The ubiquinone synthesis pathway is a promising drug target for Chagas disease.
Chagas disease is caused by infection with the protozoan parasite Trypanosoma cruzi (T. cruzi). It was originally a Latin American endemic health problem, but now is expanding worldwide as a result of increasing migration. The currently available drugs for Chagas disease, benznidazole and nifurtimox, provoke severe adverse effects, and thus the development of new drugs is urgently required. Ubiquinone (UQ) is essential for respiratory chain and redox balance in trypanosomatid protozoans, therefore we aimed to provide evidence that inhibitors of the UQ biosynthesis have trypanocidal activities. In this study, inhibitors of the human COQ7, a key enzyme of the UQ synthesis, were tested for their trypanocidal activities because they were expected to cross-react and inhibit trypanosomal COQ7 due to their genetic homology. We show the trypanocidal activity of a newly found human COQ7 inhibitor, an oxazinoquinoline derivative. The structurally similar compounds were selected from the commercially available compounds by 2D and 3D ligand-based similarity searches. Among 38 compounds selected, 12 compounds with the oxazinoquinoline structure inhibited significantly the growth of epimastigotes of T. cruzi. The most effective 3 compounds also showed the significant antitrypanosomal activity against the mammalian stage of T. cruzi at lower concentrations than benznidazole, a commonly used drug today. We found that epimastigotes treated with the inhibitor contained reduced levels of UQ9. Further, the growth of epimastigotes treated with the inhibitors was partially rescued by UQ10 supplementation to the culture medium. These results suggest that the antitrypanosomal mechanism of the oxazinoquinoline derivatives results from inhibition of the trypanosomal UQ synthesis leading to a shortage of the UQ pool. Our data indicate that the UQ synthesis pathway of T. cruzi is a promising drug target for Chagas disease.


Diagnostic potential of an iron-regulated hemin-binding protein HbpA that is widely conserved in Leptospira interrogans.
Like most bacteria, Leptospira spp. requires iron for growth. However, they face conditions of iron limitation due to the low solubility of the ferric iron and additionally due to the observation that most of the available iron is held as protein-bound iron by the mammalian host. Our experimental observations with pathogenic Leptospira showed that they do not elaborate siderophores upon iron limitation. In Leptospira interrogans serovar Lai, we demonstrated direct acquisition of iron via an iron-regulated hemin-binding protein HbpA. PCR analysis and Southern hybridization studies revealed that the hbpA gene was conserved in the serovars belonging to L. interrogans species and was absent in the non-pathogenic Leptospira biflexa serovar Patoc and Leptospira meyeri serovar Ranarum. Here, we extended the PCR-based detection of the hbpA gene to clinical isolates and demonstrated the hbpA amplicon in all the serovars belonging to L. interrogans species from a total collection of 91 clinical isolates obtained from different geographical regions. In addition, we detected anti-HbpA antibodies in the serum of patients with leptospirosis. PCR-based detection of hbpA in clinical isolates of serovars and the in vivo expression of HbpA reflects the diagnostic potential of this antigen.


Cost-effectiveness of focal psychodynamic therapy and enhanced cognitive-behavioural therapy in out-patients with anorexia nervosa.
Anorexia nervosa (AN) is a serious illness leading to substantial morbidity and mortality. The treatment of AN very often is protracted; repeated hospitalizations and lost productivity generate substantial economic costs in the health care system. Therefore, this study aimed to determine the differential cost-effectiveness of out-patient focal psychodynamic psychotherapy (FPT), enhanced cognitive-behavioural therapy (CBT-E), and optimized treatment as usual (TAU-O) in the treatment of adult women with AN. The analysis was conducted alongside the randomized controlled Anorexia Nervosa Treatment of OutPatients (ANTOP) study. Cost-effectiveness was determined using direct costs per recovery at 22 months post-randomization (n = 156). Unadjusted incremental cost-effectiveness ratios (ICERs) were calculated. To derive cost-effectiveness acceptability curves (CEACs) adjusted net-benefit regressions were applied assuming different values for the maximum willingness to pay (WTP) per additional recovery. Cost-utility and assumptions underlying the base case were investigated in exploratory analyses. Costs of in-patient treatment and the percentage of patients who required in-patient treatment were considerably lower in both intervention groups. The unadjusted ICERs indicated FPT and CBT-E to be dominant compared with TAU-O. Moreover, FPT was dominant compared with CBT-E. CEACs showed that the probability for cost-effectiveness of FTP compared with TAU-O and CBT-E was ⩾95% if the WTP per recovery was ⩾€9825 and ⩾€24 550, respectively. Comparing CBT-E with TAU-O, the probability of being cost-effective remained <90% for all WTPs. The exploratory analyses showed similar but less pronounced trends. Depending on the WTP, FPT proved cost-effective in the treatment of adult AN.


Extrinsic Factors Regulating Dendritic Patterning.
Stereotypic dendrite arborizations are key morphological features of neuronal identity, as the size, shape and location of dendritic trees determine the synaptic input fields and how information is integrated within developed neural circuits. In this review, we focus on the actions of extrinsic intercellular communication factors and their effects on intrinsic developmental processes that lead to dendrite patterning. Surrounding neurons or supporting cells express adhesion receptors and secreted proteins that respectively, act via direct contact or over short distances to shape, size, and localize dendrites during specific developmental stages. The different ligand-receptor interactions and downstream signaling events appear to direct dendrite morphogenesis by converging on two categorical mechanisms: local cytoskeletal and adhesion modulation and global transcriptional regulation of key dendritic growth components, such as lipid synthesis enzymes. Recent work has begun to uncover how the coordinated signaling of multiple extrinsic factors promotes complexity in dendritic trees and ensures robust dendritic patterning.


Aryl hydrocarbon receptor-mediated Cyp1a1 expression is modulated in a CLOCK-dependent circadian manner.
The expression of genes involved in xenobiotic detoxification is under the control of the circadian clock. The aryl hydrocarbon receptor (AhR) is one of the transcription factors responsible for the induction of detoxification enzymes in response to xenobiotic toxins, and the expression of AhR has been suggested to be regulated by a circadian oscillator. In this study, we investigated whether toxin-mediated activation of the AhR signaling pathway was modulated by CLOCK protein, a key component of the mammalian circadian clock. The expression of AhR and its DNA binding ability in the lungs of wild-type mice showed significant 24-h oscillation. Clock mutant (Clk/Clk) mice, producing CLOCK protein deficient in transcriptional activity, failed to show significant oscillation in the expression of AhR. The mRNA levels of AhR in the lungs of Clk/Clk mice were significantly lower than in wild-type mice. A single intraperitoneal injection of benzo[α]pyrene, a ligand of AhR, induced the expression of Cyp1a1 in the lungs of wild-type mice, but the induction varied depending on the benzo[α]pyrene injection time. The dosing time-dependency of benzo[α]pyrene-induced Cyp1a1 expression was also modulated by Clock gene mutation. These findings suggest that CLOCK protein affects the toxin-induced expression of detoxification enzymes through modulating the activity of AhR. Our present findings provide a molecular link between the circadian clock and xenobiotic detoxification.


Interpretation Biases in Pain: Validation of Two New Stimulus Sets.
Adults with chronic pain interpret ambiguous information in a pain and illness related fashion. However, limitations have been highlighted with traditional experimental paradigms used to measure interpretation biases. Whilst ambiguous scenarios have been developed to measure interpretation biases in adolescents with pain, no scenario sets exist for use with adults. Therefore, the present study: (i) sought to validate a range of ambiguous scenarios suitable for measuring interpretation biases in adults, whilst also allowing for two response formats (forced-choice and free response); and (ii) investigate paradigm efficacy, by assessing the effects of recent pain experiences on task responding. A novel ambiguous scenarios task was administered to adults (N = 241). Participants were presented with 62 ambiguous scenarios comprising 42 that could be interpreted in a pain/pain-illness or non-pain/non-pain illness manner: and 20 control scenarios. Participants generated their own solutions to each scenario (Word Generation Task), then rated how likely they would be to use two researcher-generated solutions to complete each scenario (Likelihood Ratings Task). Participants also rated their subjective experiences of pain in the last 3 months. Tests of reliability, including inter-rater agreement and internal consistency, produced two ambiguous scenario stimulus sets containing 18 and 20 scenarios, respectively. Further analyses revealed adults who reported more recent pain experiences were more likely to endorse the pain/pain-illness solutions in the Likelihood Ratings Task. This study provides two new stimulus sets for use with adults (including control items) in pain research and/or interventions. Results also provide evidence for a negative endorsement bias in adults.


Paraoxonase-1 is associated with corneal endothelial cell alterations in patients with chronic obstructive pulmonary disease.
To investigate the relationships between the levels of the antioxidant enzyme paraoxonase-1 (PON1) and corneal endothelial alterations in patients with chronic obstructive pulmonary disease (COPD) undergoing cataract surgery. We studied 172 patients with cataract attending our ophthalmology clinic. Based on spirometric analysis, they were segregated into two groups, 110 (64%) with COPD and 62 (36%) without COPD. Corneal endothelial cell morphology was examined by widefield noncontact specular microscopy, which allows measurements of endothelial cell density (ECD), hexagonality, and endothelial cell size coefficient of variation (ECCV). Corneal thickness was measured by noncontact pachimetry. PON1 and plasma TNFα concentrations were analyzed by ELISA. Serum PON1 activity was analyzed by spectrophotometry. Patients with COPD had significant decreases in ECD, hexagonality, and corneal thickness, and a significant increase in ECCV. They also had significant decreases in serum PON1 activity but not in PON1 concentration. Serum PON1 activity showed a significant direct association with ECD, and an inverse association with corneal thickness. Results of the present study suggest that PON1 may be involved in the pathophysiology of corneal endothelial alterations in patients with COPD.


