Double viral vector intersectional approaches for pathway-selective manipulation of motor functions and compensatory mechanisms.
Selective manipulation of particular subcomponent of neural circuits is crucial for understanding the functional architecture of neural systems and for development of the future therapeutic strategies against neurological disorders. In this article, I review how the intersectional approaches with double viral vector technique was introduced for the pathway-selective manipulation of spinal circuits. In this technique, a retrograde gene transfer vector is injected into the terminal area of the targeted neurons and an anterograde vector is injected at the location of their somata. Either by using the Tet-transactivator or Cre-loxP system, the experimenter can chemogenetically or optogenetically manipulate the transmission of the target pathway originated from the double-infected neurons. This technique was first developed for manipulation of spinal cord interneurons in the macaque monkeys by selective expression of tetanus neurotoxin and successfully affected the dexterous hand movements. Currently, this technique is widely used on a variety of neural pathways both in rodents and primates in combination with a variety of retrograde vectors and a variety of optogenetic and chemogenetic tools. The advantage of this technique is that it is not necessary to generate transgenic animals. Knowledge of the cell-type specific promotors is not needed. Manipulation is achieved primarily by injection of two viral vectors based on the anatomical knowledge and it is applicable in a variety of animal species including primates. The pros, cons and future direction of this technique are discussed.


A study of Toxoplasma and Cytomegalovirus serology in tuberculosis and in HIV-infected patients in Burkina Faso.
Seroreactivity to Toxoplasma gondii (Tg) and to Cytomegalovirus (Cmv) was compared between symptomatic HIV-infected patients (40 with pulmonary tuberculosis and 38 with AIDS) and HIV-seronegative patients (40 tuberculosis patients and 30 healthy patients), in an urban area of Burkina Faso. Prevalence of IgG antibodies to Tg antigens (> 50.0%) did not differ amongst the four groups, but tuberculosis HIV+ patients and AIDS patients showed more higher titers of Tg antibodies more often than healthy patients (p < 0.05 and p < 0.005, respectively). Prevalence of specific IgG to Cmv was higher in tuberculosis HIV-seronegative patients (97.5%) and in AIDS patients (100%) than in healthy patients (82%; p < 0.03 and p < 0.001, respectively). Higher Cmv antibodies titers were found in relation to AIDS but also to tuberculosis. Tuberculosis HIV+ as tuberculosis HIV-patients showed higher Cmv antibodies titers than healthy patients (p < 0.002 and < 0.02 respectively). These data emphasize the need for taking into account the risk of Tg reactivation during the follow-up of HIV infected patients in Burkina Faso and suggest possible relationships between Cmv and tuberculosis reactivations.


Watermelon domestication was shaped by stepwise selection and regulation of the metabolome.
Although crop domestication has greatly aided human civilization, the sequential domestication and regulation of most quality traits remain poorly understood. Here, we report the stepwise selection and regulation of major fruit quality traits that occurred during watermelon evolution. The levels of fruit cucurbitacins and flavonoids were negatively selected during speciation, whereas sugar and carotenoid contents were positively selected during domestication. Interestingly, fruit malic acid and citric acid showed the opposite selection trends during the improvement. We identified a novel gene cluster (CGC1, cucurbitacin gene cluster on chromosome 1) containing both regulatory and structural genes involved in cucurbitacin biosynthesis, which revealed a cascade of transcriptional regulation operating mechanisms. In the CGC1, an allele caused a single nucleotide change in ClERF1 binding sites (GCC-box) in the promoter of ClBh1, which resulted in reduced expression of ClBh1 and inhibition of cucurbitacin synthesis in cultivated watermelon. Functional analysis revealed that a rare insertion of 244 amino acids, which arose in C. amarus and became fixed in sweet watermelon, in ClOSC (oxidosqualene cyclase) was critical for the negative selection of cucurbitacins during watermelon evolution. This research provides an important resource for metabolomics-assisted breeding in watermelon and for exploring metabolic pathway regulation mechanisms.


APOL1: a case in point for replacing race with genetics.
Ethnicity-specific differences in apolipoprotein L1 (APOL1) polymorphisms are associated with racial disparities in kidney transplantation outcomes. APOL1 genotyping may better help define graft outcome risk pre-transplantation; however, more research is needed.


Occupational health surveillance and detection of emerging occupational diseases among Taiwan farmers, through analysis of national-based farmers' and medico-administrative databases.
The purpose of this study was to identify occupational injuries and diseases associated with agriculture in Asia, to provide a reference for prevention and hypotheses for future research. We matched data on agricultural workers (n = 963,124) enrolled in Taiwan's national Farmers Health Insurance since its inception in 1989, to general population controls of the same age, gender, and township. The study population was linked to the National Health Insurance Research Database from 2001 to 2016 for inpatient cases. Logistic regression was used to assess odds ratios for outcomes. Farmers had 2.76 times the risk of mycotic corneal ulcer (95% CI: 1.96-3.87) and 1.65 times the risk of typhus fever infections (95% CI: 1.47-1.85) compared to the general population. The odds ratio for poisonous animal bites was 2.22 (95% CI: 2.07-2.38), for falling into a storm drain or manhole was 2.04 (95% CI: 1.30-3.20), and for toxic effects from pesticides was 2.01 (95% CI: 1.92-2.11). The toxic effects of organophosphate and carbamate insecticides were correlated with the cultivation of rice, fruit trees, and flowers. Q fever and motorcycle accidents were associated with fruit tree cultivation. The study identifies agricultural occupational injuries and diseases that may inform occupational health policy and the development of prevention priorities to prevent occupational hazards for farmers.


Cell Mechanics at the Rear Act to Steer the Direction of Cell Migration.
Motile cells navigate complex environments by changing their direction of travel, generating left-right asymmetries in their mechanical subsystems to physically turn. Currently, little is known about how external directional cues are propagated along the length scale of the whole cell and integrated with its force-generating apparatus to steer migration mechanically. We examine the mechanics of spontaneous cell turning in fish epidermal keratocytes and find that the mechanical asymmetries responsible for turning behavior predominate at the rear of the cell, where there is asymmetric centripetal actin flow. Using experimental perturbations, we identify two linked feedback loops connecting myosin II contractility, adhesion strength and actin network flow in turning cells that are sufficient to explain the observed cell shapes and trajectories. Notably, asymmetries in actin polymerization at the cell leading edge play only a minor role in the mechanics of cell turning-that is, cells steer from the rear.


Insulated Offloading Provides Offloading Protection and Enhanced Skin Perfusion.
Locally and neurally mediated vasodilation of the cutaneous vasculature has been shown to occur in response to locally and systemically applied heat stresses. The resultant shunting of blood to the periphery can be upwards of 7 L/min to 8 L/min when profound heat stresses are applied. The increased cutaneous circulation from local heat stress may benefit extremities afflicted with a wound or area of compromised arterial supply. Insulating the extremity also may increase local cutaneous perfusion. This study aims to determine if increased local warmth from an insulated offloading boot or mitt (designed to protect an extremity from trauma, offload the extremity to prevent pressure ulcers, and insulate the extremity to minimize heat loss) also results in increased local cutaneous perfusion using indocyanine green fluorescence angiography (ICGFA). Nine patients from an outpatient wound care clinic with a wound or area of compromised arterial supply on the upper or lower extremity were studied prior to and following a minimum of a single 60-minute session of insulated offloading boot or mitt use utilizing ICGFA. Measurements taken were time to first onset of fluorescence (seconds) and ingress and egress rates for the area of concern and the remainder of the area imaged. All 9 patients exhibited signs of increased local warmth by a mean of 3.1ºF while body temperature decreased by a mean of 1.2ºF. Local cutaneous perfusion increased with a mean change of 1 for the ingress rate to the area of concern and a mean change of 0.1 to the remainder of the area imaged. Also, ICGFA was able to demonstrate preferential shunting of the increased cutaneous perfusion to the site of most need. These findings suggest enhanced skin perfusion may be an additional advantage of insulated offloading boot or mitt use.


Systematic review: Predictors of students' success in baccalaureate nursing programs.
Nursing schools strive to select a diverse student population who are likely to succeed by ensuring timely student progression through the program and effective use of educational sources. The purpose of this systematic literature review is to explore the preadmission variables and selection criteria that predict student success in 4-year baccalaureate nursing programs in the U.S. Sixteen articles met the eligibility criteria, and six measures were used to define student success: (a) early academic success, particularly during the first and second year; (b) attrition; (c) timely completion of the program; (d) graduation; (e) performance in nursing courses; and (f) academic performance in other science courses. Typically, the core set of cognitive predictors used in the admission process in nursing schools were pre-nursing GPA, pre-nursing collegiate science GPA, and scores on standardized aptitude exams. This review suggests that it is challenging to isolate one single variable as the best predictor of student success; however, using a combination of variables can offer a reliable prediction method. More researchers should consider using a theoretical basis to guide their inquiry on this topic. Additionally, researchers should examine admission variables that are most relevant across programs.


Analog quantum simulation of the Rabi model in the ultra-strong coupling regime.
The quantum Rabi model describes the fundamental mechanism of light-matter interaction. It consists of a two-level atom or qubit coupled to a quantized harmonic mode via a transversal interaction. In the weak coupling regime, it reduces to the well-known Jaynes-Cummings model by applying a rotating wave approximation. The rotating wave approximation breaks down in the ultra-strong coupling regime, where the effective coupling strength g is comparable to the energy ω of the bosonic mode, and remarkable features in the system dynamics are revealed. Here we demonstrate an analog quantum simulation of an effective quantum Rabi model in the ultra-strong coupling regime, achieving a relative coupling ratio of g/ω ~ 0.6. The quantum hardware of the simulator is a superconducting circuit embedded in a cQED setup. We observe fast and periodic quantum state collapses and revivals of the initial qubit state, being the most distinct signature of the synthesized model.An analog quantum simulation scheme has been explored with a quantum hardware based on a superconducting circuit. Here the authors investigate the time evolution of the quantum Rabi model at ultra-strong coupling conditions, which is synthesized by slowing down the system dynamics in an effective frame.


