Association between enterovirus endomyocardial infection and late severe cardiac events in some adult patients receiving heart transplants.
Enteroviruses and other cardiotropic viruses have been associated with the development of late severe adverse cardiac events in infants receiving heart transplants. However, the source and the chronology of cardiac allograft infection by an enterovirus in patients receiving heart transplants remain unknown. Using RT-PCR and immunohistochemistry assays, endomyocardial tissue samples of 30 adult patients were tested to detect the presence of specific enterovirus 5' non-coding (5'NC) sequences and of VP1 capsid protein, and this at the time of cardiac transplantation and at the 12-month biopsy for graft rejection control. Moreover, the endomyocardial detection of genomic sequences of enteroviruses, Epstein-Barr virus, herpes simplex virus, cytomegalovirus (CMV), varicella-zoster virus, adenoviruses, and parvovirus B19 was carried out by RT-PCR and polymerase chain reaction (PCR) assays at the time of late severe cardiac events. Enterovirus RNA and VP1 antigen were both detected in 4 (13%) of 30 patients at the time of the 12-month biopsy for graft rejection control, whereas no enterovirus component was detected in the explanted and implanted heart tissues taken from these 4 patients at the time of transplantation. At the time when severe cardiac events were developed, within 3 months after the positive enterovirus cardiac detection, these four patients demonstrated the presence of endomyocardial enterovirus RNA sequences whereas they were tested negative for the endomyocardial detection of genomic sequences from DNA viruses (except for CMV in two cases), and for a significant level of pp65 CMV antigenemia. Taken together, these findings indicate that enteroviruses could be acquired as a new endomyocardial infection within 12 months after transplantation in adults receiving heart transplants, and suggest that this infection might be an etiological cause for unexplained late severe adverse cardiac events in the heart-transplantated adults.


Curcumin suppresses interleukin 1beta-mediated microsomal prostaglandin E synthase 1 by altering early growth response gene 1 and other signaling pathways.
Curcumin (diferuloylmethane) is one of the phytophenolic compounds found in the turmeric plant with anti-inflammatory and anticarcinogenic activities. One possible mechanism for these activities is the inhibition of prostaglandin (PG) E(2) formation. In this study and other reports, curcumin suppresses interleukin-1beta-induced formation of prostaglandin E(2) in a concentration-dependent manner. Interleukin-1beta-induced microsomal prostaglandin E synthase 1 (mPGES-1) and cyclooxygenase-2 were attenuated by curcumin at the protein and mRNA levels, but a more dramatic inhibition of mPGES-1 expression was observed at lower concentrations of curcumin in A549 human lung epithelial cells. The inhibition of mPGES-1 expression by curcumin shifted the arachidonic acid profile from PGE(2) to PGF(2alpha) and 6-keto-PGF(1alpha) as major metabolites. The expression of early growth response gene 1 (EGR-1), a key transcription factor of cytokine-induced mPGES-1, was inhibited by curcumin. Incubation with siRNA for EGR-1 inhibited interleukin (IL)-1beta-induced mPGES-1, and the controlled expression of EGR-1 increased the mPGES-1 expression. Several proinflammatory signaling molecules, such as nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinases, are also known to affect curcumin-regulated gene expression. Curcumin inhibited IkappaBalpha phosphorylation and degradation and thus reduced the expression of mPGES-1. Curcumin suppressed cytokine-induced mPGES-1 by inhibiting phosphorylation of Jun N-terminal kinase (JNK)1/2. However, EGR-1 expression was suppressed by lower concentrations of curcumin, as compared with JNK1/2 and IkappaBalpha. These results indicate that curcumin inhibits IL-1beta-induced PGE(2) formation by inhibiting the expression of mPGES-1 that is mediated by suppression of EGR-1 expression as well as NF-kappaB and JNK1/2.


NMPylation and de-NMPylation of SARS-CoV-2 nsp9 by the NiRAN domain.
The catalytic subunit of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) contains two active sites that catalyze nucleotidyl-monophosphate transfer (NMPylation). Mechanistic studies and drug discovery have focused on RNA synthesis by the highly conserved RdRp. The second active site, which resides in a Nidovirus RdRp-Associated Nucleotidyl transferase (NiRAN) domain, is poorly characterized, but both catalytic reactions are essential for viral replication. One study showed that NiRAN transfers NMP to the first residue of RNA-binding protein nsp9; another reported a structure of nsp9 containing two additional N-terminal residues bound to the NiRAN active site but observed NMP transfer to RNA instead. We show that SARS-CoV-2 RdRp NMPylates the native but not the extended nsp9. Substitutions of the invariant NiRAN residues abolish NMPylation, whereas substitution of a catalytic RdRp Asp residue does not. NMPylation can utilize diverse nucleotide triphosphates, including remdesivir triphosphate, is reversible in the presence of pyrophosphate, and is inhibited by nucleotide analogs and bisphosphonates, suggesting a path for rational design of NiRAN inhibitors. We reconcile these and existing findings using a new model in which nsp9 remodels both active sites to alternately support initiation of RNA synthesis by RdRp or subsequent capping of the product RNA by the NiRAN domain.


"… I would have left that man long time ago but, …" exploring circumstances of and motivators for repeat adolescent birth in Eastern Uganda.
First birth before 18 years has declined in Uganda unlike repeat adolescent birth (=second or more births before age 20 years). We explored the circumstances of and motivators for repeat adolescent birth in Eastern Uganda. Between January and March 2020, we conducted a qualitative study involving 70 individual in-depth interviews with purposively selected respondents - 20-25-year-old women with and without repeat adolescent birth, their partners, and parents, in the communities of Teso sub-region. We conducted latent content analysis. Four major themes emerged: poverty, vulnerability, domestic violence, and demotivators. Sub-themes identified under poverty were: "limited provisions", "peasantry", "large families", "dropping out of school", "alcohol abuse", and "broken family structure". Vulnerability included "marital entrapment" and "partner coercion". Demotivators included: "abandonment", "stern warning", "objection to marriage", and "empowerment". Extreme poverty resulted in inadequate provision of basic needs leading to unprotected sexual activity in a bid to secure financial support. Following the first birth, more than three quarters of the women with repeat adolescent birth reported increased economic distress that forced them to remain in unwanted marriage/union, often characterized by partner coercion, despite wanting to delay that repeat birth. Women without repeat adolescent birth avoided a second birth by empowerment through: an economic activity, contraception use, and resumption of schooling. Repeat adolescent birth in Uganda is premised around attempts to address the economic distress precipitated by first birth. Many women want to delay that repeat birth but the challenges robbed them of their reproductive autonomy. Beyond efforts to prevent first birth, programs need to address economic empowerment, ensure contraceptive access, and school re-integration for adolescent mothers in order to prevent shortly-spaced repeat births.


The rationale and design of the FORomegaARD Trial: A randomized, double-blind, placebo-controlled, independent study to test the efficacy of n-3 PUFA for the maintenance of normal sinus rhythm in patients with previous atrial fibrillation.
Atrial fibrillation (AF) is associated with increased risk of death, thromboembolic complications, and a lowered quality of life. Despite this burden, pharmacologic agents for prevention of AF in patients who achieved normal sinus rhythm are of limited utility, mostly because of serious and frequent side effects. Thus, the availability of safer and more effective drugs may reduce the burden of disease. Patients aged > or =21 years with previous symptomatic AF and who have recovered normal sinus rhythm will be randomized to 1 g daily of omega-3-acid ethyl esters or identical placebo. To be included in the trial, patients must have either (a) at least 2 symptomatic episodes of documented AF in the 6 months before randomization, with the last episode occurring in the 14 to 90 days before randomization (paroxysmal AF), or (b) successful electrical or pharmacologic cardioversion for persistent AF. Ethical committees of 71 cardiology centers in 16 provinces of Argentina have qualified and approved the protocol and are expected to enroll 1,400 patients to test the primary end point of efficacy, which is survival free of AF during follow-up. The Fish Oil Reserach with omega-3 for Atrial fibrillation Recurrence Delay (FORomegaARD) trial will determine whether pharmacologic supplementation with 1 g of omega-3-acid ethyl esters can reduce AF recurrence in patients with previous AF who have recovered normal sinus rhythm.


Abdominal vagus nerve stimulation as a new therapeutic approach to prevent postoperative ileus.
Electrical stimulation of the cervical vagus nerve (VNS) prevents postoperative ileus (POI) in mice. As this approach requires an additional cervical procedure, we explored the possibility of peroperative abdominal VNS in mice and human. The effect of cervical and abdominal VNS was studied in a murine model of POI and lipopolysaccharide (LPS)-induced sepsis. Postoperative ileus was quantified by assessment of intestinal transit of fluorescent dextran expressed as geometric center (GC). Next, the effect of cervical and abdominal VNS on heart rate was determined in eight Landrace pigs to select the optimal electrode for VNS in human. Finally, the effect of sham or abdominal VNS on LPS-induced cytokine production of whole blood was studied in patients undergoing colorectal surgery. Similar to cervical VNS, abdominal VNS significantly decreased LPS-induced serum tumor necrosis factor-α (TNFα) levels (abdominal VNS: 366±33 pg/mL vs sham: 822±105 pg/mL; P<.01). In line, in a murine model of POI, abdominal VNS significantly improved intestinal transit (GC: sham 5.1±0.2 vs abdominal VNS: 7.8±0.6; P<.01) and reduced intestinal inflammation (abdominal VNS: 35±7 vs sham: 80±8 myeloperoxidase positive cells/field; P<.05). In pigs, heart rate was reduced by cervical VNS but not by abdominal VNS. In humans, abdominal VNS significantly reduced LPS-induced IL8 and IL6 production by whole blood. Abdominal VNS is feasible and safe in humans and has anti-inflammatory properties. As abdominal VNS improves POI similar to cervical VNS in mice, our data indicate that peroperative abdominal VNS may represent a novel approach to shorten POI in man.


