On the physical origin of biological handedness.
In the racemic conglomerate crystallization of over 1,000 samples of D,L-sodium-ammonium tartrate the effect of 32P beta irradiation on the weight, optical activity, and crystallite size was measured. Both weight and optical activity showed a statistical dependence on the intensity of beta irradiation. The crystallite size is also affected by the presence of 32P. Asymmetric crystals are suggested to have been potential mediators between asymmetric parity violating forces and molecular asymmetry so that stereo-selective prebiotic chemical reactions involving crystals need not be considered 'chance' processes. No measurable difference in the energy content of optical isomers was found. An upper limit for the direct contribution of weak interactions to electromagnetic ones has been calculated. The mechanism of stereoselective crystal seeding by beta particles is discussed.


Surgical management of mucosal contact headache.
Most research on mucosal contact headache has focused on mucosal contact between the nasal septum and middle or inferior turbinate. However, rarely have any studies explored how headache is related to the only one contact point between superior turbinate and nasal septum. To explore how headache is related to the only one contact point between superior turbinate and nasal septum. 80 patients with headache were selected. The mucosal contact between superior turbinate and nasal septum was removed to study the relationship between the contact point and headache, with a follow-up of 12 months. Headache symptoms in 56 cases disappeared entirely. Significant relief was observed in 20 patients, and unsatisfactory results in only 4 patients, with the success rate being 95%. Some patients with headaches who had intranasal mucosal contact areas benefitted from the surgery. Satisfactory results were achieved by endonasal surgery in 95% of our patients in whom intranasal contact points were believed to be the cause of their headaches who had a mucosal contact point between the superior turbinate and the septum.


OSCC in Never-Smokers and Never-Drinkers Is Associated with Increased Expression of Tumor-Infiltrating Lymphocytes and Better Survival.
The aim of this study was to investigate the clinical, histopathologic, and immunologic differences of oral squamous cell carcinoma of never-smokers/never-drinkers and smokers/drinkers. Immunohistochemical staining for CD4, CD8, FoxP3, CD1a, and p16 was performed in 131 oral squamous cell carcinomas from smokers/drinkers and never-smokers/never-drinkers. Associations of smoking/drinking status with clinicopathologic data, immunohistochemical antibody expression, and survival were examined. Oral squamous cell carcinoma in never-smokers/never-drinkers was associated with the female gender (p < 0.001). Never-smokers/never-drinkers were older at diagnosis than smokers/drinkers (p < 0.001). Never-smokers/never-drinkers had more tumors in the maxilla, mandible, and tongue (p < 0.001). Pre-existing oral potentially malignant disorders appeared to be more common in never-smokers/never-drinkers (p < 0.001). Perineural invasion was more common in smokers/drinkers (p = 0.039). Never-smoking/never-drinking was associated with better overall survival (p = 0.004) and disease-specific survival (p = 0.029). High CD4+ T cell infiltration was associated with never-smoking/never-drinking (p = 0.008). Never-smokers/never-drinkers also showed increased CD8+ T cell infiltration (p = 0.001) and increased FoxP3+ Treg infiltration (p = 0.023). Furthermore, the total group of tumor-infiltrating lymphocytes was associated with never smoking/never drinking (p = 0.005). To conclude oral squamous cell carcinoma of the never-smokers/never-drinkers appears to be a distinct type of tumor, as it appears to have unique clinical and pathologic features and a more immunogenic microenvironment.


Better balance: a randomised controlled trial of oculomotor and gaze stability exercises to reduce risk of falling after stroke.
To assess the effect of a domiciliary program of oculomotor and gaze stability exercises on the incidence of falls and risk of fall in stroke survivors. Two-arm, non-blinded parallel randomized controlled trial. Stroke survivors older than 60 years, with positive Romberg test and autonomous gait after the stroke. Physiotherapy outpatient clinic of a tertiary care hospital. Every participant accomplished the current rehabilitation program; the intervention group was randomly allocated into an additional three weeks intervention with a domiciliary program of oculomotor and gaze stability exercises. Primary outcome was the incidence of falls through the three weeks after the intervention started; in addition, the variation of the estimated risk for falling assessed by both Berg Balance Scale (four points) and Timed Up and Go Test (four seconds) was the secondary outcome. 79 patients were recruited and 68 completed the protocol (control group 35; intervention group 33). During the follow up, falls were registered in 4/35 participants in the control group and no event occurred in the intervention group (P = 0.064). The estimated risk for falling decreased in 11/35 control group participants and in 28/33 intervention group participants (RR 0.37; 95%CI 0.22-0.62; P < 0.001). After three weeks of a domiciliary program of oculomotor and gaze stability exercises, the estimated risk of falling significantly diminished and no falls occurred among the intervention group. These findings encourage further exploration of this promising intervention. ClinicalTrials.gov Identifier: NCT02280980.


Tri-methyl-phosphine oxide dihydrate.
The title hydrate, Me3PO·2H2O, crystallizes in the ortho-rhom-bic space group Pbca with eight formula units per unit cell. The extended structure displays O-H⋯O hydrogen bonding, with Me3PO mol-ecules as acceptors and water mol-ecules acting as donors and acceptors of hydrogen bonds, forming hydrogen-bonded layers, which propagate in the ac plane.


Lipid peroxidation in osteoarthritis: focusing on 4-hydroxynonenal, malondialdehyde, and ferroptosis.
Osteoarthritis (OA) is a multifactorial and increasingly prevalent degenerative disease that affects the whole joint. The pathogenesis of OA is poorly understood and there is a lack of therapeutic interventions to reverse the pathological process of this disease. Accumulating studies have shown that the overproduction of reactive oxygen species (ROS) and ROS-induced lipid peroxidation are involved in the pathogenesis of OA. 4-Hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA) have received considerable attention for their role in cartilage degeneration and subchondral bone remodeling during OA development. Ferroptosis is a form of cell death characterized by a lack of control of membrane lipid peroxidation and recent studies have suggested that chondrocyte ferroptosis contributes to OA progression. In this review, we aim to discuss lipid peroxidation-derived 4-HNE and MDA in the progression of OA. In addition, the therapeutic potential for OA by controlling the accumulation of lipid peroxidation and inhibiting chondrocyte ferroptosis are discussed.


The impact of different health dimensions on overall quality of life related to kyphoplasty and non-surgical management.
This study uses data from a previously published randomised trial where balloon kyphoplasty was compared to non-surgical management. Of the improved overall quality of life, 60 % was caused by decreased pain. However, ignoring other dimensions of quality of life would underestimate the procedure's effect. Acute back pain has been viewed as the most important factor lowering quality of life (QoL) for patients suffering vertebral fractures. The objective of this study was to quantify the impact of different health dimensions on overall QoL using patient-reported outcome measurements (PROMs) collected in Fracture Reduction Evaluation (FREE) trial. The analysis was based on patients included in the 2-year-long randomised controlled FREE trial studying the efficacy and safety of balloon kyphoplasty procedure (BKP) compared to non-surgical management (NSM). The PROMs included were EQ-5D, Short Form (SF)-36, visual analogue scale (VAS) pain and the Roland-Morris Disability Questionnaire (RMDQ). The health dimensional contribution to the overall QoL improvements was analysed by isolating the impact of each dimension on QoL in the SF-36 and EQ-5D, respectively. A correlation analysis of the QoL improvement was performed to investigate the relationships between the four instruments. Changes in pain explained 60 % of the quality-adjusted life years (QALY) gained in BKP vs. NSM followed by self-care (17 %), mobility (16 %) and usual activities (10 %) (EQ-5D). Health dimensions capturing the mental state had little impact on the QALY gained. The SF-36 dimensional analysis showed similar results. The correlation analysis showed that the correlation between VAS pain, RMDQ and QALY improvement was fairly weak. Changes in the pain dimension of health are the most important drivers for changes of overall QoL in patients treated with BKP or NSM. However, ignoring the impact of other dimensions would lead to an underestimation of the actual improvement in overall QoL.


Analysis of putative N-linked glycosylation sites and variable region of envelope HIV-1 CRF07_BC recombinant in intravenous drug users in Xinjiang Autonomous Region, China.
To investigate more closely the determinants of transmission and escape in HIV-1 internal proteins, we analyzed the characterization of putative N-linked glycosylation sites (PNGSs) and the variable loop of CRF07_BC recombinant human immunodeficiency virus type 1 (HIV-1), isolated from intravenous drug users (IDUs). We studied the characterization of PNGSs and the variable loop in the C1-C5 and V1-V4 regions of the HIV-1 env gene in 12 intravenous drug users (IDUs) who were divided into two groups according to the length of infection time. In addition, two IDUs were longitudinally monitored from the time of seroconversion for 1.5 and 2.5 years. The longitudinal characterization within the individuals on PNGSs and the variable loop in the C1-C5 and V1-V4 region were also observed. Based on the above analysis, we found that PNGSs and the variable loop appeared to increase over time within IDU transmission of CRF07_BC recombinant HIV-1. We argue that limited PNGSs and the length of variable loops may be involved in selective transmission and escape.


The Significance of Cutaneous Allodynia in a Woman With Chronic Pelvic Pain.
This is a case report of sensory assessment in a woman with severe chronic pelvic pain following uterine artery embolization, and a discussion of a commonly observed sensory manifestation (allodynia) associated with chronic pelvic pain due to gynaecological conditions. Allodynia, as a common sensory abnormality can be readily detected at the bedside and represents the development of pain sensitization. Emergence of abdominal and perineal allodynia (assessed by cotton swap stroking and/or questionnaire) is associated with the development of the clinical features of sensitization: continuous pelvic pain, muscle tenderness, and reduced pressure pain thresholds. A uterine artery embolization was performed on a 42-year-old woman to treat a postpartum hemorrhage. The woman experienced severe pain immediately following the procedure, and it had persisted for one year when she was referred for chronic unrelenting pain. She was found to have extensive allodynia, myofascial dysfunction, and reduced pain thresholds. A hysterectomy was undertaken. As the pain persisted, botulinum toxin was administered to the lower abdomen in the region of reduced pain thresholds. Partial resolution of pain, physical limitation, and allodynia resolved one year after the hysterectomy and shortly after the injections of four tender regions of the anterior cutaneous nerves with 2.5 and 5.0 IU of botulinum toxin. Testing for allodynia is a validated bedside test for pain sensitization. A clinical trial of botulinum toxin is indicated for the management of chronic pelvic pain associated with allodynia and pain sensitization.


