Characterization of technical skill progress in a standardized rabbit model for training in laparoscopic duodenal atresia repair.

BACKGROUND: Laboratory skills training is an essential step before conducting minimally invasive surgery in clinical practice. Our main aim was to develop an animal model for training in clinically highly challenging laparoscopic duodenal atresia repair that could be useful in establishing a minimum number of repetitions to indicate safe performance of similar interventions on humans. MATERIALS AND METHODS: A rabbit model of laparoscopic duodenum atresia surgery involving a diamond-shaped duodeno-duodenostomy was designed. This approach was tested in two groups of surgeons: in a beginner group without any previous clinical laparoscopic experience (but having undergone previous standardized dry-lab training, n = 8) and in an advanced group comprising pediatric surgery fellows with previous clinical experience of laparoscopy (n = 7). Each participant performed eight interventions. Surgical time, expert assessment using the Global Operative Assessment of Laparoscopic Skills (GOALS) score, anastomosis quality (leakage) and results from participant feedback questionnaires were analyzed. RESULTS: Participants in both groups successfully completed all eight surgeries. The surgical time gradually improved in both groups, but it was typically shorter in the advanced group than in the beginner group. The leakage rate was significantly lower in the advanced group in the first two interventions, and it reached its optimal level after five operations in both groups. The GOALS and participant feedback scores showed gradual increases, evident even after the fifth surgery. CONCLUSIONS: Our data confirm the feasibility of this advanced pediatric laparoscopic model. Surgical time, anastomosis quality, GOALS score and self-assessment parameters adequately quantify technical improvement among the participants. Anastomosis quality reaches its optimal value after the fifth operation even in novice, but uniformly trained surgeons. A minimum number of wet-lab operations can be determined before surgery can be safely conducted in a clinical setting, where the development of further non-technical skills is also required.

Cross-modality imaging of bisphosphonate-treated murine jawbones.

In this proof-of-principle study, we established and implemented a cross-modality imaging (CMI) pipeline to characterize and compare bisphosphonate (BIS)-treated jawbones of Sprague-Dawley rats after tooth extraction after physical therapies (photobiomodulation and extracorporeal shockwave therapy (PBMT and ESWT)). We showcase the feasibility of such a CMI approach and its compatibility across imaging modalities to probe the same region of interest (ROI) of the same jawbone. Jawbones were imaged in toto in 3D using micro-Computed Tomography to identify ROIs for subsequent sequential 2D analysis using well-established technologies such as Atomic Force Microscopy and Scanning Electron Microscopy, and recent imaging approaches in biomedical settings, such as micro-X-Ray Fluorescence Spectroscopy. By combining these four modalities, multiscale information on the morphology, topography, mechanical stiffness (Young's modulus), and calcium, zinc and phosphorus concentrations of the bone was collected. Based on the CMI pipeline, we characterized and compared the jawbones of a previously published clinically relevant rat model of BIS-related osteonecrosis of the jawbone (BRONJ) before and after treatment with BISs, PBMT and ESWT. While we did not find that physical therapies altered the mechanical and elemental jawbone parameters with significance (probably due to the small sample size of only up to 5 samples per group), both ESWT and PBMT reduced pore thicknesses and bone-to-enamel distances significantly compared to the controls. Although focused on BIS-treated jawbones, the established CMI platform can be beneficial in the study of bone-related diseases in general (such as osteoarthritis or -porosis) to acquire complementary hallmarks and better characterize disease status and alleviation potentials.

Frequency of syncope as a presenting symptom in channelopathies diagnosed in childhood. Can the multivariable EGSYS score unmask these children?

