting for potential confounders. The 3,330 children (0.47%) treated for type 1 diabetes were more likely to be admitted to the hospital (adjusted hazard ratio [HR] 3.97, 95% CI 3.79-4.16), die (adjusted HR 3.84, 95% CI 1.98-7.43), be absent from school (adjusted incidence rate ratio [IRR] 1.34, 95% CI 1.30-1.39), and have learning difficulties (adjusted odds ratio [OR] 1.19, 95% CI 1.03-1.38). Among children with type 1 diabetes, higher mean HbA1c (particularly HbA1c in the highest quintile) was associated with greater absenteeism (adjusted IRR 1.75, 95% CI 1.56-1.96), increased school exclusion (adjusted IRR 2.82, 95% CI 1.14-6.98), poorer attainment (adjusted OR 3.52, 95% CI 1.72-7.18), and higher risk of unemployment (adjusted OR 2.01, 95% CI 1.05-3.85). Children with type 1 diabetes fare worse than their peers in respect of education and health outcomes, especially if they have higher mean HbA1c. Interventions are required to minimize school absence and ensure that it does not affect educational attainment.


Assessment of total phenolic content and antioxidant potential of methanol extract of Peltophorum pterocarpum (DC.) Backer ex K. Heyne.
Plants are rich in a variety of chemical compounds. Many are secondary metabolites including aromatic substances most of them are phenols or their oxygen substituted derivatives. Medicinal plants are rich in antioxidant constituents such as phenols, tocopherols, ascorbic acid, carotenoids, and flavonoids etc. They are found to acquire free radical scavenging activity and used worldwide for the treatment of various immune system dependent diseases. Peltophorum pterocarpum (DC) Backer ex K. Heyne (Caesalpiniaceae) is a beautiful ornamental tree, widely grown in tropical regions and its parts are used in traditional medicine as medicinal agents. Fresh pods of Peltophorum pterocarpum was evaluated for its antioxidant potential by using various methods including DPPH, superoxide anion, nitric oxide scavenging, and metal chelating activity. TPC via Folin-Ciocalteau's reagent and anti haemolytic activity red blood cells respectively have also been measured. The methanol extract of pods of Peltophorum pterocarpum was found to possess the significant amount 439.21±0.17 mg GAE (gallic acid equivalents) / g of TPC. The antioxidant potential of pods extract at mature stage showed potent activity and measured as, free radical scavenging activity 73.29±0.81%, superoxide anion scavenging activity 89.03±1.07%, nitric oxide scavenging activity 84.25±1.18%, and metal chelating activity 64.12±0.11%. The extract also showed potent anti haemolytic activity 79.09± 0.75%. Peltophorum pterocarpum exhibited strong but varying level of antioxidant and anti haemolytic activity in various methods along with total phenolic contents.


Topical Steroid Awareness and Abuse: A Prospective Study among Dermatology Outpatients.
Topical steroids are one of the most commonly abused drugs. There are only a few studies available which have highlighted the severity of this problem in India. However, these studies have concentrated mainly on the topical steroid abuse and its side effects over the face. The aim of this study was to know the awareness among the people about various commonly available topical steroids and their combinations irrespective of usage and to know the extent of misuse of these drugs. Along with this, we also tried to find the source of recommendation of these medicines which will help to sensitize people about this menace. This was a prospective, questionnaire-based study done at a tertiary care hospital. A total of 1000 adult patients attending the dermatology outpatient department were administered a questionnaire about awareness and usage of topical steroid and its combinations. A total of 1000 adult patients were included in the study, out of which 809 (80.9%) patients had heard about at least one of the topical steroids or its combinations mentioned in the questionnaire. Six hundred and twelve (61.2%) patients had used these creams. Acne and pigmentation were the most common indications for which topical steroid was used. These medicines were recommended by general practitioners in 302 (49.5%) patients and pharmacists in 71 (11.6%) patients. Totally, 318 (51.9%) patients complained of some form of side effect after using these creams. Aggravation of the symptoms and increased pigmentation were the most common adverse effects. Misuse of topical steroids not just over the face but also as a cream for any skin problem is quite common. Most of the times, it is recommended by general practitioners or pharmacists. It is very important to sensitize these people about the possible complications of these drugs and the extent of problem the society is facing because of irrational and unregulated use of these drugs.


Systematic identification of small molecule adjuvants.
Adjuvants potentiate immune responses, reducing the amount and dosing frequency of antigen required for inducing protective immunity. Adjuvants are of special importance when considering subunit, epitope-based or more unusual vaccine formulations lacking significant innate immunogenicity. While numerous adjuvants are known, only a few are licensed for human use; principally alum, and squalene-based oil-in-water adjuvants. Alum, the most commonly used, is suboptimal. There are many varieties of adjuvant: proteins, oligonucleotides, drug-like small molecules and liposome-based delivery systems with intrinsic adjuvant activity being perhaps the most prominent. This article focuses on small molecules acting as adjuvants, with the author reviewing their current status while highlighting their potential for systematic discovery and rational optimisation. Known small molecule adjuvants (SMAs) can be synthetically complex natural products, small oligonucleotides or drug-like synthetic molecules. The author provides examples of each class, discussing adjuvant mechanisms relevant to SMAs, and exploring the high-throughput discovery of SMAs. SMAs, particularly synthetic drug-like adjuvants, are amenable to the plethora of drug-discovery techniques able to optimise the properties of biologically active small molecules. These range from laborious synthetic modifications to modern, rational, effort-efficient computational approaches, such as QSAR and structure-based drug design. In principal, any property or characteristic can thus be designed in or out of compounds, allowing us to tailor SMAs to specific biological functions, such as targeting specific cells or pathways, in turn affording the power to tailor SMAs to better address different diseases.


Database of normal human cerebral blood flow measured by SPECT: I. Comparison between I-123-IMP, Tc-99m-HMPAO, and Tc-99m-ECD as referred with O-15 labeled water PET and voxel-based morphometry.
Three accumulative tracers, iodine-123-labeled N-isopropyl-p-iodoamphetamine (I-123-IMP), technetium-99m-labeled hexamethylpropyleneamineoxime (Tc-99m-HMPAO), and technetium-99m-labeled ethyl cysteinate dimer (Tc-99m-ECD) are widely used to measure cerebral blood flow (CBF) in single-photon emission computed tomography (SPECT). In the present study, normal regional distribution of CBF measured with three different SPECT tracers was entered into a database and compared with regional distribution of CBF measured by positron emission tomography (PET) with H2(15)O. The regional distribution of tissue fractions of gray matter determined by voxel-based morphometry was also compared with SPECT and PET CBF distributions. SPECT studies with I-123-IMP, Tc-99m-HMPAO, and Tc-99m-ECD were performed on 11, 20, and 17 healthy subjects, respectively. PET studies were performed on 11 healthy subjects. Magnetic resonance (MR) imaging studies for voxel-based morphometry were performed on 43 of the 48 subjects who underwent SPECT study. All SPECT, PET, and MR images were transformed into the standard brain format with the SPM2 system. The voxel values of each SPECT and PET image were globally normalized to 50 ml/100 ml/min. Gray matter, white matter, and cerebrospinal fluid images were segmented and extracted from all transformed MR images by applying voxel-based morphometry methods with the SPM2 system. Regional distribution of all three SPECT tracers differed from that of H2150 in the pons, midbrain, thalamus, putamen, parahippocampal gyrus, posterior cingulate gyrus, temporal cortex, and occipital cortex. No significant correlations were observed between the tissue fraction of gray matter and CBF with any tracer. Differences in regional distribution of SPECT tracers were considered to be caused mainly by differences in the mechanism of retention of tracers in the brain. Regional distribution of CBF was independent of regional distribution of gray matter fractions, and consequently the blood flow per gray matter volume differed for each brain region.