Clinical and immunologic response to antigen-specific transfer factor in drug-resistant infection with Mycobacterium xenopi.
The administration of transfer factor obtained from three donors who had recovered from clinical infections with Mycobacterium xenopi to a patient who had a destructive pulmonary infection with this organism, was associated with the reversal of an unfavorable clinical course. Cavitary tuberculosis associated with resistance to all combinations of antituberculosis drugs was probably related to a concurrent depression of cell-mediated immunity of unknown origin. Antigen specific but not nonspecific transfer factor caused a rapid and prolonged improvement in both the pulmonary disease and the immunologic deficiency. Cross-reactivity between the antigenic determinants of M. xenopi and Mycobacterium tuberculosis made it possible to use transfer factor obtained from donors responsive to purified protein derivative of tuberculin. This study clearly demonstrates the additional benefits to be gained from using transfer factor that is antigen-specific in the treatment of infectious diseases.


[DNA microarray for ophthalmic research-- basic and clinical research].
The development of DNA microchip analysis continues to progress. This development provides us with new biological knowledge. DNA microchip analysis can be divided into expression profiling and genotyping. In infectious disease, DNA microchip analysis helps us to identify the pathogen.


Family correlates of oppositional and conduct disorders in children with attention deficit/hyperactivity disorder.
Comorbidities among children with ADHD are key determinants of treatment response, course, and outcome. This study sought to separate family factors (parental psychopathology and parenting practices) associated with comorbid Oppositional Defiant Disorder (ODD) from those associated with Conduct Disorder (CD) among children with Attention Deficit/Hyperactivity Disorder. Clinic-referred families (n = 149) were diagnosed using DSM-IV criteria. Parents completed measures of parenting practices. Comorbid ODD and CD were significantly associated with maternal negative/ineffective discipline. Comorbid CD, but not ODD, was significantly associated with lack of maternal warmth and involvement, paternal negative/ineffective discipline, and with paternal Antisocial Personality Disorder (APD). However, the risk of CD posed by parenting appeared concentrated among children without a father having APD. While consistent discipline appears important for addressing comorbid ODD and CD, paternal psychopathology and the quality of the relationship between mother and child may pose risk specifically for comorbid CD. Efforts to prevent and/or treat CD should consider not only provision of structure and prudent discipline, but also the affective qualities of the relationship between the primary caretaker and child.


High-resolution diffusion tensor imaging identifies hippocampal volume loss without diffusion changes in individuals with prenatal alcohol exposure.
Magnetic resonance imaging (MRI) studies of prenatal alcohol exposure (PAE) commonly report reduced hippocampal volumes, which animal models suggest may result from microstructural changes that include cell loss and altered myelination. Diffusion tensor imaging (DTI) is sensitive to microstructural changes but has not yet been used to study the hippocampus in PAE. Thirty-six healthy controls (19 females; 8 to 24 years) and 19 participants with PAE (8 females; 8 to 23 years) underwent high-resolution (1 mm isotropic) DTI, anatomical T1-weighted imaging, and cognitive testing. Whole-hippocampus, head, body, and tail subregions were manually segmented to yield DTI metrics (mean, axial, and radial diffusivities-MD, AD, and RD; fractional anisotropy-FA), volumes, and qualitative assessments of hippocampal morphology and digitations. Automated segmentation of T1-weighted images was used to corroborate manual whole-hippocampus volumes. Gross morphology and digitation counts were similar in both groups. Whole-hippocampus volumes were 18% smaller in the PAE than the control group on manually traced diffusion images, but automated T1-weighted image segmentations were not significantly different. Subregion segmentation on DTI revealed reduced volumes of the body and tail, but not the head. There were no significant differences in diffusion metrics between groups for any hippocampal region. Correlations between age and volume were not significant in either group, whereas negative correlations between age and whole-hippocampus MD/AD/RD, and head/body (but not tail) MD/AD/RD were significant in both groups. There were no significant effects of sex, group by age, or group by sex for any hippocampal metric. In controls, seven positive linear correlations were found between hippocampal volume and cognition; five of these were left lateralized and included episodic and working memory, and two were right lateralized and included working memory and processing speed. In PAE, left tail MD positively correlated with executive functioning, and right head MD negatively correlated with episodic memory. Reductions of hippocampal volumes and altered relationships with memory suggest disrupted hippocampal development in PAE.


Diagnostic value of angled oblique sagittal images of the supraspinatus tendon for the detection of rotator cuff tears on MR imaging.
The goal of this study was to evaluate the added value of sagittal T2-weighted magnetic resonance imaging (MRI) of the supraspinatus tendon by comparison with a standard MRI protocol for the evaluation of the rotator cuff. This retrospective single center study included 100 patients referred for MRI for suspected rotator cuff injuries. Two observers compared sagittal T2-weighted fat-suppressed orthogonal images of the distal portion of the supraspinatus muscle ("cuff" protocol) to those acquired according to the standard MRI protocol, which focuses on the glenoid. The two observers evaluated the appearance of each rotator cuff tendon and indicated whether the "cuff protocol" facilitated interpretation. The sensitivity and specificity for the detection of lesions ranged from 79 to 97% and 80 to 99% respectively. The interobserver variability coefficient was good for the supraspinatus (k=0.744). The new sequence helped localize and characterize rotator cuff injuries in 24-40% of the cases for the supraspinatus, in particular for partial tears and tendinopathies. The results of the specific MRI "cuff" protocol focusing on the supraspinatus are good, and helps facilitate interpretation of MRIs of the rotator cuff by non-specialist radiologists, in particular of the supraspinatus muscle.


Association between hope and burden reported by family caregivers of patients with advanced cancer.
The aim of this study, in a sample of family caregivers (FCs) of patients with advanced cancer, was to describe the level of FC burden using the Caregiver Reaction Assessment (CRA). In addition, the effects of select FC and patient characteristics on each of the CRA subscales were evaluated. FCs and patients (n = 112) completed a demographic questionnaire, and Herth Hope Index, and the Hospital Anxiety and Depression Scale. FCs completed the CRA. Data were analyzed using multiple linear regression analyses. For three of the five CRA subscales (i.e., "impact on finances", "impact on daily schedule", and "impact on health"), the mean scores were comparable to a Norwegian sample of FCs caring for patients in the late palliative phase. The variance in each of the CRA subscales was explained by different factors. Total explained variance ranged from 5.5% ("lack of family support") to 31.8% ("impact on daily schedule"). FC characteristics, such as being female and lower educational level, distress regarding the patient's pain, anxiety, depression, and level of hope, as well as the patients' number of comorbidities, depression, and hope contributed to an increase in various domains of FC burden. FCs' level of hope was a significant predictor for three of the CRA subscales (i.e., "self-esteem", "lack of family support", and "impact on health"). Findings suggest that FCs' and patients' level of hope are important determinants of caregiver burden and that FCs with lower levels of hope represent a high-risk group for higher levels of caregiver burden.


Development of continuous and discrete neural maps.
Two qualitatively different kinds of neural map have been described: continuous maps exemplified by the visual retinotopic map, and discrete maps exemplified by the olfactory glomerular map. Here, we review developmental mechanisms of retinotopic and olfactory glomerular mapping and discuss underlying commonalities that have emerged from recent studies. These include the use of molecular gradients, axon-axon interactions, and the interplay between labeling molecules and neuronal activity in establishing these maps. Since visual retinotopic and olfactory glomerular maps represent two ends of a continuum that includes many other types of neural map in between, these emerging general principles may be widely applicable to map formation throughout the nervous system.


Proteomic characterization in the hippocampus of prenatally stressed rats.
Rats exposed to early life stress are considered as a valuable model for the study of epigenetic programming leading to mood disorders and anxiety in the adult life. Rats submitted to prenatal restraint stress (PRS) are characterized by an anxious/depressive phenotype associated with neuroadaptive changes in the hippocampus. We used the model of PRS to identify proteins that are specifically affected by early life stress. We therefore performed a proteomic analysis in the hippocampus of adult male PRS rats. We found that PRS induced changes in the expression profile of a number of proteins, involved in the regulation of signal transduction, synaptic vesicles, protein synthesis, cytoskeleton dynamics, and energetic metabolism. Immunoblot analysis showed significant changes in the expression of proteins, such as LASP-1, fascin, and prohibitin, which may lie at the core of the developmental programming triggered by early life stress.


Incidence, risk factors, and feto-maternal outcomes of inappropriate birth weight for gestational age among singleton live births in Qatar: A population-based study.
Abnormal fetal growth can be associated with factors during pregnancy and at postpartum. In this study, we aimed to assess the incidence, risk factors, and feto-maternal outcomes associated with small-for-gestational age (SGA) and large-for-gestational age (LGA) infants. We performed a population-based retrospective study on 14,641 singleton live births registered in the PEARL-Peristat Study between April 2017 and March 2018 in Qatar. We estimated the incidence and examined the risk factors and outcomes using univariate and multivariate analysis. SGA and LGA incidence rates were 6.0% and 15.6%, respectively. In-hospital mortality among SGA and LGA infants was 2.5% and 0.3%, respectively, while for NICU admission or death in labor room and operation theatre was 28.9% and 14.9% respectively. Preterm babies were more likely to be born SGA (aRR, 2.31; 95% CI, 1.45-3.57) but male infants (aRR, 0.57; 95% CI, 0.4-0.81), those born to parous (aRR 0.66; 95% CI, 0.45-0.93), or overweight (aRR, 0.64; 95% CI, 0.42-0.97) mothers were less likely to be born SGA. On the other hand, males (aRR, 1.82; 95% CI, 1.49-2.19), infants born to parous mothers (aRR 2.16; 95% CI, 1.63-2.82), or to mothers with gestational diabetes mellitus (aRR 1.36; 95% CI, 1.11-1.66), or pre-gestational diabetes mellitus (aRR 2.58; 95% CI, 1.8-3.47) were significantly more likely to be LGA. SGA infants were at high risk of in-hospital mortality (aRR, 226.56; 95% CI, 3.47-318.22), neonatal intensive care unit admission or death in labor room or operation theatre (aRR, 2.14 (1.36-3.22). Monitoring should be coordinated to alleviate the risks of inappropriate fetal growth and the associated adverse consequences.


Morphologic and functional correlates of plasma membrane injury during oxidant exposure.
Plasma membrane injury by exposure to hydrogen peroxide was examined in a renal epithelial cell line (LLC-PK1). Morphologic and functional parameters of plasma membrane integrity were studied in an attempt to eludicate the sequence of membrane alterations during the evolution of hydrogen peroxide-mediated injury. These parameters included plasma membrane potential and permeability, plasma membrane bleb formation, cellular size, and plating efficiency. Plasma membrane potential was the earliest parameter affected by hydrogen peroxide exposure. Half maximal depolarization occurred within 15-30 min of exposure to 1 mM, after 10-15 min exposure to 100 mM and after over 150 min exposure to 10 microM hydrogen peroxide. After exposure to 1 mM hydrogen peroxide, the following sequence of events was seen; increased plasma membrane blebbing (30 min), cell swelling (90-125 min) and increased plasma membrane permeability (150-240 min). After a 30 min exposure to 1 mM hydrogen peroxide, cellular plating efficiency, measured at 24 h, was reduced by 50% (P less than .001). These changes were accelerated, although their order of appearance was unchanged, at higher concentrations of hydrogen peroxide. We conclude that functional and morphologic expressions of cellular injury in this model occur in a defined sequence with plasma membrane depolarization representing the earliest marker of membrane injury during hydrogen peroxide exposure.