Predictors of pregnancy and postpartum haemoglobin concentrations in low-income women.
Pregnancy and postpartum iron status is of great public health importance, yet few studies have examined predictors of haemoglobin (Hb) concentration during this time. We identified predictors of Hb from 24 weeks' gestation until delivery and from 4 to 25 weeks postpartum. Blood was drawn as many as four times during care: at the initial visit, at 24-29 weeks' gestation, at delivery and postpartum. A longitudinal, multivariable linear regression model was used to predict Hb concentration. A public health clinic in Raleigh, North Carolina. n=520 women who participated in the Iron Supplementation Study. Hb concentration at the previous blood draw, short stature, non-Hispanic white ethnicity/race, >12 years of education and smoking were positive predictors of pregnancy and postpartum Hb concentrations. Iron supplement use was a positive predictor, while inadequate weight gain and severe nausea/vomiting were negative predictors of gestational Hb. A high infant birth weight and postpartum haemorrhage were negative predictors of postpartum Hb. Pre-pregnancy body mass index had a slight positive relationship with gestational Hb, but had a strong negative relationship with postpartum Hb. The longitudinal model also confirmed the typical pattern of gestational Hb concentration. As the number of weeks between the initial visit and the 24- to 29-week visit increased, Hb at 24-29 weeks' gestation decreased. As gestational age increased from 24 weeks until delivery, Hb concentration increased as well. The predictors identified here could be used in clinical settings to target high-risk women for intervention.


Control of refractory ventricular tachycardia with biventricular assist devices.
A 65-year-old man developed incessant ventricular tachycardia following coronary artery bypass grafting while being weaned from cardiopulmonary bypass. The arrhythmia was refractory to procainamide, lidocaine, bretylium, and magnesium. Ventricular tachycardia subsided following reinitiation of cardiopulmonary bypass. Ultimately, the patient required ventricular assist devices to control his arrhythmia. This case is unique as the ventricular assist devices were used not for hemodynamic support, but for arrhythmia control. The mechanism of arrhythmia suppression may be related to contraction-excitation coupling.


Patterns of breathlessness and associated consulting behaviour: results of an online survey.
The online British Lung Foundation Breath Test provides an opportunity to study the relationship between breathlessness, common sociobehavioural risk factors and interaction with healthcare. We analysed data from 356 799 responders: 71% were ≥50 years old and 18% were smokers. 20% reported limiting breathlessness (Medical Research Council breathlessness score ≥3), and the majority of these (85%) worried about their breathing; of these, 29% had not sought medical advice. Of those who had, 58% reported that the advice received had not helped their breathlessness. Limiting breathlessness was associated with being older, physically inactive, smoking and a higher body mass index. These data suggest a considerable unmet need associated with breathlessness as well as possibilities for intervention.


Platelets in neutrophil recruitment to sites of inflammation.
This review describes the essential roles of platelets in neutrophil recruitment from the bloodstream into inflamed and infected tissues, with a focus on recent findings. Platelets are required for the recruitment of neutrophils to sites of inflammation and infection. They fulfil this role largely by enabling contacts of circulating neutrophils with the inflamed blood vessel wall prior to extravasation. Platelets promote both early stages of neutrophil recruitment (tethering, rolling, arrest, firm adhesion) and - as recent work has demonstrated - later stages (intravascular crawling and diapedesis). Recent studies have also begun to identify platelet-signaling pathways that can elicit the underlying interactions between platelets, neutrophils and vascular endothelial cells without stimulating concomitant platelet aggregation and thrombus formation. These pathways include Rho-guanine-nucleotide binding proteins and Rho-guanine-nucleotide exchange factors. Recent findings have contributed to our burgeoning understanding of the platelet-dependent mechanisms that control neutrophil recruitment to sites of inflammation and have opened up new avenues of research aimed at increasing our knowledge of these mechanisms further. These insights might lead to the development of novel anti-inflammatory drugs that will be useful in a wide range of inflammatory diseases without causing immunodeficiency.


The Function of Flavonoids in the Diurnal Rhythm under Rapidly Changing UV Conditions-A Model Study on Okra.
Flavonoids are favored compounds in plant responses to UV exposure and act in UV absorption and antioxidant activity. Here, it was investigated, with okra as a model species, how fast plants can react to changing UV conditions and to what extent these reactions take place. Okra (Abelmoschus esculentus) plants were exposed to either full or nearly no UV radiation. The diurnal rhythm of the plants was driven by the UV radiation and showed up to a 50% increase of the flavonoid content (measured optically in the +UV plants). This was reflected only in the trends in UV-absorption and antioxidant activity of the extracts but not in the soluble flavonoid glycosides and hydroxycinnamic acid derivatives. In a second experiment, a transfer from a -UV to a +UV condition at 9:00 CDT showed the immediate start of the diurnal rhythm, while this did not occur if the transfer occurred later in the day; these plants only started a diurnal rhythm the following day. After an adaptation period of seven days, clear differences between the +UV and -UV plants could be found in all parameters, whereas plants transferred to the opposite UV condition settle between the +UV and -UV plants in all parameters. Broadly, it can be seen that the flavonoid contents and associated functions in the plant are subject to considerable changes within one day and within several days due to the UV conditions and that this can have a considerable impact on the quality of plant foods.


Effect of palady and cup feeding on premature neonates' weight gain and reaching full oral feeding time interval.
Premature neonates' feeding is of great importance due to its effective role in their growth. These neonates should reach an independent oral nutrition stage before being discharged from the Neonatal Intensive care Unit. Therefore, the researcher decided to conduct a study on the effect of palady and cup feeding on premature neonates' weight gain and their reaching full oral feeding time interval. This is a clinical trial with a quantitative design conducted on 69 premature infants (gestational age between 29 and 32 weeks) who were assigned to cup (n = 34) and palady (n = 35) feeding groups through random allocation. The first feeding was administrated either by cup or palady method in each shift within seven sequential days (total of 21 cup and palady feedings). Then, the rest of feeding was administrated by gavage. Mean hospitalization time (cup = 39.01 and palady = 30.4; P < 0.001) and mean time interval to reach full oral feeding (cup = 33.7 and palady = 24.1; P < 0.001) were significantly lower in palady group compared to cup group. Mean weight changes of neonates 7 weeks after the intervention compared to those in the beginning of the intervention were significantly more in palady group compared to the cup group (cup = 146.7 and palady = 198.8; P < 0.001). The neonates in palady group reached full oral feeding earlier than those of cup group. Subjects' weight gain was also higher in palady group compared to the cup group. Premature neonates with over 30 weeks of gestational age and physiological stability can be fed by palady.


Impact of Low-Cost Point-of-Use Water Treatment Technologies on Enteric Infections and Growth among Children in Limpopo, South Africa.
Enteric infections early in life have been associated with poor linear growth among children in low-resource settings. Point-of-use water treatment technologies provide effective and low-cost solutions to reduce exposure to enteropathogens from drinking water, but it is unknown whether the use of these technologies translates to improvements in child growth. We conducted a community-based randomized controlled trial of two water treatment technologies to estimate their effects on child growth in Limpopo, South Africa. We randomized 404 households with a child younger than 3 years to receive a silver-impregnated ceramic water filter, a silver-impregnated ceramic tablet, a safe-storage water container alone, or no intervention, and these households were followed up quarterly for 2 years. We estimated the effects of the interventions on linear and ponderal growth, enteric infections assessed by quantitative molecular diagnostics, and diarrhea prevalence. The silver-impregnated ceramic water filters and tablets consistently achieved approximately 1.2 and 3 log reductions, respectively, in total coliform bacteria in drinking water samples. However, the filters and tablets were not associated with differences in height (height-for-age z-score differences compared with no intervention: 0.06, 95% CI: -0.29, 0.40, and 0.00, 95% CI: -0.35, 0.35, respectively). There were also no effects of the interventions on weight, diarrhea prevalence, or enteric infections. Despite their effectiveness in treating drinking water, the use of the silver-impregnated ceramic water filters and tablets did not reduce enteric infections or improve child growth. More transformative water, sanitation, and hygiene interventions that better prevent enteric infections are likely needed to improve long-term child growth outcomes.


High Dielectric Performance of Polyamide 66/Poly(Vinylidene Fluoride) Flexible Blends Induced by Interfacial Copolymer for Capacitors.
The copolymer VAMA was synthesized from vinyl acetic and maleic anhydride. A new all-polymeric blend with a high dielectric constant (ε) has been developed by blending polyvinylidene fluoride (PVDF) with vinyl acetic-maleic anhydride modified polyamide (PA66-g-VM). The blend shows high dielectric constants (εblend = 20) and excellent mechanical properties. The SEM investigations suggest that the enhanced dielectric behavior originates from significant interfacial interactions between polymers. The XRD demonstrates that the compatibilizer affects the crystalline behavior of each component. Furthermore, the stable dielectric constants of the all-polymeric blends can be tuned by adjusting the content of the compatibilizer. The created high-ε all-polymeric blends represent a novel type of material that is technologically simple, easy to process, and of a relatively high dielectric constant, with application for flexible electronics.


A general practice pilot audit study to assess advice and treatment offered to women following hysterectomy.
Current evidence suggests that information and treatment offered to women post-hysterectomy to prevent osteoporosis are poor. To pilot a general practice audit protocol, to assess its ability to identify hysterectomized women and to offer appropriate information on fracture prevention. A pilot audit study was designed to assess advice offered to hysterectomized women aged 25-64 years. Data on ovarian status were evaluated. Women were recalled for counselling if there was no evidence of advice on fracture prevention and if they were not taking hormone replacement therapy (HRT). Change in HRT usage was used as the outcome measure to assess the impact of the audit. Baseline data were collated for 5743 women. In 1456 (25%), both ovaries were removed and 4029 (70%) had one or both ovaries conserved; 258 (5%) had incomplete ovarian data. The average age at hysterectomy with both ovaries removed was 43.9 years, and with conservation of one or both ovaries was 40.5 years and 40.1 years, respectively. Some 2888 (50%) were ever-users of HRT (both ovaries removed 70%, one ovary removed 53%, both ovaries conserved 44%). A total of 2083 (36%) were known current users (both ovaries removed 53%, one ovary removed 40%, both ovaries conserved 30%). The mean duration of use in 2620 ever-users was 44 months. This was similar for all the women irrespective of ovarian status. Eighty per cent of those given HRT reported receiving some advice. Seventy-seven per cent of those not given HRT had not received advice. By the end of the audit, 424 had commenced HRT (20% increase). Current use rose to 44% (both ovaries removed 59%, one ovary conserved 46%, both ovaries conserved 39%). Sixty-three per cent of new users chose transdermal preparations. The mean age at hysterectomy of between 40.1 and 43.9 years indicates the potential for early ovarian failure. Use of HRT is associated with availability of counselling. Uptake was better than anticipated, but HRT usage was still well below optimum. This audit fulfills its objectives but not without cost implications. Year by year it should achieve significantly improved management and health of hysterectomized women, and improved standards of patient care.