Continuous thermal collapse of the intrinsically disordered protein tau is driven by its entropic flexible domain.
The tau protein belongs to the category of Intrinsically Disordered Proteins (IDP), which in their native state lack a folded structure and fluctuate between many conformations. In its physiological state, tau helps nucleating and stabilizing the microtubules' (MTs) surfaces in the axons of the neurons. Tau is mainly composed by two domains: (i) the binding domain that tightly bounds the MT surfaces and (ii) the projection domain that exerts a long-range entropic repulsive force and thus provides the proper spacing between adjacent MTs. Tau is also involved in the genesis and in the development of the Alzheimer disease when it detaches from MT surfaces and aggregates in paired helical filaments. Unfortunately, the molecular mechanisms behind these phenomena are still unclear. Temperature variation, rarely considered in biological studies, is here used to provide structural information on tau correlated to its role as an entropic spacer between adjacent MTs surfaces. In this paper, by means of small-angle X-ray scattering and molecular dynamics simulation, we demonstrate that tau undergoes a counterintuitive collapse phenomenon with increasing temperature. A detailed analysis of our results, performed by the Ensemble Optimization Method, shows that the thermal collapse is coupled to the occurrence of a transient long-range contact between a region encompassing the end of the proline-rich domain P2 and the first part of the repeats domain, and the region of the N-terminal domain entailing residues 80-150. Interestingly these two regions involved in the tau temperature collapse belong to the flexible projection domain that acts as an entropic bristle and regulates the MTs' architecture. Our results show that temperature is an important parameter that influences the dynamics of the tau projection domain, and hence its entropic behavior.


Selenium Attenuates HPV-18 Associated Apoptosis in Embryo-Derived Trophoblastic Cells but Not Inner Cell Mass In Vitro.
Objectives. Human papillomaviruses (HPV) are associated with cell cycle arrest. This study focused on antioxidant selenomethionine (SeMet) inhibition of HPV-mediated necrosis. The objectives were to determine HPV-18 effects on embryonic cells and to evaluate SeMet in blocking HPV-18 effects. Methods. Fertilized mouse embryos were cultured for 5 days to implanted trophoblasts and exposed to either control medium (group 1), HPV-18 (group 2), combined HPV-18 and 0.5 µM SeMet (group 3), or combined HPV-18 and 5.0 µM SeMet (group 4). After 48 hrs, trophoblast integrity and, apoptosis/necrosis were assessed using morphometric and dual-stain fluorescence assays, respectively. Results. HPV-18 exposed trophoblasts nuclei (253.8 ± 28.5 sq·µ) were 29% smaller than controls (355.6 ± 35.9 sq·µ). Supplementation with 0.5 and 5.0 µM SeMet prevented nuclear shrinkage after HPV-18 exposure. HPV-18 infected trophoblasts remained larger with SeMet supplementation. HPV-18 decreased cell viability by 44% but SeMet supplementation sustained cell viability. Apoptosis was lower when SeMet was present. HPV-18 decreased inner cell mass (ICM) viability by over 60%. Conclusions. HPV-18 decreased nuclear size and trophoblast viability but these effects were attenuated by the antioxidant SeMet. SeMet blocked HPV-18 associated apoptosis process in trophoblasts but not ICM cells suggesting involvement of different oxidative stress pathways.


The reliability of a deep learning model in clinical out-of-distribution MRI data: A multicohort study.
Deep learning (DL) methods have in recent years yielded impressive results in medical imaging, with the potential to function as clinical aid to radiologists. However, DL models in medical imaging are often trained on public research cohorts with images acquired with a single scanner or with strict protocol harmonization, which is not representative of a clinical setting. The aim of this study was to investigate how well a DL model performs in unseen clinical datasets-collected with different scanners, protocols and disease populations-and whether more heterogeneous training data improves generalization. In total, 3117 MRI scans of brains from multiple dementia research cohorts and memory clinics, that had been visually rated by a neuroradiologist according to Scheltens' scale of medial temporal atrophy (MTA), were included in this study. By training multiple versions of a convolutional neural network on different subsets of this data to predict MTA ratings, we assessed the impact of including images from a wider distribution during training had on performance in external memory clinic data. Our results showed that our model generalized well to datasets acquired with similar protocols as the training data, but substantially worse in clinical cohorts with visibly different tissue contrasts in the images. This implies that future DL studies investigating performance in out-of-distribution (OOD) MRI data need to assess multiple external cohorts for reliable results. Further, by including data from a wider range of scanners and protocols the performance improved in OOD data, which suggests that more heterogeneous training data makes the model generalize better. To conclude, this is the most comprehensive study to date investigating the domain shift in deep learning on MRI data, and we advocate rigorous evaluation of DL models on clinical data prior to being certified for deployment.


Serum uric acid level predicts the progression of amyotrophic lateral sclerosis following treatment with edaravone.
Uric acid and edaravone might exert a neuroprotective effect in amyotrophic lateral sclerosis (ALS) by reducing oxidative stress. We analyzed whether the treatment effect of edaravone is pronounced in patients whose uric acid level increased after the treatment with edaravone. Forty patients with ALS who underwent treatment with edaravone were included. Baseline uric acid level and the rate of decline in uric acid after edaravone treatment were recorded. The rate of change of ALS functional rating scale-revised (ΔALSFRS-R/month) was calculated based on baseline ALSFRS-R score and ALSFRS-R score 6-24 weeks after the treatment. The serum uric acid levels decreased after treatment in 26 (65%) patients and increased in 12 (30%) patients. The ΔALSFRS-R/month was significantly faster in patients whose uric acid decreased (median 1.5 [Q1-Q3, 0.7-3.1]) than in patients whose uric acid increased (0.2 [0-1.0], p = 0.021). A high baseline uric acid level and low rate of decline in uric acid was associated with slower disease progression after adjusting for age, initial symptoms, and riluzole administration (p = 0.030 and p = 0.041, respectively). High baseline values and low rate of decline in uric acid may predict slow disease progression in ALS patients treated with edaravone.


Gonadotropin-releasing hormone agonists suppress melanoma cell motility and invasiveness through the inhibition of alpha3 integrin and MMP-2 expression and activity.
Cutaneous melanoma represents the leading cause of skin cancer deaths. The prognosis of highly aggressive, metastatic melanoma is still very poor, due to the resistance of the disseminated tumor to existing therapies. The clarification of the molecular mechanisms regulating melanoma growth and progression might help identify novel molecular targets for the development of new therapeutic interventions. We previously showed that gonadotropin-releasing hormone (GnRH) receptors are expressed in melanoma cells; activation of these receptors by means of GnRH agonists significantly reduces cell proliferation. In the current study, we first showed that GnRH agonists significantly reduced the metastatic behavior of melanoma cells in terms of both cell motility (haptotactic assay using laminin as the chemoattractant) and invasiveness (cell invasion assay evaluating the capacity of the cells to invade a reconstituted extracellular matrix barrier). On the basis of this observation, we then investigated the molecular mechanisms underlying the antimetastatic activity of GnRH agonists. We found that, in melanoma cells, a) the activity of the alpha3 integrin subunit is crucial for the migratory behavior of the cells; b) GnRH agonists significantly reduced alpha3 integrin expression (Western blotting and immunofluorescence studies); c) GnRH agonists significantly reduced MMP-2 expression (comparative RT-PCR) and activity (zymographic analysis performed on cell culture media). These data indicate that GnRH agonists, in addition to the previously reported antiproliferative effect, elicit a strong inhibitory activity on the migratory/invasive behavior of melanoma cells expressing GnRH receptors. These compounds reduce the metastatic potential of melanoma cells by interfering with the expression/activity of cell adhesion molecules (alpha3 integrin) and matrix metalloproteinase (MMP-2).


Heterotopic calcification in abdominal wounds.
Heterotopic bone formation in abdominal incisions is a recognized but uncommon sequela of abdominal surgery. The condition of heterotopic bone formation in the abdominal scar may not only cause physical and/or emotional discomfort for the patient but also mimic a retained foreign body or recurrence of a malignant condition. All cases of two surgeons representing a wide variety of general and thoracic surgery were reviewed, and three primary cases and one recurrent case of heterotopic bone formation in an abdominal wound were identified. These cases are compared with the cases available in the English literature to enhance the recognition, appropriate diagnosis, and treatment options available for the patient with this unusual condition. All cases for two surgeons representing a variety of general and thoracic surgery were reviewed. Three patients with painful heterotopic calcification of an abdominal incision requiring excision were identified. One patient had undergone an upper midline laparotomy for pancreatitis and the other two had undergone median sternotomy for cardiac surgery. One of these patients developed a painful recurrence of upper linea alba calcification. All patients were male and ranged in age from 51 to 74 years. Primary heterotopic calcification of the upper linea alba occurred between 2 and 4 months for all patients. All cases were treated with excision and primary tissue closure. The case of recurrent calcification occurred 1 1/2 months after primary closure, and was treated with re-excision and 1,200 centirads of postoperative radiotherapy to the incision area over 3 days, starting on postoperative day 1. The 2 cases of primary heterotopic calcification successfully treated with the initial excision have been followed for 2 and 6 years respectively without recurrence. The case of recurrent heterotopic calcification treated with re-excision and postoperative radiotherapy has been followed for 10 months without recurrence.


