The Sources of Parent-Child Transmission of Risk for Suicide Attempt and Deaths by Suicide in Swedish National Samples.
The authors aimed to clarify the sources of parent-child transmission for suicide attempt and death by suicide. Three sources of parent-child resemblance (genes plus rearing, genes only, and rearing only) were examined in parents and offspring from four family types from Swedish national samples: intact nuclear families, families with a not-lived-with biological father, families with a stepfather, and adoptees and their biological and adoptive parents. Parent-child resemblance was assessed primarily by tetrachoric correlation. For suicide attempt to suicide attempt transmission, best-estimate tetrachoric correlations for genes plus rearing, genes only, and rearing only were 0.23 (95% CI=0.23, 0.24), 0.13 (95% CI=0.11, 0.15), and 0.14 (95% CI=0.11, 0.16), respectively. Suicide attempt was more strongly transmitted to male offspring compared with female offspring. Parental psychiatric disorders accounted for 40% of the genetic transmission but had no impact on rearing effects. For suicide death to suicide death transmission, best estimates of tetrachoric correlations for genes plus rearing, genes only, and rearing only were 0.16 (95% CI=0.15, 0.18), 0.07 (95% CI=0.02, 0.12), and -0.05 (95% CI=-0.17, 0.07), respectively. Although the suicide attempt-suicide death genetic correlation was high (0.84), the hypothesis that they reflect behaviors only differing in severity on the same continuum of genetic liability could be rejected. The transmission of suicide attempt across generations is moderately strong and arises equally from genetic and rearing effects. Parental psychiatric illness explains almost half of the genetic transmission of suicide attempt but none of the rearing effect. Suicide death is modestly transmitted across generations, probably via genetic effects, although rearing may play a role. While suicide attempt and suicide death share a substantial proportion of their hereditary risk, they do not, from a genetic perspective, simply reflect milder and more severe forms of the same diathesis.


Executive function after severe childhood traumatic brain injury - Age-at-injury vulnerability periods: The TGE prospective longitudinal study.
Executive function (EF) impairment is a major predictor of overall outcome after traumatic brain injury (TBI). TBI severity is a factor of poor outcome, but most studies include a majority of children with mild and moderate TBI. The aims of this study were to estimate EF impairment after severe childhood TBI and to explore factors predicting EF outcome. The secondary aim was to compare recovery trajectories by age-at-injury groups. This was a prospective longitudinal study of children with severe TBI who were tested for EFs by performance-based tests and questionnaires at 3, 12 and 24 months. Children with TBI (n=65) showed significant impairment in working memory, inhibition, attention and global EF, with little or no recovery at 24 months. For flexibility and performance-based EF score, children were impaired at 3 months only and showed normal scores by 12 months. No impairment was found in planning. At 3 and 24 months, Glasgow Coma Scale score and parental education predicted global EF. Coma length was not a significant predictor of outcome. Age at injury predicted progress in EF, but the relationship was not linear; children 10-12 years old at injury showed better outcome than older and younger children. EFs are impaired after severe TBI in childhood. The relationship between age at injury and outcome is not linear. Relying on only performance-based EF tests can underestimate EF impairment.


Protective effect of edaravone against radiation-induced ovarian injury: a histopathological and immunohistochemical evaluation in an experimental rat model.
We aimed to evaluate the protective effect of edaravone on radiation-induced ovarian damage in an experimental rat model. Thirty-two Wistar albino female rats were randomly divided into four groups. Group 1: control, no treatment, and radiation was applied throughout the study; Group 2: sham, only radiation was applied; Group 3: 45 mg/kg edaravone and radiation were applied; Group 4: 450 mg/kg edaravone and radiation were applied. Edaravone was administered intraperitoneally 30 min before radiotherapy (5 Gy). Two days after radiation exposure, the rats were sacrificed and the ovaries were removed. Histologic changes under light microscopy and immunoreactivity for anti-caspase-3 were noted and compared between the four groups. There was a statistically significant difference in follicle counts, vascular congestion, edema, cytoplasmic vacuolization, hemorrhage, and interstitial cell degeneration between the groups. Radiation causes deterioration in most histopathological parameters. Administration of edaravone at different doses seems to reverse these alterations and alleviate the injury. Antioxidant defense mechanisms appear to be enhanced by edaravone as shown by histopathologically and decreased apoptosis by reducing the expression of anti-caspase-3 activity as demonstrated immunohistochemically. This is the first study evaluating the protective effects of edaravone on radiation-induced ovarian damage. Edaravone decreased the follicular apoptosis and attenuates the radiation-induced ovarian damage in rats.


Oxygen Requirements for Acutely and Critically Ill Patients.
Oxygen administration is often assumed to be required for all patients who are acutely or critically ill. However, in many situations, this assumption is not based on evidence. Injured body tissues and cells throughout the body respond both beneficially and adversely to delivery of supplemental oxygen. Available evidence indicates that oxygen administration is not warranted for patients who are not hypoxemic, and hyperoxia may contribute to increased tissue damage and mortality. Nurses must be aware of implications related to oxygen administration for all types of acutely and critically ill patients. These implications include having knowledge of oxygenation processes and pathophysiology; assessing global, tissue, and organ oxygenation status; avoiding either hypoxia or hyperoxia; and creating partnerships with respiratory therapists. Nurses can contribute to patients' oxygen status well-being by being proficient in determining each patient's specific oxygen needs and appropriate oxygen administration.


TRADITIONAL CARDIOVASCULAR RISK-FACTORS AMONG HEALTHCARE WORKERS IN KELANTAN, MALAYSIA.
We conducted a cross sectional study of cardiovascular risk factors among healthcare workers at four government hospitals in Kelantan, Malaysia. We randomly selected 330 subjects fulfilling the following study criteria: those who had been working for at least one year at that health facility, Malaysians citizens and those with some form of direct contact with patients. We conducted an interview, obtained physical measurements, a fasting blood sugar and fasting lipid profiles among 308 subjects. The mean age of the subjects was 43.5 years, 82% were female; 30.8%, 14.3%, 10.4%, 1.3% and 1.6% of the subjects had dyslipidemia, hypertension, diabetes mellitus, a history of stroke and a history of ischemic heart disease, respectively. Forty-two percent of subjects had at least one medical condition. The mean body mass index (BMI) was 27.0 kg/M2 (SD=4.8) and 24.3% had a BMI > or =30 kg/M2. The mean systolic and diastolic blood pressures were 121.5 mmHg (SD=14.0) and 76.5 mmHg (SD=9.7), respectively and the mean waist-hip ratio was 0.84 (SD=0.1). The mean fasting blood sugar, total cholesterol, triglyceride, high density lipoprotein and low density lipoprotein were 5.8 mmol/l (SD=2.4), 5.5 mmol/l (SD=1.0), 1.4 mmol/l (SD=0.9), 1.5 mmol/l (SD=0.3) and 3.5 mmol/l (SD=0.9), respectively. Our study population had a smaller proportion of hypertension than that of the general Malaysian population. They had higher fasting total cholesterol, slightly lower fasting blood sugar, with a large proportion of them, obese and had diabetes. Immediate intervention is needed to reduce the traditional cardiovascular risk factors in this population. Keywords: cardiovascular risk factors, health care workers, Malaysia


Biosynthesis of nitric oxide activates iron regulatory factor in macrophages.
Biosynthesis of nitric oxide (NO) from L-arginine modulates activity of iron-dependent enzymes, including mitochondrial acontiase, an [Fe-S] protein. We examined the effect of NO on the activity of iron regulatory factor (IRF), a cytoplasmic protein which modulates both ferritin mRNA translation and transferrin receptor mRNA stability by binding to specific mRNA sequences called iron responsive elements (IREs). Murine macrophages were activated with interferon-gamma and lipopolysaccharide to induce NO synthase activity and cultured in the presence or absence of NG-substituted analogues of L-arginine which served as selective inhibitors of NO synthesis. Measurement of the nitrite concentration in the culture medium was taken as an index of NO production. Mitochondria-free cytosols were then prepared and aconitase activity as well as IRE binding activity and induction of IRE binding activity were correlated and depended on NO synthesis after IFN-gamma and/or LPS stimulation. Authentic NO gas as well as the NO-generating compound 3-morpholinosydnonimine (SIN-1) also conversely modulated aconitase and IRE binding activities of purified recombinant IRF. These results provide evidence that endogenously produced NO may modulate the post-transcriptional regulation of genes involved in iron homeostasis and support the hypothesis that the [Fe-S] cluster of IRF mediates iron-dependent regulation.


Clinical aspects of chronic use of alprazolam and lorazepam.
The authors' goal was to determine the clinical characteristics of persistent users of alprazolam or lorazepam who wished to discontinue their medication. Long-term users (daily use for more than 3 months) of alprazolam (N = 34) or lorazepam (N = 97) who entered an outpatient treatment program for discontinuation of benzodiazepines were carefully assessed. Detailed histories of benzodiazepine use were obtained; a structured interview was used to make psychiatric diagnoses based on DSM-III-R criteria. The majority of patients were using low therapeutic doses of medication (lorazepam: mean = 2.7 mg/day; alprazolam: mean = 1.2 mg/day) and had either maintained their initial daily dose over time or decreased it. Individuals tended to shift their use of medication from an as-prescribed to an as-needed pattern. Forty-seven percent of the patients were diagnosed with at least one current anxiety disorder, most commonly generalized anxiety. At least one diagnosable personality disorder was found in 45% of the patients, most commonly obsessive-compulsive personality disorder. Patterns of benzodiazepine use were influenced by age, gender, and past history of alcohol dependence. Long-term users of alprazolam/lorazepam seeking treatment for discontinuation had clinically important past and current psychiatric histories. They used a constant or decreasing dose of medication and made attempts to stop their use. Persistent use of alprazolam/lorazepam for therapeutic purposes did not represent abuse or addiction as the terms are usually understood. A substantial proportion of these patients may be receiving appropriate maintenance therapy for a chronic psychiatric condition.


