What is the incidence of late detection of developmental dysplasia of the hip in England?: a 26-year national study of children diagnosed after the age of one.
The aim of this study was to establish the incidence of developmental dysplasia of the hip (DDH) diagnosed after one-year of age in England, stratified by age, gender, year, and region of diagnosis. A descriptive observational study was performed by linking primary and secondary care information from two independent national databases of routinely collected data: the United Kingdom Clinical Practice Research Datalink and Hospital Episode Statistics. The study examined all children from 1 January 1990 to 1 January 2016 who had a new first diagnostic code for DDH aged between one and eight years old. The incidence of late-diagnosed DDH was 1.28 per 1000 live births. Within the study population, 754 children were identified with a diagnosis of DDH after one-year of age. Of all late diagnoses, 536 (71.1%) were detected between one to two years of age. There were 608 female patients (80.6%) and 146 male patients (19.4%), giving a female-to-male ratio of 4.2:1. Distribution was evenly spread throughout England. The incidence of late-diagnosed DDH has not been reduced from that reported 35 years ago, prior to the introduction of the national selective screening programme for DDH. Cite this article: Bone Joint J 2019;101-B:281-287.


Identification of Oropouche Orthobunyavirus in the cerebrospinal fluid of three patients in the Amazonas, Brazil.
Oropouche fever is the second most frequent arboviral infection in Brazil, surpassed only by dengue. Oropouche virus (OROV) causes large and explosive outbreaks of acute febrile illness in cities and villages in the Amazon and Central-Plateau regions. Cerebrospinal fluid (CSF) samples from 110 meningoencephalitis patients were analyzed. The RNA extracted from fluid was submitted to reverse transcription-polymerase chain reaction and sequencing to identify OROV. Three CSF samples showed the presence of OROV causing infection in the central nervous system (CNS). These patients are adults. Two of the patients had other diseases affecting CNS and immune systems: neurocysticercosis and acquired immunodeficiency syndrome, respectively. Nucleotide sequence analysis showed that the OROV from the CSF of these patients belonged to genotype I. We show here that severe Oropouche disease is occurring during outbreaks of this virus in Brazil.


Structure of a domain-opened mutant (R121D) of the human lactoferrin N-lobe refined from a merohedrally twinned crystal form.
Human lactoferrin is an iron-binding protein with a bilobal structure. Each lobe contains a high-affinity binding site for a single Fe(3+) ion and an associated CO(3)(2-) ion. Although iron binds very tightly, it can be released at low pH, with an accompanying conformational change in which the two domains move apart. The Arg121Asp (R121D) mutant of the N-lobe half-molecule of human lactoferrin was constructed in order to test whether the Asp121 side chain could substitute for the CO(3)(2-) ion at the iron-binding site. The R121D mutant protein was crystallized in its apo form as it lost iron during crystallization. The crystals were also merohedrally twinned, with a twin fraction close to 0.5. Starting from the initial molecular-replacement solution [Breyer et al. (1999), Acta Cryst. D55, 129-138], the structure has been refined at 3.0 A resolution to an R factor of 13.9% (R(free) of 19.9%). Despite the moderate resolution, the high solvent content and non-crystallographic symmetry contributed to electron-density maps of excellent quality. Weakened iron binding by the R121D mutant is explained by occlusion of the anion-binding site by the Asp side chain. The opening of the two domains in the apoR121D structure (a rotation of 54 degrees ) closely matches that of the N-lobe in full-length lactoferrin, showing that the extent of the conformational change depends on properties inherent to the N-lobe. Differences in the C-terminal portion of the N-lobe (residues 321-332) for apoR121D relative to the closed wild-type iron-bound structure point to the importance of this region in stabilizing the open form.


Comparison of pharmacokinetics between loxoprofen and its derivative with lower ulcerogenic activity, fluoro-loxoprofen.
We recently reported that, compared to loxoprofen (LOX, an non-steroidal anti-inflammatory drug), the LOX derivative fluoro-loxoprofen (F-LOX) is less ulcerogenic but has similar anti-inflammatory activity. Our previous in vitro studies suggested that both LOX and F-LOX are pro-drugs, the active metabolites of which are their trans-alcohol forms. In this study, we compared the pharmacokinetics of F-LOX and LOX in rats. Overall, the pharmacokinetic characteristics of F-LOX, including the formation of metabolites in vivo and in vitro, were comparable to those of LOX. However, F-LOX disappeared from the plasma more rapidly than LOX, which could potentially explain its lower ulcerogenicity. However, we showed that F-LOX produced fewer gastric lesions than LOX, even when a higher plasma concentration of F-LOX was maintained. Similar to LOX, F-LOX was readily metabolized to its trans- and cis-alcohol forms, with a higher level of the trans-alcohol form being observed after oral or intravenous administration of the drug. The preferential formation of the trans-alcohol form was also observed after incubation of F-LOX with rat liver homogenates in vitro. These results suggest that, similar to LOX, F-LOX acts as a pro-drug and that there is a metabolic system that selectively produces its active metabolite.


Horse IgG isotypes and cross-neutralization of two snake antivenoms produced in Brazil and Costa Rica.
Horse IgG isotypes and cross-neutralization of two snake antivenoms produced in Brazil and Costa Rica. Toxicon 000-000. This work compared the specificity, ELISA titers and IgG subclass content of the polyvalent antivenom (anti-Bothrops asper, Crotalus durissus durissus and Lachesis muta stenophrys) of Instituto Clodomiro Picado (Costa Rica) and the bothropic antivenom (anti-Bothrops jararaca, B. jararacussu, B. moojeni, B. neuwiedi and B. alternatus) of Instituto Butantan (Brazil). The role of IgG(T) and IgGa subclasses in neutralization of some venom toxic activities and the cross neutralization of the antivenoms against B. jararaca and B. asper venoms were also evaluated. Both antivenoms were able to recognize B. asper and B. jararaca venoms by immunoblotting and presented similar antibody titers when assayed by ELISA. IgG(T) was highest, followed by IgGa, IgGb and IgGc. IgGa and IgG(T) isotypes isolated from both antivenoms by affinity chromatography were tested for neutralization of lethal, hemorrhagic, coagulant and phospholipase A2 activities of the homologous venoms. In both antivenoms, IgG(T) was the major isotype responsible for neutralization of all the tested activities, followed by IgGa. These results suggest that Instituto Butantan and Instituto Clodomiro Picado antivenoms have the same IgG profile and their neutralizing ability is due mostly to the IgG(T) isotype. Also, they neutralize lethality in mice induced by homologous and heterologous venoms, the bothropic antivenom of Instituto Butantan being more effective.


Normative data and clinically significant effect sizes for single-item numerical linear analogue self-assessment (LASA) scales.
Single-item assessments have been the most often-used measures in National Cancer Institute (NCI) cancer control clinical trials, but normative data are not available. Our objective was to examine the normative data and clinically significant effect sizes for single-item numerical linear analogue self-assessment (LASA) scale for overall quality of life (QOL). We analyzed baseline data from 36 clinical trials and 6 observational studies with various populations, including healthy volunteers, cancer trial patients (patients with advanced incurable cancer or patients receiving treatment with curative intent) and hospice patients as well as their caregivers. The overall QOL LASA was rated 0 (as bad as it can be) to 10 (as good as it can be). We calculated the summary statistics and the proportion of patients reporting a clinically meaningful deficit (CMD) of a score equal to 5 or less on the 0-10 scale. In total, for the collective sample of 9,295 individuals, the average overall QOL reported was 7.39 (SD = 2.11) with a markedly skewed distribution with roughly 17% reporting a score of 5 or below indicating a clinically significant deficit in overall QOL. Hospice patients report a much worse average score of 5.7 upon entry to hospice; hospice caregivers average 7.4. Cancer patients vary within these two extremes with most patients averaging in the 7's on the 0-10 scale (range, 0 to 10 p-value < 0.0001). Men and women's QOL distributions were virtually identical (with average of 7.6 vs. 7.5, p-value = 0.046). Overall QOL was weakly related to performance status with a Spearman correlation coefficient of -0.29 (p-value < 0.0001). Overall QOL was related to tumor response (p-value = 0.0094), i.e. patients with a full or partial response reported a CMD in 11.4% of cases compared to 14.4% among those with stable disease and 18.5% among those with disease progression. Data missingness was high for performance status and tumor response associations. This study provides the normative data for cancer patients and healthy volunteers for overall QOL using the LASA. These can serve as benchmarks for future studies and inform clinical practice decision-making.


Real-world user experience with seizure detection wearable devices in the home environment.
To evaluate direct user experience with wearable seizure detection devices in the home environment. A structured online questionnaire was completed by 242 users (175 caregivers and 67 persons with epilepsy), most of the patients (87.19%) having tonic-clonic seizures. The vast majority of the users were overall satisfied with the wearable device, considered that using the device was easy, and agreed that the use of the device improved their quality of life (median = 6 on 7-point Likert scale). A high retention rate (84.58%) and a long median usage time (14 months) were reported. In the home environment, most users (75.85%) experienced seizure detection sensitivity similar (≥95%) to what was previously reported in validation studies in epilepsy monitoring units. The experienced false alarm rate was relatively low (0-0.43 per day). Due to the alarms, almost one third of persons with epilepsy (PWEs; 30.00%) experienced decrease in the number of seizure-related injuries, and almost two thirds of PWEs (65.41%) experienced improvement in the accuracy of seizure diaries. Nonvalidated devices had significantly lower retention rate, overall satisfaction, perceived sensitivity, and improvement in quality of life, as compared with validated devices. Our results demonstrate the feasibility and usefulness of automated seizure detection in the home environment.


