Lexical Influences on Categorical Speech Perception Are Driven by a Temporoparietal Circuit.
Categorical judgments of otherwise identical phonemes are biased toward hearing words (i.e., "Ganong effect") suggesting lexical context influences perception of even basic speech primitives. Lexical biasing could manifest via late stage postperceptual mechanisms related to decision or, alternatively, top-down linguistic inference that acts on early perceptual coding. Here, we exploited the temporal sensitivity of EEG to resolve the spatiotemporal dynamics of these context-related influences on speech categorization. Listeners rapidly classified sounds from a /gɪ/-/kɪ/ gradient presented in opposing word-nonword contexts (GIFT-kift vs. giss-KISS), designed to bias perception toward lexical items. Phonetic perception shifted toward the direction of words, establishing a robust Ganong effect behaviorally. ERPs revealed a neural analog of lexical biasing emerging within ∼200 msec. Source analyses uncovered a distributed neural network supporting the Ganong including middle temporal gyrus, inferior parietal lobe, and middle frontal cortex. Yet, among Ganong-sensitive regions, only left middle temporal gyrus and inferior parietal lobe predicted behavioral susceptibility to lexical influence. Our findings confirm lexical status rapidly constrains sublexical categorical representations for speech within several hundred milliseconds but likely does so outside the purview of canonical auditory-sensory brain areas.


Self-esteem and social support as moderators of depression, body image, and disordered eating for suicidal ideation in adolescents.
The current study investigated risk factors for suicidal ideation in a community sample of 392 adolescents (males 51.9 %; females 48.1 %), while also evaluating self-esteem, perceived parent support, and perceived peer support as protective factors and potential moderators between suicidal ideation and the 3 risk factors. Disordered eating, depression, parent support, and peer support were found to be significant predictors of current suicidal ideation, but body satisfaction was not. The relationship between depression and suicidal ideation was significantly moderated by both self-esteem and parent support, while the relationship between disordered eating and suicidal ideation was significantly moderated by peer support. Results underscore the importance of examining protective factors for suicide risk, as they have the potential to reduce suicidal ideation in adolescents.


Energy requirement for maintenance and growth of Nellore bulls and steers fed high-forage diets.
Data from three comparative slaughter experiments with individually fed Nellore bulls (n = 31) and steers (n = 66) were utilized to determine their NEm and NEg requirements when fed high-forage diets. The experimental design provided ranges in ME intake, BW, and ADG for the development of regression equations to predict NEm and NEg requirements. The Nellore bulls (Trial 1) were divided into two intake levels (ad libitum and 65% of the ad libitum). The steers (Trials 2 and 3) were allocated to three intake levels (ad libitum and 55 and 70% of the ad libitum). In both trials, there were three slaughter groups within each intake level. The three end points for the bulls were different days on treatment (100, 150, and 190 d and 130, 180, and 200 d, respectively, for older and younger animal subgroups). The steers were slaughtered when animals of the ad libitum treatment reached 400, 440, and 480 kg shrunk BW (SBW) on average for the first, second, and third group, respectively. For all body composition determinations, whole empty body components were weighed, ground, and subsampled for chemical analysis. In each of the trials, initial body composition was determined with equations developed from a baseline slaughter group, using SBW and empty BW (EBW), fat (EBF), and protein (EBP) as variables. The NEm was similar for bulls and steers; NEm averaged 77.2 kcal/ kg0.75 EBW. However, the efficiency of conversion of ME to net energy for maintenance was greater for steers than for bulls (68.8 and 65.6%, respectively), indicating that bulls had a greater ME requirement for maintenance than steers (5.4%; P < 0.05). Our analyses do not support the NRC (2000) conclusion that Nellore, a Bos indicus breed, has a lower net energy requirement for maintenance than Bos taurus breeds. An equation developed with the pooled data to predict retained energy (RE) was similar to the NRC (2000) equation. A second equation was developed to predict RE adjusted for degree of maturity (u): RE = (6.45 - 2.58/u) x EWG x e(0.469) x u), where u = current EBW/final EBW in which final EBW was 365 kg for steers and younger bulls and 456 kg for older bulls at 22% EBF, respectively.


Investigation of the prevalence of carbapenem resistance genes in faecal carriage of carbapenem resistant Klebsiella spp. isolates by multiplex real-time PCR method.
Increased carbapenem resistance in Klebsiella spp. strains causes high morbidity and mortality. The genes encoded for carbapenemaseare transferrable between different bacterial species. In the present study, we aimed to investigate carbapenem resistance genes in Klebsiella spp. strains. Fifty Klebsiella spp. strains were isolated from rectal swabs of patients hospitalized in the neonatal intensive care unit (NICU). All strains were identified with API20E. The minimum inhibitory concentrations (MICs) of carbapenems were determined by the broth dilution method. The major five carbapenem genes (OXA-48, NDM, VIM, KPC, and IMP) were detected by the multiplex real-time PCR method. It was found that 49 (98%) of the strains were resistant to ertapenem (MIC ≥ 2μg/mL) and imipenem(MIC ≥ 4 μg/mL), and 47 (94%) of the strains were resistant to doripenem (MIC ≥ 4 μg/mL)and meropenem(MIC ≥ 4 μg/mL).NDM was detected in 42%, OXA-48 in 16%, and VIM in one (2%) isolate, and NDM + OXA-48 co-existed in 36% of the isolates. The KPC and IMP genes were not detected. NDM and NDM co-existing with OXA-48 were prevalent in the NICU of Istanbul Medical Faculty Hospital. Paying attention to the hand hygiene of healthcare workers, screening of rectal swabs of hospitalized patients for the presence of carbapenem resistance strains, and isolation of infected patients can effectively control the spread of carbapenem-resistant strains.


Analysis of the "naming game" with learning errors in communications.
Naming game simulates the process of naming an objective by a population of agents organized in a certain communication network. By pair-wise iterative interactions, the population reaches consensus asymptotically. We study naming game with communication errors during pair-wise conversations, with error rates in a uniform probability distribution. First, a model of naming game with learning errors in communications (NGLE) is proposed. Then, a strategy for agents to prevent learning errors is suggested. To that end, three typical topologies of communication networks, namely random-graph, small-world and scale-free networks, are employed to investigate the effects of various learning errors. Simulation results on these models show that 1) learning errors slightly affect the convergence speed but distinctively increase the requirement for memory of each agent during lexicon propagation; 2) the maximum number of different words held by the population increases linearly as the error rate increases; 3) without applying any strategy to eliminate learning errors, there is a threshold of the learning errors which impairs the convergence. The new findings may help to better understand the role of learning errors in naming game as well as in human language development from a network science perspective.


Prognostic impact of telomere maintenance gene polymorphisms on hepatocellular carcinoma patients with chronic hepatitis B.
Our goal was to determine whether single-nucleotide polymorphisms (SNPs) of telomere maintenance genes influence the development and clinical outcomes of patients with hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). We evaluated 20 SNPs of five telomere maintenance genes in 702 patients with HCC and 351 hepatitis B virus surface antigen-positive controls without HCC. Significant SNPs were then validated in an independent cohort of 857 HCC patients and 429 controls. We assessed the association of each SNP with the development of HCC and overall survival through a multivariate Cox proportional analysis. A significantly increased risk of HCC development was identified for the telomerase-associated protein 1 (TEP1) rs1713449 SNP in both the discovery and replication phases (combined odds ratio = 1.42, P = 9.378 × 10(-5) ). In addition, the TEP1 rs1713449, TEP1 rs872072, protection of telomeres 1 homolog rs7784168, telomerase reverse transcriptase rs13167280, and telomeric repeat binding factor 1 rs2306494 SNPs had a significant effect on the overall survival, and a similar survival effect was validated in the replication cohort. Moreover, there was a significant dose-dependent association between the number of putatively high-risk genotypes of the five aforementioned SNPs and overall survival. The median survival time was significantly prolonged for patients with HCC with two or fewer putatively high-risk genotypes versus those with three or more high-risk genotypes (85 versus 44 months, log-rank P = 4.483 × 10(-5) ), and this was demonstrated in the replication cohort (52 versus 37 months, log-rank P = 0.026). These observations suggest that the SNPs of telomere maintenance genes play a potential role in the development of HCC and the survival of HCC patients with chronic HBV infections.


SARS-CoV-2-infected hiPSC-derived cardiomyocytes reveal dynamic changes in the COVID-19 hearts.
The ongoing coronavirus disease 2019 (COVID-19) pandemic has had an enormous impact on our societies. Moreover, the disease's extensive and sustained symptoms are now becoming a nonnegligible medical challenge. In this respect, data indicate that heart failure is one of the most common readmission diagnoses among COVID-19 patients. In this study, we used human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes to develop an in vitro model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and studied the dynamic changes occurring in cardiomyocytes after SARS-CoV-2 infection. To this end, we have created an effective time series SARS-CoV-2 infection model exhibiting different functional patterns of up- and downregulated proteins, and demonstrating that SARS-CoV-2 mainly affects (i) the lipid and the energy metabolism of hiPSC-derived cardiomyocytes during the early infection stage, and (ii) the DNA repair ability of cardiomyocytes during the late infection stage. By analyzing the proteome changes occurring at different infection timepoints, we were able to observe that the simulated disease (COVID-19) course developed rapidly, and that each of the studied timepoints was characterized by a distinct protein expression pattern. Our findings highlight the importance of early detection and personalized treatment based on the disease stage. Finally, by combing the proteomics data with virus-host interaction network analysis, we were able to identify several potential drug targets for the disease.


Why are physicians not prescribing diuretics more frequently in the management of hypertension?
Diuretics have again been recommended by the Sixth Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) as one of the first-choice medications in the management of hypertension. This recommendation is based on the results of numerous randomized, diuretic-based, long-term controlled clinical trials that have demonstrated a reduction in both cerebrovascular and cardiovascular morbidity. Despite this and other national recommendations, the use of diuretics has steadily decreased over the past 15 years. Reasons include heavy promotion of other medications and the perception that diuretics produce adverse metabolic effects and do not reduce coronary heart disease events. Data, however, indicate that (1) changes in glucose and cholesterol metabolism are minor, especially with the smaller doses now being used; (2) cardiovascular morbidity and mortality have been reduced in hypertensive patients, even in those with hyperlipidemia or diabetes, when diuretics are used; and (3) concerns about hypokalemia-induced arrhythmias have been overstated. While special indications exist for other medications in the treatment of hypertension, for example, use of an angiotensin-converting enzyme inhibitor (usually in addition to a diuretic) for a patient with heart failure or diabetic nephropathy, most patients, including those with hyperlipidemia or glucose intolerance, can be effectively treated with a diuretic as initial therapy or as part of a combination regimen. Diuretics should be used more not less frequently; use of diuretics would reduce the number of resistant hypertensive patients.