Comparison of intraocular pressure lowering by topical and systemic carbonic anhydrase inhibitors in the rabbit.
We compared the effect on intraocular pressure (IOP) of maximal doses of a topical carbonic anhydrase inhibitor (CAI) at acidic and alkaline pH where it is maximally effective with full systemic CA inhibition in ocular normotensive New Zealand Albino rabbits. Tonometric IOP levels were measured hourly during 3 hour control period. Topical MK-417 (pKa 5.8, 8.3), a close congener of MK-507 (Dorzolamide) was given as a 1.4% solution at pH 4.5 (n=6) and pH 9.2 (n=6). MK-417 was instilled to the left eye with the right eye used as an untreated control. One hour later methazolamide was given intravenously at 10 mg/kg, a dose known to give full inhibition of the enzyme. Control IOP (mm Hg) was 19.12+/-0.50. One hour following MK-417, the left eye IOP was 13.40 +/-0.70 (pH 4.5) and 13.25+/-0.70 (pH 9.2). The right eye pressure was unchanged. Methazolamide injection at this time gave no further drop in the left eye IOP at either pH. IOP in the right eye fell to 14.00+/-0.70 so that 2 hours after methazolamide injection, the 2 eyes had the same pressure. In conclusion, topical CAI in sufficient dose and correct pH yields IOP lowering equivalent to a maximally effective dose of systemic CAI in rabbits.


Intra-familial distribution of nine putative periodontopathogens in dental plaque samples analyzed by PCR.
It is of great importance to understand the distribution of periodontopathogens within family members when considering the risk of periodontitis in children. The purpose of this study was to investigate the distribution of periodontopathogens among family members. We used the polymerase chain reaction method to test 4,8, and 7 probands with healthy gingiva, gingivitis, and periodontitis, respectively, and their 60 immediate family members. Plaque samples were collected from all erupted teeth sites using a sterile toothbrush. In 161 of the 165 positive cases, if a child harbored one of the periodontopathogens then at least one of the parents was also positive for the same bacterium. The prevalence of parent-child co-infection was 42.9% for Actinobacillus actinomycetemcomitans, 21.4% for Porphyromonas gingivalis, 29.2% for Treponema denticola, 59.5% for Tannerella forsythensis (Bacteroides forsythus) and 16.7% for Prevotella intermedia. Our results indicate that parents could be an important source of periodontopathogens for the colonization that occurs in their children.


[in-hospital mortality in patient with acute ischemic and hemorrhagic stroke].
There is a lack of evidence to compare in-hospital mortality with different types of stroke. The purpose of this study was to elucidate the in-hospital mortality after acute ischemic/hemorrhagic stroke and compare the factors associated with the mortality among stroke subtypes. All patients admitted to Kurashiki Central Hospital in Japan between January 2009 and December 2009, and diagnosed with acute ischemic/hemorrhagic stroke were included in this study. Demographics and clinical data pertaining to the patients were obtained from their medical records. Out of 738 patients who had an acute stroke, 53 (7.2%) died in the hospital. The in-hospital mortality was significantly lower in the cerebral infarction group than in the intracerebral hemorrhage and subarachnoid hemorrhage group (3.5%, 15.1%, and 17.9%, respectively; P<0.0001). Age was significantly lower in the subarachnoid hemorrhage group than in the other 2 groups. With regard to past history, diabetes mellitus was significantly found to be a complication in mortality cases of intracranial hemorrhage. Further investigation is needed to clarify the effect of diabetes on mortality after intracranial hemorrhage.


Nephrotoxicity of Calcineurin Inhibitors in Kidney Epithelial Cells is Independent of NFAT Signaling.
Background: Calcineurin inhibitors (CNIs) such as cyclosporine A and tacrolimus are commonly used after renal transplantation to suppress the immune system. In lymphoid cells, cyclosporine A acts via the calcineurin/nuclear factor of activated T-cell (NFAT) axis. In non-lymphoid cells, such as kidney epithelial cells, cyclosporine A induces calcineurin inhibitor toxicity. It is unknown via which off-targets cyclosporine A induces calcineurin inhibitor toxicity in kidney epithelial cells. Methods: To measure a compound's potential to induce nephrotoxicity, the expression of the surrogate marker Fn14 was measured by flow cytometry. Compounds were tested for their potential to induce Fn14 either chemically or plasmid-mediated. Mice were injected with various compounds, and changes in nephrotoxic gene expression levels of the kidney epithelial cells were then analyzed. Results: Fn14 is specifically upregulated due to calcineurin inhibitor toxicity inducing agents. Inhibition of the NFAT axis showed no increase of the Fn14 expression on the surface of kidney cells. However, inhibition of p38 MAPK, phosphoinositide-3-kinase (PI3K)/Akt, protein kinase C (PKC), and inhibitor of nuclear factor-κB (IκB) kinase (IKK) showed clear induction of Fn14 and increased expressions of nephrotoxic, inflammatory, and fibrotic genes in vitro and in vivo. Conclusions: These findings show that cyclosporine A acts independently of NFAT on kidney epithelial cells. Moreover, inhibition of serine/threonine protein kinases mimics cyclosporine A's activity on kidney epithelial cells. This mimicking effect indicates that these protein kinases are off-targets of cyclosporine A and damage structural renal cells when inhibited and therefore contributes likely to the development and progression of calcineurin inhibitor toxicity.


Graphene nanoribbon devices produced by oxidative unzipping of carbon nanotubes.
We demonstrate that graphene nanoribbons (GNRs), produced by the chemical unzipping of carbon nanotubes, can be conveniently used from solution to hand-paint unidirectional arrays of GNRs atop silicon oxide. Through this simple alignment technique, numerous GNR-based devices, including field effect transistors, sensors, and memories can be easily fabricated on a single chip, and then used to generate statistically relevant device assessments. Such studies immediately give insights into, for example, multilayering properties on conductance, the profound effects that atmospheric adsorbates have upon the transfer characteristics of graphene, and other phenomena affecting the performance of GNR devices.


A low-cost contact system to assess load displacement velocity in a resistance training machine.
This study sought to determine the validity of a new system for assessing the displacement and average velocity within machine-based resistance training exercise using the Chronojump System. The new design is based on a contact bar and a simple, low-cost mechanism that detects the conductivity of electrical potentials with a precision chronograph. This system allows coaches to assess velocity to control the strength training process. A validation study was performed by assessing the concentric phase parameters of a leg press exercise. Output time data from the Chronojump System in combination with the pre-established range of movement was compared with data from a position sensor connected to a Biopac System. A subset of 87 actions from 11 professional tennis players was recorded and, using the two methods, average velocity and displacement variables in the same action were compared. A t-test for dependent samples and a correlation analysis were undertaken. The r value derived from the correlation between the Biopac System and the contact Chronojump System was >0.94 for all measures of displacement and velocity on all loads (p < 0.01). The Effect Size (ES) was 0.18 in displacement and 0.14 in velocity and ranged from 0.09 to 0.31 and from 0.07 to 0.34, respectively. The magnitude of the difference between the two methods in all parameters and the correlation values provided certain evidence of validity of the Chronojump System to assess the average displacement velocity of loads in a resistance training machine. Key pointsThe assessment of speed in resistance machines is a valuable source of information for strength training.Many commercial systems used to assess velocity, power and force are expensive thereby preventing widespread use by coaches and athletes.The system is intended to be a low-cost device for assessing and controlling the velocity exerted on each repetition in any resistance training machine.The system could be easily adapted in any vertical displacement barbell exercise.


Serum ferritin levels in pill and IUD users.
12 women using a low-dose combination oral contraceptive (OC) and 17 wearing a copper IUD were studied. Serum ferritin concentrations were measured before and 1, 3, and 6 months after commencing contraception. Ferritin levels in the iron-deficient range (below 50 mcg/l) were present in 5 (42%) and in 8 (47%) subjects, respectively, prior to the start of OCs or IUD insertion. The OC use induced only a temporary decrease in serum ferritin levels at the start of treatment, whereas 12 of 17 (71%) IUD users had reached iron-deficient levels by the end of the follow-up period. Thus, the use of OCs had no adverse effect on iron balance, but the monitoring of iron status and the administration of iron-replacement therapy seem to be indicated in the majority of women fitted with an IUD.


Cardiotoxicity of Antineoplastic Therapies and Applications of Induced Pluripotent Stem Cell-Derived Cardiomyocytes.
The therapeutic landscape for the treatment of cancer has evolved significantly in recent decades, aided by the development of effective oncology drugs. However, many cancer drugs are often poorly tolerated by the body and in particular the cardiovascular system, causing adverse and sometimes fatal side effects that negate the chemotherapeutic benefits. The prevalence and severity of chemotherapy-induced cardiotoxicity warrants a deeper investigation of the mechanisms and implicating factors in this phenomenon, and a consolidation of scientific efforts to develop mitigating strategies. Aiding these efforts is the emergence of induced pluripotent stem cells (iPSCs) in recent years, which has allowed for the generation of iPSC-derived cardiomyocytes (iPSC-CMs): a human-based, patient-derived, and genetically variable platform that can be applied to the study of chemotherapy-induced cardiotoxicity and beyond. After surveying chemotherapy-induced cardiotoxicity and the associated chemotherapeutic agents, we discuss the use of iPSC-CMs in cardiotoxicity modeling, drug screening, and other potential applications. Improvements to the iPSC-CM platform, such as the development of more adult-like cardiomyocytes and ongoing advances in biotechnology, will only enhance the utility of iPSC-CMs in both basic science and clinical applications.


Common principles underlie the fluctuation of auditory and visual sustained attention.
Sustained attention plays an important role in adaptive behaviours in everyday activities. As previous studies have mostly focused on vision, and attentional resources have been thought to be specific to sensory modalities, it is still unclear how mechanisms of attentional fluctuations overlap between visual and auditory modalities. To reduce the effects of sudden stimulus onsets, we developed a new gradual-onset continuous performance task (gradCPT) in the auditory domain and compared dynamic fluctuation of sustained attention in vision and audition. In the auditory gradCPT, participants were instructed to listen to a stream of narrations and judge the gender of each narration. In the visual gradCPT, they were asked to observe a stream of scenery images and indicate whether the scene was a city or mountain. Our within-individual comparison revealed that auditory and visual attention are similar in terms of the false alarm rate and dynamic properties including fluctuation frequency. Absolute timescales of the fluctuation in the two modalities were comparable, notwithstanding the difference in stimulus onset asynchrony. The results suggest that fluctuations of visual and auditory attention are underpinned by common principles and support models with a more central, modality-general controller.