Molecular dynamics simulations of viral RNA polymerases link conserved and correlated motions of functional elements to fidelity.
The viral RNA-dependent RNA polymerase (RdRp) is essential for multiplication of all RNA viruses. The sequence diversity of an RNA virus population contributes to its ability to infect the host. This diversity emanates from errors made by the RdRp during RNA synthesis. The physical basis for RdRp fidelity is unclear but is linked to conformational changes occurring during the nucleotide-addition cycle. To understand RdRp dynamics that might influence RdRp function, we have analyzed all-atom molecular dynamics simulations on the nanosecond timescale of four RdRps from the picornavirus family that exhibit 30-74% sequence identity. Principal component analysis showed that the major motions observed during the simulations derived from conserved structural motifs and regions of known function. The dynamics of residues participating in the same biochemical property, for example, RNA binding, nucleotide binding or catalysis, were correlated even when spatially distant on the RdRp structure. The conserved and correlated dynamics of functional structural elements suggest coevolution of dynamics with structure and function of the RdRp. Crystal structures of all picornavirus RdRps exhibit a template-nascent RNA duplex channel too small to fully accommodate duplex RNA. Simulations revealed opening and closing motions of the RNA and nucleoside triphosphate channels, which might be relevant to nucleoside triphosphate entry, inorganic pyrophosphate exit and translocation. A role for nanosecond timescale dynamics in RdRp fidelity is supported by the altered dynamics of the high-fidelity G64S derivative of PV RdRp relative to wild-type enzyme.


Efficacy of TachoSil patches in controlling Dacron suture-hole bleeding after abdominal aortic aneurysm open repair.
The aim of this study is evaluate the efficacy of TachoSil patches in controlling suture-hole bleeding after elective infrarenal abdominal aortic aneurysm (AAA) replacement with Dacron graft. Patients undergoing elective replacement of infrarenal AAA with Dacron grafts were prospectively randomized to TachoSil patches (Group I) or standard compression with surgical swabs (Group II).We evaluated time to haemostasis, blood loss during the operation, blood loss after cross-clamp removal, duration of operation, drain volume, requirement for blood transfusion and surgeons rating of efficacy. Twenty patients were randomized (10 patients in each treatment Group). The mean time to haemostasis was 264 +/- 127.1 s (range: 180-600 s) in Group I and 408 +/- 159.5 s (range: 120-720 s) in Group II (p = 0.026); mean blood loss during the operation was 503.5 +/- 20.7 cc (range: 474-545 cc) in Group I and 615.7 +/- 60.3 cc (range: 530-720 cc) in Group II (p < 0.001); mean blood loss after cross-clamp removal was 26.5 +/- 4 g (range: 22-34 g) in Group I and 45.4 +/- 4.6 (range: 38-52 g) in Group II (p < 0.001) and mean drain volume was 116.7 +/- 41.4 cc (range: 79-230 cc) in Group I and 134.5 +/- 42.8 cc (range: 101-250 cc) in Group II (p = 0.034). There were no serious adverse events associated with use of TachoSil patches. For patients undergoing aortic reconstruction with Dacron grafts, TachoSil patches were found to be safe and effective for the control of suture-hole bleeding.


Chromatin-dependent regulation of RNA polymerases II and III activity throughout the transcription cycle.
The particular behaviour of eukaryotic RNA polymerases along different gene regions and amongst distinct gene functional groups is not totally understood. To cast light onto the alternative active or backtracking states of RNA polymerase II, we have quantitatively mapped active RNA polymerases at a high resolution following a new biotin-based genomic run-on (BioGRO) technique. Compared with conventional profiling with chromatin immunoprecipitation, the analysis of the BioGRO profiles in Saccharomyces cerevisiae shows that RNA polymerase II has unique activity profiles at both gene ends, which are highly dependent on positioned nucleosomes. This is the first demonstration of the in vivo influence of positioned nucleosomes on transcription elongation. The particular features at the 5' end and around the polyadenylation site indicate that this polymerase undergoes extensive specific-activity regulation in the initial and final transcription elongation phases. The genes encoding for ribosomal proteins show distinctive features at both ends. BioGRO also provides the first nascentome analysis for RNA polymerase III, which indicates that transcription of tRNA genes is poorly regulated at the individual copy level. The present study provides a novel perspective of the transcription cycle that incorporates inactivation/reactivation as an important aspect of RNA polymerase dynamics.


Biological clocks and rhythms in intertidal crustaceans.
Animals with habitats within the intertidal zone are exposed to environmental cycles that include the ebb and flow of tidal waters, changes in tidal levels associated with the lunar month, the light-dark cycle and the alternation of seasons. This intricate temporal environment results in the selection of biological timing systems with endogenous clocks that can oscillate with this wide range of periodicities. Whereas great progress has been made in our understanding of the molecular and neural bases of circadian rhythms, that is, endogenous rhythms synchronized to the solar day, there is little understanding on how circatidal rhythms, namely endogenous rhythms synchronized to tides, are generated. Intertidal crustaceans have been a pivotal group for the demonstration of the endogenous nature of circatidal rhythms and their mechanisms of entrainment. We review here some of the classic work using intertidal crustaceans to unmask basic properties of circatidal systems, as well as work from our laboratory that aims to identify putative chemical signals that could be involved in the circatidal systems of decapod crustaceans.


Traditional Chinese medicine in rehabilitation nursing practice.
Traditional Chinese medicine (TCM) employs methods of treatment such as acupuncture, acupressure, and Qi Gong (treatment based on meditation). The nurse using TCM can affect rehabilitation patient outcomes positively. With TCM training, nurses have an opportunity to learn the nuances of the Oriental environment and integrate them into their skills to nurse the spirit, mind, and body of patients in a holistic manner.


Chemoattractants MDC and TARC are secreted by malignant B-cell precursors following CD40 ligation and support the migration of leukemia-specific T cells.
The use of tumor cells as vaccines in cancer immunotherapy is critically dependent on their capacity to initiate and amplify tumor-specific immunity. Optimal responses may require the modification of the tumor cells not only to increase their immunogenicity but also to improve their ability to recruit effector cells to the tumor sites or sites of tumor antigen exposure. It has been reported that CD40 cross-linking of acute lymphoblastic leukemia (ALL) cells significantly increases their immunogenicity and allows the generation and expansion of autologous antileukemia cytotoxic T lymphocytes. This study demonstrates that the CD40 ligation of these tumor cells also induces the secretion of the CC-chemokines MDC and TARC. Supernatants from malignant cells cultured in the presence of sCD40L promote the migration of activated T cells that express CCR4, the common specific receptor for MDC and TARC. More importantly, the supernatants from CD40-stimulated tumor cells also support the transendothelial migration of autologous CCR4(+) antileukemia T cells. Therefore, the results demonstrate that the delivery to leukemia cells of a single physiologic signal, that is, CD40 cross-linking, simultaneously improves tumor cell immunogenicity and induces potent chemoattraction for T cells. (Blood. 2001;98:533-540)


Fluorescent protein fusions to a human immunodeficiency virus monoclonal antibody reveal its intracellular transport through the plant endomembrane system.
In order to further understand the production and intracellular trafficking of pharmaceutical proteins in plants, the light and heavy chains (LC and HC) of the human immunodeficiency virus neutralizing monoclonal antibody 2G12 were fused to fluorescent proteins [Venus and monomeric red fluorescent protein (mRFP)] to enable the visualization of their passage through the plant cell. Co-expression of LC and HC with various markers of the endomembrane system demonstrated that LC fusions were found in mobile punctate structures, which are likely to be pre-vacuolar compartments (PVCs) as a proportion of the LC fusions were found to be located in the vacuole. In addition, apoplast labelling was also observed with a 2G12LC-RFP fusion. The HC fusion expressed alone was found only in the endoplasmic reticulum (ER). When the LC and HC fusions were expressed together, they were found to co-locate to larger punctate structures, which were morphologically distinct from any observed on expression of LC or HC alone. These structures appeared to be in close association with the ER and their labelling partially overlapped with PVC marker fluorescence, but no increase in apoplast labelling was observed. Co-immunoprecipitation data demonstrated that the presence of the fluorescent proteins did not affect the assembly of the antibody, and also showed the association of BiP with the antibody chains. The antigen-binding activity of the Venus-fused 2G12 antibody was confirmed by enzyme-linked immunosorbent assay.