Pediatric syncope raises cardiac etiology concern as it might be the first sign of life-threatening arrhythmia syndromes. Our aim was to study the incidence of syncope as the presenting symptom in children with arrhythmia syndromes, and if known, warning signs are helpful to reveal the arrhythmic origin. All data on children with channelopathy was followed by a tertiary pediatric cardiac center between 2000 and 2018 and data were reviewed retrospectively. Forty-eight patients were enrolled, representing long QT syndrome (n = 39), catecholaminergic polymorphic ventricular tachycardia (n = 5), and Brugada syndrome (n = 4). Presenting symptoms were syncope in 13 cases [27%] (including 7 initially mislabeled as epilepsy) and sudden cardiac arrest (SCA) in 9 cases [19%]. In the rest of the group, the concern for arrhythmic etiology was raised by either an abnormal ECG during sports medicine screening (n = 13) [27%] or a positive family history of channelopathy (n = 13) [27%]. None of the patients presenting with SCA had a prior syncopal history. Six patients presenting with syncope and afterward treated with ICD had an appropriate shock. Description of witnessed syncope was available in eight out of thirteen children presenting with syncope. Multivariable EGSYS score suggested cardiac origin (≥ 3 points) in 7 out of 8 (88%) patients.Conclusions: Syncope was a relatively uncommon presenting symptom of channelopathies in this sample and did not always precede sudden cardiac arrests. However, we found that multivariable EGSYS score can identify syncope of arrhythmic origin, raising suspicion for pediatric channelopathies even in patients previously misdiagnosed with epilepsy. What is known: • Cardiac syncope is rare in children but can be the first sign of a potentially fatal primary arrhythmia syndrome and is frequently misdiagnosed as atypical/therapy-resistant epilepsy. • Multivariate EGSYS score is effective to diagnose cardiac syncope in adults. What is new: • Cardiac syncope as a presenting symptom is not common in children with cardiac channelopathies and is not often present before sudden cardiac arrest. • Multivariable EGSYS score might identify cardiac syncope in children with a hereditary and secondary channelopathy.

Supraventricular tachycardias in neonates and infants: factors associated with fatal or near-fatal outcome.

Prognosis of supraventricular tachycardias in neonates and infants is thought to be excellent with rare fatal outcomes. Nevertheless, initial management can be challenging. The aim of this study was to perform a retrospective analysis in neonates/infants with non-pos-toperative supraventricular tachycardias regarding risk factors for clinical outcome and type of antiarrhythmic drug therapy. The data of 157 patients aged < 1 year who presented between 2000 and 2015 with symptomatic tachycardias were retrospectively reviewed. Pharmacological therapy was successful in 151 patients (96%); 1 patient (1%) required catheter ablation and 5 patients (3%) died (1 death linked to hemodynamical reasons after effective arrhythmia control). Serious complications following acute medical therapy occurred in 4 patients of survivors. Patients with complications or death had a lower bodyweight, more frequent intrauterine tachycardia, transplacental therapy, urgent caesarian section, higher PRISM II score, longer period to control tachycardia, more frequent proarrhythmia, and major adverse event-defined as life-threatening event without a documented new arrhythmia-compared to the group without complications. There was no significant difference between the groups regarding prematurity, structural heart disease, and type of tachycardia. Proarrhythmia occurred in 6 cases and was related to intravenous drug use with class IC antiarrhythmics in 3/6 cases, digoxin in 2/6 cases, and amiodarone in 1/6 cases. ECG signs of impending proarrhythmia without new-onset arrhythmia requiring cessation of therapy were detected in 6 patients.Conclusion: Although rare, non-post-operative supraventricular tachycardia in neonates and infants might be a serious disease. Acute intravenous pharmacological treatment to control tachycardia might pose a risk for fatal or near-fatal outcome. Detection of proarrhythmia related to class IC antiarrhythmics in neonates might be especially difficult and requires alertness. What is Known • Prognosis of supraventricular tachycardias in children are thought to be excellent with fatal outcomes being rare. • Mortality is increased in the very young and in those with structural heart disease. What is New • Complicated outcome of non-post-operative supraventricular tachycardias in neonates is associated with lower bodyweight, age, prenatal tachycardia, higher PRISM II score, longer period to control tachycardia, and proarrhythmia. • Detection of class IC proarrhythmic effect is especially difficult in neonates because of their narrow QRS and warrants alertness.

The quadrivalent HPV vaccine is protective against genital warts: a meta-analysis.