Disordered backgammon model.
In this paper we consider an exactly solvable model that displays glassy behavior at zero temperature due to entropic barriers. The new ingredient of the model is the existence of different energy scales or modes associated with different relaxational time scales. Low-temperature relaxation takes place by partial equilibration of successive lower-energy modes. An adiabatic scaling solution, defined in terms of a threshold energy scale epsilon*, is proposed. For such a solution, modes with energy epsilon>>epsilon* are equilibrated at the bath temperature, modes with epsilon<<epsilon* remain out of equilibrium, and relaxation occurs in the neighborhood of the threshold epsilon approximately epsilon*. The model is presented as a toy example to investigate the conditions related to the existence of an effective temperature in glassy systems and its possible dependence on the energy sector is probed by the corresponding observable.


Development of an in vivo animal model for skin penetration in hairless rats assessed by mass balance.
The aim of the study was to develop an in vivo animal model for studies of the penetration of topically applied drugs into the skin of hairless rats. Protective appliances were designed for non-occluded and finite-dose application of topical formulations. The design allowed 2 test sites for each rat and free mobility throughout the test period. By consecutive tape stripping, monitored by measurements of transepidermal water loss and confirmed by histological examination of skin biopsies, 10 tape strippings were found to remove the stratum corneum completely. For assessment of the model, (14)C-salicylic acid and (14)C-butyl salicylate were topically applied. Rapid and differentiated percutaneous absorption of both compounds were shown by urinary excretion data. For (14)C-salicylic acid the amount on the skin surface, in the stratum corneum and in the viable skin was determined. Total mass balance on the applied radioactivity was performed and a recovery of 90 +/- 2% was achieved. The radioactivity found in the protective appliances (<10%) was explained by lateral skin diffusion of the model compounds into the dressings.


Arthroscopic treatment of pigmented villonodular synovitis involving bilateral shoulders.
Pigmented villonodular synovitis (PVNS) is a lesion of benign proliferative synovium that invades joint, tendon sheath, and bursa. It mainly occurs in 1 joint, the knee joint or hand, and multi-joint invasion is reported to be <1%. Rare cases have been reported of PVNS occurring in the shoulder joint. Generally, total synovectomy is a standard treatment of PVNS. However, complete synovectomy is sometimes impossible because of difficulty of visualization and access to the whole joint and subacromial space. Therefore, recurrence of the disease is always of concern. This article presents a case of 64-year-old patient with pain and swelling of bilateral shoulder joints of 4 months' duration. Physical examination showed atrophy of the deltoid and infraspinatus and a mass-like protrusion on the anterior portion of left shoulder. Active forward elevation was limited to 30 degrees on the right and 90 degrees on the left. Overall synovial hyperplasia and nodular mass was observed on magnetic resonance imaging. Massive rotator cuff tear and invasion of the lesion toward the subacromial space and deltoid muscle was noted as well. Arthroscopic examination revealed a typical finding of PVNS: yellowish brown pigmentation over the overall joint capsule and subacromial space. Arthroscopic total synovectomy without rotator cuff repair was performed for both shoulders. Clinical outcomes showed good pain relief and no recurrence of the disease, although range of motion and muscle strength was not significantly improved, possibly due to accompanied massive rotator cuff tear. Arthroscopic total synovectomy in the treatment of PVNS of the shoulder joint is a minimally invasive and effective method, which makes it possible to access the whole joint space and subacromial space.


Cardiovascular effects of bevantolol, a selective beta 1-adrenoceptor antagonist with a novel pharmacological profile.
Bevantolol was more potent in blocking the chronotropic than the hypotensive effects of isoprenaline in pithed rats. Bevantolol itself induced bradycardia, so that it was not possible to estimate the pA2 from nonparallel dose-response curves relating isoprenaline concentration to tachycardia. Bevantolol caused hypertension in pithed rats, an effect attenuated by phentolamine, implying that bevantolol may be an alpha-adrenoceptor agonist. Bevantolol potentiated the pressor effects of noradrenaline, the maximum potentiation equalling that produced by prior chemical sympathectomy with guanethidine, implying that bevantolol may block noradrenaline uptake. In isolated atria bevantolol-induced bradycardia was associated with a positive shift in take-off potential, a reduction in the maximum rate of depolarization (Vmax), and a lengthening of action potential duration (APD). No change in the slope of the slow diastolic depolarization occurred except at the highest concentration (18 mumol l(-1). In atrial and ventricular muscle bevantolol reduced Vmax and overshoot potential, implying reduction of fast inward sodium current (Class I antiarrhythmic action). In pithed rats bevantolol lengthened the P-R interval in the ECG, and produced atrioventricular (A-V) block, and bundle-branch block. In isolated A-V nodal preparations, intranodal conduction time was greatly increased, implying restriction of inward current through calcium channels responsible for nodal depolarization. Bevantolol had no negative inotropic effect in pithed rats, or in isolated atria, and did not alter the positive inotropic effect of raised extracellular calcium concentration, implying absence of restriction of current through calcium channels controlling contraction of the myocardium.


Responsiveness of the Multiple Sclerosis International Quality of Life questionnaire to disability change: a longitudinal study.
Responsiveness, defined as the ability to detect a meaningful change, is a core psychometric property of an instrument measuring quality of life (QoL) rarely reported in multiple sclerosis (MS) studies. To assess the responsiveness of the Multiple Sclerosis International Quality of Life (MusiQoL) questionnaire to change in disability over 24 months, defined by change in the Expanded Disability Status Scale (EDSS) score. Patients with MS were enrolled into a multicenter, longitudinal observational study. QoL was assessed using both the MusiQoL and the 36-Item Short-Form (SF-36) instruments at baseline and every 6 months thereafter up to month 24; neurological assessments, including EDSS score, were performed at each evaluation. The 24-month EDSS was available for 524 patients. In the 107 worsened patients, two specific dimensions of MusiQoL, the sentimental and sexual life and the relationships with health care system dimensions, and 'physical' scores of SF-36 showed responsiveness. Whereas specific dimensions of MusiQoL identified EDSS changes, the MusiQoL index did not detect disability changes in worsened MS patients in a 24-month observational study. Future responsiveness validation studies should include longer follow-up and more representative samples.


Enhanced thermodynamic and kinetic stability of calix[4]arene dimers locked in the cone conformation.
Wide rim tetraurea derivatives (2a,b) have been prepared from a calix[4]arene rigidified in the cone conformation by two diethyleneglycol ether bridges between adjacent oxygens. In comparison to the analogous tetraurea derivatives (3a,b) of a tetrapentoxy calix[4]arene, 2a,b show an increased thermodynamic stability in mixtures of CDCl(3) and DMSO-d(6). Their kinetic stability as expressed by the rate of guest exchange (benzene or cyclohexane against the solvent benzene-d(6)) is also strongly increased by factors of 30-38. Noticeable differences for the inclusion of selected guests are found.


Electromagnetic field standards in Central and Eastern European countries: current state and stipulations for international harmonization.
Electromagnetic field standards in the West are based on well-established acute biological effects that could be considered as signaling a potentially adverse health effect. The specific absorption rate, which is proportional to the tissue heating (thermal effects), represents the basic restriction of exposure to Radio-Frequency (RF) fields. On the other hand, Eastern European standards are designed to protect from potential non-thermal effects that might be caused by chronic exposure to very low intensities, where a so-called "power load" (a product of field intensity and duration of exposure) represents the basic limitation. Thus, electromagnetic field standards in Eastern European countries differ considerably from those which are proposed by the International Commission of Non-ionizing Radiation Protection and the Standards Coordinating Committee 28 of the Institute of Electrical and Electronics Engineers, Inc. In the present paper, the strategies for development of exposure limit values in electromagnetic fields standards currently in force in Eastern and Central European countries are discussed. Some differences as well as similarities of the national health and safety standards and the main obstacles to harmonization of these standards with those being established by Western national and international organizations and agencies are presented.


Electroclinical features of absence seizures in childhood absence epilepsy.
To accurately define the electroclinical features of absence seizures in children with newly diagnosed, untreated childhood absence epilepsy (CAE). The authors searched an EEG database for absence seizures in normal children with new onset untreated absence epilepsy. Seventy consecutive children were classified into IGE syndromes. The clinical and EEG features of the seizures in the children with CAE were analyzed using video-EEG recordings. The authors analyzed 339 absence seizures in 47 children with CAE. The average seizure duration was 9.4 seconds and clinical features consisted of arrest of activity, loss of awareness, staring, and 3-Hz eyelid movements, but there was individual variation. Ictal EEG predominantly showed regular 3-Hz generalized spike and wave (GSW) with one or two spikes per wave; however, disorganization of discharges was common and three or more spikes per wave occurred rarely. Postictal slowing was frequent. Interictal abnormalities included fragments of GSW, posterior bilateral delta activity, and focal discharges. Although all 47 children met the current criteria for CAE, only 5 fulfilled the recently proposed criteria for CAE. The heterogeneous nature of each clinical and EEG feature of untreated absence seizures is of critical importance when determining criteria for childhood absence epilepsy.


Evaluation of WLBU2 peptide and 3-O-octyl-sn-glycerol lipid as active ingredients for a topical microbicide formulation targeting Chlamydia trachomatis.
Topical microbicides for prevention of sexually transmitted diseases (STDs) would be especially useful for women who are not able to persuade their partner(s) to take precautions. Many topical microbicides are in various stages of development, based on a variety of active ingredients. We investigated the in vitro activity of an engineered antimicrobial peptide (WLBU2) and a lipid (3-O-octyl-sn-glycerol [3-OG]) which could potentially be used as active ingredients in such a product. Using commercially available cytotoxicity reagents [Alamar Blue, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT), and lactate dehydrogenase (LDH)], we first determined the toxicity of WLBU2 and 3-OG to the host cells in our assay procedure and excluded toxic concentrations from further testing. To determine activity against Chlamydia trachomatis, we used an assay previously developed by our laboratory in which chlamydial elementary bodies (EBs) were exposed to microbicides prior to contact with epithelial cells: the minimum (microbi)cidal concentration (MCC) assay. To further simulate conditions of transmission, we carried out the same assay in the presence of a simulated vaginal fluid, a simulated seminal fluid, human serum albumin, and a range of pH values which might be found in the human vagina at the time of exposure. Last, we tested WLBU2 and 3-OG in combination to determine if adding them together resulted in synergistic activity. We found that WLBU2 and 3-OG both have excellent activity in vitro against C. trachomatis and significantly more activity when added together. The simulated fluids reduced activity, but the synergy seen is good evidence that they would be effective when combined in a microbicide formulation.