High rates of congenital cytomegalovirus infection linked with maternal HIV infection among neonatal admissions at a large referral center in sub-Saharan Africa.
Congenital cytomegalovirus (CMV) infection is the major infectious cause of birth defects and hearing loss globally. There is a growing recognition of the potential clinical impact of congenital CMV infections in high-seroprevalence settings. A cross-sectional study of neonatal admissions at a large referral center in sub-Saharan Africa to determine the prevalence of both symptomatic and asymptomatic congenital CMV infection was performed. Real-time polymerase chain reaction was used to screen DNA-extracted sera, urine, and saliva, and an enzyme-linked immunosorbent assay was used to screen serum samples for anti-CMV immunoglobulin M. Multivariate binary logistic regression was used to identify risk factors associated with increased odds of congenital CMV infection. Congenital CMV was detected in 3.8% (15/395) of neonates. Among these infants, 6 of 15 (40%) presented with jaundice, 1 of whom also had petechiae. Congenital CMV infection was detected in 9 of 79 (11.4%; 95% confidence interval [CI], 6.1%-20.3%) neonates born to human immunodeficiency virus (HIV)-infected mothers, and both maternal HIV (odds ratio [OR], 6.661 [95% CI, 2.126-20.876], P = .001) and jaundice (OR, 5.701 [95% CI, 1.776-18.306], P = .003) were independently linked with significantly increased odds of congenital CMV infection. Congenital and early infant CMV infections may have important consequences for child health in sub-Saharan Africa and other high HIV and CMV seroprevalence populations globally.


Conformation-selective synthesis and binding properties of N-benzylhexahomotriaza-p-chlorocalix[3]trinaphthylamide.
N-benzylhexahomotriaza-p-chlorocalix[3]trinaphthylamide in partial cone conformation was selectively synthesized by appropriately controlling the steric effect during the amidation reactions of N-benzylhexahomotriaza-p-chlorocalix[3]tri(ethyl acetate) in cone or partial cone conformations with use of 1-aminomethylnaphthalene. The conformation was confirmed by (1)H, (13)C, and 2D NMR and X-ray single-crystal analysis. Analyses of the complexes revealed that recognition is strongly affected by Cd(2+), Pb(2+), and F(-) ions.


A descriptive case of persistent Acanthamoeba keratitis: raising awareness of this complex ocular disease.
Acanthamoeba species are ubiquitous free-living organisms found in the environment. They can cause a sight-threatening disease of the cornea termed Acanthamoeba keratitis (AK), often associated with contact-lens wearers. This case review describes a persistent presentation of AK and raises awareness of the challenges faced when diagnosing and managing the disease. It highlights the importance of an accurate and rapid diagnosis to assist patient management and to maximize the potential for a better outcome. A 73-year-old female was admitted to hospital due to vision impairment of her left eye. Following a clinical examination, the diagnosis of herpes simplex keratitis (HSK) was reported and treated with antivirals. However, deterioration of her keratitis continued after initial treatment, which prompted an investigation into the possibility of AK. Molecular testing of sequential corneal tissue was performed using a real-time PCR assay alongside further clinical examinations. Acanthamoeba species DNA was isolated from seven out of eight corneal tissues over a 12 month period. Following prolonged drug treatment and two corneal transplants, the individual's symptoms ceased and further molecular testing of corneal tissue was negative. Acanthamoeba keratitis can be easily misdiagnosed due to the similarities in the clinical presentation to other, much more common ocular pathogens. This case highlights the importance of considering AK in the first-line diagnosis, and raises awareness that an early, accurate and rapid diagnosis is crucial to improve patient outcome.


Emphasizing the "Cultural" in Sociocultural: A Systematic Review of Research on Thin-Ideal Internalization, Acculturation, and Eating Pathology in US Ethnic Minorities.
A large body of research suggests that thin-ideal internalization is a robust predictor of eating pathology in women and, to some degree, in men. Recent research is exploring the relationships between thin-ideal internalization and culture-specific factors that may be salient to women and men who live in the US but are marginalized based on racial or ethnic background, such as acculturation. This systematic review summarizes published articles examining the relationships among thin-ideal internalization, acculturation-related constructs (including assimilation, marginalization, biculturalism, and acculturative stress), and eating pathology in US adults. Following the PRISMA method, 15 empirical studies met inclusion criteria. Although existing literature was sparse and conflicting in large part due to heterogeneity in acculturation measures, results yielded some support for positive correlational relationships between acculturative stress, thin-ideal internalization, and eating pathology for both men and women (in 4 out of 5 relevant studies). Research on other aspects of acculturation (eg, integration, assimilation) is mixed, with some existing research suggesting a positive relationship and other research finding no statistically significant relationship. Future research would particularly benefit from a gold-standard, multidimensional transcultural measure of acculturation to examine how the acculturation process relates to thin-ideal internalization and eating pathology in ethnic and racial minorities in the US.


"These issues aren't talked about at home": a qualitative study of the sexual and reproductive health information preferences of adolescents in Vanuatu.
Onset of sexual activity during adolescence is common in Vanuatu, however access to comprehensive sexual and reproductive health (SRH) information is limited. Improving adolescents' knowledge about SRH is necessary to improve health outcomes, however little is known about the information needs and preferences of adolescents in the Pacific to inform policy and programs in this region. Sixty-six focus group discussions were conducted with 341 male and female adolescents aged 15-19 years from rural and urban communities on two islands of Vanuatu. Twelve key-informant interviews were also conducted with policymakers and health service providers. Data were analysed thematically using an inductive approach. Much of the SRH information targeting adolescents focused on sexually transmitted infections and HIV. While this information was valued, important gaps were identified including prevention of pregnancy, condom use, puberty, sexuality and relationships. Peer educators and health workers were adolescents' preferred sources of information because they were considered knowledgeable and trustworthy. Parents were not a common source but were preferred, particularly by girls, despite considerable socio-cultural barriers. Schools were an important but underutilised source of information, as were a range of media sources. Providing adolescents with comprehensive SRH information can have life-long protective benefits, however there are important content gaps in information currently provided in Vanuatu. The broad range of sources preferred by adolescents highlights the need to strengthen information provision through multiple channels to reach in and out-of-school youth and respond to individual needs and contexts.


Towards the development of an autocontamination trap system to manage populations of emerald ash borer (Coleoptera: Buprestidae) with the native entomopathogenic fungus, Beauveria bassiana.
Emerald ash borer, Agrilus planipennis Fairmaire (Coleoptera: Buprestidae) is an invasive species from Asia that was discovered in North America Canada, in 2002. Herein, we describe studies to develop an autocontamination trapping system to disseminate Beauveria bassiana to control beetle populations. The standard trap for emerald ash borer in Canada is a light green prism trap covered in an insect adhesive and baited with (Z)-3-hexenol. We compared of green multifunnel traps, green intercept panel traps (both with and without fluon coating) and green prism traps for capturing emerald ash borer in a green ash plantation. The coated green multifunnel traps captured significantly more males and more females than any other trap design. We examined the efficacy of two native B. bassiana isolates, INRS-CFL and L49-1AA. In a field experiment the INRS-CFL isolate attached to multifunnel traps in autocontamination chambers retained its pathogenicity to emerald ash borer adults for up to 43 d of outdoor exposure. Conidia germination of the INRS-CFL isolate was >69% after outdoor exposure in the traps for up to 57 d. The L49-1AA isolate was not pathogenic in simulated trap exposures and the germination rate was extremely low (<5.3%). Mean (+/- SEM) conidia loads on ash borer adults after being autocontaminated in the laboratory using pouches that had been exposed in traps out of doors for 29 d were 579,200 (+/- 86,181) and 2,400 (+/- 681) for the INRS-CFL and the LA9-1AA isolates, respectively. We also examined the fungal dissemination process under field conditions using the L49-1AA isolate in a green ash plantation. Beetles were lured to baited green multifunnel traps with attached autocontamination chambers. Beetles acquired fungal conidia from cultures growing on pouches in the chambers and were recaptured on Pestick-coated traps. In total, 2,532 beetles were captured of which 165 (6.5%) had fungal growth that resembled B. bassiana. Of these 25 beetles were positive for the L49-1AA isolate.


Novel cyclopalladated and coordination palladium and platinum complexes derived from alpha-diphenyl ethanedione bis(thiosemicarbazones): structural studies and cytotoxic activity against human A2780 and A2780cisR carcinoma cell lines.
The preparation of new palladium(II) and platinum(II) complexes derived from alpha-diphenyl ethanedione bis(thiosemicarbazone), 1, and alpha-diphenyl ethanedione bis(4-ethylthiosemicarbazone), 2, is described. The palladium complexes 3 and 4 and platinum complexes 5 and 6 have been characterized by elemental analyses, fast atom bombardment mass spectrometry (FAB(+)) and spectroscopic studies (IR, (1)HNMR). The crystal and molecular structures of the dimeric cyclopalladated compound 4 and the mononuclear platinum complex 6 have been determined by single crystal X-ray diffraction. The cytotoxic activity of the free ligands and palladium and platinum complexes against human A2780 and A2780cisR (acquired resistance to cisplatin) epithelial ovarian carcinoma cells lines is also reported. The IC(50) values for compounds 1, 5 and 6 were found to be higher than that of cisplatin but the maximum antiproliferative activity was similar. Furthermore, the compounds largely retain their activity in the A2780cisR cell line, having a much better resistance factor than cisplatin in the pair of cell lines tested.


Plasma-Lyte 148 vs 0.9% saline for fluid resuscitation in diabetic ketoacidosis.
The purpose of the study was to determine the effects of Plasma-Lyte 148 (PL) vs 0.9% saline (NS) fluid resuscitation in diabetic ketoacidosis (DKA). A multicenter retrospective analysis of adults admitted for DKA to the intensive care unit, who received almost exclusively PL or NS infusion up until 12 hours, was performed. Nine patients with PL and 14 patients with NS were studied. Median serum bicarbonate correction was higher in the PL vs NS groups at 4 to 6 hours (8.4 vs 1.7 mEq/L) and 6 to 12 hours (12.8 vs 6.2 mEq/L) from baseline (P < .05). Median standard base excess improved by 10.5 vs 4.2 mEq/L at 4 to 6 hours and by 16.0 vs 9.1 mEq/L at 6 to 12 hours in the PL and NS groups, respectively (P < .05). Chloride levels increased significantly in the NS vs PL groups over 24 hours. Potassium levels were lower at 6 to 12 hours in the PL group. Mean arterial blood pressure was higher at 2 to 4 hours in the PL group, whereas cumulative urine output was lower at 4 to 6 hours in the NS group. There were no differences in glycemic control or duration of intensive care unit stay. Patients with DKA resuscitated with PL instead of NS had faster initial resolution of metabolic acidosis and less hyperchloremia, with a transiently improved blood pressure profile and urine output.