Metagenomic and small-subunit rRNA analyses reveal the genetic diversity of bacteria, archaea, fungi, and viruses in soil.
Recent studies have highlighted the surprising richness of soil bacterial communities; however, bacteria are not the only microorganisms found in soil. To our knowledge, no study has compared the diversities of the four major microbial taxa, i.e., bacteria, archaea, fungi, and viruses, from an individual soil sample. We used metagenomic and small-subunit RNA-based sequence analysis techniques to compare the estimated richness and evenness of these groups in prairie, desert, and rainforest soils. By grouping sequences at the 97% sequence similarity level (an operational taxonomic unit [OTU]), we found that the archaeal and fungal communities were consistently less even than the bacterial communities. Although total richness levels are difficult to estimate with a high degree of certainty, the estimated number of unique archaeal or fungal OTUs appears to rival or exceed the number of unique bacterial OTUs in each of the collected soils. In this first study to comprehensively survey viral communities using a metagenomic approach, we found that soil viruses are taxonomically diverse and distinct from the communities of viruses found in other environments that have been surveyed using a similar approach. Within each of the four microbial groups, we observed minimal taxonomic overlap between sites, suggesting that soil archaea, bacteria, fungi, and viruses are globally as well as locally diverse.


Dynamic pressurization induces transition of notochordal cells to a mature phenotype while retaining production of important patterning ligands from development.
Notochordal cells (NCs) pattern aneural and avascular intervertebral discs (IVDs), and their disappearance, is associated with onset of IVD degeneration. This study induced and characterized the maturation of nucleus pulposus (NP) tissue from a gelatinous NC-rich structure to a matrix-rich structure populated by small NP cells using dynamic pressurization in an ex vivo culture model, and also identified soluble factors from NCs with therapeutic potential. Porcine NC-rich NP tissue was cultured and loaded with hydrostatic pressure (0.5 to 2 MPa at 0.1 Hz for 2 hours) either Daily, for 1 Dose, or Control (no pressurization) groups for up to eight days. Cell phenotype and tissue maturation was characterized with measurements of cell viability, cytomorphology, nitric oxide, metabolic activity, matrix composition, gene expression, and proteomics. Daily pressurization induced transition of NCs to small NP cells with 73.8%, 44%, and 28% NCs for Control, 1 Dose and Daily groups, respectively (P < 0.0002) and no relevant cell death. Dynamic loading matured NP tissue by significantly increasing metabolic activity and accumulating Safranin-O-stained matrix. Load-induced maturation was also apparent from the significantly decreased glycolytic, cytoskeletal (Vimentin) and stress-inducible (HSP70) proteins assessed with proteomics. Loading increased the production of bioactive proteins Sonic Hedgehog (SHH) and Noggin, and maintained Semaphorin3A (Sema3A). NP tissue maturation was induced from dynamic hydrostatic pressurization in a controlled ex vivo environment without influence from systemic effects or surrounding structures. NCs transitioned into small nonvacuolated NP cells probably via differentiation as evidenced by high cell viability, lack of nitric oxide and downregulation of stress-inducible and cytoskeletal proteins. SHH, Sema3A, and Noggin, which have patterning and neurovascular-inhibiting properties, were produced in both notochordal and matured porcine NP. Results therefore provide an important piece of evidence suggesting the transition of NCs to small NP cells is a natural part of aging and not the initiation of degeneration. Bioactive candidates identified from young porcine IVDs may be isolated and harnessed for therapies to target discogenic back pain.


Populus GT43 family members group into distinct sets required for primary and secondary wall xylan biosynthesis and include useful promoters for wood modification.
The plant GT43 protein family includes xylosyltransferases that are known to be required for xylan backbone biosynthesis, but have incompletely understood specificities. RT-qPCR and histochemical (GUS) analyses of expression patterns of GT43 members in hybrid aspen, reported here, revealed that three clades of the family have markedly differing specificity towards secondary wall-forming cells (wood and extraxylary fibres). Intriguingly, GT43A and B genes (corresponding to the Arabidopsis IRX9 clade) showed higher specificity for secondary-walled cells than GT43C and D genes (IRX14 clade), although both IRX9 and IRX14 are required for xylosyltransferase activity. The remaining genes, GT43E, F and G (IRX9-L clade), showed broad expression patterns. Transient transactivation analyses of GT43A and B reporters demonstrated that they are activated by PtxtMYB021 and PNAC085 (master secondary wall switches), mediated in PtxtMYB021 activation by an AC element. The high observed secondary cell wall specificity of GT43B expression prompted tests of the efficiency of its promoter (pGT43B), relative to the CaMV 35S (35S) promoter, for overexpressing a xylan acetyl esterase (CE5) or downregulating REDUCED WALL ACETYLATION (RWA) family genes and thus engineering wood acetylation. CE5 expression was weaker when driven by pGT43B, but it reduced wood acetyl content substantially more efficiently than the 35S promoter. RNAi silencing of the RWA family, which was ineffective using 35S, was achieved when using GT43B promoter. These results show the utility of the GT43B promoter for genetically engineering properties of wood and fibres.


Adaptive optics binocular visual simulator to study stereopsis in the presence of aberrations.
A binocular adaptive optics visual simulator has been devised for the study of stereopsis and of binocular vision in general. The apparatus is capable of manipulating the aberrations of each eye separately while subjects perform visual tests. The correcting device is a liquid-crystal-on-silicon spatial light modulator permitting the control of aberrations in the two eyes of the observer simultaneously in open loop. The apparatus can be operated as an electro-optical binocular phoropter with two micro-displays projecting different scenes to each eye. Stereo-acuity tests (three-needle test and random-dot stereograms) have been programmed for exploring the performance of the instrument. As an example, stereo-acuity has been measured in two subjects in the presence of defocus and/or trefoil, showing a complex relationship between the eye's optical quality and stereopsis. This instrument might serve for a better understanding of the relationship of binocular vision and stereopsis performance and the eye's aberrations.


Sensory neuron death after upper limb nerve injury and protective effect of repair: clinical evaluation using volumetric magnetic resonance imaging of dorsal root Ganglia.
Extensive death of sensory neurons after nerve trauma depletes the number of regenerating neurons, contributing to inadequate cutaneous innervation density and poor sensory recovery. Experimentally proven neuroprotective neoadjuvant drugs require noninvasive in vivo measures of neuron death to permit clinical trials. In animal models of nerve transection, magnetic resonance imaging (MRI) proved a valid tool for quantifying sensory neuron loss within dorsal root ganglia (DRG) by measuring consequent proportional shrinkage of respective ganglia. This system is investigated for clinical application after upper limb nerve injury and microsurgical nerve repair. A 3-T clinical magnet was used to image and measure volume (Cavalieri principle) of C7-T1 DRG in uninjured volunteers (controls, n = 14), hand amputees (unrepaired nerve injury, n = 5), and early nerve repair patients (median and ulnar nerves transected, microsurgical nerve repair within 24 hours, n = 4). MRI was well tolerated. Volumetric analysis was feasible in 74% of patients. A mean 14% volume reduction was found in amputees' C7 and C8 DRG (P < .001 vs controls). Volume loss was lower in median and ulnar nerve repair patients (mean 3% volume loss, P < .01 vs amputees), and varied among patients. T1 DRG volume remained unaffected. MRI provides noninvasive in vivo assessment of DRG volume as a proxy clinical measure of sensory neuron death. The significant decrease found after unrepaired nerve injury provides indirect clinical evidence of axotomy-induced neuronal death. This loss was less after nerve repair, indicating a neuroprotective benefit of early repair. Volumetric MRI has potential diagnostic applications and is a quantitative tool for clinical trials of neuroprotective therapies.


Adjuvant volumetric-modulated arc therapy with simultaneous integrated boost in endometrial cancer. Planning and toxicity comparison.
To report dosimetric and acute toxicity data in prospectively enrolled high-intermediate risk endometrial cancer (HIR-EC) patients postoperatively irradiated by simultaneous integrated boost volumetric modulated arc therapy (SIB-VMAT). Thirty prospectively enrolled HIR-EC patients were postoperatively treated by SIB-VMAT. Target coverage, dose homogeneity, and sparing of organs at risk (OARs) were compared with corresponding data retrieved from an historical control (30 consecutive selected matched patients) treated by concomitant boost three-dimensional conformal radiotherapy (3D CRT CB) from a previously published study (ADA-I trial). All patients received 45 Gy on pelvic lymph nodes plus 10 Gy boost on the vaginal vault. The SIB-VMAT technique produced more inhomogeneous plans than 3D CRT CB, but showed significantly better conformity index (CIs) for both PTVs. SIB-VMAT was associated with significant reduction in the irradiated small bowel (SB) volume compared with 3D CRT CB for all dose range > 10 Gy (e.g. V15: 163.5 cm(3) vs. 341.3 cm(3), p = 0.001 and V40: 43.8 cm(3) vs. 85.2 cm(3), p = 0.008). With regard to bladder and rectum, SIB-VMAT showed a significant sparing advantage at all dose levels with respect to 3D CRT CB retrieved plans. Moreover, overall OARs Dmean were significantly reduced by the SIB-VMAT (p = 0.001). According to CTCAE v.4.0, acute (within three months) GI toxicities were more frequent in 3D CRT CB versus SIB-VMAT (90.0% vs. 66.7%; p-value 0.028). Compared to data from a historical database of patients administered 3D CRT CB, SIB-VMAT significantly improves the dose conformity and sparing of OARs in HIR-EC patients undergoing postoperative radiotherapy. The improvement in terms of acute toxicity justifies further prospective clinical evaluation.


Educating the ambulance technician, paramedic, and clinical supervisor: using factor analysis to inform the curriculum.
This project aims to use information about the desirable attributes of the ambulance technician, paramedic, and clinical supervisor to inform future curriculum development. Data generated by a Delphi study investigating the desirable attributes of ambulance technician, paramedic, and clinical supervisor were subject to factor analysis to explore inter-relations between the variables or desirable attributes. Variables that loaded onto any factor at a correlation level of >0.3 were included in the analysis. Three factors emerged in each of the occupational groups. In respect of the ambulance technician these factors may be described as; core professional skills, individual and collaborative approaches to health and safety, and the management of self and clinical situations. For the paramedic the themes are; core professional skills, management of self and clinical situations, and approaches to health and safety. For the clinical supervisor there is again a theme described as core professional skills, with a further two themes described as role model and lifelong learning. The profile of desirable attributes emerging from this study are remarkably similar to the generic benchmark statements for health care programmes outlined by the Quality Assurance Agency for Higher Education. It seems that a case is emerging for a revision of the curriculum currently used for the education and training of ambulance staff, which is more suited to a consumer led health service and which reflects the broader professional base seen in programmes associated with other healthcare professions. This study has suggested outline content, and module structure for the education of the technician, paramedic, and clinical supervisor, based on empirical evidence.


