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ImportanceThe longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown.ObjectiveTo determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes.Design, Setting, and ParticipantsPrespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022.InterventionsPatients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401).Main Outcomes and MeasuresThe main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83.ResultsAmong 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies.Conclusions and RelevanceAmong critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.

Objective: To describe a case of idiopathic cricopharyngeal achalasia (CPA) in a pediatric patient with acute onset of dysphagia managed conservatively with supportive care. Methods: Sixteen-month-old boy presented with acute onset of gagging and coughing with feeding. His exam was notable for a well-appearing child with pooling of oral secretions and coarse breath sounds. Plain film series did not show radio-opaque foreign body (FB) and an esophagram demonstrated an endoluminal filling defect of the cervical esophagus and aspiration of contrast. He was taken to the operating room for urgent endoscopy but no FB or food impaction was observed. He had persistent symptoms that required further evaluation and a multidisciplinary team approach. Bedside laryngoscopy did not reveal any abnormalities. Modified barium swallow (MBS) study revealed upper esophageal sphincter (UES) dysfunction, consistent with cricopharyngeal achalasia. Repeat upper endoscopy with biopsies demonstrated mucosal irritation overlying the UES but histologic studies were negative for infectious causes. Results: He was treated with supportive care, including nasogastric feedings for nutrition supplementation as he was unable to tolerate oral feedings without aspiration. Over the course of 3 months after discharge, his symptoms resolved and repeat MBS was normal. Conclusion: CPA is a rare cause of dysphagia in the pediatric population. Conservative management with supportive care is a reasonable approach in cases with acute onset in otherwise healthy children without underlying medical problems.

Background: Vitamin D deficiency (VDD) may be considered an independent cardiovascular (CV) risk factor, and it is well known that CV risk is higher in males. Our goal was to investigate the pharmacological reactivity and receptor expression of intramural coronary artery segments of male rats in cases of different vitamin D supply. Methods: Four-week-old male Wistar rats were divided into a control group (n = 11) with optimal vitamin D supply (300 IU/kgbw/day) and a VDD group (n = 11, &lt, 0.5 IU/kgbw/day). After 8 weeks of treatment, intramural coronary artery segments were microprepared, their pharmacological reactivity was examined by in vitro microangiometry, and their receptor expression was investigated by immunohistochemistry. Results: Thromboxane A2 (TXA2)-agonist induced reduced vasoconstriction, testosterone (T) and 17-β-estradiol (E2) relaxations were significantly decreased, a significant decrease in thromboxane receptor (TP) expression was shown, and the reduction in estrogen receptor-α (ERα) expression was on the border of significance in the VDD group. Conclusions: VD-deficient male coronary arteries showed deteriorated pharmacological reactivity to TXA2 and sexual steroids (E2, T). Insufficient vasoconstrictor capacity was accompanied by decreased TP receptor expression, and vasodilator impairments were mainly functional. The decrease in vasoconstrictor and vasodilator responses results in narrowed adaptational range of coronaries, causing inadequate coronary perfusion that might contribute to the increased CV risk in VDD.

Ibuprofen is a widely used nonsteroidal anti-inflammatory drug, which has recently been associated with increased cardiovascular risk, but its electrophysiological effects have not yet been properly studied in isolated cardiac preparations. We studied the effects of ibuprofen on action potential characteristics and several transmembrane ionic currents using the conventional microelectrode technique and the whole-cell configuration of the patch-clamp technique on cardiac preparations and enzymatically isolated ventricular myocytes. In dog (200 µM; n = 6) and rabbit (100 µM; n = 7) papillary muscles, ibuprofen moderately but significantly prolonged repolarization at 1 Hz stimulation frequency. In dog Purkinje fibers, repolarization was abbreviated and maximal rate of depolarization was depressed in a frequency-dependent manner. Levofloxacin (40 µM) alone did not alter repolarization, but augmented the ibuprofen-evoked repolarization lengthening in rabbit preparations (n = 7). In dog myocytes, ibuprofen (250 µM) did not significantly influence IK1, but decreased the amplitude of Ito and IKr potassium currents by 28.2% (60 mV) and 15.2% (20 mV), respectively. Ibuprofen also depressed INaL and ICa currents by 19.9% and 16.4%, respectively. We conclude that ibuprofen seems to be free from effects on action potential parameters at lower concentrations. However, at higher concentrations it may alter repolarization reserve, contributing to the observed proarrhythmic risk in patients.

Background & Aims Liver fibrosis is a multifactorial trait that develops in response to chronic liver injury. Our aim was to characterize the genetic architecture of carbon tetrachloride (CCl4)-induced liver fibrosis using the Hybrid Mouse Diversity Panel, a panel of more than 100 genetically distinct mouse strains optimized for genome-wide association studies and systems genetics. Methods Chronic liver injury was induced by CCl4 injections twice weekly for 6 weeks. Four hundred thirty-seven mice received CCl4 and 256 received vehicle, after which animals were euthanized for liver histology and gene expression. Using automated digital image analysis, we quantified fibrosis as the collagen proportionate area of the whole section, excluding normal collagen. Results We discovered broad variation in fibrosis among the Hybrid Mouse Diversity Panel strains, demonstrating a significant genetic influence. Genome-wide association analyses revealed significant and suggestive loci underlying susceptibility to fibrosis, some of which overlapped with loci identified in mouse crosses and human population studies. Liver global gene expression was assessed by RNA sequencing across the strains, and candidate genes were identified using differential expression and expression quantitative trait locus analyses. Gene set enrichment analyses identified the underlying pathways, of which stellate cell involvement was prominent, and coexpression network modeling identified modules associated with fibrosis. Conclusions Our results provide a rich resource for the design of experiments to understand mechanisms underlying fibrosis and for rational strain selection when testing antifibrotic drugs., Graphical abstract