[Gil-Vernet anti-reflux operation by united application of television laparoscopy and vesicourethral laparoscopy].
To discuss the possibility of united application of television laparoscopy and vesicourethral laparoscopy in Gil-Vernet operation. The animal model of vesicourethral reflux (VUR) was established using rabbits. The Gil-Vernet operation was carried out by united application of television laparoscopy and vesicourethral laparoscopy. The VUR model was successfully established in 13 rabbits, and the reflux was successfully cured by microsurgical methods. This method had the advantages of television laparoscopy, vesicourethral laparoscopy and the Gil-Vernet such as no dissection of inner part of ureter-bladder wall, small wound, less bleeding, fast recovery, less complication and possible repetitive operation. It can be used in ill children with VUR.


Tidal and hydrological periodicities of seismicity reveal new risk scenarios at Campi Flegrei caldera.
The volcano-tectonic seismicity occurring at Campi Flegrei caldera during its present unrest phase, started in 2005, is distributed into time-clustered events emerging from a background composed of earthquakes with higher inter-arrival times. Here, we show that clustered seismicity is cyclically recurrent at time scales from semidiurnal to annual, matching tidal and hydrological periodicities. These results suggest that volcano-tectonic seismicity at Campi Flegrei caldera is driven by both variations in the deep magmatic feeding system and exogenous phenomena, as rainfall or global inflation/deflation cycles of the Earth's crust, controlled by the lunisolar interaction. Consequently, the role of exogenous triggers in the evolution of the present unrest phase should be properly considered in the elaboration of volcanic risk scenarios, presently limited to the study of surface indicators of deep phenomena.


Reality monitoring and motor memory in checking-prone individuals.
Studies concerning reality monitoring and motor memory abilities in checkers have provided mixed results. The aim of this study was to re-examine this question by asking 75 undergraduate students to perform, watch the experimenter perform, imagine themselves performing, imagine the experimenter performing, or verbally repeat different daily actions. Two groups were created (checking-prone and nonchecking-prone subjects) based on participants' checking subscores on the revised version of the Obsessive-Compulsive Inventory. First, results suggested that checking-prone subjects have a poorer motor memory than nonchecking-prone participants. Second, our data indicated that checking-prone participants confused actions they had performed with actions the experimenter had performed more often than nonchecking-prone participants. In other words, checking-prone participants remembered events from an observer's viewpoint. Finally, our findings suggest that dissociation could be a mediating variable between some of the reality monitoring abilities and checking.


Mismatch between suspected pyelonephritis and microbiological diagnosis: a cohort study from a UK teaching hospital.
Urinary tract infections are a common reason for prescribing empirical antibiotics in the emergency department. This study investigated the role of microbiological culture and urinalysis in the diagnosis of pyelonephritis by extracting data on 105 patients with a clinical diagnosis of pyelonephritis at a London teaching hospital. In total, 99 of 102 patients were treated empirically with intravenous antibiotics, but only 55 of 100 patients who were sampled had microbiological evidence of infection in urine and/or blood. Almost half (10/21) of the patients with a negative urine dipstick test had a positive urine culture. Diagnostic uncertainty in this context undoubtedly drives inappropriate antibiotic use.


Effect of mercury(II) on Nrf2, thioredoxin reductase-1 and thioredoxin-1 in human monocytes.
Human blood levels of mercury are commonly 10nM, but may transiently reach 50-75nM after dental amalgam placement or removal. Controversy persists about the use of mercury because the effects of these 'trace' levels of mercury are not clear. Concentrations of mercury > or =5000nM unequivocally alter redox balance in blood cells including monocytes. In the current study, we tested a hypothesis that concentrations of mercury <100nM altered levels and activities of key proteins that maintain monocytic redox balance. Human THP1 monocytes were exposed to 10-75nM of Hg(II) for 6-72h, with or without activation by lipopolysaccharide (LPS). The redox management proteins Nrf2 and thioredoxin-1 (Trx1) were separated by electrophoresis, then quantified by immunoblotting. The activity of the seleno-enzyme thioredoxin reductase (TrxR1), important in maintaining Trx1 redox balance, was measured by cell-free and cell-dependent assays. Concentrations of Hg(II) between 10-75nM increased Nrf2 levels (3.5-4.5 fold) and decreased Trx1 levels (2-3 fold), but these changes persisted <24h. Hg(II) potently inhibited (at concentrations of 5-50nM) TrxR1 activity in both cell-free and intracellular assays. Furthermore, Hg(II) transiently amplified LPS-induced Nrf2 levels by 2-3 fold and limited LPS-induced decreases in Trx1. All effects of Hg(II) were mitigated by pre-adding N-acetyl-cysteine (NAC) or sodium selenide (Na2SeO3), supplements of cellular thiols and selenols, respectively. Our results suggest that nanomolar concentrations of Hg(II) transiently alter cellular redox balance in monocytes that trigger changes in Nrf2 and Trx1 levels. These changes indicate that monocytes have a capacity to adapt to trace concentrations of Hg(II) that are introduced into the bloodstream after dental amalgam procedures or fish consumption. The ability of monocytes to adapt suggests that low levels of mercury exposure from dental amalgam may not overtly compromise monocyte function.


Variable structure and function relationship of compressive optic neuropathy at the time of diagnosis.
To illustrate the structure-function relationship of compressive optic neuropathy (CON) at the time of diagnosis. Thirty-two eyes of newly diagnosed suprasellar CON and 60 healthy eyes were included in the study. The peripapillary retinal nerve fiber layer (RNFL) thickness and macular ganglion cell-inner plexiform layer (GCIPL) thickness were obtained using Cirrus spectral domain optical coherence tomography (SD-OCT). CON eyes were stratified based on the similar degree and pattern of both RNFL and GCIPL. From 32 eyes of newly diagnosed suprasellar CON eyes, 27 eyes had a predominantly nasal hemiretina thinning of macular GCIPL, 4 eyes showed a generalized macular thinning, and 1 eye showed a predominantly superior macular thinning. The corresponding temporal peripapillary RNFL thinning with nasal hemiretina GCIPL thinning were inconsistently manifested. Structure-function analysis of stratified CON eyes with similar thinning profiles showed that a range rather than a fixed value of visual field loss based on mean deviation (MD) index was associated to each thinning profile. The maximal limit of visual field loss range was ubiquitously nonrestricted to any structural thinning profile. While the minimal limit of the associated MD range was gradually reduced from 0 to about -16.0 dB, the nasal hemiretina macular GCIPL thinning was the only manifestation and decreased from 75 to 45 µm. However, the different degrees of temporal hemiretina macular GCIPL and superior-inferior peripapillary RNFL thinning were only seen in 10 of 32 eyes of which their nasal hemiretina GCIPL and temporal RNFL thinning had reached significant thinning. Interestingly when present, the minimal limit of associated MD range continued to decrease from -16.0 to -32.0 dB. CON eyes can present with variable structure and function relationship at the time of diagnosis. Using structural parameters at the time of diagnosis to predict the prognosis should be used with caution.


The role of Smads in skin development.
Smads are a group of signaling mediators and antagonists of the transforming growth factor-beta (TGF-beta) superfamily, responding but not limited to signaling from TGF-beta, Activin, and bone morphogenetic proteins (BMPs). As all of these three signaling pathways play important roles in skin development, we have been actively pursuing studies assessing the role of Smads in skin development. Our studies revealed that Smad-4 affects hair follicle differentiation primarily by mediating BMP signaling. Smad-7 significantly affects hair follicle development and differentiation by blocking the TGFbeta/Activin/BMP pathway and by inhibiting WNT/beta-catenin signaling via ubiquitin-mediated beta-catenin degradation. In contrast, other Smads may have redundant or dispensable functions in skin development. Here, we review the work that shows the emergence of Smad functions in skin development via traditional and novel signaling pathways.


A case of gastric adenocarcinoma of fundic gland type resected by combination of laparoscopic and endoscopic approaches to neoplasia with non-exposure technique (CLEAN-NET).
A male in his eighties attended our hospital for further evaluation of gastric cancer. A gastroscopy revealed a whitish flat elevated lesion (Paris, 0-IIa) of 15 mm in diameter on the greater curvature of the proximal fornix. The preoperative diagnosis was intra-mucosal differentiated gastric cancer, and a novel therapeutic approach, combination of laparoscopic and endoscopic approaches to neoplasia with non-exposure technique (CLEAN-NET) was applied and the lesion was resected in a single piece without any complications. Histopathological findings revealed atypical glandular epithelium proliferated in the mucosa and shallow layer (300 μm) of submucosa. These cells stained positive for pepsinogen-I and the final diagnosis was gastric cancer of fundic gland type (GAFT). There was no lymph-vascular involvement and free horizontal and vertical margins were confirmed. CLEAN-NET could be a therapeutic option for GAFT at low risk of lymph node metastasis because it prevents excess wall defect and exposure of cancer cells into the peritoneal cavity.


Cytochrome P-450-dependent oxidation of lanosterol in cholesterol biosynthesis. Microsomal electron transport and C-32 demethylation.
Electron transfer to rat liver microsomal cytochrome P-450 of 14 alpha-methyl group demethylation of 24,25-dihydrolanosterol (C30-sterol) has been studied with a new radio-high-performance liquid chromatography assay. The monooxygenase is dependent upon NADPH plus oxygen, insensitive to CN-, and sensitive to CO. Microsomal oxidation is also sensitive to trypsin digestion, and reactivation is dependent upon the addition of purified, detergent-solubilized cytochrome P-450 reductase. Electron transport of C-32 sterol demethylation can be fully supported by very low concentrations of NADPH (approximately 10 microM) only in the presence of saturating concentrations of NADH (approximately 200 microM) suggesting involvement of cytochrome b5-dependent electron transfer in addition to the NADPH-supported pathway. The cytochrome P-450 of 14 alpha-demethylation has been solubilized with detergents, resolved chromatographically from cytochrome P-450 reductase and cytochrome b5, and fully active C-32 demethylase reconstituted. Incubation of intact microsomes with NADH and very low concentrations of NADPH described above leads to interruption of demethylation without 14 alpha-methyl group elimination. Under these conditions, C-32 oxidation products of the C30-sterol substrate accumulate at the expense of formation of demethylated, C29-sterol products. This enzymic interruption of C-32 demethylation, accumulation of oxygenated C30-sterols, along with subsequent demethylation of the isolated C30-oxysterols under similar oxidative conditions supports the suggestion that 14 alpha-hydroxymethyl and aldehydic sterols are metabolic intermediates of sterol 14 alpha-demethylation. Only very modest inductions of the constitutive cytochrome P-450 isozyme of 14 alpha-methyl sterol oxidase can be obtained with just 2 out of 12 known, potent inducers of mammalian hepatic cytochrome P-450s. Alternatively, administration of complete adjuvant in mineral oil drastically reduces amounts of total microsomal cytochrome P-450 while activity of 14 alpha-methyl sterol oxidase is not affected dramatically. Thus, as much as 2.5-fold enhancement of C-32 oxidase specific activity is obtained when expressed per unit of cytochrome P-450.


