Time-delay Fizeau phase-conjugate interferometer.
A time-delay Fizeau phase-conjugate interferometer is constructed by using a BaTiO(3) crystal in a degenerate four-wave-mixing configuration. The slow response time of BaTiO(3) is used to build a phase-conjugate mirror that functions as a holographic memory. An optical wave and its time-delayed version are stored inside the crystal sequentially while their phase-conjugate waves are generated simultaneously. Superposition of the two phase-conjugate waves produces an interferogram as a result of the relative phase change of the input waves. The simplicity and real-time operation of this technique lead to several advantages over the conventional holographic interferometry. The use of photorefractive crystal eliminates the darkroom process and reposition procedure. A higher accuracy can be achieved because the interfering waves are phase-conjugate waves. The principle of this technique is presented and the experimental results and its applications are discussed.


Role of IL-10 in a neonatal mouse listeriosis model.
This study was undertaken to test the hypothesis that altered IL-10 production plays a role in the increased susceptibility of neonates to listeriosis. Plasma IL-10 levels were measured in neonatal and adult mice at various times after infection with Listeria monocytogenes. Relative to adults, neonatal mice had markedly increased IL-10 levels early in the course of infection with Listeria using a 90% lethal dose. Higher neonatal IL-10 responses were also observed after injecting adults and pups with equal doses of killed organisms. Splenic macrophages from neonates produced higher IL-10 levels than those of adults after in vitro stimulation with killed bacteria, confirming in vivo observations. Moreover, IL-10 blockade had differential effects in neonates and adults infected with live Listeria. In adult mice, anti-IL-10 Abs decreased bacterial burden early in the course of infection, but were no longer effective at 6 days or later after challenge. In the pups, however, the same treatment had beneficial effects both early and late during infection and resulted in increased survival. Collectively, our data suggest that an overproduction of IL-10 by macrophages may at least partially explain the increased susceptibility of neonates to listeriosis, and provide further evidence that cytokine production is different in adults and neonates.


Quantitative proteomics profiling of primary lung adenocarcinoma tumors reveals functional perturbations in tumor metabolism.
In this study, we have analyzed human primary lung adenocarcinoma tumors using global mass spectrometry to elucidate the biological mechanisms behind relapse post surgery. In total, we identified over 3000 proteins with high confidence. Supervised multivariate analysis was used to select 132 proteins separating the prognostic groups. Based on in-depth bioinformatics analysis, we hypothesized that the tumors with poor prognosis had a higher glycolytic activity and HIF activation. By measuring the bioenergetic cellular index of the tumors, we could detect a higher dependency of glycolysis among the tumors with poor prognosis. Further, we could also detect an up-regulation of HIF1α mRNA expression in tumors with early relapse. Finally, we selected three proteins that were upregulated in the poor prognosis group (cathepsin D, ENO1, and VDAC1) to confirm that the proteins indeed originated from the tumor and not from a stromal or inflammatory component. Overall, these findings show how in-depth analysis of clinical material can lead to an increased understanding of the molecular mechanisms behind tumor progression.


Jewish medical ethics: monetary compensation for donating kidneys.
The Israel Health Ministry is preparing legislation that would allow a person to receive monetary compensation in exchange for donating a kidney for a lifesaving transplant. Such a bill would be the first of its kind, and would seem to establish a policy that is in contrast with both existing international professional ethics and major Christian and Islamic religious ethics. In an attempt to investigate the extent to which such a bill would be consistent with traditional Jewish ethics, we reviewed the opinions of major traditional Jewish ethicists/halakhists, with emphasis on contemporary opinions, and found that compensating an organ donor for his or her time, discomfort, inconvenience, and recovery is fully consistent with traditional Jewish law and ethics. While non-altruistic sale of kidneys might be theoretically ethical from a Jewish perspective, ultimately its ethical status is inextricably connected to solving a series of pragmatic issues, such as creating a system that insures that potential vendors/donors are properly informed and not exploited, controlling and supervising medical screening and support of the donors to insure that their health is not permanently endangered, protecting minors and incompetents, and regulating payments so that they reasonably reflect compensation for pain and suffering.


Sevoflurane-induced malignant hyperthermia during cardiopulmonary bypass and moderate hypothermia.
A 56-year old man was admitted for elective mitral valve repair and coronary artery bypass surgery due to mitral valve leakage and unstable angina. After induction of anaesthesia he developed a combined metabolic and respiratory acidosis. Different diagnosis were considered and we decided to treat the patient with dantrolene due to suspicion of malignant hyperthermia (MH). The patient received one dose of dantrolene 2,5 mg/kg during cardiopulmonary bypass (CPB) and a second dose of dantrolene 2,5 mg/kg during weaning from CPB. The first arterial blood gas sample taken in the intensive care unit showed relapse of the acidosis and we administered an infusion of 150 mg dantrolene over 3 hours. The patient gradually recovered without sequel and MH was verified by muscle biopsy testing.


[Spontaneous development of idiopathic short stature. Analysis of a group of 42 children followed to their final body height].
Idiopathic short stature is a common pediatric problem that has a heterogeneous nature and an unknown outcome concerning adult height (AH). The main objective of this study was to assess the spontaneous adult height and the influence of several pre and post pubertal predictors over AH. The secondary objective was to create an historical control group to compare these patients with others that had been treated with growth-promoting therapies. A prospective observational study was made with prepubertal male patients who consulted for short stature before 1986 until they reached AH. They did not receive any treatment. The data are shown as mean and standard deviation. Student's paired t test was used for comparison of groups. Predictive and descriptive models over final height were performed with multivariant analysis. A "p" value of less than 0.05 was considered statistically significant. Data of 42 children was analyzed. Mean age was 10.8 (2.2) years. The standard deviation score (SDS) for adult height spontaneously increased in 0.37 +/- 0.24 (p < 0.05), but it was under target height by 0.59 +/- 0.26 (p = 0.05). Main predictors of AH were: initial height, prognosis of AH and initial age (R2 = 0.58). Final height was no different between children with familial or non-familial short stature. This group of children had a mean loss of 4 cms below their target height. These children may be considered as an historical control group to evaluate the treatment with growth-promoting therapies.


Inhibition of rat prostate carcinogenesis by a 5alpha-reductase inhibitor, FK143.
Androgen levels in the prostate may influence carcinogenesis in this organ. Inhibitors of the enzyme 5alpha-reductase block conversion of testosterone to the more active androgen dihydrotestosterone. The use of a 5alpha-reductase inhibitor, finasteride, in the chemoprevention of prostate cancer is being evaluated in a clinical trial. This study was conducted to determine if a 5alpha-reductase inhibitor, FK143, inhibits the development of prostate cancer in rats. Male ACI/Seg rats, which spontaneously develop prostate cancer, were randomly assigned at 80 weeks of age to receive one of three diets (n = 35/group) containing 0 (i.e., control group), 20, or 200 ppm FK143. At 140 weeks of age, the animals were killed, and the prostates were removed and examined for histopathologic features in addition to being assayed for androgen concentrations. Two-sided statistical tests were used to calculate all P values. The incidence of prostate carcinoma in the control group was 62.9% (22 of 35 rats); in the group fed the 20 ppm FK143-containing diet, it was 45.7% (16 of 35); and in the group fed the 200 ppm FK143-containing diet, it was 67.6% (23 of 34) (overall, P = .153). The corresponding incidences of macroscopic lesions were 17.1% (six of 35 rats), 0% (none of 35), and 23.5% (eight of 34), respectively (overall, P = .004). The incidence of macroscopic lesions in the prostates of rats in the 20-ppm diet group was significantly lower than that in the control group (P = .029) or that in the 200-ppm diet group (P = .003). Intraprostatic dihydrotestosterone content was significantly lower in rats in the groups fed diets containing 20 or 200 ppm FK143 (mean values: 4.51 and 4.33 pg/mg wet weight of prostate tissue, respectively) than in the control group (6.10 pg/mg) (overall, P<.001); by contrast, testosterone was higher in the 200-ppm diet group (2.09 pg/mg) than in the control group (1.08 pg/mg) or the 20-ppm diet group (1.21 pg/mg) (overall, P<.001). FK143, when fed to rats at 20 or 200 ppm, significantly reduced the level of dihydrotestosterone in their prostate tissue. However, the incidence of macroscopic cancer in the prostate was suppressed in rats consuming the 20 ppm FK143-containing diet but not in those consuming the 200-ppm diet. The lack of dose dependence for the chemopreventive activity of FK143 may be explained by the reciprocal increase of tissue testosterone in the 200-ppm diet group. The 5alpha-reductase inhibitor FK143 may, at specific doses, reduce the incidence of spontaneously developing prostate cancer; however, whether these findings in rats will apply to humans remains to be determined.


Characteristics of human chondrocytes, osteoblasts and fibroblasts seeded onto a type I/III collagen sponge under different culture conditions. A light, scanning and transmission electron microscopy study.
Hyaline cartilage has only a limited capacity of regeneration, thus, lesions of articular cartilage can lead to early osteoarthrosis. Current concepts in conservative orthopedic therapy do not always lead to satisfying results. As one new attempt to facilitate cartilage repair, autologous transplantation of articular chondrocytes is investigated in different assays. This study was designed to create a resistible and stable cell-matrix-biocomposite with viable and biosynthetically active human chondrocytes, osteoblasts or fibroblasts. This biocomposite might serve as an implant to treat deep osteochondral defects in the knee. We collected cartilage, spongiosa and skin probes from healthy patients undergoing hip-surgery and enzymatically liberated the chondrocytes, seeded them into culture flasks and cultured them until confluent. The spongiosa and the skin samples were also placed in culture flasks and cells cultured until confluent. After 4-6 weeks, cells were trypsinized and grown on a type I/III collagen matrix (Chondrogide, Geistlich Biomaterials, Wolhusen, Switzerland) for 7 days in standard Petri dishes and in a special perfusion chamber culture system. As controls, cells were seeded onto plastic surfaces. Then scaffolds were fixed and embedded for light microscopy and electron microscopy by routine methods. Light microscopically, chondrocytes grown on the surface of the scaffold form clusters or a dense layer of sometimes rather fibroblast-like and sometimes roundish, chondrocyte-like cells. Only a few cells grow deeper into the matrix. In transmission electron microscopy, the cells have a rather chondrocyte-like morphology which emphasizes the matrix-induced redifferentiation after dedifferentiation of chondrocytes in monolayer-culture in culture flasks. Chondrocytes on plastic surfaces have a spinocellular aspect with little signs of differentiation. Grown on Chondrogide, cells are more roundish and adhere firmly to the collagen fibrils of the scaffold. Osteoblasts grown on the collagen scaffold and examined by light microscopy form a thin cell-layer on the surface of the matrix with a reticular layer of dendritic cells underneath this sheet. Transmission electron micrographs show spinocellular and flat cells on the collagen fibrils. Scanning electron micrographs show large dendritic osteoblasts on plastic and a confluent layer of flattened, dendritic cells on the collagen scaffold. Fibroblasts form a thick multi-layer of typical spinocellular cells on the collagen matrix. Fibroblasts grown on plastic surfaces and examined by scanning electron microscopy also show a dense layer of fibroblast-like cells. For all three different types of cells no morphological differences could be seen when comparing cultivation in the perfusion culture system to cultivation in standard Petri dishes, although mechanical stress is believed to induce differentiation of chondrocytes. Especially the observed partially differentiated chondrocyte-matrix biocomposite might serve as an implant to treat deep cartilage defects, whereas osteoblasts and fibroblasts seem to be less suited.