Bis-pyrene-modified unlocked nucleic acids: synthesis, hybridization studies, and fluorescent properties.
Efficient synthesis of a building block for the incorporation of a bis-pyrene-modified unlocked nucleic acid (UNA) into oligonucleotides (DNA*) was developed. The presence of bis-pyrene-modified UNA within a duplex leads to duplex destabilization that is more profound in DNA*/RNA and less distinct in DNA*/DNA duplexes. Nevertheless, the destabilization effect of bis-pyrene-modified UNA is weaker than that of unmodified UNA. Some oligonucleotides with bis-pyrene-modified UNA incorporations displayed superior mismatch discrimination capabilities. UV/Vis absorption and molecular modeling studies indicate that the pyrene groups of bis-pyrene-modified UNA are located in the major groove of a duplex. Oligonucleotides containing two bis-pyrene-modified UNA monomers showed low pyrene monomer emission in bulge-containing duplexes, high pyrene monomer emission in fully matched duplexes, and 5-(pyrenyl)uracil:pyrene exciplex emission in the single-stranded form. Such fluorescent properties enable the application of bis-pyrene-modified UNA in the development of fluorescence probes for DNA/RNA detection and for detection of deletions at specific positions.


Association of Glycolysis-Enhancing α-1 Blockers With Risk of Developing Parkinson Disease.
Parkinson disease (PD) is a common neurodegenerative disease. A treatment that prevents or delays development of PD is a critical unmet need. Terazosin and closely related drugs were recently discovered to enhance glycolysis and reduce PD progression in animal models and human clinical databases. To determine whether use of terazosin, doxazosin, and alfuzosin is associated with a decreased risk of developing PD. This cohort study used active comparator control and propensity score-matched data from Danish nationwide health registries, including the Danish National Prescription Registry, the Danish National Patient Registry, and the Danish Civil Registration System, from January 1996 to December 2017 and data from the Truven Health Analytics MarketScan database from January 2001 to December 2017. Men without PD who newly initiated terazosin/doxazosin/alfuzosin therapy or tamsulosin therapy, which is used for a similar indication (benign prostatic hyperplasia or unspecified urinary problems) but does not enhance glycolysis, and had at least 1 year of follow-up after medication start were included. In Denmark, the database included all residents, while the Truven database is a compilation of insurance claims across the US. Data were analyzed from February 2019 to July 2020. Patients who used terazosin/doxazosin/alfuzosin vs tamsulosin. Additional dose-response analyses were carried out. Differences in the hazard of developing PD identified by diagnoses or use of PD-specific medications between patients who ever used terazosin/doxazosin/alfuzosin or tamsulosin. A cohort of 52 365 propensity score-matched pairs of terazosin/doxazosin/alfuzosin and tamsulosin users were identified in the Danish registries, of which all were male and the mean (SD) age was 67.9 (10.4) years, and 94 883 propensity score-matched pairs were identified in the Truven database, of which all were male and the mean (SD) age was 63.8 (11.1) years. Patients in the Danish cohort who used terazosin/doxazosin/alfuzosin had a hazard ratio (HR) for developing PD of 0.88 (95% CI, 0.81-0.98), and patients in the Truven cohort had an HR of 0.63 (95% CI, 0.58-0.69). There was a dose-response association with short-duration, medium-duration, and long-duration use of terazosin/doxazosin/alfuzosin users having a decreasing HR in both the Danish cohort (short: HR, 0.95; 95% CI, 0.84-1.07; medium: HR, 0.88; 95% CI, 0.77-1.01; long: HR, 0.79; 95% CI, 0.66-0.95) and Truven cohort (short: HR, 0.70; 95% CI, 0.64-0.76; medium: HR, 0.58; 95% CI, 0.52-0.64; long: HR, 0.46; 95% CI, 0.36-0.57). These data suggest that users of terazosin/doxazosin/alfuzosin are at lower hazard of developing PD compared with users of tamsulosin. Future work is needed to further assess this association.


Effects of pretreatment with different neuromuscular blocking agents on facilitation of intubation with rocuronium: A prospective randomized comparative study.
Priming principle refers to administration of a small dose of non-depolarising blocker, which when followed by a large intubating dose produces a relatively rapid and profound blockade to ensure suitable conditions for endotracheal intubation. We aimed to compare the effects of rocuronium, vecuronium, and atracurium as "pretreatment" drugs on intubating conditions with rocuronium facilitated endotracheal intubation. This double-blinded, randomised controlled prospective study was carried out at a tertiary health care hospital on patients undergoing surgical procedures under general anaesthesia. They were randomly allocated into three groups (n = 35) by computer generated randomisation chart to receive either rocuronium (0.06 mg/kg body weight) (Group A); vecuronium (0.01 mg/kg body weight) (Group B) or, atracurium (0.05 mg/kg body weight) (Group C), followed by intubating dose (0.6 mg/kg body weight) of rocuronium. The haemodynamic parameters and intubating conditions were studied and statistically analysed by ANOVA test and Student's t-test as applicable using statistical package for the social sciences 16.0 for windows (SPSS Inc., Chicago, IL, USA). Excellent intubating conditions were noted in maximum number of patients in Group C (97.41%). No significant differences were observed in the systolic blood pressure in all the three groups at all-time intervals. The mean arterial pressure rose significantly from baseline value to maximum, at '0' min in all the groups; however, no significant difference was observed amongst the groups (P > 0.05). Pretreatment with rocuronium bromide can facilitate endotracheal intubation in 60 s irrespective of non-depolarising muscle relaxants used for priming; however, it cannot attenuate haemodynamic changes associated with laryngoscopy and intubation.


Channel smoothing: efficient robust smoothing of low-level signal features.
In this paper, we present a new and efficient method to implement robust smoothing of low-level signal features: B-spline channel smoothing. This method consists of three steps: encoding of the signal features into channels, averaging of the channels, and decoding of the channels. We show that linear smoothing of channels is equivalent to robust smoothing of the signal features if we make use of quadratic B-splines to generate the channels. The linear decoding from B-spline channels allows the derivation of a robust error norm, which is very similar to Tukey's biweight error norm. We compare channel smoothing with three other robust smoothing techniques: nonlinear diffusion, bilateral filtering, and mean-shift filtering, both theoretically and on a 2D orientation-data smoothing task. Channel smoothing is found to be superior in four respects: It has a lower computational complexity, it is easy to implement, it chooses the global minimum error instead of the nearest local minimum, and it can also be used on nonlinear spaces, such as orientation space.


Pain and psychological health status in chronic pain patients with migration background--the Zurich study.
The objective of this paper is to investigate whether there were differences in pain and psychological health status in chronic pain patients with and without migration background before and after an 8-week interdisciplinary outpatient pain programme (IOPP). One hundred eighteen consecutively assessed patients were included. Pain and psychological health were recorded prior to and after the intervention, and at the 3-, 6- and 12-month follow-up. The migrant group experienced a statistically significant and clinically relevant higher amount of pain and worse psychological functioning than the non-migrant group at all time points. Statistically significant differences between the groups for the variables depression, anxiety, kinesiophobia and passive coping, in particular catastrophizing, were observed in the short and long term. The non-migrant group improved continuously on all outcome measurements at all time points. The results show differences in outcome for chronic pain patients with and without migration background. High pain intensity, high levels of depression, anxiety and catastrophizing at baseline appear to be major barriers for improvement in a sample of migrant patients when participating in an IOPP. Treatments may have to be tailored to the specific needs of this patient group to better address their poor psychological health status and to improve the course of the pain disorder.


Predicting contraceptive use from an egalitarian model of women's overall household power vis-à-vis conventional power models and third variables.
Research on gender power in contraceptive use has focused on whether women have an active role in household decision-making (the participation model) or on the extent of their control of domestic decisions (the control model); it has also addressed the joint effects of power, age, education and work. Findings published in this journal (Woldemicael, 2009) suggest a third power model according to which wives make joint decisions with their husbands on important domestic areas and autonomous decisions on secondary matters (the egalitarian model). In analyses of Demographic and Health Survey data sets from 46 countries, the egalitarian model explained contraceptive use better than the control and participation models in 19 out of 20 countries outside sub-Saharan Africa; its superiority was less overwhelming in this sub-continent. Power effects on contraceptive use that depend on women's education, age and work for cash are larger in sub-Saharan Africa than in other world regions, whereas independent power effects differ little regionally, suggesting the action of a personality factor. Situational specification of decision importance and direct measurement of women's assertiveness are needed to improve the explanation of contraceptive behaviour.


Identification of staphylococcal nuclease domain-containing 1 (SND1) as a Metadherin-interacting protein with metastasis-promoting functions.
Metastasis is the deadliest and most poorly understood feature of malignant diseases. Recent work has shown that Metadherin (MTDH) is overexpressed in over 40% of breast cancer patients and promotes metastasis and chemoresistance in experimental models of breast cancer progression. Here we applied mass spectrometry-based screen to identify staphylococcal nuclease domain-containing 1 (SND1) as a candidate MTDH-interacting protein. After confirming the interaction between SND1 and MTDH, we tested the role of SND1 in breast cancer and found that it strongly promotes lung metastasis. SND1 was further shown to promote resistance to apoptosis and to regulate the expression of genes associated with metastasis and chemoresistance. Analyses of breast cancer clinical microarray data indicated that high expression of SND1 in primary tumors is strongly associated with reduced metastasis-free survival in multiple large scale data sets. Thus, we have uncovered SND1 as a novel MTDH-interacting protein and shown that it is a functionally and clinically significant mediator of metastasis.


Role-blurring and ethical grey zones associated with lay interpreters: three case studies.
This article examines a context in which immigrants from the former Soviet Union must navigate the English-speaking medical system in a semi-rural area of the USA. In this setting, institutional interpretation resources are not consistently available, and various informal arrangements emerge. One type consists of naive interpreters such as family members of low bilingual capability and/or medical knowledge. Another arrangement involves relatively skilled bilinguals who have command of medical terminology but who are not professionally trained as interpreters. Three case studies of this latter category of 'lay interpreters' are presented. Among the roles reported by the lay interpreters are information source and advocate. The three interpreters are making a contribution in the absence of institutionally provided professional resources, and their help can be viewed as better than the use of naive interpreters such as patients' children. However, the lay interpreters also occasionally seemed to stray into ethically grey areas. For instance, one interpreter said he discarded a client's outdated medicine against her wishes, and another expressed envy of ungrateful clients who had better healthcare access than she did. While professionally trained interpreters are not immune from ethical challenges, such training would better safeguard both patient and interpreter.