Neurons assemble acetylcholine receptors with as many as three kinds of subunits while maintaining subunit segregation among receptor subtypes.
A family of genes encoding neuronal acetylcholine receptor (AChR) subunits has been identified and cloned from vertebrates. Expression studies have implied that as few as one or two kinds of subunits may be sufficient to construct neuronal AChRs and that multiple pair-wise combinations of the gene products are capable of generating functional receptors. We show here that a class of AChRs with a predominantly synaptic location on neurons contains receptors having at least three types of subunits and that the subunits are encoded by the alpha 3, beta 4, and alpha 5 AChR genes. In addition, we show that a class of extrasynaptic AChRs on the same neurons contains the alpha 7 subunits but lacks the alpha 3, beta 4, and alpha 5 subunits. The results demonstrate that native AChRs on neurons are more complex in composition than previously appreciated and suggest that constraints on subunit interactions limit the kinds of receptor species produced.


Stroke prevention in atrial fibrillation: current status and near-future directions.
Prevention of atrial fibrillation-related stroke is an important part of atrial fibrillation management. However, stroke risk is not homogeneous and varies with associated morbidities and risk factors. Risk stratification schemes have been developed that categorize patients' stroke risk into classes based on a combination of risk factors. According to the calculated level of risk, guidelines recommend patients with atrial fibrillation receive antithrombotic therapy either as a vitamin K antagonist or aspirin. Despite recommendations, however, many patients with atrial fibrillation do not receive adequate thromboprophylaxis. We will discuss some of the underlying reasons, in part related to the drawbacks associated with vitamin K antagonists. These highlight the need for new anticoagulants in atrial fibrillation. The novel oral anticoagulants in development may overcome some of the limitations of vitamin K antagonists and address their underuse and safety concerns.


Complexities in the treatment of coinfection with HIV, hepatitis B, hepatitis C, and tuberculosis.
HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) are commonly encountered blood-borne infectious microorganisms. Infection with these viruses typically requires long-lasting drug therapy. Coinfections, especially with tuberculosis, pose a challenge to the creation of a regimen with adequate efficacy and minimal drug-drug interactions and adverse effects. We present the case of a young man with a history of intravenous drug misuse who was diagnosed with disseminated tuberculosis and with a triple infection with HBV, HCV, and HIV. The treatment for tuberculosis was initiated first, followed 2 months later by antiretrovirals that were effective against both HIV and HBV. After 9 months of antitubercular therapy, HCV was successfully treated with 12 weeks of oral direct-acting antivirals. We describe the challenges faced in formulating a therapeutic plan for such patients and discuss the various drug interactions that can arise between antitubercular drugs, antiretrovirals, anti-HBV drugs, and direct-acting antivirals against HCV.


Review primary and secondary metabolites in phloem sap collected with aphid stylectomy.
Phloem plays a central role in assimilate transport as well as in the transport of several secondary compounds. In order to study the chemical composition of phloem sap, different methods have been used for its collection, including stem incisions, EDTA-facilitated exudation or aphid stylectomy. Each collection method has several advantages and disadvantages and, unfortunately, the reported metabolite profiles and concentrations depend on the method used for exudate collection. This review therefore primarily focusses on sugars, amino acids, inorganic ions and further transported compounds like organic acids, nucleotides, phytohormons, defense signals, and lipophilic substances in the phloem sap obtained by aphid stylectomy to facilitate comparability of the data.


Primary angioplasty of unprotected left main coronary artery for acute anterolateral myocardial infarction.
Mortality of acute unprotected left main coronary artery (LMCA) occlusion is very high. The objectives of this analysis were to determine the effect of primary angioplasty and the impact of cardiogenic shock on unprotected LMCA occlusion-induced acute anterolateral myocardial infarction (AAMI). Of 1,736 consecutive patients with acute myocardial infarction (AMI), 38 (2.2%) had LMCA occlusion-induced AAMI with Thrombolysis in Myocardial Infarction (TIMI) flow less than or equal to 2. All were given primary angioplasty. Of these 38 patients, 17 (45%) were discharged, and 21 (55%) died in-hospital. Cardiogenic shock was overt in 28 patients; 47.1% of the survival group and 95.2% of the mortality group (p=0.0008). On arrival, the survival-group had higher pH (7.40+/-0.10 vs. 7.30+/-0.14; p=0.013) and base excess (-4.5+/-3.9 vs. -10.4+/-6.0 mEq/L; p=0.0013). In the survival group reperfusion was successful in 100% of patients, as opposed to 57.1% in the mortality group (p=0.0020), and the incident of stenting was not different between the two groups (64.7% vs. 71.4%, p=0.66). Shock patients had lower successful angioplasty rate (67.9% vs. 100%, p=0.040), higher in-hospital mortality (71.4% vs. 10.0%, p=0.0008), and higher 1-year mortality rates (p=0.0064), than stable patients. All shock patients with failed angioplasty died, but the mortality rate was 57.9% (p=0.021) when angioplasty was successful. Patients presenting with AAMI, LMCA occlusion, and cardiogenic shock have poor survival regardless of primary angioplasty in conjunction with coronary stents. Nevertheless, primary angioplasty is a feasible and effective procedure, and it may save lives in this clinical setting.


In vitro and in vivo study on angiogenesis of porcine induced pluripotent stem cell-derived endothelial cells.
Pluripotent stem cells (PSCs) are a promising source of endothelial cells (ECs) for the treatment of cardiovascular diseases. Since clinical application of embryo stem cells (ESCs) involves issues of medical ethics and risk of immune rejection, induced pluripotent stem cells (iPSCs) will facilitate cell transplantation therapy for the cardiovascular diseases. Swine is identified as an ideal large-animal model for human, because of its similar organ size and physiological characteristics. However, there are very few studies on EC differentiation of porcine iPSCs (piPSCs). In recent study, we provided an efficient protocol to differentiate piPSCs into ECs with the purity of 19.76% CD31 positive cells within 16 days. Passaging of these cells yielded a nearly pure population, which also expressed other endothelial markers such as CD144, eNOS and vWF. Besides, these cells exhibited functions of ECs such as uptake of low-density lipoprotein and formation of tubes in vitro or blood vessels in vivo. Our study successfully obtained ECs from piPSCs via a feeder- and serum-free monolayer system and demonstrated their angiogenic function in vivo and in vitro. piPSC-ECs derivation is not only potential for the autologous cell transplantation and cardiovascular drug screening, but also for the mechanistic studies on EC differentiation and endothelial dysfunction.


The Selective NLRP3-Inflammasome Inhibitor CY-09 Ameliorates Kidney Injury in Diabetic Nephropathy by Inhibiting NLRP3- inflammasome Activation.
Diabetic nephropathy (DN) is one of the most serious complications of diabetes mellitus and the main cause of the end-stage renal disease (ESRD). Activation of the NLRP3 inflammasome has been proven to play an important role in the development of DN. Thus, specific and direct targets of NLRP3 inflammasome assembly may have therapeutic potential. CY-09 is a new NLRP3 inflammasome specific inhibitor that has been shown to protect against non-alcoholic fatty liver disease (NAFLD) by inhibiting the activation of the NLRP3 inflammasome. However, its role in kidney disease, especially DN, has not been reported. In this study, we used HE staining to assess renal pathological damage in each group, and RT-PCR, immunofluorescence and WB were performed to detect the expression changes in inflammatory and fibrosis proteins. The apoptosis level was detected by TUNEL staining. Here, we showed increased inflammation, oxidative stress, apoptosis and fibrosis in db/db mice, while CY-09 exerted renoprotection by inhibiting NLRP3 inflammasome activation. In vitro, CY-09 also inhibited NLRP3 and reduced caspase-1, IL-18, IL-1β and apoptosis in a dose-dependent manner. CY-09 effectively protects the kidney from hyperglycemia induced damage by inhibiting the NLRP3 inflammasome and may be a promising therapeutic strategy to prevent the progression of DKD.


Photoswitchable Nitrogen Superbases: Using Light for Reversible Carbon Dioxide Capture.
Using light as an external stimulus to alter the reactivity of Lewis bases is an intriguing tool for controlling chemical reactions. Reversible photoreactions associated with pronounced reactivity changes are particularly valuable in this regard. We herein report the first photoswitchable nitrogen superbases based on guanidines equipped with a photochromic dithienylethene unit. The resulting N-heterocyclic imines (NHIs) undergo reversible, near quantitative electrocyclic isomerization upon successive exposure to UV and visible irradiation, as demonstrated over multiple cycles. Switching between the ring-opened and ring-closed states is accompanied by substantial pKa shifts of the NHIs by up to 8.7 units. Since only the ring-closed isomers are sufficiently basic to activate CO2 via the formation of zwitterionic Lewis base adducts, cycling between the two isomeric states enables the light-controlled capture and release of CO2 .