Pregnancy and liver transplantation.
Since the first pregnancy in a transplant recipient in 1958, pregnancy in recipients of solid organ transplants has become increasingly common. Although previously considered a hazardous event, data collected over the last 50 years demonstrate that despite an increased risk of maternal and fetal complications, pregnancy in transplant recipients can have a successful outcome. As of 2006, there were over 3000 female liver transplant recipients of childbearing age in the USA. Two hundred and two pregnancies and 205 outcomes were reported in 121 liver transplant recipients in the National Transplantation Pregnancy Registry. Children born to female liver recipients have a greater risk of prematurity and low birth weight than the general population, but no malformation patterns have been observed. Mothers are more likely to experience pregnancy-induced hypertension, pre-eclampsia and caesarian section, but overall mortality is not worse. Rates of acute rejection and graft loss are similar to nonpregnant liver recipients. The optimal timing of conception post-transplant is controversial, but current recommendations suggest waiting for at least 1 year after transplantation. Choice of contraception is also debatable, although barrier methods have traditionally been preferred. Many medications used for post-transplant immunosuppression have potential effects during pregnancy and breast-feeding. The risks and benefits of each medication should be reviewed with patients contemplating pregnancy, and regimens should be tailored accordingly.


Acute pancreatitis as a rare initial manifestation of Wegener's granulomatosis. A case based review of literature.
Vasculitis is a known cause of pancreatitis and other gastrointestinal symptoms; however, most of these patients have medium vessel vasculitis like polyarteritis nodosa and often there are other associated conditions like hepatitis B or clinical manifestations that suggest the diagnosis. Wegener's granulomatosis is predominantly a reno-pulmonary disorder, rarely having gastrointestinal manifestations. We report a case of Wegener's granulomatosis initially presenting as acute pancreatitis and then rapidly progressing to severe multi-organ involvement over the next few months. Pancreatic association as an initial presentation of Wegener's granulomatosis is limited to only a few reports. This extremely rare initial presentation makes the diagnostic process challenging. Two different pancreatic manifestations have been reported: as a pancreatic mass mimicking a tumor or as acute pancreatitis. The patients who presented as pancreatic head masses underwent extensive surgical procedures before the diagnosis was established. Acute pancreatitis as the initial presentation is usually associated with an aggressive course of the vasculitis and often results in a fatal outcome. This case illustrates Wegener's granulomatosis as a rare cause of acute pancreatitis. It emphasizes the need for thorough continued systemic clinical evaluation of patients when the etiology is not readily evident. Also, since most patients with pancreatitis due to Wegener's granulomatosis rapidly progress to severe multiorgan involvement, knowledge of a broad differential of potential etiologies and a low index of suspicion is required for timely diagnosis and treatment.


Evaluation of non-metric variation in the crania of black and white perinates.
Reports in the literature suggest that diagnostic differences in craniofacial morphology between blacks and whites arise very early in development. These reports, however, have not been consistent regarding which traits are diagnostic and have failed to provide forensic anthropologists with a reliable method of assessment. In an effort to clarify the situation, 13 non-metric craniofacial traits were scored and analyzed statistically in a sample of 70 black and white perinatal specimens obtained from the Smithsonian's fetal osteology collection. Chi-square analysis revealed significant (p<0.05) differences in the distribution of five of the 13 non-metric traits examined. Compared with black perinates, white perinates more frequently possessed a relatively narrow supraoccipital portion of the occipital bone, a prominent anterior nasal spine, "deep" subnasal margins, an elongated vomer, and semi-circular temporal squamae. When these five traits were entered into a stepwise logistic regression, temporal squamous shape, vomer shape and subnasal margin definition were found to be predictive of race (79.1% overall correct classification). An independent sample of 39 black and white perinates was then used to validate the results; overall, 67.5% of the validation sample could be classified correctly. Reasons for the disparity in correct classification rates between the initial and follow-up sample are provided. Results of the present study may be useful for anthropologists who encounter unidentified cranial material from this age range.


Hantavirus pulmonary syndrome in Tucumán province associated to an unexpected viral genotype.
We describe the characterization of the viral genotype involved in the first case of hantavirus pulmonary syndrome reported in Tucumán, a Northwestern province of Argentina. A 23-year-old woman, with no record of travel history and previously diagnosed with an antiphospholipid syndrome, died after 11 days of severe cardiopulmonary insufficiency. Among the four endemic regions of hantavirus pulmonary syndrome in Argentina, the Northwest Region has the highest incidence, exceeding 50% of all reported cases in the country. Until now, only Salta and Jujuy (2 out of the 6 provinces composing the Northwest Region), reported cases of hantavirus pulmonary syndrome, all of which occurred in the Yungas Forest area. Remarkably, the viral genotype characterized in this case showed higher nucleotide identity with the Andes-BsAs genotype most prevalent in Buenos Aires province, located 1400 km apart from Tucumán, than with any of the commonly found genotypes in the Northwest Region. The Andes-BsAs genotype has been associated with 30% lethality and interhuman transmission in Buenos Aires province. Interhuman transmission cannot be ruled out in the present case.


[Adolescent sexual behavior and sexually transmitted diseases (STD). A preliminary study].
Great changes have occurred in the adolescent behaviour in the last twenty years; this has caused a great increase in the number of the transmitted by sexual intercourse diseases. These, along with the adolescent habits changing, have so widely spread among young people, that one third of the recorded case are actually referred to this group of age. So, a matter of great social interest, which would require a common effort by the adolescents' families, the teachers and by the adolescents themselves, to be faced in the most proper way, has arisen. But the greatest commitment is asked for to the specialized in infectious diseases pediatricians, who are called to state the best strategy to efficaciously fight adolescents' STD. Pediatricians' specific competence and experience can build up the major security to face the prevention and diagnostic matters and their therapy as well.


Muscles Reduce Neuronal Information Load: Quantification of Control Effort in Biological vs. Robotic Pointing and Walking.
It is hypothesized that the nonlinear muscle characteristic of biomechanical systems simplify control in the sense that the information the nervous system has to process is reduced through off-loading computation to the morphological structure. It has been proposed to quantify the required information with an information-entropy based approach, which evaluates the minimally required information to control a desired movement, i.e., control effort. The key idea is to compare the same movement but generated by different actuators, e.g., muscles and torque actuators, and determine which of the two morphologies requires less information to generate the same movement. In this work, for the first time, we apply this measure to numerical simulations of more complex human movements: point-to-point arm movements and walking. These models consider up to 24 control signals rendering the brute force approach of the previous implementation to search for the minimally required information futile. We therefore propose a novel algorithm based on the pattern search approach specifically designed to solve this constraint optimization problem. We apply this algorithm to numerical models, which include Hill-type muscle-tendon actuation as well as ideal torque sources acting directly on the joints. The controller for the point-to-point movements was obtained by deep reinforcement learning for muscle and torque actuators. Walking was controlled by proprioceptive neural feedback in the muscular system and a PD controller in the torque model. Results show that the neuromuscular models consistently require less information to successfully generate the movement than the torque-driven counterparts. These findings were consistent for all investigated controllers in our experiments, implying that this is a system property, not a controller property. The proposed algorithm to determine the control effort is more efficient than other standard optimization techniques and provided as open source.


Structure of foot-and-mouth disease virus mutant polymerases with reduced sensitivity to ribavirin.
Passage of poliovirus (PV) or foot-and-mouth disease virus (FMDV) in the presence of ribavirin selected for viruses with decreased sensitivity to R, which included different mutations in their polymerase (3D): G64S located in the finger subdomain in the case of PV and M296I located within loop beta9-alpha11 at the active site in the case of FMDV. To investigate why disparate substitutions were selected in two closely related 3Ds, we constructed FMDVs with a 3D that included either G62S (the equivalent replacement in FMDV of PV G64S), M296I, or both substitutions. G62S, but not M296I, inflicts upon FMDV a strong selective disadvantage which is partially compensated for by the substitution M296I. The corresponding mutant polymerases, 3D(G62S), 3D(M296I), and 3D(G62S-M296I), were analyzed functionally and structurally. G62S in 3D impairs RNA-binding, polymerization, and R monophosphate incorporation activities. The X-ray structures of the 3D(G62S)-RNA, 3D(M296I)-RNA, and 3D(G62S-M296I)-RNA complexes show that although the two positions are separated by 13.1 A, the loops where the replacements reside are tightly connected through an extensive network of interactions that reach the polymerase active site. In particular, G62S seems to restrict the flexibility of loop beta9-alpha11 and, as a consequence, the flexibility of the active site and its ability to bind the RNA template. Thus, a localized change in the finger subdomain of 3D may affect the catalytic domain. The results provide a structural interpretation of why different amino acid substitutions were selected to confer R resistance in closely related viruses and reveal a complex network of intra-3D interactions that can affect the recognition of both the RNA template and incoming nucleotide.