Bendamustine pharmacokinetic profile and exposure-response relationships in patients with indolent non-Hodgkin's lymphoma.
The pharmacokinetic profiles of bendamustine and active metabolites were defined in patients with rituximab-refractory, relapsed indolent B-cell non-Hodgkin's lymphoma, and supported understanding of exposure-response relationships for efficacy and safety. Bendamustine was administered as a 60-min 120 mg/m(2) intravenous infusion on days 1 and 2 of six 21-day cycles. Pharmacokinetic models were developed, with covariate assessment. Correlations between bendamustine exposure and responder status or occurrence of neutropenia, thrombocytopenia, fatigue, nausea, and vomiting were examined. Following a single dose of bendamustine HCl, concentrations declined in a triphasic manner, with rapid distribution, intermediate, and slow terminal phases. The intermediate t (1/2) (40 min) was considered the pharmacologically relevant (beta elimination) t (1/2) since the initial phases accounted for 99% of the AUC. Age, sex, mild/moderate renal, or mild liver impairment did not alter pharmacokinetics. Metabolite concentrations were low relative to parent. No correlation was observed between exposure and safety or efficacy measures because of the limited range of exposures after 120 mg/m(2) administration, except bendamustine C (max) was a significant (P value = 0.013) predictor of the probability of nausea in patients, most of whom were pretreated with antiemetics. The BSA-based dosing regimen for bendamustine achieved the targeted exposure and was associated with a high incidence of therapeutic response. Given the short t (1/2) and low concentrations of bendamustine observed by 12 h after dosing, the single-dose profile for bendamustine described by these analyses is expected to be representative of the multiple-dose profile. The occurrence of nausea was significantly related to bendamustine exposure, with the probability of nausea increasing as bendamustine C (max) increases.


Complete, closed bacterial genomes from microbiomes using nanopore sequencing.
Microbial genomes can be assembled from short-read sequencing data, but the assembly contiguity of these metagenome-assembled genomes is constrained by repeat elements. Correct assignment of genomic positions of repeats is crucial for understanding the effect of genome structure on genome function. We applied nanopore sequencing and our workflow, named Lathe, which incorporates long-read assembly and short-read error correction, to assemble closed bacterial genomes from complex microbiomes. We validated our approach with a synthetic mixture of 12 bacterial species. Seven genomes were completely assembled into single contigs and three genomes were assembled into four or fewer contigs. Next, we used our methods to analyze metagenomics data from 13 human stool samples. We assembled 20 circular genomes, including genomes of Prevotella copri and a candidate Cibiobacter sp. Despite the decreased nucleotide accuracy compared with alternative sequencing and assembly approaches, our methods improved assembly contiguity, allowing for investigation of the role of repeat elements in microbial function and adaptation.


Psychiatric residents' needs for education about informed consent, principles of ethics and professionalism, and caring for vulnerable populations: results of a multisite survey.
The authors examined psychiatric residents' perceived needs for education in informed consent, principles of ethics and professionalism, and treating vulnerable populations. A written survey was distributed to psychiatric residents (N=249) at seven U.S. residency programs in 2005. The survey contained 149 questions in 10 content domains, 6 questions regarding personal ethics experiences during training, and 5 demographic questions. Here, the authors report responses to items regarding informed consent, professional principles, and care of vulnerable populations. A total of 151 psychiatric residents responded to the survey (61% overall response rate). On a scale of 1: Much Less, to 5: Same, to 9: Much More Education Desired, psychiatric residents indicated that 9 topics relating to informed consent, 10 issues surrounding professional principles, and 25 topics relating to care of vulnerable populations should receive more educational attention than currently provided. No topics were rated as needing less education. Higher ratings of the need for additional educational attention were associated with more reported ethical conflicts encountered during training. Psychiatric residents at seven diverse U.S. training programs expressed the need for greater educational attention to issues around informed consent, ethical and professional principles, and treating vulnerable populations. These findings reflect the ongoing need for educators to devote curricular attention to these areas so that trainees can incorporate such knowledge effectively into their daily clinical practice in an always-complex, highly fragmented medical care environment.


Structural, spectroscopic, and magnetic properties of Eu3+-doped GdVO4 nanocrystals synthesized by a hydrothermal method.
New interesting aspects of the spectroscopic properties, magnetism, and method of synthesis of gadolinium orthovanadates doped with Eu(3+) ions are discussed. Gd(1-x)Eu(x)VO4 (x = 0, 0.05, 0.2) bifunctional luminescent materials with complex magnetic properties were synthesized by a microwave-assisted hydrothermal method. Products were formed in situ without previous precipitation. The crystal structures and morphologies of the obtained nanomaterials were analyzed by X-ray diffraction and transmission and scanning electron microscopy. Crystallographic data were analyzed using Rietveld refinement. The products obtained were nanocrystalline with average grain sizes of 70-80 nm. The qualitative and quantitative elemental composition as well as mapping of the nanocrystals was proved using energy-dispersive X-ray spectroscopy. The spectroscopic properties of red-emitting nanophosphors were characterized by their excitation and emission spectra and luminescence decays. Magnetic measurements were performed by means of vibrating sample magnetometry. GdVO4 and Gd0.8Eu0.2VO4 exhibited paramagnetic behavior with a weak influence of antiferromagnetic couplings between rare-earth ions. In the substituted sample, an additional magnetic contribution connected with the population of low-lying excited states of europium was observed.


Legionella pneumophila entry gene rtxA is involved in virulence.
Successful parasitism of host cells by intracellular pathogens involves adherence, entry, survival, intracellular replication, and cell-to-cell spread. Our laboratory has been examining the role of early events, adherence and entry, in the pathogenesis of the facultative intracellular pathogen Legionella pneumophila. Currently, the mechanisms used by L. pneumophila to gain access to the intracellular environment are not well understood. We have recently isolated three loci, designated enh1, enh2, and enh3, that are involved in the ability of L. pneumophila to enter host cells. One of the genes present in the enh1 locus, rtxA, is homologous to repeats in structural toxin genes (RTX) found in many bacterial pathogens. RTX proteins from other bacterial species are commonly cytotoxic, and some of them have been shown to bind to beta(2) integrin receptors. In the current study, we demonstrate that the L. pneumophila rtxA gene is involved in adherence, cytotoxicity, and pore formation in addition to its role in entry. Furthermore, an rtxA mutant does not replicate as well as wild-type L. pneumophila in monocytes and is less virulent in mice. Thus, we conclude that the entry gene rtxA is an important virulence determinant in L. pneumophila and is likely to be critical for the production of Legionnaires' disease in humans.


[Invasive fungal infection in critically ill patient: role of micafungin].
The invasive fungal infections (IFIs) have increased in critically ill patients in recent years and are a serious complication that determine the evolution and prognosis of critically ill patients, especially invasive candidiasis (IC)and candidemia. Fortunately, treatment options for these infections have increased and there is a large arsenal of antifungal agents. This review of the literature, using PubMed and Cochrane databases, assesses the situation of the IFIs in critically ill patients and discusses the role of micafungin in this context. The broader spectrum of this candin, which gets the antifungal effect with lower MICs and that translates into greater clinical efficacy with a lower rate of adverse effects and easier to use, with proven cost-effectiveness compared with other antifungal, position micafungin as a useful therapeutic option for the management of invasive candidiasis / candidemia in critically ill patients.


Surgical treatment of spinal arteriovenous malformations: vascular anatomy and surgical outcome.
Spinal arteriovenous malformations (AVMs) are rare but debilitating lesions of the central nervous system. This study evaluated the outcome in patients with spinal AVMs treated surgically, and the relationship between outcome and the vascular anatomy of the lesions. These AVMs were classified into four types: dural AVM (type I), glomus AVM (type II), juvenile AVM (type III), and intradural direct arteriovenous fistula (type IV). Either interruption of the feeding vessels or excision of the AVMs was performed in all patients. Intradural AVMs manifested as subarachnoid or intramedullary hemorrhages, whereas dural AVM manifested as epidural hemorrhage in two patients, and as an episode of subarachnoid hemorrhage in one patient. The nidus in five of the six dural AVMs was below the mid-thoracic level. In six of the seven patients with intradural AVMs, the nidus was located in the cervical region. The prognosis of patients with dural AVMs was generally good, but in patients with intradural AVMs, motor recovery was worse and resection was more difficult. Correct diagnosis and classification of spinal AVMs are the key prerequisites for successful treatment. The surgical outcome is closely related to the vascular anatomy of the lesion. For dural AVMs, only surgical interruption of the arteriovenous shunting at the dural sleeve of the nerve is required and good surgical results are often obtained. Intradural direct arteriovenous fistula responded well to surgery, whereas combined endovascular and microsurgical techniques can minimize the chance of rebleeding in intramedullary AVMs.


Distribution of Potato virus Y in potato plant organs, tissues, and cells.
The distribution of Potato virus Y (PVY) in the systemically infected potato (Solanum tuberosum) plants of the highly susceptible cultivar Igor was investigated. Virus presence and accumulation was analyzed in different plant organs and tissues using real-time polymerase chain reaction and transmission electron microscopy (TEM) negative staining methods. To get a complete insight into the location of viral RNA within the tissue, in situ hybridization was developed and optimized for the detection of PVY RNA at the cellular level. PVY was shown to accumulate in all studied leaf and stem tissues, in shoot tips, roots, and tubers; however, the level of virus accumulation was specific for each organ or tissue. The highest amounts of viral RNA and viral particles were found in symptomatic leaves and stem. By observing cell ultrastructure with TEM, viral cytoplasmic inclusion bodies were localized in close vicinity to the epidermis and in trichomes. Our results show that viral RNA, viral particles, and cytoplasmic inclusion bodies colocalize within the same type of cells or in close vicinity.