The female athletic ideal - Friend or foe? Fit, thin, and athletic body ideals and their associations with women's body image.
The internalization of body ideals is a critical predictor of body image and health behaviors. Thin and athletic ideal internalization in women need to be elucidated. The aims of the current study included: (i) describing the endorsement of thin and athletic body ideals among women and (ii) examining group differences in negative and positive self-conscious emotions and body image. Participants (N = 392 women; Mage = 25.6, SD = 5.3 years) were assigned to Fit Ideal (n = 110), Thin Ideal (n = 83), Athletic Ideal (n = 55), and Low Internalization (n = 144) groups based on scores for thin and athletic internalization. Three multivariate analyses of variance were conducted to examine Body Ideal group differences on negative appearance and fitness self-conscious emotions, and positive self-conscious emotions and body image. The Athletic Ideal and Low Internalization groups generally scored lower on negative self-conscious emotions and higher on positive self-conscious emotions and body image in comparison to the Fit and Thin Ideal groups (Cohen's d =.35 to 1.15). Results suggest that differing levels of thin and athletic internalization may intersect uniquely with women's body-related self-conscious emotions and positive body image and thus may have distinct effects on women's health and behavior.


Age-related changes in the gross anatomy of the reproductive organs, and associated steroid hormone profiles in male and female guinea fowls (Numida meleagris).
Owing to the paucity of information on the reproductive biology of guinea fowls, a study involving a total of 132 birds was conducted, and this documented the developmental changes in the gross anatomy of the reproductive organs of males and females from hatching until 32 weeks of age (WOA), and associated steroid hormone changes. Testicular anatomical biometric traits increased significantly (p < 0.0001) from 8 WOA, and stabilised between 16 and 20 WOA, while peripheral testosterone concentration peaked at 20 WOA. Correlations among all testicular biometric characteristics were strong and positive (p < 0.0001). Similarly peripheral testosterone concentrations strongly (p < 0.01) and positively correlated with all the testicular anatomical biometric traits. In the female guinea fowl, the ovary and oviduct were discernible and measurable at hatching. Significant (p < 0.0001) increases were seen in ovarian and relative ovarian weights, and oviducal weights and lengths between 24 and 28 WOA. Plasma 17β-oestradiol decreased gradually to a very minimum at 16 WOA, and then began to increase gradually until 28 WOA when it plateaued. Peripheral progesterone concentrations on the other hand increased gradually from 4 WOA and peaked at 12 WOA, and then fluctuated considerably thereafter. Correlations among ovarian/oviducal anatomical parameters were strong (p < 0.0001) and positive. Similarly, peripheral oestradiol concentrations strongly (p < 0.0001) and positively correlated with all ovarian/oviducal anatomical parameters. Testicular anatomical biometric traits stabilised between 16 and 20 WOA, coinciding with peak peripheral testosterone concentrations, while ovarian/oviducal parameters recorded huge increases between 24 and 28 WOA, and may be under the influence of oestradiol.


Frequency of bovine viral diarrhea virus detected in subpopulations of peripheral blood mononuclear cells in persistently infected animals and health outcome.
Bovine viral diarrhea viruses (BVDV) cause acute and persistent infections. Acute infection results in generalized immunosuppression characterized by a decrease in circulating lymphocytes as a result of depletion of CD4+ and CD8 + T cell populations. Persistent infection with BVDV is the result of immune tolerance and is generally not associated with lymphocytopenia. The health outcome of persistently infected (PI) calves varies widely; some die of mucosal disease, some succumb to ill thrift and others appear normal and survive to adulthood. Detection of BVDV at the single lymphoid cell level is important to the study of subpopulations of peripheral blood mononuclear cells (PBMC) during BVDV infections, however there are few methods available for the detection and quantification of BVDV at this level. To circumvent this difficulty, a novel flow cytometry-based PrimeFlow RNA assay using in-situ detection of BVDV was developed. This assay was used to evaluate differences in viral distribution within subpopulations of PBMC over time in PI calves carrying one of two different species of BVDV (type 1 and type 2). Calves were sampled at 3 different time points approximately one month apart. During the course of the study, a subset of the calves died from ill thrift. Mucosal disease was not indicated in any of the deaths. Using RNA probes specific for the BVDV Npro-Erns coding regions for each respective virus, BVDV RNA was detected in all PBMC of PI that appeared clinically healthy. Calves that succumbed to ill thrift were found to have no or little virus in T cells. The clearance of virus from T cells suggests a breakdown in immune tolerance in these calves. This is the first report of a pattern observed in the viral load in the T cell subpopulations and survival in PI calves.


Muskrats as a bellwether of a drying delta.
Wetlands worldwide are under threat from anthropogenic impacts. In large protected North American areas such as Yellowstone and Wood Buffalo National Parks, aquatic habitats are disappearing and wetland-dependent fauna are in decline1-3. Here we investigate population dynamics of an indicator species in Canada's Peace-Athabasca Delta ("the delta"), a World Heritage Site. Based on population surveys, habitat mapping and genetic data from 288 muskrats, we use agent-based modeling and genetic analyses to explain population expansion and decline of the semi-aquatic muskrat (Ondatra zibethicus). Simulations quantify a large population (~500,000 individuals) following flood-induced habitat gains, with decreased size (~10,000 individuals) during drying. Genetic analyses show extremely low long-term effective population size (Ne: 60-127), supporting a legacy of population bottlenecks. Our simulations indicate that the muskrat population in the delta is a metapopulation with individuals migrating preferentially along riparian pathways. Related individuals found over 40 km apart imply dispersal distances far greater than their typical home range (130 m). Rapid metapopulation recovery is achieved via riparian corridor migration and passive flood-transport of individuals. Source-sink dynamics show wetland loss impacts on the muskrat metapopulation's spatial extent. Dramatic landscape change is underway, devastating local fauna, including this generalist species even in a protected ecosystem.


Is more always better? Dose effect in a multidomain intervention in older adults at risk of dementia.
Little is known regarding the dose-response function in multidomain interventions for dementia prevention. The Multidomain Alzheimer Preventive Trial is a 3-year randomized controlled trial comprising cognitive training, physical activity, nutrition, and omega-3 polyunsaturated fatty acids for at-risk older adults. The dose delivered (number of sessions attended) was modeled against global cognition, memory, and fluency in 749 participants. Interaction effects were assessed for age, sex, education, dementia score (CAIDE), frailty score, and apolipoprotein E (APOE) ε4 status. The dose-response models were non-linear functions indicating benefits up to about 12 to 14 training hours or 15 to 20 multidomain sessions followed by a plateau. Participants who benefited from a higher dose included women, younger participants, frail individuals, and those with lower education or lower risk of dementia. The non-linear function indicates that a higher dose is not necessarily better in multidomain interventions. The optimal dose was about half of the potentially available sessions.


Persistence on pasture of the infective larvae of nematodes parasitizing Maine dairy cattle.
Yearling calves infected with Ostertagia ostertagi, Cooperia oncophora, and Nematodirus helvetianus were allowed to graze on a 0.8 ha pasture plot contaminated during June and August 1977. In June 1978, the plot was subdivided into 10 subplots of equal size. Grazing in 5 of these plots was allowed, each for 1 month, during June, July, August, September, and October by groups of 2 parasite-free 16-week-old calves. The procedure was repeated in 1979 with the remaining 5 subplots. Each group of calves was allowed to graze for 2 weeks, then put into stalls for 2 weeks and killed and examined for worms. There was a good survival of the 3 worm genera over the winter period of 1977-78. In June, calves averaged 250 Ostertagia, 5,345 Cooperia, and 6,955 Nematodirus. Ostertagia and Cooperia were recovered from calves grazing in September and October. The 3rd genus, Nematodirus, also became less plentiful over the summer period, but persisted in calves grazing during September and October. This genus survived a 2nd winter on pasture and worms were recovered until July, 1979.


3-Hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylates--a new class of HIV-1 integrase inhibitors.
A new class of inhibitors of HIV-1 integrase has been optimized to provide selective and highly efficient strand transfer inhibition.


Influence of peritoneal fluid from spontaneous and stimulated cycles on sperm motility in vitro.
Peritoneal fluids (PFs) from spontaneous (n = 14) and gonadotrophin-stimulated cycles (n = 20) were obtained during diagnostic laparoscopy and gamete intrafallopian transfer (GIFT) procedures, respectively. The effects of these fluids on the linear component of sperm motility and on the percentage of motile spermatozoa were studied in vitro by objective motility assessments and compared to a control medium (B2-Ménézo). Overall, the two types of PFs were found to have rather similar effects on the motility parameters studied. However, the fluids from hormonally-stimulated cycles sustained motility better (i.e., sperm velocity and percentage of motile sperm) and in a rather constant manner as a function of time (narrower range distributions of the motility measurements). Furthermore, it was observed that under identical experimental conditions motility measurements depended not only on the type of PF used but also on the sperm sample. These results suggest that assisted reproduction procedures in which PF is the medium where the gametes eventually meet and interact, such as direct peritoneal insemination (DIPI) or peritoneal oocyte and sperm transfer (POST), could have different success rates if performed in spontaneous rather than in stimulated cycles. At the same time, our results may help to explain why different pregnancy rates were reported in different studies using DIP or POST.