BACKGROUND: The quadrivalent human papillomavirus (HPV) vaccine has been assumed to give protection against genital warts (GW) as well as cervical cancer. Our main question was whether HPV vaccine has any effects on the prevention of GW reported in randomised controlled clinical trials (RCTs) and time-trend analyses. METHODS: This meta-analysis was performed according to the PRISMA guidelines using the PICO format. We searched in three electronic databases (PubMed, Embase, Cochrane Trials), and assessed heterogeneity using the Q-test and I-squared statistics, meta-regression was also performed. Odds ratios (OR) and their confidence intervals (CI) were calculated. The sensitivity was tested by leave-one-out method. We evaluated the presence of publication bias using the funnel plot graph and the Copas selection model. The strength of evidence was assessed using the GRADE approach. RESULTS: Eight RCTs (per-protocol populations) and eight time-trend ecological studies were included in this meta-analysis. A significant reduction (pooled OR = 0.03, 95% CI: 0.01-0.09; I-squared = 53.6%) of GW in young women was recorded in RCTs, and in time-trend analyses both in young women (pooled OR = 0.36, CI 95% = 0.26-0.51; I-squared = 98.2%), and in young men (pooled OR = 0.69, 95% CI = 0.61-0.78; I-squared = 92.7%). In subgroup analysis, a significant reduction of the number of GW events was observed especially in women under 21 years (pooled OR = 0.33, 95% CI = 0.17-0.63). Leave-one-out analysis showed that similar results could be obtained after excluding one study, meta-regression did not show significant difference. CONCLUSIONS: Prophylactic, quadrivalent HPV vaccination can prevent GW in healthy women and men, therefore, it should be included in routine immunization programme.

Monod-Wyman-Changeux Allosteric Shift Analysis in Mutant α1ß3γ2L GABAA Receptors Indicates Selectivity and Crosstalk among Intersubunit Transmembrane Anesthetic Sites.

Propofol, etomidate, and barbiturate anesthetics are allosteric coagonists at pentameric α1ß3γ2 GABAA receptors, modulating channel activation via four biochemically established intersubunit transmembrane pockets. Etomidate selectively occupies the two ß +/α - pockets, the barbiturate photolabel R-5-allyl-1-methyl-5-(m-trifluoromethyl-diazirynylphenyl) barbituric acid (R-mTFD-MPAB) occupies homologous α +/ß - and γ +/ß - pockets, and propofol occupies all four. Functional studies of mutations at M2-15' or M3-36' loci abutting these pockets provide conflicting results regarding their relative contributions to propofol modulation. We electrophysiologically measured GABA-dependent channel activation in α1ß3γ2L or receptors with single M2-15' (α1S270I, ß3N265M, and γ2S280W) or M3-36' (α1A291W, ß3M286W, and γ2S301W) mutations, in the absence and presence of equipotent clinical range concentrations of etomidate, R-mTFD-MPAB, and propofol. Estimated open probabilities were calculated and analyzed using global two-state Monod-Wyman-Changeux models to derive log(d) parameters proportional to anesthetic-induced channel modulating energies (where d is the allosteric anesthetic shift factor). All mutations reduced the log(d) values for anesthetics occupying both abutting and nonabutting pockets. The Δlog(d) values [log(d, mutant) - log(d, wild type)] for M2-15' mutations abutting an anesthetic's biochemically established binding sites were consistently larger than the Δlog(d) values for nonabutting mutations, although this was not true for the M3-36' mutant Δlog(d) values. The sums of the anesthetic-associated Δlog(d) values for sets of M2-15' or M3-36' mutations were all much larger than the wild-type log(d) values. Mutant Δlog(d) values qualitatively reflect anesthetic site occupancy patterns. However, the lack of Δlog(d) additivity undermines quantitative comparisons of distinct site contributions to anesthetic modulation because the mutations impaired both abutting anesthetic binding effects and positive cooperativity between anesthetic binding sites.

Neuronal Nitric Oxide Mediates the Anti-inflammatory Effects of Intestinal Ischemic Preconditioning.