Novel Naturally Occurring Dipeptides and Single-Stranded Oligonucleotide Act as Entry Inhibitors and Exhibit a Strong Synergistic Anti-HIV-1 Profile.
The availability of new classes of antiretroviral drugs is critical for treatment-experienced patients due to drug resistance to and unwanted side effects from current drugs. Our aim was therefore to evaluate the anti-HIV-1 activity of a new set of antivirals, dipeptides (WG-am or VQ-am) combined with a single-stranded oligonucleotide (ssON). The dipeptides were identified as naturally occurring and enriched in feces and systemic circulation in HIV-1-infected elite controllers and were proposed to act as entry inhibitors by binding to HIV-1 gp120. The ssON is DNA 35-mer, stabilized by phosphorothioate modifications, which acts on the endocytic step by binding to cell host receptors and inhibiting viruses through interference with binding to nucleolin. Chou-Talalay's Combination Index method for quantifying synergism was used to evaluate the drug combinations. Patient-derived chimeric viruses encoding the gp120 (env region) were produced by transient transfection and used to evaluate the antiviral profile of the combinations by drug susceptibility assays. We found that the combination WG-am:ssON or VQ-am:ssON had low combination index values, suggesting strong antiviral synergism. Of the two combinations, WG-am:ssON (1 mM:1 μM) had high efficacy against all prototype or patient-derived HIV-1 isolates tested, independent of subtype including the HIV-1-A6 sub-subtype. In addition, the antiviral effect was independent of co-receptor usage in patient-derived strains. WG-am and ssON alone significantly inhibited HIV-1 replication regardless of viral subtype and co-receptor usage, and the combination WG-am:ssON (1 mM:1 μM) was even more effective due to synergism.


Seroprevalence of hepatitis B and C virus in HIV-1 and HIV-2 infected Gambians.
The prevalence of HIV/hepatitis co-infection in sub-Saharan Africa is not well documented, while both HIV and HBV are endemic in this area. The aim of this study is to determine the seroprevalence of HBV and HCV virus in HIV-infected subjects in the Gambia. Plasma samples from HIV infected patients (190 individuals with clinically defined AIDS and 382 individuals without AIDS) were tested retrospectively for the presence of HBV sero-markers and for serum HBV DNA, screened for HCV infection by testing for anti-HCV antibody and HCV RNA. HBsAg prevalence in HIV-positive individuals is 12.2%. HIV/HBV co-infected individuals with CD4 count of <200 cells µL⁻¹ have a higher HBV DNA viral load than patients with higher CD4 count (log 4.0 vs. log 2.0 DNA copies/ml, p < 0.05). Males (OR = 1.8, 95% CI: 1.0, 3.2) were more likely to be HBsAg positive than female. HCV seroprevalence was 0.9% in HIV-positive individuals. The prevalence of HBsAg carriage in HIV- infected Gambians is similar to that obtained in the general population. However co-infected individuals with reduced CD4 levels, indicative of AIDS had higher prevalence of HBeAg retention and elevated HBV DNA levels compared to non-AIDS patients with higher CD4 count.


Insights in Immuno-Nutrition: Vitamin D as a Potent Immunomodulator.
The relationship between nutrition and the immune system is a "complicated tango", as coined earlier this year in a review in Nutrients [...].


A haemagglutination inhibition test kit for routine analysis of erythropoietin.
A commercially available haemagglutination inhibition test kit for routine analysis of erythropoietin was shown to be unable to detect elevated levels of serum Epo.


Engaging Stakeholders in a Substantive and Transparent Way When Implementing Ethics in Medical AI: A Qualitative Study.
Implementing ethics is a complex problem requiring stakeholders engagement. Engaging in fair and transparent way with stakeholders is part of the complexity. This qualitative study applies principles and techniques of Critical Systems Thinking while engaging with stakeholders in the context of implementing ethics for a COVID-19 AI. In a reflexive manner, the study examines the participatory process and its output leading to recommendations.


Specificity of an ant-lycaenid interaction.
Many lycaenid butterflies are believed to be mutualists of ants - the butterfly larvae secrete sugars and amino acids as rewards for the ants, and the ants protect the larvae from predation or parasitism. We examined the specificity of the relationship between the lycaenid Plebejus argus and ants in the genus Lasius. Eggs were not attractive to Lasius ants until the emerging larvae had broken through the chorion. First instar larvae were palpated and picked up by Lasius workers and taken to the nest. First instars were mostly ignored by Myrmica sabuleti ants and they were rarely detected by Formica fusca. Older larvae were more attractive to Lasius than to the other ant genera. Pupae were very attractive to Lasius, moderately so to Myrmica, and were ignored by Formica fusca. Teneral adults were palpated by Lasius, but were attacked by Myrmica and Formica workers. We conclude that P. argus is a specialist associate of Lasius ants. Two populations of Plebejus argus were compared: one is naturally associated with Lasius niger, and the other with Lasius alienus. In reciprocal trials, larvae were slightly more attractive to their natural host ant species. Since test larvae were reared on a single host plant species in captivity, this differentiation probably has a genetic basis.


The risk of multiple sclerosis in bereaved parents: A nationwide cohort study in Denmark.
Previous studies have suggested that psychological stress may play a role in the risk of multiple sclerosis (MS), but the evidence is very limited. To examine the association between MS and a well-defined major stressful life event: the death of a child. In this follow-up study based on nationwide and population-based registers, all 21,062 parents who lost a child younger than 18 years from 1980 to 1996 in Denmark were included in the exposed cohort and 293,745 matched parents who did not lose a child in the unexposed cohort. The two cohorts were followed for incident MS from 1980 to 1997. Hazard ratios (HR) with 95% CI were calculated as the measure of association between the exposure and MS, using the Cox proportional hazards regression model. Two hundred fifty-eight MS patients were identified (28 in the exposed cohort and 230 in the unexposed cohort). The exposed parents had an increased risk of MS (HR 1.56, 95% CI 1.05 to 2.31), which is significant only when follow-up was at least 8 years. The HR for definite/probable MS was 1.42 (95% CI 0.90 to 2.24). Parents who lost a child unexpectedly had an HR of 2.13 (95% CI 1.13 to 4.03) for all MS, which is higher than that for other bereaved parents (HR 1.33; 95% CI 0.81 to 2.16). Psychological stress may play a role in the development of MS.


Guide-independent DNA cleavage by archaeal Argonaute from Methanocaldococcus jannaschii.
Prokaryotic Argonaute proteins acquire guide strands derived from invading or mobile genetic elements, via an unknown pathway, to direct guide-dependent cleavage of foreign DNA. Here, we report that Argonaute from the archaeal organism Methanocaldococcus jannaschii (MjAgo) possesses two modes of action: the canonical guide-dependent endonuclease activity and a non-guided DNA endonuclease activity. The latter allows MjAgo to process long double-stranded DNAs, including circular plasmid DNAs and genomic DNAs. Degradation of substrates in a guide-independent fashion primes MjAgo for subsequent rounds of DNA cleavage. Chromatinized genomic DNA is resistant to MjAgo degradation, and recombinant histones protect DNA from cleavage in vitro. Mutational analysis shows that key residues important for guide-dependent target processing are also involved in guide-independent MjAgo function. This is the first characterization of guide-independent cleavage activity for an Argonaute protein potentially serving as a guide biogenesis pathway in a prokaryotic system.


Price regulation and generic competition in the pharmaceutical market.
In March 2003 the Norwegian government implemented yardstick-based price regulation schemes on a selection of drugs subjected to generic competition. The retail price cap, termed the "index price," on a drug (chemical substance) was set equal to the average of the three lowest producer prices on that drug, plus a fixed wholesale and retail margin. This is supposed to lower barriers of entry for generic drugs and to trigger price competition. Using monthly data over the period 1998-2004 for the six drugs (chemical entities) included in the index price system, we estimate a structural model enabling us to examine the impact of the reform on both demand and market power. Our results suggest that the index price helped to increase the market shares of generic drugs and succeeded in triggering price competition.


MarR-type transcriptional regulator ChlR activates expression of tetrapyrrole biosynthesis genes in response to low-oxygen conditions in cyanobacteria.
Oxygen is required for three enzyme reactions in chlorophyll and bilin biosynthesis pathways: coproporphyrinogen III oxidase (HemF), heme oxygenase (HO1), and Mg-protoporphyrin IX monomethylester cyclase (ChlA(I)). The cyanobacterium Synechocystis sp. PCC 6803 has alternative enzymes, HemN, HO2, and ChlA(II), to supply chlorophyll/bilins even under low-oxygen environments. The three genes form an operon, chlA(II)-ho2-hemN, that is induced in response to low-oxygen conditions to bypass the oxygen-dependent reactions. Here we identified a transcriptional regulator for the induction of the operon in response to low-oxygen conditions. A pseudorevertant, Δho1R, was isolated from a HO1-lacking mutant Δho1 that is lethal under aerobic conditions. Δho1R grew well even under aerobic conditions. In Δho1R, HO2 that is induced only under low-oxygen conditions was anomalously expressed under aerobic conditions to complement the loss of HO1. A G-to-C transversion in sll1512 causing the amino acid change from aspartate 35 to histidine was identified as the relevant mutation by resequencing of the Δho1R genome. Sll1512 is a MarR-type transcriptional regulator. An sll1512-lacking mutant grew poorly under low-oxygen conditions with a remarked decrease in Chl content that would be caused by the suppressed induction of the chlA(II) and hemN genes in Chl biosynthesis under low-oxygen conditions. These results demonstrated that Sll1512 is an activator in response to low-oxygen environments and that the D35H variant becomes a constitutive activator. This hypothesis was supported by a gel shift assay showing that the Sll1512-D35H variant binds to the DNA fragment upstream of the operon. We propose to name sll1512 chlR.


Identification of immunodominant surface antigens of Eimeria acervulina sporozoites and merozoites.
Immunodominant surface antigens of Eimeria acervulina sporozoites and merozoites were identified by 125I-labeling and immunoblotting studies. Using these methodologies 60% of the immunodominant sporozoite antigens and 90% of the immunodominant merozoite antigens were observed to be 125I-surface labeled. However, several major 125I-labeled sporozoite and merozoite proteins did not represent prominent antigens as measured by immunoblotting. Immunodominant surface antigens were found over a wide size range for sporozoites (21-110 kDa) and for merozoites (20-250 kDa). In order to relate these findings to a 'natural' infection, two groups of 3-week old chickens were inoculated 5 times over a 2.5 week period with either a low or high dose of E. acervulina oocysts. The serum response to sporozoites and merozoites, indicated by enzyme-linked immunosorbent assay titers, was rapid; less than or equal to 7 days post-infection with 10(4) oocysts and less than or equal to 3 days with 10(5) oocysts. Many of the antigens identified by immunoblotting of sera from sporozoite- and merozoite-immunized animals were recognized by sera from both high dose and low dose E. acervulina-infected chickens. Furthermore, the sporozoite and merozoite antigens could be grouped into those constituents which induced a serum response early or late in the infection.