Background Microstructural MRI has the potential to improve diagnosis and characterization of prostate cancer (PCa), but validation with histopathology is lacking. Purpose To validate ex vivo diffusion-relaxation correlation spectrum imaging (DR-CSI) in the characterization of microstructural tissue compartments in prostate specimens from men with PCa by using registered whole-mount digital histopathology (WMHP) as the reference standard. Materials and Methods Men with PCa who underwent 3-T MRI and robotic-assisted radical prostatectomy between June 2018 and January 2019 were prospectively studied. After prostatectomy, the fresh whole prostate specimens were imaged in patient-specific three-dimensionally printed molds by using 3-T MRI with DR-CSI and were then sliced to create coregistered WMHP slides. The DR-CSI spectral signal component fractions (fA, fB, fC) were compared with epithelial, stromal, and luminal area fractions (fepithelium, fstroma, flumen) quantified in PCa and benign tissue regions. A linear mixed-effects model assessed the correlations between (fA, fB, fC) and (fepithelium, fstroma, flumen), and the strength of correlations was evaluated by using Spearman correlation coefficients. Differences between PCa and benign tissues in terms of DR-CSI signal components and microscopic tissue compartments were assessed using two-sided t tests. Results Prostate specimens from nine men (mean age, 65 years ± 7 [standard deviation]) were evaluated; 20 regions from 17 PCas, along with 20 benign tissue regions of interest, were analyzed. Three DR-CSI spectral signal components (spectral peaks) were consistently identified. The fA, fB, and fC were correlated with fepithelium, fstroma, and flumen (all P < .001), with Spearman correlation coefficients of 0.74 (95% confidence interval [CI]: 0.62, 0.83), 0.80 (95% CI: 0.66, 0.89), and 0.67 (95% CI: 0.51, 0.81), respectively. PCa exhibited differences compared with benign tissues in terms of increased fA (PCa vs benign, 0.37 ± 0.05 vs 0.27 ± 0.06; P < .001), decreased fC (PCa vs benign, 0.18 ± 0.06 vs 0.31 ± 0.13; P = .01), increased fepithelium (PCa vs benign, 0.44 ± 0.13 vs 0.26 ± 0.16; P < .001), and decreased flumen (PCa vs benign, 0.14 ± 0.08 vs 0.27 ± 0.18; P = .004). Conclusion Diffusion-relaxation correlation spectrum imaging signal components correlate with microscopic tissue compartments in the prostate and differ between cancer and benign tissue. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Lee and Hectors in this issue.

BackgroundBetter understanding of the association between characteristics of patients hospitalized with coronavirus disease 2019 (COVID-19) and outcome is needed to further improve upon patient management.MethodsImmunophenotyping Assessment in a COVID-19 Cohort (IMPACC) is a prospective, observational study of 1164 patients from 20 hospitals across the United States. Disease severity was assessed using a 7-point ordinal scale based on degree of respiratory illness. Patients were prospectively surveyed for 1 year after discharge for post-acute sequalae of COVID-19 (PASC) through quarterly surveys. Demographics, comorbidities, radiographic findings, clinical laboratory values, SARS-CoV-2 PCR and serology were captured over a 28-day period. Multivariable logistic regression was performed.FindingsThe median age was 59 years (interquartile range [IQR] 20); 711 (61%) were men; overall mortality was 14%, and 228 (20%) required invasive mechanical ventilation. Unsupervised clustering of ordinal score over time revealed distinct disease course trajectories. Risk factors associated with prolonged hospitalization or death by day 28 included age ≥ 65 years (odds ratio [OR], 2.01; 95% CI 1.28-3.17), Hispanic ethnicity (OR, 1.71; 95% CI 1.13-2.57), elevated baseline creatinine (OR 2.80; 95% CI 1.63- 4.80) or troponin (OR 1.89; 95% 1.03-3.47), baseline lymphopenia (OR 2.19; 95% CI 1.61-2.97), presence of infiltrate by chest imaging (OR 3.16; 95% CI 1.96-5.10), and high SARS-CoV2 viral load (OR 1.53; 95% CI 1.17-2.00). Fatal cases had the lowest ratio of SARS-CoV-2 antibody to viral load levels compared to other trajectories over time (p=0.001). 589 survivors (51%) completed at least one survey at follow-up with 305 (52%) having at least one symptom consistent with PASC, most commonly dyspnea (56% among symptomatic patients). Female sex was the only associated risk factor for PASC.InterpretationIntegration of PCR cycle threshold, and antibody values with demographics, comorbidities, and laboratory/radiographic findings identified risk factors for 28-day outcome severity, though only female sex was associated with PASC. Longitudinal clinical phenotyping offers important insights, and provides a framework for immunophenotyping for acute and long COVID-19.FundingNIH.

Transient receptor potential melastatin 4 (TRPM4) plays an important role in many tissues, including pacemaker and conductive tissues of the heart, but much less is known about its electrophysiological role in ventricular myocytes. Our earlier results showed the lack of selectivity of 9-phenanthrol, so CBA ((4-chloro-2-(2-chlorophenoxy)acetamido) benzoic acid) was chosen as a new, potentially selective inhibitor. Goal: Our aim was to elucidate the effect and selectivity of CBA in canine left ventricular cardiomyocytes and to study the expression of TRPM4 in the canine heart. Experiments were carried out in enzymatically isolated canine left ventricular cardiomyocytes. Ionic currents were recorded with an action potential (AP) voltage-clamp technique in whole-cell configuration at 37 °C. An amount of 10 mM BAPTA was used in the pipette solution to exclude the potential activation of TRPM4 channels. AP was recorded with conventional sharp microelectrodes. CBA was used in 10 µM concentrations. Expression of TRPM4 protein in the heart was studied by Western blot. TRPM4 protein was expressed in the wall of all four chambers of the canine heart as well as in samples prepared from isolated left ventricular cells. CBA induced an approximately 9% reduction in AP duration measured at 75% and 90% of repolarization and decreased the short-term variability of APD90. Moreover, AP amplitude was increased and the maximal rates of phase 0 and 1 were reduced by the drug. In AP clamp measurements, CBA-sensitive current contained a short, early outward and mainly a long, inward current. Transient outward potassium current (Ito) and late sodium current (INa,L) were reduced by approximately 20% and 47%, respectively, in the presence of CBA, while L-type calcium and inward rectifier potassium currents were not affected. These effects of CBA were largely reversible upon washout. Based on our results, the CBA induced reduction of phase-1 slope and the slight increase of AP amplitude could have been due to the inhibition of Ito. The tendency for AP shortening can be explained by the inhibition of inward currents seen in AP-clamp recordings during the plateau phase. This inward current reduced by CBA is possibly INa,L, therefore, CBA is not entirely selective for TRPM4 channels. As a consequence, similarly to 9-phenanthrol, it cannot be used to test the contribution of TRPM4 channels to cardiac electrophysiology in ventricular cells, or at least caution must be applied.

The SARS-CoV-2 pandemic, which started in December 2019, has been posing significant challenges to the health care system worldwide. As the pandemic spreads with rapidly increasing number of positive cases, early diagnosis of infected patients is crucial to successfully limit the spread of the virus. Although the real-time reverse-transcription polymerase chain reaction (RT-qPCR) is the recommended laboratory method to diagnose COVID-19 infection, many factors such as availability of laboratory equipment, reagents and trained personnel affect the use of time-consuming molecular techniques. To facilitate on-the-spot diagnosis of COVID-19, SARS-CoV-2 rapid antigen tests were developed by several different manufacturers. The evaluation of such rapid tests is particularly important due to the recent unanimous agreement by the European Commission Member States on a recommendation setting out a framework for the use of antigen rapid tests that contains a list of the mutually recognized assays and the basis of independent validation protocols. To evaluate the on-field performance of ten commercially available SARS-CoV-2 antigen rapid tests (CLINITEST Rapid COVID-19 Antigen Test, GenBody COVID-19 Antigen Test, GENEDIA W COVID-19 Ag Test, Healgen Coronavirus Antigen Rapid Test, Humasis COVID-19 Ag Test, VivaDiag SARS-CoV-2 Ag Rapid Test, Helix i-SARS-CoV-2 Ag Rapid Test, Roche SARS-CoV-2 Rapid Antigen Test, Abbot COVID-19 Ag Rapid Test and Vazyme SARS-CoV-2 Antigen Detection Kit) and compare with RT-qPCR as a reference method, the Hungarian National Public Health Center provided 1,597 antigen rapid tests to the National Ambulance Service, COVID-testing trucks and two hospitals treating COVID-19 patients. Sensitivity, specificity and accuracy were determined by performing the rapid test directly from nasopharyngeal swab samples of symptomatic individuals. For strongly positive samples (Ct < 25) sensitivities ranged between 66.7% and 100%, while for positive samples (Ct < 30) they gave a maximum sensitivity of 87.5%. The specificity of the tests was ranging between 79% to 100%. The results presented here are of high importance to the European Commission and also help governmental decision-making regarding the application of the proper rapid tests for screening different at-risk populations. Nonetheless, SARS-Cov-2 rapid tests play an important role in early and on-the-spot diagnosis of potentially infected individuals.