A survey on missing data in machine learning.
Machine learning has been the corner stone in analysing and extracting information from data and often a problem of missing values is encountered. Missing values occur because of various factors like missing completely at random, missing at random or missing not at random. All these may result from system malfunction during data collection or human error during data pre-processing. Nevertheless, it is important to deal with missing values before analysing data since ignoring or omitting missing values may result in biased or misinformed analysis. In literature there have been several proposals for handling missing values. In this paper, we aggregate some of the literature on missing data particularly focusing on machine learning techniques. We also give insight on how the machine learning approaches work by highlighting the key features of missing values imputation techniques, how they perform, their limitations and the kind of data they are most suitable for. We propose and evaluate two methods, the k nearest neighbor and an iterative imputation method (missForest) based on the random forest algorithm. Evaluation is performed on the Iris and novel power plant fan data with induced missing values at missingness rate of 5% to 20%. We show that both missForest and the k nearest neighbor can successfully handle missing values and offer some possible future research direction.


Recyclable chemosensor for oxalate based on bimetallic complexes of a dinucleating bis(iminopyridine) ligand.
Herein we describe bimetallic di-nickel and di-copper complexes [Ni2(L)Br4] (1) and [Cu2(L)Br4(NCMe)2] (2) (L = (1E,1'E)-N,N'-(1,4-phenylenebis(methylene))bis(1-(6-(2,4,6-triisopropylphenyl)pyridin-2-yl)methanimine)) that bind oxalate intramolecularly to form [Ni2(L)Br2(C2O4)(NCMe)] (3) and [Cu2(L)Br2(C2O4)] (4). For the di-nickel complex 1, oxalate incorporation is accompanied by a significant colour change, from red-pink (1) to deep green (3). Mass spectrometric experiments demonstrate that the compound 1 is selective for oxalate versus related mono- and di-carboxylates tested. Oxalate can be released by the addition of slight excess of calcium bromide that forms insoluble calcium oxalate and restores the original Ni2(L)Br4 species. The product of the oxalate release was crystallized as [Ni2(L)Br4]·CaBr2(THF)4 species.


High-temperature ratchets driven by deterministic and stochastic fluctuations.
We consider the overdamped dynamics of a Brownian particle in an arbitrary spatial periodic and time-dependent potential on the basis of an exact solution for the probability density in the form of a power series in the inverse friction coefficient. The expression for the average velocity of a Brownian ratchet is simplified in the high-temperature consideration when only the first terms of the series can be used. For the potential of an additive-multiplicative form (a sum of a time-independent contribution and a time-dependent multiplicative perturbation), general explicit expressions are obtained which allow comparative analysis of frequency dependencies of the average velocity, implying deterministic and stochastic potential energy fluctuations. For qualitative and quantitative analysis of these dependences, we choose illustrative examples for spatial harmonic fluctuations: with deterministic time dependences of a relaxation type and stochastic time dependences describing Markovian dichotomous and harmonic noise processes. We explore the influence of fluctuation types on the ratchet effect and demonstrate its enhancement in the case of harmonic noise.


Processing of musical structure by high-functioning adolescents with autism spectrum disorders.
Enhanced pitch perception and memory have been cited as evidence of a local processing bias in autism spectrum disorders (ASD). This bias is argued to account for enhanced perceptual functioning ( Mottron & Burack, 2001 ; Mottron, Dawson, Soulières, Hubert, & Burack, 2006 ) and central coherence theories of ASD ( Frith, 1989 ; Happé & Frith, 2006 ). A local processing bias confers a different cognitive style to individuals with ASD ( Happé, 1999 ), which accounts in part for their good visuospatial and visuoconstructive skills. Here, we present analogues in the auditory domain, audiotemporal or audioconstructive processing, which we assess using a novel experimental task: a musical puzzle. This task evaluates the ability of individuals with ASD to process temporal sequences of musical events as well as various elements of musical structure and thus indexes their ability to employ a global processing style. Musical structures created and replicated by children and adolescents with ASD (10-19 years old) and typically developing children and adolescents (7-17 years old) were found to be similar in global coherence. Presenting a musical template for reference increased accuracy equally for both groups, with performance associated to performance IQ and short-term auditory memory. The overall pattern of performance was similar for both groups; some puzzles were easier than others and this was the case for both groups. Task performance was further found to be correlated with the ability to perceive musical emotions, more so for typically developing participants. Findings are discussed in light of the empathizing-systemizing theory of ASD ( Baron-Cohen, 2009 ) and the importance of describing the strengths of individuals with ASD ( Happé, 1999 ; Heaton, 2009 ).


Critical appraisal of emergency medicine educational research: the best publications of 2010.
The objective was to critically appraise and highlight medical education research studies published in 2010 that were methodologically superior and whose outcomes were pertinent to teaching and education in emergency medicine (EM). A search of the English language literature in 2010 querying PubMed, Scopus, Education Resources Information Center (ERIC), and PsychInfo identified 41 EM studies that used hypothesis-testing or observational investigations of educational interventions. Five reviewers independently ranked all publications based on 10 criteria, including four related to methodology, that were chosen a priori to standardize evaluation by reviewers. This method was used previously to appraise medical education published in 2008 and 2009. Five medical education research studies met the a priori criteria for inclusion and are reviewed and summarized here. Comparing the literature of 2010 to 2008 and 2009, the number of published educational research papers increased from 30 to 36 and then to 41. The number of funded studies remained fairly stable over the past 3 years at 13 (2008), 16 (2009), and 9 (2010). As in past years, research involving the use of technology accounted for a significant number of publications (34%), including three of the five highlighted studies. Forty-one EM educational studies published in 2010 were identified. This critical appraisal reviews and highlights five studies that met a priori quality indicators. Current trends and common methodologic pitfalls in the 2010 papers are noted.


PPARα Modulation-Based Therapy in Central Nervous System Diseases.
The burden of neurodegenerative diseases in the central nervous system (CNS) is increasing globally. There are various risk factors for the development and progression of CNS diseases, such as inflammatory responses and metabolic derangements. Thus, curing CNS diseases requires the modulation of damaging signaling pathways through a multitude of mechanisms. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors (PPARα, PPARβ/δ, and PPARγ), and they work as master sensors and modulators of cellular metabolism. In this regard, PPARs have recently been suggested as promising therapeutic targets for suppressing the development of CNS diseases and their progressions. While the therapeutic role of PPARγ modulation in CNS diseases has been well reviewed, the role of PPARα modulation in these diseases has not been comprehensively summarized. The current review focuses on the therapeutic roles of PPARα modulation in CNS diseases, including those affecting the brain, spinal cord, and eye, with recent advances. Our review will enable more comprehensive therapeutic approaches to modulate PPARα for the prevention of and protection from various CNS diseases.


Oculomotor performance in obsessive-compulsive disorder.
Neuroimaging studies have shown abnormalities of the frontal cortex and basal ganglia in persons with obsessive-compulsive disorder. Since lesions in the frontal cortex and basal ganglia areas affect performance on goal-guided saccadic eye movements, this study investigated the relation between the diagnosis of obsessive-compulsive disorder and oculomotor performance. Eleven patients with the clinical diagnosis of obsessive-compulsive disorder and 14 normal subjects were assessed with respect to their performance on both visual-guided and goal-guided oculomotor tasks. Fixation performance was also measured. The group with obsessive-compulsive disorder had a very significantly greater error rate and a significantly greater rate of inaccurate saccades on the goal-guided antisaccade task, whereas they were not different from the normal group in reaction time, saccadic velocity, and accuracy on the visual-guided saccade task. The distribution of error rates for the patients with obsessive-compulsive disorder was broad, with more than one-half outside the range of the normal group. Most of the abnormal findings were among male patients. The results support the hypothesis of a relationship between impaired performance on goal-guided saccadic eye movement tasks and the diagnosis of obsessive-compulsive disorder, but they also suggest a gender-related subgroup within the group with obsessive-compulsive disorder.