Structure and Unprecedented Reactivity of a Mononuclear Nonheme Cobalt(III) Iodosylbenzene Complex.
A mononuclear nonheme cobalt(III) iodosylbenzene complex, [CoIII (TQA)(OIPh)(OH)]2+ (1), is synthesized and characterized structurally and spectroscopically. While 1 is a sluggish oxidant in oxidation reactions, it becomes a competent oxidant in oxygen atom transfer reactions, such as olefin epoxidation, in the presence of a small amount of proton. More interestingly, 1 shows a nucleophilic reactivity in aldehyde deformylation reaction, demonstrating that 1 has an amphoteric reactivity. Another interesting observation is that 1 can be used as an oxygen atom donor in the generation of high-valent metal-oxo complexes. To our knowledge, we present the first crystal structure of a CoIII iodosylbenzene complex and the unprecedented reactivity of metal-iodosylarene adduct.


3,3'-Disubstituted bipolar biphenyls as inhibitors of nuclear receptor coactivator binding.
A series of bipolar biphenyl compounds was synthesized as proteomimetic analogs of the LXXLL penta-peptide motif responsible for the binding of coactivator proteins to the nuclear hormone receptor coactivator binding domain. These compounds were subjected to multiple in vitro assays to evaluate their effectiveness as competitive binding inhibitors. The results from this initial study indicate that these proteomimetics possess the ability to inhibit this protein-protein interaction.


The "peripheral-type" benzodiazepine (omega 3) receptor in hyperammonemic disorders.
Increased levels of brain ammonia occur in both congenital and acquired hyperammonemic syndromes including hepatic encephalopathy, fulminant hepatic failure, Reye's syndrome and congenital urea cycle disorders. In addition to its effect on neurotransmission and energy metabolism, ammonia modulates the expression of various genes including the astrocytic "peripheral-type" benzodiazepine (or omega 3) receptor (PTBR). Increased expression of the isoquinoline carboxamide binding protein (IBP), one of the components of the PTBR complex, is observed in brain and peripheral tissues following chronic liver failure as well as in cultured astrocytes exposed to ammonia. Increased densities of binding sites for the PTBR ligand [3H]-PK11195 are also observed in these conditions as well as in brains of animals with acute liver failure, congenital urea cycle disorders and in patients who died in hepatic coma. The precise role of PTBR in brain function has not yet fully elucidated, but among other functions, PTBR mediates the transport of cholesterol across the mitochondrial membrane and thus plays a key role in the biosynthesis of neurosteroids some of which modulate major neurotransmitter systems such as the gamma-aminobutyric acid (GABA(A)) and glutamate (N-methyl-D-aspartate (NMDA)) receptors. Activation of PTBR in chronic and acute hyperammonemia results in increased synthesis of neurosteroids which could lead to an imbalance between excitatory and inhibitory neurotransmission in the CNS. Preliminary reports suggest that positron emission tomography (PET) studies using [11C]-PK11195 may be useful for the assessment of the neurological consequences of chronic liver failure.


Skin Carotenoid Status Over Time and Differences by Age and Sex Among Head Start Children (3-5 Years).
Examine differences in skin carotenoid status (SCS) based on time, age, and sex of preschool-aged children enrolled in Head Start (HS) in North Carolina. Data were collected using surveys from participating families. preschool-aged children's SCS were measured 3 times over a 6-month period. Three HS centers in North Carolina. One hundred twelve children aged 3-5 years, enrolled in HS. Differences in SCS assessed using the Veggie Meter (Longevity Link, Salt Lake City, UT) based on time, sex, and age. One-way ANOVA to assess SCS at time 1 between sex and age (n = 112). Repeated measures ANOVA with a Greenhouse-Geisser correction for assessment of SCS over time (n = 45) using Bonferroni correction. On average, children were aged 4 years, African American (81.3%), male (57%), and had a mean SCS of 266 (SD = 82.9). Skin carotenoid status (Veggie Meter units) were significantly different over time (P < 0.001). Significant differences were observed between ages (P = 0.01) and sex (P < 0.01). The Veggie Meter is a promising tool to assess fruit and vegetable intake but needs to be validated in preschool-aged children as it has been in adults. Sex and age are potential confounders which should be assessed in future studies using the Veggie Meter.


Have I grooved to this before? Discriminating practised and observed actions in a novel context.
Learning a new motor skill typically requires converting actions observed from a third-person perspective into fluid motor commands executed from a first-person perspective. In the present study, we test the hypothesis that during motor learning, the ability to discriminate between actions that have been observed and actions that have been executed is associated with learning aptitude, as assessed by a general measure of physical performance. Using a multi-day dance-training paradigm with a group of dance-naïve participants, we investigated whether actions that had been regularly observed could be discriminated from similar actions that had been physically practised over the course of three days, or a further set of similar actions that remained untrained. Training gains and performance scores at test were correlated with participants' ability to discriminate between observed and practised actions, suggesting that an individual's ability to differentiate between visual versus visuomotor action encoding is associated with general motor learning.


Temporal Activity Patterns of Sympatric Species in the Temperate Coniferous Forests of the Eastern Qinghai-Tibet Plateau.
Temporal niche partitioning is an important strategy for sympatric species or populations when utilizing limited resources while minimizing competition. Different resource availability across seasons may also influence the intensity of competition, resulting in a varied temporal niche partitioning pattern between species. These competitive interactions are important drivers for the formation of biodiversity patterns and species coexistence on the eastern Qinghai-Tibet Plateau. To clarify these interspecies relationships among sympatric species, we carried out a camera trap survey from 2017 to 2020. We deployed 60 camera traps in the temperate coniferous forests of the eastern Qinghai-Tibet Plateau. We analyzed the daily activity patterns of birds and mammals to reveal the temporal niches and seasonal relationships among the species-specific activity rhythms. The results are summarized as follows: (1) Eight major species, including mammals and birds, have different temporal peak activity rhythms to reduce intense competition for resources. (2) The activity rhythm of a species varies seasonally, and the competition among species is more intense in the warm season than in the cold season. (3) Among 15 pairs of competitor species, seven pairs had significantly different coefficients, with higher winter values than summer values, perhaps due to the abundance of resources in summer and the scarcity of resources in winter causing intensified competition. Among the predators and prey, the summertime coefficients were higher than those in winter, perhaps due to the need to replenish energy during the summer breeding season. The main purpose of animals in winter is to survive the harsh environment. Our results provide important information on temporal and interspecies relationships and contribute to a better understanding of species-coexistence mechanisms.


Binary and ternary solid dispersions of an anticancer preclinical lead, IIIM-290: In vitro and in vivo studies.
The objective of this study was to formulate an anticancer preclinical lead, IIIM-290, loaded in solid dispersions to enhance its solubility, dissolution, and oral pharmacokinetics. IIIM-290 is an in-house preclinical anticancer lead prepared by semisynthetic modification of the natural product rohitukine. It is an orally bioavailable Cdk inhibitor showing efficacy in xenograft models of pancreatic, colon and leukemia cancer. It demonstrated in vivo efficacy at a relatively higher dose owing to its poor aqueous solubility (~8.6 µg/mL). Binary and ternary solid dispersions containing PVP K-30, xanthan gum, and PEG-PPG-PEG were selected after solubility screening of various hydrophilic polymers. Several formulations with varying ratios of polymers, alone and in combination, were prepared and investigated for their effects on the solubility enhancement of IIIM-290. The binary solid dispersion VKB-SD75, prepared with PVP K-30 at the ratio of 1:4 w/w, was identified as the optimized composition that displayed 17-fold improvement in the aqueous solubility of IIIM-290. VKB-SD75 was scaled up to a 100-g scale. IIIM-290 and VKB-SD75 were evaluated for DSC, p-XRD, FTIR, 1H NMR, SEM, in vitro dissolution, and oral pharmacokinetics, as well as for in vivo anticancer activity in the Ehrlich solid tumor model. The oral administration of VKB-SD75 in BALB/c mice resulted in a 1.9-fold improvement in plasma exposure. These findings also correlated well when the formulation was administered to mice in the Ehrlich solid tumor model. The newly developed solid dispersion is expected to reduce the dose of IIIM-290 by ~40-50% in preclinical and clinical studies.