Shared metabolic pathways in a coevolved insect-bacterial symbiosis.
The symbiotic bacterium Buchnera aphidicola lacks key genes in the biosynthesis of five essential amino acids (EAAs), and yet its animal hosts (aphids) depend on the symbiosis for the synthesis of these EAAs (isoleucine, leucine, methionine, phenylalanine, and valine). We tested the hypothesis, derived from genome annotation, that the missing Buchnera reactions are mediated by host enzymes, with the exchange of metabolic intermediates between the partners. The specialized host cells bearing Buchnera were separated into a Buchnera fraction and a Buchnera-free host cell fraction (HF). Addition of HF to isolated Buchnera preparations significantly increased the production of leucine and phenylalanine, and recombinant enzymes mediating the final reactions in branched-chain amino acid and phenylalanine synthesis rescued the production of these EAAs by Buchnera preparations without HF. The likely precursors for the missing proximal reactions in isoleucine and methionine synthesis were identified, and they differed from predictions based on genome annotations: synthesis of 2-oxobutanoate, the aphid-derived precursor of isoleucine synthesis, was stimulated by homoserine and not threonine via threonine dehydratase, and production of the homocysteine precursor of methionine was driven by cystathionine, not cysteine, via reversal of the transsulfuration pathway. The evolution of shared metabolic pathways in this symbiosis can be attributed to host compensation for genomic deterioration in the symbiont, involving changes in host gene expression networks to recruit specific enzymes to the host cell.


Four species of Zygophiala (Schizothyriaceae, Capnodiales) are associated with the sooty blotch and flyspeck complex on apple.
Sooty blotch and flyspeck (SBFS) is a complex of fungi that cause late-season blemishes of apple and pear fruit that cosmetically damage the cuticle, which result in fruit that are unacceptable to consumers. Previous studies reported that a single, wide-host-range species, Schizothyrium pomi (presumed anamorph Zygophiala jamaicensis), caused flyspeck on apple. In the present study we compared morphology and DNA phylogeny (ITS, LSU) of 139 fungal strains isolated from flyspeck signs from 39 apple orchards in 14 midwestern and eastern states (USA). Parsimony analysis, supported by cultural characteristics and morphology in vitro, provided support to delimit the flyspeck isolates into four species of Zygophiala, two of which are known to be sexual. Three of these species are described as new. Based on DNA phylogeny, species of Schizothyrium were shown to cluster with members of the genus Mycosphaerella in the Capnodiales, having similar asci and ascospores but morphologically distinct ascomata. These data question the value of ascomatal morphology at the ordinal level, although it still appears to be relevant at the family level, delimiting the thyrothecial Schizothyriaceae from other families in the Capnodiales.


Appraisal of Function After Rehabilitation With Tongue Prosthesis.
Prosthetic rehabilitation following total glossectomy is very complex procedure from clinical as well as laboratory point of view. The basic objective of prosthodontic rehabilitation is to deliver a comfortable as well as esthetically suitable prosthesis, which restores the impaired speech and deglutition function. Prosthetic rehabilitation of patients after total glossectomy with tongue prosthesis to evaluate improvement in speech as well as swallowing function. Tongue prostheses were fabricated with high-temperature vulcanizing silicone and heat-polymerizing acrylic to restore the functions affected after surgical resection of tongue. Patient's speech was evaluated with Dr Speech software version 4. The speech software was used to assess different speech parameters such as maximum phonation time, fundamental frequency, intensity, jitter, and shimmer. Deglutition assessment was done subjectively by using a standardized questionnaire designed by the speech pathologist. Speech was recorded for assessment before prosthetic rehabilitation and 2 weeks after delivery of the tongue prosthesis. After analysis of various speech parameters frequency range was improved with prosthesis (ie, 172.19 Hz) as compared to without prosthesis (ie, 111.47 Hz). Speech intelligibility was improved with tongue prosthesis. Deglutition assessment revealed that patient's deglutition abilities were improved. Tongue prosthesis helps to improve speech and articulation in patients with total glossectomy. Apart from that deglutition capability is also significantly improved. Total glossectomy affects speech, mastication, and swallowing to a greater proportion. It may also lead to psychological impairment of the patient. Tongue prosthesis efficiently improves speech and deglutition abilities of the patient leading to a better quality of life.


A network that performs brute-force conversion of a temporal sequence to a spatial pattern: relevance to odor recognition.
A classic problem in neuroscience is how temporal sequences (TSs) can be recognized. This problem is exemplified in the olfactory system, where an odor is defined by the TS of olfactory bulb (OB) output that occurs during a sniff. This sequence is discrete because the output is subdivided by gamma frequency oscillations. Here we propose a new class of "brute-force" solutions to recognition of discrete sequences. We demonstrate a network architecture in which there are a small number of modules, each of which provides a persistent snapshot of what occurs in a different gamma cycle. The collection of these snapshots forms a spatial pattern (SP) that can be recognized by standard attractor-based network mechanisms. We will discuss the implications of this strategy for recognizing odor-specific sequences generated by the OB.


Role of ROS in ischemia-induced lung angiogenesis.
Pulmonary artery obstruction and subsequent lung ischemia have been shown to induce systemic angiogenesis despite preservation of normoxia. The underlying mechanisms, however, remain poorly understood. In a mouse model of lung ischemia induced by left pulmonary artery ligation (LPAL), we showed previously, the formation of a new systemic vasculature to the ischemic lung. We hypothesize that LPAL in the mouse increases reactive oxygen species (ROS) production, and these molecules play an initiating role in subsequent lung neovascularization. We used oxidant-sensitive dyes (DHE and H(2)DCF-DA) to quantify ROS and measured the antioxidant-reduced glutathione (GSH) and its oxidized form (GSSG) as indicators of ROS levels after LPAL. The magnitude of systemic neovascularization was determined by measuring systemic blood flow to the left lung with radiolabeled microspheres 14 days after LPAL. An increase in ROS was observed early (30 min: 55% increase in H(2)DCF-DA) after LPAL, with a return to baseline by 24 h. GSH/GSSG was decreased (∼50%) 4 h after LPAL, suggesting earlier ROS upregulation. Mice treated with the antioxidant N-acetylcysteine showed attenuated angiogenesis (62% of wild-type LPAL), and mice lacking Nrf2, a transcription factor important for antioxidant synthesis, resulted in increased neovascularization (207% of wild-type LPAL). Overall, GSH/GSSG was inversely associated with the magnitude of neovascularization. These results demonstrate that LPAL induces an early and transient ROS upregulation, and ROS appear to play a role in promoting ischemia-induced angiogenesis.


[Basic principles of the organization of ion channels determining the electric stimulation of the neuronal membrane].
The paper provides comparative characteristics for different types of electrically operated ionic channels in the neuronal membrane of invertebrate (molluscs) and vertebrate (rats) animals. It was shown that ion-selecting characteristics of sodium channels are identical for all the investigated membranes. In addition, main selective filter of calcium channels also possesses a similar characteristic; apart of it they have an external binding group which prevents the influx of monovalent cations into the channel and thus maintains its selectivity towards divalent cations. A natural intermediate modification of ionic channels is found, which has no such external binding group. There are two different mechanisms of maintenance of electrically operated ionic channels in a functioning state--a metabolically-independent and metabolically-dependent one. In the latter case in order to preserve the ability of the channel for activation, it is essential to maintain a certain level of cAMP inside the cell which determines, in turn, the presence of corresponding membrane proteins in a phosphorylated state. This mechanism of regulation of the function of electrically operated ionic channels is also identical in both invertebrate and vertebrate membranes. It is suggested that the molecular structures providing the electrical excitability represent the most ancient product of evolution used for the generation of basic forms of nervous activity in all types of nerve cells of existing animal species.


General outbreaks of infectious intestinal disease in England and Wales 1992 to 1994.
Data from the surveillance scheme of general outbreaks of infectious intestinal disease in England and Wales, reported to the PHLS Communicable Disease Surveillance Centre (CDSC), were used to review 1280 of the 1594 outbreaks identified between 1 January 1992 and 31 December 1994 for which a minimum data set was captured. The number of outbreaks reported in each regional health authority ranged from 31 in Mersey to 221 in Yorkshire. The commonest pathogens reported were salmonellas in 32% (412) of outbreaks, small round structured virus (SRSV) in 27% (342), Clostridium perfringens in 7% (90), and Shigella sonnei in 4% (46). The main mode of transmission was described as foodborne in 50% (642), over half of which were caused by salmonellas, and person to person in 39% (496), over half of which were caused by SRSV. Most outbreaks transmitted from person to person occurred in hospitals and in residential institutions for elderly people. Outbreaks lasted from one to 217 days (median five days) and their duration varied with the pathogen. The median attack rate was 37%. Illness was reported in 34,158 people, 751 of whom (2%) were admitted to hospital. There were 55 deaths, 28 of which were associated with salmonella and 12 with SRSV. Most of the outbreaks reported and the associated morbidity and mortality could have been prevented by following standard food hygiene practices, implementing infection control policies, and ensuring that food entering kitchens was of the highest microbiological quality possible.


Is Male Rheumatoid Arthritis an Occupational Disease? A Review.
Rheumatoid arthritis (RA) is a systemic, inflammatory disease with an estimated global prevalence of 0.3-1.0%. An unexplained association exists between low formal education and the development of RA independent of smoking. It is established that RA is initiated in the lungs and that various occupations associated with dust, fume and metal inhalation can increase the risk of RA development. The objective of this review is to evaluate published clinical reports related to occupations associated with RA development. We highlight the concept of a "double-hit" phenomenon involving adsorption of toxic metals from cigarette smoke by dust residing in the lung as a result of various work exposures. We discuss the relevant pathophysiological consequences of these inhalational exposures in relation to RA associated autoantibody production. A thorough literature search was performed using available databases including Pubmed, Embase, and Cochrane database to cover all relative reports, using combinations of keywords: rheumatoid arthritis, rheumatoid factor, anti-citrullinated peptide antibody silica, dust, fumes, metals, cadmium, cigarette smoking, asbestos, mining, bronchial associated lymphoid tissue, heat shock protein 70, and adsorption. We postulate that the inhalation of dust, metals and fumes is a significant trigger factor for RA development in male patients and that male RA should be considered an occupational disease. To the best of our knowledge, this is the first review of occupations as a risk factor for RA in relation to the potential underlying pathophysiology.


The sensitivity of the modified viterbi algorithm to the source statistics.
The modified Viterbi algorithm is a powerful, and increasingly used, tool for using contextual information in text recognition in its various forms. As yet, no known studies have been published concerning its robustness with respect to source statistics. This paper describes experiments performed to determine the sensitivity of the algorithm to variations in source statistics. The results of the experiments show that a character-recognition machine incorporating the modified Viterbi algorithm, using N-gram statistics estimated from source A does not deteriorate in performance when operating on a passage from source B even if A and B differ significantly in N-gram distributions or entropy.