The purpose of this study was to examine the epidemiology, demographics, injury characteristics and outcomes of patients who presented to Swiss trauma centers following severe penetrating trauma.Swiss Trauma Registry (STR)-cohort analysis including patients with severe (ISS ≥ 16 or AIS head ≥ 3) penetrating trauma between 2017 and 2019. Primary outcome was mortality. Secondary outcomes were hospital and intensive care unit (ICU) length of stay (LOS), and prehospital times.During the 3-year study period, 134 (1.6% of entire STR) patients with severe penetrating trauma were identified [64 (48%) gunshot wounds (GSW), 70 (52%) stab wounds (SW)]. Median age was 40.5 (IQR 29.0-59.0) and 82.8% were male. Mortality rate was 50% for GSW; 9% for SW. Overall, prehospital time [incident to arrival emergency department (ED)] was 65 (IQR 45-94) minutes. The median number of patients admitted for a severe GSW/SW per center and year was 2 (range 0-14). Of 64 patients who sustained a GSW, 42 (65.6%) were self-inflicted. Mortality in self-inflicted GSW reached 66.7%, with the head being severely injured in 78.6%. The 67 patients with severe isolated torso GSW/SW had an ISS of 20 (IQR 16-26) and a mortality of 15%. Multivariable analysis identified severe chest trauma, ED Glasgow Coma Scale ≤ 8, age, self-infliction, massive blood transfusion and ISS as independent predictors for mortality.Severe penetrating trauma is very rare in Switzerland. Mortality ranges from 9% in SW to 67% in self-inflicted GSW. Particularly in the setting of GSW/SW to the torso, reduction in prehospital time may further improve patient outcomes.

Background and Objectives: West Nile virus (WNV) is one of the most important viral zoonotic infections in Hungary; however, no transfusion-transmitted WNV infections have been confirmed s...

Background The anterior cingulate cortex (ACC) is a key structure of the pain processing network. Several structural and functional alterations of this brain area have been found in migraine. In addition, altered serotonergic neurotransmission has been repeatedly implicated in the pathophysiology of migraine, although the exact mechanism is not known. Thus, our aim was to investigate the relationship between acute increase of brain serotonin (5-HT) level and the activation changes of the ACC using pharmacological challenge MRI (phMRI) in migraine patients and healthy controls. Methods Twenty-seven pain-free healthy controls and six migraine without aura patients participated in the study. All participant attended to two phMRI sessions during which intravenous citalopram, a selective serotonin reuptake inhibitor (SSRI), or placebo (normal saline) was administered. We used region of interest analysis of ACC to compere the citalopram evoked activation changes of this area between patients and healthy participants. Results Significant difference in ACC activation was found between control and patient groups in the right pregenual ACC (pgACC) during and after citalopram infusion compared to placebo. The extracted time-series showed that pgACC activation increased in migraine patients compared to controls, especially in the first 8–10 min of citalopram infusion. Conclusions Our results demonstrate that a small increase in 5-HT levels can lead to increased phMRI signal in the pregenual part of the ACC that is involved in processing emotional aspects of pain. This increased sensitivity of the pgACC to increased 5-HT in migraine may contribute to recurring headache attacks and increased stress-sensitivity in migraine.

Context Microscopic measurement of adipocyte size is the gold standard for determining adipose tissue (AT) quality. AT density on CT may also reflect adipocyte quality (lower density = poorer quality). Objective We used abdominal subcutaneous AT (SAT) specimens and CT scans to validate CT SAT density as a marker of SAT quality in adults living with HIV. Setting and Design Secondary data analysis from completed trial of antiretroviral therapy (ART) initiation (ACTG A5224s). CT abdominal SAT density was measured in HU. SAT specimens were digitally scanned for calculation of mean adipocyte area. Participants Participants had SAT biopsy and CT data at baseline (n = 54) and HIV-1 RNA Outcome Measures Spearman correlations and linear regression models adjusting for participant characteristics examined associations between SAT density and adipocyte area. Results Baseline median age was 40 years, CD4+ T lymphocyte count 219 cells per cubic millimeter, and body mass index 26.0 kg/m2; 89% were male and 67% white. Median SAT area and density were 199 cm2 and −100 HU. Over 96 weeks, SAT area increased (+18%) and SAT density decreased (−3%). Mean SAT adipocyte area correlated with SAT density (P < 0.01) off and on ART after adjustment for SAT area, age, race, sex, CD4+ T lymphocyte count, and HIV-1 RNA. Conclusions CT SAT density correlates with biopsy-quantified SAT adipocyte size in adults with HIV on and off ART, suggesting that CT is a useful tool for noninvasive assessment of SAT quality.

We present a case of the rare Kikuchi-Fujimoto disease (KFD) in a 14-year-old patient admitted to UCLA Medical Center with fever, weight loss, and pancytopenia. Physical examination revealed tender subcutaneous nodules and cervical lymphadenopathy. A lymph node biopsy showed findings consistent with KFD. The skin biopsy showed mild superficial dermal edema with neutrophil-predominant inflammation. In addition, rare atypical monocytoid cells were seen. This histologic finding of a Sweet-like morphology has not been reported previously in the literature in association with KFD. The differential diagnosis included Sweet syndrome arising in association with KFD, underlying connective tissue, and an infectious etiology.

