Preclinical proof of principle for orally delivered Th17 antagonist miniproteins.

Interleukin (IL)-23 and IL-17 are well-validated therapeutic targets in autoinflammatory diseases. Antibodies targeting IL-23 and IL-17 have shown clinical efficacy but are limited by high costs, safety risks, lack of sustained efficacy, and poor patient convenience as they require parenteral administration. Here, we present designed miniproteins inhibiting IL-23R and IL-17 with antibody-like, low picomolar affinities at a fraction of the molecular size. The minibinders potently block cell signaling in vitro and are extremely stable, enabling oral administration and low-cost manufacturing. The orally administered IL-23R minibinder shows efficacy better than a clinical anti-IL-23 antibody in mouse colitis and has a favorable pharmacokinetics (PK) and biodistribution profile in rats. This work demonstrates that orally administered de novo-designed minibinders can reach a therapeutic target past the gut epithelial barrier. With high potency, gut stability, and straightforward manufacturability, de novo-designed minibinders are a promising modality for oral biologics.

Feasibility of virtual reality and comparison of its effectiveness to biofeedback in children with Duchenne and Becker muscular dystrophies.

INTRODUCTION/AIMS: The utilization of virtual reality (VR) and biofeedback training, while effective in diverse populations, remains limited in the treatment of Duchenne and Becker muscular dystrophies (D/BMD). This study aimed to determine the feasibility of VR in children with D/BMD and compare the effectiveness of VR and biofeedback in children with D/BMD. METHODS: The study included 25 children with D/BMD. Eight children in the control group participated in a routine follow-up rehabilitation program, while the remaining children were randomly assigned to the VR (n = 9) and biofeedback (n = 8) groups for a 12-week intervention. The following evaluations were performed before, during (week 6), and after treatment: Muscle pain and cramps, laboratory studies, muscle strength, timed performance, function (Motor Function Measurement Scale-32, Vignos, and Brooke Scales), and balance (Pediatric Functional Reach Test and Balance Master System). Motivation for rehabilitation was determined. RESULTS: The median ages were 9.00 (VR), 8.75 (biofeedback), and 7.00 (control) years. The study found no significant differences between groups in pretreatment assessments for most measures, except for tandem step width (p < .05). VR and biofeedback interventions significantly improved various aspects (pain intensity, cramp frequency, cramp severity, muscle strength, timed performance, functional level, and balance) in children with D/BMD (p < .05), while the conventional rehabilitation program maintained patients' current status without any changes. The study found VR and biofeedback equally effective, with VR maintaining children's motivation for rehabilitation longer (p < .05). DISCUSSION: The study showed that both VR and biofeedback appear to be effective for rehabilitation this population, but additional, larger studies are needed.

Motor-cognitive exercise with variability of practice and feedback improves functional ability and cognition in older individuals.

BACKGROUND: Motor-cognitive dual-task training seems the most favorable form of exercise for functional and cognitive improvements in older individuals.  The optimal exercise regime is still uncertain, and the potential benefits of qualitative parameters of exercise prescription such as feedback provision and practice variability are mostly unknown. AIMS: To verify the effects of a motor-cognitive dual-task training with feedback provision and variability of practice for improving functional ability and cognition in older individuals. METHODS: Thirty individuals (3 men) aged over 65 years were tested on walking speed, static and dynamic balance, lower limb strength, and cognition before and after a 5-week motor-cognitive intervention. Training consisted of twice weekly, 30 min gross-motor coordination exercises with variable practice conditions combined with stimulus-response cognitive tasks generated by an interactive device. Participants were divided into an experimental group and a control group, respectively receiving and nonreceiving feedback during training. A 2 × 2 ANOVA was used to verify the effects of training. RESULTS: Both groups improved static and dynamic balance (p < 0.05), walking speeds (p < 0.05), lower limb strength (p < 0.05) and cognitive functions with greater gains observed in the experimental group (p < 0.01). DISCUSSION: Variability of practice applied to motor-cognitive dual-task training is effective for improving, in only 5 weeks, functional ability and cognitive processing in older individuals. These changes were possibly afforded through motor and cognitive enhancement induced by exercise complexity. Provision of feedback seems to particularly benefit cognitive functions. CONCLUSIONS: Brief motor-cognitive dual-task training using practice variability and feedback seems effective for counteracting the age-related cognitive and functional decline.