[Radioprotective and pharmacological properties of certain phenylethylamine derivatives].
The toxicity of radioprotective and some pharmacological properties of 33 compounds, phenylethylamine derivatives, substituted in the phenyl ring were studied. Some of these display radioprotective and curative properties and also produce anesthetizing, coronary dilating, antiarrhythmic and other effects.


Human urothelial cells grown on collagen adsorbed to surface-modified polymers.
Tissue engineering methods can be applied to regenerate diseased, or congenitally missing, urinary tract tissues. Urinary tract tissue cell cultures must be established in vitro and adequate matrices, acting as cell carriers, must be developed. Although degradable and nondegradable polymer matrices offer adequate mechanical stability, they are not optimal for cell adherence and growth. To overcome this problem, extracellular matrix proteins, permitting cell adhesion and regulation of cell proliferation and differentiation, can be adsorbed to the surface-modified polymer. In this study, nondegradable polymer films, poly(ethylene terephthalate), were used as an experimental model. Films were modified by graft polymerization of acrylic acid to subsequently allow collagen type I and III immobilization. The following adhesion, proliferation of human urothelial cells, and induction of their stratification were analyzed. Collagen adsorption on 0.2 microg/cm2 poly(acrylic acid)-grafted polymer films rendered the matrix apt for human urothelial cell adhesion and proliferation. Furthermore, stratification of urothelial cells was demonstrated on these surface-modified matrices. These results have shown that surface-modified polymer matrices can be used to act as cell carriers for cultured human urothelial cells. Such a cell-matrix construct could be applied in reparative surgery of the urinary tract.


Cardiovascular magnetic resonance determinants of left ventricular noncompaction.
Insufficient precision remains in accurately identifying left ventricular noncompaction (LVNC) from the healthy normal morphologic spectrum. We aim to provide a better distinction between normal left ventricular trabeculations and LVNC. We used a previously well-defined cohort of 120 healthy volunteers for normal reference values of the trabecular/compacted ratio derived from a consistent selection of short-axis cardiovascular magnetic resonance images. We performed forward selection of logistic regression models, selecting the best model that was subsequently assessed for discrimination and calibration, validated, and converted into a clinical diagnostic chart to benchmark the boundaries of detection from a cohort of 30 patients considered to have LVNC. We showed that 3 combinations of a maximal end-diastolic trabecular/compacted ratio (≥1 [apex], >1.8 [midcavity]), (>2 [apex], ≥0.6 [midcavity]), or (>0.5 [base], >1.8 [midcavity]) separate the cohorts with the highest accuracy (C statistic [95% confidence interval] of 0.9749 (0.9748 to 0.9751) for the diagnostic chart). Quantitative cardiovascular magnetic resonance also shows that patients considered to have LVNC have a significantly reduced ejection fraction compared with normal volunteers. At midcavity and apical level, it is difficult to identify papillary muscles that are replaced by a dense trabecular meshwork. In conclusion, we developed a new, refined, diagnostic tool for identifying LVNC, based on an a priori assessment of the trabecular architecture in healthy volunteers.


Evaluation of electronic cigarette use (vaping) topography and estimation of liquid consumption: implications for research protocol standards definition and for public health authorities' regulation.
Although millions of people are using electronic cigarettes (ECs) and research on this topic has intensified in recent years, the pattern of EC use has not been systematically studied. Additionally, no comparative measure of exposure and nicotine delivery between EC and tobacco cigarette or nicotine replacement therapy (NRTs) has been established. This is important, especially in the context of the proposal for a new Tobacco Product Directive issued by the European Commission. A second generation EC device, consisting of a higher capacity battery and tank atomiser design compared to smaller cigarette-like batteries and cartomizers, and a 9 mg/mL nicotine-concentration liquid were used in this study. Eighty subjects were recruited; 45 experienced EC users and 35 smokers. EC users were video-recorded when using the device (ECIG group), while smokers were recorded when smoking (SM-S group) and when using the EC (SM-E group) in a randomized cross-over design. Puff, inhalation and exhalation duration were measured. Additionally, the amount of EC liquid consumed by experienced EC users was measured at 5 min (similar to the time needed to smoke one tobacco cigarette) and at 20 min (similar to the time needed for a nicotine inhaler to deliver 4 mg nicotine). Puff duration was significantly higher in ECIG (4.2 ± 0.7 s) compared to SM-S (2.1 ± 0.4 s) and SM-E (2.3 ± 0.5 s), while inhalation time was lower (1.3 ± 0.4, 2.1 ± 0.4 and 2.1 ± 0.4 respectively). No difference was observed in exhalation duration. EC users took 13 puffs and consumed 62 ± 16 mg liquid in 5 min; they took 43 puffs and consumed 219 ± 56 mg liquid in 20 min. Nicotine delivery was estimated at 0.46 ± 0.12 mg after 5 min and 1.63 ± 0.41 mg after 20 min of use. Therefore, 20.8 mg/mL and 23.8 mg/mL nicotine-containing liquids would deliver 1 mg of nicotine in 5 min and 4 mg nicotine in 20 min, respectively. Since the ISO method significantly underestimates nicotine delivery by tobacco cigarettes, it seems that liquids with even higher than 24 mg/mL nicotine concentration would be comparable to one tobacco cigarette. EC use topography is significantly different compared to smoking. Four-second puffs with 20-30 s interpuff interval should be used when assessing EC effects in laboratory experiments, provided that the equipment used does not get overheated. Based on the characteristics of the device used in this study, a 20 mg/mL nicotine concentration liquid would be needed in order to deliver nicotine at amounts similar to the maximum allowable content of one tobacco cigarette (as measured by the ISO 3308 method). The results of this study do not support the statement of the European Commission Tobacco Product Directive that liquids with nicotine concentration of 4 mg/mL are comparable to NRTs in the amount of nicotine delivered to the user.


On the horns of a dilemma: choosing total intravenous anaesthesia or volatile anaesthesia for cancer surgery, an enduring controversy.
Two methods for administering general anaesthesia are widely used: propofol-based total intravenous anaesthesia (propofol-TIVA) and inhalation volatile agent-based anaesthesia. Both modalities, which have been standards of care for several decades, boast a robust safety profile. Nevertheless, the potential differential effects of these anaesthetic techniques on immediate, intermediate, and extended postoperative outcomes remain a subject of inquiry. We discuss a recently published longitudinal analysis stemming from a multicentre randomised controlled trial comparing sevoflurane-based inhalation anaesthesia with propofol-TIVA in older patients with cancer, which showed a reduced incidence of emergence and postoperative delirium, comparable postoperative complication rates within 30 days after surgery, and comparable long-term survival rates. We undertake an assessment of the trial's methodological strengths and limitations, contextualise its results within the broader scientific evidence, and explore avenues for resolving the extant controversies in anaesthetic choice for cancer surgery. We aim to pave the way for the incorporation of precision medicine paradigms into the evolving landscape of perioperative care for patients with cancer.


[Optical diagnosis of colorectal polyps: electronic chromoendoscopy].
Polyps of 1-5 mm are often detected during colonoscopy; these are only sporadically malignant. The removal, collection and pathological analysis of these polyps accounts for a significant part of the costs of a colonoscopy. The histologist's assessment is the gold standard and is endorsed in all guidelines for determination of the recommended interval for surveillance colonoscopy. If, however, it was possible to make a reliable endoscopic diagnosis of a polyp during colonoscopy the pathologist's assessment would not be needed. This strategy is known as optical diagnosis, and application would lead to cost-savings in the Netherlands. Before this strategy can be safely applied in practice minimal requirements for precision have to be met, and these are not fulfilled during use of white-light endoscopy. The development of electronic chromoendoscopy will lead to improved accuracy in endoscopic diagnosis of polyps.


Rapid and sensitive techniques for identification and analysis of 'reactive-centre' mutants of C1-inhibitor proteins contained in type II hereditary angio-oedema plasmas.
Novel procedures for structural analysis of the 'reactive-centre' residues, particularly the P1 residue, of the dysfunctional C1-inhibitor proteins found in the plasmas of type II hereditary angio-oedema (HAE) patients are described. C1-inhibitor is adsorbed directly from plasma on to Sepharose-anti-(C1 inhibitor) beads. The P1 residue of C1 inhibitor is arginine and hence a potential cleavage site for trypsin. Thus trypsin digestion of the immobilized protein, followed by SDS/PAGE of the released fragments, identifies P1 residue mutations. Pseudomonas aeruginosa elastase digestion of the immobilized protein, followed by purification of the released C-terminal peptide (by h.p.l.c.) and N-terminal sequence analysis defines the new P1 residue (or other mutations in the reactive-centre region). The techniques are both rapid and highly sensitive, requiring only 400 microliters of plasma. In addition, they permit accurate assessment of the level of normal (functional) inhibitor in a subclass of type II HAE plasmas, those containing P1-residue mutant proteins.


Reliability, validity, and accuracy of the intervention selection profile-Function: A brief functional assessment tool.
The purpose of this study was to evaluate the reliability, validity, and accuracy of scores from the Intervention Selection Profile-Function (ISP-Function): a brief functional assessment tool founded upon Direct Behavior Rating (DBR) methodology. Participants included 34 teacher-student dyads. Using the ISP-Function, teachers rated the extent to which students exhibited disruptive behavior, as well as the frequency with which disruptions were met with four consequences. Ratings were completed across three 10-min sessions, during which a research assistant also collected systematic direct observation (SDO) data regarding the same behavior and consequences. Results indicated adequate temporal reliability (≥.70) was attained for the adult attention and peer attention targets across the three ratings; in contrast, up to 8-18 data points would be needed to achieve adequate reliability across the remaining targets. Findings further suggested that while ISP-Function ratings of disruptive behavior, adult attention, and peer attention were moderately to highly correlated with SDO data, correlations were in the low range for the access to items/activities and escape/avoidance targets. Finally, analysis of difference scores showed that on average, mean ISP-Function scores fell within only 0.33 to 1.81 points of mean SDO scores (on the 0-10 DBR scale). Agreement coefficients indicative of exact score agreement were less consistent, suggesting accuracy ranged from poor to substantial. Results are promising, but future research is necessary to support applied ISP-Function use. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Low-frequency repetitive transcranial magnetic stimulation of the anterior temporal lobes does not dissociate social versus nonsocial semantic knowledge.
Social conceptual knowledge is imperative to communicate with, interact with, and interpret human society; however, little is known about the neural basis of social concepts. Previous research has predominantly suggested that the right anterior temporal lobe (ATL) may specifically represent social conceptual knowledge, whereas the left ATL is necessary for general semantic processing. However, this view has not always been supported by empirical studies. Employing a lateralized design and two different semantic tasks and a nonsemantic control task, we aimed to clarify some of these ambiguities by potentially dissociating left from right functionality and social from nonsocial concepts, using inhibitory repetitive transcranial magnetic stimulation (rTMS) coupled with a sham and control site stimulation (N = 56). The results showed that stimulation of the left ATL led to overall faster processing times without affecting accuracy, whilst the right ATL and control groups did not significantly change in reaction times or accuracy. No difference occurred between social and nonsocial concepts after stimulation. This study is the first to show that inhibition of the left temporal lobe may improve performance on a semantic task and provides evidence that the ATLs may be lateralized in conceptual processing. The results do not confirm that the right temporal lobe is crucial for social conceptual processing, as inhibition did not significantly affect performance for social concepts.