Targeting Brain Tumors with Mesenchymal Stem Cells in the Experimental Model of the Orthotopic Glioblastoma in Rats.
Despite multimodal approaches for the treatment of multiforme glioblastoma (GBM) advances in outcome have been very modest indicating the necessity of novel diagnostic and therapeutic strategies. Currently, mesenchymal stem cells (MSCs) represent a promising platform for cell-based cancer therapies because of their tumor-tropism, low immunogenicity, easy accessibility, isolation procedure, and culturing. In the present study, we assessed the tumor-tropism and biodistribution of the superparamagnetic iron oxide nanoparticle (SPION)-labeled MSCs in the orthotopic model of C6 glioblastoma in Wistar rats. As shown in in vitro studies employing confocal microscopy, high-content quantitative image cytometer, and xCelligence system MSCs exhibit a high migratory capacity towards C6 glioblastoma cells. Intravenous administration of SPION-labeled MSCs in vivo resulted in intratumoral accumulation of the tagged cells in the tumor tissues that in turn significantly enhanced the contrast of the tumor when high-field magnetic resonance imaging was performed. Subsequent biodistribution studies employing highly sensitive nonlinear magnetic response measurements (NLR-M2) supported by histological analysis confirm the retention of MSCs in the glioblastoma. In conclusion, MSCs due to their tumor-tropism could be employed as a drug-delivery platform for future theranostic approaches.


SDF-1 promotes ox-LDL induced vascular smooth muscle cell proliferation.
The mechanism of the regulatory roles of stromal cell derived factor-1 (SDF-1)/C-X-C motif receptor 4 (CXCR4) on cell proliferation and apoptosis in vascular smooth muscle cells (VSMCs) via the protein kinase C (PKC) and nuclear factor-kappa B (NF-κB) signalling pathways have been investigated. Rat aortic VSMCs were treated with control or an oxidised low-density lipoprotein (ox-LDL) atherosclerosis (AS) model. Cells exposed to the AS model were treated with SDF-1 plus inhibitors specific for PKC (Ro31-8220), CXCR4 (12G5) or NF-κB (pyrrolidine dithiocarbamate, PDTC). Cell proliferation was measured with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and apoptosis by flow cytometry. NF-κB protein expression was analysed using Western blotting. The proliferation rate in the AS model group was significantly higher than the control group, but lower than the SDF-1 group (P < 0.05). Apoptosis in the AS model group (ox-LDL) was significantly higher than the normal control group (P < 0.05). In addition, the apoptosis rate in the SDF-1 group was significantly lower than the normal control group (P < 0.05); however, there was no difference from the Ro31-8220 group. NF-κB protein expression in the SDF-1 group was significantly higher than the AS model (ox-LDL) group (P < 0.05). In conclusion, SDF-1 can promote the proliferation of VSMCs induced by ox-LDL and inhibit cell apoptosis, via the SDF-1/CXCR4 axis.


Sense of belonging in secondary schools: a survey of LGB and heterosexual students in Flanders.
This study focuses on differences in sense of belonging between lesbian, gay, and bisexual (LGB) and heterosexual students. Data from 1,745 secondary school students were collected with an online survey. Step-wise multiple regression analyses was used to investigate the relationship between sexual orientation and sense of school belonging. The results show that sexual orientation has an impact on sense of belonging for girls, but not for boys. Perceived discrimination and LGB friendliness of the school appeared to be important indicators of sense of belonging for all the respondents, irrespective of their sexual orientation.


2E4/Kaptin (KPTN)--a candidate gene for the hearing loss locus, DFNA4.
Stereocilia of the inner ear play an integral role in the mechanotransduction of sound. Their structural support is derived from actin filaments and actin-binding proteins. We have identified a novel actin-binding protein, 2E4-kaptin (KPTN), which appears to be involved in this structural network. Using double label immunofluorescence, we now show that KPTN extends beyond the barbed ends of actin filaments at the tips of stereocilia, and using cloned human cDNA, we mapped KPTN to chromosome 19q13.4. A combination of FISH, radiation hybrid mapping and YAC screening localized KPTN between markers D19S412 and NIB1805, making this gene an excellent functional and positional candidate for DFNA4, a form of autosomal dominant non-syndromic hearing loss. We identified a second family with inherited deafness that also maps to the DFNA4 region. To screen KPTN for deafness-causing mutations, we first determined its genomic structure and then completed a mutational analysis by direct sequencing and SSCP in affected family members. Although no deafness-causing mutations were identified in the coding region, KPTN remains an excellent candidate gene for hearing loss; by synteny, its murine orthologue also remains a candidate gene for the Nijmegan waltzer (nv) mouse mutant, which has vestibular defects and a variable sensorineural hearing loss.


Methods and errors in measurements of synovial fluid volume in stifles with low volume and high viscosity synovial fluid. An experimental study in goats.
Synovial fluid (SF) volume was calculated using various methods in the stifles of goats, in which the cranial cruciate ligament had been transected on one side. Measurements were performed prior to surgery and again 4, 8, and 18 weeks following surgery, by measuring the dilution of an injected radioactive tracer diluted by the SF. Later, 7 months following surgery, SF volume measurements using simple arthrocentesis were performed on stifles in 9 of the goats, and the SF that could not be aspirated, was calculated using 2 indirect methods simultaneously on identical fluids in 3 of these goats. SF was also collected directly during staged arthrotomy of the stifles in 4 goats. There were conflicting results between methods, but the resulting calculated SF volumes seemed to be larger in the operated stifles compared to the controls for all the methods at about the same degree. The 2 indirect methods used to calculate the fluid remaining in the joints following arthrocentesis gave disparate volume calculations. The experiments revealed sources of error in all methods. Direct methods failed to acquire the total fluid volume, and indirect methods were subject to improper mixing and escape of the injected fluid or synovial fluid or both. It was concluded that none of the methods could be used to measure the "true" volume of SF, if such a concept exists and can be defined. None of the methods were considered reliable to compare volumes in different type of joints containing this type of fluid. It was, however, concluded that all the methods gave indication of increased SF volume present on a relative basis when paired joints were compared.


A ventricular thrombus mimicking a tumour.
Primary cardiac tumours are a rare occurrence in clinical practice. Mural or pedunculated thrombi are other infrequent findings. These are usually associated with underlying heart disease, present in the left atrium or occupying aneurysms in the ventricular wall, usually the apex. The case of a 33-year-old woman with a pedunculated cardiac mass not having these latter characteristics is reported. She had experienced dyspnoea and lower extremity oedema for 3 years on referral. Echocardiography revealed a mass emerging from the interventricular septum, and a myxoma was suspected. Heart surgery was performed and the findings were a thrombus and large extent of septal and apical mural fibrosis. An endoaneurysmorraphy was performed with exclusion of fibrotic walls from the ventricular cavity.


Group meetings of caretakers of patients with schizophrenia and bipolar mood disorders.
In India, there is a paucity of trained professionals to execute psychosocial interventions. Families are thus assigned the role of primary caretakers of individuals with chronic mental illness. To assess the perceived benefits and difficulties of group meetings among caregivers of persons with schizophrenia and bipolar mood disorders, and to evaluate the utilization pattern of general hospital psychiatric unit (GHPU) services by caregivers who regularly attend such group meetings. Persons with schizophrenia and those with bipolar mood disorders with associated psychosocial problems and on maintenance medication were identified at the Psychiatric Rehabilitation Unit of the Department of Psychiatry, Father Muller Medical College. Significant caregivers of the identified patients were informed about the group meeting. Group meetings were conducted for about 45 minutes once a month for caregivers of patients with schizophrenia and bipolar mood disorders. Data regarding the psychosocial aspects of caregivers were collected before entry to the meeting and after 17 months of their participation. Participants who attended the meetings irregularly were excluded from the study. The group meetings led to effective monitoring of the functioning of individuals, a reduction in the subjective family burden and family distress, a better support system with adequate coping skills and good compliance with treatment programmes. Conducting regular group meetings for a homogeneous population at a GHPU is feasible and beneficial.


Nurses and nurse assistants' experiences with using a design thinking approach to innovation in a nursing home.
The aim of this study was to evaluate nurses' and nurse assistants' experiences with a design thinking approach to innovation used in a nursing home in Norway. A design thinking approach to innovation that focuses on users' needs can be employed to address many of the challenges facing health care providers in a field facing a growing ageing population, complex diseases and financial shortfalls. This study is based on a thematic analysis of four focus group interviews with nurses and nurse assistants (n = 23). In the initial phase of developing the new service model, which included defining staff roles and responsibilities, participating nurses and nurse assistants felt engaged and motivated by the designers' inclusive and creative methods. However, during the new model's testing phase, they were critical of management's lack of involvement in the model`s implementation and therefore became less motivated about the project. The findings of the study highlight the importance of the designers cooperating with management and staff for the duration of the innovation process. Challenging innovation processes require strong managers who engage with designers, patients, staff and volunteers throughout all phases of an innovation process using a design thinking approach.


Description of an approach based on maximum likelihood to adjust an excess hazard model with a random effect.
To adjust an excess hazard regression model with a random effect associated with a geographical level, the Département in France, and compare its parameter estimates with those obtained using a "fixed-effect" excess hazard regression model. An excess hazard regression model with a piecewise constant baseline hazard was used and a normal distribution was assumed for the random effect. Likelihood maximization was performed using a numerical integration technique, the Quadrature of Gauss-Hermite. Results were obtained with colon-rectum and thyroid cancer data from the French network of cancer registries. The results were in agreement with what was theoretically expected. We showed a greater heterogeneity of the excess hazard in thyroid cancers than in colon-rectum cancers. The hazard ratios for the covariates as estimated with the mixed-effect model were close to those obtained with the fixed-effect model. However, unlike the fixed-effect model, the mixed-effect model allowed the analysis of data with a large number of clusters. The shrinkage estimator associated with Département is an optimal measure of Département-specific excess risk of death and the variance of the random effect gave information on the within-cluster correlation. An excess hazard regression model with random effect can be used for estimating variation in the risk of death due to cancer between many clusters of small sizes.