Összefoglaló. A varicella zoster vírus (VZV-) fertőzés típusos első megjelenése a bárányhimlő, később a reaktiváció során a herpes zoster. Szemészeti tünet az V/I-es agyideget érintő zoster esetén gyakori. A legrettegettebb szemészeti manifesztáció az akut retinanekrózis, mely fulmináns lefolyású, és súlyos szöveti destrukciót, valamint jelentős funkcionális károsodást, gyakran vakságot hagy maga után. Központi idegrendszeri vascularis érintettség előfordulhat bárányhimlőhöz társulóan vagy a későbbi reaktivációk során is, súlyos következményekhez vezetve. A Semmelweis Egyetem Szemészeti Klinikáján akut retinanekrózis tünetével érkező 65 éves férfi esetét ismertetjük. Az Amerikai Szemorvostársaság (AAO) diagnosztikus kritériumainak mindenben megfelelő klinikai kép alapján azonnal indított adekvát dózisú antivirális kezelés mellett 3 nap múlva, contralateralis hemiparesis hátterében, a képalkotó vizsgálat ipsilateralis ischaemiás stroke-ot igazolt. Intraocularis mintából PCR-vizsgálat bizonyította a vírus jelenlétét. Liquormintában enyhe anti-VZV-IgA-pozitivitás mutatkozott. Az aktuális szemészeti betegség és a stroke társulásának hátterében az észlelt paraméterek, valamint a releváns irodalmi adatok alapján a varicella zoster vírus okozta vasculopathiát valószínűsítettük. Gyermekkorban ez az ischaemiás stroke leggyakoribb oka, felnőttkorban pedig az V/I-es agyideg herpeses érintettsége esetén négy és félszeres a kockázat stroke kialakulására. A VZV-reaktiváció okozta akut retinanekrózis és a stroke társulásának lehetősége, bár ismert a nemzetközi irodalomban, magyar szakirodalom tudomásunk szerint eddig nem tárgyalta, ez kiemeli esetünk közlésének jelentőségét. Orv Hetil. 2021; 162(48): 1940-1945. Summary. The typical first onset of varicella zoster virus (VZV) infection is chickenpox, later herpes zoster during reactivation. Ophthalmic symptoms are common in herpes zoster affecting the V/I cranial nerve. The most dreaded ophthalmic manifestation is acute retinal necrosis, which has a fulminant course and leaves severe tissue damage as well as significant functional impairment, often blindness. Vascular involvement in the central nervous system may occur in association with chickenpox or during subsequent reactivations leading to severe consequences. We report the case of a 65-year-old male patient with symptoms of acute retinal necrosis at the Department of Ophthalmology, Semmelweis University. The clinical picture fulfilled the diagnostic criteria of the American Academy of Ophthalmology (AAO) and after 3 days of the immediately initiated adequate therapy, contralateral hemiparesis appeared, that was confirmed as an ipsilateral stroke by imaging study. The PCR analysis of an intraocular sample confirmed the presence of VZV. Mild anti-VZV IgA positivity was observed in the cerebrospinal fluid sample. Based on the current ophthalmic disease, the associated stroke alongside with the relevant literature data, varicella zoster vasculopathy was probable. VZV vasculopathy is the most common cause of ischemic stroke in childhood and in adulthood herpetic involvement of the V/I cranial nerve elevates 4.5 times the risk of stroke formation. Though the possible association of acute retinal necrosis and stroke caused by VZV reactivation is known in the international literature, to the best of our knowledge it has not been discussed in Hungary so far, which highlights the importance of reporting our case. Orv Hetil. 2021; 162(48): 1940-1945.

Transient receptor potential cation channel subfamily M member 4 (TRPM4) is a Ca2+-activated nonselective cation channel that mediates membrane depolarization. Although, a current with the hallmarks of a TRPM4-mediated current has been previously reported in pancreatic acinar cells (PACs), the role of TRPM4 in the regulation of acinar cell function has not yet been explored. In the present study, we identify this TRPM4 current and describe its role in context of Ca2+ signaling of PACs using pharmacological tools and TRPM4-deficient mice. We found a significant Ca2+-activated cation current in PACs that was sensitive to the TRPM4 inhibitors 9-phenanthrol and 4-chloro-2-[[2-(2-chlorophenoxy)acetyl]amino]benzoic acid (CBA). We demonstrated that the CBA-sensitive current was responsible for a Ca2+-dependent depolarization of PACs from a resting membrane potential of −44.4 ± 2.9 to −27.7 ± 3 mV. Furthermore, we showed that Ca2+ influx was higher in the TRPM4 KO- and CBA-treated PACs than in control cells. As hormone-induced repetitive Ca2+ transients partially rely on Ca2+ influx in PACs, the role of TRPM4 was also assessed on Ca2+ oscillations elicited by physiologically relevant concentrations of the cholecystokinin analog cerulein. These data show that the amplitude of Ca2+ signals was significantly higher in TRPM4 KO than in control PACs. Our results suggest that PACs are depolarized by TRPM4 currents to an extent that results in a significant reduction of the inward driving force for Ca2+. In conclusion, TRPM4 links intracellular Ca2+ signaling to membrane potential as a negative feedback regulator of Ca2+ entry in PACs.

Enhancement of the late Na+ current (INaL) increases arrhythmia propensity in the heart, while suppression of the current is antiarrhythmic. GS967 is an agent considered as a selective blocker of INaL. In the present study, effects of GS967 on INaL and action potential (AP) morphology were studied in canine ventricular myocytes by using conventional voltage clamp, action potential voltage clamp and sharp microelectrode techniques. The effects of GS967 (1 µM) were compared to those of the class I/B antiarrhythmic compound mexiletine (40 µM). Under conventional voltage clamp conditions, INaL was significantly suppressed by GS967 and mexiletine, causing 80.4 ± 2.2% and 59.1 ± 1.8% reduction of the densities of INaL measured at 50 ms of depolarization, and 79.0 ± 3.1% and 63.3 ± 2.7% reduction of the corresponding current integrals, respectively. Both drugs shifted the voltage dependence of the steady-state inactivation curve of INaL towards negative potentials. GS967 and mexiletine dissected inward INaL profiles under AP voltage clamp conditions having densities, measured at 50% of AP duration (APD), of −0.37 ± 0.07 and −0.28 ± 0.03 A/F, and current integrals of −56.7 ± 9.1 and −46.6 ± 5.5 mC/F, respectively. Drug effects on peak Na+ current (INaP) were assessed by recording the maximum velocity of AP upstroke (V+ max) in multicellular preparations. The offset time constant was threefold faster for GS967 than mexiletine (110 ms versus 289 ms), while the onset of the rate-dependent block was slower in the case of GS967. Effects on beat-to-beat variability of APD was studied in isolated myocytes. Beat-to-beat variability was significantly decreased by both GS967 and mexiletine (reduction of 42.1 ± 6.5% and 24.6 ± 12.8%, respectively) while their shortening effect on APD was comparable. It is concluded that the electrophysiological effects of GS967 are similar to those of mexiletine, but with somewhat faster offset kinetics of V+ max block. However, since GS967 depressed V+ max and INaL at the same concentration, the current view that GS967 represents a new class of drugs that selectively block INaL has to be questioned and it is suggested that GS967 should be classified as a class I/B antiarrhythmic agent.