Fiber delivered probe for efficient CARS imaging of tissues.
We demonstrate a fiber-based probe for maximum collection of the coherent anti-Stokes Raman scattering (CARS) signal in biological tissues. We discuss the design challenges including capturing the backscattered forward generated CARS signal in the sample and the effects of fiber nonlinearities on the propagating pulses. Three different single mode fibers (fused silica fiber, photonic crystal fiber and double-clad photonic crystal fiber) were tested for the probe design. We investigated self-phase modulation, stimulated Raman scattering (SRS) and four-wave-mixing (FWM) generation in the fiber: nonlinear processes expected to occur in a two-beam excitation based probe. While SPM and SRS induced spectral broadening was negligible, a strong non phase-matched FWM contribution was found to be present in all the tested fibers for excitation conditions relevant to CARS microscopy of tissues. To spectrally suppress this strong contribution, the pro design incorporates separate fibers for excitation light delivery and for signal detection, in combination with dichroic optics. CARS images of the samples were recorded by collecting the back-scattered forward generated CARS signal in the sample through a multi-mode fiber. Different biological tissues were imaged ex vivo in order to assess the performance of our fiber-delivered probe for CARS imaging, a tool which we consider an important advance towards label-free, in vivo probing of superficial tissues.


A Pilot Study on Mandibular Overdentures Retained By Mini Dental Implants: Marginal Bone Level Changes and Patient-Based Ratings of Clinical Outcome.
The aim of this study was to investigate the effect of immediately loaded mini dental implants (MDIs) used to support mandibular overdentures on the peri-implant bone level as well as patients' related levels of satisfaction and quality of life. Four MDIs were placed in the interforaminal region of 10 completely edentulous patients, and the implants were loaded immediately (same day) with an overdenture. Radiographic assessment of the bone loss during a period of 18 months was performed by measuring the bone level changes at the mesial and distal aspects of each implant on panoramic radiographs. At the end of this period, patients' satisfaction level on the visual analog scale (VAS) and oral health-related quality of life was assessed by means of questionnaires. A mean bone loss of 1.04 mm on the mesial and distal sides was recorded during the 18-month period after loading of the implants. The score for general satisfaction level was 95.67 ± 5.68. Similarly high VAS scores were given by the patients in all other specific items on patient satisfaction. The total score for the Oral Health Impact Profile-20 (OHIP-20) was 34.07 ± 13.90, which was comparable to that recorded in other studies. The short-term radiographic peri-implant bone level changes of MDIs immediately loaded with overdentures in the edentulous mandible were within the physiologic limits. The patients expressed a high level of satisfaction and oral health-related quality of life with this treatment modality.


A manganese porphyrin suppresses oxidative stress and extends the life span of streptozotocin-diabetic rats.
Enhanced oxidative stress due to hyperglycemia has been implicated in diabetic complications and is considered a major cause of cell and tissue damage. The aim of the present study was to investigate whether synthetic manganese porphyrin, Mn(III) 5,10,15,20-tetrakis(N-methylpyridinium-2-yl)porphyrin (MnTM-2-PyP5+) can ameliorate diabetes-induced oxidative stress and affect life span of diabetic rats. Diabetes was induced by a single (60 mg/kg) intraperitoneal injection of streptozotocin in male Wistar rats. Oxidative stress was monitored by measuring malondialdehyde levels (MDA) in blood plasma and erythrocytes using HPLC. The antioxidant status was assessed by measuring the total radical-trapping potential (TRAP) of blood plasma. Life span of the animals was used as an indication of the overall effect of MnTM-2-PyP5+. MnTM-2-PyP5+ was administered subcutaneously at 1 mg/kg for the duration of the experiment, five times/week followed by one week of rest. Diabetes increased plasma and erythrocyte levels of MDA and decreased TRAP. MnTM-2-PyP5+ had no effect on blood glucose and glycosylated hemoglobin, but significantly increased TRAP and lowered MDA. This Mn porphyrin decreased mortality and markedly extended the life span of the diabetic animals. MnTM-2-PyP5+ suppressed diabetes-induced oxidative stress, which presumably accounts for its beneficial effect on the life span of the diabetic rats. The results indicate that Mn(III) N-alkylpyridylporphyrins can be used as potent therapeutic agents in diabetes.


Theoretical model for cellular shapes driven by protrusive and adhesive forces.
The forces that arise from the actin cytoskeleton play a crucial role in determining the cell shape. These include protrusive forces due to actin polymerization and adhesion to the external matrix. We present here a theoretical model for the cellular shapes resulting from the feedback between the membrane shape and the forces acting on the membrane, mediated by curvature-sensitive membrane complexes of a convex shape. In previous theoretical studies we have investigated the regimes of linear instability where spontaneous formation of cellular protrusions is initiated. Here we calculate the evolution of a two dimensional cell contour beyond the linear regime and determine the final steady-state shapes arising within the model. We find that shapes driven by adhesion or by actin polymerization (lamellipodia) have very different morphologies, as observed in cells. Furthermore, we find that as the strength of the protrusive forces diminish, the system approaches a stabilization of a periodic pattern of protrusions. This result can provide an explanation for a number of puzzling experimental observations regarding cellular shape dependence on the properties of the extra-cellular matrix.


Role of NKG2D in cytokine-induced killer cells against multiple myeloma cells.
The cytokine-induced killer cells (CIK) have been reported to have potent cytotoxicity against a variety of tumor cells including multiple myleoma (MM) cells. The mechanisms that CIK cell recognizing MM cells remain unknown. Recent studies indicated that the interaction between NKG2D receptor and NKG2D ligands plays an important role in inducing cytotoxicity against various target cells by natural killer cells (NK). We suspect whether NKG2D receptor and NKG2D ligands interaction is also responsible for the killing of MM cells by CIK as the same way did NK cells. We expanded CIK cells from healthy controls with interferon (IFN)-γ, CD3 monoclonal antibodies (mAb) and interleukin-2 (IL-2), and checked expression of NK cell receptors on CIK cells by flow cytometry. About 86% bulk CIK cells expressed NKG2D receptor but not other NK receptors, such as CD158a, CD158b and NCRs. We analyzed NKG2D ligands expression in MM patients by flow cytometry, primary plasma cells from 8 out of 13 (62%) MM patients expressed different levels of ULBPs or MICA/B on the cell surface. Interestingly, when stimulated with MM cell line U266 that expressed some levels of MICA/B, only NKG2D expressing CIK cells released IFN-γ. CIK cells showed cytotoxicity against NKG2D ligands expressing U266 and primary MM cells, and the cytotoxicity was partially blocked by treating CIK with anti-NKG2D antibody. We conclude that NKG2D-NKG2D ligand interaction may be one of the mechanisms by which CIK cells kill MM cells.


Intervention Design of High-Intensity Interval Training in Individuals With Spinal Cord Injury: Narrative Review and Future Perspectives.
Individuals with spinal cord injury (SCI) have lower levels of physical activity compared to the nondisabled population. Exercise guidelines recommend moderate or vigorous exercise to improve cardiovascular health and reduce cardiometabolic risk factors in persons with SCI. High-intensity interval training (HIIT) is a popular exercise choice and encompasses brief periods of vigorous exercise paired with intermittent periods of recovery. This review describes the available literature on HIIT for individuals with SCI, including differences in protocol design and suggested areas of further investigation. Our institution's library system performed the comprehensive search. The primary keywords and phrases used to search included spinal cord injury, high-intensity interval training, tetraplegia, paraplegia, and several other related terms. Initially 62 records were screened, and 36 were deemed outside the scope of this review. Twenty-six studies published between 2001 and 2021 fulfilled the eligibility criteria and were divided among two researchers for review and analysis. All records required persons with SCI and a standardized HIIT intervention. Study design varied widely with respect to mode of exercise, prescribed intensity, duration of performance intervals, and session duration. This variability necessitates further investigation into the specifics of a HIIT prescription and the associated outcomes for persons with SCI. Standardization of HIIT protocols may lead to more robust conclusions regarding its effects on cardiorespiratory fitness as well as mitigation of cardiometabolic risk factors. Meta-analyses will eventually be needed on proper dosing and session parameters to improve cardiorespiratory fitness and cardiometabolic risk factors.


Prostate-specific antigen in the early detection of prostate cancer.
Throughout Canada, the United States and much of Europe, prostate-specific antigen (PSA) screening for prostate cancer has proliferated over the past 2 decades, leading to dramatic increases in detection rates of prostate cancer. Although it has unquestionably led to increased detection of cancer and a migration to lower-stage and -volume tumours, it is still unknown whether PSA screening significantly reduces mortality from prostate cancer. Often thought to be dichotomous (i.e., either normal or elevated), PSA measurements actually reflect cancer risk, with the risks of cancer and of aggressive cancer increasing with the level of PSA. The recently developed risk calculator from the Prostate Cancer Prevention Trial, which integrates family history of prostate cancer, digital rectal examination findings, PSA test result, age, ethnicity, and history of a prior prostate biopsy with a negative result, allows clinicians to assess a patient's individual risk of cancer. This risk should be examined in the context of a patient's life expectancy and comorbidity as well as his concern about the possibility of prostate cancer. The terms "normal" and "elevated" as descriptors of PSA results should be abandoned.


Multiple lateral transfers of dissimilatory sulfite reductase genes between major lineages of sulfate-reducing prokaryotes.
A large fragment of the dissimilatory sulfite reductase genes (dsrAB) was PCR amplified and fully sequenced from 30 reference strains representing all recognized lineages of sulfate-reducing bacteria. In addition, the sequence of the dsrAB gene homologs of the sulfite reducer Desulfitobacterium dehalogenans was determined. In contrast to previous reports, comparative analysis of all available DsrAB sequences produced a tree topology partially inconsistent with the corresponding 16S rRNA phylogeny. For example, the DsrAB sequences of several Desulfotomaculum species (low G+C gram-positive division) and two members of the genus Thermodesulfobacterium (a separate bacterial division) were monophyletic with delta-proteobacterial DsrAB sequences. The most parsimonious interpretation of these data is that dsrAB genes from ancestors of as-yet-unrecognized sulfate reducers within the delta-Proteobacteria were laterally transferred across divisions. A number of insertions and deletions in the DsrAB alignment independently support these inferred lateral acquisitions of dsrAB genes. Evidence for a dsrAB lateral gene transfer event also was found within the delta-Proteobacteria, affecting Desulfobacula toluolica. The root of the dsr tree was inferred to be within the Thermodesulfovibrio lineage by paralogous rooting of the alpha and beta subunits. This rooting suggests that the dsrAB genes in Archaeoglobus species also are the result of an ancient lateral transfer from a bacterial donor. Although these findings complicate the use of dsrAB genes to infer phylogenetic relationships among sulfate reducers in molecular diversity studies, they establish a framework to resolve the origins and diversification of this ancient respiratory lifestyle among organisms mediating a key step in the biogeochemical cycling of sulfur.