Waste not, want not: the use of AlloDerm in secondary rhinoplasty.
This article describes the author's successful experience with AlloDerm onlay grafts for the correction of nasal contour deformities in secondary rhinoplasty. AlloDerm is a cadaver dermal filler graft, an off-the-shelf product that is readily available, pliable, and affordable. It is particularly suited for secondary rhinoplasty patients who are graft-depleted. The maximum dorsal augmentation is less than or equal to 3 mm; it is not a support graft. The major indication in this study was dorsal augmentation in the overresected secondary rhinoplasty patient to create a soft, smooth bridge and pleasing dorsal aesthetic lines. Twenty-five secondary rhinoplasty patients underwent multiple nasal corrections and were followed for 2 to 8 years. Analysis demonstrated no contour changes between year 1 and year 2, showing the dermal grafts to be stable after 1 year. Long-term follow-up for 2 years or longer showed good results, although partial graft resorption (defined to be < or = 50 percent) occurred in 45 percent of patients. Resorption was most common over the bony dorsum, with approximately 20 to 30 percent of the graft absorbing; over the tip, approximately 10 to 15 percent of the graft absorbed. Absorption did not seem to relate to the number of layers used. AlloDerm does not shift. Overall, the experience for nasal augmentation in secondary rhinoplasty was encouraging. Partial absorption, especially over the bony dorsum in a thin-skinned patient, is a definite disadvantage. Complete absorption was not seen in this study. The author has discovered that it is imperative to overcorrect the defect intraoperatively. Regrafting is possible and sometimes necessary.


How to conduct an effective literature search.
The ability to describe and analyse published literature on a topic and develop discussion and argument is central to evidence-based patient care. A literature review is an assessment procedure that is commonly applied in nursing settings. Effective literature searching is a crucial stage in the process of writing a literature review, the significance of which is often overlooked. Although many current textbooks refer to the subject, information is often of insufficient depth to guide an effective search. This article outlines important considerations in the search strategy and recommends practical advice for students to ensure best use of their valuable time. It is suggested that a systematic, organised search of the literature, that uses available resources effectively, is more likely to produce quality work.


Dermatofibrosarcoma protuberans of the scalp with fibrosarcomatous degeneration and pulmonary metastasis.
Dermatofibrosarcoma protuberans is a rare locally aggressive cutaneous tumor of intermediate malignancy. It is a slow-growing neoplasm with a marked propensity to recur after resection. Head and neck involvement is unusual and distant metastases are quite rare but tend to be more frequent in tumors that undergo fibrosarcomatous degeneration. We present the imaging and corresponding histopathology in a case of dermatofibrosarcoma protuberans of the scalp demonstrating fibrosarcomatous degeneration and lung metastasis.


Improving safe street-crossing behaviors among primary school students: a randomized controlled trial.
Background: Child pedestrian injury is a global public health concern. Our aim in the present study was to investigate the effects of active learning-based educational intervention on street-crossing behavior among male primary school students in Mehriz county, Iran. Methods: In this randomized controlled trial, 90 first grade elementary school students(experiment = 50, control group = 48) participated. The "ASSURE Model" was applied to design the template of this active learning-based educational program, which was implemented for the experiment group in eight sessions. Behaviors of the students about ''looking for vehicles on the street'', "being cautious of dangers'' and ''crossing from safe places'' were observed and documented in actual traffic environments before, 1 week, and 6 months after intervention. Results: One week and 6 months after the intervention, the experiment group's performance in all 3 behaviors were significantly improved (P < 0.001). Distraction-adjusted differences in the mean scores of behaviors between the experiment (Mean = 2.62) and control (Mean = 3.19)groups before and 6 months after intervention (Mean in experiment groups = 6.3, Mean in control group = 4.24) were also statistically significant (P < 0.001). Conclusion: Our educational intervention was found to be helpful in promoting the street crossing behaviors of primary school-aged children. School healthcare professionals may apply active learning education as the core category of their interventional programs to promote street-crossing behaviors among primary school students.


Location-Specific Spectral and Thermal Effects in Tracking and Fixed Tilt Photovoltaic Systems.
The efficiency of photovoltaic modules in the field is generally lower than the efficiency under standard testing conditions due to temperature and spectral effects. Using the latest spectral dataset available from the National Solar Radiation Database, we report spectral correction factors ranging from -2% to 1.3% of the produced energy for silicon modules depending on location and collector geometry. We find that spectral effects favor trackers if silicon modules are used, but favor a fixed tilt instead if perovskites or CdTe are used. In high-irradiance locations, the energy yield advantage of silicon-based trackers is underestimated by 0.4% if spectral sensitivity effects are neglected. As the photovoltaic market grows to a multi-terawatt size, these seemingly small effects are expected to have an economic impact equivalent to tens of billions of dollars in the next few decades, far outweighting the cost of the required research effort.


A cluster of four transfer RNA genes in mosquito mitochondrial DNA.
We have sequenced a 342 base-pair segment of mosquito (Aëdes albopictus) mitochondrial DNA. This segment contains genes corresponding to two of the more unusual of the mosquito mitochondrial tRNAs that we sequenced earlier, tRNAargUCG and tRNAserGCU, as well as genes for tRNAalaUGC and tRNAasnGUU and a portion of a gene that is homologous to mammalian mitochondrial unidentified reading frame 3. There are differences in gene order and directions of transcription between the mosquito mitochondrial sequence on the one hand, and corresponding Drosophila and mammalian mitochondrial sequences on the other, that indicate the occurrence of multiple discrete transpositional events during mitochondrial DNA evolution.


Multilocus genotyping indicates that the ability to invade the bloodstream is widespread among Candida albicans isolates.
Multilocus genotyping was used to compare populations of Candida albicans from oral mucosa and blood. No significant differences in allele frequencies between the two samples were detected, and in a dendrogram of genotypic similarities, genotypes from both types of samples were finely interspersed. This is evidence for widespread distribution of invasive potential.


Estimates of the effects of a statewide sealant initiative on dentists' knowledge and attitudes.
The effects of a statewide initiative promoting the use of dental sealants were evaluated by assessing dentists' knowledge and attitudes before the initiative and 18 months later. Immediate changes also were determined for participants in continuing education (CE) sessions, a principal component of the initiative. Results of these assessments indicate that minor improvements in knowledge and attitudes occurred, that the effects were stronger but still modest for those dentists who participated in CE sessions, and that respondents believed the initiative had resulted in increased use of sealants. This evaluation highlights the need for controlled assessments of the effectiveness of future promotional campaigns.


Various forms of depression.
The current subtyping of depression is based on the Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision (DSM-IV-TR) categorical division of bipolar and depressive disorders. Current evidence, however, supports a dimensional approach to depression, as a continuum/spectrum of overlapping disorders, ranging from bipolar I depression to major depressive disorder. Types of depression which have recently been the focus of most research will be reviewed: bipolar II depression, mixed depression, agitated depression, atypical depression, melancholic depression, recurrent brief depression, minor depressive disorder, seasonal depression, and dysthymic disorder. Most research has focused on bipolar II depression, mixed depression (defined by depression and superimposed manic/hypomanic symptoms), and atypical depression. Mixed depression, by its combination of opposite polarity symptoms, has been found to be common by systematic probing for co-occurring manic/hypomanic symptoms. Mixed depression is a treatment challenge for clinicians, because antidepressants alone (ie, not protected by mood-stabilizing agents) may worsen its manic/hypomanic symptoms, such as irritability and psychomotor agitation, which the Food and Drug Administration (FDA) has listed as possible precursors to suicidality.


Transient silencing of Npr3 gene expression improved the circulatory levels of atrial natriuretic peptides and attenuated β-adrenoceptor activation- induced cardiac hypertrophic growth in experimental rats.
Natriuretic peptide receptor-C (NPR-C) is considered as a clearance receptor that maintains the circulatory levels of natriuretic peptides. It has been suggested that augmented expression of NPR-C as a cause for the diminished anti-hypertrophic action of natriuretic peptides in the failing heart. Hence, we sought to determine the level of Npr3 gene (coding for NPR-C) expression in the Isoproterenol (ISO) treated Wistar rats. In addition, we studied the effect of Npr3 gene silencing on the hypertrophic growth. A significant increase in heart weight-to-body weight ratio (HW/BW-24%,P<0.01), an indicator of cardiac hypertrophic growth was observed in the ISO (10mg/kg BW/day,i.p for 7 days) treated rats. As expected, the cardiac NPR-C protein expression was significantly increased by 4 fold as compared to control rats. In parallel, the circulatory atrial natriuretic peptide (ANP) level was significantly decreased (2 fold) in ISO treated rats. Upon treatment with siRNA-Npr3, a significant decrease in the cardiac NPR-C protein expression (70%,P<0.01), HW/BW ratio (70%,P<0.01) and hypertrophic marker genes (α-Sk, β-MHC, c-fos, P<0.01, respectively) mRNA expression were observed. Interestingly, the circulatory ANP level was increased by 1.5 fold in the siRNA-Npr3 treated rats as compared to ISO treated rats. Moreover, the cardiac collagen content, matrixmetalloprotinases-2 (MMP-2) and enzymatic antioxidant status (P<0.01, respectively) were found to be restored back to near normal upon siRNA-Npr3 treatment. Taken together, the results of this study indicates that specific down-regulation of Npr3 gene improves the circulatory levels of ANP and antioxidant system and there by attenuates the β-adrenoceptor over-activation mediated cardiac hypertrophic growth in experimental rats.


Drug-induced exanthem following dabigatran.
To report an incident of a drug-induced exanthem during treatment with dabigatran in a patient without prior exposure to the drug. A 20-year-old white male was prescribed oral dabigatran 150 mg twice daily for thromboembolic prevention because of nonvalvular atrial fibrillation. After 2 weeks of dabigatran therapy, a raised, pruritic, erythematous rash developed on the patient's inner thigh and forearm. Upon discontinuation of dabigatran and initiation of oral corticosteroid treatment, the rash resolved. Dabigatran therapy was not readministered and thromboembolic prevention therapy with warfarin was instituted. The clinical evidence for efficacy of dabigatran was derived largely from the RE-LY trial, which provided an open-label comparison with warfarin for the reduction of stroke and systemic embolism in nonvalvular atrial fibrillation. The most frequent adverse reactions leading to discontinuation of dabigatran were bleeding and gastrointestinal events. In the RE-LY study, drug hyper-sensitivity, allergic edema, anaphylactic reaction, and anaphylactic shock were reported in <0.1% of patients receiving dabigatran. Despite the low incidence of hypersensitivity reported in the RE-LY trial, the use of the Naranjo probability scale indicated a probable relationship between the rash and dabigatran therapy in this patient. Upon initiation of dabigatran therapy, surveillance for hyper-sensitivity reactions should be included as part of routine drug monitoring.