Background: Several reports prove interconnection between vitamin D (VD) deficiency and increased cardiovascular risk. Our aim was to investigate the effects of VD status on biomechanical and oxidative&ndash, nitrative (O&ndash, N) stress parameters of coronary arterioles in rats. Methods: 4-week-old male Wistar rats were divided into a control group (11 animals) with optimal VD supply (300 IU/kgbw/day) and a VD-deficient group (11 animals, &lt, 5 IU/kg/day). After 8 weeks, coronary arteriole segments were prepared. Geometrical, elastic, and biomechanical characteristics were measured by in vitro arteriography. O&ndash, N stress markers were investigated by immunohistochemistry. Results: Inner radius decreased, wall thickness and wall-thickness/lumen diameter ratio increased, tangential wall stress and elastic modulus were reduced in VD-deficient group. No difference could be found in wall-cross-sectional area, intima-media area %. While the elastic elements of the vessel wall decreased, the &alpha, smooth muscle actin (&alpha, SMA) immunostaining intensity showed no changes. Significant elevation was found in the lipid peroxidation marker of 4-hidroxy-2-nonenal (HNE), while other O&ndash, N stress markers staining intensity (poly(ADP)ribose, 3-nitrotyrosine) did not change. Conclusions: Inward eutrophic remodeling has developed. The potential background of these impairments may involve the initial change in oxidative damage markers (HNE). These mechanisms can contribute to the increased incidence of the cardiovascular diseases in VD deficiency.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited.Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19.Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020.Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108).Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%).Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively.Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

We examined whether childhood externalizing group subtypes were uniquely related to maternal depression and victimization and whether these subtypes differentially predicted adolescent delinquency. Data were drawn from the Longitudinal Study on Child Abuse and Neglect (LONGSCAN) consortium (N = 1091; 51.3% female, 52.2% African American). Latent class analysis indicated three groups at age 4 (titled "well-adjusted," "hyperactive/oppositional," and "aggressive/rule-breaking"). Caregiver victimization and depression significantly predicted group membership such that aggressive/rule-breaking group had higher levels of maternal depression and victimization although the well-adjusted group had higher levels of maternal victimization relative to the hyperactive/oppositional group. Further, membership in higher externalizing groups at age four is associated with greater risk of adolescent delinquency at age 16. These findings underscore the need to address maternal risk factors in the treatment of childhood disruptive behavior and provide evidence of the continuity of disruptive behaviors from early childhood to adolescence.

Background Although controversial, there are data suggesting that clinical parameters can predict the probability of sphincter preserving procedures in rectal cancer. The purpose of this study was to investigate the association between clinical parameters and the sphincter-preserving surgery rate in patients who had undergone neoadjuvant combination therapy for advanced low rectal cancer. Methods In this single center study, the charts of 540 patients with locally advanced rectal cancer who had been treated with induction chemotherapy-and/or neoadjuvant concomitant radiochemotherapy (nRCT) over an 11-year period were reviewed in order to identify patients with rectal cancer ≤6 cm from the anal verge, who had received the prescribed nRCT only. Univariate and multivariate analyses were used to identify pretreatment patient- and tumor associated parameters correlating with sphincter preservation. Survival rates were calculated using Kaplan-Meier analyses. Results Two hundred eighty of the 540 patients met the selection criteria. Of the 280 patients included in the study, 158 (56.4%) underwent sphincter-preserving surgery. One hundred sixty-four of 280 patients (58.6%) had a downsizing of the primary tumor (ypT p = 0.003), relative lymphocyte value (HR = 0.94, CI95%: 0.89–0.99, p = 0.029), and interval between nRCT and surgery (HR = 2.39, CI95%: 1.17–4.88, p = 0.016) remained as independent predictive parameters. Conclusions These clinical parameters can be considered in the prognostication of sphincter-preserving surgery in case of low rectal adenocarcinoma. More future research is required in this area.

BACKGROUND: Equisetum arvense L., commonly known as field horsetail is a perennial fern of which extracts are rich sources of phenolic compounds, flavonoids, and phenolic acids. Activation of SIRT1 that was shown to be involved in well-known signal pathways of diabetic cardiomyopathy has a protective effect against oxidative stress, inflammatory processes, and apoptosis that are the basis of diseases such as obesity, diabetes mellitus, or cardiovascular diseases. The aim of our study was to evaluate the antidiabetic and cardioprotective effects of horsetail extract in streptozotocin induced diabetic rats. METHODS: Diabetes was induced by a single intraperitoneal injection of 45 mg/kg streptozotocin. In the control groups (healthy and diabetic), rats were administered with vehicle, whilst in the treated groups, animals were administered with 50, 100, or 200 mg/kg horsetail extract, respectively, for six weeks. Blood glucose levels, glucose tolerance, and insulin sensitivity were determined, and SIRT1 levels were measured from the cardiac muscle. RESULTS: The horsetail extract showed moderate beneficial changes in blood glucose levels and exhibited a tendency to elevate SIRT1 levels in cardiomyocytes, furthermore a 100 mg/kg dose also improved insulin sensitivity. CONCLUSIONS: Altogether our results suggest that horsetail extract might have potential in ameliorating manifested cardiomyopathy acting on SIRT1.

Cluster headache (CH), which affects 0.1% of the population, is one of the most painful human conditions: despite adequate treatment, the frequent and severe headaches cause a significant burden to the patients. According to a small number of previous studies, CH has a serious negative effect on the sufferers' quality of life (QOL). In the current study, we set out to examine the quality of life of the CH patients attending our outpatient service between 2013 and 2016, using generic and headache-specific QOL instruments.A total of 42 CH patients (16 females and 26 males; mean age: 39.1±13.5 years) completed the SF-36 generic QOL questionnaire and the headache- specific CHQQ questionnaire (Comprehensive Headache- related Quality of life Questionnaire), during the active phase of their headache. Their data were compared to those of patients suffering from chronic tension-type headache (CTH) and to data obtained from controls not suffering from significant forms of headache, using Kruskal-Wallis tests.During the active phase of the CH, the patients' generic QOL was significantly worse than that of normal controls in four of the 8 domains of the SF-36 instrument. Apart from a significantly worse result in the 'Bodily pain' SF-36 domain, there were no significant differences between the CH patients' and the CTH patients' results. All the dimensions and the total score of the headache-specific CHQQ instrument showed significantly worse QOL in the CH group than in the CTH group or in the control group.Cluster headache has a significant negative effect on the quality of life. The decrease of QOL experienced by the patients was better reflected by the headache-specific CHQQ instrument than by the generic SF-36 instrument.A lakosság körülbelül 0,1%-át érintő cluster fejfájás (CF) az egyik leghevesebb humán fájdalomszind­róma: a gyakori, erőteljes rohamok megfelelő kezelés mellett is nagy terhet jelentenek a betegek számára. Korábbi, elszórt vizsgálatok szerint a CF jelentősen rontja a betegek életminőségét. Kutatásunk során a fejfájáscent­rumunkban 2013 és 2016 között gondozott CF-betegek életminőségét vizsgáltuk, általános és fejfájás-specifikus életminőség-kérdőívek segítségével.Összesen 42 CF-beteg (16 nő és 26 férfi; átlagos életkor: 39,1 ± 13,5 év) töltötte ki az „SF-36” általános életminőség-kérdőívet és a fejfájás-specifikus „CHQQ” kérdőívet (Átfogó Fejfájással Kapcsolatos Életminőség-kérdőív) a cluster fejfájás aktív időszakában. A kérdőívek által nyert adatokat krónikus tenziós fejfájásban (KTF) szenvedő betegek és lényeges fejfájást nem tapasztaló kontrollok adataival hasonlítottuk össze Kruskal-Wallis-tesztek segítségével.A fejfájás aktív időszakában a CF-betegek általános életminősége az SF-36 kérdőív nyolc területe közül négyben bizonyult szignifikánsan rosszabbnak, mint a kontrolloké; ugyanakkor a „Testi fájdalom” terület kivételével nem volt szignifikáns különbség a CF- és KTF-betegek életminősége között. A fejfájás-specifikus életminőség-kérdőív mindhárom dimenziója és összesített mutatója is szignifikánsan rosszabb életminőséget mutatott a CF-betegek körében, mint a KTF-betegek, illetve a kont­rollok csoportjában.A cluster fejfájás jelentősen rontja a betegek életminőségét. A betegek által megélt életminőség-romlást az Átfogó Fejfájással Kapcsolatos Életminőség kérdőív érzékenyebben mutatta ki, mint az általános életminőséget vizsgáló SF-36 kérdőív.