Fat Grafting in the Management of War Injuries.
The healing potential of fat grafting was empirically noted by the surgeons who were confronted with the dramatic facial disfigurements resulting from World War 1. Fat was transplanted into the wounds either en bloc or in parcels to promote the healing capacity or to correct the uneven, depressed scars from gunshot wounds, enabling the poor soldiers to step back to society and families in a shorter period of time.The idea of transplanting fat into the wound of the facially disfigured started with Hippolyte Morestin (1869-1919), surgeon in chief at Val-de Grace Military Hospital in Paris and was widely adopted by HD Gillies (1882-1960), Erich Lexer (1867-1937), Gustavo Sanvenero Rosselli (1897-1974), and others, achieving amazing results. Successful treatment of facially injured individuals showed the importance of plastic surgical procedures, the social role of the discipline, basis for obtaining the official recognition as surgical specialty.


Movement deviation and asymmetry assessment with three dimensional gait analysis of both upper- and lower extremity results in four different clinical relevant subgroups in unilateral cerebral palsy.
In unilateral cerebral palsy, movement pattern can be difficult to define and quantify. The aim was to assess the degree of deviation and asymmetry in upper and lower extremities during walking. Forty-seven patients, 45 Gross Motor Function Classification Scale (GMFCS) I and 2 patients GMFCS II, mean age 17.1 years (range 13.1 to 24.0) and 15 matched controls were evaluated. Gait profile score (GPS) and arm posture score (APS) were calculated from three-dimensional gait analysis (GA). Asymmetry was the calculated difference in deviation between affected and unaffected sides. The GPS was significantly increased compared to the control group on the affected side (6.93 (2.08) versus 4.23 (1.11) degrees) and on the unaffected side (6.67 (2.14)). The APS was also significantly increased on the affected side (10.39 (5.01) versus 5.52 (1.71) degrees) and on the unaffected side (7.13 (2.23)). The lower extremity asymmetry increased (significantly) in comparison with the control group (7.89 (3.82) versus 3.90 (1.01)) and correspondingly in the upper extremity (9.75 (4.62) versus 5.72 (1.84)). The GPS was not different between affected and unaffected sides, however the APS was different (statistically significant). We calculated deviation and asymmetry of movement during walking in unilateral CP, identifying four important clinical groups: close to normal, deviations mainly in the leg, deviations mainly in the arm and those with deviation in the arm and leg. This method can be applied to any patient group, and aid in diagnosing, planning treatment, and prognosis.


Social circumstances and medical complications in children with intestinal failure.
Although most children discharged on home parenteral nutrition (HPN) will achieve enteral autonomy, some remain parenteral nutrition dependent; those who develop life-threatening complications may undergo small bowel transplantation (SBTx). The aim of this study was to investigate the relationship between social circumstances, compliance and complications. An observational study in 2008-2012 on 64 children (34 HPN, 30 SBTx) from three units (two regional gastroenterology; one transplant). Social circumstances were assessed routinely as part of discharge planning; adherence by families to home care management was scored, and episodes of catheter-related blood stream infection and graft rejection were recorded for 2 years and related to compliance and social circumstances. A quarter of families had a disadvantaged parent: non-English speaking (n=11), unable to read (n=5), physical disability (n=3), mental health problems disclosed (n=10); 20% children were cared for by a lone parent. Discharge home was delayed by social factors (n=9) and need for rehousing (n=17, 27%). 17/34 (50%) of HPN and 12/30 (40%) of transplant families were assessed as fully adherent. 10 families were assessed as non-adherent, eight were subject to child protection review and care was taken over by another family member (n=3) or foster parents (n=2). The risk of catheter-related blood stream infection was increased by parental disadvantage and age <3 years (p<0.05). Poor compliance was associated with complications in HPN and SBTx recipients. Children receiving complex home care may be socially isolated and measures to support improved compliance such as increased community support, social care involvement and respite care may improve outcomes.


Image-guided biopsy in patients with suspected ovarian carcinoma: a safe and effective technique?
In patients with suspected advanced ovarian carcinoma, a precise histological diagnosis is required before commencing neo-adjuvant chemotherapy. This study aims to determine the diagnostic accuracy and complication rate of percutaneous biopsies performed under ultrasound or computed tomography guidance. Between 2002 to 2007, 60 consecutive image-guided percutaneous biopsies were performed in patients with suspected ovarian cancer. The following variables were recorded: tissue biopsied, imaging technique, experience of operator, biopsy needle gauge, number of passes, complications, and final histology. Forty-seven patients had omental biopsies, 12 pelvic mass biopsies, and 1 para-aortic lymph node biopsy. Thirty-five biopsies were performed under ultrasound, 25 under computed tomography guidance. Biopsy needle gauges ranged from 14-20 swg with two to five passes for each patient. There were no complications. Histology was obtained in 52 (87%) patients. Percutaneous image-guided biopsy of peritoneal disease or pelvic mass is safe with high diagnostic accuracy. The large-gauge biopsy needle is as safe as the small gauge needle, but has the added value of obtaining tissue samples for immunohistochemistry and genomic studies.


Guidelines for elderly patients with multimorbidity: how to cope with a dark night without fear.
The epidemiological transition has produced a society with a growing number of the elderly affected by multiple chronic diseases which often requires polypharmacy. Despite being the main users of medications, the elderly are largely underrepresented in clinical trials, especially if they have multimorbidity. It follows that the results of these trials are not applicable in the real world and potentially harmful. In order to breach the wall of this complexity, several suggestions have been put forward, from new clinical trial methodology, simulation models, and the use of patient-centered as opposed to disease-centered indicators. It is likely that comparative effectiveness research will accelerate the shift toward a focus on "universal" outcomes on which all diseases exert an effect. I believe that there is no "one-size-fits-all" solution in this area, but two ideas come to my mind. Why do we not invest more in educating our future geriatricians? And why do we not invest in public awareness campaigns?


Impact of nicotine metabolism on nicotine's pharmacological effects and behavioral responses: insights from a Cyp2a(4/5)bgs-null mouse.
Nicotine metabolism is believed to affect not only nicotine's pharmacological effects but also nicotine addiction. As a key step toward testing this hypothesis, we have studied nicotine metabolism and nicotine's pharmacological and behavioral effects in a novel knockout mouse model [named Cyp2a(4/5)bgs-null] lacking a number of cytochrome P450 genes known to be or possibly involved in nicotine metabolism, including two Cyp2a and all Cyp2b genes. We found that, compared with wild-type mice, the Cyp2a(4/5)bgs-null mice showed >90% decreases in hepatic microsomal nicotine oxidase activity in vitro, and in rates of systemic nicotine clearance in vivo. Further comparisons of nicotine metabolism between Cyp2a(4/5)bgs-null and Cyp2a5-null mice revealed significant roles of both CYP2A5 and CYP2B enzymes in nicotine clearance. Compared with the behavioral responses in wild-type mice, the decreases in nicotine metabolism in the Cyp2a(4/5)bgs-null mice led to prolonged nicotine-induced acute pharmacological effects, in that null mice showed enhanced nicotine hypothermia and antinociception. Furthermore, we found that the Cyp2a(4/5)bgs-null mice developed a preference for nicotine in a conditioned place preference test, a commonly used test of nicotine's rewarding effects, at a nicotine dose that was 4-fold lower than what was required by wild-type mice. Thus, CYP2A/2B-catalyzed nicotine clearance affects nicotine's behavioral response as well as its acute pharmacological effects in mice. This result provides direct experimental support of the findings of pharmacogenetic studies that suggest linkage between rates of nicotine metabolism and smoking behavior in humans.


Numerical simulator of atmospherically distorted phase screen for multibeam time-dependent scenario.
A numerical simulator of a turbulence phase screen based on turbulence power spectrum density is described in this paper. The low-frequency adding technique used in the fast-Fourier-transform-based method is extended to the whole frequency domain. The frequency range and spatial coordinates are no longer limited by the spatial sampling, so that the phase screens can be applied in the multibeam time-dependent scenario. Several spectrums can be applied in this simulator. The structure function, modulation transfer function, and variance of the Zernike coefficient are calculated with the Kolmogorov model for validation. The simulation results have shown good agreement with the theoretical results.


Characteristics and in-hospital mortality of patients with myocardial infarction in the absence of obstructive coronary artery disease in super-aging society.
Myocardial infarction with nonobstructive coronary arteries (MINOCA) is a common presentation of acute myocardial infarction (AMI) and has a better prognosis. However, there were few reports on large-scale, high aged population. The aim of this study was to determine the differences in the clinical characteristics and short-term prognosis between MINOCA and myocardial infarction with obstructive coronary artery disease (MI-CAD) using a nationwide administrative database in the super-aging society, Japan. This was an observational study using data of 137,678 AMI patients who underwent angiography between April 2012 through March 2016. Using the international classification of diseases 10th revision, AMI patients were divided into two groups based on the presence or absence of revascularization and coronary atherosclerosis, identifying 123,633 MI-CAD and 14,045 working diagnosis of MINOCA patients. The true MINOCA (n = 13,022) was defined as the MINOCA excluding non-ischemic causes. We assessed in-hospital mortality within 30 days. Both MINOCA groups were typically found in non-obese, non-smoker young females, with a low grade on Killip classification, and non-low ADL status. Compared to MI-CAD, chronic pulmonary diseases, peripheral vascular diseases, liver diseases, renal diseases, and cerebrovascular diseases were more common, whereas diabetes was less common in the MINOCA groups. In-hospital mortality within 30 days was higher in both MINOCA groups than in MI-CAD. Multivariate frailty model identified both MINOCA groups as an independent risk factor for in-hospital mortality. Our large-population study demonstrated that MINOCA was associated with a high risk of in-hospital mortality compared with MI-CAD in the super-aging society.


Optical levitation of absorbing particles with a nominally Gaussian laser beam.
We use a Gaussian laser beam to study the levitation of absorbing Mie particles. Several metal oxide particles are stably levitated, and their movement over time is recorded. Our studies show that the position of each particle is highly dependent on the other particles' locations. The observations are explained by the phenomenon of thermal creep. The increased local pressure that is due to a temperature gradient along the particle's surface induces levitation. The particles rest close to minima in the intensity distribution near the optical axis. An experiment is suggested that can be used to locate these minima in a laser beam.