The Dominance of Anticipatory Prefrontal Activity in Uncued Sensory-Motor Tasks.

Anticipatory event-related potentials (ERPs) precede upcoming events such as stimuli or actions. These ERPs are usually obtained in cued sensory-motor tasks employing a warning stimulus that precedes a probe stimulus as in the contingent negative variation (CNV) paradigms. The CNV wave has been widely studied, from clinical to brain-computer interface (BCI) applications, and has been shown to emerge in medial frontoparietal areas, localized in the cingulate and supplementary motor areas. Several dated studies also suggest the existence of a prefrontal CNV, although this component was not confirmed by later studies due to the contamination of ocular artifacts. Another lesser-known anticipatory ERP is the prefrontal negativity (pN) that precedes the uncued probe stimuli in discriminative response tasks and has been localized in the inferior frontal gyrus. This study aimed to characterize the pN by comparing it with the CNV in cued and uncued tasks and test if the pN could be associated with event preparation, temporal preparation, or both. To achieve these aims, high-density electroencephalographic recording and advanced ERP analysis controlling for ocular activity were obtained in 25 volunteers who performed 4 different visuomotor tasks. Our results showed that the pN amplitude was largest in the condition requiring both time and event preparation, medium in the condition requiring event preparation only, and smallest in the condition requiring temporal preparation only. We concluded that the prefrontal CNV could be associated with the pN, and this activity emerges in complex tasks requiring the anticipation of both the category and timing of the upcoming stimulus. The proposed method can be useful in BCI studies investigating the endogenous neural signatures triggered by different sensorimotor paradigms.

The effect of pre-anesthesia with a needle-free system versus topical anesthesia on injection pain of the inferior alveolar nerve block: a randomized clinical trial.

OBJECTIVE: The aim of this study was to compare the effectiveness of pain control between a needle-free system and topical anesthesia applied prior to inferior alveolar nerve block (IANB). MATERIALS AND METHODS: The present study was designed as a randomized controlled cross-over clinical study on 60 children (aged 6 to 12 years) requiring dental treatment with IANB in bilateral mandibular molars. As pre-anesthesia, topical anesthesia (TA) was applied on one side and the Comfort-in™ injection system (CIS) on the other side in two separate sessions before IANB. The injection pain during IANB, at both the needle insertion and solution deposition phases, was analyzed using the Wong-Baker Faces Pain Rating Scale (PRS) and the Face, Legs, Activity, Cry, Consolability Scale (FLACC). The data were analyzed using the Wilcoxon signed-rank test, Spearman correlation, and Mann-Whitney U test. RESULTS: There were statistically significant differences between TA and CIS in subjective and objective pain evaluations during both the needle insertion and solution deposition. The use of a needle-free system in pre-anesthesia yielded a significant decrease in subjective and objective pain scores (p < 0.001). No statistical difference was found between TA and CIS in terms of patient preference, but patient preference for CIS was significantly higher in older patients (p < 0.01). CONCLUSIONS: It was determined that the use of a needle-free system in pre-anesthesia yielded a decrease in injection pain of IANB. CLINICAL RELEVANCE: Pediatric dentists should be aware of the new injection system in order to decrease the level of injection pain.

Could interleukin-33 and its suppressor of tumorigenicity 2 (ST2) receptor have a role in cervical human papillomavirus (HPV) infections?