Purpose Composite flaps used in reconstructive surgery may intra- and postoperatively suffer from hypoperfusion and/or ischemia-reperfusion influencing wound healing. We aimed to follow-up the effect of ischemia on adipocutaneous flaps’ wound healing and microcirculation. Methods In anesthetized rats groin flaps were formed bilaterally. In Control group the flaps were repositioned and sutured back. In Ischemia-Reperfusion (I/R) group before repositioning and suturing the flap pedicles were clamped for 60 minutes. Laser Doppler (LD) fluxmetry and temperature probes were applied on the cranial, central and caudal flap regions before/after preparation and ischemia, re-suturing, and on the 1st-3rd-5th-7th-14th postoperative days, before the final examinations and biopsies for histology. Results Flaps’ skin temperature quickly recovered after repositioning. LD values were lower in the I/R group, reaching a significant level by the 3rd postoperative day, and remained lowered till the 14th day. The magnitude of alterations differed in the flap regions. Histologically normal wound healing process was seen, except for some I/R flaps, where hypertrophized mammary glands were found. Conclusions Short-term ischemia could influence flap microcirculation and wound healing, and may result in hypertrophized mammary glands. Laser Doppler could be used to evaluate intra- and postoperative microcirculatory changes and may have significance in predicting complications.

Purpose: Prostate-specific membrane antigen (PSMA) targeting radioligands deliver radiation to PSMA-expressing cells. However, the relationship between PSMA levels and intralesion heterogeneity of PSMA expression, and cytotoxic radiation by radioligand therapy (RLT) is unknown. Here we investigate RLT efficacy as function of PSMA levels/cell, and the fraction of PSMA+ cells in a tumor. Experimental Design: RM1 cells expressing different levels of PSMA (PSMA−, PSMA+, PSMA++, PSMA+++; study 1) or a mix of PSMA+ and PSMA− RM1 (study 2, 4) or PC-3/PC-3-PIP (study 3) cells at various ratios were injected into mice. Mice received 177Lu- (studies 1–3) or 225Ac- (study 4) PSMA617. Tumor growth was monitored. Two days post-RLT, tumors were resected in a subset of mice. Radioligand uptake and DNA damage were quantified. Results: 177Lu-PSMA617 efficacy increased with increasing PSMA levels (study 1) and fractions of PSMA positive cells (studies 2, 3) in both, the RM1 and PC-3-PIP models. In tumors resected 2 days post-RLT, PSMA expression correlated with 177Lu-PSMA617 uptake and the degree of DNA damage. Compared with 177Lu-PSMA617, 225Ac-PSMA617 improved overall antitumor effectiveness and tended to enhance the differences in therapeutic efficacy between experimental groups. Conclusions: In the current models, both the degree of PSMA expression and the fraction of PSMA+ cells correlate with 177Lu-/225Ac-PSMA617 tumor uptake and DNA damage, and thus, RLT efficacy. Low or heterogeneous PSMA expression represents a resistance mechanism to RLT. See related commentary by Ravi Kumar and Hofman, p. 2774

Congenital cataracts are the prime cause for irreversible blindness in children. The global incidence of congenital cataract is 2.2–13.6 per 10,000 births, with the highest prevalence in Asia. Nearly half of the congenital cataracts are of familial nature, with a predominant autosomal dominant pattern of inheritance. Over 38 of the 45 mapped loci for isolated congenital or infantile cataracts have been associated with a mutation in a specific gene. The clinical and genetic heterogeneity of congenital cataracts makes the molecular diagnosis a bit of a complicated task. Hence, whole exome sequencing (WES) was utilized to concurrently screen all known cataract genes and to examine novel candidate factors for a disease-causing mutation in probands from 11 pedigrees affected with familial congenital cataracts. Analysis of the WES data for known cataract genes identified causative mutations in six pedigrees (55%) in PAX6, FYCO1 (two variants), EPHA2, P3H2,TDRD7 and an additional likely causative mutation in a novel gene NCOA6, which represents the first dominant mutation in this gene. This study identifies a novel cataract gene not yet linked to human disease. NCOA6 is a transcriptional coactivator that interacts with nuclear hormone receptors to enhance their transcriptional activator function., International Journal of Molecular Sciences, 21 (24), ISSN:1422-0067

Optic nerve hypoplasia (ONH) is a congenital optic nerve abnormality caused by underdevelopment of retinal ganglion cells (RGCs). Despite being a rare disease, ONH is the most common optic disc anomaly in ophthalmological practice. So far, mutations in several genes have been identified as causative, however many cases of ONH remain without a molecular explanation. The early transcription factor atonal basic-helix-loop-helix (bHLH) transcription factor 7 (ATOH7) is expressed in retinal progenitor cells and has a crucial role in RGC development. Previous studies have identified several mutations in the ATOH7 locus in cases of eye developmental diseases such as nonsyndromic congenital retinal nonattachment and persistent hyperplasia of the primary vitreous. Here we present two siblings with a phenotype predominated by bilateral ONH, with additional features of foveal hypoplasia and distinct vascular abnormalities, where whole-exome sequencing identified two compound heterozygous missense mutations affecting a conserved amino acid residue within the bHLH domain of ATOH7 (NM_145178.3:c.175G>A; p.(Ala59Thr) and c.176C>T; p.(Ala59Val)). ATOH7 expression constructs with patient single nucleotide variants were cloned for functional characterization. Protein analyses revealed decreased protein amounts and significantly enhanced degradation in the presence of E47, a putative bHLH dimerization partner. Protein interaction assays revealed decreased heterodimerization and DNA-binding of ATOH7 variants, resulting in total loss of transcriptional activation of luciferase reporter gene expression. These findings strongly support pathogenicity of the two ATOH7 mutations, one of which is novel. Additionally, this report highlights the possible impact of altered ATOH7 dimerization on protein stability and function.