Homeogenetic inductive mechanism of segmentation in polychaete tail regeneration.
Segmentation is a body-patterning strategy in which new segments are specified from a segment-addition zone containing uncommitted cells. However, the cell-recruitment process is poorly understood. Here we investigated in detail the segmentation in a polychaete annelid, Perinereis nuntia (Lophotrochozoa), in which new segments emerge at the boundary between the posterior end of the segmented region and the terminal pygidium. Cells at this border synchronously remodel their chromatin, enter the cell cycle, and undergo oriented cell division, before being added to new segments. wingless is expressed at the posterior edge of the pre-existing segment, abutted by hedgehog in the first row of the new segment. Overstimulation of Wingless signaling caused excess cells to enter the cell cycle, prolonging segmentation and widening the new segment. Thus, segment addition may occur by a homeogenetic mechanism, in which Wingless expressed in the differentiated segment coordinates the stepwise recruitment of undifferentiated cells from the segment/pygidium boundary.


[How evidence-based are print- and online mass media in Austria? A quantitative analysis].
We rated the body of evidence for 219 health-related questions that had been covered by 990 media articles in Austrian print and online media. In 59.5 % of these articles, the evidence for medical facts is reported in a highly distorted (exaggerated or understated) manner; only 10.8 % adequately reflect the actual strength of evidence. While 61.3% of the articles imply that the reported effects are based on the highest level of evidence, it really only applies to 2.6% of the articles. Compared to quality media, tabloid media report in a more distorted way. However, this is mainly due to a different subject coverage, since the degree of distorted reporting does not significantly differ for subjects covered by both tabloid and quality media. Online media do not report in a more distorted way than print media, with the exception of the newspaper "Der Standard". A clear difference can be seen in the reporting on different subjects. Articles on medications regulated by governmental authorities or interventions which only physicians are allowed to perform were significantly less distorted than articles on nutritional supplements or interventions that may be provided by non-physician staff. Reports on cosmetic or weight loss interventions were most distorted.


The impact of decentralised drug-budgets in Sweden - a survey of physicians' attitudes towards costs and cost-effectiveness.
In Sweden decentralised drug-budgets at health-care facility levels were introduced in 1997 in an attempt to contain increasing pharmaceutical expenditures. This paper reports the findings of a postal survey which investigates whether decentralised drug-budgets according to a so-called primary-care based model in Swedish health care have led to increased cost awareness and changed attitudes towards cost-minimisation and cost-effectiveness as decision-making criteria among physicians. In particular, it was investigated whether there were differences in this respect between general practitioners (GPs) and specialists. The postal survey was sent to 1,520 Swedish physicians from a stratified sample of Swedish county councils. A total of 738 physicians responded (response rate 49%). Statistical analysis was performed of logistic regression analysis and independent or paired samples t-tests. The results suggest that GPs have a higher degree of cost awareness than specialists. Physicians with experience of decentralised drug-budgets have a higher degree of cost awareness than other physicians. However, the rating of the top four decision-making criteria; therapeutic effects, side effects, compliance and cost-effectiveness, were not significantly different when comparing GPs against specialists, and physicians practising in county councils with decentralised drug-budgets against other physicians. The main barriers to considering costs to a greater extent were perceived difficulties in switching drugs and a fear among physicians of losing credibility among patients. In conclusion, decentralisation of drug-budgets according to the Swedish primary-care based model increases cost awareness, especially among GPs. Such responsibility, however, does not create strong incentives for physicians to reconsider the importance of cost-effectiveness in relation to other decision-making criteria when prescribing. Parallel interventions are needed to meet the objective of cost-effective prescribing.


Congenital cystic adenoid malformation in a pre-term infant: management considerations.
This report describes a case of a pre-term infant with congenital cystic adenomatoid malformation involving the whole lung who received a life-saving pneumonectomy. The challenges in decision-making, surgery, and subsequent management are discussed. The principles are applicable in general to a number of babies in a paediatric intensive care unit.


Treatment of partial thickness burns of the hand with the preshaped, semipermeable Procel Burn Cover: results of a multicentre study in the burn centres of Berlin, Duisburg and Munich.
The results of a prospective clinical study conducted in three German burn centres are reported. The subject of the evaluation was to show the effectiveness of a new, preshaped, semipermeable burn dressing that is resistant to fluids and bacteria but highly permeable to vapour. The dressing was used in conjunction with 1 per cent silver sulphadiazine cream in treating partial thickness burns of the hand. In 49 patients, 72 partial thickness burned hands were treated. The application proved to be very easy. The time for a dressing change was short (5-10 min). The duration of treatment was 13 days on average. Complications due to infections did not occur. Because of the semipermeable properties of the dressing material, skin macerations occurred in only a few instances (13 per cent) as a result of inappropriate cream application or extremely high exudation rates, and these did not adversely affect the healing process. Patients achieved the ability to perform activities of daily living early with positive results for the patients, the physician and the nursing team.


Genetic and physical interactions between Polη and Rev1 in response to UV-induced DNA damage in mammalian cells.
In response to UV irradiation, translesion DNA synthesis (TLS) utilizes specialized DNA polymerases to bypass replication-blocking lesions. In a well-established polymerase switch model, Polη is thought to be a preferred TLS polymerase to insert correct nucleotides across from the thymine dimer, and Rev1 plays a scaffold role through physical interaction with Polη and the Rev7 subunit of Polζ for continual DNA synthesis. Defective Polη causes a variant form of xeroderma pigmentosum (XPV), a disease with predisposition to sunlight-induced skin cancer. Previous studies revealed that expression of Rev1 alone is sufficient to confer enhanced UV damage tolerance in mammalian cells, which depends on its physical interaction with Polζ but is independent of Polη, a conclusion that appears to contradict current literature on the critical roles of Polη in TLS. To test a hypothesis that the Rev1 catalytic activity is required to backup Polη in TLS, we found that the Rev1 polymerase-dead mutation is synergistic with either Polη mutation or the Polη-interaction mutation in response to UV-induced DNA damage. On the other hand, functional complementation of polH cells by Polη relies on its physical interaction with Rev1. Hence, our studies reveal critical interactions between Rev1 and Polη in response to UV damage.


Polyunsaturated fatty acids in serum lipids of reindeer during the close postnatal period.
We examined serum fatty acid composition in reindeer during the close postnatal period (from < 8 h to 3 weeks) by using maternal serum as a reference point and focusing on the proportions of polyunsaturated fatty acids (PUFAs) in serum lipids. A striking dissimilarity was found in the serum PUFAs between the neonatals and their mothers. In particular, the proportions of linoleic acid (18:2) and alpha-linolenic acid in serum cholesteryl esters and phospholipids of the newborn reindeer were significantly lower than those of the mothers. Furthermore, serum phospholipids of the newborns had lower arachidonic acid and docosapentaenoic acid but higher docosahexaenoic acid proportions than the maternal phospholipids. Although the proportions of the principal C18 PUFAs were low in reindeer milk, they increased sharply in serum cholesteryl esters and phospholipids of the calves during the first few days after birth. In particular, there were significant positive correlations in the proportions of 18:2 between serum and milk lipids. We conclude that the proportions of the serum C18 PUFAs are low in the newborn reindeer, but they are increased during the close perinatal period by a rate which suggests an efficient mechanism for selective retention of these fatty acids from milk lipids.


Efficacy of Felpreva®, a new spot-on formulation containing tigolaner, emodepside and praziquantel, applied as a single application to cats artificially infested with ear mites (Otodectes cynotis).
The efficacy of Felpreva® (Vetoquinol), a new spot-on application containing the novel acaricide and insecticide tigolaner in combination with emodepside and praziquantel, was evaluated in cats artificially infested with ear mites (Otodectes cynotis). A total of three pivotal dose confirmation studies were conducted, two of them designed as non-interference studies. Cats were artificially infested with O. cynotis mites and randomly allocated into groups of 8 cats based on pre-treatment mite counts. Cats were treated once on Day 0, either with Felpreva® (14.5 mg/kg tigolaner, 3 mg/kg emodepside and 12 mg/kg praziquantel) or with placebo. Studies with a non-interference design included two additional groups of cats, treated with Profender® spot-on solution (Vetoquinol) (3 mg/kg emodepside and 12 mg/kg praziquantel) and tigolaner as a mono product (14.5 mg/kg tigolaner). Efficacy was evaluated on Day 28/Day 30 based on total live mite counts after ear flushing. Efficacy was claimed when: (i) at least six control cats per group were adequately infested with mites; (ii) calculated efficacy was ≥ 90% based on geometric mean mite counts; and (iii) the difference in mite counts between Felpreva®-treated cats and control cats was statistically significant (P ≤ 0.05). In two of the three studies, Felpreva®-treated cats were mite-free (100% efficacy) on Day 28/Day 30 and almost full efficacy (99.6%) was seen in the third study. The difference in mite counts between Felpreva®-treated cats and control cats was significant (P < 0.0001) in all three studies. All control cats were adequately infested in all three studies. The efficacy of Felpreva® against ear mite (Otodectes cynotis) infection in cats was confirmed.


Development of S-Fluxametamide for Bioactivity Improvement and Risk Reduction: Systemic Evaluation of the Novel Insecticide Fluxametamide at the Enantiomeric Level.
Increasing numbers of novel pesticides have been applied in agriculture. However, traditional evaluation of pesticides does not distinguish between their enantiomers, which may lead to inaccurate results. In this study, systematic research on the chiral insecticide fluxametamide was conducted at the enantiomeric level. The methods for enantioseparation and semipreparative separation of fluxametamide enantiomers were developed. The optical rotation and absolute configuration of two enantiomers were determined, and their stability was verified in solvents and soils. Enantioselective bioactivities against four target pests (Plutella xylostella, Spodoptera exigua, Aphis gossypii, and Tetranychus cinnabarinus) were tested. Acute toxicities of fluxametamide enantiomers toward honeybees were also evaluated. S-(+)-Isomer exhibited 52.1-304.4 times and 2.5-3.7 times higher bioactivity than R-(-)-isomer and rac-fluxametamide, respectively. Meanwhile, rac-fluxametamide was more toxic than S/R-isomer, and S-(+)-isomer showed >30-fold higher acute toxicity than R-(-)-isomer. Molecular docking studies were performed with γ-aminobutyric acid receptor (GABAR) to monitor the mechanism of stereoselective bioactivity. The better Grid score of S-(+)-fluxametamide (-60.12 kcal/mol) than R-(-)-enantiomer (-56.59 kcal/mol) indicated higher bioactivity of S-(+)-isomer than of R-(-)-isomer. The dissipation of fluxametamide in cabbage, Chinese cabbage, and soil was nonenantioselective under field conditions. Development of S-(+)-fluxametamide could maintain the high-efficacy and low-risk properties, which should attract attention of producers, applicators, and managers of pesticides.