SOME BIOCHEMICAL CHANGES IN THE GUINEA PIG DURING INFECTION WITH COXIELLA BURNETII.
Paretsky, D. (University of Kansas, Lawrence), C. M. Downs, and C. W. Salmon. Some biochemical changes in the guinea pig during infection with Coxiella burnetii. J. Bacteriol. 88:137-142. 1964.-Guinea pigs infected with Coxiella burnetii, the rickettsial agent of Q fever, were studied for 11 days postinfection. Maximal changes in liver lipids, liver phosphorylase, and uridine diphosphate glucose (UDPG)-glycogen glucosyl-transferase activities occurred 3 to 4 days post-infection. In this period, total liver lipids increased from 1.26 to 5.46 mg/mg of N, with the largest increment in the glyceride fraction. Liver glycogen virtually disappeared by the second day, with no chemically detectable restoration until the eleventh day. A pattern of altered phosphorylase and UDPG-glycogen transglucosylase activities was observed, with maximal phosphorylase and minimal glucosyltransferase activities at the third and fourth days. Histochemical observations confirmed chemical analyses for lipids and glycogen.


Carpal kinematics during simulated active and passive motion of the wrist.
The purpose of this study was to investigate the effect of experimental control mechanisms, simulated active (tendon-driven) and passive (externally assisted), on carpal motion. Kinematics of the carpal bones in five fresh-frozen cadaver upper extremities were studied using an optical motion analysis system. The wrist extensors and flexors were dissected and loaded. For passive motion, the tendons were loaded to simulate muscle tone while the investigator passively moved the wrist using a pin placed in the third metacarpal. To simulate active, patient-driven motion, the tendons were attached directly to guide bars while the investigator used a puppeteer mechanism to move the wrist. There were no significant differences in carpal motion (flexion-extension motion or radial-ulnar deviation) when the wrist was moved in simulated active motion through the extensor and flexor tendons or in passive motion, with a constant force applied to the tendons. Kinematics for simulated active motion, in general, was more difficult to control and was less smooth than the kinematics for passive motion. Carpal bone kinematics (excluding the pisiform) in a healthy normal joint are similar in both simulated active (tendon-driven) and passive (externally assisted) wrist motion because the carpal bones are passively moved during wrist motion (there are no direct tendon-to-muscle attachments to the proximal carpal bones and minimal attachments to the distal carpal bones).


[The patient with psychogenic and psychosomatic pain. Outline of psychoanalytically oriented nosology].
Starting with the contribution of G. L. Engel (1959) a systematization of the psychodynamic conceptions of pain and pain disorder is given. Four different explanations for the genesis and maintenance of pain states are worked out: (1) The narcissistic mechanism (substitution), (2) the conversion mechanism (symbolization), introduced by S. Freud himself, (3) the psychovegative mechanism (resomatization), and (4) learning principles. These four conceptions are presented. Finally concern is expressed as the conceptual range of three of these explanatory principles is thought to cover a relevant range by far not reached by other pain theories more en vogue.


Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome.
Type 2 congenital long QT syndrome (LQT-2) is linked to mutations in the human ether a-go-go-related gene (HERG) and is characterized by rate-corrected QT interval (QTc) prolongation, ventricular arrhythmias, syncope, and sudden death. Recognized triggers of these cardiac events include emotional and acoustic stimuli. Here we investigated the repeated occurrence of fever-induced polymorphic ventricular tachycardia and ventricular fibrillation in 2 LQT-2 patients with A558P missense mutation in HERG. ECG analysis showed increased QTc with fever in both patients. WT, A558P, and WT+A558P HERG were expressed heterologously in HEK293 cells and were studied using biochemical and electrophysiological techniques. A558P proteins showed a trafficking-deficient phenotype. WT+A558P coexpression caused a dominant-negative effect, selectively accelerated the rate of channel inactivation, and reduced the temperature-dependent increase in the WT current. Thus, the WT+A558P current did not increase to the same extent as the WT current, leading to larger current density differences at higher temperatures. A similar temperature-dependent phenotype was seen for coexpression of the trafficking-deficient LQT-2 F640V mutation. We postulate that the weak increase in the HERG current density in WT-mutant coassembled channels contributes to the development of QTc prolongation and arrhythmias at febrile temperatures and suggest that fever is a potential trigger of life-threatening arrhythmias in LQT-2 patients.


Preparation of PEG-modified PAMAM dendrimers having a gold nanorod core and their application to photothermal therapy.
This study was conducted to attempt development of a new type of hybrid dendrimer consisting of a gold nanorod (GNR) core and PEG-modified PAMAM (PEG-PAMAM) dendrons by adding PEG-PAMAM G2-G4 dendrimers with a cystamine core at various timings during the GNR growing reaction. We obtained hybrids of the dendrimers and GNRs exhibiting surface plasmon resonance in the near infrared region. Whereas the PEG-PAMAM G4 dendrimer-GNR hybrid formed an aggregate in an aqueous solution, PEG-PAMAM G2 and G3 dendrimers respectively gave hybrids with average diameters of 24 nm and 31 nm. Especially, the spherical PEG-PAMAM G3 dendrimer-GNR hybrid might be regarded as a GNR-cored PEG-PAMAM dendrimer in which the GNR core was well stabilized by highly hydrated PEG-PAMAM G3 dendrons. The GNR-cored PEG-PAMAM G3 dendrimer exhibited excellent heat-generation capability under near-infrared light irradiation. Incubation with the GNR-cored PEG-PAMAM G3 dendrimer showed no damage to HeLa cells. However, dendrimer-treated cells were killed effectively by near-infrared laser irradiation, indicating excellent photothermal capability of the GNR-cored PEG-PAMAM G3 dendrimer. Furthermore, the GNR-cored PEG-PAMAM G3 dendrimer injected into mice tumor tissues significantly increased the temperature of the tumor when irradiated with near infrared light, resulting in a decreased tumor volume. These results demonstrate that GNR-cored PEG-PAMAM dendrimers might be a new nanomaterial for biomedical applications such as photothermal therapy.


Long-term efficacy of a hepatitis E vaccine.
Hepatitis E virus (HEV) is a leading cause of acute hepatitis. The long-term efficacy of a hepatitis E vaccine needs to be determined. In an initial efficacy study, we randomly assigned healthy adults 16 to 65 years of age to receive three doses of either a hepatitis E vaccine (vaccine group; 56,302 participants) or a hepatitis B vaccine (control group; 56,302 participants). The vaccines were administered at 0, 1, and 6 months, and the participants were followed for 19 months. In this extended follow-up study, the treatment assignments of all participants remained double-blinded, and follow-up assessments of efficacy, immunogenicity, and safety were continued for up to 4.5 years. During the 4.5-year study period, 60 cases of hepatitis E were identified; 7 cases were confirmed in the vaccine group (0.3 cases per 10,000 person-years), and 53 cases in the control group (2.1 cases per 10,000 person-years), representing a vaccine efficacy of 86.8% (95% confidence interval, 71 to 94) in the modified intention-to-treat analysis, rather than (95% confidence interval, 71 to 84) [corrected]. Of the participants who were assessed for immunogenicity and were seronegative at baseline, 87% of those who received three doses of the hepatitis E vaccine maintained antibodies against HEV for at least 4.5 years; HEV antibody titers developed in 9% in the control group. The rate of adverse events was similar in the two groups. Immunization with this hepatitis E vaccine induced antibodies against HEV and provided protection against hepatitis E for up to 4.5 years. (Funded by the Chinese Ministry of Science and Technology and others; ClinicalTrials.gov number, NCT01014845.).


Computer simulations of efficacy of air-cell-based cushions in protecting against reoccurrence of pressure ulcers.
For individuals with a spinal cord injury (SCI) who depend on a wheelchair for mobility, sitting-acquired pressure ulcers (PUs) are a common and life-endangering complication. In the short time following an SCI, pathoanatomical and pathophysiological changes that affect the weight-bearing tissues of the buttocks may increase the risk for PUs, exposing this already-at-risk population to the additional potential risk caused by soft tissue scarring. In this work, we evaluated the biomechanical efficacies of an air-cell-based (ACB) cushion for individuals with SCI who have previously experienced PUs that healed but left scars in their soft tissues. We used 11 finite element model variants of the buttocks describing various scar shapes and severities to study the effects of the scars on soft tissue stresses during sitting on an ACB cushion and the resulting theoretical risk for the reoccurrence of PUs. Interestingly, the ACB cushion induced, in general, lower peak stress values in the soft tissues of the buttocks when scarring was present with respect to the stress levels in the (nonscarred) reference case. Our simulations therefore suggest that the ACB cushion is generally better protecting patients with a history of severe PUs manifested by large, possibly deep tissue scarring in their buttocks.


A model of conflict and leadership: Is there a hawkish drift in politics?
We analyze conflict between a citizenry and an insurgent group over a fixed resource such as land. The citizenry has an elected leader who proposes a division such that, the lower the land ceded to the insurgents, the higher the cost of conflict. Leaders differ in ability and ideology such that the higher the leader's ability, the lower the cost of conflict, and the more hawkish the leader, the higher his utility from retaining land. We show that the conflict arises from the political process with re-election motives causing leaders to choose to cede too little land to signal their ability. We also show that when the rents of office are high, the political equilibrium and the second best diverge; in particular, the policy under the political equilibrium is more hawkish compared to the second best. When both ideology and ability are unknown, we provide a plausible condition under which the probability of re-election increases in the leader's hawkishness, thereby providing an explanation for why hawkish politicians may have a natural advantage under the electoral process.