Correction: Reisser, C.M.O. et al. Population Connectivity and Genetic Assessment of Exploited and Natural Populations of Pearl Oysters within a French Polynesian Atoll Lagoon. Genes 2020, 11, 426.
The authors wish to make the following corrections to this paper [...].


Aspirin Protects Melanocytes and Keratinocytes against UVB-Induced DNA Damage In Vivo.
UVR promotes skin cancer through multiple mechanisms, including induction of inflammation, oxidative stress, and DNA damage such as 8-oxoguanine and cyclobutane pyrimidine dimers. We investigated whether the anti-inflammatory activities of aspirin (acetylsalicylic acid [ASA]) could protect against UVB-induced DNA damage and skin carcinogenesis. ASA reduced UVB-induced 8-oxoguanine and cyclobutane pyrimidine dimers in Melan-A melanocytes and HaCaT keratinocytes. Skin from UVB-irradiated C57BL/6 mice receiving 0.4 mg ASA daily by gavage exhibited less inflammation, fewer sunburn cells, and reduced 8-oxoguanine lesions than skin from irradiated control animals. ASA similarly reduced UVB-induced sunburn cells, 8-oxoguanine, and cyclobutane pyrimidine dimer lesions in skin of melanoma-prone TN61R mice, and this was associated with decreased prostaglandin E2 in plasma and skin. These effects of ASA, however, did not delay melanoma onset in TN61R mice exposed to a single neonatal dose of UVB. In SKH1-E mice prone to squamous cell carcinoma, ASA reduced plasma and skin prostaglandin E2 levels and indices of UVB-induced DNA damage and delayed squamous cell carcinoma onset induced by chronic UVB. These results indicate that ASA can protect against UVB-induced inflammation in skin and reduce UVB-induced DNA damage in both melanocytes and keratinocytes. These effects translated into greater chemopreventive efficacy for UVB-induced squamous cell carcinoma than melanoma mouse models.


A mechanistic principle for proton pumping by cytochrome c oxidase.
In aerobic organisms, cellular respiration involves electron transfer to oxygen through a series of membrane-bound protein complexes. The process maintains a transmembrane electrochemical proton gradient that is used, for example, in the synthesis of ATP. In mitochondria and many bacteria, the last enzyme complex in the electron transfer chain is cytochrome c oxidase (CytcO), which catalyses the four-electron reduction of O2 to H2O using electrons delivered by a water-soluble donor, cytochrome c. The electron transfer through CytcO, accompanied by proton uptake to form H2O drives the physical movement (pumping) of four protons across the membrane per reduced O2. So far, the molecular mechanism of such proton pumping driven by electron transfer has not been determined in any biological system. Here we show that proton pumping in CytcO is mechanistically coupled to proton transfer to O2 at the catalytic site, rather than to internal electron transfer. This scenario suggests a principle by which redox-driven proton pumps might operate and puts considerable constraints on possible molecular mechanisms by which CytcO translocates protons.


Using a novel polysaccharide BM2 produced by Bacillus megaterium strain PL8 as an efficient bioflocculant for wastewater treatment.
In this study, the purification and characterization of a novel polysaccharide-based bioflocculant BM2 produced by a bacterium Bacillus megaterium strain PL8 with self-flocculating property were investigated. The results showed that BM2 was an acidic polysaccharide composed of Gal, GalUA, Glc, GlcUA and Man at a molar ratio of 45.1: 33.8:9.3:9.2:2.4, respectively. The molecular weight of BM2 was 4.55 × 106 Da. BM2 had high flocculation efficiencies across a wide pH ranged from 4 to 11 and a wide temperature ranged from 20 to 100 °C towards kaolin clay. BM2 was a cation-independent bioflocculant which could achieve high flocculation activity without the addition of other cations. Adsorption bridging was the main mechanism in the flocculation process of BM2 towards kaolin clay. The BM2 also displayed a high removal efficiency in terms of Congo red (88.14%) and Pb2+ ions (82.64%). These results suggested that BM2 had a great potential as an efficient bioflocculant candidate in wastewater treatment.


Patient perceptions of the readability and helpfulness of bilingual clinical forms: a survey study.
Patients with limited English proficiency (LEP) are rarely provided with translated clinical materials. Typically, healthcare clinics cite high costs of translation and lack of professional translators as barriers to this service. The purpose of the current study was to investigate the perceptions of LEP dental patients regarding the readability, understanding, and helpfulness of translated clinical forms produced by dental student doctor translators. We used a survey design and convenience sampling to recruit LEP patients from a dental school clinic. Participants completed a 9-question (8 Likert-type items and 1 open-ended item) paper survey about translated forms. The bilingual survey was a combination of English and 8 other languages (Arabic, Dari, Pashto, Russian, Spanish, Ukrainian, Urdu, or Vietnamese) and assessed the type of form received; self-reported literacy; design, readability, and helpfulness of the form; overall understanding of the form; understanding of medical and dental terms; helpfulness for patient-provider communication; and comfort level with dental care after receiving the form. Demographic characteristics of participants were collected from the clinic's electronic health record. Survey responses were analyzed descriptively, and Spearman's correlation was used to examine the relationship between outcomes. Ninety-seven LEP patients (61.9% [60] female, 78.4% [70] Spanish speakers) completed 140 surveys for various translated forms in Dari, Pashto, Spanish, Urdu, or Vietnamese. Participants positively rated translated clinical forms: range, 50.4% (70) for design of the form to 80.0% (112) for comfort level with dental care after receiving the form. For the open-ended item, participants indicated the translations were good, and no improvements were needed. They also thought providing the form was evidence of good customer service. When examining relationships between outcomes, positive correlations were found between self-reported literacy and readability (Spearman r = .57, P < .001), overall understanding and understanding of medical and dental terms (Spearman r = .58, P < .001), and type of form and helpfulness for patient-provider communication (Spearman r = .26, P = .005). Study results suggested the translated clinical forms were perceived as helpful and beneficial by LEP dental patients. Similar approaches should be considered to reduce language barriers in healthcare.


Effect of erythromycin and amoxycillin on Bordetella pertussis in the nasopharynx.
The effectiveness of oral erythromycin and amoxycillin in eradicating Bordetella pertussis from the nasopharynx was compared. Erythromycin in a dosage of 40--50 mg/kg/day was significantly more effective than amoxycillin in a dosage of 25--30 mg/kg/day. The organism did not disappear in three cases receiving a lower dosage of erythromycin. As antibiotic treatment does not affect the clinical course of fully-developed whooping cough, erythromycin is indicated primarily when particularly susceptible individuals are threatened by exposure. In such cases erythromycin should be given as soon as whooping cough is suspected.


Natural duck hepatitis B virus infection in Australia.
Natural Duck Hepatitis B Virus (DHBV) infection has been studied in Australian ducks. Sera from 430 Pekin Aylesbury cross-bred ducks taken from three separate flocks were examined for duck hepatitis B virus (DHBV) DNA using a DNA dot hybridisation assay. In one flock there was significant infection with DHBV (98/140), but none was detectable in the other two flocks. Episomal DHBV DNA in liver tissue was demonstrated by gel blot hybridisation only in birds with DHBV DNA in serum. Polymerase-labelled DHBV DNA migrated as expected for linear double-stranded DNA 3.1 kilobase (kb) in length. Virus particles with characteristic DHBV morphology were observed in DHBV DNA-positive serum on electron microscopy. No overt morbidity has been noted in naturally infected ducks, but moderately severe hepatitis was found in 3/40 ducks examined histologically. These 3 ducks had DHBV DNA in serum and liver tissue. Mild hepatitis was observed in 27 ducks, but, in these, there was no correlation between the hepatitis and the presence of DHBV in serum or in liver tissue. This is the first report of DHBV in Australia. An animal model may now be established to study aspects of Hepadna virus infection which are pertinent to Hepatitis B virus (HBV) disease in man.


Serum levels of granzyme B decrease in patients with rheumatoid arthritis responding to abatacept.
A possible role of granzyme B (GZMB) in the pathogenesis of joint erosions in rheumatoid arthritis (RA) has been suggested. Since CD28neg T-cells may be an important source of GZMB, and we have previously shown that co-stimulation blockade by abatacept can prevent the generation of the CD28neg T-cell populations, we evaluated the effect of abatacept therapy on GZMB serum levels in patients with RA. The serum levels of GZMB were evaluated by an indirect solid-phase enzyme immunoassay before the start of treatment with abatacept (T0) in 53 patients with RA and after 6 months of therapy (T6) in 25 patients. At T0, GZMB serum levels were correlated with disease activity measured by DAS28-CRP (p=0.0022) and percentages of circulating CD4+CD28neg and CD8+CD28neg T-cells (p=0.007; p=0.031). The levels of GZMB in 18 patients with a moderate or good EULAR clinical response to ABA significantly decreased from T0 to T6 (p=0.023), whereas no variation was observed in 7 non responders. The variation of GZMB levels was directly correlated with that of DAS28-PCR (p=0.040), but not with those of circulating CD28-neg T-cell subsets. Costimulation blockade by ABA can decrease the serum levels of GZMB in RA patients responding to the treatment, suggesting that this might be one of the mechanism by which abatacept can prevent radiographic erosions. However, the lack of correlation of such decrease with the numbers of circulating CD28-neg T cells suggests that these cells probably are not the main source of serum GZMB.


An improved experimental method for simultaneously isolating hepatocytes and hepatic stellate cells in mouse liver infected with Echinococcus multilocularis.
Alveolar echinococcosis (AE) is a zoonotic disease caused by the larval stage of Echinococcus multilocularis parasitizing in the human liver, causing local pathological changes in the liver and manifesting as hyperplasia, liver fibrosis, atrophy, degeneration, and necrosis. Here, we report a method that can simultaneously isolate hepatocytes and hepatic stellate cells (HSCs) from mice infected with Echinococcus multilocularis. A mouse model of AE was established. Hepatocytes and HSCs were isolated from mouse liver using a two-step method combining in situ collagenase perfusion and gradient centrifugation. Expressions of Alb, Desmin, and α-SMA were detected with immunofluorescence to identify the isolated hepatocytes and HSCs. The viability and purity of hepatocytes and HSCs both reached 90% or above. For hepatocytes, clear cell boundaries were observed, and the nuclei were round or oval, with clear nucleoli. There was a homogeneous distribution of the hepatocyte marker Alb in the cytoplasm of hepatocytes. Lipid droplets and Desmin expression were observed in the cytoplasm of freshly isolated HSCs. During the activation of HSCs, the lipid droplets gradually decreased and disappeared with a high expression of α-SMA. Hepatocytes and HSCs are simultaneously isolated. This may provide a research tool to investigate the interaction between hepatocytes and HSCs and to investigate the mechanism of Echinococcus multilocularis infection-induced liver pathological changes.