This study investigated the inhibitory effect of arctigenin, a novel anti-inflammatory lignan, on prostate cancer in obese conditions both in vitro and in vivo. In vitro obese models were established by co-culture of mouse adipocytes 3T3-L1 with androgen-sensitive LNCaP human prostate cancer cells, or by culturing LNCaP cells in adipocytes-conditioned medium. Arctigenin significantly inhibited LNCaP proliferation, along with decreased androgen receptor (AR) and increased Nkx3.1 cellular expression. Male severe combined immunodeficiency mice were subcutaneously implanted with human prostate cancer LAPC-4 xenograft tumors for in vivo study. Mice were fed high-fat (HF) diet and orally given arctigenin at 50 mg/kg body weight daily or vehicle control for 6 weeks. Tumor bearing HF control mice showed a significant increase in serum free fatty acids (FFAs) and decrease in subcutaneous/peritoneal fat depots compared to non-tumor bearing control mice. Arctigenin intervention significantly reduced tumor growth by 45%, associated with decreased circulating FFAs and adipokines/cytokines including IGF-1, VEGF, and MCP-1, along with decreased AR, Ki67, and microvessel density and increased Nkx3.1 expression in tumors. These results indicate the strong ability of arctigenin to co-target obesity and tumor itself in inhibition of prostate tumor growth at a lower concentration compared to most phytochemicals.

Background Micro-rheological relations of renal ischemia-reperfusion (I/R) have not been completely elucidated yet. Concerning anti-inflammatory agents, it is supposed that sigma-1 receptor agonist N,N-dimethyl-tryptamin (DMT) can be useful to reduce I/R injury. Objective To investigate the micro-rheological and metabolic parameters, and the effects of DMT in renal I/R in rats. Methods In anesthetized rats from median laparotomy both kidneys were exposed. In Control group (n = 6) no other intervention happened. In I/R group (n = 10) the right renal vessels were ligated and after 60 minutes the organ was removed. The left renal vessels were clamped for 60 minutes followed by 120-minute reperfusion. In I/R+DMT group (n = 10) DMT was administered 15 minutes before the ischemia. Blood samples were taken before/after ischemia and during the reperfusion for testing hematological, metabolic parameters, erythrocyte deformability and aggregation. Results Lactate concentration significantly increased and accompanied with decreased blood pH. Enhanced erythrocyte aggregation and impaired deformability were observed from the 30th minute of reperfusion. In I/R+DMT group we found diminished changes compared to the I/R group (lactate, pH, electrolytes, red blood cell deformability and aggregation). Conclusions Metabolic and micro-rheological parameters impair during renal I/R. DMT could reduce but not completely prevent the changes in this rat model.

Aims Right- and left-side-dominant individuals reveal target-matching asymmetries between joints of the dominant and non-dominant upper limbs. However, it is unclear if such asymmetries are also present in lower limb’s joints. We hypothesized that right-side-dominant participants perform knee joint target-matching tasks more accurately with their non-dominant leg compared to left-side-dominant participants. Methods Participants performed position sense tasks using each leg by moving each limb separately and passively on an isokinetic dynamometer. Results Side-dominance affected (p Conclusions In conclusion, right-side-dominant participants tend to perform a target-matching task more accurately with the non-dominant leg compared to left-side-dominant participants. Our results extend the literature by showing that right-hemisphere specialization under proprioceptive target-matching tasks may be not evident at the lower limb joints.

The present study sought to assess the performance of the Borderline Features (BOR) Scale of the adolescent version of the Personality Assessment Inventory (Morey, 2007b) in 2 high-risk samples: inpatient and justice-involved adolescents. This study is the first to evaluate the BOR scale in high-risk adolescent samples, outside the initial standardization studies. Across both samples (NClinical = 327, NForensic = 151), results indicated good internal consistency. Confirmatory factor analysis indicated poor fit of the 4-factor structure proposed by the measure's authors. Convergent validity and receiver-operating characteristics analyses, conducted in the clinical sample, indicated that the adolescent version of the Personality Assessment Inventory BOR scale had good diagnostic accuracy for predicting a borderline personality disorder diagnosis (via structured interview). Findings suggest that the BOR scale has adequate internal consistency, convergent validity, and clinical utility, although areas for future measure evaluation (including factor structure) remain. Still, the BOR scale may partially address the current hesitation to assess borderline personality disorder features in high-risk youth because it is embedded within a broadband psychopathology measure. (PsycINFO Database Record

Background Intestinal ischemia-reperfusion (I/R) is a potentially life-threatening situation and its pathomechanism is not fully understood yet. Objective To investigate the early micro-rheological, microcirculatory and morphological consequences of intestinal I/R in a rat model. Methods CD rats were anesthetized and subjected to Control (n = 7) or I/R (n = 7) groups. Left femoral artery cannulation and median laparotomy were performed. In the I/R group the superior mesenteric artery was clamped for 30 minutes. Blood samples were taken before (Base) and after the ischemia, at the 30th, 60th and 120th minutes of the reperfusion (R-30, R-60, R-120). Hematological parameters, erythrocyte deformability and aggregation were determined. On the jejunum, the liver and the right kidney laser Doppler flowmetry tests were completed. At the end of experiment histological samples were taken. Results Hematocrit, leukocyte and platelet counts increased during the reperfusion. Erythrocyte deformability worsened versus Control. All erythrocyte aggregation index values of I/R group increased gradually. Intestinal microcirculatory blood flux units (BFU) did not recover completely after ischemia, at R-30 liver BFU values were lower, and kidney values decreased by R-120. Histology showed signs of I/R injury. Conclusions Micro-rheological parameters may show early and significant deterioration during the reperfusion that might contribute further to microcirculatory alterations.

Background Childhood obesity proves to be an important public health issue, since it serves as a potential risk factor for multiple diseases. Food addiction could also serve as an important etiological factor. As childhood obesity plays a serious issue also in Hungary, we aimed to adapt and validate the Hungarian version of the Yale Food Addiction Scale for Children (H-YFAS-C). Methods A total of 191 children were assessed with the H-YFAS-C and the Eating Disorder Inventory (EDI). The following psychometric properties were analyzed: internal consistency, construct validity, convergent, and discriminant validity. Results A good construct validity was revealed by confirmatory factor analysis (RMSEA = 0.0528, CFI = 0.896, χ2 value = 279.06). Question 25 proved to have no significant effect on its group and was removed from further analyses. The Kuder–Richardson 20 coefficient indicated good internal consistency (K20 = 0.82). With the use of the eight EDI subscales, a good convergent and discriminant validity could be determined. Food addiction was diagnosed in 8.9% of children. The mean symptom count was 1.7 ± 1.2 (range: 0–7). Females were more often diagnosed with food addiction than males (p = .016; OR = 3.6, 95% CI: 1.2–10.6). BMI percentiles were significantly higher in children with diagnosed food addiction (p = .003). There proved to be no correlation between age and the occurrence of food addiction. Discussion and conclusion Our results show that H-YFAS-C is a good and reliable tool for addictive-like behavior assessment.