Impact of bile duct obstruction on hepatic E. coli infection: role of IL-10.
Biliary obstruction in the setting of hepatic bacterial infection has great morbidity and mortality. We developed a novel murine model to examine the effect of biliary obstruction on the clearance of hepatic Escherichia coli infection. This model may allow us to test the hypothesis that biliary obstruction itself adversely affects clearance of hepatic infections even if the bacteria are introduced into the liver by a nonbiliary route. We ligated the bile ducts of C57BL/6 mice on days -1, 0, or +1, relative to a day 0 portal venous injection of E. coli. We monitored survival, hepatic bacterial growth, pathology, and IL-10 protein levels. The role of IL-10 in this model was further examined using IL-10 knockout mice. Mice with bile duct ligation at day +1 or 0, relative to portal venous infection at day 0, had decreased survival compared with mice with only portal venous infection. The impaired survival was associated with greater hepatic bacterial growth, hepatic necrosis, and increased production of IL-10. Interestingly, the transgenic knockout of IL-10 resulted in impaired survival in mice with bile duct ligation and portal venous infection. Biliary obstruction had a dramatic detrimental effect on hepatic clearance of portal venous E. coli infection. This impaired clearance is associated with increased IL-10 production. However, transgenic knockout of IL-10 increased mortality after hepatic infection.


ACE inhibitors, angiotensin II antagonists and cough. The Losartan Cough Study Group.
One hundred and thirty five non-smoking hypertensive patients with ACE inhibitor cough confirmed by lisinopril rechallenge and placebo dechallenge were recruited into a double-blind random parallel-group comparison of losartan 50 mg, lisinopril 20 mg and hydrochlorothiazide 25 mg each given once daily for a maximum of 8 weeks. The aim of the study was to compare the incidence of cough with the angiotensin II antagonist losartan, the ACE inhibitor lisinopril and the hydrochlorothiazide in hypertensive patients with previous ACE inhibitor cough. Cough detected by self-administered questionnaire was the primary end-point, and cough frequency by visual analogue scale a secondary end-point. The incidence of cough with losartan (29%) was lower than that for lisinopril (72%, P < 0.01) and similar to that for hydrochlorothiazide (34%). Cough frequency by visual analogue scale was lower for losartan than lisinopril (P < 0.01) and similar to that for hydrochlorothiazide. The specific selective AT1 angiotensin II receptor antagonist losartan is significantly less likely than lisinopril to cause cough in patients who previously have had ACE inhibitor cough. ACE inhibitor cough is likely to be related to non-specific kininase II inhibition.


Transgenic rice is a source of iron for iron-depleted rats.
Iron deficiency is one of the most prevalent nutrient deficiencies in the world. A sustainable solution to dietary iron deficiency may be achieved in part by increasing bioavailable iron in seeds used for foods such as rice. Because ferritin is used as a natural source of iron in the early development of humans, other animals and plants, the bioavailability of iron in rice seeds, provided in amounts equal to ferrous sulfate, and in transgenic rice with ferritin was tested in iron-deficient rats. A standard hemoglobin (Hb) repletion bioassay was used with rats made anemic followed by complete diets containing equivalent amounts of iron as FeSO(4) or one of three different bioengineered rice varieties (Kitaake and two transgenic derivatives with ferritin targeted to the seed, FK11 and FK22). Rice diets were as effective as the FeSO(4) diet in replenishing hematocrit, Hb concentration and liver iron concentrations. These data suggest that Mendelian and biotechnological approaches to manipulating ferritin expression of seed iron in rice may contribute to a sustainable solution to global problems of iron deficiency.


A lipophilic ionic liquid based on formamidinium cations and TFSI: the electric response and the effect of CO2 on the conductivity mechanism.
This work describes the preparation of the new lipophilic ionic liquid tetraoctyl-formamidinium bis(trifluoromethanesulfonyl) imide (TOFATFSI), which is miscible with lower alkanes. In particular, this work focuses on the electric behaviour of TOFATFSI in the particularly challenging highly apolar environment of supercritical CO2. The conductivity and relaxation phenomena are revealed through the analysis of the broadband electric spectra with a particular emphasis on the effect of temperature and CO2 uptake on the IL conductivity. It is found that temperature boosts the conductivity via an increase in the charge carrier mobility. Also, CO2 absorption affects both the conductivity and the permittivity of the material due to the presence of CO2-IL interactions that modulate the nanostructure and the size of the TOFATFSI aggregates, which increases both the mobility and the density of the charge carriers.


Constraints on drivers for visible light communications emitters based on energy efficiency.
In this work we analyze the energy efficiency constraints on drivers for Visible light communication (VLC) emitters. This is the main reason why LED is becoming the main source of illumination. We study the effect of the waveform shape and the modulation techniques on the overall energy efficiency of an LED lamp. For a similar level of illumination, we calculate the emitter energy efficiency ratio η (PLED/PTOTAL) for different signals. We compare switched and sinusoidal signals and analyze the effect of both OOK and OFDM modulation techniques depending on the power supply adjustment, level of illumination and signal amplitude distortion. Switched and OOK signals present higher energy efficiency behaviors (0.86≤η≤0.95) than sinusoidal and OFDM signals (0.53≤η≤0.79).


Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial.
Despite the introduction of plasmapheresis and immunoglobulin therapy, many patients with Guillain-Barré syndrome still have an incomplete recovery. Evidence from pathogenesis studies suggests the involvement of complement-mediated peripheral nerve damage. We aimed to investigate the safety and efficacy of eculizumab, a humanised monoclonal antibody against the complement protein C5, in patients with severe Guillain-Barré syndrome. This study was a 24 week, multicentre, double-blind, placebo-controlled, randomised phase 2 trial done at 13 hospitals in Japan. Eligible patients with Guillain-Barré syndrome were aged 18 years or older and could not walk independently (Guillain-Barré syndrome functional grade 3-5). Patients were randomly assigned (2:1) to receive 4 weeks of intravenous immunoglobulin plus either eculizumab (900 mg) or placebo; randomisation was done via a computer-generated process and web response system with minimisation for functional grade and age. The study had a parallel non-comparative single-arm outcome measure. The primary outcomes were efficacy (the proportion of patients with restored ability to walk independently [functional grade ≤2] at week 4) in the eculizumab group and safety in the full analysis set. For the efficacy endpoint, we predefined a response rate threshold of the lower 90% CI boundary exceeding 50%. This trial is registered with ClinicalTrials.gov, number, NCT02493725. Between Aug 10, 2015, and April 21, 2016, 34 patients were assigned to receive either eculizumab (n=23) or placebo (n=11). At week 4, the proportion of the patients able to walk independently (functional grade ≤2) was 61% (90% CI 42-78; n=14) in the eculizumab group, and 45% (20-73; n=5) in the placebo group. Adverse events occurred in all 34 patients. Three patients had serious adverse events: two in the eculizumab group (anaphylaxis in one patient and intracranial haemorrhage and abscess in another patient) and one in the placebo group (depression). The possibility that anaphylaxis and intracranial abscess were related to eculizumab could not be excluded. No deaths or meningococcal infections occurred. The primary outcome measure did not reach the predefined response rate. However, because this is a small study without statistical comparison with the placebo group, the efficacy and safety of eculizumab could be investigated in larger, randomised controlled trials. The Japan Agency for Medical Research and Development, Ministry of Health, Labor and Welfare, and Alexion Pharmaceuticals.


Polarization microscopy by use of digital holography: application to optical-fiber birefringence measurements.
We present a digital holographic microscope that permits one to image polarization state. This technique results from the coupling of digital holographic microscopy and polarization digital holography. The interference between two orthogonally polarized reference waves and the wave transmitted by a microscopic sample, magnified by a microscope objective, is recorded on a CCD camera. The off-axis geometry permits one to reconstruct separately from this single hologram two wavefronts that are used to image the object-wave Jones vector. We applied this technique to image the birefringence of a bent fiber. To evaluate the precision of the phase-difference measurement, the birefringence induced by internal stress in an optical fiber is measured and compared to the birefringence profile captured by a standard method, which had been developed to obtain high-resolution birefringence profiles of optical fibers.


The EADC-ADNI Harmonized Protocol for manual hippocampal segmentation on magnetic resonance: evidence of validity.
An international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance. Fourteen tracers segmented 10 Alzheimer's Disease Neuroimaging Initiative (ADNI) cases scanned at 1.5 T and 3T following local protocols, qualified for segmentation based on the HarP through a standard web-platform and resegmented following the HarP. The five most accurate tracers followed the HarP to segment 15 ADNI cases acquired at three time points on both 1.5 T and 3T. The agreement among tracers was relatively low with the local protocols (absolute left/right ICC 0.44/0.43) and much higher with the HarP (absolute left/right ICC 0.88/0.89). On the larger set of 15 cases, the HarP agreement within (left/right ICC range: 0.94/0.95 to 0.99/0.99) and among tracers (left/right ICC range: 0.89/0.90) was very high. The volume variance due to different tracers was 0.9% of the total, comparing favorably to variance due to scanner manufacturer (1.2), atrophy rates (3.5), hemispheric asymmetry (3.7), field strength (4.4), and significantly smaller than the variance due to atrophy (33.5%, P < .001), and physiological variability (49.2%, P < .001). The HarP has high measurement stability compared with local segmentation protocols, and good reproducibility within and among human tracers. Hippocampi segmented with the HarP can be used as a reference for the qualification of human tracers and automated segmentation algorithms.


Eph-dependent tyrosine phosphorylation of ephexin1 modulates growth cone collapse.
Ephs regulate growth cone repulsion, a process controlled by the actin cytoskeleton. The guanine nucleotide exchange factor (GEF) ephexin1 interacts with EphA4 and has been suggested to mediate the effect of EphA on the activity of Rho GTPases, key regulators of the cytoskeleton and axon guidance. Using cultured ephexin1-/- mouse neurons and RNA interference in the chick, we report that ephexin1 is required for normal axon outgrowth and ephrin-dependent axon repulsion. Ephexin1 becomes tyrosine phosphorylated in response to EphA signaling in neurons, and this phosphorylation event is required for growth cone collapse. Tyrosine phosphorylation of ephexin1 enhances ephexin1's GEF activity toward RhoA while not altering its activity toward Rac1 or Cdc42, thus changing the balance of GTPase activities. These findings reveal that ephexin1 plays a role in axon guidance and is regulated by a switch mechanism that is specifically tailored to control Eph-mediated growth cone collapse.