Perceiving identical sounds as speech or non-speech modulates activity in the left posterior superior temporal sulcus.
The left superior temporal cortex shows greater responsiveness to speech than to non-speech sounds according to previous neuroimaging studies, suggesting that this brain region has a special role in speech processing. However, since speech sounds differ acoustically from the non-speech sounds, it is possible that this region is not involved in speech perception per se, but rather in processing of some complex acoustic features. "Sine wave speech" (SWS) provides a tool to study neural speech specificity using identical acoustic stimuli, which can be perceived either as speech or non-speech, depending on previous experience of the stimuli. We scanned 21 subjects using 3T functional MRI in two sessions, both including SWS and control stimuli. In the pre-training session, all subjects perceived the SWS stimuli as non-speech. In the post-training session, the identical stimuli were perceived as speech by 16 subjects. In these subjects, SWS stimuli elicited significantly stronger activity within the left posterior superior temporal sulcus (STSp) in the post- vs. pre-training session. In contrast, activity in this region was not enhanced after training in 5 subjects who did not perceive SWS stimuli as speech. Moreover, the control stimuli, which were always perceived as non-speech, elicited similar activity in this region in both sessions. Altogether, the present findings suggest that activation of the neural speech representations in the left STSp might be a pre-requisite for hearing sounds as speech.


Action spectroscopy of the isolated red Kaede fluorescent protein chromophore.
Incorporation of fluorescent proteins into biochemical systems has revolutionized the field of bioimaging. In a bottom-up approach, understanding the photophysics of fluorescent proteins requires detailed investigations of the light-absorbing chromophore, which can be achieved by studying the chromophore in isolation. This paper reports a photodissociation action spectroscopy study on the deprotonated anion of the red Kaede fluorescent protein chromophore, demonstrating that at least three isomers-assigned to deprotomers-are generated in the gas phase. Deprotomer-selected action spectra are recorded over the S1 ← S0 band using an instrument with differential mobility spectrometry coupled with photodissociation spectroscopy. The spectrum for the principal phenoxide deprotomer spans the 480-660 nm range with a maximum response at ≈610 nm. The imidazolate deprotomer has a blue-shifted action spectrum with a maximum response at ≈545 nm. The action spectra are consistent with excited state coupled-cluster calculations of excitation wavelengths for the deprotomers. A third gas-phase species with a distinct action spectrum is tentatively assigned to an imidazole tautomer of the principal phenoxide deprotomer. This study highlights the need for isomer-selective methods when studying the photophysics of biochromophores possessing several deprotonation sites.


Persistence and adherence to non-vitamin K antagonist oral anticoagulant treatment in patients with atrial fibrillation across five Western European countries.
To assess persistence and adherence to non-vitamin K antagonist oral anticoagulant (NOAC) treatment in patients with atrial fibrillation (AF) in five Western European healthcare settings. We conducted a multi-country observational cohort study, including 559 445 AF patients initiating NOAC therapy from Stockholm (Sweden), Denmark, Scotland, Norway, and Germany between 2011 and 2018. Patients were followed from their first prescription until they switched to a vitamin K antagonist, emigrated, died, or the end of follow-up. We measured persistence and adherence over time and defined adequate adherence as medication possession rate ≥90% among persistent patients only. Overall, persistence declined to 82% after 1 year and to 63% after 5 years. When including restarters of NOAC treatment, 85% of the patients were treated with NOACs after 5 years. The proportion of patients with adequate adherence remained above 80% throughout follow-up. Persistence and adherence were similar between countries and was higher in patients starting treatment in later years. Both first year persistence and adherence were lower with dabigatran (persistence: 77%, adherence: 65%) compared with apixaban (86% and 75%) and rivaroxaban (83% and 75%) and were statistically lower after adjusting for patient characteristics. Adherence and persistence with dabigatran remained lower throughout follow-up. Persistence and adherence were high among NOAC users in five Western European healthcare settings and increased in later years. Dabigatran use was associated with slightly lower persistence and adherence compared with apixaban and rivaroxaban.


Comparison of plasma tryptophan-related metabolites in crossbred Piétrain and Duroc pigs.
Besides being incorporated into proteins, Trp, an indispensable AA, is involved in numerous metabolic pathways. Previous data showed that Trp conversion into kynurenine (Kyn) and nicotinamide (Nam) differs among studies, and such differences cannot be explained by different dietary niacin supplies. We hypothesized that pig genotype influences Trp metabolism and thus the conversion of Trp into its metabolites. The objective of this study was to compare plasma appearance of Trp and related metabolites in 12 Duroc and 12 Piétrain crossbred postweaning pigs fed 2 contrasting dietary Trp levels. Within each genotype, 6 pigs were fed a basal (B-Trp: 17% and 15% standardized ileal digestible [SID] Trp:Lys for starter and prestarter diets) or supplemented (S-Trp: 24% and 23% SID Trp:Lys for starter and prestarter diets) Trp diet. Growth was monitored, and plasma fasted concentrations were measured over 4 wk, and then pigs were fitted with a jugular catheter for frequent blood samplings. After overnight fasting, 350 g of the experimental diets were offered to each pig, and plasma concentrations of Trp, Kyn, Nam, and 5-hydroxytryptamine (5-HT) were measured for 6 h. The activities of Trp-degrading enzymes were measured in different tissues collected after pig slaughtering. Plasma Trp fasted concentrations did not differ between B-Trp and S-Trp diets and increased from weaning to 2 and 4 wk after weaning for Piétrain but not for Duroc crossbred pigs (time × genotype, = 0.001). Plasma Kyn concentrations were greater 4 wk after weaning ( = 0.002) than at weaning and for Piétrain compared to Duroc genetics ( = 0.008). Plasma Nam concentrations were greater for pigs fed the S-Trp diet than for those fed the B-Trp diet ( = 0.0001) and for Duroc than for Piétrain genetic lines ( = 0.001); this difference tends to be greater at weaning than after ( = 0.055). Our data showed an increase in plasma concentrations of Trp, Kyn, Nam, and 5-HT according to time after a meal and to the dietary Trp content. However, postprandial plasma concentrations of Trp metabolites and enzyme activities were not significantly different between Duroc and Piétrain crossbred pigs. In conclusion, our results suggest that Nam endogenous synthesis capacity from Trp is greater in Duroc than in Piétrain crossbred pigs, but this was apparent only at weaning.


[Breast reconstruction with latissimus dorsi musculocutaneous flap].
In breast reconstruction we try to achieve the greatest possible symmetry with the contralateral breast, with the smallest number of interventions, the least possible sequel and the greatest safety. When we find poor cutaneous quality in the thorax we must use techniques that provide a well vascularised tissue of good quality, which we obtain at a certain distance instead of using the thorax tissues themselves. This article reviews the latissimus dorsi musculocutaneous flap, the technique of elevation, variations of the flap, and the advantages and drawbacks involved. This is a very safe and versatile technique, with few sequels in the donor area, with a relatively short surgery time and with good aesthetic results.


A quantitative study of steroid bioconversions in the testis of the African catfish, Clarias gariepinus (Burchell), under natural spawning and natural and cultivated non-spawning conditions.
Quantitative aspects of bioconversions in the testes of the African catfish (Clarias gariepinus) were studied in vitro by incubation of tissue with [3H]pregnenolone or [3H]androstenedione. During the breeding period, spawning and non-spawning animals were collected from their natural habitat, the Hula nature reserve, in northern Israel. In the same period, non-spawning animals were collected from a fish pond in the same region. It was shown that spawning was accompanied by significant changes in steroid bioconversions, i.e. a reduction in androgen synthesis, especially of 11 beta-hydroxyandrostenedione and 11 beta-hydroxytestosterone and an increase in the production of C21-steroids, especially progesterone, 17 alpha-hydroxyprogesterone and a pregnenolone ester. These changes resulted from a decreased contribution of the cytochrome P-450 enzymes 17 alpha-hydroxylase, C17-20-lyase and 11 beta-hydroxylase. A rise in plasma gonadotrophin concentration was observed only in spawning catfish. In the absence of such an increase in plasma gonadotrophin, steroid synthesis in the testes of non-spawning feral and pond catfish was primarily directed towards the production of 11-oxygenated androgens and 5 beta-pregnane-3 alpha,17 alpha,20 alpha-triol. It is suggested that spawning is induced by gonadotrophin and the ensuing change in steroidogenesis. It is possible that husbandry conditions inhibit the necessary increase in gonadotrophin release.