Beighton score: a valid measure for generalized hypermobility in children.
To evaluate the validity of the Beighton score as a generalized measure of hypermobility and to measure the prevalence of hypermobility and pain in a random population of school age children. Prospective study of 551 children attending various Dutch elementary schools participated; 47% were males (258) and 53% (293) females, age range was 6 to 12 years. Children's joints and movements were assessed according to the Beighton score by qualified physiotherapists and by use of goniometry measuring 16 passive ranges of motion of joints on both sides of the body. More than 35% of children scored more than 5/9 on the Beighton score. Children who scored high on the Beighton score also showed increased range of motion in the other joints measured. Moreover 12.3% of children had symptoms of joint pain, and 9.1% complained of pain after exercise or sports. Importantly, this percentage was independent of the Beighton score. There were no significant differences in Beighton score for sex in this population. The Beighton score, when goniometry is used, is a valid instrument to measure generalized joint mobility in school-age children 6 to 12 years. No extra items are needed to improve the scale.


SARS-CoV-2 Cell Entry Factors ACE2 and TMPRSS2 Are Expressed in the Microvasculature and Ducts of Human Pancreas but Are Not Enriched in β Cells.
Isolated reports of new-onset diabetes in individuals with COVID-19 have led to the hypothesis that SARS-CoV-2 is directly cytotoxic to pancreatic islet β cells. This would require binding and entry of SARS-CoV-2 into β cells via co-expression of its canonical cell entry factors, angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2); however, their expression in human pancreas has not been clearly defined. We analyzed six transcriptional datasets of primary human islet cells and found that ACE2 and TMPRSS2 were not co-expressed in single β cells. In pancreatic sections, ACE2 and TMPRSS2 protein was not detected in β cells from donors with and without diabetes. Instead, ACE2 protein was expressed in islet and exocrine tissue microvasculature and in a subset of pancreatic ducts, whereas TMPRSS2 protein was restricted to ductal cells. These findings reduce the likelihood that SARS-CoV-2 directly infects β cells in vivo through ACE2 and TMPRSS2.


Evaluation of early versus delayed lymphoscintigraphic imaging in detecting internal mammary sentinel lymph nodes in breast cancer: a multicenter study to establish an optimal lymphatic mapping protocol.
Metastases in the internal mammary lymph nodes have an important prognostic value in breast cancer. Lymphatic mapping and sentinel node biopsy of internal mammary nodes improves staging and permits specific therapeutic strategies, thereby possibly improving final outcome. Therefore, optimal lymphoscintigraphic results are needed. Visualization of internal mammary lymph drainage, however, is influenced by several factors. We evaluated the effect of different time intervals between radioactive tracer injection and lymphoscintigraphy on visualization of internal mammary sentinel lymph nodes. From February 1997 to August 2001 a total of 682 eligible breast cancer patients underwent sentinel lymph node mapping. The technique involved the injection of 370 MBq (10 mCi) (99m)Tc-nanocolloid peritumorally. In 470 patients (group A) the time interval between injection of the radiocolloid and lymphoscintigraphy was 16 h, compared to 2.5 h in 212 patients (group B). Patient characteristics showed no statistically significant difference between both groups for age and location of the tumour. Axillary hotspots were visualized in 97% in group A and 96% in group B. Lymphoscintigraphy showed internal mammary hotspots in 21% in group A, compared to 27% in group B. The mean number of internal mammary hotspots per patient was 1.9 in group A and 1.8 in group B. We found no significant differences between early and delayed lymphoscintigraphic imaging in visualizing internal mammary sentinel lymph nodes.


Public participation in, and awareness about, medical research opportunities in the era of clinical and translational research.
In the United States, levels of public participation in medical research in the era of Clinical and Translational Science Awards (CTSAs) are unknown. In 2011, a household survey was administered to a sample of U.S. adults, asking whether they (and children <18 years old) had participated, or were aware of opportunities to participate, in medical research. Respondents living within 100 miles of CTSA sites were identified. Regression analyses of participation and awareness (PA) were performed, applying sampling weights to permit nationally representative inferences. Overall, 2,150 individuals responded (completion rate = 60%); 65% of adults and 63% of families with children resided within 100 miles of ≥1 CTSA location. Research participation rates were 11% among adults and 5% among children. Among nonparticipants, awareness rates were 64% among adults and 12% among parents of children. PA among adults was associated with higher income and education, older age, presence of chronic conditions, and living within 100 miles of four specific CTSA locations. For children, PA was associated with higher household income and parents' chronic health conditions. PA of medical research opportunities is substantially higher for adults than children. Higher PA levels near specific CTSAs merit investigation to identify their successful approaches.


The HLA histocompatibility system in autoimmune states.
The HLA system of antigens identified serologically and, in some cases, by cellular techniques has shown important associations with numerous autoimmune diseases. As DNA technology becomes more widely used, there is great expectation that restriction fragment length polymorphisms (RFLP) and oligonucleotide probing of the HLA genes will soon provide for clinical use even more definitive relationships with these diseases and possibly insights into their pathogenetic mechanisms.


Patient education objectives in Healthy People 2000: policy and research issues.
The extensive nationwide involvement in the development of year 2000 health objectives, and the breadth of the 298 objectives produced, illustrate the scope of contemporary public health and preventive medicine in the United States. Patient education is an essential element of numerous year 2000 priority targets; full accomplishment of the patient education objectives will be influenced by several policy issues. This paper discusses special needs in three areas: data for decision-making, prevention effectiveness and research gaps. One major data issue is difficulty in documenting the existence and scope of patient education, and better measurement systems are desirable. A renewed interest in prevention effectiveness suggests that patient education would benefit from emphasis on five elements of prevention effectiveness: guidelines development; guidelines dissemination; demonstrations and technical assistance; monitoring; and research. Emerging research needs are identified, with particular focus on quality-of-life measurement and on integrated patient education and health communication strategies.


Intranasal Bifidobacterium longum protects against viral-induced lung inflammation and injury in a murine model of lethal influenza infection.
Prophylactic strategies are urgently needed for prevention of severe inflammatory responses to respiratory viral infections. Bacterial-host interactions may modify the immune response to viral infections. We examined the contribution of Intranasal administration of two different Bifidobacterium longum strains or its isolated cell wall in controlling viral induced inflammation using a murine model of influenza infection. We monitored mortality and morbidity over a 10-day period and viral load, differential broncho alveolar lavage (BAL) fluid inflammatory cell counts, Lung tissue histology, BAL and serum cytokines, markers of vascular damage and cell death were quantified. Intranasal administration of Bifidobacterium longum35624® or its isolated cell wall prior to virus inoculation significantly reduced viral load within the lungs and significantly improved survival. Reduced viral load was associated with reduced lung injury as suggested by cell death and vascular leakage markers, a shift from neutrophil to macrophage recruitment, reduced inflammatory cytokine levels (including IL-6), reduced type 1 and 2 interferon levels, but increased levels of interferon-λ and surfactant protein D. These protective effects were maintained when the bifidobacterial cell wall preparation was administered 24 h after viral inoculation. The protective effects were also observed for the Bifidobacterium longumPB-VIR™ strain. Exposure to these bifidobacterial strains protect against the inflammatory sequelae and damage associated with uncontrolled viral replication within the lung. This work has been funded, in part, by a research grant from GlaxoSmithKline, PrecisionBiotics Group Ltd., Swiss National Science Foundation grants (project numbers CRSII3_154488, 310030_144219, 310030_127356 and 310030_144219) and Christine Kühne - Center for Allergy Research and Education (CK-CARE).


The K+/site and H+/site stoichiometry of mitochondrial electron transport.
Electrode measurements of the average number of H+ ejected and K+ taken up (in the presence of valinomycin) per pair of electrons passing the energy-conserving sites of the respiratory chain of rat liver and rat heart mitochondria have given identical values of the H+/site and 5+/site ratios very close to 4 in the presence of N-ethylmaleimide, an inhibitor of interfering respiration-coupled uptake of H+ + H2PO4-. The K+/site uptake ratio of 4 not only shows that inward movement of K+ provides quantitative charge-compensation for the 4 H+ ejected, but also confirms that 4 charges are separated per pair of electrons per site. When N-ethylmaleimide is omitted, the H+/site ejection ratio is depressed, because of the interfering secondary uptake of H/+ with H2PO4- on the phosphate carrier, but the K+/site uptake ratio remains at 4.0. Addition of phosphate or acetate, which can carry H+ into respiring mitochondria, further depresses the H+/site ratio, but does not affect the K+/site ratio, which remains at 4.0. These and other considerations thus confirm our earlier stoichiometric measurements that the average H+/site ratio is 4.0 and also show that the K+/site uptake ratio can be used as a measure of the intrinsic H+/site ratio, regardless of the presence of phosphate in the medium and without the necessity of adding N-ethylmaleimide or other inhibitors of H+ + H2PO4- transport.


[ISCHEMIA trial : Is coronary CT angiography the new gatekeeper?]
The ISCHEMIA trial systematically compared two major principles in the therapy of coronary artery disease (CAD): medical therapy versus revascularization in patients with a positive noninvasive test for myocardial ischemia. Specifically, it was designed to answer the question whether in patients with demonstrated ischemia, after ruling out left main stenosis by coronary computed tomography angiography (CTA), a routine interventional strategy in addition to optimal medical therapy would improve clinical outcome over an initial strategy of medical therapy alone. Overall, this hypothesis could not be confirmed. In several ways, the trial yields interesting information in the field of cardiac imaging. First, a positive stress test result was not associated with a prognostic benefit of revascularization. Second, even though the evaluation of coronary CTA was not part of the protocol, the good outcome achieved by using coronary CTA as a "gatekeeper" during randomization supports the potential of coronary CTA as a diagnostic tool-both first- and second-line-when CAD is suspected. However, the trial also raises new questions in the field of cardiac imaging which will need to be addressed in future studies.


Combined immunotherapy for metastatic triple-negative breast cancer based on PD-1/PD-L1 immune checkpoint blocking.
Metastatic triple negative breast cancer is not only the worst prognosis and the strongest invasive subtype of breast cancer, but also the most immunogenic subtype, so it can be reasonably predicted that immunotherapy can play a positive role in the treatment of metastatic triple negative breast cancer. However, the effect of using PD-1/PD-L1 immune checkpoint inhibitors alone is not very ideal. In recent years, the regimen of combined therapy has been emerging. This article reviews the application of combined immunotherapy based on PD-1/PD-L1 inhibitors in metastatic triple negative breast cancer, including chemotherapy, targeted therapy, radiotherapy and oncolytic virus therapy. The problems existing in combined therapy and the possibility of future research are discussed, which can provide a reference for the selection of treatment options for patients with metastatic triple negative breast cancer in different situations.