Evaluation of diagnostic procedures in Swedish patients with schizophrenia and related psychoses.
We aimed to estimate the value of structured interviews, medical records and Swedish register diagnoses for assessing lifetime diagnosis of patients with schizophrenia. Psychiatric records and diagnostic interviews of 143 Swedish patients diagnosed by their treating physician with schizophrenia and related disorders were scrutinized. Based on record analysis only, or a combined record and interview analysis, DSM-IV diagnoses were obtained by the OPCRIT algorithm. Independent of the OPCRIT algorithm, a standard research DSM-IV diagnosis, based on both record and interview analysis, was given by the research psychiatrist. Concordance rates for the different psychosis diagnoses were calculated. DSM-IV diagnoses based on records only, showed a good to excellent agreement with diagnoses based on records and interviews. Swedish register diagnoses displayed generally poor agreement with the research diagnoses. Nevertheless, 94% of subjects sometimes registered with a diagnosis of schizophrenic psychoses (i.e. schizophrenia, schizoaffective psychosis or schizophreniform disorder) displayed a standard research DSM-IV diagnosis of these disorders. For patients in long-term treatment for schizophrenia in Sweden, psychiatric record reviews should be optimal, cost effective and sufficient for assessment of lifetime research diagnoses of schizophrenia. For these patients a research interview adds little new information. The results further indicate that a Swedish register diagnosis of schizophrenic psychoses has a high positive predictive power to a standard research DSM-IV diagnosis of the disorders. It is concluded that for future Swedish large-scale genetic studies focusing on a broad definition of schizophrenia, it would be sufficient to rely on the Swedish register diagnoses of schizophrenic psychosis.


Treatment Changes in General Practice Patients With Chronic Mental Disorders Following a Psychiatric-Psychosomatic Consultation.
To determine whether a psychiatric-psychosomatic consultation can identify unmet treatment needs and improve treatment of patients with mental disorders in general practice. In 40 primary care practices, 307 consecutive primary patients who met criteria for chronic mental disorders were assessed by a psychiatric-psychosomatic consultant. After random assignment, general practitioners (GPs) were informed for half of the patients about the results of the assessment and received recommendations on how to improve treatment. Changes in treatment and patient status were reevaluated after 6 months. Patients were mostly having depression, adjustment, or anxiety disorders, with 28.8% on sick leave. Contact with their respective GPs was longer than a year in 77.2% of cases. Patients had already received pharmacotherapy (60.9%), psychotherapeutic counseling by GPs themselves (27.7%), psychotherapy by specialists (73.9%), psychiatric outpatient care (57%), inpatient psychiatric treatment (12.1%), inpatient psychosomatic rehabilitation (ie, specialized behavioral medicine facilities for patients with work problems; 41.4%), and a broad spectrum of other diagnostic and therapeutic measures. Newly recommended interventions included leisure activities (42%), a new specialist psychotherapy (37.5%), or inpatient psychosomatic treatment (15.3%). Most recommendations were agreed upon by the GP. Nevertheless, there was only a limited increase in therapeutic actions 6 months later, and no statistically significant improvement in the status of patients. General practitioners undertake a broad spectrum of therapeutic interventions in patients with chronic mental disorders. According to our results, additional psychiatric-psychosomatic consultations can intensify treatment but does not significantly change the general course of chronic mental disorders.


Optical immunosensors.
The development of biochemical detection systems that use antibodies as the recognition element, also known as immunosensors, has generated considerable interest from science and industry alike. This is due to the practically inexhaustible number of applications for which such a technology could conceivable lend itself, such as medicine, process control, and environmental monitoring. The potentially high sensitivity of such systems makes them ideal for situations where the utmost speed and accuracy are demanded. Moreover, there is theoretically no limit to the chemical and biological moieties for which an immunosensor can be manufactured. This critical review emphasizes both the biological and transduction aspects of optical immunosensors. The basic concepts of antibody-antigen interactions in solution are reviewed, and factors affecting the kinetics at the solid-liquid interface are characterized. In addition, the aspects of reagent immobilization, inherent to immunosensor design, are discussed. Finally, a comprehensive overview describing the mechanisms, advantages, and shortcomings of several immunosensing formats such as fiber-optic, planar waveguide, surface plasmon resonance, and continuous-flow immunosensor is presented. The future of these sensors, we well as the integration of fluorescence lifetime sensing and fluorescent polarization technologies with immunosensing technologies, is contemplated, posing the question: What place will immunosensors secure in tomorrow's market?


[Ways of coping in stressful situations and anxiety-state or anxiety-trait among women with symptoms of perinatal depression].
The aim of the following study was to establish whether there is any connection between an elevation of anxiety experienced by women during pregnancy or postpartum and their styles of coping with stressful situations, as well as to assess if those factors influence higher risk of incidence of perinatal depressive symptoms. A total of 229 patients admitted to the Department of Foeto-Maternal Medicine, Pomeranian Medical University, Szczecin in 2006-2007, were recruited for the study. By means of the Edinburgh Postnatal Depression Scale (EPDS), a study group of 76 pregnant and postpartum women with high risk of perinatal depression was assigned, as well as a control group of 153 patients without such risk. The level of anxiety and ways of coping in stressful situations were measured by means of the CISS (Coping Inventory for Stressful Situations) and STAI (State-Trait Anxiety Inventory) questionnaires. It has been shown that specific styles of coping in stressful situations and Anxiety-state or Anxiety-trait have substantial influence on higher risk of perinatal depressive symptoms in women. 1) The risk of perinatal depressive symptoms is associated with ways of coping with stressful situations or Anxiety-state and Anxiety-trait, 2) the risk of perinatal depression among pregnant women increases with an elevation of emotion-concentrated styles of coping in stressful situations, 3) the risk of perinatal depression among postpartum women increases with an elevation of emotion-concentrated ways of coping in stressful situations and engagement in substitute activities, 4) analysis of undertaken research indicate for suitableness of early diagnosis of specific styles of coping in stressful situations in order to implement proper therapy directed at the reduction of the risk of perinatal depression.


Malignant orbital and orbitomaxillary tumors: surgical considerations.
Malignant tumors of the orbit and the orbitomaxillary region constitute 4-8% of head and neck malignancies. The lesions can be primary orbital malignant tumors or can invade the orbit from the eyelids, the eyeball or the paranasal sinuses, especially the maxillary sinus and ethmoids. The commonest primary malignant tumors of the orbit are lymphomas, rhabdomyosarcomas and lacrimal gland epithelial tumors. These tumors are excluded from the present study since their management differs from that of metastatic tumors. Our experience is based on a series of 48 patients operated during the last five years. There was an equal distribution according to both age and sex, with two-thirds of the patients being over 60 years of age. Histologically, the basal cell carcinomas (B.C.C.) prevailed with 19 cases, followed by squamous cell carcinomas (Sq.C.C.) in 12, adenocarcinomas (AdenoCa) in 10 and orbital melanomas (O.M.) in 7. In 13 cases the maxilla was also affected. Surgical treatment varied from exenteration to wide cran iofacial resections; immediate reconstruction followed in all cases. Only 10 patients were treated with surgery alone. In the remaining 38 patients radiotherapy was given, alone or in combination with chemotherapy. The surgical techniques included exente ration with split-thickness skin grafting in 19 cases, exenteration with coverage with median forehead flap in 16, and maxillectomy with forehead and temporalis flaps in 7 cases. The tumors recurred in 12 patients, all of them in the first postoperative year. Ten patients died from intracranial involvement or distant metastases. In six of these patients the lesions were Sq.C.C., in two AdenoCa and in two O.M. It is concluded that the surgical treatment of orbital and orbitomaxillary malignancies, although subject to broad guidelines that determine the operability of the tumors, should be individualized according to the extent of the lesion and the experience of the surgeon.


Altered dynamic intrinsic brain activity of the default mode network in Alzheimer's disease: A resting-state fMRI study.
Static regional homogeneity (ReHo) based on the resting-state functional magnetic resonance imaging (rs-fMRI) has been used to study intrinsic brain activity (IBA) in Alzheimer's disease (AD). However, few studies have examined dynamic ReHo (dReHo) in AD. In this study, we used rs-fMRI and dReHo to investigate the alterations in dynamic IBA in patients with AD to uncover dynamic imaging markers of AD. In total, 111 patients with AD, 29 patients with mild cognitive impairment (MCI), and 73 healthy controls (HCs) were recruited for this study ultimately. After the rs-fMRI scan, we calculated the dReHo values using the sliding window method. ANOVA and post hoc two-sample t-tests were used to detect the differences among the three groups. We used the mini-mental state examination (MMSE) and Montreal Cognitive Assessment (MoCA) to evaluate the cognitive function of the subjects. The associations between the MMSE score, MoCA score, and dReHo were assessed by the Pearson correlation analysis. Significant dReHo variability in the right middle frontal gyrus (MFG) and right posterior cingulate gyrus (PCG) was detected in the three groups through ANOVA. In post hoc analysis, the AD group exhibited significantly greater dReHo variability in the right MFG than the MCI group. Compared with the HC group, the AD group exhibited significantly increased dReHo variability in the right PCG. Furthermore, dReHo variability in the right PCG was significantly negatively correlated with the MMSE and MoCA scores of patients with AD. Disrupted dynamic IBA in the DMN might be an important characteristic of AD and could be a potential biomarker for the diagnosis or prognosis of AD.