Genetic engineering of human and mouse CD4+ and CD8+ Tregs using lentiviral vectors encoding chimeric antigen receptors.
The last decade has seen a significant increase of cell therapy protocols using effector T cells (Teffs) in particular, but also, more recently, non-engineered and expanded polyclonal regulatory T cells (Tregs) to control pathological immune responses such as cancer, autoimmune diseases, or transplantation rejection. However, limitations, such as stability, migration, and specificity of the cell products, have been seen. Thus, genetic engineering of these cell subsets is expected to provide the next generation of T cell therapy products. Lentiviral vectors are commonly used to modify Teffs; however, Tregs are more sensitive to mechanical stress and require specific culture conditions. Also, there is a lack of reproducible and efficient protocols to expand and genetically modify Tregs without affecting their growth and function. Due to smaller number of cells and poorer viability upon culture in vitro, mouse Tregs are more difficult to transduce and amplify in vitro than human Tregs. Here we propose a step-by-step protocol to produce both human and mouse genetically modified CD8+ and CD4+ Tregs in sufficient amounts to assess their therapeutic efficacy in humanized immunocompromised mouse models and murine models of disease and to establish pre-clinical proofs of concept. We report, for the first time, an efficient and reproducible method to isolate Tregs from human blood or mouse spleen, transduce with a lentiviral vector, and culture, in parallel, CD8+ and CD4+ Tregs while preserving their function. Beyond chimeric antigen receptor (CAR)-Treg cell therapy, this protocol will promote the development of potential new engineered T cell therapies to treat autoimmune diseases and transplantation rejection.


Impact of beta-blocker treatment on the prognostic value of currently used risk predictors in congestive heart failure.
This prospective study tested the impact of beta-blocker treatment on currently used risk predictors in congestive heart failure (CHF). Given the survival benefit obtained by beta-blockade, risk stratification by factors established in the "pre-beta-blocker era" may be questioned. The study included 408 patients who had CHF with left ventricular ejection fraction (LVEF) <45%, all treated with an angiotensin-converting enzyme inhibitor or angiotensin type 1 receptor antagonist, who were classified into those receiving a beta-blocker (n = 165) and those who were not (n = 243). In all patients, LVEF, peak oxygen consumption (peakVO(2)), plasma norepinephrine (NE) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were determined. Although the New York Heart Association functional class (2.2 +/- 0.7 vs. 2.3 +/- 0.7), peakVO(2) (14.4 +/- 5.2 ml/min per kg vs. 14.4 +/- 5.5 ml/min per kg) and NT-proBNP (337 +/- 360 pmol/l vs. 434 +/- 538 pmol/l) were similar in the groups with and without beta-blocker treatment, the group with beta-blocker treatment had a lower heart rate (68 +/- 30 beats/min vs. 76 +/- 30 beats/min), lower NE (1.7 +/- 1.2 nmol/l vs. 2.5 +/- 2.2 nmol/l) and higher LVEF (24 +/- 10% vs. 21 +/- 9%; all p < 0.05). Within one year, 34% of patients without beta-blocker treatment, but only 16% of those with beta-blocker treatment (p < 0.001), reached the combined end point, defined as hospital admission due to worsening CHF and/or cardiac death. A beneficial effect of beta-blocker treatment was most obvious in the advanced stages of CHF, because the end-point rates were markedly lower (all p < 0.05) in the group with beta-blocker treatment versus the group without it, as characterized by peakVO(2) <10 ml/min per kg (26% vs. 64%), LVEF < or = 20% (25% vs. 45%), NE >2.24 nmol/l (18% vs. 40%) and NT-proBNP >364 pmol/l (27% vs. 45%), although patients with beta-blocker treatment received only 37 +/- 21% of the maximal recommended beta-blocker dosages. The prognostic value of variables used for risk stratification of patients with CHF is markedly influenced by beta-blocker treatment. Therefore, in the beta-blocker era, a re-evaluation of the selection criteria for heart transplantation is warranted.


A Novel Modification of the Murine Elastase Infusion Model of Abdominal Aortic Aneurysm Formation.
To create a novel procedure that will decrease the mortality of experimental animals in the intraarterial infusion of elastase abdominal aortic aneurysm (AAA) model. Novel models were created by means of direct puncture in the infrarenal abdominal aortic aorta, intraluminal elastase in the 1-cm segment of abdominal aorta. Femoral artery cannula approach and infusing with elastase was considered as the traditional group and that infusing with saline solution as the control group. Survival rate, morphology and histology of aneurysms, and inflammation mediators were calculated. Among the 36 rats, the average length from testicular arteries to left iliolumbar artery was 1.18 ± 0.22 cm, and 77.8% of them were longer than 1 cm. Procedure time was significantly shorter in novel group than that in 2 other groups (P = 0.006; P < 0.0001). During 24 hr postoperation, no death was observed in the novel group. Within 4 wk, survival rate in the control group was 60.6% and 80.8% in the novel group whereas 41.0% in the traditional group. Till the second week, all rats in the traditional and novel group had formed AAAs. And then, the survival rates and rupture rates of AAA between the 2 groups were similar within the following 2 wk (P = 0.487; P = 0.539). Inflammation degree and elastase content in intima media of aneurysms were similar (P = 0.720). However, Tumor necrosis factor alpha and Interleukin-1 beta levels were significantly lower in the novel group than those in the traditional group (P < 0.0001; P < 0.0001). A novel rat AAA model was created by intraluminal elastase infusion through direct puncture the infrarenal aorta. This model is efficient and reliable, with a high survival rate and with similar morphology and histology of aortic aneurysms.


Highly efficient photocatalytic oxidation of antibiotic ciprofloxacin using TiO2@g-C3N4@biochar composite.
In this present study, a novel indirect Z-scheme TiO2@g-C3N4@biochar (TiO2@g-C3N4@BC) composite photocatalyst was successfully fabricated and characterized with SEM, TEM, EDS, XRD, FTIR, PL, XPS, and UV-vis DRS. The photocatalytic degradation behavior of ciprofloxacin (CIP) on the TiO2@g-C3N4@BC was evaluated under UV-vis and visible light irradiation, and the possible reaction mechanism of photocatalytic oxidation of CIP on the TiO2@g-C3N4@BC was explained. The TiO2@g-C3N4@BC composite photocatalyst exhibited stronger photocatalytic oxidation activity for CIP in comparison with TiO2, g-C3N4, TiO2@BC, and TiO2@g-C3N4. After 60 min of UV-vis and visible light irradiation, the photocatalytic removal efficiency of CIP by TiO2@g-C3N4@BC was 99.3 and 89.2%, respectively. The photocatalytic removal performance of CIP was affected by the initial concentration of CIP, catalyst dosage, and pH value. The composite photocatalyst presented excellent stability and reusability after five cycles. An indirect Z-scheme principle of the CIP photocatalytic oxidation reaction on TiO2@g-C3N4@BC was clearly proposed, and the whole process of photocatalytic degradation was the results of the interaction between CIP and reactive active species (·O2-, h+, and ·OH), of which ·O2- is the main active substance. Four CIP degradation pathways were proposed. This work may provide an effective strategy to remove antibiotics in wastewater.


Analgesia for major laparoscopic abdominal surgery: a randomised feasibility trial using intrathecal morphine.
Effective pain control enhances patient recovery after surgery. Laparoscopic techniques for major abdominal surgery are increasingly utilised to reduce surgical trauma. Intrathecal morphine is an attractive analgesic option that is gaining popularity. However, limited evidence guides its use in the setting of laparoscopic surgery. In addition, enhanced recovery after surgery pathways advocate opioid-sparing techniques. We conducted a feasibility trial to compare intrathecal morphine with non-neuraxial analgesia in laparoscopic or laparoscopic-assisted major abdominal surgery to inform the design of a future large clinical trial. This multicentre, double-blind, randomised controlled trial was conducted at two tertiary hospitals in Australia. Fifty-one patients were randomly allocated to receive either intrathecal morphine (intervention group) or a sham subcutaneous injection of normal saline in the lumbar area (control group) immediately before the induction of general anaesthesia. Co-primary outcomes were patient recruitment and successful adherence to treatment allocation as per the study protocol. The primary endpoints of feasibility and protocol adherence were met with a 46% recruitment rate (51 of 110 eligible patients) and 96% protocol adherence. There was only one patient with failed access to the intrathecal space. For secondary endpoints, fewer patients in the intrathecal morphine group required opioids in the post-anaesthesia care unit, their postoperative pain scores at rest were lower across the four time-points measured (p = 0.007), but not dynamic pain scores (p = 0.061), and pruritus was more common following intrathecal morphine (p = 0.007). Total oral morphine equivalents until postoperative day 3 were less in the intrathecal morphine group (median (95%CI) difference 82 (-13 to 168) mg), but this reduction was not statistically significant (p = 0.10). These findings support conducting a definitive clinical trial.


Interactive association of serum uric acid and total bilirubin with renal dysfunction among community-dwelling subjects.
Chronic kidney disease is a major public health concern. Serum uric acid (SUA) at high levels was oxidative stress agents, and total bilirubin (T-BiL) at mildly increased levels was potent antioxidants, but whether SUA and T-BiL produce an additive interaction for the risk of renal dysfunction remains unclear. The subjects comprised 567 men aged 71 ± 8 (mean ± standard deviation) years and 853 women aged 70 ± 8 years from a rural village. We examined the relationship between SUA and T-BiL, and renal function was evaluated by estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease Study Group equation. Stepwise multiple regression analysis using eGFR as an objective variable, adjusted for risk factors as explanatory variables, showed that SUA (β = -0.358, p < 0.001) as well as age (β = -0.534, p < 0.001), drinking status (β = 0.119, p < 0.001), and the presence of antihypertensive medication (β = -0.058, p = 0.005) were significantly and independently associated with eGFR, but T-BiL was not associated with eGFR. While in the group with the highest tertile of SUA, T-BiL (β = 0.081, p = 0.032) was significantly and independently associated with eGFR, and in the group with the lowest to middle tertile of SUA, T-BiL was not associated with eGFR. In addition, interaction between SUA and T-BiL (F = 8.512, p = 0.004) as well as age, drinking status, the presence of antihypertensive medication, SUA, and T-BiL was a significant and independent determinant for eGFR. Our data demonstrated that low T-BiL could be important as a potential risk factor for renal dysfunction in those with high SUA.