Redox homeostasis protects mitochondria through accelerating ROS conversion to enhance hypoxia resistance in cancer cells.
Mitochondria are the powerhouses of eukaryotic cells and the main source of reactive oxygen species (ROS) in hypoxic cells, participating in regulating redox homeostasis. The mechanism of tumor hypoxia tolerance, especially the role of mitochondria in tumor hypoxia resistance remains largely unknown. This study aimed to explore the role of mitochondria in tumor hypoxia resistance. We observed that glycolysis in hypoxic cancer cells was up-regulated more rapidly, with far lesser attenuation in aerobic oxidation, thus contributing to a more stable ATP/ADP ratio. In hypoxia, cancer cells rapidly convert hypoxia-induced O(2˙)(-) into H2O2. H2O2 is further decomposed by a relatively stronger antioxidant system, causing ROS levels to increase lesser compared to normal cells. The moderate ROS leads to an appropriate degree of autophagy, eliminating the damaged mitochondria and offering nutrients to promote mitochondria fusion, thus protects mitochondria and improves hypoxia tolerance in cancer. The functional mitochondria could enable tumor cells to flexibly switch between glycolysis and oxidative phosphorylation to meet the different physiological requirements during the hypoxia/re-oxygenation cycling of tumor growth.


Fluctuations of time averages for Langevin dynamics in a binding force field.
We derive a simple formula for the fluctuations of the time average x(t) around the thermal mean <x>(eq) for overdamped brownian motion in a binding potential U(x). Using a backward Fokker-Planck equation, introduced by Szabo, Schulten, and Schulten in the context of reaction kinetics, we show that for ergodic processes these finite measurement time fluctuations are determined by the Boltzmann measure. For the widely applicable logarithmic potential, ergodicity is broken. We quantify the large nonergodic fluctuations and show how they are related to a superaging correlation function.


Acute and chronic stressor effects on the antibody response to sheep red blood cells.
Exposure to inescapable foot-shock 72 h following immunization with sheep red blood cells resulted in a marked suppression of the peak splenic immunoglobulin (Ig)M plaque-forming cell response and plasma antibody titers in CD-1 mice. However, the nature of this effect was influenced by the animal's stressor history. In particular, if mice were initially exposed to a single stressor session immediately or 24 h following antigen treatment subsequent reexposure to the stressor (72 h following inoculation) did not provoke the immunosuppression. Moreover, reexposure to the stressor-related cues elicited a marked immunoenhancement. In contrast, if animals were exposed to a single stressor session 48 h prior to inoculation then later reexposure to the stressor-related cues provoked an immunosuppression. Among mice that had been exposed to a repeated stressor regimen on successive days prior to inoculation, the immunosuppression ordinarily elicited by an acute stressor was absent. Indeed, chronic stressor exposure typically favored potentiation of the immune response. However, the immunofacilitation elicited by the chronic stressor treatment likely was unrelated to the immunoenhancing effects of pairing a stressor with antigenic challenge.


[Construction of eucaryotic expression plasmid carrying the BMP7 gene and expression in mesenchymal stem cells].
To construct an eucaryotic expression plasmid carrying the BMP7 gene and express in MSCs. The BMP7 gene was cloned into the eucaryotic expression vector pcDNA3.1. At the same time, mesenchymal stem cells (MSCs) were isolated and cultured in vitro. The plasmid carrying the BMP7 gene was transfected into MSCs. PCR and digesting demonstrated that the eucaryotic expression plasmid -pcDNA-BMP7 was obtained. RT-PCR and immunohistochemical methods showed that the BMP7 gene was expressed in MSCs. Construction of an eucaryotic expression plasmid carrying BMP7 gene and expression in MSCs provide a sound basis for gene therapy using the BMP7 gene and the ideal seeds for tissue engineering.


High Frequency Repetitive Transcranial Magnetic Stimulation Therapy For Chronic Neuropathic Pain: A Meta-analysis.
Increasing evidence supports an analgesic effect of repetitive transcranial magnetic stimulation (rTMS) for neuropathic pain (NP). However, the optimal parameters of rTMS (stimulation frequency and treatment sessions) for achieving long-term analgesic effects remain unknown. This study analyzed the current findings in the literature. The aim of this study was to assess the optimal parameters of rTMS for NP, including the rTMS sessions needed for inducing acute as well as long-term analgesic effects. A meta-analysis of the analgesic effect of high frequency rTMS (HF- rTMS) for neuropathic patients. This meta-analysis examined all studies involving the analgesic efficacy of HF-rTMS for NP. PubMed, Embase, and the Cochrane library were searched for clinical studies of rTMS treatment on NP published before December 31, 2014. Crude standardized mean differences (SMD) with 95% confidence interval (CI) were calculated for pain intensity after different treatment sessions (from 1 to 10) and follow-up of one or 2 months after rTMS treatment using random effect models. Twenty-five studies (including 32 trials and 589 patients) were selected for the meta-analysis according to the inclusion and exclusion criteria. All 3 HF-rTMS treatments (5, 10, and 20 Hz) produced pain reduction, while there were no differences between them, with the maximal pain reduction found after one and 5 sessions of rTMS treatment. Further, this significant analgesic effect remained forone month after 5 sessions of rTMS treatment. There are limitations of this meta-analysis. For example, the long-term analgesic effects of different HF-rTMS and low frequency (LF) rTMS sessions, including the single session of rTMS on different NP of varying origins have yet not been evaluated; the full degree of pain relief is still unclear for many rTMS studies. HF-rTMS stimulation on primary motor cortex is effective in relieving pain in NP patients. Although 5 sessions of rTMS treatment produced a maximal analgesic effect and may be maintained for at least one month, further large-scale and well-controlled trials are needed to determine if this enhanced effect is specific to certain types of NP such as post-stroke related central NP.


Changing pattern of primary glomerulonephritis in a south Indian hospital.
Data were reviewed on 2805 patients with primary glomerulonephritis admitted to a south Indian hospital in 1972-1987. A decrease in the proportion of endocapillary proliferative, crescentic and mesangial proliferative types was noted. There was also a decrease in group A beta-haemolytic streptococcal isolates among the 24,657 throat swab cultures made during the same period. This suggests a decreasing prevalence of nephritogenic streptococcal infections in this tropical region.


Campylobacter hepaticus in the Production Environment and Stagnant Water as a Potential Source of C. hepaticus Causing Spotty Liver Disease in Free-Range Laying Hens in Georgia, United States.
Spotty liver disease (SLD) has emerged as an important cause of disease in egg-producing flocks in countries such as the United Kingdom and Australia and has emerged in the United States. The organisms implicated in SLD include Campylobacter hepaticus and, more recently, Campylobacter bilis. These organisms have been found to cause focal lesions on the livers of infected birds. Campylobacter hepaticus infection results in reduced egg production, decreased feed consumption resulting in reduced egg size, and increased mortality of highly valuable hens. In the fall of 2021, birds from two flocks (A and B) of organic pasture-raised laying hens were submitted to the Poultry Diagnostic Research Center at the University of Georgia with a history suspicious of SLD. Postmortem examination of Flock A found 5/6 hens had small multifocal lesions on the liver and were PCR positive for C. hepaticus from pooled swab analysis of samples of the liver and gall bladder. Necropsy of Flock B found 6/7 submitted birds had spotty liver lesions. In pooled bile swabs, 2/7 hens from Flock B were also PCR positive for C. hepaticus. A follow-up visit to Flock A was scheduled 5 days later, as well as a visit to a flock where SLD has not been reported (Flock C), which was used as a comparative control. Samples of the liver, spleen, cecal tonsil, ceca, blood, and gall bladder were collected from six hens per house. Additionally, feed, water nipples, and environmental water (stagnant water outside the house) were collected from the affected farm and the control farm. To detect the organism, all samples collected were subjected to direct plating on blood agar and enrichment in Preston broth with incubation under microaerophilic conditions. After multiple phases of bacterial culture purification from all samples, single bacterial cultures displaying characteristics of C. hepaticus were tested by PCR to confirm identity. From Flock A, liver, ceca, cecal tonsils, gall bladder, and environmental water were PCR positive for C. hepaticus. No positive samples were detected in Flock C. After another follow-up visit, 10 wk later, Flock A was PCR positive for C. hepaticus from gall bladder bile and feces and one environmental water sample displayed a weak positive reaction for C. hepaticus. Flock C was PCR negative for C. hepaticus. To gain more knowledge about C. hepaticus prevalence, a survey of 6 layer hens from 12 different layer hen flocks between the ages of 7 to 80 wk, raised in different housing systems, were tested for C. hepaticus. The 12 layer hen flocks were culture and PCR negative for C. hepaticus. Currently, there are no approved treatments for C. hepaticus and no vaccine is available. The results of this study suggest that C. hepaticus may be endemic in some areas of the United States, and free-range laying hens may be exposed from the environment/stagnant water in areas where they range.


Comparison of Yarrowia lipolytica lipase immobilization yield of entrapment, adsorption, and covalent bond techniques.
The purpose of this study was to immobilize lipase from Yarrowia lipolytica using three methods including inclusion, adsorption, and covalent bond to study enzyme leaching, storage, and catalytic properties. Sodium alginate and chitosan were the polymers selected to immobilize lipase by inclusion. The beads of each polymer were dried by freeze drying and fluidization. The results show that chitosan was more adapted to the inclusion of lipase. Even though freeze dried, bead activity was low compared to that of fluidized beads. The freeze-drying process seems to produce suitable beads for storage at 4 and 20 degrees C. The immobilization by adsorption was carried out on both celite and silica gel. Maximum immobilization yield of 76% was obtained with celite followed by 43% in silica gel. The enzyme adsorbed on the two supports exhibited greater stability at a certain temperature (50 degrees C) and in no polar solvents (Isooctane, n-heptane, and n-hexane). In addition, the lipase immobilized by covalent bond retained residual activity equitable to 70%. It was demonstrated that the enzyme immobilized by covalent bond showed greater activity (80%) after 5 months of storage.