Endothelial cells and CMV dissemination.
Using the murine CMV animal model and the well-established model of Cre-lox-P-mediated green-fluorescence tagging of endothelial cell (EC)-derived mouse CMV to quantify the role of infected ECs in transplantation-associated CMV dissemination (in mice expressing Cre recombinase under the control of either the Tie2 or the Tek promoter selectively expressed in vascular EC-Tie-Cre and Tek-Cre mice), it was shown that EC-derived virus contributed to 50% of the total viral load during primary infection, and there was no preference for dissemination of EC-derived viruses over viruses produced by other cell types. In addition, during secondary viremia, there was only a negligible contribution of EC-derived virus to dissemination to other organs. These results are novel in the methodology employed and are somewhat interesting. However, the data are limited to the mouse model with a short-term follow-up, and the immunodeficient host has not yet been studied. In humans, these conclusions must be taken with caution. First, in primary infection occurring through natural routes, epithelial cells are infected first, then ECs, unless primary infection occurs through blood transfusion, in which case endothelial vascular cells may become infected first. In both cases, the virus transport occurs through the intervention of leukocytes, namely monocytes and polymorphonuclear leukocytes. As monocytes differentiate to macrophages, they become highly susceptible to human CMV replication inside organ tissues, while polymorphonuclear leukocytes are active in virus capturing from infected endothelial vascular cells and transporting to distant sites.


Experimental reproduction of White Feces Syndrome in whiteleg shrimp, Penaeus vannamei.
White Feces Syndrome (WFS) is an emergent disease of penaeid shrimp (Penaeus monodon and P. vannamei) that is identified by the presence of floating white fecal strings on pond water in grow-out ponds. Although the clinical manifestations of WFS are well defined, the underling etiology remains obscure. WFS has been associated with several enteric pathogens, including Enterocytozoon hepatopenaei (EHP). The association is based on studies that found areas where WFS has been reported, the prevalence and severity of EHP infection are high. In this study, we describe an experimental reproduction of WFS in P. vannamei pre-infected with EHP and challenged with a unique isolate of Vibrio parahaemolyticus isolated from the gastrointestinal tract of a shrimp displaying WFS. Upon laboratory challenge, shrimp displaying white fecal strings and white discoloration of the gastrointestinal tract were analyzed by histopathology, in-situ hybridization and quantitative PCR. Histological analysis confirmed the lesions of EHP and septic hepatopancreatic necrosis in the hepatopancreas of shrimp exposed to both pathogens. Quantitative PCR showed shrimp infected with both EHP and V. parahaemolyticus had a significantly higher load of EHP compared to shrimp infected with EHP alone. This is the first demonstration of experimental reproduction of WFS under laboratory conditions when animals are infected with EHP and V. parahaemolyticus concurrently. The data revealed a synergistic relation between EHP and V. parahaemolyticus isolate that led to the manifestation of WFS. We propose the gross signs of WFS can be used as an indicator of the presence of EHP infection in association with a particular strain of an enteric Vibrio spp. in countries where EHP is endemic.


Use of human MAR elements to improve retroviral vector production.
Retroviral vectors have many favorable properties for gene therapies, but their use remains limited by safety concerns and/or by relatively lower titers for some of the safer self-inactivating (SIN) derivatives. In this study, we evaluated whether increased production of SIN retroviral vectors can be achieved from the use of matrix attachment region (MAR) epigenetic regulators. Two MAR elements of human origin were found to increase and to stabilize the expression of the green fluorescent protein transgene in stably transfected HEK-293 packaging cells. Introduction of one of these MAR elements in retroviral vector-producing plasmids yielded higher expression of the viral vector RNA. Consistently, viral titers obtained from transient transfection of MAR-containing plasmids were increased up to sixfold as compared with the parental construct, when evaluated in different packaging cell systems and transfection conditions. Thus, use of MAR elements opens new perspectives for the efficient generation of gene therapy vectors.


Impact of corona virus disease 2019 pandemic on paediatric surgery in a sub-saharan tertiary hospital: An observational study.
The impact of the corona virus disease 2019 (COVID-19) pandemic on global health, has reached far beyond that caused by the disease itself. With ongoing mutations and the emergence of new strains of the virus alongside repeated waves of the pandemic, the full impact of the pandemic is still evolving and remains difficult to predict or evaluate. In paediatric surgery, it has led to significant disruptions in patient care, the extent and consequence of which are not fully documented in Nigeria. This study aims to evaluate the impact of COVID-19 on services, training and research in a busy paediatric surgery unit during the initial 3-month period of the COVID-19 pandemic lockdown. This study was an ambispective evaluation of the preceding 3 months before lockdown and the initial 3 months of lockdown. Clinic cancellations, elective and emergency surgeries, delays in access, extra cost of care to patients, impact on training and research, and the psychologic impact of the pandemic on staff and guardians were evaluated. During the 3-month lockdown period, an estimated 78 new cases and 637 follow-up cases could not access care. Ninety-seven elective surgeries in 91 patients were postponed. Two (2.2%) patients' symptoms progressed. All emergency patients received care. Out-of-pocket expenditure increased averagely by $124. The pandemic contributed to delays in seeking (13%), reaching (20%) and receiving care (6%). Trainee participation in surgeries was reduced and academic programmes were suspended. Five staff were exposed to the virus and 3 infected. Paediatric surgery has been negatively impacted by COVID-19. Efforts must focus on planning and implementing interventions to mitigate the long-term impact.


Microbial successional pattern along a glacier retreat gradient from Byers Peninsula, Maritime Antarctica.
The retreat of glaciers in Antarctica has increased in the last decades due to global climate change, influencing vegetation expansion, and soil physico-chemical and biological attributes. However, little is known about soil microbiology diversity in these periglacial landscapes. This study characterized and compared bacterial and fungal diversity using metabarcoding of soil samples from the Byers Peninsula, Maritime Antarctica. We identified bacterial and fungal communities by amplification of bacterial 16 S rRNA region V3-V4 and fungal internal transcribed spacer 1 (ITS1). We also applied 14C dating on soil organic matter (SOM) from six profiles. Physico-chemical analyses and attributes associated with SOM were evaluated. A total of 14,048 bacterial ASVs were obtained, and almost all samples had 50% of their sequences assigned to Actinobacteriota and Proteobacteria. Regarding the fungal community, Mortierellomycota, Ascomycota and Basidiomycota were the main phyla from 1619 ASVs. We found that soil age was more relevant than the distance from the glacier, with the oldest soil profile (late Holocene soil profile) hosting the highest bacterial and fungal diversity. The microbial indices of the fungal community were correlated with nutrient availability, soil reactivity and SOM composition, whereas the bacterial community was not correlated with any soil attribute. The bacterial diversity, richness, and evenness varied according to presence of permafrost and moisture regime. The fungal community richness in the surface horizon was not related to altitude, permafrost, or moisture regime. The soil moisture regime was crucial for the structure, high diversity and richness of the microbial community, specially to the bacterial community. Further studies should examine the relationship between microbial communities and environmental factors to better predict changes in this terrestrial ecosystem.


Peer Victimization and Forms of Aggression During Middle Childhood: The Role of Emotion Regulation.
The current short-term longitudinal study evaluated whether anger and sadness regulation moderated the associations between peer victimization and physical and relational forms of aggression over a 6-month period. Participants included 278 predominantly Caucasian children (51.8% female) between 8 and 12 years of age (M = 9.33, SD = 0.99). Peer victimization was assessed at Time 1 using child- and teacher-reports, and teachers provided ratings of children's aggressive behavior at Time 1 and Time 2. Children also completed self-report measures of anger and sadness regulation at Time 1. Results from multilevel models provided support for the notion that children's ability to effectively regulate their feelings of anger and sadness influences the relations among peer victimization and forms of aggression over time. As anticipated, high levels of anger regulation attenuated the link between child-reported peer victimization and physical aggression. Further, when levels of anger regulation were high, teacher-reported peer victimization predicted subsequent decreases in physical aggression. Contrary to expectations, however, high levels of anger and sadness regulation exacerbated the association between child-reported peer victimization and relational aggression, and teacher-reported peer victimization predicted decreases in relational aggression over time when levels of anger regulation were low. Directions for future research and implications for practice are discussed.


Cutting Weights of Deep Learning Models for Heart Sound Classification: Introducing a Knowledge Distillation Approach.
Cardiovascular diseases (CVDs) are the number one cause of death worldwide. In recent years, intelligent auxiliary diagnosis of CVDs based on computer audition has become a popular research field, and intelligent diagnosis technology is increasingly mature. Neural networks used to monitor CVDs are becoming more complex, requiring more computing power and memory, and are difficult to deploy in wearable devices. This paper proposes a lightweight model for classifying heart sounds based on knowledge distillation, which can be deployed in wearable devices to monitor the heart sounds of wearers. The network model is designed based on Convolutional Neural Networks (CNNs). Model performance is evaluated by extracting Mel Frequency Cepstral Coefficients (MFCCs) features from the PhysioNet/CinC Challenge 2016 dataset. The experimental results show that knowledge distillation can improve a lightweight network's accuracy, and our model performs well on the test set. Especially, when the knowledge distillation temperature is 7 and the weight α is 0.1, the accuracy is 88.5 %, the recall is 83.8 %, and the specificity is 93.6 %.Clinical relevance- A lightweight model of heart sound classification based on knowledge distillation can be deployed on various hardware devices for timely monitoring and feedback of the physical condition of patients with CVDs for timely provision of medical advice. When the model is deployed on the medical instruments of the hospital, the condition of severe and hospitalised patients can be timely fed back and clinical treatment advice can be provided to the clinicians.