BACKGROUND Wilms' tumor is a common renal malignancy of early childhood with a generally favorable prognosis depending upon histological subtype. It is becoming increasingly clear that differences in miRNA (microRNA) expression signature represent important clues helping us predict a tumor's response to chemotherapy. In our study, we aimed to reveal miRNAs deregulated in regressive Wilms' tumors from FFPE (formalin-fixed, paraffin-embedded) samples, also showing whether such samples are reliable miRNA sources in Wilms' tumor. MATERIAL AND METHODS Samples from 8 Hungarian patients (3 males, 5 females, aged 1 to 7 years) were analyzed by qRT-PCR (quantitative real-time PCR). A PCR array was used in a pilot experiment, and selected miRNAs (miR-128-3p, miR-184, miR-194-5p, miR-203a) were studied in the rest of the samples using individual primers. RESULTS miR-194-5p was underexpressed in all tumor samples. miR-184 and miR-203a were underexpressed in 7 cases, the exception being a case with a high ratio of necrotic blastemal tissue. Results obtained with miR-128-3p are difficult to interpret due to varying directions of expression changes. CONCLUSIONS We conclude that a downregulation of miR-184, miR-194-5p, and miR-203a expression is observed in both regressive and blastemal tumors, but larger-scale studies are needed to confirm whether the degree of their underexpression correlates with the number of blastemal elements in a sample. In most of our FFPE samples aged up to 9 years, RNA extraction provided miRNA with quantity and quality sufficient for qRT-PCR-based analysis, emphasizing the relevance of pathological archives as miRNA sources in future studies.

Aims The aim of this study was to examine the effects of gender on the relationship between Functional Movement Screen (FMS) and treadmill-based gait parameters. Methods Twenty elite junior athletes (10 women and 10 men) performed the FMS tests and gait analysis at a fixed speed. Between-gender differences were calculated for the relationship between FMS test scores and gait parameters, such as foot rotation, step length, and length of gait line. Results Gender did not affect the relationship between FMS and treadmill-based gait parameters. The nature of correlations between FMS test scores and gait parameters was different in women and men. Furthermore, different FMS test scores predicted different gait parameters in female and male athletes. FMS asymmetry and movement asymmetries measured by treadmill-based gait parameters did not correlate in either gender. Conclusion There were no interactions between FMS, gait parameters, and gender; however, correlation analyses support the idea that strength and conditioning coaches need to pay attention not only to how to score but also how to correctly use FMS.

DSM-5 recently added the specifier "Limited Prosocial Emotions" (LPE) to the Conduct Disorder (CD) diagnosis, yet little is known about how these traits will affect attitudes toward CD youth. Laypersons attending jury duty (N = 326) were randomly assigned to one of four case vignette conditions in which a male juvenile offender was identified as having (a) CD symptoms only, (b) CD symptoms plus a diagnostic label, (c) CD symptoms plus a diagnostic label and description of LPE traits, or (d) CD symptoms plus a description of LPE traits and a "psychopath" label. LPE traits led to more negative perceptions of the youth (e.g., more dangerous, evil, and psychopathic) and adding the psychopath label to the LPE specifier resulted in somewhat stronger support for punishment and mandated treatment. The LPE specifier may provide useful diagnostic information, but these findings raise serious concerns that it will stigmatize youth in the legal system.

Objective To examine whether response to first treatment with onabotulinumtoxinA is predictive of long-term treatment outcome in neurogenic detrusor overactivity (NDO) patients. Patients and Methods NDO patients in a 3-year extension study (following a 52-week phase 3 study) received onabotulinumtoxinA ‘as needed’ based on fulfilment of prespecified retreatment criteria. This post-hoc analysis included patients who received only the 200U dose during the phase 3 and extension studies. Data were analysed by mean percent reduction from baseline in urinary incontinence (UI) episodes at week 6 after the first treatment and stratified into 3 response groups

Although late sodium current (INa-late) has long been known to contribute to plateau formation of mammalian cardiac action potentials, lately it was considered as possible target for antiarrhythmic drugs. However, many aspects of this current are still poorly understood. The present work was designed to study the true profile of INa-late in canine and guinea pig ventricular cells and compare them to INa-late recorded in undiseased human hearts. INa-late was defined as a tetrodotoxin-sensitive current, recorded under action potential voltage clamp conditions using either canonic- or self-action potentials as command signals. Under action potential voltage clamp conditions the amplitude of canine and human INa-late monotonically decreased during the plateau (decrescendo-profile), in contrast to guinea pig, where its amplitude increased during the plateau (crescendo profile). The decrescendo-profile of canine INa-late could not be converted to a crescendo-morphology by application of ramp-like command voltages or command action potentials recorded from guinea pig cells. Conventional voltage clamp experiments revealed that the crescendo INa-late profile in guinea pig was due to the slower decay of INa-late in this species. When action potentials were recorded from multicellular ventricular preparations with sharp microelectrode, action potentials were shortened by tetrodotoxin, which effect was the largest in human, while smaller in canine, and the smallest in guinea pig preparations. It is concluded that important interspecies differences exist in the behavior of INa-late. At present canine myocytes seem to represent the best model of human ventricular cells regarding the properties of INa-late. These results should be taken into account when pharmacological studies with INa-late are interpreted and extrapolated to human. Accordingly, canine ventricular tissues or myocytes are suggested for pharmacological studies with INa-late inhibitors or modifiers. Incorporation of present data to human action potential models may yield a better understanding of the role of INa-late in action potential morphology, arrhythmogenesis, and intracellular calcium dynamics.

Background/Aims Recent evidence indicates that the intake of atypical antipsychotics (AAP) is associated with gray matter abnormalities in patients with psychiatric disorders. We explored if patients with bipolar disorder (BD) who are medicated with AAP exhibit total gray matter volume (TGV) reduction compared to BD individuals not medicated with AAP and healthy controls (HC). Methods In a cross-sectional design, 124 individuals with BD and 86 HC underwent 3T-MRI of the brain and clinical assessment as part of our BIPFAT-study. The TGV was estimated using Freesurfer. We used univariate covariance analysis (ANCOVA) to test for normalized TGV differences and controlled for covariates. Results ANCOVA results indicated that 75 BD individuals taking AAP had significantly reduced normalized TGV as compared to 49 BD not taking AAP (F = 9.995, p = .002., Eta = 0.084) and 86 HC (F = 7.577, p = .007, Eta = 0.046). Limitations Our cross-sectional results are not suited to draw conclusions about causality. We have no clear information on treatment time and baseline volumes before drug treatment in the studied subjects. We cannot exclude that patients received different psychopharmacologic medications prior to the study point. We did not included dosages into the calculation. Many BD individuals received combinations of psychopharmacotherapy across drug classes. We did not have records displaying quantitative alcohol consumption and drug abuse in our sample. Conclusions Our data provide further evidence for the impact of AAP on brain structure in BD. Longitudinal studies are needed to investigate the causal directions of the proposed relationships.