Propensity Score Analysis of an Enhanced Recovery Programme in Upper Gastrointestinal Cancer Surgery.
The aim of this study was to examine the influence of an enhanced recovery programme (ERP) on outcomes of upper gastrointestinal (UGI) cancer surgery by means of propensity score-matched analysis. Three hundred consecutive patients diagnosed with UGI cancer were studied prospectively before and after the introduction of an ERP. Multiple regression models, including propensity scores, were developed to assess confounding variables associated with undergoing surgery, and the risk adjusted association between treatment and length of hospital stay (LOHS). After regression for confounding factors, a cohort of 252 patients was available of whom 160 received ERP [median age 66 years (IQR 58-73), 119 male, 81 oesophageal, 79 gastric cancer] and 92 control [66 years (IQR 58-74), 74 male, 58 oesophageal, 34 gastric cancer]. ERP operative morbidity (Clavien-Dindo ≥3) and mortality were 13.8 and 3.1 % compared with 17.4 (p = 0.449) and 2.2 % (p = 0.658) in controls. Median ERP critical care and total LOS were 1 (IQR 0-1) and 13 (IQR 10-17) days, compared with 1 (IQR 1-2, p = 0.009) and 16 (IQR 13-26, p < 0.001) days. Multivariable analysis revealed ERP (HR 1.477, 95 % CI 1.084-2.013, p = 0.013), tumour location (HR 2.420, 95 % CI 1.624-3.606, p < 0.001), operative procedure (HR 1.143, 95 % CI 1.032-1.265, p = 0.010), and operative morbidity (HR 0.277, 95 % CI 0.179-0.429, p < 0.001) to be associated with LOHS. An ERP in UGI cancer surgery was feasible, safe, and effective.


Effects of parachlorophenylalanine and 5, 6-dihydroxytryptamine on the free-running rhythms of locomotor activity and plasma corticosterone in the rat exposed to continuous light.
Parachlorophenylalanine (PCPA) and 5,6-dihydroxytryptamine (5,6-DHT), depletors of brain serotonin, were administered to the rat and circadian rhythms of locomotor activity and plasma corticosterone were determined simultaneously in individual rats in light-dark cycles (LD) and in 200 lux continuous light (LL). Free-running periods and acrophases on the 12th day in LL (LL12) were calculated by a least squares spectrum method. In PCPA-treated rats which showed 70% depletion of brain serotonin, circadian rhythms of locomotor activity in LL and of plasma corticosterone and ACTH in LD disappeared for several days after the drug injection. Circadian rhythms of locomotor activity reappeared after the LL7 day and free-ran with a phase shift. Free-running periods of these rats did not differ significantly from that of control rats. However, the acrophase of PCPA-treated group on the LL11 day was 5 h advanced as compared to that of control. Circadian rhythm of plasma corticosterone in the PCPA-treated rats was detected on the LL12 day but their peak times were distributed around 24:00 h instead 08:00 h observed rats. The 5,6-DHT-treated rats which showed only 40% depletion of brain serotonin exhibited normal free-running rhythms in both locomotor activity and plasma corticosterone in LL and no difference in the acrophases of these functions on the LL12 day as compared to controls. These results suggest that PCPA affects the circadian clock (or clocks) itself in such a way that it blocks the clock to free-run or at least it effectively shortens the free-running periods of locomotor activity and plasma corticosterone in the rat.


Untargeted lipidomic analysis of human tears: A new approach for quantification of O-acyl-omega hydroxy fatty acids.
The purpose of this work was to optimize methodology to analyze the human tear film lipids by using untargeted, direct infusion electrospray ionization-mass spectrometry (ESI-MS) to establish the analytical approach for a large-scale clinical translational study of tear film lipids in ocular surface disease, particularly associated with the O-acyl-omega hydroxy fatty acids (OAHFAs). Meibum and tear samples were collected from both eyes of five normal subjects without ocular disease using two different microcapillary collection tubes, glass and polytetrafluoroethylene (PTFE). An untargeted lipidomics approach was used to analyze the lipids in human tear and meibum samples using direct infusion ESI-MS in positive and negative ion modes. Direct and indirect quantification methods were evaluated. The amount of OAHFAs measured in tears using these techniques was approximately 0.7-0.8% of the total lipids. More phospholipids, including phosphatidylcholine and sphingomyelin, were detected in the tear samples associated with glass microcapillaries compared to PTFE. Reliable assessment of lipids in small volumes of tear film is possible using high resolution, untargeted ESI-MS in positive and negative ion modes. Using this technique, the concentration of OAHFAs can be quantified, as can the presence of other polar lipids.


Hyperthermic intraperitoneal chemoperfusion in the treatment of locally advanced intra-abdominal cancer.
Surgical treatment of intra-abdominal cancer is often followed by local recurrence. In a subgroup of patients, local recurrence is the sole site of disease, reflecting biologically low-grade malignancy. These patients might, therefore, benefit from local treatment. Recently, debulking surgery followed by hyperthermic chemoperfusion has been proposed in the treatment of locally advanced or recurrent intra-abdominal cancer. This paper reviews the rationale and assesses the currently accepted indications for and results of this novel treatment. A systematic web-based literature review was performed. Information was also retrieved from handbooks, congress abstracts and ongoing clinical trials. A growing body of experimental evidence supports the use of hyperthermia combined with chemotherapy as an adjunct to cytoreductive surgery. Randomized clinical trials are available to support its use in the treatment and prevention of peritoneal carcinomatosis following resection of pathological tumour stage pT3 or pT4 gastric cancer; several other phase III trials are ongoing. Numerous phase I and II trials have reported good results for various other indications, with acceptable morbidity and mortality rates. Case mix, limited patient numbers and absence of a standardized technique are, however, a drawback in many of these series. For a subgroup of patients with peritoneal cancer without distant disease, debulking surgery followed by hyperthermic chemoperfusion may offer a chance of cure or palliation in this otherwise untreatable condition. This novel therapy should, however, be considered experimental until further results from ongoing phase III trials become available.


Atf6α-null mice are glucose intolerant due to pancreatic β-cell failure on a high-fat diet but partially resistant to diet-induced insulin resistance.
Activating transcription factor 6α (ATF6α) is essential for the endoplasmic reticulum (ER) stress response. Since recent studies suggested that ER stress is involved in the pathogenesis of type 2 diabetes mellitus, we have analyzed Atf6α-null (Atf6α(-/-)) mice challenged with metabolic overload or genetic manipulations. Atf6α(-/-) mice were fed a high-fat diet to create diet-induced obese (DO) mice, and were subjected to examination of glucose homeostasis with biochemical and morphological analysis of the pancreatic β-cell and liver tissues. Atf6α-null mice were also crossed with genetic models of diabetes caused either by insulin resistance (Agouti obese mice) or by impaired insulin secretion (Ins2(WT/C96Y) mice). Atf6α(-/-) DO mice were less glucose tolerant with blunted insulin secretion compared to littermates on a high-fat diet. Pancreatic insulin content was lower in Atf6α(-/-) DO mice with the swollen β-cell ER, a typical feature of cells with ER stress. In the liver of Atf6α(-/-) DO mice, XBP-1 splicing was increased, suggesting that higher ER stress was present. ATF6-deficient mice showed increased mRNA expressions of glucose-6-phosphatase and SREBP1c associated with a tendency for a higher degree of steatosis in the liver. However, Atf6α(-/-) DO mice exhibited higher insulin sensitivity with lower serum triglyceride levels. Similar phenotypes were observed in ATF6α-deficient Agouti mice. In addition, ATF6α-deficiency accelerated reduction in pancreatic insulin content in Ins2(WT/C96Y) mice. These data suggested that ATF6α contributes to both prevention and promotion of diabetes; it protects β-cells from ER stress and suppresses hepatosteatosis, but plays a role in the development of hyperlipidemia and insulin resistance.


Glycine-immunoreactivity in the auditory brain stem of the chick.
Glycine-immunoreactivity (Gly-I) was studied in the auditory brain stem of chick using a polyclonal antiserum to glycine conjugated to bovine serum albumin (Wenthold et al., 1987). During embryonic development, little Gly-I is present in nucleus magnocellularis (NM), nucleus laminaris (NL), or nucleus angularis (NA). In posthatch chicks, a few Gly-I terminals are found on nerve cell bodies in NM. Gly-labeled terminals are rare in NL and NA. When present in NL, they appear to be apposed to neuronal somata and not to dendrites. Occasionally, a Gly-labeled cell can be found in NM. After unilateral cochlea removal, Gly-labeled terminals are still present in NM. Thus, the cochlea does not appear to be the source of the glycinergic afferents to NM. The pattern of staining of Gly-I contrasts sharply with that of gamma-aminobutyric acid-immunoreactivity (GABA-I). The number of Gly-I terminals in NM, NL and NA appears to be much less than that of GABA-I. In addition, GABA-I terminals are very abundant around both the cell bodies and dendrites of neurons in NM and NL, whereas Gly-I terminals are found only on neuronal somata. Gly-I in NM also appears to be much less than that in its mammalian homologue, the anteroventral cochlear nucleus.


The effect of in vivo T cell depletion with alemtuzumab on reduced-intensity allogeneic hematopoietic cell transplantation for chronic lymphocytic leukemia.
Reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation is increasingly considered for patients with chronic lymphocytic leukemia (CLL). To investigate the impact of in vivo T cell depletion with alemtuzumab on the incidence of graft-versus-host disease (GVHD), nonrelapse mortality (NRM), progression-free survival (PFS), and overall survival (OS), we retrospectively analyzed the outcomes of 62 consecutive CLL patients conditioned with fludarabine and melphalan at 4 institutions. For GVHD prophylaxis, 41 patients (cohort 1) received alemtuzumab and cyclosporin; and 21 patients (cohort 2) received cyclosporin plus methotrexate or mycophenolate. Donors were 50 siblings and 12 unrelated volunteers. Twenty-two (36%) patients received donor lymphocyte infusions (DLI), 20 (49%) from cohort 1 and 2 (10%) from cohort 2 (P=.002). Grade III-IV acute GVHD (aGVHD) was observed in 20% and 38% of patients from cohorts 1 and 2, respectively (P=.14). Extensive chronic GVHD (cGVHD) was observed in 10% and 48% of patients from cohorts 1 and 2, respectively (P=.03). There was a trend toward a higher viral infection rate in cohort 1 compared to cohort 2 (68% versus 43%, P=.062), but the incidence of cytomegalovirus (CMV) reactivation was not significantly different. The 3-year OS, PFS, NRM, and relapse rates were 65%, 39%, 28%, and 32%, respectively, for cohort 1; and 57%, 47%, 34%, and 20%, respectively, for cohort 2 (P=.629, P=.361, P=.735, and P=0.112, respectively). In conclusion, both methods of GVHD prophylaxis were equivalent in terms of survival. The administration of alemtuzumab led to reduced cGVHD, possibly improving quality of life.