[Chronic inflammatory demyelinating polyradiculoneuropathy in childhood: outcomes after methylprednisolone pulse therapy].
Chronic inflammatory demyelinating polyneuropathy (CIDP) in children is relatively rare and treatment is based primarily on intravenous immunoglobulins or oral corticosteroids. Boluses of methylprednisolone (MP) are a seldom used alternative. We report the case of an 8-year-old child, first presented at the age of 3 years, with recurring episodes of functional impotence of both lower limbs and walking impairment, partially reversible without treatment. Clinical, progressive, and electrophysiological data and the analysis of the cerebrospinal fluid were compatible with CIDP. MP boluses were administered: after a total eight monthly boluses, very satisfactory progression on the clinical and electrophysiological fronts was noted after 24 months. Childhood CIDP presents clinical, electrophysiological, progressive, and prognostic particularities, they recur readily and the outcome is good. Boluses of methylprednisolone are an alternative to the treatment of these neuropathies in childhood.


I-125 seeds brachytherapy with transcatheter arterial chemoembolization for subcapsular hepatocellular carcinoma.
I-125 seeds brachytherapy (ISB) has been used to improve the clinical effectiveness of transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). We aim to appraise the safety and clinical efficacy of combined ISB and TACE for the treatment of subcapsular HCC. A retrospective investigative study extending from January 2017 to December 2020, involved individuals suffering from subcapsular HCC, who were subjected to TACE treatment with or without ISB in our center. The clinical effectiveness was compared between 2 groups. Sixty-four patients, in total, with subcapsular HCC had to undergo TACE with (n = 32) or without (n = 32) ISB in our center. After CT-guided ISB, only 2 (6.3%) patients experienced a self-limited pneumothorax. Combined treatment resulted in a significantly higher complete response (56.3% vs. 18.8%, P = 0.002) and total response (90.7% vs. 59.4%, P = 0.004) rates than that of TACE alone. In comparison to the TACE alone group, the median progression-free survival was substantially longer in the combined treatment group (11 months vs. 5 months, P = 0.016). Further, 15 and 28 patients in combined and TACE alone groups respectively died within the follow-up. The median OS was comparable between combined and TACE alone groups (22 months vs. 18 months, P = 0.529). Combined TACE and ISB therapy is a safe treatment method for individuals suffering from subcapsular HCC. When compared, combined treatment had significantly enhanced clinical efficacy as a subcapsular HCC therapy, in comparison to TACE alone.


Outcome of Whole Exome Sequencing for Diagnostic Odyssey Cases of an Individualized Medicine Clinic: The Mayo Clinic Experience.
To describe the experience and outcome of performing whole-exome sequencing (WES) for resolution of patients on a diagnostic odyssey in the first 18 months of an individualized medicine clinic (IMC). The IMC offered WES to physicians of Mayo Clinic practice for patients with suspected genetic disease. DNA specimens of the proband and relatives were submitted to WES laboratories. We developed the Genomic Odyssey Board with multidisciplinary expertise to determine the appropriateness for IMC services, review WES reports, and make the final decision about whether the exome findings explain the disease. This study took place from September 30, 2012, to March 30, 2014. In the first 18 consecutive months, the IMC received 82 consultation requests for patients on a diagnostic odyssey. The Genomic Odyssey Board deferred 7 cases and approved 75 cases to proceed with WES. Seventy-one patients met with an IMC genomic counselor. Fifty-one patients submitted specimens for WES testing, and the results have been received for all. There were 15 cases in which a diagnosis was made on the basis of WES findings; thus, the positive diagnostic yield of this practice was 29%. The mean cost per patient for this service was approximately $8000. Medicaid supported 27% of the patients, and 38% of patients received complete or partial insurance coverage. The significant diagnostic yield, moderate cost, and notable health marketplace acceptance for WES compared with conventional genetic testing make the former method a rational diagnostic approach for patients on a diagnostic odyssey.


Nitrosation of sarcosine, proline and 4-hydroxyproline by exposure to nitrogen oxides.
The nitrosation of amino acids (sarcosine, proline and 4-hydroxyproline) was investigated in model experiments. The compounds were exposed in crystalline form and as aqueous solutions to defined concentrations of nitrogen oxides (in the range of 1-100 ppm) in the atmosphere of a reaction chamber. Nitrosated amino acids were analysed by GC/TEA after silylation. Generally the extent of nitrosation increased with NOx concentration, reaction time and air humidity. Nitrosation of aqueous amino acid solutions decreased markedly with increasing pH.


Pharmacological evaluation of Euphorbia hirta, Fagonia indica and Capparis decidua in hypertension through in-vivo and in vitro-assays.
This study determines the efficacy and probable underlying mode of action to the folk usage of Euphorbia hirta, Fagonia indica and Capparis decidua in hypertension. The aqueous-methanol extracts of E. hirta (EH.Cr), F. indica (FI.Cr) and C. decidua (CD.Cr) were tested for antihypertensive effects in rats using non-invasive and in-vasive blood pressure measuring apparatus. In-vitro assays were carried out using isolated rat aortae using PowerLab station. EH.Cr, FI.Cr and CD.Cr at 500 mg/kg (orally) caused a fall in the mean systolic blood pressure in arsenic-induced hypertensive and normotensive rats, similar to nifedipine. In rat aortae, EH.Cr, CD.Cr and FI.Cr reversed low (20 mM), high (80 mM) K+ and phenylephrine (P.E)-driven contractions, while F. indica partially inhibited high K+ contractions. In the presence of TEA, F. indica remained unable to relax low K+ contractions. EH.Cr and CD.Cr moved Ca++ concentrations response curves to the right, like nifedipine. All fractions of EH.Cr and CD.Cr except aqueous, pet-ether and chloroform fractions of FI.Cr displayed Ca++ antagonistic activity. FI.Cr, its ethyl acetate and aqueous fraction exhibited TEA-sensitive potassium channel activation. On baseline tension, test materials also produced phentolamine-sensitive vasospasm. E. hirta, F. indica and C. decidua possess antihypertensive activity in arsenic-induced hypertensive rats possibly mediated via endothelium-dependent vasorelaxation. In normotensive rats, E. hirta and C. decidua showed antihypertensive activities through endothelium-dependent and Ca++ antagonistic pathways, while F. indica exhibited potassium channel activation and Ca++ antagonistic like effects in its vasorelaxation. Additional weaker vasospastic effects were derived through α-adrenergic like pathways.


A complementary learning systems approach to temporal difference learning.
Complementary Learning Systems (CLS) theory suggests that the brain uses a 'neocortical' and a 'hippocampal' learning system to achieve complex behaviour. These two systems are complementary in that the 'neocortical' system relies on slow learning of distributed representations while the 'hippocampal' system relies on fast learning of pattern-separated representations. Both of these systems project to the striatum, which is a key neural structure in the brain's implementation of Reinforcement Learning (RL). Current deep RL approaches share similarities with a 'neocortical' system because they slowly learn distributed representations through backpropagation in Deep Neural Networks (DNNs). An ongoing criticism of such approaches is that they are data inefficient and lack flexibility. CLS theory suggests that the addition of a 'hippocampal' system could address these criticisms. In the present study we propose a novel algorithm known as Complementary Temporal Difference Learning (CTDL), which combines a DNN with a Self-Organizing Map (SOM) to obtain the benefits of both a 'neocortical' and a 'hippocampal' system. Key features of CTDL include the use of Temporal Difference (TD) error to update a SOM and the combination of a SOM and DNN to calculate action values. We evaluate CTDL on Grid World, Cart-Pole and Continuous Mountain Car tasks and show several benefits over the classic Deep Q-Network (DQN) approach. These results demonstrate (1) the utility of complementary learning systems for the evaluation of actions, (2) that the TD error signal is a useful form of communication between the two systems and (3) that our approach extends to both discrete and continuous state and action spaces.


Do religious beliefs influence the acceptance of xenotransplantation? Veterinary students.
Xenotransplantation could be a source of organs for transplantation given the global organ shortage. It is important to know the opinion and variables that influence the acceptance of xenotransplantation of the professionals who will work in the genetic manipulation, production, and care of animals to be used for this purpose. Analyze the influence of religious beliefs on the attitude toward xenotransplantation in veterinary students. The study population included 2683 veterinary students from different courses and Spanish Universities. Instrument evaluation included a validated self-administered and anonymously completed questionnaire (PCID-XENOTx-Ríos). The survey was self-administered and completed anonymously. Consent to collaborate in the study was requested. Variables for the study included attitude toward xenotransplantation and toward religion, considering the following options: practicing Catholic, nonpracticing Catholic, non-Catholic, and atheist/agnostic. Statistics were performed using descriptive analysis, Student t test, -X2, and Fisher's exact test. Of the total number of participants, 7 did not answer this question. Those in favor of xenotransplantation were 92.9% (n = 247) of practicing Catholics, 92.8% (n = 812) of nonpracticing Catholics, and 87.3% (n = 69) of those professing another non-Catholic religion compared with 93.5% (n = 1361) of those considering themselves agnostic/atheist (P = .037). Religion is an influential factor in attitudes toward organ xenotransplantation. Those who practice Catholicism and those who consider themselves agnostic/atheist are more accepting of organ procurement for transplantation than those who practice other religious doctrines.


The presence of corticotropin-releasing factor-like immunoreactive synaptic vesicles in axon terminals with nicotinic acetylcholine receptor-like immunoreactivity in the median eminence of the rat.
Whether or not corticotropin-releasing factor (CRF) containing synaptic vesicles are located in axon terminals with nicotinic acetylcholine receptor (nAChR) in the median eminence (ME) of the rat was examined by electron microscopic double-labeling immunocytochemistry combining the pre-embedding avidin-biotin-peroxidase complex (ABC) method for nAChR with the post-embedding immunogold staining method for CRF. nAChR-like immunoreactivity (nAChR-LI) was found in the cell membranes of the axon terminals in the ME. CRF-like immunoreactivity (CRF-LI) was found in dense granular vesicles (about 100 nm in diameter) in the axon terminals. Double-labeling method revealed that some of nAChR-LI axon terminals were found to contain CRF-LI dense granular vesicles. The results indicate that nicotine may act on nAChR in axon terminals to release CRF.