A 2-year prospective cohort study of antidementia drug non-persistency in mild-to-moderate Alzheimer's disease in Europe : predictors of discontinuation and switch in the ICTUS study.
There is no consensus on when and how to discontinue cholinesterase inhibitors (ChEI). Predictors of non-persistency of antidementia drugs have been poorly investigated, mostly during short-term periods and using administrative data. The aim of this study was to investigate the incidence and predictors of ChEI switch and discontinuation among subjects with ascertained Alzheimer's disease (AD). A total of 557 community-dwelling, mild-to-moderate AD subjects initiating ChEIs in 29 European clinic centres were assessed twice-yearly for 2 years. Antidementia drug exposure was recorded through a physician-administered structured questionnaire to document any change in drug therapy (start and stop dates, reasons). Discontinuation was defined as >35 days without any antidementia drug. Switch was defined as a change for any antidementia drug strategy within 35 days after ChEI cessation. Two separate time-dependent multivariate Cox survival analyses were conducted to identify predictors of discontinuation and switch. The incidences of discontinuation and switch were 9.65 and 12.47/100 person-years, respectively. Behavioural disturbances, low body mass index, falls, decline in Mini-Mental State Examination (MMSE) score, and AD-related hospitalization predicted discontinuation. MMSE score, decline in activities of daily living score, aberrant motor behaviour, shorter AD duration and higher nurse resource use predicted a switch. An ineffective ChEI dose and clinic specialty predicted both outcomes. Sensitivity analyses using a 60-day cut-off provided stable results. Several predictors were identified: adverse drug events and their predisposing factors, perceived loss of efficacy or disease progression on cognitive or functional scales, behavioural disturbances, hospitalization and professional practices. The latter implies a need for harmonization in AD drug prescription practice.


The effect of particle shape on the deformation and stress reduction of a gravel soil due to wetting.
This paper investigates the effect of particle shape on the stress reduction and collapse deformation of gravelly soil using a medium-scale direct shear test apparatus under different relative densities, normal stress, and shear stress levels. A new method based on the Micro-Deval test was introduced to produce sub-angular particles from angular particles. Therefore, two series of soil specimens were obtained with the same rock origin, particle size distribution, and relative density but different particle shapes. In addition to traditional direct shear tests on dry and wet specimens, a specific test procedure was applied to explore the stress reduction and collapse of soil specimens due to wetting. The results of the tests, including shear stress-shear displacement and vertical displacement-shear displacement, were compared. The results showed that the stress reduction and settlement due to wetting increased with vertical and shear stress levels in both types of particle shapes, with higher values in angular particle shapes. The particle breakage of the soil specimens was also studied quantitatively using the change in the particle size distribution before and after the test. It was shown that the wetting of the samples had more impact on the particle breakage in angular gravel than sub-angular gravel, which increased linearly with the normal stress.


Photothermally enhanced photodynamic therapy based on mesoporous Pd@Ag@mSiO2 nanocarriers.
In this work, we have demonstrated that mesoporous silica-coated Pd@Ag nanoparticles (Pd@Ag@mSiO2) can be used as an excellent nanoplatform for photodynamic therapy (PDT) drug delivery. Photosensitizer molecules, Chlorin e6 (Ce6), are covalently linked to the mesoporous shell and the prepared Pd@Ag@mSiO2-Ce6 nanoparticles exhibit excellent water solubility, good stability against leaching and high efficiency in photo-generating cytotoxic singlet oxygen. More importantly, the photothermal effect of Pd@Ag nanoplates under the irradiation of a NIR laser can enhance the uptake of Pd@Ag@mSiO2-Ce6 nanoparticles by cells, further increasing the PDT efficiency toward cancer cells. The photothermally enhanced PDT effects were demonstrated both in vitro and in vivo. When the Pd@Ag@mSiO2-Ce6 nanoparticles were injected intratumorally into the S180 tumor-bearing mice, the tumors were completely destroyed without recurrence of tumors upon irradiation with both 808 nm and 660 nm lasers, while the irradiation with 808 nm or 660 nm alone did not. These results indicate that the Pd@Ag@mSiO2 nanoparticles may be a valuable new tool for application in cancer phototherapy.


Central fatness and risk of all cause mortality: systematic review and dose-response meta-analysis of 72 prospective cohort studies.
To quantify the association of indices of central obesity, including waist circumference, hip circumference, thigh circumference, waist-to-hip ratio, waist-to-height ratio, waist-to-thigh ratio, body adiposity index, and A body shape index, with the risk of all cause mortality in the general population, and to clarify the shape of the dose-response relations. Systematic review and meta-analysis. PubMed and Scopus from inception to July 2019, and the reference lists of all related articles and reviews. Prospective cohort studies reporting the risk estimates of all cause mortality across at least three categories of indices of central fatness. Studies that reported continuous estimation of the associations were also included. A random effects dose-response meta-analysis was conducted to assess linear trend estimations. A one stage linear mixed effects meta-analysis was used for estimating dose-response curves. Of 98 745 studies screened, 1950 full texts were fully reviewed for eligibility. The final analyses consisted of 72 prospective cohort studies with 2 528 297 participants. The summary hazard ratios were as follows: waist circumference (10 cm, 3.94 inch increase): 1.11 (95% confidence interval 1.08 to 1.13, I2=88%, n=50); hip circumference (10 cm, 3.94 inch increase): 0.90 (0.81 to 0.99, I2=95%, n=9); thigh circumference (5 cm, 1.97 inch increase): 0.82 (0.75 to 0.89, I2=54%, n=3); waist-to-hip ratio (0.1 unit increase): 1.20 (1.15 to 1.25, I2=90%, n=31); waist-to-height ratio (0.1 unit increase): 1.24 (1.12 to 1.36, I2=94%, n=11); waist-to-thigh ratio (0.1 unit increase): 1.21 (1.03 to 1.39, I2=97%, n=2); body adiposity index (10% increase): 1.17 (1.00 to 1.33, I2=75%, n=4); and A body shape index (0.005 unit increase): 1.15 (1.10 to 1.20, I2=87%, n=9). Positive associations persisted after accounting for body mass index. A nearly J shaped association was found between waist circumference and waist-to-height ratio and the risk of all cause mortality in men and women. A positive monotonic association was observed for waist-to-hip ratio and A body shape index. The association was U shaped for body adiposity index. Indices of central fatness including waist circumference, waist-to-hip ratio, waist-to-height ratio, waist-to-thigh ratio, body adiposity index, and A body shape index, independent of overall adiposity, were positively and significantly associated with a higher all cause mortality risk. Larger hip circumference and thigh circumference were associated with a lower risk. The results suggest that measures of central adiposity could be used with body mass index as a supplementary approach to determine the risk of premature death.


Identification of Genetic Variants Associated with Severe Myocardial Bridging through Whole-Exome Sequencing.
Myocardial bridging (MB) is a congenital coronary artery anomaly and an important cause of angina. The genetic basis of MB is currently unknown. This study used a whole-exome sequencing technique and analyzed genotypic differences. Eight coronary angiography-confirmed cases of severe MB and eight age- and sex-matched control patients were investigated. In total, 139 rare variants that are potentially pathogenic for severe MB were identified in 132 genes. Genes with multiple rare variants or co-predicted by ClinVar and CADD/REVEL for severe MB were collected, from which heart-specific genes were selected under the guidance of tissue expression levels. Functional annotation indicated significant genetic associations with abnormal skeletal muscle mass, cardiomyopathies, and transmembrane ion channels. Candidate genes were reviewed regarding the functions and locations of each individual gene product. Among the gene candidates for severe MB, rare variants in DMD, SGCA, and TTN were determined to be the most crucial. The results suggest that altered anchoring proteins on the cell membrane and intracellular sarcomere unit of cardiomyocytes play a role in the development of the missed trajectory of coronary vessels. Additional studies are required to support the diagnostic application of cardiac sarcoglycan and dystroglycan complexes in patients with severe MB.


RNA Modifications and RNA Metabolism in Neurological Disease Pathogenesis.
The intrinsic cellular heterogeneity and molecular complexity of the mammalian nervous system relies substantially on the dynamic nature and spatiotemporal patterning of gene expression. These features of gene expression are achieved in part through mechanisms involving various epigenetic processes such as DNA methylation, post-translational histone modifications, and non-coding RNA activity, amongst others. In concert, another regulatory layer by which RNA bases and sugar residues are chemically modified enhances neuronal transcriptome complexity. Similar RNA modifications in other systems collectively constitute the cellular epitranscriptome that integrates and impacts various physiological processes. The epitranscriptome is dynamic and is reshaped constantly to regulate vital processes such as development, differentiation and stress responses. Perturbations of the epitranscriptome can lead to various pathogenic conditions, including cancer, cardiovascular abnormalities and neurological diseases. Recent advances in next-generation sequencing technologies have enabled us to identify and locate modified bases/sugars on different RNA species. These RNA modifications modulate the stability, transport and, most importantly, translation of RNA. In this review, we discuss the formation and functions of some frequently observed RNA modifications-including methylations of adenine and cytosine bases, and isomerization of uridine to pseudouridine-at various layers of RNA metabolism, together with their contributions to abnormal physiological conditions that can lead to various neurodevelopmental and neurological disorders.


Salt-tolerant and -sensitive alfalfa (Medicago sativa) cultivars have large variations in defense responses to the lepidopteran insect Spodoptera litura under normal and salt stress condition.
In nature, plants are often exposed to multiple stress factors at the same time. Yet, little is known about how plants modulate their physiology to counteract simultaneous abiotic and biotic stresses, such as soil salinity and insect herbivory. In this study, insect performance bioassays, phytohormone measurements, quantification of transcripts, and protein determination were employed to study the phenotypic variations of two alfalfa (Medicago sativa) cultivars in response to insect Spodoptera litura feeding under normal and salt stress condition. When being cultivated in normal soil, the salt-tolerant alfalfa cultivar Zhongmu-1 exhibited lower insect resistance than did the salt-sensitive cultivar Xinjiang Daye. Under salinity stress, the defense responses of Xinjiang Daye were repressed, whereas Zhongmu-1 did not show changes in resistance levels. It is likely that salinity influenced the resistance of Xinjiang Daye through suppressing the accumulation of jasmonic acid-isoleucine (JA-Ile), which is the bioactive hormone inducing herbivore defense responses, leading to attenuated trypsin proteinase inhibitor (TPI) activity. Furthermore, exogenous ABA supplementation suppressed the insect herbivory-induced JA/JA-Ile accumulation and levels of JAR1 (jasmonate resistant 1) and TPI, and further decreased the resistance of Xinjiang Daye, whereas Zhongmu-1 showed very little response to the increased ABA level. We propose a mechanism, in which high levels of abscisic acid induced by salt treatment may affect the expression levels of JAR1 and consequently decrease JA-Ile accumulation and thus partly suppress the defense of Xinjiang Daye against insects under salt stress. This study provides new insight into the mechanism by which alfalfa responds to concurrent abiotic and biotic stresses.