Molecular cloning and expression of Mn(2+)-dependent sphingomyelinase/hemolysin of an aquatic bacterium, Pseudomonas sp. strain TK4.
We report here the molecular cloning and expression of a hemolytic sphingomyelinase from an aquatic bacterium, Pseudomonas sp. strain TK4. The sphingomyelinase gene was found to consist of 1,548 nucleotides encoding 516 amino acid residues. The recombinant 57.7-kDa enzyme hydrolyzed sphingomyelin but not phosphatidylcholine, phosphatidylserine, phosphatidylglycerol, phosphatidic acid, or phosphatidylethanolamine, indicating that the enzyme is a sphingomyelin-specific sphingomyelinase C. The hydrolysis of sphingomyelin by the enzyme was found to be most efficient at pH 8.0 and activated by Mn(2+). The enzyme shows quite a broad specificity, i.e., it hydrolyzed 4-nitrobenz-2-oxa-1,3-diazole (NBD)-sphingomyelin with short-chain fatty acids and NBD-sphingosylphosphorylcholine, the latter being completely resistant to hydrolysis by any sphingomyelinase reported so far. Significant sequence similarities were found in sphingomyelinases from Bacillus cereus, Staphylococcus aureus, Listeria ivanovii, and Leptospira interrogans, as well as a hypothetical protein encoded in Chromobacterium violaceum, although the first three lacked one-third of the sequence corresponding to that from the C terminus of the TK4 enzyme. Interestingly, the deletion mutant of strain TK4 lacking 186 amino acids at the C-terminal end hydrolyzed sphingomyelin, whereas it lost all hemolytic activity, indicating that the C-terminal region of the TK4 enzyme is indispensable for the hemolytic activity.


Congenital chromosome anomalies.
The introduction of chromosome banding techniques has led to the detection of a greatly increased number of congenital chromosome anomalies, especially those involving duplication and/or deficiency of short segments of chromosomes. Of most widespread use are the general banding techniques: Q-, G- and R-banding. Special staining methods provide help in certain cases. These include C-banding, G11 staining of some C-bands, Ag-staining of active ribosomal RNA gene clusters, differential staining of sister chromatids and differential staining of early or late replicating bands. Every banding method that can be produced by a fluorescent or nonfluorescent dye can be duplicated by the use of antinucleoside antibodies, providing strong support for the idea that the organization of DNA of particular nucleotide base composition and sequence is responsible for chromosome banding. As a result of the application of banding methods, a wealth of structural chromosmoe changes have been detected. In the balanced form, as translocations or inversions, these may have no effect on their carrier. However, such carriers have a markedly increased risk of having children with congenital chromosome anomalies. Most of these can be diagnosed prenatally using the generally available banding techniques.


Single crystal neutron and magnetic measurements of Rb2Mn3(VO4)2CO3 and K2Co3(VO4)2CO3 with mixed honeycomb and triangular magnetic lattices.
Two new alkali vanadate carbonates with divalent transition metals have been synthesized as large single crystals via a high-temperature (600 °C) hydrothermal technique. Compound I, Rb2Mn3(VO4)2CO3, crystallizes in the trigonal crystal system in the space group P3[combining macron]1c, and compound II, K2Co3(VO4)2CO3, crystallizes in the hexagonal space group P63/m. Both structures contain honeycomb layers and triangular lattices made from edge-sharing MO6 octahedra and MO5 trigonal bipyramids, respectively. The honeycomb and triangular layers are connected along the c-axis through tetrahedral [VO4] groups. The MO5 units are connected with each other by carbonate groups in the ab-plane by forming a triangular magnetic lattice. The difference in space groups between I and II was also investigated with Density Functional Theory (DFT) calculations. Single crystal magnetic characterization of I indicates three magnetic transitions at 77 K, 2.3 K, and 1.5 K. The corresponding magnetic structures for each magnetic transition of I were determined using single crystal neutron diffraction. At 77 K the compound orders in the MnO6-honeycomb layer in a Néel-type antiferromagnetic orientation while the MnO5 triangular lattice ordered below 2.3 K in a colinear 'up-up-down' fashion, followed by a planar 'Y' type magnetic structure. K2Co3(VO4)2CO3 (II) exhibits a canted antiferromagnetic ordering below TN = 8 K. The Curie-Weiss fit (200-350 K) gives a Curie-Weiss temperature of -42 K suggesting a dominant antiferromagnetic coupling in the Co2+ magnetic sublattices.


Initial evaluations for multiple sclerosis in a university multiple sclerosis center: outcomes and role of magnetic resonance imaging in referral.
To evaluate diagnostic outcomes, especially as they relate to reason for referral, of patients referred to a university-based multiple sclerosis (MS) center for possible MS. Retrospective medical record review of all new patient visits to University of Colorado Multiple Sclerosis Center, Denver, from January 1, 2001, to June 30, 2003. Of 281 patients referred to evaluate the possibility of MS, after initial review 33% were diagnosed with MS or possible MS by the McDonald criteria. The rest had other neurological conditions (31.5%), probable psychiatric diagnoses (22.5%), or no clear diagnosis was made (12.5%). Of patients with typical, possible, or atypical demyelinating syndromes, 71%, 27%, and 0%, respectively (P<.001), had MS or possible MS. Of the 63% of patients referred on the basis of clinical symptoms and signs, 46% were diagnosed with MS or possible MS vs 11% of patients referred primarily on the basis of abnormal brain magnetic resonance imaging (MRI) results (P<.001). Of patients referred because of abnormal MRI results who did not have MS or possible MS, 70% had a clear alternative etiology for the abnormal MRI results, including migraine, age older than 50 years, other neurological disease, or hypertension. A significant percentage of patients referred to a university-based MS center have little or no likelihood of having MS, and many have undiagnosed, untreated psychiatric illness or common conditions with abnormal brain MRI results. With respect to the diagnosis of MS, greater training of primary care professionals, neurologists, and radiologists is necessary.


Type I interferons produced by hematopoietic cells protect mice against lethal infection by mammalian reovirus.
We defined the function of type I interferons (IFNs) in defense against reovirus strain type 1 Lang (T1L), which is a double-stranded RNA virus that infects Peyer's patches (PPs) after peroral inoculation of mice. T1L induced expression of mRNA for IFN-alpha, IFN-beta, and Mx-1 in PPs and caused localized intestinal infection that was cleared in 10 d. In contrast, T1L produced fatal systemic infection in IFNalphaR1 knockout (KO) mice with extensive cell loss in lymphoid tissues and necrosis of the intestinal mucosa. Studies of bone-marrow chimeric mice indicated an essential role for hematopoietic cells in IFN-dependent viral clearance. Dendritic cells (DCs), including conventional DCs (cDCs), were the major source of type I IFNs in PPs of reovirus-infected mice, whereas all cell types expressed the antiviral protein Mx-1. Neither NK cells nor signaling via Toll-like receptor 3 or MyD88 were essential for viral clearance. These data demonstrate a requirement for type I IFNs in the control of an intestinal viral infection and indicate that cDCs are a significant source of type I IFN production in vivo. Therefore, innate immunity in PPs is an essential component of host defense that limits systemic spread of pathogens that infect the intestinal mucosa.