Why most women can clear human papillomavirus (HPV) infections while others can develop permanent infections. The stimulation of immunotolerance of the immune system of the host by the persistent HPV infection may be the answer to this question. Interleukin-33 (IL-33) may play a role in the pathogenesis of HPV infection, this hypothesis was thought to be due to the rapid release of IL-33 from damaged cells following tissue damage, necrosis, and activation of the inflammasome. Thus, in this study, the role of IL-33/suppressor of tumorigenicity 2 (ST2) was emphasized in HPV positive and HPV negative cervical tissues. A total of 80 were assessed. The reduced levels of IL-33 and ST2 are associated with cervical HPV infections. There was a statistically significant 42% positive correlation between IL-33 and ST2 in the HPV-positive group. Surprisingly, our data showed no significant difference between the expression levels of IL-33 or ST2 and working status, type of delivery, pre- and post-operative pathology, cigarette, educational status, locality, birth control method, gynecological, and colposcopic findings. We found that as a result of our study; low IL-33 and ST2 levels were associated with HPV infections.

Digital versus conventional impression method in children: Comfort, preference and time.

BACKGROUND: The comfortness and effectiveness of digital and conventional impression methods in children have not yet been compared. AIM: To assess the digital and conventional impression methods in children in terms of comfort, preference, and the time required to take impressions. DESIGN: Digital impressions were taken by using an intraoral scanner, and conventional impressions were taken by using alginate from 28 patients by the same operator. In each impression-taking-process, comfort was assessed by both the children and the clinician, and the chairside times were written. Student's t tests and Mann-Whitney U tests were used for statistical analyses, and P < .05 was considered to be significant. RESULTS: The digital impression was considered to be more comfortable in the assessments by both the children and the clinician (P < .001). The total time the digital impression took was 465.89 ± 76.71 second(s) while that of the conventional impression was 450.25 ± 64.08 s when the chairside times of the two impression methods were compared. There was no statistically significant difference (P = .41). CONCLUSION: The digital impression method compared with the conventional impression method was found to be both more comfortable and preferable by the children, but there was no difference in terms of the time required to take impressions.

Role of Ozone Therapy in Preventing Testicular Damage in an Experimental Cryptorchid Rat Model.

BACKGROUND Cryptorchidism is the most common developmental abnormality of the male reproductive system. If left untreated, it results with infertility and testicular cancer. According to current evidence, surgery is the mainstay of treatment, and hormonal therapy approaches are still under investigation. For the protection of testicular functions, antioxidants have emerged as novel options. This study aimed to evaluate the protective properties of ozone, a strong antioxidant, on testicular tissue. MATERIAL AND METHODS Thirty-five male Wistar-albino rats, 1-month-old, were used for the study. Groups were formed as follows: 1) control, 2) sham surgery (cryptorchidism), 3) cryptorchidism plus ozone, 4) cryptorchidism plus human chorionic gonadotropin (hCG), and 5) ozone plus hCG. Surgical procedures were performed on all rats except the control group. All rats except the control group were used to create an experimental cryptorchidism model, and left testes of animals were surgically placed into the abdomen. After 1 month of surgery, groups 3, 4, and 5 were given corresponding treatments intraperitoneally for 4 weeks. At the end of the study period, testicular atrophy index (TAI) and testicular sperm motility (TSM) were assessed and biochemical, histopathological, and immunohistochemical tests were performed. RESULTS TAI and TSM were higher in the ozone, hCG, and ozone plus hCG groups than in the sham surgery group (p=0.001). TSM in the ozone group was significantly higher than in the hCG and ozone plus hCG groups. In biochemical analyses, the parameters of oxidative stress (GPx1, MDA, CAT, GSH, SOD) indicated increased oxidative activity in cryptorchidism, which was resolved by applying ozone and hCG (p=0.001). In addition, apoptotic markers, Caspase 3 and bcl-2 were significantly decreased by applying ozone and hCG (p=0.001). CONCLUSIONS Results of this study suggest that ozone therapy, either as a single agent or in combination with hCG, is a promising approach for protection of testicular functions.

Evaluation of epidemiological, clinical, and laboratory characteristics and mortality rate of patients with Crimean-Congo hemorrhagic fever in the northeast region of Turkey.