Hydroxychloroquine affects bone resorption both in vitro and in vivo.
We recently showed that patients with primary Sjögren syndrome (pSS) have significantly higher bone mineral density (BMD) compared to healthy controls. The majority of those patients (69%) was using hydroxychloroquine (HCQ), which may have favorable effects on BMD. The aim of the study was to evaluate whether HCQ modulates osteoclast function. Osteoclasts were cultured from PBMC-sorted monocytes for 14 days and treated with different HCQ doses (controls 1 and 5 μg/ml). TRAP staining and resorption assays were performed to evaluate osteoclast differentiation and activity, respectively. Staining with an acidification marker (acridine orange) was performed to evaluate intracellular pH at multiple timepoints. Additionally, a fluorescent cholesterol uptake assay was performed to evaluate cholesterol trafficking. Serum bone resorption marker β-CTx was evaluated in rheumatoid arthritis patients. HCQ inhibits the formation of multinuclear osteoclasts and leads to decreased bone resorption. Continuous HCQ treatment significantly decreases intracellular pH and significantly enhanced cholesterol uptake in mature osteoclasts along with increased expression of the lowdensity lipoprotein receptor. Serum β-CTx was significantly decreased after 6 months of HCQ treatment. In agreement with our clinical data, we demonstrate that HCQ suppresses bone resorption in vitro and decreases the resorption marker β-CTx in vivo. We also showed that HCQ decreases the intracellular pH in mature osteoclasts and stimulates cholesterol uptake, suggesting that HCQ induces osteoclastic lysosomal membrane permeabilization (LMP) leading to decreased resorption without changes in apoptosis. We hypothesize that skeletal health of patients with increased risk of osteoporosis and fractures may benefit from HCQ by preventing BMD loss.


Consensus and diversity: an action research study designed to analyse the roles of a group of mental health consultant nurses.
The purpose of this action research study was to enable a group of mental health consultant nurses in the UK to map the scope and dimensions of their roles. This initial benchmarking exercise is a precursor to the development of plans for role improvement and evaluation. There is a growing body of literature that addresses advanced nursing practice roles. There is, however, no international agreement on what constitutes an advanced practice role. A few countries have addressed the statutory requirements governing such roles. Consultant nurses' roles in the UK are relatively new innovations that aim to enhance care. However, only a few investigations have evaluated the dimensions and impact of these roles. The study was framed by use of action research as a form of self-reflective enquiry. Initial data were generated through use of four focus group discussions, which were held with a group of consultant nurses employed predominately at a mental health National Health Service Trust. Five structured confirmatory questionnaires developed from the focus group data were also administered. Analysis of the focus group data gave five themes, 71 categories and 271 items that were used to inform development of the questionnaires. Responses to the questionnaire showed that 61% (n = 166) of the items had non-consensus responses. It was found there was most consensus relating to leadership theme with 63% (n = 19) items having consensus responses. Least agreement was found in the education theme where there was <15% (n = 5) agreement to individual items. The study demonstrated complexity and variety in how the consultant nurses' roles in the UK are being developed. The potential for consultant nurse roles to enhance patient care is tremendous. This study provides initial indicators, which the practitioners involved, can use to plot future developments and changes to their roles.


Adipose-derived regenerative cells in patients with ischemic cardiomyopathy: The PRECISE Trial.
Adipose-derived regenerative cells (ADRCs) can be isolated from liposuction aspirates and prepared as fresh cells for immediate administration in cell therapy. We performed the first randomized, placebo-controlled, double-blind trial to examine the safety and feasibility of the transendocardial injections of ADRCs in no-option patients with ischemic cardiomyopathy. Procedural, postoperative, and follow-up safety end points were monitored up to 36 months. After baseline measurements, efficacy was assessed by echocardiography and single-photon emission computed tomography (6, 12, and 18 months), metabolic equivalents and maximal oxygen consumption (MVO2) (6 and 18 months), and cardiac magnetic resonance imaging (6 months). We enrolled 21 ADRC-treated and 6 control patients. Liposuction was well tolerated, ADRCs were successfully prepared, and transendocardial injections were feasible in all patients. No malignant arrhythmias were seen. Adverse events were similar between groups. Metabolic equivalents and MVO2 values were preserved over time in ADRC-treated patients but declined significantly in the control group. The difference in the change in MVO2 from baseline to 6 and 18 months was significantly better in ADRC-treated patients compared with controls. The ADRC-treated patients showed significant improvements in total left ventricular mass by magnetic resonance imaging and wall motion score index. Single-photon emission computed tomography results suggested a reduction in inducible ischemia in ADRC-treated patients up to 18 months. Isolation and transendocardial injection of autologous ADRCs in no-option patients were safe and feasible. Our results suggest that ADRCs may preserve ventricular function, myocardial perfusion, and exercise capacity in these patients.


Nanoparticles assembled via pH-responsive reversible segregation of cyclodextrins in polyrotaxanes.
Supramolecular polymers with monomers bound together by secondary interactions, such as polyrotaxanes (PRXs), consisting of alpha cyclodextrin (αCD) threaded onto poly(ethylene glycol) (PEG), have attracted interest as a result of their ability to overcome physical limitations present in conventional, covalently structured polymers. Herein, we describe the formation of pH-responsive supramolecular assemblies from carboxyethylester bearing αCD and PEG PRXs. These PRXs were formed using PEG of Mw 20 kDa and a threading degree of 28%. Upon charge neutralisation the threaded αCDs co-localise, resulting in aggregation of the PRXs and the formation of a suspension by self-assembly. This process is shown to be reversible and possible via the mobility of CDs along the PEG guest chain. As a result of the inherent properties of PRXs, such as enhanced multivalent interactions and degradation, these responsive supramolecular polymers are expected to be of interest in fields where PRX-based materials have already found application, including paints, self-healing materials, surface coatings, and polymer therapeutics.


Improved tractography using asymmetric fibre orientation distributions.
Diffusion MRI allows us to make inferences on the structural organisation of the brain by mapping water diffusion to white matter microstructure. However, such a mapping is generally ill-defined; for instance, diffusion measurements are antipodally symmetric (diffusion along x and -x are equal), whereas the distribution of fibre orientations within a voxel is generally not symmetric. Therefore, different sub-voxel patterns such as crossing, fanning, or sharp bending, cannot be distinguished by fitting a voxel-wise model to the signal. However, asymmetric fibre patterns can potentially be distinguished once spatial information from neighbouring voxels is taken into account. We propose a neighbourhood-constrained spherical deconvolution approach that is capable of inferring asymmetric fibre orientation distributions (A-fods). Importantly, we further design and implement a tractography algorithm that utilises the estimated A-fods, since the commonly used streamline tractography paradigm cannot directly take advantage of the new information. We assess performance using ultra-high resolution histology data where we can compare true orientation distributions against sub-voxel fibre patterns estimated from down-sampled data. Finally, we explore the benefits of A-fods-based tractography using in vivo data by evaluating agreement of tractography predictions with connectivity estimates made using different in-vivo modalities. The proposed approach can reliably estimate complex fibre patterns such as sharp bending and fanning, which voxel-wise approaches cannot estimate. Moreover, histology-based and in-vivo results show that the new framework allows more accurate tractography and reconstruction of maps quantifying (symmetric and asymmetric) fibre complexity.


The use of Easy-Barriers to control soil and water losses in fire-affected land in Quesada, Andalusia, Spain.
Soil erosion is enhanced by wildfire, mainly due to the loss of vegetation cover and changes in soil properties. After wildfires, there is a need to control the non-sustainable soil and water losses. Of the strategies commonly applied, the use of contour felled log debris barriers to sediment trapping is widespread, but this is not always successful in Mediterranean Ecosystems. This paper evaluates the effectiveness of a new barrier which can be applied on steep terrains affected by wildfires. The hydrological response and sediment delivery were measured to test a innovative design, which are easy to transport and use. The Easy-Barriers (EB) size is 0.8 × 0.1 × 0.2 m and were designed to restore degraded areas which need a quick, low-cost solution, such as after a wildfire. The experimental design was based on the analysis of a simulated runoff flow of 0.6 l·s-1 circulated on 6 plots of 24 m2 (0.8 × 30 m), on each of which 2 treatments were systematically applied: Control and EB. The EB were set up after the assessment of the runoff generation and the site rainfall characteristics for "extraordinary" events. We measured the rills, the sediments collected on each slope and the topographical changes. The total load and runoff in the outlet of the plots were also quantified using sediment volume and concentration measurements. The EB resulted in a decrease in the peak flow and a delay in the runoff time at the outlet. The sediment trapping rate of the barriers was 42.7%. The soil moisture was higher in the EB plots due to the accumulated sediment. In addition to these features, the EB allow us to save between 30 and 40% of total restoration costs in comparison with traditional barriers, due to the reduction in labour costs. Moreover, all its components are biodegradable.


The physical and chemical stability of suspensions of sustained-release diclofenac microspheres.
The major challenge in liquid sustained-release oral suspensions is to minimize drug diffusion into the suspending medium and to retain the original properties of the microparticles during storage. Diclofenac wax microspheres prepared by the hydrophobic congealable disperse phase method were formulated as a sustained release suspension and stored at three different temperatures (25, 37 and 45 degrees C) for 3 months, to evaluate the physical and chemical stability of the suspended microspheres. Suspensions of microspheres stored at ambient temperatures were both physically and chemically stable, but at higher temperatures, up to 45 degrees C, there was a decrease in drug release due to scaling and melting on the microsphere surface as observed by scanning electron microscopy. However, on prolonged storage, up to 90 days, especially at 45 degrees C, temperature became a dominant factor causing an increase in drug release. The suspension of diclofenac microspheres was chemically stable for 3 months, while the plain drug suspension exhibited slight degradation.