Relationships among several different non-homologous polypeptide hormones.
Several polypeptide hormones of apparently diverse structure and function have a number of similarities which suggest that there may be common features in their mechanism of action. These hormones are all composed of a single linear sequence of about 30 amino acids; their hydrophobic amino acids are regularly spaced at every third or fourth amino acid residue, allowing them to form amphipathic structures which can interact with phospholipids; a fragment at or near their N-terminus is required for biological activity. These hormones include glucagon, beta-endorphin, parathyroid hormone and calcitonin. A model is proposed in which all regions of the hormone bind to the receptor with comparable affinity except for a small segment which, when intact, triggers a conformational change in the receptor resulting in a further stabilization of the hormone-receptor complex. The activity of partial sequences and chemically modified forms of beta-endorphin, parathyroid hormone and glucagon are discussed in relation to this model.


Updates to the modern diagnosis of GERD: Lyon consensus 2.0.
The Lyon Consensus provides conclusive criteria for and against the diagnosis of gastro-oesophageal reflux disease (GERD), and adjunctive metrics that consolidate or refute GERD diagnosis when primary criteria are borderline or inconclusive. An international core and working group was assembled to evaluate research since publication of the original Lyon Consensus, and to vote on statements collaboratively developed to update criteria. The Lyon Consensus 2.0 provides a modern definition of actionable GERD, where evidence from oesophageal testing supports revising, escalating or personalising GERD management for the symptomatic patient. Symptoms that have a high versus low likelihood of relationship to reflux episodes are described. Unproven versus proven GERD define diagnostic strategies and testing options. Patients with no prior GERD evidence (unproven GERD) are studied using prolonged wireless pH monitoring or catheter-based pH or pH-monitoring off antisecretory medication, while patients with conclusive GERD evidence (proven GERD) and persisting symptoms are evaluated using pH-impedance monitoring while on optimised antisecretory therapy. The major changes from the original Lyon Consensus criteria include establishment of Los Angeles grade B oesophagitis as conclusive GERD evidence, description of metrics and thresholds to be used with prolonged wireless pH monitoring, and inclusion of parameters useful in diagnosis of refractory GERD when testing is performed on antisecretory therapy in proven GERD. Criteria that have not performed well in the diagnosis of actionable GERD have been retired. Personalisation of investigation and management to each patient's unique presentation will optimise GERD diagnosis and management.


Prospective Cohort Study of Caffeinated Beverage Intake as a Potential Trigger of Headaches among Migraineurs.
We aimed to evaluate the role of caffeinated beverage intake as a potential trigger of migraine headaches on that day or on the following day. In this prospective cohort study, 101 adults with episodic migraine completed electronic diaries every morning and evening. Ninety-eight participants completed at least 6 weeks of diaries in March 2016-October 2017. Every day, participants reported caffeinated beverage intake, other lifestyle factors, and the timing and characteristics of each migraine headache. We compared a participant's incidence of migraines on days with caffeinated beverage intake to the incidence of migraines among the same individual on days with no intake, accounting for day of week. We used conditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals. Among 98 participants (86 women, 12 men) with mean age 35.1 years, 83% white, and 10% Hispanic or Latino, the average age when headaches started was 16.3 years. In total, the participants reported 825 migraines during 4467 days of observation. There was a statistically significant nonlinear association between the number of caffeinated beverages and the odds of migraine headache occurrence on that day (P-quadratic trend = .024), though estimates for each level of intake were not statistically significant. The associations varied according to habitual intake and oral contraceptive use. There was a nonlinear association between caffeinated beverage intake and the odds of migraine headache occurrence on that day. This suggests that high levels of caffeinated beverage intake may be a trigger of migraine headaches on that day.


Long-term study of infliximab in Japanese patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma.
The efficacy and safety of infliximab in patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis (excluding localized type) and psoriatic erythroderma were assessed in clinical practice. Without washout of the existing treatment of psoriasis, treatment was switched to infliximab, which was given at a dose of 5 mg/kg at weeks 0, 2 and 6 and then every 8 weeks up to week 46. The primary end-points were 75% improvement in Psoriasis Area and Severity Index score (PASI 75 response rate) for plaque psoriasis, 20% improvement in American College of Rheumatology criteria (ACR 20 response rate) for psoriatic arthritis, and global improvement in pustular psoriasis and psoriatic erythroderma. The PASI 75 response rate in plaque psoriasis was 72.2% at week 10 and 53.6% at week 50. The ACR 20 response rate in psoriatic arthritis was 66.7% at week 14 and 80.0% at week 46. The response defined as global improvement in pustular psoriasis was between 66.7% and 100.0% during the 2–50-week period. The response defined as global improvement in psoriatic erythroderma was between 75.0% and 100.0% during the week-2–50 period. There were 14 discontinued patients. The most frequently reported reason for discontinuation was the development of adverse events. However, there were no serious respiratory diseases, infections or infusion reactions. In patients with plaque psoriasis, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma, infliximab was well tolerated, regardless of prior treatment, and also showed superior efficacy over a period of approximately 1 year.


Epigenetic Aberrations in Major Psychiatric Diseases Related to Diet and Gut Microbiome Alterations.
Nutrition and metabolism modify epigenetic signatures like histone acetylation and DNA methylation. Histone acetylation and DNA methylation in the central nervous system (CNS) can be altered by bioactive nutrients and gut microbiome via the gut-brain axis, which in turn modulate neuronal activity and behavior. Notably, the gut microbiome, with more than 1000 bacterial species, collectively contains almost three million functional genes whose products interact with millions of human epigenetic marks and 30,000 genes in a dynamic manner. However, genetic makeup shapes gut microbiome composition, food/nutrient metabolism, and epigenetic landscape, as well. Here, we first discuss the effect of changes in the microbial structure and composition in shaping specific epigenetic alterations in the brain and their role in the onset and progression of major mental disorders. Afterward, potential interactions among maternal diet/environmental factors, nutrition, and gastrointestinal microbiome, and their roles in accelerating or delaying the onset of severe mental illnesses via epigenetic changes will be discussed. We also provide an overview of the association between the gut microbiome, oxidative stress, and inflammation through epigenetic mechanisms. Finally, we present some underlying mechanisms involved in mediating the influence of the gut microbiome and probiotics on mental health via epigenetic modifications.


Molecular Characterization of Extended-Spectrum β-Lactamase-Producing Multidrug Resistant Escherichia coli From Swine in Northwest China.
Objectives: The aim of the present study was to explore the prevalence and molecular characterization of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli collected from pig farms in Northwest China. Methods: Between May 2015 and June 2017, a total of 456 E. coli isolates were collected from fecal samples of healthy and diarrheal pigs in Northwest China to screen the ESBL producers. The β-lactamases, plasmid-mediated quinolone resistance (PMQR) genes and virulence genes among ESBL producers were corroborated by PCR and sequencing. Finally, ESBL producers were further grouped according to phylogenetic background and genetic relatedness. Results: Forty-four (9.6%) out of the 456 E. coli isolates were identified as ESBL-producing isolates. All ESBL producers exhibited multidrug resistance (MDR) phenotype, and more than 90% of the ESBL producers were resistant to amoxicillin, amoxicillin-clavulanic acid, oxytetracycline, enrofloxacin and sulfamethoxazole/trimethoprim. All ESBL producers harbored at least one type of β-lactamase, with blaCTX-M, blaTEM, blaSHV, blaOXA-48, and blaKPC-2 being detected in forty, thirty, seven, four, two and one isolates, respectively. Sequencing revealed the most common blaCTX-M subtype was blaCTX-M-14 (n = 24), followed by blaCTX-M-15 (n = 14), blaCTX-M-64 (n = 11), blaCTX-M-9 (n = 10) and blaCTX-M-123 (n = 9). qnrS (n = 23) was the predominant PMQR gene, and all PMQR genes were detected in co-existence with β-lactamase genes. estA (n = 18) and F4 (n = 18) were the most prevalent enterotoxin and fimbrial adhesin, respectively, and 27 different virotypes were found with respect to the association of enterotoxins and fimbrial adhesins. Twenty-four different sequence types (STs) were identified among 44 ESBL producers, and clones ST405, ST10 and ST648 were strongly present in more than one-third (34.1%) of ESBL producers. Conclusion: All ESBL-producing E. coli isolates exhibited MDR phenotype, and showed high prevalence of β-lactamase and PMQR genes. Especially, one isolate harbored ESBL genes blaTEM, blaSHV, blaCTX-M-9, blaCTX-M-14, blaCTX-M-64, and carbapenemase gene blaOXA-48 and blaKPC-2, as well as PMQR genes qnrS, qnrB, qnrD, qepA and aac(6')-Ib-cr.


Methods for orientation and phase identification of nano-sized embedded secondary phase particles by 4D scanning precession electron diffraction.
The diffraction patterns acquired with transmission electron microscopes gather reflections from all crystallites that overlap in the foil thickness. The superimposition renders automated orientation or phase mapping difficult, in particular when secondary phase particles are embedded in a dominant diffracting matrix. Several numerical approaches specifically developed to overcome this issue for 4D scanning precession electron diffraction data sets are described. They consist either in emphasizing the signature of the particles or in subtracting the matrix information out of the collected set of patterns. The different strategies are applied successively to a steel sample containing precipitates that are in Burgers orientation relationship with the matrix and to an aluminium alloy with randomly oriented Mn-rich particles.