The effect of global SSTR5 gene ablation on the endocrine pancreas and glucose regulation in aging mice.
The purpose of this study was to examine the effect of global gene ablation of SSTR5 on the endocrine pancreas, insulin secretion, and glucose tolerance in aging mice, as SSTR5 is a primary regulator of insulin secretion in the mouse pancreas. Global SSTR5-/- mice were generated and genotypes were verified using Southern blot and RT-PCR. Glucose tolerance and in vivo insulin secretion in SSTR5-/- and WT mice were examined using intraperitoneal glucose tolerance test (IPGTT;1.2-2.0 mg/kg) at 3 and 12 months of age (n = 8 per group). Basal and glucose-stimulated insulin secretion in vitro was studied using the isolated perfused mouse pancreas model at 3 and 12 months. Pancreata were removed and levels of insulin, glucagon, somatostatin, and SSTR1 were studied using immunohistochemical analysis along with H&E staining of the pancreata. Genotyping verified the absence of SSTR5 in SSTR5-/- mice. IPGTT demonstrated that 3-month-old SSTR5-/- mice were glucose intolerant despite similar insulin secretion both in vivo and in vitro and enlarged islets. At 12 months of age, SSTR5-/- mice had basal hypoglycemia and improved glucose intolerance associated with hyperinsulinemia in vivo and in vitro and enlarged islets. SSTR5-/- mice had increased insulin clearance at 3 and 12 months of age. SSTR1 expression was significantly increased in islets at 3 months of age, but was nearly absent in islets at 12 months of age, as was somatostatin staining in SSTR5-/- mice. These results suggest that both SSTR5 and SSTR1 play a pivotal role in insulin secretion and glucose regulation in mice and that their regulatory effects are age-related.


Effect of verapamil on the transmural energy metabolism in the isoproterenol-induced myocardial lesion.
The effect of verapamil on the isoproterenol (ISO)-induced transmural metabolic lesion in the left ventricular wall was investigated in the rat heart. The treatment with ISO 2.5 mg/Kg s.c. on 2 consecutive days resulted in significant decreases of creatine phosphate in the subendocardium (ENDO) and of adenosine triphosphate in the ENDO and the subepicardium. On the other hand, inorganic phosphate (Pi) and lactate (LA) were increased in both layers. These changes were more prominent in the ENDO. Pretreatment with verapamil 25 mg/Kg s.c. prevented the reduction of high energy phosphate compounds and the increases of Pi and LA in both layers by ISO.


Predictors of Left Ventricular Outflow Tract Obstruction After Conventional Repair for Patients with Interrupted Aortic Arch or Coarctation of the Aorta, Combined with Ventricular Septal Defect: A Single-Center Experience.
Left ventricular outflow tract obstruction (LVOTO) affects survival and reoperation rates after surgical treatment of patients with interruption of the aortic arch (IAA) or coarctation of the aorta (CoA) with ventricular septal defect (VSD). The aim of the study was to determine predictors of LVOTO and to evaluate the relationship between aortic valve (AoV) morphology and the re-intervention rate. Retrospective review of patients, who underwent a conventional repair for IAA/CoA with VSD at a tertiary referral center between 1996 and 2017. The preoperative demographic data as well as pre- and post-operative echocardiographic parameters and re-interventions were reviewed. In the median follow-up of 8.3 years (range of 6.15-10.27) 5 patients (11.9%) from a total of 47 patients included in the study presented with a significant LVOTO. Four of them required reoperation after median period of 2.3 years (range of 0.3-7.9) after the initial surgery. Multivariable logistic regression identified AoV z-score (OR 0.44, p = 0.017) as predictor of LVOTO. The mean AoV z-score before the primary repair was significantly smaller in those with LVOTO as compared to those with unobstructed flow from the LV (- 3.58 ± 1.96 vs. - 1.44 ± 1.55; p = 0.0016). At 1-year follow-up, both groups showed an increase in the AoV z-score (p = 0.98). The re-intervention rate after primary repair (both surgical procedures and percutaneous interventions), either for LVOTO or reCoA, was higher in patients with AoV z-score ≤ - 3 (p = 0.007 vs. p = 0.46) and those, whose aortic annulus was less or equal than patient's weight (kg) + 1.5 mm as compared to those with larger aortic annulus (p = 0.03 vs. p = 0.16). In patients after surgical treatment of IAA/CoA with VSD, the AoV z-score at diagnosis is a significant risk factor for reoperation for LVOTO. With age, AoV growth and z-score improvement is expected. Small AoV at diagnosis is correlated with increased rate of re-intervention for LVOTO and reCoA.


Use of the tracheostoma valve in the marking of contrastive stress and sentence intonation.
Two proficient tracheoesophageal speakers experienced in use of the tracheostoma valve (TSV) produced a total of 64 examples of "Bev loves Bob." These productions varied with location of contrastive stress, type of sentence intonation, and use of TSV. Thirty-four listeners judged the utterances in terms of stress placement and intonation contour simultaneously. An analysis of variance of the perceptual results indicated that TSV use reduced speaker ability to signal the two suprasegmental features; however, locus of the suprasegmental features, particularly stress placement, appeared to exert a stronger effect.


Computational guided identification of a citrus flavonoid as potential inhibitor of SARS-CoV-2 main protease.
Although vaccine development is being undertaken at a breakneck speed, there is currently no effective antiviral drug for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19. Therefore, the present study aims to explore the possibilities offered by naturally available and abundant flavonoid compounds, as a prospective antiviral drug to combat the virus. A library of 44 citrus flavonoids was screened against the highly conserved Main Protease (Mpro) of SARS-CoV-2 using molecular docking. The compounds which showed better CDocker energy than the co-crystal inhibitor of Mpro were further revalidated by flexible docking within the active site; followed by assessment of drug likeness and toxicity parameters. The non-toxic compounds were further subjected to molecular dynamics simulation and predicted activity (IC50) using 3D-QSAR analysis. Subsequently, hydrogen bonds and dehydration analysis of the best compound were performed to assess the binding affinity to Mpro. It was observed that out of the 44 citrus flavonoids, five compounds showed lower binding energy with Mpro than the co-crystal ligand. Moreover, these compounds also formed H-bonds with two important catalytic residues His41 and Cys145 of the active sites of Mpro. Three compounds which passed the drug likeness filter showed stable conformation during MD simulations. Among these, the lowest predicted IC50 value was observed for Taxifolin. Therefore, this study suggests that Taxifolin, could be a potential inhibitor against SARS-CoV-2 main protease and can be further analysed by in vitro and in vivo experiments for management of the ongoing pandemic.


Surgical treatment of the celiac axis compression syndrome.
Six patients with symptomatic celiac axis compression syndrome are reported on. Four were treated surgically with arterial reconstruction. None of these four patients was benefited more than temporarily by the corrective surgery. One patient had an abdominal exploration and highly selective vagotomy unrelated to the celiac axis and is symptom-free ten months after surgery. One patient had no surgery and remains symptomatic. Angiographic evaluation in all patients demonstrated that despite high grade stenosis of the celiac axis, there was no radiographically discernible reduction in constrast flow to the celiac axis because of well developed collaterals from the superior mesenteric artery. These results indicate that compression of the celiac axis may be merely an incidental angiographic finding, so this syndrome needs cautious evaluation.


Tebentafusp, A TCR/Anti-CD3 Bispecific Fusion Protein Targeting gp100, Potently Activated Antitumor Immune Responses in Patients with Metastatic Melanoma.
Tebentafusp is a first-in-class bispecific fusion protein designed to target gp100 (a melanoma-associated antigen) through a high affinity T-cell receptor (TCR) binding domain and an anti-CD3 T-cell engaging domain, which redirects T cells to kill gp100-expressing tumor cells. Here, we report a multicenter phase I/II trial of tebentafusp in metastatic melanoma (NCT01211262) focusing on the mechanism of action of tebentafusp. Eighty-four patients with advanced melanoma received tebentafusp. Treatment efficacy, treatment-related adverse events, and biomarker assessments were performed for blood-derived and tumor biopsy samples obtained at baseline and on-treatment. Tebentafusp was generally well-tolerated and active in both patients with metastatic uveal melanoma and patients with metastatic cutaneous melanoma. A 1-year overall survival rate of 65% was achieved for both patient cohorts. On-treatment cytokine measurements were consistent with the induction of IFNγ pathway-related markers in the periphery and tumor. Notably, tebentafusp induced an increase in serum CXCL10 (a T-cell attractant) and a reduction in circulating CXCR3+ CD8+ T cells together with an increase in cytotoxic T cells in the tumor microenvironment. Furthermore, increased serum CXCL10 or the appearance of rash (likely due to cytotoxic T cells targeting gp100-expressing skin melanocytes) showed a positive association with patient survival. These data suggest that redirecting T cells using a gp100-targeting TCR/anti-CD3 bispecific fusion protein may provide benefit to patients with metastatic melanoma. Furthermore, the activity observed in these two molecularly disparate melanoma classes hints at the broad therapeutic potential of tebentafusp.


Systematic review and meta-analysis of open surgical and endovascular management of thoracic outlet vascular injuries.
Junctional vascular trauma such as that at the thoracic outlet poses particular challenges in surgical management. The use of endovascular techniques for such injuries is attractive as repair may be facilitated without the need for thoracotomy; however, the utility of such techniques is currently based on opinion, small retrospective series, and literature reviews of narrative and not systematic quality. The objective of this study is to provide a complete and systematic analysis of the literature pertaining to open surgery (OS) and endovascular management (EM) of thoracic outlet vascular injuries. An electronic search using the MEDLINE, Embase, Cochrane Library, Science Citation Index, and LILACS databases was performed for articles published from 1947 to November 2011. The review conformed to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement standards. Prospective studies and retrospective cohorts of more than 10 patients were included. The primary outcome was all-cause mortality. One prospective noncomparative study and 73 retrospective series met the inclusion criteria. There were no randomized studies. All studies were at high risk of bias. Fifteen studies described outcomes for both OS and EM (549 patients). The majority of these studies described EM for traumatic arteriovenous fistulas or false aneurysms in stable patients. Direct comparison between OS and EM was possible in only three studies (comprising 23 OS and 25 EM patients), which showed no difference in all-cause mortality (odds ratio, 0.67; 95% confidence interval [CI], 0.11-4.05), but a shorter operating time with EM (mean difference = 58.34 minutes; 95% CI, 17.82-98.85). These three series included successful EM of unstable patients and those with vessel transection. There were 55 studies describing only OS (2057 patients) with a pooled mortality rate of 12.4% (95% CI, 9.9%-15.2%). Four studies described only EM (101 patients) with a pooled mortality rate of 26% (95% CI, 8%-51%), but these represented a distinct subgroup of cases (mainly iatrogenic injuries in older patients). The current evidence is weak and fails to show superiority of one modality over the other. EM is currently used primarily in highly selected cases, but there are reports of a broader applicability in trauma. High-quality randomized studies or large-scale registry data are needed to further comment on the relative merits or disadvantages of EM in comparison to OS.