[Blindness in Germany - comparison between retrospective data and predictions for the future].
There are no exact figures on the number of blind and visually impaired persons in Germany. The purpose of this study was to compare the development over the last years with earlier predictions and an outlook into the future. Data from scientific publications as well as the Federal Statistical Office and from organizations for the blind on the frequency of blindness was compared to the forecast development of blindness. In addition the development of the frequency of age-related macular degeneration (ARMD) was taken into consideration. While the proportion of over 60-year-olds has steadily increased from 21% in 1993 to 25.9% in 2009, the ratio of blind people has risen from 8.9 per 10,000 inhabitants in 1993 to 10.6 per 10,000 inhabitants in 2003. However, up to 2009 decreased every year to 9.7 which is approximately the same as 1995, although ARMD has also become much more frequent as the main cause. Additionally there are considerable differences up to a factor two between the various studies on the number of blind people in different regions of Germany. At present there are approximately 150,000 blind and about 500,000 visually impaired persons in Germany. However, these numbers are only on the basis of estimates and according to studies in other European nations. Similar uncertainty exists concerning the diseases causing blindness. A transfer from epidemiological studies is limited especially because of the different definition of blindness. The expected increase of visually impaired and blind persons for the last 20 years as a result of the increasing age cannot be confirmed from the present data. It would be desirable to extensively register the specifications to prevalence and incidence of visual impairment and blindness including valid information on the corresponding cause to confirm the rising importance of visual impairment.


Biomimetic polyelectrolyte coating of stem cells suppresses thrombotic activation and enhances its survival and function.
Mesenchymal stem cells (MSCs) therapy is a promising approach for treating inflammatory diseases due to their immunosuppressive and tissue repair characteristics. However, allogenic transplantation of MSCs induces thrombotic complications in some patients which limits its potential for clinical translation. To address this challenge, we have exploited the bioactivity of heparin, a well-known anticoagulant and immunosuppressive polysaccharide that is widely used in clinics. We have developed a smart layer-by-layer (LbL) coating strategy using gelatin and heparin polymers exploiting their overall positive and negative charges that enabled efficient complexation with the MSCs' glycocalyx. The stable coating of MSCs suppressed complement attack and mitigated thrombotic activation as demonstrated in human whole blood. Gratifyingly, the MSC coating retained its immunosuppressive properties and differentiation potential when exposed to inflammatory conditions and differentiation factors. We believe the simple coating procedure of MSCs will increase allogenic tolerance and circumvent the major challenge of MSCs transplantation.


The development of the Toddler Behavior Screening Inventory.
The purpose of the present study was to develop the Toddler Behavior Screening Inventory (TBSI) for rapidly assessing maternal reports of toddler behavior problems. The TBSI is a 40-item measure intended for use by pediatricians, psychologists, and other child-care professionals. A group of mothers (n = 312) rated the initial 93-item TBSI in terms of behavior frequency and parental perception of the behavior as problematic. Following item elimination, 40 items were retained due to being both frequent and problematic at all toddler age levels. Data were obtained with a new sample of mothers (n = 581) and showed the TBSI to possess good reliability and validity.


Cypermethrin-induced histopathological and biochemical changes in Nile tilapia (Oreochromis niloticus), and the protective and recuperative effect of ascorbic acid.
The objective of this study was to investigate the effects of ascorbic acid on the toxicity of cypermethrin's on histopathological lesions in tissues and protein, glycogen levels in Oreochromis niloticus. Nile tilapia was exposed to 0.22 and 0.44 μg/l cypermethrin+control diet, 0.22 and 0.44 μg/l cypermethrin+ascorbic acid supplemented diet for 20 days. The fish were allowed recuperation period of 15 days in pesticide-free water and fed with ascorbic acid suplementation diet. In light microscopic investigation, histopathological lesions were observed in the gill, liver and kidney. The severity of lesions accreted depending on increased pesticide concentration and control diet. Some of the lesions were reversible or at least were less pronounced after recuperation period. Protein levels decreased in some groups after treatment period according to control groups (p<0.05). The highest depletions in liver, muscle and gill protein levels were found in 0.44 μg/l cypermethrin+ascorbic acid supplemented diet group (62.23%), in 0.22 μg/l cypermethrin+control diet group (53.12%) and in 0.44 μg/l cypermethrin+control diet group (61.87%) after 10 days, respectively. These levels increased at the end of the recuperation period. The highest depletion in liver glycogen levels was found in 0.22 μg/l cypermethrin+control diet group (50.50%) after 10 days (p<0.05). At the end of recuperation period, there was no difference between the groups (except 0.22 μg/l cypermethrin+ascorbic acid supplemented diet group) and controls. The decrease of muscle glycogen, except 0.22 μg/l cypermethrin+ascorbic acid supplemented diet group, was recorded at the end of 10 and 20 days. In the recuperation period, an increase was observed at all groups. These results revealed that the histopathology, protein and glycogen can work as good indicators of stress of a toxicant on fish. Ascorbic acid serves fish as an antitoxic agent against pesticide toxicity.


Shock.
Critically ill patients with undifferentiated shock are complex and challenging cases in the ED. A systematic approach to assessment and management is essential to prevent unnecessary morbidity and mortality. The simplified, systematic approach described in this article focuses on determining the presence of problems with cardiac function (the pump), intravascular volume (the tank), or systemic vascular resistance (the pipes). With this approach, the emergency physician can detect life-threatening conditions and implement time-sensitive therapy.


Brønsted acid-enhanced copper-catalyzed atroposelective cycloisomerization to axially chiral arylquinolizones via dearomatization of pyridine.
The construction of axially chiral N-heterobiaryls is of great interest as a result of their occurrence in organocatalysts, chiral ligands, natural products, and biologically active molecules. Despite remarkable achievements in this area, strategies for the preparation of new classes of axially chiral N-heterobiaryls remain to be further explored. Herein, we report the enantioselective synthesis of axially chiral arylquinolizones through an intramolecular atroposelective cycloisomerization. The reaction proceeds via the Brønsted acid-enhanced dearomatization of pyridine by a copper catalyst that allows for the formation of the desired products in excellent yields and enantioselectivities. The utility of this methodology is illustrated by a synthesis on gram scale production and transformation of the products into chiral thiourea catalysts. Mechanistic studies demonstrate that Brønsted acid plays a significant role in promoting the reactivity of the reaction, while both the steric and electronic effects of aryl substituents in substrate play a role in controlling the stereoselectivity.


Microsolvation effect and hydrogen-bonding pattern of taurine-water TA-(H2O)n (n = 1-3) complexes.
The microsolvation of taurine (TA) with one, two or three water molecules was investigated by a density functional theory (DFT) approach. Quantum theory of atoms in molecules (QTAIM) analyses were employed to elucidate the hydrogen bond (H-bond) interaction characteristics in TA-(H(2)O)(n) (n = 1-3) complexes. The results showed that the intramolecular H-bond formed between the hydroxyl and the N atom of TA are retained in most TA-(H(2)O)(n) (n = 1-3) complexes, and are strengthened via cooperative effects among multiple H-bonds from n = 1-3. A trend of proton transformation exists from the hydroxyl to the N atom, which finally results in the cleavage of the origin intramolecular H-bond and the formation of a new intramolecular H-bond between the amino and the O atom of TA. Therefore, the most stable TA-(H(2)O)(3) complex becomes a zwitterionic complex rather than a neutral type. A many-body interaction analysis showed that the major contributors to the binding energies for complexes are the two-body energies, while three-body energies and relaxation energies make significant contributions to the binding energies for some complexes, whereas the four-body energies are too small to be significant.


Nutritional advantages of sous-vide cooking compared to boiling on cereals and legumes: Determination of ashes and metals content in ready-to-eat products.
In order to guarantee the highest quality of ready-to-eat cereals and legumes, two different cooking methods have been applied: traditional cooking and sous-vide. Ashes and metals content (magnesium, potassium, iron, zinc, and copper) has been determined and compared in 50 samples of red lentils, peas, Borlotti beans, pearl barley, and cereals soup. All the samples cooked with sous-vide showed a significant increase in the content of minerals with the exception of potassium in cereal soup, iron in Borlotti beans, and magnesium in pearl barley. Ash content increased in legumes and in cereal soup cooked with sous-vide method. The higher different ashes concentration between total samples cooked with traditional cooking and with sous-vide was registered in zinc (+862 mg), iron (+314 mg), potassium (+109 mg), and copper (+95 mg). Sous-vide is preferred as it provides products with a higher concentration of metals compared to the ones cooked with traditional cooking.