Hepatitis C virus NS5A inhibits mixed lineage kinase 3 to block apoptosis.
Hepatitis C virus (HCV) infection results in the activation of numerous stress responses including oxidative stress, with the potential to induce an apoptotic state. Previously we have shown that HCV attenuates the stress-induced, p38MAPK-mediated up-regulation of the K(+) channel Kv2.1, to maintain the survival of infected cells in the face of cellular stress. We demonstrated that this effect was mediated by HCV non-structural 5A (NS5A) protein, which impaired p38MAPK activity through a polyproline motif-dependent interaction, resulting in reduction of phosphorylation activation of Kv2.1. In this study, we investigated the host cell proteins targeted by NS5A to mediate Kv2.1 inhibition. We screened a phage-display library expressing the entire complement of human SH3 domains for novel NS5A-host cell interactions. This analysis identified mixed lineage kinase 3 (MLK3) as a putative NS5A interacting partner. MLK3 is a serine/threonine protein kinase that is a member of the MAPK kinase kinase (MAP3K) family and activates p38MAPK. An NS5A-MLK3 interaction was confirmed by co-immunoprecipitation and Western blot analysis. We further demonstrate a novel role of MLK3 in the modulation of Kv2.1 activity, whereby MLK3 overexpression leads to the up-regulation of channel activity. Accordingly, coexpression of NS5A suppressed this stimulation. Additionally we demonstrate that overexpression of MLK3 induced apoptosis, which was also counteracted by NS5A. We conclude that NS5A targets MLK3 with multiple downstream consequences for both apoptosis and K(+) homeostasis.


From information technology to informatics: the information revolution in dental education.
The capabilities of information technology (IT) have advanced precipitously in the last fifty years. Many of these advances have enabled new and beneficial applications of IT in dental education. However, conceptually, IT use in dental schools is only in its infancy. Challenges and opportunities abound for improving how we support clinical care, education, and research with IT. In clinical care, we need to move electronic dental records beyond replicating paper, connect information on oral health to that on systemic health, facilitate collaborative care through teledentistry, and help clinicians apply evidence-based dentistry and preventive management strategies. With respect to education, we should adopt an evidence-based approach to IT use for teaching and learning, share effective educational content and methods, leverage technology-mediated changes in the balance of power between faculty and students, improve technology support for clinical teaching, and build an information infrastructure centered on learners and organizations. In research, opportunities include reusing clinical care data for research studies, helping advance computational methods for research, applying generalizable research tools in dentistry, and reusing research data and scientific workflows. In the process, we transition from a focus on IT-the mere technical aspects of applying computer technology-to one on informatics: the what, how, and why of managing information.


A human relevant mixture of persistent organic pollutants (POPs) and perfluorooctane sulfonic acid (PFOS) enhance nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells.
Disruption of neurite outgrowth is a marker for neurotoxicity. Persistent organic pollutants (POPs) are potential developmental neurotoxicants. We investigated their effect on neurite outgrowth in PC12 rat pheochromocytoma cells, in absence or presence of nerve growth factor (NGF), an inducer of neuronal differentiation. Cells were exposed for 72 h to a defined mixture of POPs with chemical composition and concentrations based on blood levels in the Scandinavian population. We also evaluated perfluorooctane sulfonic acid (PFOS) alone, the most abundant compound in the POP mixture. Only higher concentrations of POP mixture reduced tetrazolium salt (MTT) conversion. High-content analysis showed a decrease in cell number, but no changes for nuclear and mitochondrial cellular health parameters. Robust glutathione levels were observed in NGF-differentiated cells. Live imaging, using the IncuCyte ZOOM platform indicated ongoing cell proliferation over time, but slower in presence of NGF. The pollutants did not inhibit neuritogenesis, but rather increased NGF-induced neurite length. PFOS induced neurite outgrowth to about 50 % of the level seen with the POP mixture. Neither the POP mixture nor PFOS affected neurite length in the absence of NGF. Our observations indicate that realistic complex mixtures of environmental pollutants can affect neuronal connectivity via NGF-induced neurite outgrowth.


Recovery potential of cold press byproducts obtained from the edible oil industry: physicochemical, bioactive, and antimicrobial properties.
Physicochemical, bioactive, and antimicrobial properties of different cold press edible oil byproducts (almond (AOB), walnut (WOB), pomegranate (POB), and grape (GOB)) were investigated. Oil, protein, and crude fiber content of the byproducts were found between 4.82 and 12.57%, between 9.38 and 49.05%, and between 5.87 and 45.83%, respectively. GOB had very high crude fiber content; therefore, it may have potential for use as a new dietary fiber source in the food industry. As GOB, POB, and WOB oils were rich in polyunsaturated fatty acids, AOB was rich in monounsaturated fatty acids. Oil byproducts were also found to be rich in dietary mineral contents, especially potassium, calcium, phosphorus, and magnesium. WOB had highest total phenolic (802 ppm), flavonoid (216 ppm), and total hydrolyzed tannin (2185 ppm) contents among the other byproducts. Volatile compounds of all the byproducts are mainly composed of terpenes in concentration of approximately 95%. Limonene was the dominant volatile compound in all of the byproducts. Almond and pomegranate byproduct extracts showed antibacterial activity depending on their concentration, whereas those of walnut and grape byproducts showed no antibacterial activity against any pathogenic bacteria tested. According to the results of the present study, walnut, almond, pomegranate, and grape seed oil byproducts possess valuable properties that can be taken into consideration for improvement of nutritional and functional properties of many food products.


MCUb Induction Protects the Heart From Postischemic Remodeling.
Mitochondrial Ca2+ loading augments oxidative metabolism to match functional demands during times of increased work or injury. However, mitochondrial Ca2+ overload also directly causes mitochondrial rupture and cardiomyocyte death during ischemia-reperfusion injury by inducing mitochondrial permeability transition pore opening. The MCU (mitochondrial Ca2+ uniporter) mediates mitochondrial Ca2+ influx, and its activity is modulated by partner proteins in its molecular complex, including the MCUb subunit. Here, we sought to examine the function of the MCUb subunit of the MCU-complex in regulating mitochondria Ca2+ influx dynamics, acute cardiac injury, and long-term adaptation after ischemic injury. Cardiomyocyte-specific MCUb overexpressing transgenic mice and Mcub gene-deleted (Mcub-/-) mice were generated to dissect the molecular function of this protein in the heart. We observed that MCUb protein is undetectable in the adult mouse heart at baseline, but mRNA and protein are induced after ischemia-reperfusion injury. MCUb overexpressing mice demonstrated inhibited mitochondrial Ca2+ uptake in cardiomyocytes and partial protection from ischemia-reperfusion injury by reducing mitochondrial permeability transition pore opening. Antithetically, deletion of the Mcub gene exacerbated pathological cardiac remodeling and infarct expansion after ischemic injury in association with greater mitochondrial Ca2+ uptake. Furthermore, hindlimb remote ischemic preconditioning induced MCUb expression in the heart, which was associated with decreased mitochondrial Ca2+ uptake, collectively suggesting that induction of MCUb protein in the heart is protective. Similarly, mouse embryonic fibroblasts from Mcub-/- mice were more sensitive to Ca2+ overload. Our studies suggest that Mcub is a protective cardiac inducible gene that reduces mitochondrial Ca2+ influx and permeability transition pore opening after ischemic injury to reduce ongoing pathological remodeling.


The human ribosomal protein genes: sequencing and comparative analysis of 73 genes.
The ribosome, as a catalyst for protein synthesis, is universal and essential for all organisms. Here we describe the structure of the genes encoding human ribosomal proteins (RPs) and compare this class of genes among several eukaryotes. Using genomic and full-length cDNA sequences, we characterized 73 RP genes and found that (1) transcription starts at a C residue within a characteristic oligopyrimidine tract; (2) the promoter region is GC rich, but often has a TATA box or similar sequence element; (3) the genes are small (4.4 kb), but have as many as 5.6 exons on average; (4) the initiator ATG is in the first or second exon and is within plus minus 5 bp of the first intron boundaries in about half of cases; and (5) 5'- and 3'-UTRs are significantly smaller (42 bp and 56 bp, respectively) than the genome average. Comparison of RP genes from humans, Drosophila melanogaster, Caenorhabditis elegans, and Saccharomyces cerevisiae revealed the coding sequences to be highly conserved (63% homology on average), although gene size and the number of exons vary. The positions of the introns are also conserved among these species as follows: 44% of human introns are present at the same position in either D. melanogaster or C. elegans, suggesting RP genes are highly suitable for studying the evolution of introns.


Low-frequency pulsed electromagnetic field therapy in fibromyalgia: a randomized, double-blind, sham-controlled clinical study.
To evaluate the clinical effectiveness of low-frequency pulsed electromagnetic field (PEMF) therapy for women with fibromyalgia (FM). Fifty-six women with FM, aged 18 to 60 years, were randomly assigned to either PEMF or sham therapy. Both the PEMF group (n=28) and the sham group (n=28) participated in therapy, 30 minutes per session, twice a day for 3 weeks. Treatment outcomes were assessed by the fibromyalgia Impact questionnaire (FIQ), visual analog scale (VAS), patient global assessment of response to therapy, Beck Depression Inventory (BDI), and Short-Form 36 health survey (SF-36), after treatment (at 4 wk) and follow-up (at 12 wk). The PEMF group showed significant improvements in FIQ, VAS pain, BDI score, and SF-36 scale in all domains at the end of therapy. These improvements in FIQ, VAS pain, and SF-36 pain score during follow-up. The sham group also showed improvement were maintained on all outcome measures except total FIQ scores after treatment. At 12 weeks follow-up, only improvements in the BDI and SF-36 scores were present in the sham group. Low-frequency PEMF therapy might improve function, pain, fatigue, and global status in FM patients.


Augmented reality visualization system for intravascular neurosurgery.
We aimed to construct an augmented reality-based visualization system to support intravascular neurosurgery and evaluate it in clinical environments. Three-dimensional (3D) vascular models are overlaid on motion pictures from X-ray fluoroscopy by 2D/3D registration using fiducial markers. The models are reconstructed from 3D data obtained from X-ray computed tomographic angiography or from magnetic resonance angiography using the marching-cube algorithm. Intraoperative X-ray images are mapped as texture patterns on a screen object which is displayed with the vascular models. Distortion of X-ray fluoroscopy is eliminated by a new technique of screen mesh deformation. A quantity called reprojection distance was introduced to evaluate the reliability of the displayed images. It predicts the maximum registration error around the registered objects. Analyses of reprojection distances were performed using synthetic data consisting of marker coordinates with 2D or 3D errors. The tolerance of reprojection distance for the clinical environment was determined to be 3.0 mm. The system was tested in two clinical cases in which reprojection distances of 2.6 and 2.09 mm were obtained. Construction and evaluation of our prototype system were successfully carried out. Further development is planned employing a range sensor to permit markerless registration.