BACKGROUND: Ischemic preconditioning (IPC) can provide a defense against ischemia-reperfusion (IR)-induced acute inflammation and barrier dysfunction in many organs. Because nitric oxide (NO) has been implicated as a trigger or mediator in the IPC mechanism and because neuronal NO synthase (nNOS) is a dominant isoform of NOS in the gastrointestinal tract, our aim was to investigate the role of nNOS in IPC-induced protection after mesenteric IR. MATERIALS AND METHODS: Intestinal IR was induced in sodium pentobarbital-anesthetized dogs by clamping the superior mesenteric artery for 60 min followed by 2 h of reperfusion (IR group; n = 7). In further groups, IPC was used (three cycles of 5-min ischemia/5-min reperfusion periods) before IR in the presence or absence of selective inhibition of nNOS with 7-nitroindazole (5 mg/kg, intravenously, in a bolus 15 min before IPC, n = 6 each). Changes in mesenteric vascular resistance, intramucosal pH (pHi), and small bowel motility were monitored. Plasma nitrite/nitrate levels, intestinal NO synthase activity, leukocyte accumulation, mast cell degranulation, and histologic injury were also determined. RESULTS: Ischemia significantly decreased mesenteric vascular resistance and pHi, whereas IR induced a temporary bowel hypermotility and acute inflammatory reaction. IPC facilitated pHi recovery, attenuated motility dysfunction, elevated NOS-dependent NO production, and reduced leukocyte accumulation, mast cell degranulation, and mucosal injury. Pretreatment with 7-nitroindazole halted the IPC-induced increase in NO availability, pHi recovery, and the anti-inflammatory and morphologic effects. CONCLUSIONS: Our data demonstrate that NO generated by intestinal nNOS plays a pivotal role in IPC-linked tissue protection by inhibiting an IR-related acute inflammatory response.

Abdominal obesity increases metabolic risk factors in non-obese adults: a Hungarian cross-sectional study.

BACKGROUND: The prevalence of abdominal obesity is increasing worldwide. Adults with abdominal obesity have been reported to have increased risk of cardiometabolic disorders. The aim of this study was to examine whether non-obese subjects (body mass index (BMI) < 25 kg/m2) with abdominal obesity examined in the framework of the Swiss-Hungarian Cooperation Programme had increased metabolic risk compared to participants without abdominal obesity. METHODS: A cross-sectional study was carried out in 5228 non-obese individuals. Data were collected between July 2012 and February 2016. Descriptive statistics, Pearson's correlation analysis and multiple logistic regression models were applied, odds ratios (OR) with 95% confidence interval (CI) being the outcomes. RESULTS: 607 (11.6%) out of the 5228 non-obese individuals had abdominal obesity. The correlation analysis indicated that the correlation coefficients between BMI and waist circumference (WC) were 0.610 in males and 0.526 in females. In this subgroup, the prevalence of high systolic blood pressure, high fasting blood glucose, and high total cholesterol and triglyceride levels were significantly higher. The logistic regression model based on these data showed significantly higher risk for developing high systolic blood pressure (OR = 1.53; 95% CI = 1.20-1.94), low HDL cholesterol (OR = 2.06; 95% CI = 1.09-3.89), and high trygliceride level (OR = 1.65; 95% CI = 1.27-2.16). CONCLUSIONS: There was a very high, significant, positive correlation between WC and BMI. Abdominal obesity was found to be strongly related to certain metabolic risk factors among non-obese subjects. Hence, measuring waist circumference could be recommended as a simple and efficient tool for screening abdominal obesity and related metabolic risk even in non-obese individuals.

Effects of goal-directed crystalloid vs. colloid fluid therapy on microcirculation during free flap surgery: A randomised clinical trial.