BACKGROUND & OBJECTIVES: : Crimean-Congo hemorrhagic fever (CCHF), an illness characterized by fever and hemorrhage, is caused by a CCHF virus (CCHFV). It is an important public health problem in Turkey. The objective of this study was to evaluate the demographic, clinical, and laboratory characteristics and mortality rates of CCHF patients in the northeast region of Turkey. METHODS: : A total of 206 patients, diagnosed with CCHF, from northeast region of Turkey were included and evaluated between 2011 and 2017. Real-time reverse transcriptase polymerase chain reaction (RT-PCR) and immunofluorescence (IFA) methods were used for the diagnoses. RESULTS: : Of the patients included in the study, 77.2% were farmers/livestockers, while 22.8% had other occupations. The incidence of tick bite or tick contact with bare hands was 52.9%. About 94.2% of the patients were living in rural areas and 5.8% in city centers. However, all the patients living in city centers had a history of visit to rural areas. The disease was more common in May, June, and July months. The most common symptoms at the time of admission included fatigue, fever, and widespread body pain, while laboratory findings were thrombocytopenia, leukopenia, and anemia. Bleeding, tachycardia, and rash were the most common findings on physical examination. Of all the patients, 95.6% were identified by RT-PCR and 4.4% by IFA methods. Severe cases constituted 22.3% (46) of the included patients. Throughout the course of this study, 7 (3.4%) patients died, and the remaining 96.6% (199) patients were discharged with a full recovery. Disease severity was significantly correlated with mortality rate and duration of hospitalization (p <0.001 and p = 0.013). INTERPRETATION & CONCLUSION: : In this study, the mortality rate observed was lower than that reported in the literature because of accessibility of early supportive therapy. It would be beneficial in CCHF treatment to recognize the disease at an early stage, begin supportive treatment quickly, and educate the people living in high-risk areas as well as health care personnel working in these areas.

Metalloproteinases and Their Inhibitors in Patients with Inguinal Hernia.

AIM: The aim of this prospective study is to investigate if there is a relationship between inguinal hernia, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs). MATERIALS AND METHODS: This case control study was performed on patients admitted to the general surgery department of Erzincan University Hospital. Four groups were created: control, indirect hernia, direct hernia, and bilateral hernia. All groups were comprised of 11 patients. Serum and tissue levels of MMP-1, MMP-2, MMP-9, MMP-13, TIMP-1, TIMP-2, TIMP-3, and hydroxyproline were evaluated. RESULTS: MMPs values were significantly high at hernia groups, especially at bilateral hernia group (p < 0.05), whereas TIMPs values were significantly low at bilateral hernia group (p < 0.05). MMPs values were increasing at hernia groups in an order as control, indirect, direct, and bilateral. TIMPs values were decreasing at hernia groups in an order as control, indirect, direct, and bilateral. CONCLUSION: Increased levels of MMP-1-2-9-13 and decreased levels of TIMP-1-2-3 may have played role in the formation of inguinal hernia. Hernia is not only a local defect, but a reflection of systemic disease. This is even more significant for bilateral hernias.

The seroprevalence of Coxiella burnetii in Erzincan, Turkey: Identification of the risk factors and their relationship with geographical features.