Microbial Imbalance and Intestinal Permeability in the Pathogenesis of Rheumatoid Arthritis: A Mechanism Review with a Focus on Bacterial Translocation, Citrullination, and Probiotic Intervention.
This review aims to investigate the role of intestinal permeability (IP) in rheumatoid arthritis (RA), following the hypotheses that leakage of intestinal microbes can influence increased citrullination of peptides leading to anti-citrullinated protein antibody (ACPA) production and inflammation in RA; and that leaked microbes can migrate to the peripheral joints, leading to immune responses and synovitis in peripheral joints. This review explored the evidence for the link between microbial dysbiosis and increased IP in the inflammatory state in RA, as well as the role of increased citrullination and bacterial translocation in the link between microbiota and immune responses in RA. Furthermore, this research aims to evaluate the potential effect of probiotics on RA symptoms and pathogenesis via proposed mechanisms, including the support of microbial balance and suppression of inflammatory factors in RA. A systematic literature search was conducted in three tranches (review, mechanism, intervention). 71 peer-reviewed papers met the inclusions criteria and are summarized in a narrative analysis. Primary studies were critically appraised, synthesized and their relevance to clinical practice evaluated. Evidence found in this mechanism review consistently supported intestinal dysbiosis and increased IP in arthritis. An altered intestinal microbiome was demonstrated in RA with specific microbes such as Collinsella and Eggerthella correlating with increased IP, mucosal inflammation, and immune responses. Hypercitrullination and ACPA production correlated with arthritic symptoms and intestinal microbes were shown to influence hypercitrullination. Some in vitro and animal studies demonstrated a link between leakage of microbes and bacterial translocation, but further research is needed to elucidate the link between IP and citrullination. Probiotic intervention studies evidenced reductions in inflammatory markers IL-6 and TNFα, associated with proliferation of synovial tissue and pain perception in RA joint inflammation. Despite some conflict in the literature, probiotics may present a promising nutritional intervention in the suppression of both, disease activity and inflammatory markers.Key teaching pointsThere is evidence for a dysbiotic profile of the RA gut with specific RA-associated microbes.Increased intestinal permeability and leakage of PAD enzyme facilitates citrullination of peptides.Hypercitrullination and ACPA production correlate to arthritic signs.Microbial leakage and translocation plays a role in the pathogenesis of RA.Probiotics (e.g. L. Casei 01) may reduce inflammation and ameliorate RA symptoms.


Teacher Network of Relationships Inventory: measurement invariance of academically at-risk students across ages 6 to 15.
We tested the longitudinal measurement invariance of the Teacher Network of Relationships Inventory (TNRI), a teacher-report measure of teacher-student relationship quality (TSRQ), on a sample of 784 academically at-risk students across ages 6 to 15 years by comparing the model for each subsequent year with that of the previous year(s). The TNRI was constructed with 22 items to form 3 correlated factors: Warmth, Conflict, and Intimacy. Cronbach's alphas ranged from .87 to .96 across 9 years. Both metric and scalar measurement invariance held for 9 years, indicating that scores on the TNRI have similar meaning across these ages. The TNRI also demonstrated measurement invariance across gender and race/ethnicity. Findings support that the TNRI is an appropriate measure for investigating substantive issues related to developmental changes in TSRQ from early childhood through adolescence, including gender and ethnic/racial differences in TSRQ across these ages. Based on repeated-measures ANOVAs, each scale decreased across the 9 years, although the growth patterns for scales differed somewhat: Conflict had a linearly decreasing pattern, Warmth declined most notably as students make the transition to adolescence, whereas Intimacy scores dropped off noticeably at the transition from early to late childhood. Research limitations and implications for practice are discussed.


Expression and detection of LINE-1 ORF-encoded proteins.
LINE-1 (L1) elements are endogenous retrotransposons active in mammalian genomes. The L1 RNA is bicistronic, encoding two non-overlapping open reading frames, ORF1 and ORF2, whose protein products (ORF1p and ORF2p) bind the L1 RNA to form a ribonucleoprotein (RNP) complex that is presumed to be a critical retrotransposition intermediate. However, ORF2p is expressed at a significantly lower level than ORF1p; these differences are thought to be controlled at the level of translation, due to a low frequency ribosome reinitiation mechanism controlling ORF2 expression. As a result, while ORF1p is readily detectable, ORF2p has previously been very challenging to detect in vitro and in vivo. To address this, we recently tested several epitope tags fused to the N- or C-termini of the ORF proteins in an effort to enable robust detection and affinity purification from native (L1RP) and synthetic (ORFeus-Hs) L1 constructs. An analysis of tagged RNPs from both L1RP and ORFeus-Hs showed similar host-cell-derived protein interactors. Our observations also revealed that the tag sequences affected the retrotransposition competency of native and synthetic L1s differently although they encode identical ORF proteins. Unexpectedly, we observed apparently stochastic expression of ORF2p within seemingly homogenous L1-expressing cell populations.


CD38 Defines a Subset of B Cells in Rainbow Trout Kidney With High IgM Secreting Capacities.
CD38 is a multifunctional molecule that functions both as a transmembrane signaling receptor and as an ectoenzyme with important roles in cell adhesion, calcium regulation and signal transduction. Within the B cell linage, CD38 is expressed in diverse murine B cell subsets, with highest levels in innate B cell subpopulations such as marginal zone (MZ) B cells or B1 cells. In humans, however, CD38 is transiently expressed on early lymphocyte precursors, is lost on mature B cells and is consistently expressed on terminally differentiated plasma cells. In the present work, we have identified two homologues of mammalian CD38 in rainbow trout (Oncorhynchus mykiss), designating them as CD38A and CD38B. Although constitutively transcribed throughout different tissues in homeostasis, both CD38A and CD38B mRNA levels were significantly up-regulated in head kidney (HK) in response to a viral infection. In this organ, after the generation of a specific monoclonal antibody (mAb) against CD38A, the presence of CD38A+ populations among IgM+ B cells and IgM- leukocytes was investigated by flow cytometry. Interestingly, the percentage of IgM+CD38A+ B cells increased in response to an in vitro stimulation with inactivated Aeromonas salmonicida. Finally, we demonstrated that HK IgM+CD38A+ B cells had an increased IgM secreting capacity than that of cells lacking CD38A on the cell surface, also showing increased transcription levels of genes associated with B cell differentiation. This study strongly suggests a role for CD38 on the B cell differentiation process in teleosts, and provides us with novel tools to discern between B cell subsets in these species.


Does proteasome [corrected] inhibition decrease or accelerate toxin-induced dopaminergic neurodegeneration?
Parkinson's disease (PD) is pathologically characterized by dopaminergic (DA) cell death and the presence of Lewy bodies (LB) in the brain. alpha-Synuclein (alpha-syn) and ubiquitin (Ub) are the major components of LB, however, the process of their accumulation and their relationship to DA cell loss has not yet been resolved. Now, in this journal, Inden et al. showed the protective effect of proteasome inhibitors (PSI) on DA cell death in the rat PD model using 6-hydroxyl dopamine (6-OHDA). Co-administration of PSI, lactacystin, or MG-132 significantly prevented the nigral degeneration and apomorphine-induced rotational asymmetry of the model with increased appearance of alpha-syn- and Ub-positive inclusions in the substantia nigra. This study indicates that in their model, accelerated formation of inclusions via proteasome inhibition protects against DA cell death. Previous literature linked the impairments or inhibitions of the ubiquitin-proteasome system (UPS) and DA cell death. However, this report implies that the relationship between the UPS and the pathogenesis of PD may be more complex than we thought.


Imaging of morphological and biochemical hallmarks of apoptosis with optimized optogenetic tools.
Creation of optogenetic switches for specific activation of cell death pathways can provide insights into apoptosis and could also form a basis for noninvasive, next-generation therapeutic strategies. Previous work has demonstrated that cryptochrome 2 (Cry2)/cryptochrome-interacting β helix-loop-helix (CIB), a blue light-activated protein-protein dimerization module from the plant Arabidopsis thaliana, together with BCL2-associated X apoptosis regulator (BAX), an outer mitochondrial membrane-targeting pro-apoptotic protein, can be used for light-mediated initiation of mitochondrial outer membrane permeabilization (MOMP) and downstream apoptosis. In this work, we further developed the original light-activated Cry2-BAX system (hereafter referred to as OptoBAX) by improving the photophysical properties and light-independent interactions of this optogenetic switch. The resulting optogenetic constructs significantly reduced the frequency of light exposure required for membrane permeabilization activation and also decreased dark-state cytotoxicity. We used OptoBAX in a series of experiments in Neuro-2a and HEK293T cells to measure the timing of the dramatic morphological and biochemical changes occurring in cells after light-induced MOMP. In these experiments, we used OptoBAX in tandem with fluorescent reporters to image key events in early apoptosis, including membrane inversion, caspase cleavage, and actin redistribution. We then used these data to construct a timeline of biochemical and morphological events in early apoptosis, demonstrating a direct link between MOMP-induced redistribution of actin and apoptosis progression. In summary, we created a next-generation Cry2/CIB-BAX system requiring less frequent light stimulation and established a timeline of critical apoptotic events, providing detailed insights into key steps in early apoptosis.


Association between self-reported marijuana use and incident diabetes in women and men with and at risk for HIV.
Marijuana use is common among persons living with HIV, but whether it's use increases the risk of type 2 diabetes in this population has not been explored. To determine whether self-reported marijuana use is associated with incident type 2 diabetes in women and men living with and at risk for HIV. We analyzed data from the Women's Interagency HIV Study (WIHS) and Multicenter AIDS Cohort Study (MACS), between 2000-2017 (WIHS) and 1999-2017 MACS. The association between self-reported marijuana use and incident type 2 diabetes was analyzed using time-dependent Cox regression models among 3578 and 2682 participants in the WIHS and MACS respectively. Over the follow-up period, 452 (WIHS) and 326 (MACS) incident type 2 diabetes cases occurred. In multivariable models, the hazard ratios, collectively indicate a reduced risk of type 2 diabetes, in marijuana users compared to none users, although all associations were not statistically significant. The results were similar for HIV-positive and HIV-negative participants in both cohorts. In this prospective analysis of nearly 20 years of data for women and men with and at risk for HIV in the WIHS and MACS, although we found a pattern of reduced risk of type 2 diabetes among self-reported marijuana users, the associations were not statistically significant. To better inform clinical decisions and legal policy regarding marijuana use in this population, further longitudinal investigations that biologically quantify marijuana use to assess risk for incident diabetes is warranted.


Chemical composition, antibacterial and antioxidant profile of essential oil from Murraya koenigii (L.) leaves.
This study is designed to extract and examine chemical composition, antimicrobial and antioxidant activity of the hydro-distillated essential oil of Murraya koenigii leaves from the south region of Tamilnadu, India. Matherials and Methods: Gas Chromatography (GC) and Gas Chromatography-Mass Spectrometry (GC-MS) analysis of the essential oil result was indicates the 33 different compounds representing 97.56 % of the total oil. Major compounds detected in the oil were Linalool (32.83%), Elemol (7.44%), Geranyl acetate (6.18%), Myrcene (6.12%), Allo-Ocimene (5.02), α-Terpinene (4.9%), and (E)-β-Ocimene (3.68%) and Neryl acetate (3.45%). From the identified compounds, they were classified into four groups that are oxygenated monoterpenes (72.15%), monoterpene hydrocarbons (11.81%), oxygenated sesquiterpenes (10.48%) and sesquiterpenes hydrocarbons (03.12%). The antibacterial activity of essential oil has pronounced by Disc Diffusion Method against various pathogenic microbes. The oil has a maximum zone of inhibition ability against Corynebacterium tuberculosis, Pseudomonas aeruginosa, Streptococcus pyogenes, Klebsiella pneumonia and Enterobacter aerogenes. The antioxidant profile of the sample was determined by different test systems. In all the systems, essential oil showed a strongest activity profile within the concentration range.