Regulation of the G(2)/M transition in Xenopus oocytes by the cAMP-dependent protein kinase.
Vertebrate oocytes are arrested in G(2) phase of the cell cycle at the prophase border of meiosis I. Progesterone treatment of Xenopus oocytes releases the G(2) block and promotes entry into the M phases of meiosis I and II. Substantial evidence indicates that the release of the G(2) arrest requires a decrease in cAMP and reduced activity of the cAMP-dependent protein kinase (PKAc). It has been reported and we confirm here that microinjection of either wild type or kinase-dead K72R PKAc inhibits progesterone-dependent release of the G(2) arrest with equal potency and that inhibition can be reversed by a second injection of the heat-stable inhibitor of PKAc, PKI. However, a mutant enzyme predicted to be completely kinase-dead from the crystal structure of PKAc, K72H PKAc, was much less inhibitory when carrying additional mutations that block interaction with either type I or type II regulatory subunit. Moreover, inhibition by K72H PKAc was reversed by PKI at a 30-fold lower concentration and with more rapid kinetics compared with wild type PKAc. K72R PKAc was found to have low but detectable activity after incubation in an oocyte extract. These results indicate that inhibition of the progesterone-dependent G(2)/M transition in oocytes after microinjection of dead PKAc reflects either low residual activity or binding to regulatory subunits with a resulting net increase in the level of endogenous wild type PKAc. Consistent with this hypothesis, the induction of mitosis in Xenopus egg extracts by the addition of cyclin B was blocked by wild type PKAc but not by K72H PKAc. The identification of substrates for PKAc that maintain cell cycle arrest in G(2) remains an important goal for future work.


Analyses of structural polypeptides of seven different isolates of influenza C virus.
The major structural polypeptides (gp88, NP and M) of seven different influenza C virus strains isolated between 1947 and 1981 in U.S.A. and Japan were compared by SDS-polyacrylamide gel electrophoresis and one-dimensional mapping of the peptide fragments produced after limited proteolysis with various proteases. Of the three polypeptides analysed, the membrane (M) protein appeared to be the most highly conserved since the electrophoretic mobility as well as the mapping pattern of this protein was found to be identical among all seven strains. The structure of nucleoprotein (NP) was also found to be highly conserved. The proteins of five isolates from 1964 to 1981 showed migration rates and mapping patterns indistinguishable from each other though they were slightly different in mapping patterns from the earlier isolates, C/Taylor/1233/47 and C/JJ/50. The similarities between influenza C strains were also evident with the surface glycoprotein, gp88. The gp88 proteins of the five strains isolated in 1947, 1950, 1971 and 1981 were virtually identical in migration rates as well as in mapping patterns, while the two isolates of 1964 and 1974 showed minor differences. These results strongly suggest that the surface glycoprotein of influenza C virus is structurally much more stable than the haemagglutinin and neuraminidase glycoproteins of influenza A and B viruses. Further, the findings that differences from the original influenza C strain, Taylor/1233/47 were detectable in the strains isolated in 1964 and 1974 but not in the strains isolated in 1971 and 1981 suggest that unlike the antigenic drift of types A and B influenza viruses, the structural variation of gp88 may not be a sequential event.


Variation in fat, lactose, and protein composition in breast milk over 24 hours: associations with infant feeding patterns.
Data regarding the association between breast milk composition and infant feeding patterns (frequency and amount of breast milk taken) would help in understanding the regulation of food intake in breastfed infants. This study examined the relationship between breast milk macronutrient concentration and patterns of milk intake in breastfeeding infants over a 24-hour breastfeeding period. Mothers of healthy term infants (n = 15) collected pre- and postfeed breast milk samples from each feed at each breast over a 24-hour period. Breast milk samples were analyzed for fat, lactose, total protein, casein, and whey protein content. The energy content for each feed was calculated. Breastfeeding patterns and milk composition varied greatly between individuals. The fat content of milk significantly differed over 24 hours (P = .01), whereas the concentration of lactose and protein content remained the same. The mean 24-hour total protein, whey, and casein intake was inversely (P < .01), whereas lactose concentration was positively (P = .03) related to the number of breast feeds per day. No relationship was seen either between fat or energy content and feeding patterns. The mean (SD) concentration of fat, lactose, and total protein over the 24-hour period was 43 (12) g/L, 68 (7) g/L, and 13 (2) g/L, respectively. The association between milk protein intake and the breastfeeding frequency suggests that the protein intake may play a role in infant appetite control.


Ca2+ dependence of stimulated 45Ca efflux in skinned muscle fibers.
Stimulation of sarcoplasmic reticulum Ca release by Mg reduction of caffeine was studied in situ, to characterize further the Ca2+ dependence observed previously with stimulation by Cl ion. 45Ca efflux and isometric force were measured simultaneously at 19 degrees C in frog skeletal muscle fibers skinned by microdissection; EGTA was added to chelate myofilament space Ca either before or after the stimulus. Both Mg2+ reduction (20 or 110 microM to 4 microM) and caffeine (5 mM) induced large force responses and 45Ca release, which were inhibited by pretreatment with 5 mM EGTA. In the case of Mg reduction, residual efflux stimulation was undetectable, and 45Ca efflux in EGTA at 4 microM Mg2+ was not significantly increased. Residual caffeine stimulation at 20 microM Mg2+ was substantial and was reduced further in increased EGTA (10 mM); at 600 microM Mg2+, residual stimulation in 5 mM EGTA was undetectable. Caffeine appears to initiate a small Ca2+-insensitive efflux that produces a large Ca2+-dependent efflux. Additional experiments suggested that caffeine also inhibited influx. The results suggest that stimulated efflux is mediated mainly or entirely by a channel controlled by an intrinsic Ca2+ receptor, which responds to local [Ca2+] in or near the channel. Receptor affinity for Ca2+ probably is influenced by Mg2+, but inhibition is weak unless local [Ca2+] is very low.


New method of measuring subjective well-being: prospective validation study of the 'Daily Experience Sampling Questionnaire' (DESQ) in patients with psoriasis and healthy subjects in Germany.
To validate the newly developed Daily Experience Sampling Questionnaire (DESQ) that measures affective subjective well-being (SWB). The DESQ is an end-of-day diary in which respondents retrospectively rate their SWB at six different, randomly determined moments; it is completed over 1 week. The DESQ shall provide an alternative or complementary approach to existing methods of near-time SWB measurement (experience sampling, Day Reconstruction Method). The primary research objective was to determine criterion validity of the DESQ. Prospective, non-interventional study. Participants were recruited in Hamburg, Germany, at a specialised outpatient clinic (patients) and via different channels (healthy participants). 101 adults with diagnosed and stable psoriasis (46 women, 55 men); 105 adults without psoriasis (49 women, 56 men). Participants completed the DESQ for 3 weeks. In weeks 2 and 3, they also performed experience sampling. Criterion validity was determined by weekwise intraclass correlations (ICC) between both methods. Sensitivity to change was determined by the correlation between changes in both methods from weeks 2 to 3. For convergent validity, related concepts such as life satisfaction were measured. Retest reliability was determined using DESQ values of weeks 2 and 3. Criterion validity was excellent (ICC: patients=0.86, 95% CI 0.81 to 0.91; healthy participants=0.86, 95% CI 0.79 to 0.91). Sensitivity to change was r=0.57 and r=0.56, respectively. Correlations with convergent criteria were mostly significant and higher in constructs more proximal to SWB. The ICC indicating retest reliability was 0.77 in patients (95% CI 0.68 to 0.84) and 0.81 in healthy participants (95% CI 0.73 to 0.86). The DESQ is a valid, reliable and feasible instrument for SWB measurement in people with psoriasis and healthy people. Its approach of end-of-day evaluations of single moments may also lend itself to the measurement of other highly time-variant constructs such as pain, fatigue or depression.


New cell-based technologies in bone and cartilage tissue engineering. II. Cartilage regeneration.
A tissue engineering, cell-based therapeutic approach could be essential for extensive bone or cartilage reconstruction. This article is divided in two chapters and describes new cell-based surgical techniques for cartilage and bone reconstruction. The second part of the article, regarding cartilage repair, describes a new arthroscopic surgical technique for tissue engineered cartilage grafting. A 3-dimensional hyaluronic acid support is used for autologous chondrocyte culturing. The technique reduces morbidity of classic autologous implant avoiding open surgery and periosteal flap use. With this technique is possible to reduce the patient morbidity, time and cost of surgery.


Molecular diagnostics of soft tissue tumors.
Soft tissue pathology encompasses a remarkably diverse assortment of benign and malignant soft tissue tumors. Rendering a definitive diagnosis is complicated not only by the large volume of existing histologic subtypes (>100) but also frequently by the presence of overlapping clinical, histologic, immunohistochemical, and/or radiographic features. During the past 3 decades, mesenchymal tumor-specific, cytogenetic and molecular genetic abnormalities have demonstrated an increasingly important, ancillary role in mesenchymal tumor diagnostics. To review molecular diagnostic tools available to the pathologist to further classify specific soft tissue tumor types and recurrent aberrations frequently examined. Advantages and limitations of individual approaches will also be highlighted. Previously published review articles, peer-reviewed research publications, and the extensive cytogenetic and molecular diagnostic experience of the authors to include case files of The University of Nebraska Medical Center. Cytogenetic and molecular genetic assays are used routinely for diagnostic purposes in soft tissue pathology and represent a powerful adjunct to complement conventional microscopy and clinicoradiographic evaluation in the formulation of an accurate diagnosis. Care should be taken, however, to recognize the limitations of these approaches. Ideally, more than one technical approach should be available to a diagnostic laboratory to compensate for the shortcomings of each approach in the assessment of individual specimens.


Chromosome fusions following telomere loss are mediated by single-strand annealing.
Progressive telomere shortening eventually results in chromosome fusions and genome instability as the cell's ability to distinguish chromosome ends from DNA double-strand breaks is compromised. In fission yeast, such events frequently produce stable survivors with all circular chromosomes. To shed light on the repair pathways that mediate chromosome end fusions and generate circular chromosomes, we have examined a diverse array of DNA repair factors. We show that telomere attrition-induced chromosome fusions are dependent on the fission yeast homologs of Rad52, the ERCC1/XPF endonuclease, the single-stranded DNA-binding protein RPA, and the Srs2 and Werner/Bloom helicases, but not Ku and ligase 4. Consistent with a recombinational mechanism of single-strand annealing, cloned junctions map to four of five homology regions in subtelomeric DNA. A comparison with telomere uncapping caused by the absence of the double-stranded telomere-binding protein Taz1 demonstrates that the circumstances and cause of telomere dysfunction profoundly affect which DNA repair pathway is engaged.


Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks.
Chronic stalling of DNA replication forks caused by DNA damage can lead to genomic instability. Cells have evolved lesion bypass pathways such as postreplication repair (PRR) to resolve these arrested forks. In yeast, one branch of PRR involves proliferating cell nuclear antigen (PCNA) polyubiquitination mediated by the Rad5-Ubc13-Mms2 complex that allows bypass of DNA lesion by a template-switching mechanism. Previously, we identified human SHPRH as a functional homologue of yeast Rad5 and revealed the existence of RAD5-like pathway in human cells. Here we report the identification of HLTF as a second RAD5 homologue in human cells. HLTF, like SHPRH, shares a unique domain architecture with Rad5 and promotes lysine 63-linked polyubiquitination of PCNA. Similar to yeast Rad5, HLTF is able to interact with UBC13 and PCNA, as well as SHPRH; and the reduction of either SHPRH or HLTF expression enhances spontaneous mutagenesis. Moreover, Hltf-deficient mouse embryonic fibroblasts show elevated chromosome breaks and fusions after methyl methane sulfonate treatment. Our results suggest that HLTF and SHPRH are functional homologues of yeast Rad5 that cooperatively mediate PCNA polyubiquitination and maintain genomic stability.


Role of inhibiting LIM-kinase2 in improving erectile function through suppression of corporal fibrosis in a rat model of cavernous nerve injury.
We evaluated whether LIM-kinase 2 inhibitor (LIMK2i) could improve erectile function by suppressing corporal fibrosis through the normalization of the Rho-associated coiled-coil protein kinase 1 (ROCK1)/LIMK2/Cofilin pathway in a rat model of cavernous nerve crush injury (CNCI). Sixty 11-week-old male Sprague-Dawley rats were divided equally into five groups: sham surgery (S), CNCI (I), and CNCI treated with low-dose (L), medium-dose (M), and high-dose (H) LIMK2i. The L, M, and H groups were treated with a daily intraperitoneal injection of LIMK2i (2.5, 5.0, and 10.0 mg kg-1 body weight, respectively) for 1 week after surgery. The erectile response was assessed using electrostimulation at 1 week, postoperatively. Penile tissues were processed for Masson's trichrome staining, double immunofluorescence, and Western blot assay. Erectile responses in the H group improved compared with the I group, while the M group showed only partial improvement. A significantly decreased smooth muscle/collagen ratio and an increased content of fibroblasts positive for phospho-LIMK2 were noted in the I group. The M and H groups revealed significant improvements in histological alterations and the dysregulated LIMK2/Cofilin pathway, except for LIMK2 phosphorylation in the M group. The inhibition of LIMK2 did not affect the ROCK1 protein expression. The content of fibroblasts positive for phospho-LIMK2 in the H group returned to the level found in the S group, whereas it did not in the M group. However, the L group did not exhibit such improvements. Our data suggest that the inhibition of LIMK2, particularly with administration of 10.0 mg kg-1 body weight LIMK2i, can improve corporal fibrosis and erectile function by normalizing the LIMK2/Cofilin pathway.


Electrical properties of acupuncture points and meridians: a systematic review.
According to conventional wisdom within the acupuncture community, acupuncture points and meridians are special conduits for electrical signals. This view gained popularity after anecdotal reports and clinical studies asserted that these anatomical structures are characterized by lower electrical impedance compared to adjacent controls. To ascertain whether evidence exists to support or refute this claim, we conducted a systematic review of studies directly evaluating the electrical characteristics of acupuncture structures and appropriate controls. We searched seven electronic databases until August 2007, hand-searched references, and consulted technical experts. We limited the review to primary data human studies published in English. A quality scoring system was created and employed for this review. A total of 16 articles representing 18 studies met inclusion criteria: 9 examining acupuncture points and 9 examining meridians. Five out of 9 point studies showed positive association between acupuncture points and lower electrical resistance and impedance, while 7 out of 9 meridian studies showed positive association between acupuncture meridians and lower electrical impedance and higher capacitance. The studies were generally poor in quality and limited by small sample size and multiple confounders. Based on this review, the evidence does not conclusively support the claim that acupuncture points or meridians are electrically distinguishable. However, the preliminary findings are suggestive and offer future directions for research based on in-depth interpretation of the data.


Radioactive isotopes reveal a non sluggish kinetics of grain boundary diffusion in high entropy alloys.
High entropy alloys (HEAs) have emerged as a new class of multicomponent materials, which have potential for high temperature applications. Phase stability and creep deformation, two key selection criteria for high temperature materials, are predominantly influenced by the diffusion of constituent elements along the grain boundaries (GBs). For the first time, GB diffusion of Ni in chemically homogeneous CoCrFeNi and CoCrFeMnNi HEAs is measured by radiotracer analysis using the 63Ni isotope. Atom probe tomography confirmed the absence of elemental segregation at GBs that allowed reliable estimation of the GB width to be about 0.5 nm. Our GB diffusion measurements prove that a mere increase in number of constituent elements does not lower the diffusion rates in HEAs, but the nature of added constituents plays a more decisive role. The GB energies in both HEAs are estimated at about 0.8-0.9 J/m2, they are found to increase significantly with temperature and the effect is more pronounced for the CoCrFeMnNi alloy.


Cardiac biomarkers associated with epilepsy in a captive baboon pedigree.
The epileptic baboon provides a natural model of idiopathic generalized epilepsy and sudden unexpected death in epilepsy (SUDEP). This retrospective, case-controlled study aims to evaluate cardiac biomarkers of epilepsy, specifically QT-interval prolongation and heart rate variability (HRV), in pedigreed, captive baboons undergoing scalp electroencephalography (EEG). We retrospectively identified 21 epileptic (nine females, mean age = 11.4 ± 5.4 years) and 19 asymptomatic control (12 females, mean age = 10.5 ± 6.3 years) baboons, who had undergone scalp EEG studies with an artifact-free, 10-beat electrocardiogram sample. All baboons were sedated with subanesthetic doses of ketamine prior to electrode placement. PR, QT, and RR intervals were measured, and Fridericia-corrected QT duration (QTcF) and root mean square of successive differences between RR intervals (RMSSD; representative of HRV) values were compared between the groups. The epilepsy group had significantly prolonged QT and QTcF intervals (P = .005) compared to controls. RMSSD values were nonsignificantly decreased in epileptic baboons compared to the control group. This study demonstrates cardiac repolarization anomalies and reduction of HRV in epileptic baboons, providing new cardiac biomarkers in pedigreed baboons and potential risk factors for SUDEP.


The pressure-flow response of the pulmonary circulation in patients with heart failure and pulmonary vascular disease.
Although it is well known that the pulmonary circulation is altered in patients with pulmonary arterial or venous hypertension, the resultant hemodynamic behavior has not been systematically studied. We undertook to do so in a group of patients with pulmonary hypertension of diverse etiology. We measured pulmonary arterial (PAP) and occlusive wedge pressures and cardiac output at rest (i.e., standing) and during progressive upright treadmill exercise in 51 patients. Forty-two had chronic, stable, cardiac failure secondary to ischemic, myopathic or valvular heart disease and were grouped according to whether their mean PAP was less than (normotensive) or greater than (hypertensive) 19 mm Hg, and nine had pulmonary vascular disease of diverse etiology and were considered separately. In the majority of patients, we found that irrespective of whether the hypertension was arterial or venous in origin or etiology: the mean PAP-flow relationship was linear; pulmonary capillary wedge pressure was greater than or equal to the average closure pressure of the pulmonary vascular bed and could therefore be used as the downstream pressure in calculating pulmonary vascular resistance; and pulmonary vascular resistance declined with exercise. Notable exceptions to the third observation were patients with valvular heart disease or a resting pulmonary vascular resistance greater than 800 dyne-sec-cm-5.


Modeling and Simulation of the Simultaneous Absorption/Stripping of CO2 with Potassium Glycinate Solution in Membrane Contactor.
Global warming is an environmental problem caused mainly by one of the most serious greenhouse gas, CO2 emissions. Subsequently, the capture of CO2 from flue gas and natural gas is essential. Aqueous potassium glycinate (PG) is a promising novelty solvent used in the CO2 capture compared to traditional solvents; simultaneous solvent regeneration is associated with the absorption step. In present work, a 2D mathematical model where radial and axial diffusion are considered is developed for the simultaneous absorption/stripping process. The model describes the CO2/PG absorption/stripping process in a solvent-gas membrane absorption process. Regeneration data of rich potassium glycinate solvent using a varied range of acid gas loading (mol CO2 per mol PG) were used to predict the reversible reaction rate constant. A comparison of simulation results and experimental data validated the accuracy of the model predictions. The stripping reaction rate constant of rich potassium glycinate was determined experimentally and found to be a function of temperature and PG concentration. Model predictions were in good agreement with the experimental data. The results reveal that the percent removal of CO2 is directly proportional to CO2 loading and solvent stripping temperature.


Novel method of signal analysis for ablation of Wolff-Parkinson-White syndrome.
Identification of the site of successful radiofrequency catheter ablation (RFCA) for Wolff-Parkinson-White (WPW) syndrome may be subjective. The purpose of this study was to develop an automated signal analysis program to predict a successful ablation site. Patients who underwent successful RFCA for WPW from 2008- 2010 at our center were analyzed. Inclusion criteria were age <21 years, loss of preexcitation in <5 seconds, and sustained success at 3 months. Exclusion criteria were congenital heart disease and pacing during RFCA. The standard recording system signal was filtered into low frequency (LF 0-≤0.02 Hz) and high frequency (HF >0.02-≤0.45 Hz). Software identified the beginning of the HF signal, LF and R-wave peaks, LF/HF signal amplitude, and area under the HF/LF signals. Successful and unsuccessful (radiofrequency energy applied without accessory pathway block) signals were compared. Thirty patients were analyzed; 16 had both successful and unsuccessful signals, and 14 had a successful ablation with 1 radiofrequency application. Mean age was 13.7 ± 3.1 years, weight 54.9 ± 22.4 kg, and time to accessory pathway ablation 1.7 ± 1.4 seconds. Significant differences were found between successful and unsuccessful signals in area under HF signal, LF amplitude, LF to R time, HF ratio, and HF area × HF ratio. A receiver operating curve of HF area × HF ratio produced an area under the curve of 0.89. An HF area × HF ratio of 3.1 distinguished successful from unsuccessful signals with 100% specificity and 81% sensitivity. Automated signal analysis retrospectively differentiated successful from unsuccessful signals in patients undergoing RFCA for WPW. This software may improve the safety and efficacy of RFCA in children.