BACKGROUND & OBJECTIVES: Coxiella burnetii (C. burnetii) bacterium, the causative agent of Q fever has regained importance due to the increasing cases of infections and outbreaks. A cross-sectional descriptive study was conducted to investigate the seroprevalence of C. burnetii in human populations of Erzincan province located in the eastern Turkey, identify the risk factors, and to explore the relationship between geographical features. METHODS: A total of 368 people residing in the rural (306) and urban (62) areas of the province were included in the study. Serum samples were analyzed for the presence of C. burnetii phase II IgG antibody using ELISA (Virion/ Serion, Wurzburg, Germany). Spatial analyses were performed to evaluate correlations between seroprevalence and geographical features. RESULTS: The overall seroprevalence of C. burnetii was found to be 8.7% (32/368). In rural residents it was 8.5% (26/306), while in urban population it was 9.7% (6/62). Cattle breeding and contact with animal afterbirth waste were found to be major risk factors, and were significantly correlated with seropositive cases (p<0.05). The seropositive cases were only observed in the areas between 1067 and 1923 masl. Of the total seropositive cases, 65.6% were within 1000 m and 87.5% within 4000 m of rivers and their main tributaries. Around 59.4% cases were observed in areas with a slope of 0 to 5°. INTERPRETATION & CONCLUSION: The results of the study showed that C. burnetii seroprevalence was higher than expected, and significantly differs according to geographical features of a region. Significant risk factors include raising cattle and exposure to infected animals or their birth products/secretions. It is also more frequent in areas with higher number of rivers and streams, higher altitude and lower slope.

Lack of evidence of HPV etiology of prostate cancer following radical surgery and higher frequency of the Arg/Pro genotype in Turkish men with prostate cancer.

OBJECTIVES: The aim of this study was to assess the possible role of HPV in the development of prostate cancer (PCa) and investigate the distribution of the p53 codon 72 polymorphism in PCa in a Turkish population. MATERIALS AND METHODS: A total of 96 tissues, which had been obtained using a radical surgery method, formalin-fixed and parafin-embedded, were used in this study. The study group consisted of 60 PCa tissues (open radical prostatectomy) and the control group contained 36 benign prostatic hyperplasia tissues (BPH) (transvesical open prostatectomy). The presence of HPV and the p53 codon 72 polymorphism was investigated in both groups using real-time PCR and pyrosequencing. RESULTS: The results of the real-time PCR showed no HPV DNA in any of the 36 BPH tissue samples. HPV-DNA was positive in only 1 of the 60 PCa samples (1.7%). The HPV type of this sample was identified as HPV-57. The distribution of the three genotypes, Arg/Arg, Arg/Pro and Pro/Pro was found to be 45.6, 45.6, and 8.8% in the PCa group and 57.1%, 34.3% and 8.6% in the control group, respectively. Compared with the control group, patients with PCa had a higher frequency of the Arg/Pro genotype and Proline allele (odds ratio (OR)=1.67, 95% confidence interval (CI)=0.68-4.09, p=0.044; OR=1.13, 95% CI=0.76-1.68, p=0.021, respectively). CONCLUSIONS: The results of the study do not support the hyphothesis that prostate cancer is associated with HPV infection but indicated that Proline allele can be a risk factor in the development of PCa in the Turkish population.

Neural effects of methylphenidate and nicotine during smooth pursuit eye movements.

INTRODUCTION: Nicotine and methylphenidate are putative cognitive enhancers in healthy and patient populations. Although they stimulate different neurotransmitter systems, they have been shown to enhance performance on overlapping measures of attention. So far, there has been no direct comparison of the effects of these two stimulants on behavioural performance or brain function in healthy humans. Here, we directly compare the two compounds using a well-established oculomotor biomarker in order to explore common and distinct behavioural and neural effects. METHODS: Eighty-two healthy male non-smokers performed a smooth pursuit eye movement task while lying in an fMRI scanner. In a between-subjects, double-blind design, subjects either received placebo (placebo patch and capsule), nicotine (7mg nicotine patch and placebo capsule), or methylphenidate (placebo patch and 40mg methylphenidate capsule). RESULTS: There were no significant drug effects on behavioural measures. At the neural level, methylphenidate elicited higher activation in left frontal eye field compared to nicotine, with an intermediate response under placebo. DISCUSSION: The reduced activation of task-related regions under nicotine could be associated with more efficient neural processing, while increased hemodynamic response under methylphenidate is interpretable as enhanced processing of task-relevant networks. Together, these findings suggest dissociable neural effects of these putative cognitive enhancers.

Use of Ozone to Treat Ileostomy Dermatitis in an Experimental Rat Model.