BACKGROUND: Macro, and microcirculatory effects of crystalloids and colloids are difficult to compare, because interventions to achieve haemodynamic stability seldom follow similar criteria. OBJECTIVES: Our aim was to compare the effects of crystalloids and colloids on the microcirculation during free flap surgery when management was guided by detailed haemodynamic assessment. DESIGN: A randomised, controlled clinical trial. SETTINGS: The investigation was performed at the University of Szeged, Hungary. PATIENTS: Patients undergoing maxillofacial tumour resection and free flap reconstruction were randomised into groups treated with either intra-operative crystalloid (Ringerfundin, n = 15) or colloid (6% hydroxyethyl starch, HES, n = 15) solutions. INTERVENTIONS: Macrohaemodynamics were monitored by a noncalibrated device (PulsioFlex-PULSION). Central venous oxygen saturation, venous-to-arterial PCO2-gap, lactate levels and urine output were measured hourly. Maintenance fluid was Ringerfundin (1 ml kg h), and a multimodal, individualised, approach-based algorithm was applied to guide haemodynamic support. Hypovolaemia was treated with Ringerfundin or HES fluid boluses, respectively. The microcirculatory effects were assessed by laser-Doppler flowmetry (PeriFlux 5000 LDPM), with the probe placed on the flap and on a control area. Measurements were performed after the flap was prepared, then 1 and 12 h later. MAIN OUTCOME MEASURES: The primary end-point was microcirculatory perfusion as determined by laser-Doppler flowmetry. RESULTS: There was no difference between the groups regarding patient characteristics. Both groups remained haemodynamically stable throughout due to the use of approximately a 1.5 times higher total fluid volume in the Ringerfundin group than in the HES group: mean ±â€ŠSD: 2581 ±â€Š986 and 1803 ±â€Š497) ml, respectively, (P = 0.011). There was no significant difference in the microcirculatory blood flow between the groups. CONCLUSION: Our results showed that when fluid management was guided by detailed haemodynamic assessment, more crystalloid than colloid was needed to maintain haemodynamic stability, but there was no difference between the effects of crystalloids and colloids on the microcirculation. TRIAL REGISTRATION: ClinicalTrials.gov NCT03288051.

Alphaxalone Binds in Inner Transmembrane ß+-α- Interfaces of α1ß3γ2 γ-Aminobutyric Acid Type A Receptors.

BACKGROUND: Neurosteroids like alphaxalone are potent anxiolytics, anticonvulsants, amnestics, and sedative-hypnotics, with effects linked to enhancement of γ-aminobutyric acid type A (GABAA) receptor gating in the central nervous system. Data locating neurosteroid binding sites on synaptic αßγ GABAA receptors are sparse and inconsistent. Some evidence points to outer transmembrane ß-α interfacial pockets, near sites that bind the anesthetics etomidate and propofol. Other evidence suggests that steroids bind more intracellularly in ß-α interfaces. METHODS: The authors created 12 single-residue ß3 cysteine mutations: ß3T262C and ß3T266C in ß3-M2; and ß3M283C, ß3Y284C, ß3M286C, ß3G287C, ß3F289C, ß3V290C, ß3F293C, ß3L297C, ß3E298C, and ß3F301C in ß3-M3 helices. The authors coexpressed α1 and γ2L with each mutant ß3 subunit in Xenopus oocytes and electrophysiologically tested each mutant for covalent sulfhydryl modification by the water-soluble reagent para-chloromercuribenzenesulfonate. Then, the authors assessed whether receptor-bound alphaxalone, etomidate, or propofol blocked cysteine modification, implying steric hindrance. RESULTS: Eleven mutant ß3 subunits, when coexpressed with α1 and γ2L, formed functional channels that displayed varied sensitivities to the three anesthetics. Exposure to para-chloromercuribenzenesulfonate produced irreversible functional changes in ten mutant receptors. Protection by alphaxalone was observed in receptors with ß3V290C, ß3F293C, ß3L297C, or ß3F301C mutations. Both etomidate and propofol protected receptors with ß3M286C or ß3V290C mutations. Etomidate also protected ß3F289C. In α1ß3γ2L structural homology models, all these protected residues are located in transmembrane ß-α interfaces. CONCLUSIONS: Alphaxalone binds in transmembrane ß-α pockets of synaptic GABAA receptors that are adjacent and intracellular to sites for the potent anesthetics etomidate and propofol.