Insulin-like growth factor-1 prevents loss of electrochemical gradient in cardiac muscle mitochondria via activation of PI 3 kinase/Akt pathway.
Insulin-like growth factor-1 (IGF 1) suppresses myocardial apoptosis and improves myocardial function in experimental models of cardiomyopathy. Apoptosis is triggered by mitochondria dysfunction and subsequent activation of caspases. We had previously shown that IGF 1 inhibited cardiomyocyte apoptosis via suppression of caspase, however, how IGF 1 and its signaling pathway modulates mitochondria function in cardiac muscle is not yet known. In this study we investigated how IGF 1 signaling modulates mitochondria membrane depolarization in the cardiomyocytes treated with doxorubicin. Doxorubicin rapidly induced loss of mitochondria electrochemical gradient and triggered mitochondria depolarization in primary cardiomyocytes, whereas addition of IGF 1 restored mitochondria electrochemical gradient. The effects of IGF 1 was blocked by a chemical inhibitor of PI 3 kinase and a dominant negative Akt, suggesting that IGF 1 signaling to mitochondria involves the PI 3 kinase-Akt pathway. Transducing cardiomyocytes with constitutive active PI 3 kinase partially restored the mitochondria electrochemical gradient in doxorubicin-treated cells. These findings provide direct evidence that IGF 1 modulation of mitochondria function is mediated through activation of PI 3 kinase and Akt. Additional experiments using agonist and antagonist of mitochondria K(ATP) channel suggest that IGF 1 signaling to mitochondria membrane does not directly involve K(ATP) channel. These findings suggest that cytosolic signaling to mitochondria may play a fundamental role in the cardiotoxic actions of doxorubicin and cardioprotective actions of IGF 1.


Lessons learned with molecular methods targeting the BCSP-31 membrane protein for diagnosis of human brucellosis.
Brucellosis remains an emerging and re-emerging zoonosis worldwide causing high human morbidity. It usually affects persons who are permanently exposed to fastidious microorganisms of the Brucella genus and has a nonspecific clinical picture. Thus, diagnosis of brucellosis can sometimes be difficult. Molecular techniques have recently been found very useful in the diagnosis of brucellosis together with its common and very diverse focal complications. We herein review all the lessons learned by our group concerning the molecular diagnosis of human brucellosis over the last twenty years. The results, initially using one-step conventional PCR, later PCR-ELISA and more recently real-time PCR, using both fluorescent intercalating reagents (SYBR-Green I) and specific probes (Taqman), have shown that these techniques are all much more sensitive than bacteriological methods and more specific than the usual serological techniques for the diagnosis of primary infection, the post-treatment control of the disease, early detection of relapse and the diagnosis of focal complications. Optimization of the technique and improvements introduced over the years show that molecular methods, currently accessible for most clinical laboratories, enable easy rapid diagnosis of brucellosis at the same time as they avoid any risk to laboratory personnel while handling live Brucella spp.


Is blue dye indicated for sentinel lymph node biopsy in breast cancer patients with a positive lymphoscintigram?
The use of isosulfan blue dye in sentinel node biopsy for breast cancer has been questioned because of its risk of allergic reaction. We hypothesized that blue dye could be safely omitted in the subgroup of patients who have evidence of successful sentinel node localization by lymphoscintigraphy. A retrospective review of patients with breast cancer and sentinel node biopsy was conducted. Information was collected on lymphoscintigraphy results, use of blue dye, and intraoperative and pathologic findings of sentinel nodes. We identified 475 patients with breast cancer who underwent 478 sentinel node biopsies. Both dye and isotope were given in 418 cases, of which 380 had a positive lymphoscintigram. In 5 of the 380 cases with a positive lymphoscintigram, the sentinel nodes obtained were blue but not hot, for a 1.3% marginal benefit of dye in the technical success of the procedure. Sentinel nodes positive for metastasis were found in 102 of 380 cases; in 3 cases, the only positive sentinel node was blue but not hot. Omission of the blue dye tracer would have increased the false-negative rate of the sentinel node procedure by approximately 2.5%. Even in sentinel node biopsy cases with a positive lymphoscintigram, the use of blue dye is beneficial for both improving the technical success of the procedure and reducing the false-negative rate of the procedure. Because the marginal benefits of dye justify its routine use, strategies to minimize the toxicity of blue dye are warranted.


Localization of an origin of replication in Corynebacterium diphtheriae broad host range plasmid pNG2 that also functions in Escherichia coli.
Subcloning and protoplast transformation studies identified a 2.6 kb fragment of Corynebacterium diphtheriae plasmid pNG2 which contains an origin of replication (oriR). Molecular combination of the 2.6 kb oriR cartridge with Escherichia coli plasmid pUC18CmR enabled the E. coli cloning vector to replicate within several species of Corynebacterium host cells. A 2.6 kb plasmid formed from the oriR cartridge alone is capable of replicating in E. coli. This suggests that a single origin could be used in vectors shuttling between Corynebacterium spp. and E. coli.


Changing number and distribution of endodontists: a continuing imbalance--1987-1995.
A review of the 1995 and past American Dental Association studies on the distribution of dentists provides specific information on the evolving numbers of endodontists at the national, regional, and state levels. Despite an increase in numbers of endodontists, major differences continue in practitioner-to-population ratios in different geographic areas.


Iron and copper-associated cirrhosis in infants. Acquired metal toxicity or genetic disorder?
Iron and Copper are essential trace elements for growth and development of the human infant but are toxic in excess. Lethal cirrhotic syndromes in the neonate and infant have been associated with both copper and iron overload. The relative importance of underlying genetic susceptibility and acquired excess of iron or copper in the pathogenesis of these chronic metal toxicity states is controversial and both syndromes probably encompass a spectrum of conditions.


Successful treatment of a bulky seminoma in an abdominal undescended testis: a case report.
An undescended testis is a major risk factor for the development of testicular malignancy. Herein we report the case of a 40-year-old man with a bulky seminoma arising in an uncorrected abdominal undescended testis. The definitive diagnosis was established by results of sonoguided biopsy and tumor marker studies. The patient was successfully treated with initial cisplatin and etoposide combination chemotherapy followed by resection of the residual tumor. The optimal diagnosis and treatment of this rare disease is discussed.


[Doubling of the arteria testicularis sinistra with variations of origin and course--an embryological consideration (author's transl)].
During dissection of a human body anomalies in the origin and the course of the testicular artery have been observed. Besides a left testicular artery arching over the left renal vein there existed an additional testicular artery on the same side originating from the distal part of the left renal artery. The development of those anomalies is discussed under embryological aspects.


Impaired interactions between mouse Eyal harboring mutations found in patients with branchio-oto-renal syndrome and Six, Dach, and G proteins.
Mutations in the EYA1 gene are responsible for branchio-oto-renal (BOR) syndrome as well as for other ocular defects. Most of the mutations are located within or in the vicinity of the EYA domain, which is highly conserved in the EYA protein family. The EYA domain is required for protein-protein interactions, which are important to the biological function of EYA proteins. To determine how EYA1 mutations cause BOR syndrome and/or ocular defects, we tested the effects of Eya1 mutations on interactions with Six. Dach, and G proteins by mammalian two-hybrid and GST-pulldown assays. Defective interactions were noted between BOR-type mutations S486P and L504R of Eya1 and Dach1, G proteins, and some Six proteins. These mutations impaired the activation of transcription from a Six-responsive gene, myogenin, with Six5. S486P and L504R showed an altered digestion pattern with trypsin, and L504R also decreased the sensitivity to V8 protease digestion and produced a peptide fragment with a different M(r). Our results suggest that defective protein-protein interactions of the mutations in the EYA domain underlie BOR syndrome and that SIX, DACH, and/or G proteins are possibly involved in the pathogenic processes.


Effects of polystyrene microparticles on inflammation, antioxidant enzyme activities, and related gene expression in Nile tilapia (Oreochromis niloticus).
Due to the importance of Nile tilapia in the aquaculture sector, the present study aimed to evaluate the adverse impacts of the polystyrene microparticles (PS-MPs) on inflammation, immune, and antioxidative responses. For this reason, fish were exposed to waterborne PS-MPs at two sizes (9 μm and 0.35 μm) beside the control group for 28 days. Regardless of particle size, the final weight, weight gain, specific growth rate, and feed conversion ratio of Nile tilapia were not influenced by the PS-MPs exposure (P > 0.05). Superoxide dismutase (SOD), glutathione peroxidase (GPX), and malondialdehyde (MDA) levels were significantly increased in the group exposed to 9 μm and followed by those exposed to 0.35 μm while the lowest SOD, GPX, and MDA were in the control group. The expression of catalase (CAT) and lysozyme genes were upregulated in the group of fish exposed to 9 μm (P < 0.05). The expression of the interferon-gamma (IFN-γ) gene was upregulated in fish exposed to 9 μm and 0.35 μm when compared with the control (P < 0.05). The expression of interleukin 8 (IL8), interleukin (IL-1β), and tumor necrosis factor (TNF-α) genes was upregulated in the group of fish exposed to 9 μm (P < 0.05). The hepatic mRNA levels of cytochrome P450 (CYP450) gene were significantly upregulated in the group of fish exposed to 9 μm when compared with the control (P < 0.05) without significant differences with those exposed to 0.35 μm (P > 0.05). The obtained results refer to the adverse effects of PS-MPs on the antioxidative, inflammatory, and detoxification-related genes of Nile tilapia.


Airborne cat (Fel d I), dog (Can f I), and mite (Der I and Der II) allergen levels in the homes of Japan.
We measured the airborne and floor dust allergen levels of the cat (Fel d I), dog (Can f I), and mite (Der I and Der II) allergens in 13 houses. Airborne allergens were sampled with a low-noise air sampler for 5 to 7 days in the living rooms where the inhabitants were living as usual. The mean levels of airborne Fel d I and Can f I in houses with cats or dogs were 5960 and 2880 pg/m3, respectively, which were about 160 and 100 times higher than levels of airborne Der I. In floor dust the mean levels of Fel d I and Can f I were 322 and 236 micrograms/gm fine dust, respectively, which were 59 and 10 times higher than the levels of Der I. These results suggest that the airborne cat and dog allergens might be important sources of allergens for persons who live in a house with those animals, because the absolute allergen levels in both the air and dust are significantly higher than those of mite.