Anti-ischemic effects of the potassium channel activators pinacidil and cromakalim and the reversal of these effects with the potassium channel blocker glyburide.
The direct cardioprotective efficacy of the potassium channel activators pinacidil and cromakalim was determined in isolated globally ischemic rat hearts. Isolated buffer-perfused rat hearts were subjected to 25 min of ischemia followed by 30 min of reperfusion. These hearts were pretreated with 1 to 100 microM pinacidil, 1 to 7 microM cromakalim or vehicle. Pinacidil resulted in significant improvements in reperfusion function and cardiac compliance, though it did not significantly reduce lactate dehydrogenase release at any concentration. The protective effects of pinacidil were greatest at a 10 microns concentration and were slightly diminished at higher concentrations (30 and 100 microns). Although not affecting the severity of ischemia alone, 10 microM glyburide (potassium channel blocker) completely reversed the protective effects of pinacidil on reperfusion function and compliance. Cromakalim (7 microM) resulted in a greater than 50% improvement in reperfusion function and compliance and unlike pinacidil significantly reduced lactate dehydrogenase release by approximately 50%. At 1 microM, glyburide alone did not significantly affect the severity of ischemia but reversed the protective effects of cromakalim. Not only did glyburide reverse the protective effects of cromakalim, it resulted in a worsening of ischemia compared to vehicle, an effect not seen with glyburide alone. Thus, both pinacidil and cromakalim appear to have direct cardioprotective efficacy, though some differences between them may be possible. The mechanism of their protective effects appears to be via potassium channel opening as the potassium channel blocker glyburide reverses the protective effect of these compounds. Intracellular electrophysiological studies showed that ischemia-induced depolarization was reversed with cromakalim, which increased the resting potential nearly back to preischemic levels.(ABSTRACT TRUNCATED AT 250 WORDS)


Evidence for variation in abundance of antisense transcripts between multicellular animals but no relationship between antisense transcriptionand organismic complexity.
Given that humans have about the same number of genes as mice and not so many more than worm, what makes us more complex? Antisense transcripts are implicated in many aspects of gene regulation. Is there a functional connection between antisense transcription and organismic complexity, that is, is antisense regulation especially prevalent in humans? We used the same robust protocol to identify antisense transcripts in humans and five other metazoan genomes (mouse, rat, chicken, fruit fly, and nematode), and found that the estimated proportions of genes involved in antisense transcription are highly sensitive to the number of transcripts included in the analysis. By controlling for transcript abundance, we find that the probability that any given transcript is putatively involved in sense-antisense regulation is no higher in humans than in other vertebrates but appears unusually high in flies and especially low in nematodes. Similarly, there is no evidence that the proportion of sense-antisense transcripts is especially higher in humans than other vertebrates in a given subset of transcript sequences such as mRNAs, coding sequences, conserved, or nonconserved transcripts. Although antisense transcription might be enriched in mammalian brains compared with nonbrain tissues, it is no more enriched in human brain than in mouse brain. Overall, therefore, while we see striking variation between multicellular animals in the abundance of antisense transcripts, there is no evidence for a link between antisense transcription and organismic complexity. More particularly, we see no evidence that humans are in any way unusual among the vertebrates in this regard. Instead, our results suggest that antisense transcription might be prevalent in almost all metazoan genomes, nematodes being an unexplained exception.


Crowding in children's visual acuity tests--effect of test design and age.
The aim of this study was to investigate the effect of test design (crowding) and age on visual acuity in a sample of young children. Vision was measured in 103 children aged between 4 and 9 years using five different visual acuity tests. The tests included three crowded tests: logMAR Crowded test, the Sonksen logMAR test, and the Crowded Kay Picture test, and two single optotype tests: the Single Kay Picture and Sheridan Gardiner tests. Tests were presented in a random order using standardized instructions and a defined end-point. Results were analyzed in two age groups, younger (4 to 6 years) and older (7 to 9 years). In both groups, there was a significant main effect of test on acuity (younger: F = 63.92, dF = 4, p < 0.001; older: F = 63.59, dF = 4, p < 0.001). In the younger group, an effect of crowding was seen in all three crowded tests, but in the older group, an effect of crowding was seen only in the crowded letter tests. In both groups, mean acuity was lowest with the logMAR Crowded test, which has the closest interoptotype spacing (0.5), slightly higher with the Sonksen test (with interoptotype spacing of 1.0) and highest with the single optotype tests (no crowding). More crowding was seen in the younger children. Our results show that maturation of line acuity is still taking place between the ages of 4 and 9 years. Measured acuity is affected by the amount of contour interaction induced by the type of optotype (letter or picture) and by the interoptotype separation. Another factor, probably a maturation of gaze control or selective attention is responsible for the reduction in crowding with age.


Common mental disorders in asylum seekers and refugees: umbrella review of prevalence and intervention studies.
In recent years there has been a progressive rise in the number of asylum seekers and refugees displaced from their country of origin, with significant social, economic, humanitarian and public health implications. In this population, up-to-date information on the rate and characteristics of mental health conditions, and on interventions that can be implemented once mental disorders have been identified, are needed. This umbrella review aims at systematically reviewing existing evidence on the prevalence of common mental disorders and on the efficacy of psychosocial and pharmacological interventions in adult and children asylum seekers and refugees resettled in low, middle and high income countries. We conducted an umbrella review of systematic reviews summarizing data on the prevalence of common mental disorders and on the efficacy of psychosocial and pharmacological interventions in asylum seekers and/or refugees. Methodological quality of the included studies was assessed with the AMSTAR checklist. Thirteen reviews reported data on the prevalence of common mental disorders while fourteen reviews reported data on the efficacy of psychological or pharmacological interventions. Although there was substantial variability in prevalence rates, we found that depression and anxiety were at least as frequent as post-traumatic stress disorder, accounting for up to 40% of asylum seekers and refugees. In terms of psychosocial interventions, cognitive behavioral interventions, in particular narrative exposure therapy, were the most studied interventions with positive outcomes against inactive but not active comparators. Current epidemiological data needs to be expanded with more rigorous studies focusing not only on post-traumatic stress disorder but also on depression, anxiety and other mental health conditions. In addition, new studies are urgently needed to assess the efficacy of psychosocial interventions when compared not only with no treatment but also each other. Despite current limitations, existing epidemiological and experimental data should be used to develop specific evidence-based guidelines, possibly by international independent organizations, such as the World Health Organization or the United Nations High Commission for Refugees. Guidelines should be applicable to different organizations of mental health care, including low and middle income countries as well as high income countries.


Morphological Evolution of Physical Robots through Model-Free Phenotype Development.
Artificial evolution of physical systems is a stochastic optimization method in which physical machines are iteratively adapted to a target function. The key for a meaningful design optimization is the capability to build variations of physical machines through the course of the evolutionary process. The optimization in turn no longer relies on complex physics models that are prone to the reality gap, a mismatch between simulated and real-world behavior. We report model-free development and evaluation of phenotypes in the artificial evolution of physical systems, in which a mother robot autonomously designs and assembles locomotion agents. The locomotion agents are automatically placed in the testing environment and their locomotion behavior is analyzed in the real world. This feedback is used for the design of the next iteration. Through experiments with a total of 500 autonomously built locomotion agents, this article shows diversification of morphology and behavior of physical robots for the improvement of functionality with limited resources.


Player preferences among new and old violins.
Most violinists believe that instruments by Stradivari and Guarneri "del Gesu" are tonally superior to other violins--and to new violins in particular. Many mechanical and acoustical factors have been proposed to account for this superiority; however, the fundamental premise of tonal superiority has not yet been properly investigated. Player's judgments about a Stradivari's sound may be biased by the violin's extraordinary monetary value and historical importance, but no studies designed to preclude such biasing factors have yet been published. We asked 21 experienced violinists to compare violins by Stradivari and Guarneri del Gesu with high-quality new instruments. The resulting preferences were based on the violinists' individual experiences of playing the instruments under double-blind conditions in a room with relatively dry acoustics. We found that (i) the most-preferred violin was new; (ii) the least-preferred was by Stradivari; (iii) there was scant correlation between an instrument's age and monetary value and its perceived quality; and (iv) most players seemed unable to tell whether their most-preferred instrument was new or old. These results present a striking challenge to conventional wisdom. Differences in taste among individual players, along with differences in playing qualities among individual instruments, appear more important than any general differences between new and old violins. Rather than searching for the "secret" of Stradivari, future research might best focused on how violinists evaluate instruments, on which specific playing qualities are most important to them, and on how these qualities relate to measurable attributes of the instruments, whether old or new.


Hyperthermic overdrive: oxygen delivery does not limit thermal tolerance in Drosophila melanogaster.
The causes of thermal tolerance limits in animals are controversial. In many aquatic species, it is thought that the inability to deliver sufficient oxygen at high temperatures is more critical than impairment of molecular functions of the mitochondria. However, terrestrial insects utilize a tracheal system, and the concept of a mismatch between metabolic demand and circulatory performance might not apply to them. Using thermo-limit respirometry, it has been shown earlier in Drosophila melanogaster that CO(2) release rates at temperatures above the upper thermal limit (CT(max)) exceed the rate at CT(max). The nature of this post-CT(max), or "post-mortal" peak, is unknown. Either its source is increased aerobic mitochondrial respiration (hyperthermic overdrive), or an anaerobic process such as liberation of stored CO(2) from the hemolymph. The post-mortal peak of CO(2) release was found to be oxygen dependent. As the rate of CO(2) emission is a conservative indicator of rate of O(2) consumption, aerobic flux at the thermal limit is submaximal, which contradicts the theory that oxygen availability limits metabolic activity at high temperatures in insects. Consequently, the tracheal system should be capable of delivering sufficient oxygen for aerobic activity of the mitochondria at and above Ct(max).


Signals from a self-antigen induce positive selection in early B cell ontogeny but are tolerogenic in adults.
Positive and negative signals from self-Ags shape the B cell repertoire and the development of distinct B cell subsets, but little is known about what distinguishes these signals. To address this question, we have studied the development of anti-hen egg lysozyme MD4 Ig transgene B cells while systematically varying the level, distribution, and timing of exposure to different forms of hen egg lysozyme as a self-Ag. This process has allowed us to explore the effects of Ag independent of BCR specificity. Our findings show how the selection of autoreactive B cells is a competitive process involving immunogenic and tolerogenic forms of self-Ags. Due to a developmental switch during B cell ontogeny, autoreactive anti-hen egg lysozyme MD4 Ig transgene B cells are negatively selected by self-Ags in adult bone marrow but susceptible to positive selection by some of the same self-Ags in fetal and neonatal life. However, the persistence of B1 cells and IgM autoantibodies from early ontogeny enables autoreactive B cells from the adult bone marrow to escape negative selection. Our data suggest that this rescue may be due to the clearance or masking of self-Ag by IgM autoantibody. We discuss the implications of these findings in terms of B cell selection and the maintenance of self-tolerance during early and adult life.