Microcirculatory effects of sildenafil in experimental testicular torsion in rats.

PURPOSE: Investigate the short-term effect of sildenafil on microcirculation, especially the velocity, the pattern of the flow and the recruitment of the leukocyte in postcapillaries. METHODS: In male Sprague-Dawley rats, the microcirculatory consequences of 60 min experimental testicular torsion, followed by 240 min of reperfusion, were examined. Using fluorescence intravital microscopy, changes in red blood cell velocity in post-capillary venules and rolling as well as adhesion of leukocytes in the postcapillary venules were examined before the torsion and every hour during the reperfusion period. Sildenafil was given 10 min prior to reperfusion (iv 0.7 mg/kg, n = 6), while control animals received saline vehicle (n = 5). RESULTS: The characteristic flow motion disappeared in the affected testicular during the torsion. Red blood cell velocity values were dramatically decreased (by > 50%) and both rolling and adhesion of leukocytes increased during the reperfusion phase. Sildenafil treatment resulted in significantly higher red blood cell velocity values during the entire reperfusion period, but exerted only a temporary positive effect on the plost-ischaemic leukocyte-endothelial interactions. CONCLUSIONS: Intraoperative administration of sildenafil during surgical detorsion may provide marked testicular microperfusion benefits, but failed to influence the overall leukocyte-driven microcirculatory inflammatory reactions.

Capsaicin-induced rapid neutrophil leukocyte activation in the rat urinary bladder microcirculatory bed.

AIMS: This study was initiated to investigate the involvement of neutrophil leukocyte activation in neurogenic inflammation, a process also involved in human urinary pathologies, elicited in the rat urinary bladder by the local administration of capsaicin, the archetypal TRPV1 agonist. The contribution of afferent nerves and sensory neuropeptides to leukocyte activation in the urinary bladder microcirculatory bed was examined. METHODS: Following a 15-min topical application of capsaicin (50 µM), leukocyte-endothelial interactions were examined for an observation period of 45 min with intravital microscopy. Expression of adhesion molecules E-selectin and ICAM-1 implicated in these interactions was assessed by immunohistochemistry. Selective sensory denervation was performed by neonatal treatment with capsaicin. The role of the TRPV1 receptor and two sensory neuropeptides (CGRP and substance P [SP]) were studied using the selective antagonists capsazepine, CGRP8-37 and RP67580, respectively. RESULTS: Capsaicin induced rapid increases in leukocyte rolling and adhesion and increased the expression of E-selectin and ICAM-1 in the postcapillary venules. Sensory chemodenervation via capsaicin and also TRPV1 receptor antagonism effectively prevented these changes. A similar reduction was observed in leukocyte adhesion after topical application of CGRP8-34 or RP67580, but only CGRP8-34 reduced the capsaicin-evoked leukocyte rolling. CONCLUSIONS: Topical application of capsaicin induces early neurogenically mediated cellular microcirculatory inflammatory reactions via the activation of the TRPV1 receptor and the release of CGRP and SP from sensory nerves in the bladder. Co-administration of SP and CGRP receptor antagonists may ameliorate microcirculatory inflammatory changes elicited by capsaicin in the urinary bladder.

The periosteal microcirculation in health and disease: An update on clinical significance.

Apart from its nutritive functions, the periosteum critically affects bone regeneration via its stem/osteoprogenitor cell content. Normal healing after bone fractures, trauma-orthopedic interventions and invasive dental procedures is critically linked to the reestablishment of the periosteal microcirculation, but the reconstruction, replacement or repair of lost tissues may also be performed with autologous periosteum. Besides the initiation of cell differentiation during bone repair and remodeling processes, the periosteum together with the endosteum plays significant roles in the pathogenesis of both hormone-related and trauma-induced osteoporotic alterations in the bone metabolism. Nevertheless, the axial bones, and in particular the jawbones, and the appendicular bones display differences not only in their blood supply and fracture healing characteristics, but also in respect of the development of osteoporosis and their reactions to treatment modalities (i.e. bisphosphonates). These reactions may also be linked to the differences in periosteal microcirculatory reactions. The present overview summarizes the relevant data of microcirculatory studies focusing on the periosteal reactions in different anatomical locations together with the optimal background methodologies, study models and the most significant observations.