Stress, epigenetic control of gene expression and memory formation.
Making memories of a stressful life event is essential for an organism's survival as it allows it to adapt and respond in a more appropriate manner should the situation occur again. However, it may be envisaged that extremely stressful events can lead to formation of traumatic memories that are detrimental to the organism and lead to psychiatric disorders such as post-traumatic stress disorder (PTSD). The neurotransmitter glutamate and the ERK MAPK signaling pathway play a principal role in learning and memory. Glucocorticoid hormones acting via the glucocorticoid receptor have been shown to strengthen the consolidation of memories of stressful events. The ERK MAPK signaling pathway and glucocorticoid receptor-mediated actions have recently been shown to drive epigenetic modifications and conformational changes in the chromatin, stimulating the expression of neuroplasticity-related genes involved in stress-related learning and memory processes. The main epigenetic regulatory mechanisms are histone modifications and DNA (de-)methylation. Recently, studies have demonstrated that these processes are acting together in concert to regulate gene expression required for memory consolidation. This review explores the role of stress in learning and memory paradigms and the participating signaling pathways and epigenetic mechanisms and the enzymes that control these modifications during the consolidation process of memory formation.


Poor knowledge of COVID-19 and unfavourable perception of the response to the pandemic by healthcare workers at the Bafoussam Regional Hospital (West Region-Cameroon).
WHO warned against a dramatic impact of COVID-19 in Africa unless adequate response strategies are implemented. Whatever the strategy, the role of health staff is pivotal. Objective: Assess knowledge and perception of the response to COVID-19 among health staff. we used a convenience non probabilistic sample to conduct a survey with a self-administered questionnaire from April 14 - 29, 2020 at the Bafoussam Regional Hospital (BRH). All the staff was invited to participate. Analyses were done with Microsoft Excel 2010 and Epi-Info version 188.8.131.52. response rate was 76.1% (464/610). Mean age (SD) was 35.0 (8.9) years. Sex ratio (M/F) was 101/356. Nursing/midwifery staff (56.8%) and in-patients units (49.94%) were predominant. Origin and transmission of SARS-CoV-2 were poorly known while knowledge of clinical signs and the role of laboratory tests were good. For 53.2% of respondents all therapeutic regimens are supportive and only 31.6% trusted state-recommended drugs. For 169 of respondents (36.9%), herbal remedies prevent/cure COVID-19. Seventy percent (70%) felt they were not knowledgeable enough to handle COVID-19 cases. Eighty-five point six percent (85.6%) thought the BRH had insufficient resources to fight COVID-19 and 55.6% were dissatisfied with its response (weaknesses: medicines/technologies (74.5%), service delivery (28.1%), staff (10.9%)). Sixty-eight percent (68%) reported insufficient protection on duty. Seventy-six point five percent (76.5%) reported a drop in non-COVID-19 services. Eighty-five point five (85.5%) percent said they complied with community preventive measures. For 44% of respondents, regulations on COVID-19 corpses should be made more culture-sensitive. Fifty one point two percent (51.2%) of respondents were against vaccine trial in their community. knowledge was poor and perception of the response to COVID-19 was unfavourable.


Results and complications of single-stage total knee arthroplasty and high tibial osteotomy.
Long-term survival in total knee arthroplasty (TKA) depends on multiple factors, including restoration of mechanical alignment and obtaining optimal ligament balance. The aim of this study was to document the results of single-stage TKA combined with high tibial osteotomy for managing femorotibial arthrosis with significant frontal-plane deformity. Patients with osteoarthritis of the knee and extra-articular deformity in > 10° and operated between 1997 and 2001 were reviewed retrospectively. In each case, a high tibial osteotomy combined with a posterior stabilised TKA was performed. Patients were assessed using the Knee Society Score (KSS). The femorotibial mechanical angle was measured on radiographs pre- and postoperatively and at the most recent follow-up. Fifteen knees in 12 patients were included in the study. Mean age was 68.2; average follow-up was 78 months (22.1-145.9). The KSS improved significantly from 47.1 (28-58) to 60.7 (40-94) points (p < 0.05), with the KSS functional score improving from 45.1 (21-69) to 72.3 (30-100) points (p < 0.05). The femorotibial mechanical axis (mFTA) also improved significantly, from 161.7° (156-170°) preoperatively to 175.8° (170-182°) postoperatively (p = 0.002). There were four intra-operative tibial plateau fractures and two revisions for nonunion at the osteotomy site. Survival at 22 months was 86.7% [95% confidence interval (CI) 64.5-99.5%]. The combination of a TKA and high tibial osteotomy is a valid option for treating arthrosis with large extra-articular frontal-plane deformity. Rigid fixation of the osteotomy is essential.


Hyperostosis frontalis interna mimicking Mount Fuji sign.
We report an interesting case of 'Hyperostosis frontalis interna' in a 73-yr-old female whose MRI pictures mimics the CT appearance of 'Mount Fuji sign' in tension pneumocephalus a neurological emergency.


DL-3-n-butylphthalide promotes dendrite development in cortical neurons subjected to oxygen-glucose deprivation/reperfusion.
The limited degree of functional recovery is closely associated with the condition of the periinfarct cortex after ischemic stroke. The model of oxygen-glucose deprivation in cultured neurons could partly simulate this condition. Proper dendritic morphology is crucial for the correct wiring of neuronal function. Hence, the question of how to facilitate the plasticity of neural dendrites is of great significance. DL-3-n-butylphthalide is an efficient medication for ischemic stroke. In this study, in addition to having neuroprotective effects, DL-3-n-butylphthalide could increase the number of primary and secondary dendrites and of dendritic tips as confirmed by Sholl analysis. This study further demonstrated that DL-NBP inactivates PI3K/AKT signaling to positively regulate dendritic branching.


Scapular fracture following electronic muscle stimulation.
We present the case of a transverse fracture of the scapula resulting from the use of electronic muscle stimulation (EMS): highlighting the dangers of these devices that are commonly used for massage and body-building purposes.


Bubble nucleation and dynamics in acoustic droplet vaporization: a review of concepts, applications, and new directions.
The development of phase-shift droplets has broadened the scope of ultrasound-based biomedical applications. When subjected to sufficient acoustic pressures, the perfluorocarbon phase in phase-shift droplets undergoes a phase-transition to a gaseous state. This phenomenon, termed acoustic droplet vaporization (ADV), has been the subject of substantial research over the last two decades with great progress made in design of phase-shift droplets, fundamental physics of bubble nucleation and dynamics, and applications. Here, we review experimental approaches, carried out via high-speed microscopy, as well as theoretical models that have been proposed to study the fundamental physics of ADV including vapor nucleation and ADV-induced bubble dynamics. In addition, we highlight new developments of ADV in tissue regeneration, which is a relatively recently exploited application. We conclude this review with future opportunities of ADV for advanced applications such as in situ microrheology and pressure estimation.


"Ficus johannis Boiss. leaves ethanolic extract ameliorate streptozotocin-induced diabetes in rats by upregulating the expressions of GCK, GLUT4, and IGF and downregulating G6P".
The leaves of Ficus johannis Boiss (F. johannis), commonly known as Fig tree, Anjir, and Teen, are used by the folk medicinal practitioners in Iran for controlling hyperglycemia in diabetic patients. This study investigated the pharmacological basis for antidiabetic effect of the ethanolic extract of F. johannis leaves using in vitro and in vivo experimental models. Qualitative screening of phytochemicals, estimation of total phenolic and flavonoid contents, and in vitro antioxidant and α-amylase inhibition assays were performed. Moreover, the High-performance liquid chromatography (HPLC) quantification, acute toxicity, glucose tolerance, and in vivo antidiabetic effect along with the evaluation of gene expressions involved in diabetes mellitus were carried out. Significant quantities of phenolic (71.208 ± 2.89 mgg-1 GAE) and flavonoid (26.38 ± 3.53 mgg-1 QE) were present. Inhibitory concentration (IC50) of the plant extract exhibited an excellent in vitro antioxidant (IC50 = 33.81 µg/mL) and α-amylase (IC50 = 12.18 µg/mL) inhibitory potential. The HPLC analysis confirmed the gallic acid (257.79 mgg-1) as main constituent of the extract followed by kaempferol (22.86 mgg-1), myricetin (0.16 mgg-1), and quercetin (3.22 mgg-1). Ethanolic extract displayed glucose tolerance in normo-glycemic rats. Streptozotocin-induced hyperglycemia declined dose dependently in the extract treated rats with improvement in lipid profile and liver and renal function biomarkers. The F. johannis-treated groups showed an increase in mRNA expressions of glucose transporter 4 (GLUT-4), glucokinase, insulin growth like factor 1 and peroxisomal proliferator activating receptor gamma in pancreas. However, the Glucose-6-phosphatase was downregulated. Present study suggests that the ethanolic extract of F. johannis leaves demonstrates a good anti-diabetic profile by improving insulin sensitivity, GLUT-4 translocation, and carbohydrate metabolism while inhibiting lipogenesis.