Partial characterization of specific inducers of a cuticle-degrading protease from the insect pathogenic fungus Metarhizium anisopliae.
The insect pathogenic fungus Metarhizium anisopliae produces several extracellular cuticle-degrading proteases and evidence is consistent with one of these, PR1, which is a chymoelastase, being a determinant of pathogenicity. We have shown previously that PR1 production is regulated by both carbon catabolite and nitrogen metabolite repression and also by specific induction under derepressed conditions by insect cuticle. In the present work we have established that an enzymically released proteinaceous component(s) of insect cuticle is capable of inducing PR1 (based on appearance of extracellular activity). Cuticle of the desert locust Schistocerca gregaria treated with KOH to remove protein failed to induce PR1 production, whereas cuticle treated with either chloroform or ether to remove lipids still induced PR1. Cuticle digested with either PR1 or the trypsin-like PR2 of M. anisopliae released peptides mainly in the range 150-2000 Da; addition of these peptides generated by PR1 or PR2 at 3 micrograms alanine equivalents ml-1 induced PR1 production to a level similar (75%) to that obtained with untreated insect cuticle. Several amino acids and peptides which are abundant in insect cuticular protein (Ala, Gly, Ala-Ala, Ala-Ala-Ala, Ala-Pro and Pro-Ala) were tested at a range of concentrations and in restricted cultures for their ability to induce PR1. None induced the protease to the levels seen with cuticle or peptides enzymically released from cuticle, although some dimers and notably the monomers Ala and Gly gave 2-2.7-fold enhanced PR1 activity above depressed basal levels (up to 48-57% of that achieved with induced synthesis on cuticle).(ABSTRACT TRUNCATED AT 250 WORDS)


Growth condition optimization for docosahexaenoic acid (DHA) production by Moritella marina MP-1.
The marine organism Moritella marina MP-1 produces the polyunsaturated fatty acid docosahexaenoic acid (DHA). While the basic metabolic pathway for DHA production in this organism has been identified, the impact of growth conditions on DHA production is largely unknown. This study examines the effect of supplemental carbon, nitrogen and salts, growth temperature and media composition and pH on DHA and biomass production and the fatty acid profile. The addition of supplemental nitrogen significantly increased the overall DHA titer via an increase in biomass production. Supplemental glucose or glycerol increased biomass production, but decreased the amount of DHA per biomass, resulting in no net change in the DHA titer. Acidification of the baseline media pH to 6.0 increased DHA per biomass. Changes in growth temperature or provision of supplemental sodium or magnesium chloride did not increase DHA titer. This organism was also shown to grow on defined minimal media. For both media types, glycerol enabled more DHA production per biomass than glucose. Combination of these growth findings into marine broth supplemented with glycerol, yeast extract, and tryptone at pH 6.0 resulted in a final titer of 82±5 mg/L, a nearly eightfold increase relative to the titer of 11±1 mg/L seen in the unsupplemented marine broth. The relative distribution of other fatty acids was relatively robust to growth condition, but the presence of glycerol resulted in a significant increase in myristic acid (C14:0) and decrease in palmitic acid (C16:0). In summary, DHA production by M. marina MP-1 can be increased more than fivefold by changing the growth media. Metabolic engineering of this organism to increase the amount of DHA produced per biomass could result in additional increases in titer.


Anisocotyly and meristem initiation in an unorthodox plant, Streptocarpus rexii (Gesneriaceae).
In common with most Old World Gesneriaceae; Streptocarpus Lindl. shows anisocotylous growth, i.e., the continuous growth of one cotyledon after germination. Linked to this phenomenon is an unorthodox behaviour of the shoot apical meristem (SAM) that determines the growth pattern of acaulescent species (subgenus Streptocarpus). In contrast caulescent species develop a conventional central post-embryonic SAM (mainly subgenus Streptocarpella). We used S. rexii Lindl. as a model to investigate anisocotyly and meristem initiation in Streptocarpus by using histological techniques and analyses of the expression pattern of the meristematic marker SrSTM1 during ontogeny. In contrast to Arabidopsis thaliana (L.) Heynh., S. rexii does not establish a SAM during embryogenesis, and the first evidence of a SAM-like structure occurs during post-embryonic development on the axis (the petiolode) between the two cotyledons. The expression pattern of SrSTM1 suggests a function in maintaining cell division activity in the cotyledons before becoming localized in the basal meristem, initially at the proximal ends of both cotyledons, later at the base of the continuously growing macrocotyledon, and the groove meristem on the petiolode. The latter is equivalent to a displaced SAM seemingly originating de novo under the influence of endogenous factors. Applied cytokinin retains SrSTM1expression in the small cotyledon, thus promoting isocotyly and re-establishment of a central post-embryonic SAM. Hormone-dependent delocalization of the process of meristem development could underlie anisocotyly and the unorthodox SAM formation in Streptocarpus.


Immunologic activation of human syncytiotrophoblast by Plasmodium falciparum.
Malaria during pregnancy is characterized by the sequestration of malaria-infected red blood cells (iRBC) in the intervillous spaces of the placenta, often accompanied by the infiltration of maternal mononuclear cells, causing substantial maternal and foetal/infant morbidity. The iRBC bind to receptors expressed by the syncytiotrophoblast (ST). How ST responds to this interaction remains poorly understood. Because it is known that ST is immunoactive and can respond to infectious agents, the consequences of this ST-iRBC interaction should be investigated. An in vitro system was used to assess the biochemical and immunological changes induced in ST by ST-adherent iRBCs. Changes in ST mitogen-activated protein kinase (MAPK) activation were assessed by immunoblotting and mRNA expression levels of selected cytokine and chemokines in primary ST bound by iRBC were determined using real-time, reverse transcription PCR. In addition, secreted cytokine and chemokine proteins were assayed by standard ELISA, and chemotaxis of PBMC was assessed using a two-chamber assay system. Following iRBC/ST interaction, ST C-Jun N-terminal kinase 1 (JNK1) was activated and modest increases in the mRNA expression of TGF-beta and IL-8/CXCL8 were observed. In addition, this interaction increased secretion of MIF and MIP-1alpha/CCL3 by ST and induced migration of PBMC towards iRBC-stimulated ST. Results from this study provide the first evidence that ST participates in shaping the local immunological milieu and in the recruitment of maternal immune cells to the maternal blood space during placental malaria infection.


C1 esterase inhibitor: new preparation. A major advance in emergency treatment of hereditary angioneurotic oedema.
(1) The reference prophylaxis of attacks of hereditary angioneurotic oedema is oral danazol, an androgenic steroid, which takes a few days to act. There was previously no curative treatment authorised in France. (2) C1 esterase inhibitor is now licensed in France as replacement therapy for patients with hereditary angioneurotic oedema due to a quantitative or qualitative deficiency in this protein. (3) The clinical evaluation file partly answers the practical questions that arise in this setting, but it does not include trials versus danazol. (4) In 36 patients with acute attacks of angioneurotic oedema, a double-blind trial showed that symptom relief was achieved in less than half an hour in 69% of attacks treated with C1 esterase inhibitor, compared to only 2% of attacks treated with placebo. (5) In the prophylactic setting, a crossover trial involving six patients refractory to conventional androgen therapy showed that injections of C1 esterase inhibitor every three days were more effective than a placebo in reducing the risk of attacks. (6) No major adverse effects have been attributed so far to C1 esterase inhibitor, but the fact that the drug is derived from human blood means that treatment carries a theoretical risk of infection by conventional infectious agents (especially nude viruses) and prions. (7) In practice, for life-threatening attacks of angioneurotic oedema, C1 esterase inhibitor is rapidly effective in two-thirds of patients and is now the reference treatment. In the absence of comparative trials, danazol remains the first-line prophylaxis when patients are scheduled for surgery a few days later, but C1 esterase inhibitor is useful when danazol is ineffective. C1 esterase inhibitor is the only available prophylaxis for patients undergoing emergency surgery (within a few hours).


Clinical Impact and Economic Burden of Hospital-Acquired Conditions Following Common Surgical Procedures.
Retrospective review of prospectively collected data. To assess the clinical impact and economic burden of the three most common hospital-acquired conditions (HACs) that occur within 30-day postoperatively for all spine surgeries and to compare these rates with other common surgical procedures. HACs are part of a non-payment policy by the Centers for Medicare and Medicaid Services and thus prompt hospitals to improve patient outcomes and safety. Patients more than 18 years who underwent elective spine surgery were identified in American College of Surgeons' National Surgical Quality Improvement Program (ACS-NSQIP) database from 2005 to 2013. Primary outcomes were cost associated with the occurrence of three most common HACs. Cost associated with HAC occurrence derived from the PearlDiver database. Ninety thousand five hundred fifty one elective spine surgery patients were identified, where 3021 (3.3%) developed at least one HAC. Surgical site infection (SSI) was the most common HAC (1.4%), then urinary tract infection (UTI) (1.3%) and venous thromboembolism (VTE) (0.8%). Length of stay (LOS) was longer for patients who experienced a HAC (5.1 vs. 3.2 d, P < 0.001). When adjusted for age, sex, and Charlson Comorbidity Index, LOS was 1.48 ± 0.04 days longer (P < 0.001) and payments were $8893 ± $148 greater (P < 0.001) for patients with at least one HAC. With the exception of craniotomy, patients undergoing common procedures with HAC had increased LOS and higher payments (P < 0.001). Adjusted additional LOS was 0.44 ± 0.02 and 0.38 ± 0.03 days for total knee arthroplasty and total hip arthroplasty, and payments were $1974 and $1882 greater. HACs following hip fracture repair were associated with 1.30 ± 0.11 days LOS and $4842 in payments (P < 0.001). Compared with elective spine surgery, only bariatric and cardiothoracic surgery demonstrated greater adjusted additional payments for patients with at least one HAC ($9975 and $10,868, respectively). HACs in elective spine surgery are associated with a substantial cost burden to the health care system. When adjusted for demographic factors and comorbidities, average LOS is 1.48 days longer and episode payments are $8893 greater for patients who experience at least one HAC compared with those who do not. 3.