Effect of ethyl cellulose coating as an evaluation agent against contamination on the bond strength of zirconia restorations: An in vitro study.
During the trial placement of zirconia restorations, contamination of the bonding surface is inevitable. Although cleaning methods for contaminated surfaces have been described, a method of preventing saliva contamination of the bonding surface of zirconia restorations is lacking. The purpose of this in vitro study was to investigate an ethyl cellulose coating as an evaluation agent to mitigate the effects of saliva contamination on the bond strength of zirconia restorations. Experimental groups representing different cleaning methods of tetragonal yttria-stabilized tetragonal zirconia polycrystal (4Y-TZP) surfaces were investigated for shear bond strength with a resin luting agent, and the failure mode was analyzed. The 9.0×7.0×5.0-mm zirconia blocks (n=72) were assigned as follows: Group N: uncontaminated control; Group CU: contaminated with saliva, followed by ultrasonic cleaning with ethanol; Group CI: contaminated with saliva, followed by application of a zirconia cleaner; Group PCW: preapplication of a zirconia primer, contaminated with saliva, followed by cleaning with water spray; Group ECU: precoating with the ethyl cellulose agent, contaminated with saliva, followed by removal of the agent in an ultrasonic bath with ethanol. Each group was divided into 3 subgroups (immediate, short-term aging, and long-term aging), and the shear bond strength was measured (n=24). To analyze the bonding surface characteristics, the contact angle was measured (n=5). The surfaces of the zirconia specimens in each experimental group were evaluated by using a field emission scanning electron microscope (n=5). Time-of-flight secondary ion mass spectroscopy was used for the chemical analysis of the conditioned surfaces (n=3). A 2-way analysis of variance (ANOVA) with main effect model for shear bond strength results and a 1-way ANOVA for contact angle data were performed as statistical analysis, followed by the Bonferroni post hoc test (α=.05). The shear bond strength was significantly higher in the ECU group than in the groups with the other cleaning methods (P<.05). After the removal of ethyl cellulose with ethanol, the contact angle and surface topography were found to be similar to those of the control group, and no saliva contaminants were identified in the spectroscopy analysis. Coating with ethyl cellulose may protect the bonding surface of zirconia restorations from salivary contamination better than cleaning a contaminated surface.


[Super-selective angiography: analysis of angio-architecture and embolization of cerebral arterio-venous malformation].
The angiograms of cerebral arterio-venous malformation (AVM) were analysed through 198 super-selective procedures. The AVM nidus as a whole can be classified as: single supply artery and multi-drainage veins; multi-supply arteries and single drainage vein; multi-supply arteries and multi-drainage veins. Angioarchitecture was divided into five types: terminal supply, penetrating supply, A-V shunt, combined with aneurysm and with anomalous venous structure. Supper-selective angiography was also used for regional functional test and A-V circulation time calculation, as a correct guidance for embolization treatment.


Inhibition of aflatoxin metabolism and growth of Aspergillus flavus in liquid culture by a DNA methylation inhibitor.
Aflatoxins (AFs) are a group of highly oxygenated polyketidese-derived toxins mainly produced by Aspergillus flavus and A. parasiticus, whose biosynthesis mechanisms are extremely sophisticated. Methylation is known as the major form of epigenetic regulation, which is correlated with gene expression. As the DNA methylation inhibitor 5-azacytidine (5-AC) blocks AF production, we studied AFB1 metabolism and morphological changes of A. flavus by treatment with 5-AC in liquid culture. The results show that 5-AC caused a decrease in AF production and concurrent changes in morphology. In addition, we isolated a non-aflatoxigenic mutant of A. flavus, showing a significant reduction in pigment production, after 5-AC treatment. This mutant showed significant reduction in the expression of genes in the AF biosynthesis pathway, and conidia formation. Furthermore, as AF biosynthesis and oxidative stress are intimately related events, we assessed the viability of A. flavus to oxidative stress after treatment with 5-AC, which showed that the mutant was more sensitive to the strong oxidant hydrogen peroxide. We found that the non-aflatoxigenic mutant showed a decrease in reactive oxygen species (ROS) and metabolites indicative of oxidative stress, which may be caused by the disruption of the defence system against excessive ROS formation after 5-AC treatment. These data indicate that 5-AC, as an inactivator of DNA methyltransferase, plays a very important role in AFB1 metabolism and the development of A. flavus, which might provide an effective strategy to pre- or post-harvest control of AFs.


Hydrogen-bonding-driven preorganized zinc porphyrin receptors for efficient complexation of C60, C70, and C60 derivatives.
This paper describes the self-assembly of a new class of foldamer-based molecular tweezers, whose rigid folded conformations are stabilized by intramolecular hydrogen bonding. Two zinc porphyrin units are introduced to the ends of molecular tweezers Zn(2)1 and Zn(2)2, while three zinc porphyrin units are incorporated to the S-shaped bi-tweezers Zn(3)3, which may be regarded as a combination of two Zn(2)1 molecules. Due to the preorganized U-shaped feature, Zn(2)1 and Zn(2)2 are able to strongly complex C60, C70, and C60 derivative 25 in chloroform or toluene in a 1:1 binding stoichiometry, whereas Zn(3)3, which possesses two tweezer units, complexes the guests in a 1:2 stoichiometry. More stable complex Zn(3)3.24 is formed between Zn(3)3 and 24, a linear molecule bearing two C60 moieties at the ends, as a result of the cooperative interaction of two binding sites. Chiral induction is observed for all the three receptors upon complexation with C60-incoporated chiral phenylalanine derivative 29, although the complexation of 29 by the folding receptors is pronouncedly weaker than that of C60 and 25 due to increased steric hindrance. The driving force for the formation of the complexes is the well established pi-pi stacking between the zinc porphyrin and fullerene units. The 1H and 13C NMR, UV-vis, fluorescent, and circular dichroism spectroscopy have been used to investigate the complexing behavior of the folding receptors and the fullerene guests. The association constants of the corresponding complexes in toluene and chloroform (if possible) have been evaluated with the UV-vis and fluorescent titration experiments.


Sexual attitudes and behaviors among medical students in Dokuz Eylul university, Turkey.
Gaining a healthy sexual attitude and behavior and being able to show appropriate approaches to patients in terms of sexual issues are important acquisitions for medical students. The aim of the present study was to determine, compare, and evaluate the sexual attitudes and behaviors of Dokuz Eylul University Faculty of Medicine students. An anonymous questionnaire was filled in by first- and sixth-year students in order to determine their sexual attitudes and behaviors. While information sources in the adolescence period for both genders were friends in the first place, these sources were mostly mothers, books, newspapers--magazines for females, and newspapers--magazines and television for males. The opinion of males about having sexual intercourse before marriage for males was positive, and females were more tolerant about males having this experience before marriage as compared to females having sexual experience before marriage. Rates of expression of having sexual intercourse and masturbation were found to be higher for male students. The first sexual experience with a sex worker or sentimentally insignificant partner was high among males. In general, the rate of condom use was lower, and the rate of coitus interruptus was found to be higher than in foreign studies. All the students declared 'my own will and values' as the most frequent factor affecting their sexual attitudes and behaviors, and high rates for 'social factors', 'religious requirements', 'the expectations of families', and 'protection from sexually transmitted diseases' were observed. The findings lead to the conclusions that gender differences exist in the sexual attitudes and behaviors of medical students; the enhancing effect of the traditional structure on gender discrimination is still continuing; students are not provided with sufficient scientific approach or training prior to the university education; and beyond biomedical training, they should receive more support in those fields during their medical education.


Inside the Noonan "universe": Literature review on growth, GH/IGF axis and rhGH treatment: Facts and concerns.
Noonan syndrome (NS) is a disorder characterized by a typical facial gestalt, congenital heart defects, variable cognitive deficits, skeletal defects, and short stature. NS is caused by germline pathogenic variants in genes coding proteins with a role in the RAS/mitogen-activated protein kinase signaling pathway, and it is typically associated with substantial genetic and clinical complexity and variability. Short stature is a cardinal feature in NS, with evidence indicating that growth hormone (GH) deficiency, partial GH insensitivity, and altered response to insulin-like growth factor I (IGF-1) are contributing events for growth failure in these patients. Decreased IGF-I, together with low/normal responses to GH pharmacological provocation tests, indicating a variable presence of GH deficiency/resistance, in particular in subjects with pathogenic PTPN11 variants, are frequently reported. Nonetheless, short- and long-term studies have demonstrated a consistent and significant increase in height velocity (HV) in NS children and adolescents treated with recombinant human GH (rhGH). While the overall experience with rhGH treatment in NS patients with short stature is reassuring, it is difficult to systematically compare published data due to heterogeneous protocols, potential enrolment bias, the small size of cohorts in many studies, different cohort selection criteria and varying durations of therapy. Furthermore, in most studies, the genetic information is lacking. NS is associated with a higher risk of benign and malignant proliferative disorders and hypertrophic cardiomyopathy, and rhGH treatment may further increase risk in these patients, especially as dosages vary widely. Herein we provide an updated review of aspects related to growth, altered function of the GH/IGF axis and cell response to GH/IGF stimulation, rhGH treatment and its possible adverse events. Given the clinical variability and genetic heterogeneity of NS, treatment with rhGH should be personalized and a conservative approach with judicious surveillance is recommended. Depending on the genotype, an individualized follow-up and close monitoring during rhGH treatments, also focusing on screening for neoplasms, should be considered.


Analysis of pedestrian accident injury-severities at road junctions and crossings using an advanced random parameter modelling framework: The case of Scotland.
This paper investigates the determinants of injury severities in pedestrian-motor vehicle accidents at signalised and unsignalised junctions, and at physically-controlled and human-controlled crossings in Scotland. The accident data were drawn from the official police crash report database of the UK spanning a period between 2010 and 2018. Correlated random parameter ordered probit models with heterogeneity in the means were developed in order to account for the multi-layered impact of unobserved heterogeneity on statistical estimation. The model estimation results showed that the severities of accident injuries are affected by roadway, location, weather, vehicle, and driver characteristics as well as temporal attributes (including time and day of the accident). Factors such as the urban context, lighting and weather conditions and road surface conditions were found to result in correlated random parameters, thus capturing the intricate, yet interactive effects of unobserved heterogeneity, and particularly the unobserved behavioural response of road users to different traffic control types at junctions and crossings. Vehicle type, driver's gender and day-of-the-week were observed to influence the random parameters' distributions. Empirically, the results showcase variations in the determinants of injury severities at signalised and unsignalised junctions, and at physically-controlled and human-controlled crossings. Even though most of these variations were related to the magnitude of impact of the determinants, differences in the directional effects on injury severities were also identified, mainly for factors related to weather conditions, hazard presence on the road, and temporal characteristics of the accidents.