Nonuniform ensembles of diverse resonances in one-dimensional layered media.
The transmission spectra perform huge fluctuations even in the mostly suitable one-dimensional localized multilayer system. Fluctuations of layer thicknesses will cause random resonances between light waves and layers. We reveal that the nonuniform ensembles of the resonances are the key for the fluctuations of transmission spectra. The transmission spectra of each stack of layers are numerically calculated through the transfer-matrix method.


Accuracy of epidemiological inferences based on publicly available information: retrospective comparative analysis of line lists of human cases infected with influenza A(H7N9) in China.
Appropriate public health responses to infectious disease threats should be based on best-available evidence, which requires timely reliable data for appropriate analysis. During the early stages of epidemics, analysis of 'line lists' with detailed information on laboratory-confirmed cases can provide important insights into the epidemiology of a specific disease. The objective of the present study was to investigate the extent to which reliable epidemiologic inferences could be made from publicly-available epidemiologic data of human infection with influenza A(H7N9) virus. We collated and compared six different line lists of laboratory-confirmed human cases of influenza A(H7N9) virus infection in the 2013 outbreak in China, including the official line list constructed by the Chinese Center for Disease Control and Prevention plus five other line lists by HealthMap, Virginia Tech, Bloomberg News, the University of Hong Kong and FluTrackers, based on publicly-available information. We characterized clinical severity and transmissibility of the outbreak, using line lists available at specific dates to estimate epidemiologic parameters, to replicate real-time inferences on the hospitalization fatality risk, and the impact of live poultry market closure. Demographic information was mostly complete (less than 10% missing for all variables) in different line lists, but there were more missing data on dates of hospitalization, discharge and health status (more than 10% missing for each variable). The estimated onset to hospitalization distributions were similar (median ranged from 4.6 to 5.6 days) for all line lists. Hospital fatality risk was consistently around 20% in the early phase of the epidemic for all line lists and approached the final estimate of 35% afterwards for the official line list only. Most of the line lists estimated >90% reduction in incidence rates after live poultry market closures in Shanghai, Nanjing and Hangzhou. We demonstrated that analysis of publicly-available data on H7N9 permitted reliable assessment of transmissibility and geographical dispersion, while assessment of clinical severity was less straightforward. Our results highlight the potential value in constructing a minimum dataset with standardized format and definition, and regular updates of patient status. Such an approach could be particularly useful for diseases that spread across multiple countries.


Delivery of therapeutic oligonucleotides with cell penetrating peptides.
Oligonucleotide-based drugs have received considerable attention for their capacity to modulate gene expression very specifically and as a consequence they have found applications in the treatment of many human acquired or genetic diseases. Clinical translation has been often hampered by poor biodistribution, however. Cell-penetrating peptides (CPPs) appear as a possibility to increase the cellular delivery of non-permeant biomolecules such as nucleic acids. This review focuses on CPP-delivery of several classes of oligonucleotides (ONs), namely antisense oligonucleotides, splice switching oligonucleotides (SSOs) and siRNAs. Two main strategies have been used to transport ONs with CPPs: covalent conjugation (which is more appropriate for charge-neutral ON analogues) and non-covalent complexation (which has been used for siRNA delivery essentially). Chemical synthesis, mechanisms of cellular internalization and various applications will be reviewed. A comprehensive coverage of the enormous amount of published data was not possible. Instead, emphasis has been put on strategies that have proven to be effective in animal models of important human diseases and on examples taken from the authors' own expertise.


Bone marrow involvement by lymphoproliferative disorders post liver transplantation: PTLD Int Survey.
to analyze cases of BM PTLD in liver transplant recipients to find any specific predictor or prognostic factor associated with this disease localization. a comprehensive search of the existing literature was performed, and 173 liver recipients who had developed PTLD in their post transplant course from 19 studies were found and enrolled into analysis. 36 of the patients were BM PTLD cases and the remaining was used as controls. liver transplant recipients with BM PTLD were significantly more likely to represent in male patients (p=0.042) and the elderly (p=0.08). BM PTLD was significantly more likely to complicate liver allograft (p=0.027) and spleen (p=0.013). Histopathological evaluations showed that BM PTLD lesions were more likely of monomorphic type (p=0.025). Multi-organ and disseminated PTLD were significantly more prevalent among BM PTLD patients (p<0.001, both) The BM PTLD group represented relatively lower survival than patients with other localizations, although it did not reach significant level (p=0.1). our findings alert us to use more sensitive methods to find potential simultaneous metastatic lesions in the mentioned organs for liver recipients developing BM PTLD. Future studies with prospective approaches are needed to confirm our findings.


Relationship between atypical depression and social anxiety disorder.
In this study, we aimed to investigate the effects of atypical and non-atypical depression comorbidity on the clinical characteristics and course of social anxiety disorder (SAD). A total of 247 patients with SAD were enrolled: 145 patients with a current depressive episode (unipolar or bipolar) with atypical features, 43 patients with a current depressive episode with non-atypical features and 25 patients without a lifetime history of depressive episodes were compared regarding sociodemographic and clinical features, comorbidity rates, and severity of SAD, depression and functional impairment. Thirty four patients with a past but not current history of major depressive episodes were excluded from the comparisons. 77.1% of current depressive episodes were associated with atypical features. Age at onset of SAD and age at initial major depressive episode were lower in the group with atypical depression than in the group with non-atypical depression. History of suicide attempts and bipolar disorder comorbidity was more common in the atypical depression group as well. Atypical depression group has higher SAD and depression severity and lower functionality than group with non-atypical depression. Our results indicate that the presence of atypical depression is associated with more severe symptoms and more impairment in functioning in patients with SAD.


Association of body mass with price of bushmeat in Nigeria and Cameroon.
Spatially extensive patterns of bushmeat extraction (and the processes underlying these patterns) have not been explored. We used data from a large sample (n= 87) of bushmeat trading points in urban and rural localities in Nigeria and Cameroon to explore extraction patterns at a regional level. In 7,594 sample days, we observed 61,267 transactions involving whole carcasses. Rural and urban trading points differed in species for sale and in meat condition (fresh or smoked). Carcass price was principally associated with body mass, with little evidence that taxonomic group (primate, rodent, ungulate, or mammalian carnivore) affected price. Moreover, meat condition was not consistently associated with price. However, some individual species were more expensive throughout the region than would be expected for their size. Prices were weakly positively correlated with human settlement size and were highest in urban areas. Supply did not increase proportionally as human settlement size increased, such that per capita supply was significantly lower in urban centers than in rural areas. Policy options, including banning hunting of more vulnerable species (those that have low reproductive rates), may help to conserve some species consumed as bushmeat because carcass prices indicate that faster breeding, and therefore the more sustainable species, may be substituted and readily accepted by consumers.


Color filters based on enhanced optical transmission of subwavelength-structured metallic film for multicolor organic light-emitting diode display.
Using metallic film perforated with a subwavelength periodic structure, a novel concept of a color filter for multicolor organic light-emitting diode (OLED) display is proposed. Based on the phase-matching condition for extraordinary optical transmission, three primary color emissions can be obtained by optimizing the structure's periodicity. Two periodic structures, an array of one-dimensional periodic slits and a two-dimensional periodic hole array, are studied using coupled mode theory. Also, the feasibility of applying these structures as color filters is analyzed. The relative intensity at the unwanted wavelength, which is generated by higher resonant transmission, had been calculated to eliminate its effect on the purity of these filters. It is important that this type of color filter simultaneously solves the low emission efficiency problem for OLEDs with the aid of enhanced transmission of metal film.


Noninvasive detection of temozolomide in brain tumor xenografts by magnetic resonance spectroscopy.
Poor drug delivery to brain tumors caused by aberrant tumor vasculature and a partly intact blood-brain barrier (BBB) and blood-brain tumor barrier (BTB) can significantly impair the efficacy of chemotherapy. Determining drug delivery to brain tumors is a challenging problem, and the noninvasive detection of drug directly in the tumor can be critically important for accessing, predicting, and eventually improving effectiveness of therapy. In this study, in vivo magnetic resonance spectroscopy (MRS) was used to detect an anticancer agent, temozolomide (TMZ), in vivo in murine xenotransplants of U87MG human brain cancer. Dynamic magnetic resonance imaging (MRI) with the low-molecular-weight contrast agent, gadolinium diethylenetriaminepentaacetic acid (GdDTPA), was used to evaluate tumor vascular parameters. Carbon-13-labeled TMZ ([(13)C]TMZ, 99%) was intraperitoneally administered at a dose of approximately 140 mg/kg (450 mg/m(2), well within the maximal clinical dose of 1000 mg/m(2) used in humans) during the course of in vivo MRS experiments. Heteronuclear multiple-quantum coherence (HMQC) MRS of brain tumors was performed before and after i.p. administration of [(13)C]TMZ. Dynamic MRI experiments demonstrated slower recovery of MRI signal following an intravenous bolus injection of GdDTPA, higher vascular flow and volume obtained by T*(2)-weighted MRI, as well as enhanced uptake of the contrast agent in the brain tumor compared with normal brain detected by T(1)-weighted MRI. These data demonstrate partial breakdown of the BBB/BTB and good vascularization in U87MG xenografts. A [(13)C]TMZ peak was detected at 3.9 ppm by HMQC from a selected volume of about 0.15 cm(3) within the brain tumor with HMQC pulse sequences. This study clearly demonstrates the noninvasive detection of [(13)C]TMZ in xenografted U87MG brain tumors with MRS. Noninvasive tracking of antineoplastic agents using MRS can have a significant impact on brain tumor chemotherapy.