Chronic diet-induced hyperhomocysteinemia impairs eNOS regulation in mouse mesenteric arteries.
Hyperhomocysteinemia (HHcy) impairs endothelium-dependent vasodilation by increasing reactive oxygen species, thereby reducing nitric oxide (NO.) bioavailability. It is unclear whether reduced expression or function of the enzyme that produces NO., endothelial nitric oxide synthase (eNOS), also contributes. It is also unclear whether resistance vessels that utilize both NO.and non-NO.vasodilatory mechanisms, undergo alteration of non-NO.mechanisms in this condition. We tested these hypotheses in male C57BL/6 mice with chronic HHcy induced by 6-wk high methionine/low-B vitamin feeding (Hcy: 89.2 +/- 49.0 microM) compared with age-matched controls (Hcy: 6.6 +/- 1.9 microM), using first-order mesenteric arteries. Dilation to ACh (10(-9)-10(-4) M) was measured in isolated, cannulated, and pressurized (75 mmHg) arteries with and without N(G)-nitro-l-arginine methyl ester (l-NAME) (10(-4) M) and/or indomethacin (10(-5) M) to test endothelium-dependent dilation and non-NO.-dependent dilation, respectively. The time course of dilation to ACh (10(-4) M) was examined to compare the initial transient dilation due to non-NO., non-prostacyclin mechanism and the sustained dilation due to NO.. These experiments indicated that endothelium-dependent dilation was attenuated (P < 0.05) in HHcy arteries due to downregulation of only NO.-dependent dilation. Western blot analysis indicated significantly less (P < 0.05) basal eNOS and phospho-S1179-eNOS/eNOS in mesenteric arteries from HHcy mice but no difference in phospho-T495-eNOS/eNOS. S1179 eNOS phosphorylation was also significantly less in these arteries when stimulated with ACh ex vivo or in situ. Real-time PCR indicated no difference in eNOS mRNA levels. In conclusion, chronic diet-induced HHcy in mice impairs eNOS protein expression and phosphorylation at S1179, coincident with impaired NO.-dependent dilation, which implicates dysfunction in eNOS post-transcriptional regulation in the impaired endothelium-dependent vasodilation and microvascular disease that is common with HHcy.


Bartonella genotypes in fleas (insecta: siphonaptera) collected from rodents in the negev desert, Israel.
Fleas collected from rodents in the Negev Desert in southern Israel were molecularly screened for Bartonella species. A total of 1,148 fleas, collected from 122 rodents belonging to six species, were pooled in 245 pools based on flea species, sex, and rodent host species. Two Bartonella gene fragments, corresponding to RNA polymerase B (rpoB) and citrate synthase (gltA), were targeted, and 94 and 74 flea pools were found positive by PCR, respectively. The Bartonella 16S-23S internal transcribed spacer (ITS) region was also targeted, and 66 flea pools were found to be positive by PCR. Sixteen different Bartonella gltA genotypes were detected in 94 positive flea pools collected from 5 different rodent species, indicating that fleas collected from each rodent species can harbor several Bartonella genotypes. Based on gltA analysis, identified Bartonella genotypes were highly similar or identical to strains previously detected in rodent species from different parts of the world. A gltA fragment 100% similar to Bartonella henselae was detected in one flea pool. Another 2 flea pools contained gltA fragments that were closely related to B. henselae (98% similarity). The high sequence similarities to the zoonotic pathogen B. henselae warrant further investigation.


Exome Sequencing Reveals AMER1 as a Frequently Mutated Gene in Colorectal Cancer.
Somatic mutations occur at early stages of adenoma and accumulate throughout colorectal cancer progression. The aim of this study was to characterize the mutational landscape of stage II tumors and to search for novel recurrent mutations likely implicated in colorectal cancer tumorigenesis. The exomic DNA of 42 stage II, microsatellite-stable colon tumors and their paired mucosae were sequenced. Other molecular data available in the discovery dataset [gene expression, methylation, and copy number variations (CNV)] were used to further characterize these tumors. Additional datasets comprising 553 colorectal cancer samples were used to validate the discovered mutations. As a result, 4,886 somatic single-nucleotide variants (SNV) were found. Almost all SNVs were private changes, with few mutations shared by more than one tumor, thus revealing tumor-specific mutational landscapes. Nevertheless, these diverse mutations converged into common cellular pathways, such as cell cycle or apoptosis. Among this mutational heterogeneity, variants resulting in early stop codons in the AMER1 (also known as FAM123B or WTX) gene emerged as recurrent mutations in colorectal cancer. Losses of AMER1 by other mechanisms apart from mutations such as methylation and copy number aberrations were also found. Tumors lacking this tumor suppressor gene exhibited a mesenchymal phenotype characterized by inhibition of the canonical Wnt pathway. In silico and experimental validation in independent datasets confirmed the existence of functional mutations in AMER1 in approximately 10% of analyzed colorectal cancer tumors. Moreover, these tumors exhibited a characteristic phenotype.


[Development of new synthetic method and function of ynolate anions].
Ynolates are carbanions having a triple bond in place of the double bond in enolate anions. Ynolates are ketene anion equivalents, thus ynolates introduce a ketene unit into substrates and the resulting products possess high reactivity. This allows ynolates to undergo unique reaction sequences. For the past 20 years, several methods for the generation of ynolates and their reactions have been developed. Recently, we have developed a novel efficient method for their generation via cleavage of ester dianions. Starting from this success, we have found new reactions of ynolate anions. Ynolate anions react with carbonyl compounds to give beta-lactone enolates, which are converted into olefins with high E-selectivity. It is noteworthy that high E-selectivity was achieved in the synthesis of tetrasubstituted olefins. Utilizing the strong nucleophilicity of the beta-lactone enolates, we have succeeded in the first tandem [2 + 2] cycloaddition-Dieckmann condensation to lead synthetically useful 2,3-disubstituted-2-cycloalkenones in good yields. Ynolate anions were found to react with N-sulfonyl aldimines to give beta-lactams. N-2-methoxyphenyl aldimines efficiently activate their cycloaddition of lithium ynolates via chelation to give beta-lactams and alpha,beta-unsaturated amides. We have demonstrated the high functionality of ynolate anions. Ynolate chemistry has begun and much remains to be discovered.


Degree of conversion in denture base materials for varied polymerization techniques.
New processing techniques for denture base acrylic resins have been introduced which have not comparatively quantified the residual monomer content. While proper processing keeps the residual monomer in a tolerable range for most patients, tissue irritation and reaction due to potentially higher residual monomer in these alternative techniques could be a clinical concern. Decreased degree of conversion may influence physical properties as well as biocompatibility. This investigation evaluated the residual monomer content of acrylic resins cured by three different polymerization modes. Materials (polymerization system) evaluated were: Lucitone 199 (conventional process), Accelar 20 (rapid boil-out), and Acron MC (microwave). Fourier transform infrared spectrometry (FTIR) was employed to determine the degree of conversion. All curing methods produced similar results (Lucitone 199 = 92.7% (0.21), Acron MC = 92.6% (0.57), Accelar 20 = 90.9% (0-73). Conversion for Accelar 20 (rapid boil-out technique), though statistically different (P < 0.05, ANOVA) from the other two materials and polymerization techniques, was only slightly less. It is unlikely that the rapid boil-out technique would induce more adverse tissue responses than the other techniques included in this study.


Fundamentals and Applications of Photo-Cross-Linking in Bioprinting.
This review provides a detailed overview of the rapidly advancing field of biofabrication, particularly with regards to the use of photo-cross-linking (i.e., light-based) techniques. The major emphasis of this review is on the fundamentals of photo-cross-linking and key criteria identified for the successful design and implementation of photo-cross-linked bioinks and bioresins in extrusion-based and lithography-based bioprinting. The general mechanisms associated with photo-cross-linking (e.g., free-radical chain polymerization, thiol-ene, photomediated redox) of natural and synthetic materials are described to inform bioink and bioresin design, which includes the selection of polymers, functional group modifications, photoinitiators, and light sources that enable facile and cytocompatible photo-cross-linking. Depending on material selection and the bioprinting technique of interest, we describe the specific bioink or bioresin properties and criteria that must be achieved to ensure optimal printability and utility. Finally, examples of current state-of-the-art applications of light-based bioprinting for in vitro tissue models, tissue engineering, and regenerative medicine are provided to further motivate future opportunities within the bioprinting landscape that are facilitated with light.


High Ligation of the Inferior Mesenteric Artery in Left-Sided Colon and Rectal Cancer Resection: Rates of Success and Outcomes.
High ligation of the inferior mesenteric artery, defined as ligation before the takeoff of the left colic artery, is often described as the gold standard in low left-sided colon and rectal cancer surgery. The aim of this study is to quantify the rate of ligation at the described level at a single academic center. Additionally, we examined the relationship between level of ligation and cancer-related outcomes. This retrospective cohort study included patients ages 18 and over with low left-sided colon, rectal, and anal cancers undergoing surgical resection. Radiographic evidence of high ligation was defined as ligation of the inferior mesenteric artery before the takeoff of the left colic artery. Patients with and without radiographic evidence of high ligation on CT were compared. Secondary outcomes include lymph node yield and positivity, need for adjuvant therapy, and time from surgery to adjuvant therapy. 169 patients (54% male) were included in the study. 61.5% of operative reports described high ligation of the IMA. There was radiographic evidence of high ligation in 55.6% of total patients and in 70.2% of patients where high ligation was intended. There was no significant difference in surgeon experience, surgical procedure, or surgical approach. There was no difference in lymph node yield, time to adjuvant chemotherapy, or recurrence rates. This study demonstrates good technical success rate of high ligation of the inferior mesenteric artery but shows no difference in short-term patient-measured outcomes between high and low ligation (or successful and unsuccessful high ligation).