Categorization of postoperative pain descriptors in the sensitive, affective and evaluative dimensions of painful experiences.
The main purpose of this study was categorizing 20 descriptors of post-operative pain sensory, affective and evaluative dimensions. Sixty-one physicians participated. They were between 24 and 63 years old and categorized 20 descriptors by considering their level of attribution in the description of post-operative pain sensory, affective and evaluative qualities. The categorization showed that the most frequently attributed descriptors of sensitive pain qualities were: lacerating, unbearable, fulminating, intense and deep; and, for the affective qualities: hallucinating, annihilating, maddening, despairing, inhuman, blinding, terrible, monstrous and dreadful; whereas for the evaluative qualities, they were: unbearable, strong, intense and violent. The most frequently attributed descriptors in the description of post-operative pain are those mostly judged adequate to describe the affective qualities of this experience.


Qualify: a randomized head-to-head study of aripiprazole once-monthly and paliperidone palmitate in the treatment of schizophrenia.
To directly compare aripiprazole once-monthly 400mg (AOM 400) and paliperidone palmitate once-monthly (PP) on the Heinrichs-Carpenter Quality-of-Life Scale (QLS), a validated health-related quality of life and functioning measure in schizophrenia. This 28-week, randomized, non-inferiority, open-label, rater-blinded, head-to-head study (QUALIFY) of AOM 400 and PP in adult patients (18-60 years) comprised oral conversion, initiation of AOM 400 or PP treatment, and continuation with intramuscular injections every 4weeks. The primary endpoint assessed non-inferiority and superiority on QLS total score analyzed using a mixed model for repeated measurements. Of 295 randomized patients, 100/148 (67.6%) of AOM 400 and 83/147 (56.5%) of PP patients completed 28weeks of treatment. A statistically significant least squares mean difference in change from baseline to week 28 on QLS total score (4.67 [95%CI: 0.32;9.02], p=0.036) confirmed non-inferiority and established superiority of AOM 400 vs PP. There were also significant improvements in Clinical Global Impression - Severity scale and the Investigator's Assessment Questionnaire for AOM 400 vs PP, and pre-defined sub-group analyses revealed a consistent pattern of significance favoring AOM 400 in patients ≤35years. Common treatment-emergent adverse events in the treatment continuation phase were more frequent with PP vs AOM 400, and adverse events were the most frequent reason for discontinuation (27/137 [19.7%] for PP and 16/144 [11.1%] for AOM 400). All-cause discontinuation was numerically lower with AOM 400. Superior improvements on clinician-rated health-related quality of life and a favorable tolerability profile suggest greater overall effectiveness for aripiprazole once-monthly vs paliperidone palmitate. ClinicalTrials.gov identifier:NCT01795547.


Health insurance disparities among racial/ethnic minorities in same-sex relationships: an intersectional approach.
We examined disparities in health insurance coverage for racial/ethnic minorities in same-sex relationships. We used data from the 2009 to 2011 American Community Survey on nonelderly adults (aged 25-64 years) in same-sex (n = 32 744), married opposite-sex (n = 2 866 636), and unmarried opposite-sex (n = 268 298) relationships. We used multinomial logistic regression models to compare differences in the primary source of health insurance while controlling for key demographic and socioeconomic factors. Adults of all races/ethnicities in same-sex relationships were less likely than were White adults in married opposite-sex relationships to report having employer-sponsored health insurance. Hispanic men, Black women, and American Indian/Alaska Native women in same-sex relationships were much less likely to have employer-sponsored health insurance than were their White counterparts in married opposite-sex relationships and their White counterparts in same-sex relationships. Differences in coverage by relationship type and race/ethnicity may worsen over time as states follow different paths to implementing health care reform and same-sex marriage.


IL-15 in the Combination Immunotherapy of Cancer.
We completed clinical trials of rhIL-15 by bolus, subcutaneous, and continuous intravenous infusions (CIV). IL-15 administered by CIV at 2 mcg/kg/day yielded a 38-fold increase in 10- day number of circulating NK cells, a 358-fold increase in CD56bright NK cells and a 5.8-fold increase in CD8 T cells. However, IL-15 preparations administered as monotherapy were ineffective, due to actions of immunological checkpoints and due to the lack of tumor specific targeting by NK cells. To circumvent checkpoints, trials of IL-15 in combination with other anticancer agents were initiated. Tumor-bearing mice receiving IL-15 with antibodies to CTLA-4 and PD-L1 manifested marked prolongation of survival compared to mice receiving IL-15 with either agent alone. In translation, a phase I trial was initiated involving IL-15 (rhIL-15), nivolumab and ipilimumab in patients with malignancy (NCT03388632). In rhesus macaques CIV IL-15 at 20 μg/kg/day for 10 days led to an 80-fold increase in number of circulating effector memory CD8 T cells. However, administration of γc cytokines such as IL-15 led to paralysis/depression of CD4 T-cells that was mediated through transient expression of SOCS3 that inhibited the STAT5 signaling pathway. This lost CD4 helper role could be restored alternatively by CD40 agonists. In the TRAMP-C2 prostate tumor model the combination of IL-15 with agonistic anti-CD40 produced additive effects in terms of numbers of TRAMP-C2 tumor specific Spas/SCNC/9H tetramer positive CD8 T cells expressed and tumor responses. A clinical trial is being initiated for patients with cancer using an intralesional anti-CD40 in combination with CIV rhIL-15. To translate IL-15-mediated increases in NK cells, we investigated combination therapy of IL-15 with anticancer monoclonal antibodies including rituximab in mouse models of EL-4 lymphoma transfected with human CD20 and with alemtuzumab (CAMPATH-1H) in a xenograft model of adult T cell leukemia (ATL). IL-15 enhanced the ADCC and therapeutic efficacy of both antibodies. These results provided the scientific basis for trials of IL-15 combined with alemtuzumab (anti-CD52) for patients with ATL (NCT02689453), with obinutuzumab (anti-CD20) for patients with CLL (NCT03759184), and with avelumab (anti-PD-L1) in patients with T-cell lymphoma (NCT03905135) and renal cancer (NCT04150562). In the first trial, there was elimination of circulating ATL and CLL leukemic cells in select patients.


A systematic review of mindfulness and acceptance-based treatments for social anxiety disorder.
The cultivation of mindfulness and acceptance has been theoretically and empirically associated with psychological ancillary well-being and has demonstrated efficacy in the treatment of various disorders. Hence, mindfulness and acceptance-based treatments (MABTs) have recently been explored for the treatment of social anxiety disorder (SAD). This review aims to evaluate the benefits of MABTs for SAD. Systematic review of studies investigating an MABT for individuals with SAD, using PsycInfo, Medline, PubMed, and Cochrane Central Register of Controlled Trials. Nine studies were identified. Significant improvements in symptomatology were demonstrated following the MABT, but benefits were equivalent or less than yielded by cognitive-behavioral therapy (CBT). The few treatment studies available were compromised by significant methodological weaknesses and high risk of bias across domains. Studies were largely uncontrolled with small sample sizes. The hybrid nature of these interventions creates ambiguity regarding the specific utility of treatment components or combinations. MABTs demonstrate significant benefits for reducing SAD symptomatology; however, outcomes should be interpreted with caution until appropriate further research is conducted. Furthermore, the benefit of MABTs above and beyond CBT must be considered tentative at best; thus, CBT remains best practice for first-line treatment of SAD.


Small heat shock proteins and the endoplasmic reticulum: potential attractive therapeutic targets?
The endoplasmic reticulum(ER) is crucial for protein and lipid synthesis, folding and cellular homeostasis. Function impairment of ER would induce ER stress, which might play an important role in many different pathological states. Small heat shock proteins (sHsps) are known to be widely expressed throughout many tissues. SHsps are found to regulate many different pathological and pathophysiological processes and they are supposed to be potential therapeutic targets. Recent studies indicate that multiple sHsps localize to the mammalian and plant ER and sHsps confer protection against ER stress in multiple cellular processes. The mechanisms responsible for the cytoprotective effects of sHsps are related to maintaining ER homeostasis. Improved understanding of sHsps-related cytoprotective action on ER and successful strategies which could specifically target components of ER stress signalling responses amelioration of their toxic effects by sHsps is of great importance in the development of therapeutic approach for the disorders induced by dysfunction of ER.