A concept to transfer a therapeutic splint position into permanent occlusion with a customized lingual appliance.
The role of occlusion concerning temporomandibular disorder is still unclear but seems to be the only component of the stomathognathic system dentists are able to change morphologically. The aim of the paper is to describe the orthodontist's approach for transferring and maintaining a therapeutic splint position into permanent occlusion using a fully customized lingual appliance. Fixed acrylic bite planes on lower molars were used to maintain a symptom-free condyle position prior to orthodontic treatment. Silicone impressions of the arches including the fixed bite planes were used for the Incognito laboratory procedure. Two digital setups were made. One setup represents the target occlusion. A second setup including the bite planes was used to fabricate an additional set of lower molar brackets. In the leveling stage all teeth except the lower molars were settled to maintain the therapeutic condyle position. Finally, the fixed bite planes were stepwise removed and molar brackets were replaced to establish the permanent occlusion planned with the first setup. The advantage of an individual lingual appliance consists in the high level of congruence between the fabricated setups and the final clinical result. Both the individual scope for design and the precision of the appliance were vitally important in the treatment of a patient with a functional disorder of the masticatory system.


Flotillin is a Novel Diagnostic Blood Marker of Alzheimer's Disease.
Currently, best-characterized indicators for Alzheimer's disease (AD) diagnosis are the decreased levels of amyloid-β protein 42 and increased levels of phosphorylated tau in cerebrospinal fluid (CSF). The positron emission tomography (PET) imaging with Pittsburgh compound B (PiB) is also used in AD diagnosis by visualizing amyloid deposition in the brain. These methods are invasive or expensive; therefore, less invasive and easily detectable blood biomarkers are required. Because our previous study showed that flotillin release, a marker of exosomes, was attenuated by Aβ, we designed the present study to determine whether flotillin level could be reduced in CSF and/or serum of patients with AD. In this study, we analyzed flotillin levels in CSF and serum of non-AD controls, patients with AD and mild cognitive impairment (MCI) by western blotting. Flotillin levels in cerebroventricular fluid (CVF) and serum of AD, vascular dementia (VaD), and non-AD autopsy cases were also analyzed. Flotillin levels significantly decreased in the CSF and serum of AD patients compared with those of non-AD controls, respectively. Moreover, in patients with MCI due to AD determined by PiB-PET, CSF and serum flotillin levels significantly decreased compared with those of patients with MCI due to non-AD. Flotillin levels remained unchanged in CVF and serum of autopsy cases diagnosed as VaD. Serum flotillin level is negatively associated with brain amyloid deposition indicated as PiB uptake. These results demonstrate that serum flotillin level can serve as one of the blood markers for estimation of brain amyloid deposition and early diagnosis of AD.


Distribution of rotavirus genotypes associated with acute diarrhoea in Zimbabwean children less than five years old before and after rotavirus vaccine introduction.
Sentinel surveillance for diarrhoea is important to monitor changes in rotavirus epidemiological trends and circulating genotypes among children under 5 years before and after vaccine introduction. The Zimbabwe Ministry of Health and Child Care introduced rotavirus vaccine in national immunization program in May 2014. Active hospital-based surveillance for diarrhoea was conducted at 3 sentinel sites from 2008 to 2016. Children aged less than 5 years, who presented with acute gastroenteritis as a primary illness and who were admitted to a hospital ward or treated at the emergency unit, were enrolled and had a stool specimen collected and tested for rotavirus by enzyme immunoassay (EIA). Genotyping of positive stools was performed using reverse-transcription polymerase chain reaction and genotyping assays. Pre-vaccine introduction, 10% of all positive stool specimens were genotyped and all adequate positive stools were genotyped post-vaccine introduction. During the pre-vaccine period, a total of 6491 acute gastroenteritis stools were collected, of which 3016 (46%) tested positive for rotavirus and 312 (10%) of the rotavirus positive stools were genotyped. During the post-vaccine period, a total of 3750 acute gastroenteritis stools were collected, of which 937 (25%) tested positive for rotavirus and 784 (84%) were genotyped. During the pre-vaccine introduction the most frequent genotype was G9P[8] (21%) followed by G2P[4] (12%), G1P[8] (6%), G2P[6] (5%), G12P[6] (4%), G9P[6] (3%) and G8P[4] (3%). G1P[8] (30%) was most dominant two years after vaccine introduction followed by G9P[6] (20%), G2P[4] (15%), G9P[8] (11%) and G1P[6] (4%). The decline in positivity rate is an indication of early vaccine impact. Diversity of circulating strains underscores the importance of continued monitoring and strain surveillance after vaccine introduction.


On the Supposed Evidence for Libertarian Paternalism.
Can the general public learn to deal with risk and uncertainty, or do authorities need to steer people's choices in the right direction? Libertarian paternalists argue that results from psychological research show that our reasoning is systematically flawed and that we are hardly educable because our cognitive biases resemble stable visual illusions. For that reason, they maintain, authorities who know what is best for us need to step in and steer our behavior with the help of "nudges." Nudges are nothing new, but justifying them on the basis of a latent irrationality is. In this article, I analyze the scientific evidence presented for such a justification. It suffers from narrow logical norms, that is, a misunderstanding of the nature of rational thinking, and from a confirmation bias, that is, selective reporting of research. These two flaws focus the blame on individuals' minds rather than on external causes, such as industries that spend billions to nudge people into unhealthy behavior. I conclude that the claim that we are hardly educable lacks evidence and forecloses the true alternative to nudging: teaching people to become risk savvy.


Both noncoding and protein-coding RNAs contribute to gene expression evolution in the primate brain.
Despite striking differences in cognition and behavior between humans and our closest primate relatives, several studies have found little evidence for adaptive change in protein-coding regions of genes expressed primarily in the brain. Instead, changes in gene expression may underlie many cognitive and behavioral differences. Here, we used digital gene expression: tag profiling (here called Tag-Seq, also called DGE:tag profiling) to assess changes in global transcript abundance in the frontal cortex of the brains of 3 humans, 3 chimpanzees, and 3 rhesus macaques. A substantial fraction of transcripts we identified as differentially transcribed among species were not assayed in previous studies based on microarrays. Differentially expressed tags within coding regions are enriched for gene functions involved in synaptic transmission, transport, oxidative phosphorylation, and lipid metabolism. Importantly, because Tag-Seq technology provides strand-specific information about all polyadenlyated transcripts, we were able to assay expression in noncoding intragenic regions, including both sense and antisense noncoding transcripts (relative to nearby genes). We find that many noncoding transcripts are conserved in both location and expression level between species, suggesting a possible functional role. Lastly, we examined the overlap between differential gene expression and signatures of positive selection within putative promoter regions, a sign that these differences represent adaptations during human evolution. Comparative approaches may provide important insights into genes responsible for differences in cognitive functions between humans and nonhuman primates, as well as highlighting new candidate genes for studies investigating neurological disorders.


The effect of inhaled IFN-β on worsening of asthma symptoms caused by viral infections. A randomized trial.
Ex vivo, bronchial epithelial cells from people with asthma are more susceptible to rhinovirus infection caused by deficient induction of the antiviral protein, IFN-β. Exogenous IFN-β restores antiviral activity. To compare the efficacy and safety of inhaled IFN-β with placebo administered to people with asthma after onset of cold symptoms to prevent or attenuate asthma symptoms caused by respiratory viruses. A total of 147 people with asthma on inhaled corticosteroids (British Thoracic Society Steps 2-5), with a history of virus-associated exacerbations, were randomized to 14-day treatment with inhaled IFN-β (n = 72) or placebo (n = 75) within 24 hours of developing cold symptoms and were assessed clinically, with relevant samples collected to assess virus infection and antiviral responses. A total of 91% of randomized patients developed a defined cold. In this modified intention-to-treat population, asthma symptoms did not get clinically significantly worse (mean change in six-item Asthma Control Questionnaire <0.5) and IFN-β treatment had no significant effect on this primary endpoint, although it enhanced morning peak expiratory flow recovery (P = 0.033), reduced the need for additional treatment, and boosted innate immunity as assessed by blood and sputum biomarkers. In an exploratory analysis of the subset of more difficult-to-treat, Step 4-5 people with asthma (n = 27 IFN-β; n = 31 placebo), Asthma Control Questionnaire-6 increased significantly on placebo; this was prevented by IFN-β (P = 0.004). Although the trial did not meet its primary endpoint, it suggests that inhaled IFN-β is a potential treatment for virus-induced deteriorations of asthma in difficult-to-treat people with asthma and supports the need for further, adequately powered, trials in this population. Clinical trial registered with www.clinicaltrials.gov (NCT 01126177).


Primary care management of non-English-speaking refugees who have experienced trauma: a clinical review.
Refugees are a vulnerable class of immigrants who have fled their countries, typically following war, violence, or natural disaster, and who have frequently experienced trauma. In primary care, engaging refugees to develop a positive therapeutic relationship is challenging. Relative to care of other primary care patients, there are important differences in symptom evaluation and developing treatment plans. To discuss the importance of and methods for obtaining refugee trauma histories, to recognize the psychological and physical manifestations of trauma characteristic of refugees, and to explore how cultural differences and limited English proficiency affect the refugee patient-clinician relationship and how to best use interpreters. MEDLINE and the Cochrane Library were searched from 1984 to 2012. Additional citations were obtained from lists of references from select research and review articles on this topic. Engagement with a refugee patient who has experienced trauma requires an understanding of the trauma history and the trauma-related symptoms. Mental health symptoms and chronic pain are commonly experienced by refugee patients. Successful treatment requires a multidisciplinary approach that is culturally acceptable to the refugee. Refugee patients frequently have experienced trauma requiring a directed history and physical examination, facilitated by an interpreter if necessary. Intervention should be sensitive to the refugee's cultural mores.


Physiological cost of walking in those with chronic fatigue syndrome (CFS): a case-control study.
To examine the physiological cost of walking in subjects with chronic fatigue syndrome (CFS) and a matched control group, walking at their preferred and at matched walking speeds. Seventeen people with CFS and 17 matched-controls participated in this observational study of physiological cost during over-ground gait. Each subject walked for 5 min at their preferred walking speed (PWS). Controls then walked for 5 min at the same pace of their matched CFS subject. Gait speed and oxygen uptake, gross and net were measured and oxygen uptake was expressed per unit distance ambulated. CFS subjects completed the CFS-Activities and Participation Questionnaire (CFS-APQ). At PWS the CFS group walked at a slower velocity of 0.84 +/- 0.21 m s(-1) compared to controls with a velocity of 1.19 +/- 0.13 m s(-1) (p < 0.001). At PWS both gross and net oxygen uptake of CFS subjects was significantly less than controls (p = 0.023 and p = 0.025 respectively). At matched-velocity both gross and net physiological cost of gait was greater for CFS subjects than controls (p = 0.048 and p = 0.001, respectively). The physiological cost of walking was significantly greater for people with CFS compared with healthy subjects. The reasons for these higher energy demands for walking in those with CFS have yet to be fully elucidated.