[Alanine dehydrogenase from the cyanobacterium Plectonema boryanum].
Alanine dehydrogenase activity of Plectonema boryanum cells was studied. It was found, that only NAD(H) may be used as the coenzyme. Kinetical parameters for substrates and coenzymes were determined. 2 pH-optima of action have been established for biosynthetic and anabolic reactions. Two isoenzymes of ADG were cleaned using the methods of ion-exchange chromatography and isoelectric focusing. Some physical-chemical properties were studied: pHopt--9-10 and 4.0; temperature optimum -40 degrees C; pI--8.2 and 6.4; molecular weight--50.65 and 52.48 kDa for ADG-1 and ADG-2, respectively. Both enzymes have the subunit structure. Every enzyme is composed by 4 identical polypeptides.


Limb interventions in patients undergoing treatment with an unsupported bifurcated aortic endograft system: a review of the Phase II EVT Trial.
Both supported and unsupported bifurcated endograft limbs develop flow-restricting lesions, including kinks, stenoses, and occlusions, which can be identified during or after surgery. Recognition and intervention are essential to achieve long-term graft patency and a satisfactory functional result. This report represents a comprehensive retrospective review of graft limb interventions from the Phase II EVT Trial with the Endovascular Grafting System unsupported bifurcated endograft (Guidant/EVT, Menlo Park, Calif). The study population consists of 242 patients who underwent treatment with bifurcated endografts implanted during the EVT Phase II Trial. Graft limb interventions have been divided into two groups: those in whom the intervention occurred during surgery versus those in whom the intervention occurred after surgery. Parameters studied included type, incidence, and timing of graft limb intervention, indications for intervention, procedures performed, and overall patient outcome. The mean follow-up period was 31 months. Primary, primary assisted, and secondary limb patency rates were 61.6%, 93.7%, and 97.1%, respectively. Technical success rate at case completion was 97.5%. In 68 of the 242 cases, limb interventions were performed during surgery to assure patency (28.1%). In 28 cases, interventions were performed after surgery (11.6%). Of these postoperative limb problems, 82% occurred during the first 6 months. Repeat limb interventions were necessitated in three patients (1.2%). Within the intraoperative intervention group, perceived indications included kinks (15%), stenosis (57%), dissection (6%), graft redundancy (12%), and instances of twists, thrombosis, and pressure gradients (10%). These findings were successfully managed with percutaneous transluminal angioplasty only (41%), percutaneous transluminal angioplasty and stent (50%), and various combined interventions. Within the postoperative intervention group, symptomatic indications included stenosis (46%) and thrombosis/occlusion (54%). These postoperative limb events were successfully managed with stent (64%), thrombolysis (32%), and femoral-femoral bypass (21%). When limb dysfunction developed in the postoperative setting, it most often occurred within the first 6 months of implantation. Only one patient in this Phase II cohort had a lower extremity amputation unrelated to a graft limb abnormality. The unsupported bifurcated limbs of this endograft necessitated primary adjunctive intervention in 40% of cases. Primary intervention was two times more likely to be performed at the time of the implant rather than after surgery. Repeat limb interventions were not common. Endograft limb flow problems were successfully treated with standard endovascular or surgical interventions or both. These data may support prophylactic stenting of unsupported Ancure graft limbs. A strategy that includes both intraoperative and early postoperative graft limb surveillance is essential to detect reduced limb flow.


Characterization of non-covalent oligomers of proteins treated with hypochlorous acid.
Hypochlorous acid (HOCl) is a potent oxidant produced by myeloperoxidase that causes aggregation of many proteins. Treatment of apohaemoglobin and apomyoglobin with HOCl produced a regular series of oligomer bands when the proteins were separated by SDS/PAGE under reducing conditions. Aggregation was detectable at a HOCl/protein molar ratio of 0.5:1 and was maximal at ratios of 10:1-20:1. Dimers formed within 1 min of adding HOCl, and further aggregation occurred over the next 30 min. No convincing evidence for covalent cross-linking was obtained by amino acid analysis, peptide analysis or electrospray ionization-MS of HOCl-modified apomyoglobin. The latter showed an increase in mass consistent with conversion of the two methionine residues into sulphoxides. A 5-fold excess of HOCl generated approximately three chloramines on the apomyoglobin. These underwent slow decay. Protein carbonyls were formed and were almost entirely located only on the polymer bands. Conversion of positively into negatively charged groups on the protein by succinylation caused preformed aggregates to dissociate. Treatment of apomyoglobin with taurine chloramine generated methionine sulphoxides but few protein carbonyls, and did not result in aggregation. We conclude that aggregation was due to strong, non-covalent interactions between protein chains. We propose that formation of protein carbonyls and possibly chloramines, along with methionine oxidation, alters protein folding to expose hydrophobic areas on neighbouring molecules that associate to form dimers and higher-molecular-mass aggregates. This process could lead to the formation of aggregated proteins at sites of myeloperoxidase activity and contribute to inflammatory tissue injury.


A Retrospective Review of Laser Therapy for Treatment of Hidradenitis Suppurativa.
Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by painful and foul-smelling cystic nodules and sinus tracts in the apocrine gland-bearing regions. The treatment options include topical, intralesional, systemic, and surgical modalities. Currently, the most novel therapy is laser therapy to provide localized treatment without systemic adverse effects. However, data regarding patient outcomes after laser treatment are limited because of the low prevalence of this disease. This study aimed to evaluate the efficacy of laser therapy as a treatment modality for patients with HS. A retrospective review cohort analysis of patients with HS undergoing laser treatment between 2016 and 2021 was conducted. Patient demographics, lesion location(s), Hurley stage, age of onset and diagnosis, treatment length, type, outcomes, and complications were analyzed. Ninety-four patients met the inclusion criteria; on average, patients were treated with 5.8 laser sessions for 14.8 months with no complications and minor blood loss. Hidradenitis suppurativa progression commonly starts during puberty, with a median onset of 13.8 years and diagnosis of HS at 16.2 years. All patients (n = 94) showed an improvement in HS disease severity: 59.6% completed treatment, 12.0% are currently undergoing treatment, and 26.0% were lost to follow-up. Laser therapy is an effective and safe therapy for HS leading to improved quality of life and should be considered in the treatment and management of HS.


[The essential fatty acids omega-6 and omega-3: from their discovery to their use in therapy].
In 1929 Burr and Burr discovered the essential fatty acids omega-6 and omega-3. Since then, researchers have shown a growing interest in unsaturated essential fatty acids as they form the framework for the organism's cell membranes, particularly the neurones in the brain, are involved in the energy-transformation process, regulate the information flows between cells. Polyunsaturated fatty acids are also precursors of ''hormonal'' molecules, often with opposing effects, prostaglandins, prostacyclins, thromboxanes, leukotrienes, lipossines, resolvines, protectines that regulate immunity, platelet aggregation, inflammation, etc. They showed that raised levels of polyunsaturated fatty acids omega-3 in tissue correlate with a reduced incidence of degenerative cardiovascular disease, some mental illnesses such as depression, and neuro-degenerative diseases such as Alzheimer's. The balance between omega-3 and omega-6 acids allows the cell membranes to develop with exactly the right flexibility and fluidity, to carry messages between neurones, that is a determining factor in physical and mental well-being and has a profound influence on all the body's inflammatory responses. The results of a number of scientific studies suggest that omega-3 acids contribute to measuring and restricting inflammatory symptoms, whereas omega-6 acids (and saturated fats) give free range to inflammatory responses and amplify allergic reactions. Today in the Western countries, the ratio of omega-3 acids to omega-6 in the diet is weighted 1:10 in favour of omega-6 to up to 1:25 in some areas, while for proper functioning a 4:1 ratio of omega-6 acids to omega-3 acids is generally considered the optimum. In addition, the type of diet followed in the Western countries is very rich in saturated fats like butter and animal fats, but because of an excessive supply of these less noble fats, the cell membranes lose flexibility and this can affect the way they work. An appropriate supplement can be an efficient, effective and often necessary way to meet the body's needs, enhance its daily functions and promote health and longevity.


[Prevention of analgetics nephropathy].
Abuse of analgesics is associated with the development of renal damage which can lead to end stage renal failure. Moreover, an increased incidence of urothelial cancer is reported in abusers of analgesics. In Belgium, AN still remains a serious problem with a prevalence of 18% in dialysis patients. However AN is a preventable disease but in Belgium no adequate measurements were taken for prevention. The results of our study showed that AN is caused by the abuse of analgesic mixtures. Apart from the analgesic components, most mixtures contained caffeine. This component is considered as the principal causative agent in creating a psychic dependence to analgesics. Initially phenacetin was implicated as the nephrotoxic culprit. In recent years, however, it has become increasingly clear that phenacetin is unlikely to be the primary cause of AN. Moreover, abuse of phenacetin-containing analgesics does not exist any longer because the product is disappeared from the Belgian market. In view of the actual knowledge concerning AN, we will recommend that analgesic mixtures be put under prescription, limiting over-the-counter medication to single analgesics, in order to eliminate the occurrence of AN in Belgium.


An Explainable EEG-Based Human Activity Recognition Model Using Machine-Learning Approach and LIME.
Electroencephalography (EEG) is a non-invasive method employed to discern human behaviors by monitoring the neurological responses during cognitive and motor tasks. Machine learning (ML) represents a promising tool for the recognition of human activities (HAR), and eXplainable artificial intelligence (XAI) can elucidate the role of EEG features in ML-based HAR models. The primary objective of this investigation is to investigate the feasibility of an EEG-based ML model for categorizing everyday activities, such as resting, motor, and cognitive tasks, and interpreting models clinically through XAI techniques to explicate the EEG features that contribute the most to different HAR states. The study involved an examination of 75 healthy individuals with no prior diagnosis of neurological disorders. EEG recordings were obtained during the resting state, as well as two motor control states (walking and working tasks), and a cognition state (reading task). Electrodes were placed in specific regions of the brain, including the frontal, central, temporal, and occipital lobes (Fz, C1, C2, T7, T8, Oz). Several ML models were trained using EEG data for activity recognition and LIME (Local Interpretable Model-Agnostic Explanations) was employed for interpreting clinically the most influential EEG spectral features in HAR models. The classification results of the HAR models, particularly the Random Forest and Gradient Boosting models, demonstrated outstanding performances in distinguishing the analyzed human activities. The ML models exhibited alignment with EEG spectral bands in the recognition of human activity, a finding supported by the XAI explanations. To sum up, incorporating eXplainable Artificial Intelligence (XAI) into Human Activity Recognition (HAR) studies may improve activity monitoring for patient recovery, motor imagery, the healthcare metaverse, and clinical virtual reality settings.