Gene expression profiling of midbrain dopamine neurons upon gestational nicotine exposure.
Maternal smoking during pregnancy is associated with low birth weight, increased risk of stillbirth, conduct disorder, attention-deficit/hyperactivity disorder and neurocognitive deficits. Ventral tegmental area dopamine (DA) neurons in the mesocorticolimbic pathway were suggested to play a critical role in these pathological mechanisms induced by nicotine. Nicotine-mediated changes in genetic expression during pregnancy are of great interest for current researchers. We used patch clamp methods to identify and harvest DA and non-DA neurons separately and assayed them using oligonucleotide arrays to elucidate the alterations in gene expressions in these cells upon gestational nicotine exposure. Microarray analysis identified a set of 135 genes as significantly differentially expressed between DA and non-DA neurons. Some of the genes were found to be related to neurological disease pathways, such as Alzheimer's disease, Parkinson's disease and Huntington's disease. Significantly up-/down-regulated genes found in DA neurons were mostly related to G-protein-coupled protein receptor signaling and developmental processes. These alterations in gene expressions may explain, partially at least, the possible pathological mechanisms for the diseases induced by maternal smoking.


Facial distortion secondary to idiopathic gingival hyperplasia: surgical management and oral reconstruction with endosseous implants.
Little information exists regarding the surgical and oral reconstructive options for the patient with idiopathic gingival hyperplasia, especially with regard to endosseous implant placement and recurrence of the disease. The authors report a case of severe gingival enlargement and bone resorption involving the maxillary and mandibular arches in a 21-year-old female causing distortion of facial features. The etiology could not be established but the condition was exacerbated during pregnancy, causing chewing, speaking, and esthetic problems. The hyperplastic tissue and all the teeth were removed surgically, followed by immediate placement of 2 endosseous implants. Restoration of esthetics and function with a maxillary denture and mandibular overdenture were completed 3 months later. No disease recurrence was noted at the 6-month postoperative interval.


Synthesis and antitumor activity of novel pyrimidinyl pyrazole derivatives. II. Optimization of the phenylpiperazine moiety of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-phenylpiperazinyl-1-trans-propenes.
A series of novel 3-substituted-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-propenes in order to improve the in vitro and in vivo activity of our prototype 3-[4-(3-chlorophenyl)-1-piperazinyl]-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-propene (2) were synthesized and evaluated by assays of growth inhibition against several tumor cell lines in vitro and antitumor activity against some tumor models when dosed both intraperitoneally and orally in vivo. Compounds 7a and 7e, the 3,5-difluorophenyl and 3,5-dichlorophenyl analogues of 2, respectively, showed significantly more potent cytotoxicity than 2 in vitro and potent antitumor activities without causing decrease of body temperature related to side effects.


Effect of ascorbic acid on the consequences of acute alcohol consumption in humans.
This study examines the influence of ascorbic acid pretreatment on ethanol clearance, toxicity, and behavioral impairment after an acute dose of ethanol in humans. Ascorbic acid or a placebo was given to 20 healthy male subjects for 2 weeks before ethanol consumption. The dose of ethanol was 0.95 gm/kg body weight and was consumed during a 2 1/2-hour period. Thirty minutes after ethanol consumption, motor coordination and intellectual function were assessed by Goldberg's "Finger-Finger" and "Serial Sevens" tests. In addition, color discrimination was measured with the use of the Farnsworth-Munsell 100 Hue Color Test. Hourly blood samples were taken for 10 hours after ethanol consumption to measure serum triglyceride levels, blood lactate/pyruvate ratios, and serum enzymes. Blood ethanol clearance was also determined. Ethanol consumption elevated serum triglyceride levels and blood lactate/pyruvate ratios and impaired performance of the behavioral tests but did not alter serum enzyme levels. Ascorbic acid pretreatment resulted in significant enhancement in blood ethanol clearance and an increase in serum triglyceride levels after ethanol consumption in half of the subjects. Ascorbic acid pretreatment also resulted in improved motor coordination and color discrimination after ethanol consumption in half of the subjects. Ascorbic acid pretreatment did not influence elevated blood lactate/pyruvate ratios or impaired intellectual function.


Optimising the recovery and re-use of phosphorus from wastewater effluent for sustainable fertiliser development.
Recovery and re-use of phosphorus (P) from wastewater treatment systems as agricultural fertiliser presents an important and viable target for P waste reduction and recycling. In this study novel biochar materials for P filtration of wastewater were designed and produced using waste feedstocks, with consideration of the plant accessibility of the P captured by the biochars. The biochars were produced using batch slow pyrolysis at 450 °C and 550 °C from a) AD: anaerobically digested sewage sludge and b) OCAD: a 1:1 mixture of anaerobically digested sewage sludge and ochre, a mineral product from mine drainage treatment. A set of experiments was designed using pH buffering to provide a robust framework for assessing the P recovery capacity and affinity of the biochars compared to other potential P recovery materials (unprocessed ochre, activated carbon and zeolite). After 5 days of repeated exposure to a P solution at a wastewater-relevant concentration (0.02 g P l(-1)) replenished each 24 h, relatively high masses of P were recovered by ochre (1.73 ± 8.93×10(-3) mg P g(-1)) and the biochars OCAD550 (1.26 ± 4.66×10(-3) mg P g(-1)), OCAD450 (1.24 ± 2.10×10(-3) mg P g(-1)), AD450 (1.06 ± 3.84×10(-3) mg P g(-1)), and AD550 (0.986 ± 9.31×10(-3) mg P g(-1)). The biochar materials had higher removal rates than both activated carbon (0.884 ± 1.69×10(-2) mg P g(-1)) and zeolite (0.130 ± 1.05×10(-2) mg P g(-1)). To assess the extractability of recovered P, P exposure was followed by repeated extraction for 4 days with pH 7-buffered deionised water. The AD biochars retained 55% of the P recovered, OCAD biochars 78% and ochre 100%. Assessment of potentially toxic element concentrations in the biochars against guideline values indicated low risk associated with their use in the environment. Our successful demonstration of biochar materials highlights the potential for further development of P filters for wastewater treatment systems from anaerobic digestate produced and pyrolysed on-site with energy recovery.


Paediatric critical care nurses' attitudes and experiences of parental presence during cardiopulmonary resuscitation: a European survey.
Although recent resuscitation guidelines are supportive of family presence during cardiopulmonary resuscitation literature from the last decade suggests that it is often discouraged, and the subject remains a controversial issue. To determine the experiences and attitudes of European paediatric critical care nurses about parental presence during the resuscitation of a child. A survey design was employed. A convenience sample of European paediatric critical care nurses was used. A structured questionnaire was used, which incorporated a series of attitude statements that were rated using a 5-point Likert scale. Differences in attitudes were explored in three areas: decision-making, processes and outcomes of resuscitation. The results from this survey suggest that European paediatric nurses are very supportive of parental presence during cardiopulmonary resuscitation. Only a few nurses reported that their unit had a policy that covered parental presence during cardiopulmonary resuscitation and most nurses did not support the use of a dedicated nurse to look after the parents during resuscitation. Compared with previous studies relating to adult cardiopulmonary resuscitation, paediatric nurses experience family member presence more frequently than adult critical care nurses and appear to be more supportive of relatives' presence. It is recommended that paediatric intensive care units establish local policies that cover parental presence during cardiopulmonary resuscitation.


Laboratory performance on analysis of mandatory nutrients and preparation of nutrition labelling.
This study assessed the performance of 17 laboratories in Thailand in analysing mandatory nutrients in salted, fried broad bean and in using data to prepare nutrition labels. Nutrient levels in the test material, as robust mean (x(∗)) and robust standard deviation (s(∗)), were assigned in line with ISO 13528. Data obtained from the laboratories were statistically evaluated against these values. Laboratories with satisfactory, questionable and unsatisfactory results for each nutrient were identified based on robust z-score. Laboratories achieving satisfactory analytical results (z-score⩽2) were for lipid, 82%; protein, 85%; Na, 82%; Ca, 62%; Fe, 81%; ash, 70%; and moisture, 62%. Reference values for some nutrients in broad bean powder were developed using data from satisfactorily performing laboratories. Less than 20% of the laboratories demonstrated good performance in preparing nutrition labels. Common mistakes were the nutrition information format, estimation of serving size and serving(s) per package.


AKT/GSK-3β/β-catenin signaling pathway participates in erythropoietin-promoted glioma proliferation.
Although erythropoietin (EPO) has been proven to significantly promote the proliferation of cancer cells, the mechanism for promoting glioma proliferation is poorly understood. Here, we examined the functional role of the AKT/GSK-3β/β-catenin signaling pathway in the EPO-mediated proliferation of glioma. The distribution of EPO and Ki-67 among clinical samples with different WHO grades was plotted by Immunological Histological Chemistry analysis. U87 and U251 glioma cell lines were treated with short hairpin RNA targeting (shEPO), recombinant human erythropoietin (rhEPO) and/or AKT-specific inhibitor (MK-2206). The changes in phosphorylated AKT, nuclear β-catenin, cyclin D1 and p27kip1 expression were detected. Cell cycle distributions and glioma proliferation in vitro and in vivo were analyzed. The expression level of EPO was significantly elevated with the increase of WHO grade and Ki67 in clinical glioma specimens. In vitro, knockdown of endogenous EPO in U87 and U251 cells effectively block the phosphorylation of AKT and GSK-3β and the expression of nuclear β-catenin. shEPO treatment also significantly decreased the expression of cyclin D1 and increased the expression of p27kip1. The cell cycle transition then slowed down and the proliferation of glioma cells or mouse xenograft tumors both decreased. Treatment of cells or tumors with extra rhEPO reversed the above biological effects mediated by shEPO. rhEPO-induced activation of the AKT/GSK-3β/β-catenin pathway and proliferation were abolished by MK-2206. Our study identified the AKT/GSK-3β/β-catenin axis as a critical mediator of EPO-induced glioma proliferation and further provided a clinically significant dimension to the biology of EPO.


The association between microRNA polymorphisms and the risk of childhood acute lymphoblastic leukemia: A meta-analysis.
The aim of this meta-analysis was to determine the relationship between microRNA polymorphisms and the risk of childhood acute lymphoblastic leukemia comprehensively. PubMed, EMBASE, Scopus, Web of Science, the Cochrane Library, Global Index Medicus, Clinicaltrials.gov, ProQuest, and Open Grey databases were used to find relevant papers. Using the STATA 16.0 and CMA 3.0 software, the significance of relationships between microRNA polymorphisms and childhood acute lymphoblastic leukemia risk was evaluated using odds ratios (ORs) and 95 % confidence intervals (95 % CIs) for five genetic models. The results of the meta-analysis showed that there was no significant association between the polymorphism of miR-146a rs2910164 and childhood acute lymphoblastic leukemia risk in different genetic models. Also, in the sensitivity analysis, removing Xue's study from the analysis indicated that both the homozygote and recessive models are significantly affected. Additionally, there was a statistically significant relationship between the polymorphisms of pri-miR-34b/c rs4938723 (in the homozygote and recessive models) and miR-612 rs12803915 (in the allele and dominant models) and childhood acute lymphoblastic leukemia risk. These findings suggest that the rs4938723 and rs12803915 polymorphisms may have a role in the development of childhood acute lymphoblastic leukemia.