Engineering ER-stress dependent non-conventional mRNA splicing.
The endoplasmic reticulum (ER) protein folding capacity is balanced with the protein folding burden to prevent accumulation of un- or misfolded proteins. The ER membrane-resident kinase/RNase Ire1 maintains ER protein homeostasis through two fundamentally distinct processes. First, Ire1 can initiate a transcriptional response through a non-conventional mRNA splicing reaction to increase the ER folding capacity. Second, Ire1 can decrease the ER folding burden through selective mRNA decay. In Saccharomyces cerevisiae and Schizosaccharomyces pombe, the two Ire1 functions have been evolutionarily separated. Here, we show that the respective Ire1 orthologs have become specialized for their functional outputs by divergence of their RNase specificities. In addition, RNA structural features separate the splicing substrates from the decay substrates. Using these insights, we engineered an S. pombe Ire1 cleavage substrate into a splicing substrate, which confers S. pombe with both Ire1 functional outputs.


[Tobacco use and plasma lipid-lipoprotein profile in adolescents].
To analyze the impact of tobacco use on plasma lipid lipoprotein profile in representative sample of adolescents. A sample of 452 subjects (246 girls and 206 boys) 15 to 18 years old were included in the study. Each participant completed a structured and self-administered questionnaire concerning tobacco use. Plasma lipid-lipoprotein concentrations were measured by standard procedures. Differences between mean values were evaluated by analysis of covariance, controlling for saturated fat and cholesterol intake. Odds ratio was used to estimate the relative risk of the smokers being classified with an undesirable level of a plasma lipidlipoprotein parameter. The proportion of smokers was 20.9% for boys and 15.4% for girls. The average consumption of cigarettes per day was 9.2+/-4.7 for boys and 5.6+/-3.1 for girls. When compared with non-smokers, boy and girl smokers showed a significantly higher serum levels of total cholesterol, LDL-cholesterol, triglycerides and apolipoprotein B100, and significantly lower serum levels of HDL-cholesterol. Adolescent smokers tended to show a two-fold higher risk of altered lipid-lipoprotein levels than non-smokers. The present data could imply that intervention promoting a healthy lifestyle, including non smoking, should start at an early age to prevent or delay development of atherosclerotic lesions and ultimately to minimize the appearance of premature coronary heart disease in adults.


The ethics conundrum in Recall by Genotype (RbG) research: Perspectives from birth cohort participants.
Recall by genotype (RbG) research recruits on the basis of genetic variation. Increased use of this approach presents an ethical conundrum for cohort studies/biobanks: whether to inform individuals of their genetic information and deviate from standard practice of non-disclosure of results, or mask this information at the level of the individual participant. This paper examines the perspectives of research study participants on RbG research. Fifty-three semi-structured interviews were conducted with young adult participants of the Avon Longitudinal Study of Parents and Children (ALSPAC). Topics included understandings of RbG research, expectations around recruitment and communication of research findings. Participants uniformly expressed a deep trust and faith in ALSPAC and considered themselves part of the ALSPAC team. Such perspectives, alongside a limited knowledge of genetics and modest interest in reported research outcomes, meant few participants reported immediate concerns about being recruited by genotype. Our findings highlight the responsibility and duty of care on RbG researchers, and longitudinal studies more generally, and the importance of solidarity, reciprocity and co-production in study-participant relations. As such, we consider existing recommendations for conducting RbG research in longitudinal studies in light of our results and speak to recent changes in the approach used by ALSPAC.


Studies on the 2,4-diamino-6-substituted quinazolines. III. The capacity of sulfadiazine to enhance the activities of WR-158,122 and WR-159,412 against infections with various drug-susceptible and drug-resistant strains of Plasmodium falciparum and Plasmodium vivax in owl monkeys.
Previous studies showed: 1) that the activities of the 2,4-diamino-6-substituted quinazolines. WR-158,122 and WR-159,412, against Plasmodium falciparum and Plasmodium vivax infections in owl monkeys, were seriously impaired when infecting strains were pyrimethamine-resistant; and 2) that primary treatment failure with either agent led frequently to emergence of parasites resistant to these derivatives. Taking advantage of the potencies of WR-158,122 and WR-159,412 as dihydrofolic acid reductase inhibitors, the current studies were aimed at determining whether the above liabilities could be reduced to manageable levels or eliminated by concomitant administration of a rho-aminobenzoic acid inhibitor such as sulfadiazine. Application of these combinations prevented emergence of parasites resistant to WR-158,122 or WR-159,412, but did not abolish the differences in effectiveness of either compound against infections with pyrimethamine-susceptible and pyrimethamine-resistant strains; however, activities against infections with either susceptible or resistant strains were enhanced markedly. With WR-158,122, this enhancement ranged from greater than 7-fold to 75-fold; with WR-159,412, it ranged from greater than 5-fold to 13-fold. Maximal increases in activity were attained with a remarkedly small dose of sulfadiazine, 5.0 mg per kg of body weight daily. With this augmentation of activity, acceptably small doses of WR-158,122 regularly cured infections with even the most highly pyrimethamine-resistant strain.


Three-way interaction effect of 5-HTTLPR, BDNF Val66Met, and childhood adversity on depression: a replication study.
Both the serotonin transporter linked promoter region (5-HTTLPR) and the brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms have been shown to interact with unfavourable environment in relation to depression symptoms and to depression diagnosis. Several attempts have been made to study a three-way interaction effect of these factors on depression, however with contradictory results. We aimed to test the hypothesis of a three-way interaction effect and to attempt at replication in an independent population-based sample. Family maltreatment, sexual abuse and depression were self-reported by an adolescent population-based cohort (N=1393) from the county of Västmanland, Sweden. DNA was isolated from saliva, and used for genotyping of the 5-HTTLPR and BDNF Val66Met polymorphisms. Neither 5-HTTLPR or BDNF genotypes separately, nor in interaction with each other had any relation to depression, however in an environment adjusted model a two-way interaction and a three-way interaction effect was found. Both 5-HTTLPR and BDNF Val66Met interacted with unfavourable environment in relation to depressive symptoms (Adj R²=0.19). Depressive symptoms and depression were more common among carriers of either the ss/sl+Val/Val or the ll+Met genotypes in the presence of early-life adversities. This three-way effect was more pronounced among girls. The current study, with a virtually similar set-up compared to previous studies, can partially confirm previous findings and their generalizability. The study also shows the importance of genetic plasticity in individuals with different environmental exposure, for different phenotypic expression.


Mechanisms determining the fate of hematopoietic stem cells.
Successful in vitro expansion of hematopoietic stem cells (HSCs) will facilitate the application of HSC transplantation for the treatment of various diseases, including hematological malignancies. To achieve this expansion, the molecular mechanisms that control the fate of HSCs must be deciphered. Leukemia-initiating cells (LICs) or leukemia stem cells (LSCs) may originate from normal HSCs, which suggest that the dysregulation of the mechanisms that regulate the cell fate of HSCs may underlie leukemogenesis. Here we review the recent progress in the application of HSCs, the regulatory mechanisms of the fate of HSCs, and the origins of leukemia.


Enkephalin surges in dorsal neostriatum as a signal to eat.
Compulsive overconsumption of reward characterizes disorders ranging from binge eating to drug addiction. Here, we provide evidence that enkephalin surges in an anteromedial quadrant of dorsal neostriatum contribute to generating intense consumption of palatable food. In ventral striatum, mu opioid circuitry contributes an important component of motivation to consume reward. In dorsal neostriatum, mu opioid receptors are concentrated within striosomes that receive inputs from limbic regions of prefrontal cortex. We employed advanced opioid microdialysis techniques that allow detection of extracellular enkephalin levels. Endogenous >150% enkephalin surges in anterior dorsomedial neostriatum were triggered as rats began to consume palatable chocolates. In contrast, dynorphin levels remained unchanged. Furthermore, a causal role for mu opioid stimulation in overconsumption was demonstrated by observations that microinjection in the same anterior dorsomedial quadrant of a mu receptor agonist ([D-Ala2, N-MePhe4, Gly-ol]-enkephalin; DAMGO) generated intense >250% increases in intake of palatable sweet food (without altering hedonic impact of sweet tastes). Mapping by "Fos plume" methods confirmed the hyperphagic effect to be anatomically localized to the anteromedial quadrant of the dorsal neostriatum, whereas other quadrants were relatively ineffective. These findings reveal that opioid signals in anteromedial dorsal neostriatum are able to code and cause motivation to consume sensory reward.


Is urban growing of fruit and vegetables associated with better diet quality and what mediates this relationship? Evidence from a cross-sectional survey.
Urban agriculture (UA), the growing of fruits and vegetables in urban and peri-urban areas, may improve food security and access, public health and dietary quality on both a broad and personal scale. However, there is little research on the relationship between UA and diet, and potential mediating factors are also unclear. This study aimed to investigate if proximity to and engagement with UA is associated with better diet quality, and what accounts for this relationship. UK-based adults (N = 583, 69% Female) completed measures of proximity to and engagement with UA, perceived access to fruits and vegetables, health and ethical food choice motivations, connection with nature, psychological distress and dietary quality in an online survey. Participants were recruited from UA-related groups and the general public. Proposed relationships were analysed using a structural equation model. Greater proximity to and engagement with UA was associated with greater perceived access to fruits and vegetables, more health-related food choice motivations, more ethical-related food choice, feeling more connected with nature, and, surprisingly greater psychological distress. Furthermore, proximity to and engagement with UA was indirectly associated with better diet quality via health-, and ethical-related, food choice motivations. While the direct pathway between proximity to and engagement with UA and diet quality was not significant, UA is associated with better diet quality, partly via healthier and ethical food choice motivations. Upscaling UA may have benefits for dietary quality via these factors, and more research is needed to test causal relationships and understand these complex interactions.