Patient research priority setting partnership in human T-cell lymphotropic virus type I.
Human T-cell lymphotropic virus type 1 (HTLV-1) is a chronic infection affecting 5-10 million people worldwide. Ten percent develop HTLV-1-associated diseases, and 3%-5% develop HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis. Low health-related quality of life (HRQoL) is a significant concern for those with HTLV-1, and little is known about how it impacts daily life or what patients need from healthcare services. To address this, we report on patient involvement workshops aimed at identifying research priorities for HTLV-1 health service provision. Participants recruited through HTLV-1 clinics in England attended six 90-min virtual workshops over 10 months, and two 60-min consolidation workshops. Content developed iteratively from topic focussed group discussions. All workshops were video-recorded with consent, transcribed verbatim and thematically analysed. Using consensus voting rounds, participants individually ranked their top six and then collectively their top three research priorities from the themes inferred from the analysis. A final feedback session explored the experiences of participating in the workshops. Twenty-seven people with HTLV-1 engaged with the workshops with up to 22 participants attending each meeting. The majority were diagnosed with HAM (n = 22). The top three research priorities were identified as understanding disease progression, psychosocial wellbeing, and information and knowledge. Participants valued being asked to set research priorities that directly addressed their needs and enjoyed the workshops. They stressed the importance of patient advocates for promoting research that positively impacts everyday life. This is the first of this type of research engagement with people with HTLV-1 in the United Kingdom. Participants identified several avenues of investigation that could lead to improvements in healthcare services and HRQoL. Participants believed the workshops signified the start of a conversation to progress person-centred and meaningful research in HTLV-1. People living with HTLV-1 were involved in the iterative design, conduct, analysis, writing and dissemination of this project through the patient involvement workshops. As a result of this engagement, a patient led advisory group has been set up to assist with the dissemination of the findings.


Filament-induced breakdown spectroscopy with structured beams.
Filament-induced ablation represents an attractive scheme for long-range material identification via optical spectroscopy. However, the delivery of laser energy to the target can be severely hindered by the stochastic nature of multiple-filamentation, ionization of ambient gas, and atmospheric turbulence. In order to mitigate some of these adverse effects, we examine the utility of beam shaping for femtosecond filament-induced breakdown spectroscopy with Gaussian and structured (Laguerre-Gaussian, Airy, and Bessel-Gaussian) beams in the nonlinear regime. Interaction of filaments with copper, zinc, and brass targets was studied by recording axially-resolved broadband emission from the filament-induced plasma. The laser-solid coupling efficacy was assessed by inferring thermodynamic parameters such as excitation temperature and electron density. While under our experimental conditions the ablation rate with Gaussian- and Laguerre-Gaussian beams is found to be similar, the Airy and Bessel-Gaussian beams offer the advantage of longitudinally extended working zones. These results provide insights into potential benefits of structuring ultrafast laser beams for standoff sensing applications.


The effect of a restraint reduction program on physical restraint rates in rehabilitation settings in Hong Kong.
Background. In view of the adverse effects of using restraints, studies examining the use of restraint reduction programs (RRPs) are needed. Objectives. To investigate the effect of an RRP on the reduction of physical restraint rates in rehabilitation hospitals. Methods. A prospective quasi-experimental clinical trial was conducted. Demographic data, medical and health-related information on recruited patients from two rehabilitation hospitals, as well as facility data on restraint rates were collected. Results. The increase in the restraint rate in the control site was 4.3 times greater than that in the intervention site. Changes in the restraint mode, from continuous to intermittent, and the type of restraint used were found between the pre- and postintervention periods in both the control site and the intervention site. Discussion. Compared with that in the control site, the RRP in the intervention site helped arrest any increase in the restraint rate although it had no effect on physical restraint reduction. The shift of restraint mode from continuous to intermittent in the intervention site was one of the positive outcomes of the RRP.


Derivation of the San Francisco Syncope Rule to predict patients with short-term serious outcomes.
The causes of syncope are usually benign but are occasionally associated with significant morbidity and mortality. We derive a decision rule that would predict patients at risk for short-term serious outcomes and help guide admission decisions. This prospective cohort study was conducted at a university teaching hospital and used emergency department (ED) patients presenting with syncope or near syncope. Physicians prospectively completed a structured data form when evaluating patients with syncope. Serious outcomes (death, myocardial infarction, arrhythmia, pulmonary embolism, stroke, subarachnoid hemorrhage, significant hemorrhage, or any condition causing a return ED visit and hospitalization for a related event) were defined at the start of the study. All patients were followed up to determine whether they had experienced a serious outcome within 7 days of their ED visit. Univariate analysis was performed with chi2 and nonparametric techniques on all predictor variables. kappa Analysis was performed on variables requiring interpretation. Variables with kappa more than 0.5 and a P value less than.1 were analyzed with recursive partitioning techniques to develop a rule that would maximize the determination of serious outcomes. There were 684 visits for syncope, and 79 of these visits resulted in patients' experiencing serious outcomes. Of the 50 predictor variables considered, 26 were associated with a serious outcome on univariate analysis. A rule that considers patients with an abnormal ECG, a complaint of shortness of breath, hematocrit less than 30%, systolic blood pressure less than 90 mm Hg, or a history of congestive heart failure has 96% (95% confidence interval [CI] 92% to 100%) sensitivity and 62% (95% CI 58% to 66%) specificity. If applied to this cohort, the rule has the potential to decrease the admission rate by 10%. The San Francisco Syncope Rule derived in this cohort of patients appears to be sensitive for identifying patients at risk for short-term serious outcomes. If prospectively validated, it may offer a tool to aid physician decision making.


Food allergy. Part 1: immunopathogenesis and clinical disorders.
Up to 8% of children less than 3 years of age and approximately 2% of the adult population experience food-induced allergic disorders. A limited number of foods are responsible for the vast majority of food-induced allergic reactions: milk, egg, peanuts, fish, and tree nuts in children and peanuts, tree nuts, fish, and shellfish in adults. Food-induced allergic reactions are responsible for a variety of symptoms involving the skin, gastrointestinal tract, and respiratory tract and may be caused by IgE-mediated and non-IgE-mediated mechanisms. In part 1 of this series, immunopathogenic mechanisms and clinical disorders of food allergy are described.


Predicting the target genes of microRNA based on microarray data.
MicroRNAs (miRNAs) are small non-coding RNAs of approximately 22 nucleotides in length, which play important roles in regulating gene expression post-transcriptionally. Several computational methods and algorithms have been developed to predict miRNA targets. In this study, we described a method that can be used to integrate miRNA target prediction data from multiple sources and gene expression data to predict target genes of particular miRNAs. We used hsa-miR-375 as an example to test the feasibility of our method. A total of 5645 target genes of hsa-miR-375 were identified from five prediction programs, and among them, 2440 target genes were shared by at least 2 of these 5 programs. By using our method, the number was further reduced to 149 and 5 of the 149 target genes had been validated by previous study. This is a simple yet highly effective approach.


Extracting stability increases the SNP heritability of emotional problems in young people.
Twin studies have shown that emotional problems (anxiety and depression) in childhood and adolescence are moderately heritable (~20-50%). In contrast, DNA-based 'SNP heritability' estimates are generally <15% and non-significant. One notable feature of emotional problems is that they can be somewhat transient, but the moderate stability seen across time and across raters is predominantly influenced by stable genetic influences. This suggests that by capturing what is in common across time and across raters, we might be more likely to tap into any underlying genetic vulnerability. We therefore hypothesised that a phenotype capturing the pervasive stability of emotional problems would show higher heritability. We fitted single-factor latent trait models using 12 emotional problems measures across ages 7, 12 and 16, rated by parents, teachers and children themselves in the Twins Early Development Study sample. Twin and SNP heritability estimates for stable emotional problems (N = 6110 pairs and 6110 unrelated individuals, respectively) were compared to those for individual measures. Twin heritability increased from 45% on average for individual measures to 76% (se = 0.023) by focusing on stable trait variance. SNP heritability rose from 5% on average (n.s.) to 14% (se = 0.049; p = 0.002). Heritability was also higher for stable within-rater composites. Polygenic scores for both adult anxiety and depression significantly explained variance in stable emotional problems (0.4%; p = 0.0001). The variance explained was more than in most individual measures. Stable emotional problems also showed significant genetic correlation with adult depression and anxiety (average = 52%). These results demonstrate the value of examining stable emotional problems in gene-finding and prediction studies.