Missing Cl conductance in cystic fibrosis.
The specific conductance of the epithelium of the reabsorptive duct of the human eccrine sweat gland was determined by cable analysis of microperfused segments of the duct taken from normal (N) and cystic fibrosis (CF) subjects. Conditions were designed to compare the total conductance and relative contributions of Cl, Na, and residual ion conductance components in the two populations. The total conductance (Gt) of the N ducts was 125 +/- 14 mS/cm2, which was sixfold higher than the Gt of CF ducts. Removal of Cl from the media decreased Gt of the N ducts to the same value as that of the CF ducts (15 +/- 2 mS/cm2). Addition of amiloride to the Cl-free perfusate resulted in a further decline in Gt of approximately 5 mS/cm2 in both tissues. However, the effect of amiloride on Gt of the N duct was more than an order of magnitude greater in Cl-containing than in Cl-free media, but its effect on Gt of the CF duct (with or without Cl) was the same as on that of the N duct in Cl-free media. We conclude that the Cl impermeability that is characteristic of the CF tissue is due to the almost complete absence of an electrodiffusive shunt for Cl across this epithelium, while the remaining conductance components are probably not altered.


An advanced FeCoNi nitro-sulfide hierarchical structure from deep eutectic solvents for enhanced oxygen evolution reaction.
A tri-metal material system of FeCoNi-based nitro-sulfide (FeCoNi-NS) hierarchical structure has been successfully synthesized via a deep eutectic solvent annealing process. The as-prepared FeCoNi-NS possesses interesting N,S-binary heteroatoms evenly doped with Fe, Co, and Ni. By taking advantage of the unique structure including multi-metal sites, high BET area and porous structures, the as-prepared FeCoNi-NS exhibited excellent oxygen evolution reaction (OER) performance, achieving a current density of 10 mA cm-2 at an overpotential of 251 mV and a low Tafel slope of 58 mV dec-1 in 1 M KOH. Furthermore, FeCoNi-NS also demonstrated highly efficient mass/charge transportation, long-term stability with 2% deactivation after ten hours continuous operation and high faradaic efficiency of 98%. Such a facile synthetic strategy is applicable to the fabrication of more mutil-metal hierarchical structures for energy conversion and storage.


An LGR4 agonist activates the GSK‑3β pathway to inhibit RANK‑RANKL signaling during osteoclastogenesis in bone marrow‑derived macrophages.
The binding between receptor‑activated nuclear factor‑κB (RANK) and the RANK ligand (RANKL) during osteoclast development is an important target for drugs that treat osteoporosis. The leucine‑rich repeat‑containing G‑protein‑coupled receptor 4 (LGR4) acts as a negative regulator of RANK‑RANKL that suppresses canonical RANK signaling during osteoclast differentiation. Therefore, LGR4 agonists may be useful in inhibiting osteoclastogenesis and effectively treating osteoporosis. In the present study, bone marrow‑derived macrophages and a mouse model of RANKL‑induced bone loss were used to investigate the effect of mutant RANKL (MT RANKL), which was previously developed based on the crystal structure of the RANKL complex. In the present study, the binding affinity of wild‑type (WT) RANKL and MT RANKL to RANK and LGR4 was determined using microscale thermophoresis analysis, and the effect of the ligands on the AKT‑glycogen synthase kinase‑3β (GSK‑3β)‑nuclear factor of activated T cells, cytoplasmic, calcineurin‑dependent 1 (NFATc1) signaling cascade was investigated using western blotting and confocal microscopy. In addition, the expression of LGR4 and the colocalization of LGR4 with MT RANKL were analyzed in a mouse model of RANKL‑induced bone loss. The results showed that in osteoclast precursor cells, MT RANKL bound with high affinity to LGR4 and increased GSK‑3β phosphorylation independently of AKT, resulting in the inhibition of NFATc1 nuclear translocation. In the mouse model, MT RANKL colocalized with LGR4 and inhibited bone resorption. These results indicated that MT RANKL may inhibit RANKL‑induced osteoclastogenesis through an LGR4‑dependent pathway and this could be exploited to develop new therapies for osteoporosis.


Phosphodiesterase II, the cGMP-activatable cyclic nucleotide phosphodiesterase, regulates cyclic AMP metabolism in PC12 cells.
Analysis of cyclic nucleotide phosphodiesterase (PDE) activity in cellular fractions from cultured rat pheochromocytoma (PC12) cells has shown that the predominant hydrolytic activity in both cytosolic and particulate compartments is characteristic of a PDE II, the cGMP-activatable family of PDE isozymes. Cytosolic PDE activity was purified to a high degree utilizing DE-52 anion exchange and cGMP-Sepharose affinity chromatographies. The physicochemical properties of PC12 PDE II were similar to those of PDE II isolated from particulate or soluble fractions of other tissues, including subunit molecular weight of approximately 102,000, activation of cAMP hydrolysis by cGMP, and positive cooperative kinetic behavior for cAMP and cGMP hydrolysis. The potential role of PDE II in regulating cAMP metabolism in intact PC12 cells was studied using an [3H]adenine prelabeling technique. Stimulation of PC12 cell adenosine receptors resulted in a 5-8-fold increase in cAMP accumulation. Removal of the adenosine stimulus by the addition of exogenous adenosine deaminase resulted in a rapid decay of cAMP to prestimulated basal levels within 2 min. Treatment of PC12 cells with atrial natriuretic factor or sodium nitroprusside caused 1) increased intracellular cGMP levels, 2) attenuation of adenosine-stimulated cAMP accumulation, and 3) increased rates of cAMP decay after removal of the adenosine stimulus. Treatment of PC12 cells with HL-725 (a potent inhibitor of isolated PDE II activity in vitro) caused 1) increased basal cAMP accumulation, 2) potentiation of adenosine-stimulated cAMP accumulation, and 3) retardation of the rate of cAMP decay after removal of the adenosine stimulus. HL-725 blocked both the attenuation of cAMP accumulation and the accelerated rate of cAMP decay observed with the cGMP-elevating agents. These results suggest that, in PC12 cells, drugs or hormones that inhibit PDE II or increase intracellular cGMP levels to activate PDE II can modulate cAMP metabolism by altering the catalytic status of the enzyme.


Cost-Effectiveness of Testing and Treatment for Hepatitis B Virus and Hepatitis C Virus Infections: An Analysis by Scenarios, Regions, and Income.
Testing and treatment for hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are highly effective, high-impact interventions. This article aims to estimate the cost-effectiveness of scaling up these interventions by scenarios, regions, and income groups. We modeled costs and impacts of hepatitis elimination in 67 low- and middle-income countries from 2016 to 2030. Costs included testing and treatment commodities, healthcare consultations, and future savings from cirrhosis and hepatocellular carcinomas averted. We modeled disease progression to estimate disability-adjusted life-years (DALYs) averted. We estimated incremental cost-effectiveness ratios (ICERs) by regions and World Bank income groups, according to 3 scenarios: flatline (status quo), progress (testing/treatment according to World Health Organization guidelines), and ambitious (elimination). Compared with no action, current levels of testing and treatment had an ICER of $807/DALY for HBV and -$62/DALY (cost-saving) for HCV. Scaling up to progress scenario, both interventions had ICERs less than the average gross domestic product/capita of countries (HBV: $532/DALY; HCV: $613/DALY). Scaling up from flatline to elimination led to higher ICERs across countries (HBV: $927/DALY; HCV: $2528/DALY, respectively) that remained lower than the average gross domestic product/capita. Sensitivity analysis indicated discount rates and commodity costs were main factors driving results. Scaling up testing and treatment for HBV and HCV infection as per World Health Organization guidelines is a cost-effective intervention. Elimination leads to a much larger impact though ICERs are higher. Price reduction strategies are needed to achieve elimination given the substantial budget impact at current commodity prices.


Acute atrial fibrillation during dengue hemorrhagic fever.
Dengue fever is a viral infection transmitted by the mosquito, Aedes aegypti. Cardiac rhythm disorders, such as atrioventricular blocks and ventricular ectopic beats, appear during infection and are attributed to viral myocarditis. However, supraventricular arrhythmias have not been reported. We present a case of acute atrial fibrillation, with a rapid ventricular rate, successfully treated with intravenous amiodarone, in a 62-year-old man with dengue hemorrhagic fever, who had no structural heart disease.


Vaccine-associated corneal graft rejection following SARS-CoV-2 vaccination: a CDC-VAERS database analysis.
To evaluate the cases of corneal graft rejection following SARS-CoV-2 vaccination reported to Centers for Disease Control and Prevention Vaccine Adverse Event Reporting System. A descriptive analysis of the demographics, clinical history and presentation was performed. We evaluated the correlation between the vaccines and duration of vaccine-associated graft rejection (VAR) onset following vaccination using a one-way analysis of variance test. A post hoc analysis was performed between VAR onset-interval following vaccination dose and vaccine type. Finally, a 30-day cumulative incidence analysis was performed to assess the risk of VAR in short term following different doses, vaccines and type of corneal transplantation. A total of 55 eyes of 46 patients were diagnosed with VAR following vaccination with BNT162b2 (73.91%) and mRNA-1273 (26.09%). The mean age of the patients was 62.76±15.83 years, and 28 (60.87%) were female. The patients diagnosed with VAR had undergone penetrating keratoplasty (61.82%), Descemet membrane endothelial keratoplasty (12.73%), descemet stripping endothelial keratoplasty (18.18%), anterior lamellar keratoplasty (3.64%) and corneal limbal allograft transplantation (1.82%). The mean time for VAR since penetrating and endothelial keratoplasty was 8.42±9.23 years and 4.18±4.40 years, respectively. 45.65% of the cases of VAR were reported after the second dose of vaccine. The duration of VAR onset was significantly shorter after the second dose compared with the first and booster doses (p=0.0165) and in patients who underwent endothelial keratoplasty compared with penetrating keratoplasty (p=0.041). This study outlines a possible temporal relationship between corneal graft rejection and SARS-CoV-2 vaccination. An earlier onset of VAR was observed in patients who had a history of endothelial keratoplasty and following the second dose of vaccination.