BACKGROUND: Dermatitis associated with ileostomy is an important problem that affects many people, especially children. The aim of this study was to investigate the therapeutic effects of ozone on dermatitis due to ileostomy, and to develop an alternative treatment option. MATERIAL/METHODS: A total of 28 rats were divided into 4 groups: control, ileostomy, ozone, and zinc oxide. Ileostomy was performed in all rats except the control group. After a 1-week waiting time, the ozone group was administered ozone therapy and the zinc oxide group was administered zinc oxide cream locally once a day for a total of 7 days. All rats were sacrificed at the end of this period. The efficacy of treatment was examined by biochemical, histopathological, and immunohistochemical parameters. The levels of malondialdehyde (MDA), total glutathione (tGSH), total antioxidant capacity (TAC), and total oxidant status (TOS) were measured from tissue. Vascular endothelial growth factor (VEGF) and proliferating cell nuclear antigen (PCNA) were examined immunohistochemically. RESULTS: Dermatitis occurred pathologically in all rats that underwent ileostomy surgery. The lowest dermatitis score was in the ozone treatment group (p<0.05). Ileostomy dermatitis caused increased levels of MDA and TOS. Ozone treatment resulted in reduced MDA and TOS levels, while the levels of tGSH and TAC were increased (p<0.05). Both VEGF and PCNA immunostaining were augmented in the ozone treatment group (p<0.05). CONCLUSIONS: Local ozone application may be a good alternative compared to the conventional treatment methods for the prevention of skin lesions that develop after ileostomy.

In vitro Activity of Colistin in Combination with Tigecycline against Carbapenem-Resistant Acinetobacter baumannii Strains Isolated from Patients with Ventilator-Associated Pneumonia.

OBJECTIVE: This study investigated the minimum inhibitory concentration (MIC) values and in vitro activity of colistin in combination with tigecycline against carbapenem-resistant Acinetobacter baumannii strains isolated from patients with ventilator-associated pneumonia (VAP) using the E-test method. METHODS: A total of 40 A. baumannii strains, identified using the Phoenix Automated Microbiology System (Becton, Dickinson and Co., Franklin Lakes, NJ, USA) by conventional methods, were included in this study. Pulsed-field gel electrophoresis was performed to examine the clonal relationships between isolates. The carbapenem resistance of the strains to colistin and tigecycline was assessed using the E-test method (Liofilchem, Roseto Degli Abruzzi, Italy). The in vitro activity of colistin in combination with tigecycline was evaluated using the fractional inhibitor concentration (FIC) index. RESULTS: While only 1 of 40 A. baumannii strains was determined to be colistin resistant, 6 were tigecycline resistant. The MIC50, MIC90, and MIC intervals of the A. baumannii strains were 0.19, 1.5, and 0.064‒4 µg/ml for colistin and 1, 8, and 0.094‒256 µg/ml for tigecycline, respectively. No synergistic effect was observed using the FIC index; 8 strains exhibited an indifferent effect and 32 exhibited an antagonist effect. Three of the six strains that were resistant to tigecycline were indifferent; the remaining three were antagonistic. The colistin-resistant strain also exhibited an antagonist effect. CONCLUSION: In contrast to their synergistic effect against carbapenem-resistant A. baumannii isolates, colistin and tigecycline were highly antagonistic to carbapenem-resistant A. baumannii strains isolated from patients with VAP when the drugs were administered together. Therefore, alternative treatment options should be used during the treatment of VAP attributed to A. baumannii.

New inflammatory markers for prediction of non-dipper blood pressure pattern in patients with essential hypertension: Serum YKL-40/Chitinase 3-like protein 1 levels and echocardiographic epicardial adipose tissue thickness.

The aim of the present study was to investigate whether YKL-40 levels and epicardial adipose tissue (EAT) thickness were associated with non-dipping pattern in essential hypertension (HT). Age- and sex-matched 40 dipper hypertensive patients and 40 non-dipper hypertensive patients were included in the study. Non-dippers had significantly increased EAT thickness and higher YKL-40 and high-sensitivity C-reactive protein levels than dippers. Multivariate logistic regression analysis showed that the EAT thickness and serum levels of YKL-40 and high-sensitivity C-reactive protein were independent predictors of non-dipping pattern in essential HT. In essential HT, presence of non-dipping pattern is associated with increased inflammatory response.