Neurotoxic effects of subchronic intratracheal Mn nanoparticle exposure alone and in combination with other welding fume metals in rats.

Manganese (Mn) is a toxic heavy metal exposing workers in various occupational settings and causing, among others, nervous system damage. Metal fumes of welding, a typical source of Mn exposure, contain a complex mixture of metal oxides partly in nanoparticle form. As toxic effects of complex substances cannot be sufficiently understood by examining its components separately, general toxicity and functional neurotoxicity of a main pathogenic welding fume metal, Mn, was examined alone and combined with iron (Fe) and chromium (Cr), also frequently found in fumes. Oxide nanoparticles of Mn, Mn + Fe, Mn + Cr and the triple combination were applied, in aqueous suspension, to the trachea of young adult Wistar rats for 4 weeks. The decrease of body weight gain during treatment, caused by Mn, was counteracted by Fe, but not Cr. At the end of treatment, spontaneous and evoked cortical electrical activity was recorded. Mn caused a shift to higher frequencies, and lengthened evoked potential latency, which were also strongly diminished by co-application of Fe only. The interaction of the metals seen in body weight gain and cortical activity were not related to the measured blood and brain metal levels. Fe might have initiated protective, e.g. antioxidant, mechanisms with a more general effect.

Protective effect of green tea against neuro-functional alterations in rats treated with MnO2 nanoparticles.

BACKGROUND: Inhalation of manganese-containing metal fumes at workplaces can cause central nervous damage including a Parkinson-like syndrome. Oxidative stress is likely to be involved in the pathomechanism, due to the presence of nano-sized metal oxide particles with high biological and chemical activity. Oxidative damage of the nervous system could be prevented or ameliorated by properly applied antioxidants, preferably natural ones such as green tea, a popular drink. The aim of this work was to see if orally applied green tea brew could diminish the functional neurotoxicity of manganese dioxide nanoparticles introduced into the airways of rats. RESULTS: Young adult male Wistar rats were treated intratracheally for 6 weeks with a suspension of synthetic MnO2 nanoparticles (4 mg/kg body weight), and received green tea brew (1 g leaves 200 mL-1 water) as drinking fluid. Reduced body weight gain, indicating general toxicity of the nanoparticles, was not influenced by green tea. However, in rats receiving green tea the nervous system effects - changes in the spontaneous and evoked cortical activity and peripheral nerve action potential - were diminished. CONCLUSION: The use of green tea as a neuroprotective functional drink seems to be a viable approach. © 2016 Society of Chemical Industry.

Tryptophan and Cysteine Mutations in M1 Helices of α1ß3γ2L γ-Aminobutyric Acid Type A Receptors Indicate Distinct Intersubunit Sites for Four Intravenous Anesthetics and One Orphan Site.