The relation of airway obstruction to asthma, chronic rhinosinusitis and age: results from a population survey of adults.
There is conflicting evidence on whether patients with asthma experience an accelerated decline in lung function with age. We examined the association between postbronchodilator lung function, asthma, chronic rhinosinusitis (CRS), and atopy with age using a large European sample. In 17 centers in 11 European countries, case-control studies were nested within representative cross-sectional surveys of adults aged less than 75 years. Representative samples of participants with asthma, CRS or both and controls were assessed for postbronchodilator ventilatory function, smoking history, atopy, and treatment. Multiple regression was used to assess the interactive effects of age and diagnostic group on decline in postbronchodilator ventilatory function. A total of 3337 participants provided adequate data (778 with asthma, 399 with CRS, 244 with both asthma and CRS and 1916 controls who had neither asthma nor CRS). Participants with asthma had lower FEV1 /FVC (-4.09% (95% CI: -5.02, -3.15, P < 0.001) and a steeper slope of FEV1 /FVC against age (-0.14%/annum [95%CI: -0.19, -0.08]) equivalent to smoking 1-2 packs of cigarettes per day. Those with atopy had a slope equivalent to controls. People with asthma have a steeper decline in postbronchodilator lung function with age, but neither CRS nor atopy alone were associated with such decline.


Cost-Effectiveness Analysis of Erenumab Versus OnabotulinumtoxinA for Patients with Chronic Migraine Attacks in Greece.
Migraine is a common, chronic neurovascular brain disorder with non-negligible multifaceted economic costs. Existing preventive treatments involve the selective use of onabotulinumtoxinA, which aims at migraine morbidity reduction for patients who have failed initial preventive treatment with oral agents. Erenumab is a new preventive treatment for migraines. To evaluate the differences in costs and outcomes of the preventive treatment with erenumab versus onabotulinumtoxinA in patients with chronic migraines (CM) in Greece to assess the economic value of this treatment. We conducted a cost-effectiveness analysis from both the payer and the societal perspective using a decision-tree analytic model. Outcomes were expressed in migraines avoided and in quality-adjusted life-years (QALYs). We obtained model inputs from the existing literature. The decision path adjusted for variation in the probability of adherence and the resulting differential effectiveness between the two treatments. Direct costs included the cost of the two drugs and administration costs, the costs of acute drugs used under usual care, and the costs of hospitalization, physician, and emergency department visits. Indirect costs for the societal perspective analyses included wages lost on workdays. The time-horizon of the analysis was 1 year and all costs were calculated in 2019 euros (€). Sensitivity analyses were conducted to control for parameter uncertainty and to evaluate the robustness of the findings. Our results indicate that treatment of CM with erenumab compared to onabotulinumtoxinA resulted in incremental cost-effectiveness ratios (ICERs) of €218,870 and €231,554 per QALY gained and €620 and €656 per migraine avoided, from the societal and the payer's perspective, respectively. Using a common cost-effectiveness threshold equal to three times the local gross domestic product (GDP) per capita (€49,000), for the erenumab ICERs to fall below this threshold, the erenumab price would have to be no more than €192 (societal perspective) or €173 (payer perspective). The prophylactic treatment of CM with erenumab in Greece might be cost effective compared to the existing alternative of onabotulinumtoxinA from both the payer and the societal perspective, but only at a highly discounted price. Nevertheless, erenumab could be considered a therapeutic option for patients who fail treatment with onabotulinumtoxinA.


Development of an intermolecular transposition assay system in Bacillus subtilis 168 using IS4Bsu1 from Bacillus subtilis (natto).
Most of the spontaneous poly-gamma-glutamate (gamma-PGA)-deficient mutants of Bacillus subtilis (natto) appear to have resulted from the insertion of IS4Bsu1 exclusively into the comP gene. However, complete genomic analysis of B. subtilis 168, a close relative of B. subtilis (natto), revealed no IS4Bsu1 insertion. Preliminary experiments using a transformable 'natto' strain indicated that the frequency of transposition of IS4Bsu1 was exceptionally high under competence-developing conditions. On the other hand, such high-frequency transposition was not observed when cells were grown in a rich medium, such as LB medium, suggesting that there must be suitable environmental conditions that give rise to the transposition of IS4Bsu1. To assess the behaviour of IS4Bsu1 and explore any host factors playing roles in IS transposition, an intermolecular transposition assay system was constructed using a modified IS4Bsu1 element in B. subtilis 168. Here, the details of the intermolecular transposition assay system are given, and the increase in transposition frequency observed under high-temperature and competence-inducing conditions is described.


Expanded criteria donors in deceased donor kidney transplantation - An Asian perspective.
There is an increasing gulf between demand and supply for kidneys in end-stage renal failure patients worldwide, especially Asia. Renal transplantation is often the treatment of choice for long-suffering patients who have to undergo dialysis on a regular basis. The utilization of expanded criteria donors (ECDs) to address the donor pool shortage has been proven to be a legitimate solution. Metzger first described the classification of standard criteria donor and ECD in 2002. Since then, the criterion has undergone various modifications, with the key aims of optimizing organ procurement rate while minimizing discard and rejection rates. We review the methods to improve selection, characterization of risks, and surgical techniques. Although the ECD kidneys have a higher risk of impaired donor and recipient outcome than the "standard criteria" transplants, it may be justified by the improved overall survival of these patients compared to those who remained on dialysis. It is, therefore, crucial that we perform meticulous selection, along with state of the art surgical techniques to maximize the use of this scarce resource. In this article, we review the pre-procurement and post-procurement processes implemented to preserve outcomes.


Homophily and the speed of social mobilization: the effect of acquired and ascribed traits.
Large-scale mobilization of individuals across social networks is becoming increasingly prevalent in society. However, little is known about what affects the speed of social mobilization. Here we use a framed field experiment to identify and measure properties of individuals and their relationships that predict mobilization speed. We ran a global social mobilization contest and recorded personal traits of the participants and those they recruited. We studied the effects of ascribed traits (gender, age) and acquired traits (geography, and information source) on the speed of mobilization. We found that homophily, a preference for interacting with other individuals with similar traits, had a mixed role in social mobilization. Homophily was present for acquired traits, in which mobilization speed was faster when the recuiter and recruit had the same trait compared to different traits. In contrast, we did not find support for homophily for the ascribed traits. Instead, those traits had other, non-homophily effects: Females mobilized other females faster than males mobilized other males. Younger recruiters mobilized others faster, and older recruits mobilized slower. Recruits also mobilized faster when they first heard about the contest directly from the contest organization, and decreased in speed when hearing from less personal source types (e.g. family vs. media). These findings show that social mobilization includes dynamics that are unlike other, more passive forms of social activity propagation. These findings suggest relevant factors for engineering social mobilization tasks for increased speed.


The influence of neurohypophysial hormones on renal function in the acutely hypophysectomized rat.
1. Renal function and the effect of neurohypophysial hormone replacement was investigated in anaesthetized, acutely hypophysectomized, male rats. 2. Although urine production was only slightly lower over the 8 h post-operative study period in hypophysectomized rats, sodium excretion was greatly depressed reaching only 3.5 +/- 1.4 mumol/min compared with a peak of 13.2 +/- 1.0 mumol/min in intact animals. 3. In association with a decline in mean arterial blood pressure, glomerular filtration rate in hypophysectomized rats fell to 2.1 +/- 0.2 ml/min 8 h after operation by comparison with a mean rate in intact rats of 3.2 +/- 0.2 ml/min. 4. Plasma corticosterone levels were much lower in hypophysectomized (4 +/- 2 ng/ml) than in intact (36 +/- 4 ng/ml) rats, plasma aldosterone was reduced to a lesser extent (0.41 +/- 0.08 compared with 0.76 +/- 0.04 ng/ml). While oxytocin was not detectable in hypophysectomized rat plasma, trace levels of vasopressin (0.16 +/- 0.04 mu u./ml) were found. In intact unanaesthetized rats basal plasma levels of oxytocin were 0.32 +/- 0.13 mu u./ml and vasopressin were 0.85 +/- 0.19 mu u./ml. 5. Administration of oxytocin at 150 mu u./min, which produced plasma hormone levels (24.0 +/- 2.5 mu u./ml) greatly in excess of basal concentrations, increased renal sodium excretion but did not alter urine flow. Oxytocin administration at the lower rate of 15 mu u./min producing plasma hormone levels of 2.60 +/- 0.1 mu u./ml, did not alter renal sodium excretion. 6. Arginine vasopressin administered at 12 mu u./min induced plasma hormone levels of 1.54 +/- 0.09 mu u./ml and produced a large antidiuresis and small increase in the rate of sodium excretion. 7. The natriuretic response to vasopressin was potentiated by concurrent administration of oxytocin at 15 mu u./min. The peak sodium excretion of 5.8 +/- 1.0 mumol/min, however, remained well below that seen in intact rats. 8. It is concluded that, as restoration of posterior pituitary hormones at or above the physiological range only partially restored sodium excretion, the absence of anterior pituitary factors may also contribute directly or indirectly to the renal sodium retention of the hypophysectomized rat.


Ants in a labyrinth: a statistical mechanics approach to the division of labour.
Division of labour (DoL) is a fundamental organisational principle in human societies, within virtual and robotic swarms and at all levels of biological organisation. DoL reaches a pinnacle in the insect societies where the most widely used model is based on variation in response thresholds among individuals, and the assumption that individuals and stimuli are well-mixed. Here, we present a spatially explicit model of DoL. Our model is inspired by Pierre de Gennes' 'Ant in a Labyrinth' which laid the foundations of an entire new field in statistical mechanics. We demonstrate the emergence, even in a simplified one-dimensional model, of a spatial patterning of individuals and a right-skewed activity distribution, both of which are characteristics of division of labour in animal societies. We then show using a two-dimensional model that the work done by an individual within an activity bout is a sigmoidal function of its response threshold. Furthermore, there is an inverse relationship between the overall stimulus level and the skewness of the activity distribution. Therefore, the difference in the amount of work done by two individuals with different thresholds increases as the overall stimulus level decreases. Indeed, spatial fluctuations of task stimuli are minimised at these low stimulus levels. Hence, the more unequally labour is divided amongst individuals, the greater the ability of the colony to maintain homeostasis. Finally, we show that the non-random spatial distribution of individuals within biological and social systems could be caused by indirect (stigmergic) interactions, rather than direct agent-to-agent interactions. Our model links the principle of DoL with principles in the statistical mechanics and provides testable hypotheses for future experiments.