The effect of ankle taping on functional performance in participants with functional ankle instability.
To investigate the effect of rigid ankle tape on functional performance, self-efficacy and perceived stability, confidence and reassurance during functional tasks in participants with functional ankle instability. Clinical measurement, crossover design. Participants (n = 25) with functional ankle instability (Cumberland Ankle Instability Score < 25) were recruited from university students and sporting clubs. Participants performed five functional tests with and without the ankle taped. The tests were: figure-8 hopping test, hopping obstacle course, star excursion balance test (SEBT), single-leg stance and stair descent test. Secondary outcome measures were self-efficacy and perception measures. Rigid tape significantly decreased the stair descent time by 4% (p = 0.014), but had no effect on performance in the other tests. Self-efficacy increased significantly (p < 0.001). Perceived stability, confidence and reassurance also increased with the ankle taped (p < 0.05) during the stair and two hopping tasks, but not during the SEBT or single-leg stance test. Although taping the ankle did not affect performance, except to improve stair descent, it increased self-efficacy and perceived confidence in dynamic tasks. These findings suggest that taping may reduce apprehension without affecting functional performance in those with functional ankle instability and permit continued physical activity or sport participation.


Pre-emptive skin treatments to prevent skin toxicity caused by anti-EGFR antibody: the real-world evidence in Japan.
Clinically managing skin toxicity associated with anti-EGFR antibody usage to treat colorectal cancer improves quality of life for colorectal cancer patients. This study assesses trends of pre-emptive skin treatments and their impact on subsequent dermatologist visits in Japanese colorectal cancer patients. Pre-emptive treatment status and dermatologist visit data were investigated for 9461 colorectal cancer patients who experienced anti-EGFR antibody treatment. Data were collected from an electronic hospital-based claims database. Pre-emptive treatments increased around 2013. Furthermore, subsequent dermatologist visits decreased significantly among the pre-emptive treatment group (p < 0.05). Pre-emptive skin treatments seem to be related to reducing subsequent dermatologist visits by severe skin toxicity prevention and gained popularity in Japan.


Morphological and physiological responses to increased salinity in marsh and dune ecotypes ofSporobolus virginicus (L.) Kunth.
Sporobolus virginicus (L.) Kunth is a halophytic grass native to tropical and warm temperate coasts throughout the world. A rhizomatous perennial with erect culms,S. virginicus occurs as two genetically distinct growth forms, which are designated by their characteristic habitats as "marsh" and "dune". What accounts for the specific distribution and maintenance of two separate ecotypes ofS. virginicus is not known. The present study examined the effects of seawater salinity on several morphological and physiological responses of hydroponically cultivated marsh and dune plants to determine whether differential tolerance to substrate salinity might contribute to the observed pattern of habitation. Both marsh and dune form plants survived prolonged exposure to full-strength seawater and reproduced vegetatively via culms and rhizomes. Salinity-induced reductions in culm height, internode length, and leaf size led to a miniaturization of marsh and dune plants. Sodium ion levels were low (<1.0 mmol/g dry weight) in various organs of salinized plants irrespective of ecotype, and potassium ion content increased in all salt-challenged plants, as did quarternary ammonium compounds and proline. Significant differences, however, between marsh and dune plants with respect to the effects of salinity on resource allocation, flowering phenology, and protein composition suggested that external salt concentration has a role in determining ecotype distribution.


Dual host-virus arms races shape an essential housekeeping protein.
Transferrin Receptor (TfR1) is the cell-surface receptor that regulates iron uptake into cells, a process that is fundamental to life. However, TfR1 also facilitates the cellular entry of multiple mammalian viruses. We use evolutionary and functional analyses of TfR1 in the rodent clade, where two families of viruses bind this receptor, to mechanistically dissect how essential housekeeping genes like TFR1 successfully balance the opposing selective pressures exerted by host and virus. We find that while the sequence of rodent TfR1 is generally conserved, a small set of TfR1 residue positions has evolved rapidly over the speciation of rodents. Remarkably, all of these residues correspond to the two virus binding surfaces of TfR1. We show that naturally occurring mutations at these positions block virus entry while simultaneously preserving iron-uptake functionalities, both in rodent and human TfR1. Thus, by constantly replacing the amino acids encoded at just a few residue positions, TFR1 divorces adaptation to ever-changing viruses from preservation of key cellular functions. These dynamics have driven genetic divergence at the TFR1 locus that now enforces species-specific barriers to virus transmission, limiting both the cross-species and zoonotic transmission of these viruses.


Differential effects of agents enhancing purinergic transmission upon the antielectroshock efficacy of carbamazepine, diphenylhydantoin, diazepam, phenobarbital, and valproate in mice.
L-phenylisopropyladenosine (L-PIA; a preferential A1 adenosine agonist-0.05 mg/kg) offered no protection against electroconvulsions in mice but potentiated the anticonvulsant action of diazepam and valproate against maximal electroshock-induced seizures, decreasing the respective ED50 values from 9.5 to 4.0 mg/kg and from 250 to 185 mg/kg. However, it remained without effect on the protective activity of phenobarbital, carbamazepine and diphenylhydantoin. 5'-N-ethylcarboxamidoadenosine (NECA; a preferential A2 adenosine agonist-0.5 mg/kg) potentiated the efficacy of valproate. On the other hand, NECA (1 mg/kg) diminished the anticonvulsant action of phenobarbital (ED50 was elevated from 16.5 to 20.5 mg/kg), possessing no effect upon the protective action of carbamazepine. In addition, papaverine (20 mg/kg) significantly enhanced the protective efficacy of valproate and up to 40 mg/kg remained without influence upon the protective action of carbamazepine. However, papaverine (20 and 40 mg/kg) inhibited the anticonvulsive potential of phenobarbital. In the light of the results obtained A1 and A2 adenosine receptor-mediated events seem to possess different influences upon the protective effects of antiepileptic drugs.


Topography of the lesion in idiopathic sudden sensorineural hearing loss.
Etiology of ISSNHL includes cessation of vascular perfusion, viral infection and cochlear membrane injury. Precise location of injury should be defined for a target-oriented treatment. Vestibular complaints in ISSNHL are hypothesized as involvement of vestibule. Vestibular complaints can be either due to involvement of inner ear or neural tract at any level. In the present study we aimed to demonstrate involvement of vestibular organs in the absence of vestibular symptoms. It was aimed to evaluate superior and inferior vestibular neural pathways. c-vemp and o-vemp were applied to patients suffering ISSNHL without vertigo. Pure tone averages, audiogram configurations, degree of hearing loss were analyzed. Latencies of P1 and N1 waves, amplitudes of P1-N1 waves were evaluated. Asymmetrical vemp wave patterns were compared between two ears regarding difference of PTA. Latencies of c-vemp waves were longer and amplitudes were smaller. o-vemp parameters were similar on both sides. Positive correlation was observed between c-vemp latencies and degree hearing loss. Inferior vestibular nerve pathway is affected in the absence of vertigo in ISSNHL with spared superior vestibular nerve pathway. Damage in IVN pathway correlates with degree of ISSNHL.


Adverse health consequences of the Iraq War.
The adverse health consequences of the Iraq War (2003-11) were profound. We conclude that at least 116,903 Iraqi non-combatants and more than 4800 coalition military personnel died over the 8-year course. Many Iraqi civilians were injured or became ill because of damage to the health-supporting infrastructure of the country, and about 5 million were displaced. More than 31,000 US military personnel were injured and a substantial percentage of those deployed suffered post-traumatic stress disorder, traumatic brain injury, and other neuropsychological disorders and their concomitant psychosocial problems. Many family members of military personnel had psychological problems. Further review of the adverse health consequences of this war could help to minimise the adverse health consequences of, and help to prevent, future wars.


Monitoring of relapse and remission in acute leukaemias by DNA-fingerprint analysis.
DNA-fingerprint (DNA-F) analysis was successfully performed with DNA from 22 adult patients with acute leukaemia, including 13 patients with acute myeloid leukaemia (AML) and nine patients with acute lymphoblastic leukaemia (ALL). The purpose of this study was to detect differences between the leukaemic phase (at diagnosis or relapse) and remission-phase DNA. We applied one simple repeat probe (GTG)5 and one minisatellite (M13) after DNA-digestion with different restriction endonucleases (HinfI and HaeIII) and agarose gel electrophoresis. In 7/13 patients with AML and 5/9 patients with ALL it was possible to detect loss of bands, additional bands or band shift with at least one of the probes. Together the probes M13 and (GTG)5 unveiled deviating fingerprint patterns in 54.6% of patients between leukaemic cells and remission-phase leucocytes. Allogeneic bone marrow transplantation was performed on six patients. In each case the DNA-F pattern of the donor was different from the relapse and the remission-phase pattern. We conclude from our studies that the probes M13 and (GTG)5 are useful in the detection of relapse and remission in acute leukaemias after chemotherapy and bone marrow transplantation.


Predictors of pruritus in patients with chronic liver disease and usefulness of nalfurafine hydrochloride.
Pruritus is one of the complications of chronic liver disease, and it is important to investigate the predictors. Six hundred and seventy-three consecutive Japanese patients with chronic liver disease were retrospectively investigated for itch severity. Furthermore, 138 of all 673 patients were introduced to nalfurafine hydrochloride, and the improvement of itch severity was evaluated. The itch severity was self-assessed using the pruritus scores by Kawashima's criteria and visual analog scale. Two hundred and twenty-nine of the 673 patients (34.0%) were evaluated as 1 point or more of pruritus severity of Kawashima's criteria, and 46 patients (6.8 %) as 3 points or more. Multivariate analysis established that being negative for hepatitis B surface antigen (HBsAg) and presence of hepatocellular carcinoma (HCC) were significant determinants of pruritus (≥1 point of Kawashima's criteria), and being negative for HBsAg and having lower levels of platelet count were significant determinants of severe pruritus (≥3 points). Ninety-three of the 138 patients (67.4%) with nalfurafine hydrochloride indicated improvement of itch, defined as a decrease in VAS of 50 mm or more. There were no significant differences in treatment efficacy of nalfurafine hydrochloride, regardless of the three predictors of pruritus (HBsAg, HCC and platelet count). The present retrospective study indicated the predictors for pruritus, based on the large number of patients with chronic liver disease. Furthermore, this study demonstrated that nalfurafine hydrochloride may be useful for pruritus, regardless of the predictors.