Kinetics of heterogeneous photocatalytic degradation of reactive dyes in an immobilized TiO2 photocatalytic reactor.
The photocatalytic degradation of two reactive dyes has been investigated by UV/TiO2/H2O2 using an immobilized TiO2 photocatalytic reactor. Reactive Blue 8 (RB 8) and Reactive Blue 220 (RB 220) textile dyes were used as model compounds. Photocatalytic degradation processes were performed using a 5-L solution containing dyes. The initial concentrations of dyes were 50 mg/L. The radiation source was two 15 W UV-C lamps. A batch mode immersion photocatalytic reactor was utilized. UV-vis and ion chromatography (IC) analyses were employed to obtain the details of the photodegradation of the selected dyes. Colored synthetic waters were completely decolorized in relatively short time after UV irradiation in the presence of various concentrations of hydrogen peroxide. Formate, acetate, oxalate, and glyoxylate anions were detected as dominant aliphatic intermediates where they were further oxidized slowly to CO2. The UV/TiO2/H2O2 process was able to oxidize the dyes with partial mineralization of carbon, nitrogen, and sulfur heteroatoms into CO2, NO3-, and SO4(2-), respectively. Kinetics analysis indicates that the photocatalytic decolorization rates of the dye can be approximated by a pseudo-first-order model. The UV/TiO2/H2O2 process proved to be capable of decolorization and mineralization of the reactive dyes (RB 8 and RB 220).


Nonlinear examination of the 'Heat Wave' and 'Meteor Shower' effects between spot and futures markets of the precious metals.
This paper researches two volatility transmission phenomena that take place within ('heat wave') and between ('meteor shower') spot and futures markets of four precious metals-gold, silver, platinum and palladium. We create conditional volatilities by considering three types of Markov switching GARCH models in combination with three different distribution functions. Conditional volatilities are subsequently embedded in Markov switching mean model. We find that 'heat wave' effect is more intense than 'meteor shower' effect, and this applies for both spot and futures markets of all precious metals. The results indicate that 'heat wave' effect is more intense in high than in low volatility periods, and also this effect is stronger in futures markets than in spot markets. 'Meteor shower' effect is stronger in low volatility regime than in high volatility regime, which is particularly true for the futures markets. Rolling regression results are in line with switching parameters. In addition, we find that 'meteor shower' effect, from futures to spot market, is stronger when short-term futures are analysed vis-à-vis long-term futures.


Changes in VIP-, SP- and CGRP- like immunoreactivity in intramural neurons within the pig stomach following supplementation with low and high doses of acrylamide.
Acrylamide is one of the food toxins to which the human body is exposed. Although researchers' interest in acrylamide has been growing in recent years, the knowledge of its effect on the gastrointestinal tract, especially on intramural neurons which form the enteric nervous system is scarce. The aim of this experiment was to determine the influence of acrylamide, administered at doses equivalent to the human tolerable daily intake (TDI, 0.5 μg/kg b.w./day) and ten times higher than the TDI (5 μg/kg b.w./day), on the distribution of vasoactive intestinal peptide (VIP), substance P (SP), and calcitonin gene related peptide (CGRP) in intramural neurons of the domestic pig stomach. Using double immunofluorescent labelling we revealed that the ENS neurons underwent adaptive changes in response to the supplementation of acrylamide, which manifested themselves as increased expression of VIP, SP and CGRP, both in intramural neurons and by an increase in the nerve density in submucous and muscular layers in the porcine stomach. These substances take part in defensive reactions of neurons and transmission of sensory reactions may play an important role in protecting the stomach against the harmful effect of acrylamide. Moreover, it has been shown that acrylamide induces a significant response of ENS neurons even in TDI dose, which suggests that it is not neutral to the body. These findings may be the basis for further toxicological studies addressing the question if currently permitted minimal content of acrylamide in the food does jeopardize the health of human consumers?


Structural characteristics of the brain reward circuit regions in patients with bipolar I disorder: A voxel-based morphometric study.
Bipolar I disorder (BD-I) is often misdiagnosed, leading to inadequate treatment and significant disability along with reduced quality of life. Recent neural models suggest that the reward circuitry is affected in bipolar disorder. The purpose of the present study was to identify structural abnormalities in the brain reward-processing neural circuitry among patients with BD-I. 21 patients with BD-I and 21 healthy controls (HC) participated in this study. Structural magnetic resonance imaging was performed. Region-of-interest (ROI) voxel-based morphometry analysis was applied to assess the presence of structural changes between the BD-I patient group and the control group. The results of the reward circuitry ROI analysis revealed lower gray matter volumes in the left ventromedial prefrontal cortex (VMPFC), left dorsomedial prefrontal cortex (DMPFC), and left ventrolateral prefrontal cortex (VLPFC) in patients with BD-I compared to HC. Our results suggest that abnormalities in the brain reward-processing neural circuitry, especially those in the left VMPFC, left DMPFC, and left VLPFC, may play an important role in the pathophysiology of BD-I.


Cobalt and corrinoid transport and biochemistry.
In this chapter, we focus on the biochemistry of non-corrin cobalt and on a subset of corrinoid-containing enzymes. We review the import of cobalt in prokaryotes and discuss two members of the non-corrin cobalt-dependent enzymes, nitrile hydratase and methionine aminopeptidase. Cobalt is best known for its central role in alkylcorrinoid cofactors, where the unique properties of the cobalt-carbon bond are exploited to catalyze chemically challenging biotransformations. We discuss the import of corrinoids and the reactions catalyzed by the acyl-CoA mutases, the -fastest-growing subfamily of adenosylcobalamin (AdoCbl)-dependent enzymes. AdoCbl is used as a radical reservoir to catalyze 1,2 rearrangement reactions. The loading of AdoCbl-dependent enzymes with the correct cofactor form is critically important for their functions and is gated by chaperones that use the chemical energy of GTP hydrolysis to ensure the fidelity of the process. Recent insights into the organization and editing functions of G-protein chaperones in the context of AdoCbl-dependent enzymes that they support, are discussed.


Antinociceptive and anti-inflammatory effects of Croton malambo bark aqueous extract.
Croton malambo (K.) bark aqueous extract, popularly known in Venezuela as "palomatias" or "torco" was tested for acute toxicity and for its anti-inflammatory and antinociceptive effects using tail flick and writhing syndrome tests models, respectively. Croton malambo aqueous extract (6.15 mg/kg i.p.) administered intraperitoneally had a significant antinociceptive and anti-inflammatory effects compared to acetylsalicylic acid (200mg/kg p.o.) and sodium diclofenac (5.64 mg/kg p.o.). Studies to determine correlation between chemical composition and pharmacological activity are underway.


[Bacterial resistance to antibiotics, an exemplary model of directed molecular evolution].
The simplest conceivable event that can occur at the gene level can result in the development of efficacious resistance tot antibiotics. The bacterial world behaves as an enormous organism whose cells can exchange their genes very easily. Accordingly, opportunities for the exchange of genetic material in nature are probably unlimited. This knowledge cannot be ignored. It leads to the important conclusion that the antibiotics are societal drugs. A resistance gene which has appeared somewhere in the world can travel far and fast.


A modification of primary closure for the treatment of pilonidal disease in day-care setting.
The best surgical technique for treating sacrococcygeal pilonidal disease (PD) is still controversial. We evaluated the outcome of a modified primary closure for the treatment of pilonidal sinus. One hundred and fifty-two consecutive patients with PD, who underwent excision and primary closure under local anaesthesia according to our method, participated in this prospective study. The duration of operation and of hospitalization, postoperative pain, time to first mobilization, postoperative complications, time to resumption of work were assessed. The median operative time was 30 min (range: 15-40); the median postoperative pain visual analogue scale score was 1 (range 0-3). All patients were mobilized between 2 and 4 h after surgery and discharged within 10 h. Postoperative complications included eight small debridements of an infected wound (5.3%) and one case of wound dehiscence (0.6%). No recurrence was detected during a median follow-up of 22 months (range: 10-34 months). The low complication rate, near total absence of wound dehiscence, the compliance of the patients, the type of anaesthesia and the patient satisfaction makes this method effective. A randomized trial with long-term follow-up is warranted.


Nickel Retention on Callovo-Oxfordian Clay: Applicability of Existing Adsorption Models for Dilute Systems to Real Compact Rock.
In a waste management context, predicting the mobility of contaminants is essential. A key issue entails assessing the applicability of current knowledge on adsorption processes to natural systems. Such is the focus herein for nickel in interaction with Callovo-Oxfordian (COx) clay rock, a formation selected in France for possible radioactive waste disposal. The challenge is to link predictive modeling results with the experimental data characterizing the behavior of the labile and naturally occurring Ni fraction by implementing a new simple method. Retention studies on compact systems serve to complete this work. Combined electron microprobe and laser ablation high-resolution inductively coupled plasma mass spectrometry data show that natural Ni (∼39 mg kg-1) is homogeneously distributed within the clay matrix, which corresponds to the main reservoir (∼70%). Data interpretation of desorption tests yields an in situ Kd value of ∼80 L kg-1 and a labile Ni amount of ∼5 mg kg-1, that is, ∼13% of the Ni inventory. Predictive modeling explains the sorption data in considering that only weak clay fraction sites take part in the adsorption. The role of the clay matrix in Ni retention is confirmed by analyzing the Ni-spiked compact COx samples, whereby an increase of the Ni content in the clay fraction is observed following the retention experiment.


Peroxyoxalate High-Energy Intermediate is Efficiently Decomposed by the Catalyst Imidazole.
The peroxyoxalate reaction is a highly efficient chemiluminescence system, its chemiexcitation process involving the intermolecular interaction between an activator (ACT) and the high-energy intermediate (HEI) of the reaction. Typically, the HEI is generated through the reaction of an oxalate ester with H2 O2 , in the presence of a basic/nucleophilic catalyst, such as imidazole (IMI-H). IMI-H, besides catalyzing the formation of the HEI, is also known to decompose this peroxidic intermediate. Despite that, up to now, no rate constant value has been determined for such significant interaction. Through kinetic measurements, we have observed that IMI-H is roughly four times more efficient than 9,10-diphenylanthracene (DPA), a classic ACT, in catalyzing the decomposition of the HEI by a bimolecular electron transfer reaction through a Chemically Initiated Electron Exchange Luminescence-like process. For instance, when IMI-H and DPA are at the same concentration, 78% of the generated HEI is actually consumed by the nonemissive bimolecular interaction with IMI-H. We have obtained an average singlet excited state formation quantum yield, at infinite ACT concentration, of (5.5 ± 0.5) × 10(-2) E mol(-1) , determined at five different IMI-H concentrations. This ultimately suggests that the yield of formation of HEI actually does not depend on the IMI-H concentration.