[Investigation of antibiotic resistance patterns and reduced vancomycin susceptibilities of methicillin-resistant Staphylococcus aureus isolates: a multi-center study]. / Metisiline dirençli Staphylococcus aureus izolatlarinin antibiyotik direnci ve azalmis vankomisin duyarliliginin arastirilmasi: Çok merkezli bir çalisma.

The aims of this study were to determine the minimum inhibitory concentration (MIC) values of vancomycin, teicoplanin, daptomycin, quinupristin/dalfopristin, linezolid, tigecycline, chloramphenicol, rifampicin, ofloxacin and tetracycline and to investigate the reduced vancomycin susceptibility among methicillin-resistant Staphylococcus aureus (MRSA) strains isolated in hospitals located in different geographical regions of Turkey. A total of 100 MRSA strains isolated from patients (of which 50% were from intensive care units) hospitalized in seven centers in Turkey [Istanbul (n= 15), Ankara (n= 15), Izmir (n= 15), Adana (n= 15), Diyarbakir (n=15), Erzincan (n= 15), Van (n= 10)], between August 2013 - August 2014, were included in the study. Fourty-three strains were isolated from blood, whereas 21 were from lower respiratory tract, 17 from wounds, eight from catheters, six from urine, four from nasal swab and one from cerebrospinal fluid samples. Methicillin resistance of the isolates was determined by using cefoxitin (30 µg) disk with standard disk diffusion method, while the MIC values of other antibiotics were determined with E-test in accordance with the recommendations of Clinical and Laboratory Standards Institute (CLSI). MIC results obtained for quinupristin-dalfopristin (Q/D) were evaluated according to the CLSI criteria used for methicillin-susceptible S.aureus and for tigecycline according to the criteria recommended by the Food and Drug Administration for MRSA. Primarily, agar screening method (ASM) was used for determination of vancomycin-intermediate S.aureus (VISA) and heterogeneous VISA (hVISA) strains. Brain heart infusion agar containing 6 µg/ml vancomycin was used in ASM, and the strains with suspicion of VISA/hVISA were screened by standard E-test and macro E-test methods. All MRSA strains were susceptible to vancomycin, teicoplanin, daptomycin, Q/D and linezolid by E-test method; and their rates of susceptibility for tigecycline, chloramphenicol, rifampicin, ofloxacin and tetracycline were detected as 89%, 97%, 40%, 39% and 32%, respectively. MIC50/MIC90 values were 1.5/2 µg/ml for vancomycin, 2/4 µg/ml for teicoplanin, 0.19/0.38 µg/ml for daptomycin, 0.19/0.38 µg/ml for Q/D, 0.75/1 µg/ml for linezolid, 0.19/0.75 µg/ml for tigecycline, 3/6 µg/ml for chloramphenicol, 32/32 µg/ml for rifampicin, 32/32 µg/ml for ofloxacin and 32/64 µg/ml for tetracycline, respectively. For the evaluation of reduced vancomycin susceptibility, 2% (2/100) of MRSA strains were defined as VISA and 5% (5/100) as hVISA with ASM. One of those seven isolates identified as VISA/hVISA with ASM was evaluated as suspected hVISA by using both standard E-test and macro E-test methods. In conclusion, no MRSA resistant strain to vancomycin, teicoplanin, daptomycin, Q/D and linezolid was determined in our study. However tigecycline resistance (11%) was found higher than expected. As the glycopeptide resistance is increasing in the world and because of the intense use of these drugs in Turkey, the rates of vancomycin resistance among MRSA strains should be investigated periodically.

Bayesian interpretation of the prefrontal P2 ERP component based on stimulus/response mapping uncertainty.