BACKGROUND: γ-Aminobutyric acid type A (GABAA) receptors mediate important effects of intravenous general anesthetics. Photolabel derivatives of etomidate, propofol, barbiturates, and a neurosteroid get incorporated in GABAA receptor transmembrane helices M1 and M3 adjacent to intersubunit pockets. However, photolabels have not been consistently targeted at heteromeric αßγ receptors and do not form adducts with all contact residues. Complementary approaches may further define anesthetic sites in typical GABAA receptors. METHODS: Two mutation-based strategies, substituted tryptophan sensitivity and substituted cysteine modification-protection, combined with voltage-clamp electrophysiology in Xenopus oocytes, were used to evaluate interactions between four intravenous anesthetics and six amino acids in M1 helices of α1, ß3, and γ2L GABAA receptor subunits: two photolabeled residues, α1M236 and ß3M227, and their homologs. RESULTS: Tryptophan substitutions at α1M236 and positional homologs ß3L231 and γ2L246 all caused spontaneous channel gating and reduced γ-aminobutyric acid EC50. Substituted cysteine modification experiments indicated etomidate protection at α1L232C and α1M236C, R-5-allyl-1-methyl-5-(m-trifluoromethyl-diazirinylphenyl) barbituric acid protection at ß3M227C and ß3L231C, and propofol protection at α1M236C and ß3M227C. No alphaxalone protection was evident at the residues the authors explored, and none of the tested anesthetics protected γ2I242C or γ2L246C. CONCLUSIONS: All five intersubunit transmembrane pockets of GABAA receptors display similar allosteric linkage to ion channel gating. Substituted cysteine modification and protection results were fully concordant with anesthetic photolabeling at α1M236 and ß3M227 and revealed overlapping noncongruent sites for etomidate and propofol in ß-α interfaces and R-5-allyl-1-methyl-5-(m-trifluoromethyl-diazirinylphenyl) barbituric acid and propofol in α-ß and γ-ß interfaces. The authors' results identify the α-γ transmembrane interface as a potentially unique orphan modulator site.

Green tea and vitamin C ameliorate some neuro-functional and biochemical signs of arsenic toxicity in rats.

BACKGROUND/OBJECTIVES: Nervous system damage is one of the consequences of oral exposure to waterborne inorganic arsenic. In this work, the role of oxidative status in the neurotoxicity of arsenic and the possible role of two foodborne antioxidants in ameliorating arsenic-related oxidative stress were investigated. METHODS: Male Wistar rats were given 10 mg/kg b.w. of trivalent inorganic arsenic (in the form of NaAsO2), 5 day/week for 6 weeks by gavage, combined with vitamin C solution (1 g/l) or green tea infusion (2.5 g in 500 ml boiled water) as antioxidants given in the drinking fluid. RESULTS: Body weight gain was reduced by arsenic from the second week and the antioxidants had no effect on that. Cortical evoked potentials had increased latency, tail nerve conduction velocity was reduced, and this latter effect was counteracted by the antioxidants. The effect of green tea was stronger than that of vitamin C, and green tea also diminished lipid peroxidation induced by As. There was fair correlation between brain As levels, electrophysiological changes, and lipid peroxidation, suggesting a causal relationship. DISCUSSION: Natural antioxidants might be useful in the protection of the central nervous system against the toxicity of oral As.

[Long-term adalimumab therapy in ulcerative colitis in clinical practice: result of the Hungarian multicenter prospective study]. / Az adalimumab hatékonysága és biztonságossága hagyományos kezelésre refrakter colitis ulcerosában.

INTRODUCTION: Adalimumab was approved for the treatment of ulcerative colitis refractory to conventional therapy several years later than infliximab in Europe. Due to the relatively low remission rate observed in Ultra trials, data on the efficacy of adalimumab in ulcerative colitis are really helpful in the daily practice. AIM: The aim of this study was to prospectively collect data on induction and maintenance adalimumab therapy in patients with ulcerative colitis treated in Hungarian centres. METHOD: This prospective study collected data of all patients with ulcerative colitis treated with adalimumab in 10 Hungarian centres. The primary endpoints of the study were rates of remission, response and primary failure at week 12, and the rate of continuous clinical response, remission and loss of response at weeks 30, and 52. Secondary endpoints were endoscopic outcome at week 52 and comparison of the efficacy of adalimumab between treatment naive and infliximab-experienced patients. RESULTS: 73 patients with active ulcerative colitis were enrolled in the study. 75.3% of the patients exhibited clinical response after the induction at week 12. The probability of maintaining adalimumab treatment was 48.6% at week 52 with a continuous clinical response in 92% of these patients. Mucosal healing was achieved in 48.1% of the patients at week 52. Dose intensification was performed in 17.6% of the patients. Minor side effects developed in 4% of the patients and 5.4% of the patients underwent colectomy during the 1-year treatment period. CONCLUSIONS: These results coming from the real clinical setting demonstrate a favourable efficacy of adalimumab induction and maintenance therapy in patients with ulcerative colitis.