The brain can be seen as a predictive system continuously computing prior information to guess posterior probabilities minimizing sources of uncertainty. To test this Bayesian view of the brain, event-related potentials (ERP) methods have been used focusing on the well-known P3 component, traditionally associated with decision-making processes and sources of uncertainty regarding target probability. Another ERP component linked with decision-making is the prefrontal P2 (pP2) component, which has never been considered within the Bayesian framework. To test which source of uncertainty could be associated with the pP2, uncertainty induced by target probability and stimulus-response (S/R) mapping were modulated in three visuomotor tasks. Results showed that the pP2 had the largest amplitude in the task with the largest uncertainty regarding the S/R mapping and degraded as the S/R mapping became more predictable. The P3 was maximal in the tasks with larger uncertainty regarding the target probability. While we confirmed the P3 association with target probability, we extended our knowledge on the pP2 associating it with S/R mapping uncertainty. This component, which has been previously localized within the anterior insular cortex, may minimize S/R mapping uncertainty allowing response-related evidence accumulation and comparing current events with internal representations to extract action-related probabilities.

Artemisinin May Disrupt Hyphae Formation by Suppressing Biofilm-Related Genes of Candida albicans: In Vitro and In Silico Approaches.

This study aimed to assess the antifungal and antibiofilm efficacy of artemisinin against Candida (C.) species, analyze its impact on gene expression levels within C. albicans biofilms, and investigate the molecular interactions through molecular docking. The antifungal efficacy of artemisinin on a variety of Candida species, including fluconazole-resistant and -susceptible species, was evaluated by the microdilution method. The effect of artemisinin on C. albicans biofilm formation was investigated by MTT and FESEM. The mRNA expression of the genes related to biofilm was analyzed by qRT-PCR. In addition, molecular docking analysis was used to understand the interaction between artemisinin and C. albicans at the molecular level with RAS1-cAMP-EFG1 and EFG1-regulated genes. Artemisinin showed higher sensitivity against non-albicans Candida strains. Furthermore, artemisinin was strongly inhibitory against C. albicans biofilms at 640 µg/mL. Artemisinin downregulated adhesion-related genes ALS3, HWP1, and ECE1, hyphal development genes UME6 and HGC1, and hyphal CAMP-dependent protein kinase regulators CYR1, RAS1, and EFG1. Furthermore, molecular docking analysis revealed that artemisinin and EFG1 had the highest affinity, followed by UME6. FESEM analysis showed that the fluconazole- and artemisinin-treated groups exhibited a reduced hyphal network, unusual surface bulges, and the formation of pores on the cell surfaces. Our study suggests that artemisinin may have antifungal potential and showed a remarkable antibiofilm activity by significantly suppressing adhesion and hyphal development through interaction with key proteins involved in biofilm formation, such as EFG1.

Effect of anticipatory multisensory integration on sensory-motor performance.

Multisensory integration (MSI) is a phenomenon that occurs in sensory areas after the presentation of multimodal stimuli. Nowadays, little is known about the anticipatory top-down processes taking place in the preparation stage of processing before the stimulus onset. Considering that the top-down modulation of modality-specific inputs might affect the MSI process, this study attempts to understand whether the direct modulation of the MSI process, beyond the well-known sensory effects, may lead to additional changes in multisensory processing also in non-sensory areas (i.e., those related to task preparation and anticipation). To this aim, event-related potentials (ERPs) were analyzed both before and after auditory and visual unisensory and multisensory stimuli during a discriminative response task (Go/No-go type). Results showed that MSI did not affect motor preparation in premotor areas, while cognitive preparation in the prefrontal cortex was increased and correlated with response accuracy. Early post-stimulus ERP activities were also affected by MSI and correlated with response time. Collectively, the present results point to the plasticity accommodating nature of the MSI processes, which are not limited to perception and extend to anticipatory cognitive preparation for task execution. Further, the enhanced cognitive control emerging during MSI is discussed in the context of Bayesian accounts of augmented predictive processing related to increased perceptual uncertainty.