Obesity and Obstructive Sleep Apnea.
Obstructive sleep apnea (OSA) is characterized by upper airway collapse during sleep. Chronic intermittent hypoxia, sleep fragmentation, and inflammatory activation are the main pathophysiological mechanisms of OSA. OSA is highly prevalent in obese patients and may contribute to cardiometabolic risk by exerting detrimental effects on adipose tissue metabolism and potentiating the adipose tissue dysfunction typically found in obesity. This chapter will provide an update on: (a) the epidemiological studies linking obesity and OSA; (b) the studies exploring the effects of intermittent hypoxia and sleep fragmentation on the adipose tissue; (c) the effects of OSA treatment with continuous positive airway pressure (CPAP) on metabolic derangements; and (d) current research on new anti-diabetic drugs that could be useful in the treatment of obese OSA patients.


Effects of intralipid-induced hypertriglyceridemia on plasma high-density lipoprotein metabolism in the cynomolgus monkey.
Low plasma levels of high-density lipoprotein (HDL) and apolipoprotein (apo) A-I often accompany human hypertriglyceridemia. In an animal model of hypertriglyceridemia, the lipoprotein lipase (LPL)-inhibited cynomolgus monkey, we reported that plasma levels of apo A-I were decreased and the fractional catabolic rate (FCR) of HDL apo was increased. To explore whether hypertriglyceridemia alone would alter plasma apo A-I levels and catabolism, hypertriglyceridemia was produced by intravenous (IV) infusion of 20% Intralipid into female cynomolgus monkeys. Baseline plasma triglyceride (TG) levels averaged 106 mg/dL. With infusion of 200 mg/kg/h Intralipid TG, plasma TG levels peaked at 967 mg/dL (range, 413 to 1,069; n = 6). More prolonged or more severe hypertriglyceridemia caused serious complications in several monkeys. Despite the severe hypertriglyceridemia, HDL TG content, HDL apoproteins, and plasma apo A-I levels did not markedly change, suggesting that very little HDL remodeling had occurred. Kinetic studies of HDL protein and apo A-I were performed in four pairs of monkeys. The two tracers were removed from the plasma at identical rates. In five pairs of animals, apo A-I turnover during control and Intralipid-induced hypertriglyceridemia was not significantly different. We hypothesize that apo A-I FCR is a function of HDL composition. Because Intralipid infusion did not alter HDL composition to the same degree as did LPL inhibition, its effects on HDL apo catabolism were not apparent.


Thalidomide ameliorates cisplatin-induced nephrotoxicity by inhibiting renal inflammation in an experimental model.
Cisplatin is a platinum-based chemotherapy drug. However, its chemotherapeutic use is restricted by serious side effects, especially nephrotoxicity. Inflammatory mechanisms have a significant role in the pathogenesis of cisplatin-induced nephrotoxicity. Thalidomide is an immunomodulatory and anti-inflammatory agent and is used for the treatment of various inflammatory diseases. The purpose of this study was to investigate the potential nephroprotective effect of thalidomide in a mouse model of cisplatin-induced nephrotoxicity. Nephrotoxicity was induced in mice by a single injection of cisplatin (15 mg/kg, i.p.) and treated with thalidomide (50 and 100 mg/kg/day, orally) for 4 days, beginning 24 h prior to the cisplatin injection. Renal toxicity induced by cisplatin was demonstrated by increasing plasma levels of creatinine and blood urea nitrogen (BUN). Cisplatin increased the renal production of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and transforming growth factor (TGF)-β1. In addition, kidney levels of malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) were increased by cisplatin. Biochemical results showed that thalidomide reduced cisplatin-induced increase in plasma creatinine and BUN. Thalidomide treatment also significantly reduced tissue levels of the proinflammatory cytokines, MDA, MPO, and NO and increased anti-inflammatory cytokine IL-10. Furthermore, histological examination indicated that thalidomide ameliorated renal damage caused by cisplatin. These data suggest that thalidomide attenuates cisplatin-induced nephrotoxicity possibly by inhibition of inflammatory reactions. Taken together, our findings indicate that thalidomide might be a valuable candidate for the prevention of nephrotoxicity in patients receiving cisplatin.


Emotional and behavioural problems in migrant adolescents in Belgium.
Refugee and migrant adolescents may be at increased risk for the development of emotional and behavioural problems. Since studies on this topic are rather scarce and results inconsistent, this large-scale screening study aims at investigating the prevalence of emotional and behavioural problems in recently arrived migrant adolescents in Belgium, compared to Belgian peers. About 1,249 migrant adolescents and 602 Belgian adolescents filled in four self-report questionnaires on the prevalence of emotional and behavioural problems, traumatic experiences and symptoms of post-traumatic stress. Migrant adolescents experienced more traumatic events than their Belgian peers, and show higher levels of peer problems and avoidance symptoms. On the contrary, non-migrant adolescents reveal more symptoms of anxiety, externalizing problems and hyperactivity. Factors influencing the prevalence of emotional and behavioural problems are the number of traumatic events experienced, gender and the living situation. Although migrant and non-migrant adolescents don't differ much in the prevalence of emotional and behavioural symptoms, attention should be given to the screening and support of risk groups within the population of migrant adolescents, such as girls, those who experienced a lot of traumatic events and unaccompanied refugee children and adolescents.


Knee MR Using a Body Coil is Equivalent to CT in Measuring the TT-TG Distance: Removing the Systematic Bias.
Objective To compare magnetic resonance imaging (MRI) using a body coil with computed tomography (CT) in measuring the tibial tubercle-trochlear groove distance (TT-TG) and the patellar tendon-cartilaginous trochlear groove (PT-CTG) distances, and evaluate interrater reliability. Methods The study group consisted of 34 knees from 17 asymptomatic subjects with no history of knee pathology, trauma or surgery. A low-dose CT scan and an axial T1-weighted MRI sequence of the knees were performed with rigorous standardization of the positioning with full extension of the knees and parallel feet. Two musculoskeletal radiologists performed the measurements independently. The reliability of the TT-TG and PT-CTG distances on CT (17.1 ± 4.2 mm and 17.3 ± 4.2 mm) and of MRI (16.2 ± 3.7 mm and 16.5 ± 4.1 mm) was assessed by intraclass correlation coefficient (ICC [2,1]) and Bland-Altman graphs, as well as the interrater reliability for both methods. Results Good reliability and agreement was observed between CT and MRI measurements for TT-TG and PT-CTG, with an ICC of 0.774 ( p < 0.001) and 0.743 ( p < 0.001), respectively, and no systematic bias was observed. The interrater reliability was excellent for all measurements on both imaging methods. Conclusion This was the first study that compared MRI using a body coil with CT in measuring the TT-TG distance, with the potential clinical implication that the CT in this clinical setting could be avoided.


Managing vulvovaginal hematoma by arterial embolization as first-line hemostatic therapy.
A puerperal vulvovaginal hematoma may continue to grow after a surgical procedure and may require blood transfusion. Thus, we selected arterial embolization for hemostasis as the first-line management in two cases of large vulvovaginal hematoma. Case 1 was a 32-year-old pregnant woman. After delivery, a 10-cm vulvar hematoma developed. An enhanced computed tomography (CT) scan revealed active bleeding. Arterial embolization was performed and complete hemostasis was obtained. Case 2 was a 34-year-old woman with a recurring hematoma after delivery. An enhanced CT scan revealed extravasation in the hematoma. Gelatin sponges were applied and complete hemostasis was obtained. In both cases, arterial embolization was successful without requiring blood transfusions. We successfully managed two cases of puerperal vulvovaginal hematoma by arterial embolization based on the evaluation of an enhanced CT scan. In conclusion, we suggest arterial embolization to be a viable option for first-line treatment in the management of vulvovaginal hematomas.


Behavior genetics of olfactory responses in Drosophila. I. Olfactometry and strain differences in Drosophila melanogaster.
A simple olfactometer was constructed for measuring the responses of adult Drosophila to odoriferous substances, and an index (attractability index, AI) is proposed to evaluate the response. Five strains of Drosophila melanogaster of different geographic origins were tested for their responses to five chemical attractants: ethyl alcohol, acetic acid, lactic acid, ethyl acetate, and n-butyraldehyde. Statistical analysis has shown that the differences of AI among strains are highly significant for all the odorants except acetic acid and that male flies are, in general, less sensitive than females. The number of flies which were inactive in the olfactometer also varied with strain, sex, and odorant, suggesting the involvement of some other behaviors, and this raises some difficulties in interpreting the heterogeneities of AI. Nevertheless, these results suggest that a considerable amount of genetic variation for olfactory response exists in natural population of D. melanogaster.


Mixed-mode hydrophobic ion exchange for the separation of oligonucleotides and DNA fragments using HPLC.
Hydrophobic anion exchangers were formed by cobonding both ionic and hydrophobic ligands to silica gel. These phases were used to separate single-stranded oligonucleotides and double-stranded DNA restriction fragments. By varying the ratio of n-octyldimethylsilane and either 3-chloropropyldimethylsilane or 4-chlorobutyldimethylsilane added during silanization a series of mixed-ligand or mixed-mode stationary phases was created. Concentration and ratio of bonded ligands were determined using a new gas chromatography fluorination method. Total ligand coverage was found to approach 2.1 ligands nm-2 for n-octyldimethylsilane. Bonding reproducibility for mixed-mode phases was good. Nucleic acid separations were achieved under gentle mobile phase conditions by using the stationary phase as an easily modifiable variable.


Optimized culture methods for isolating small extracellular vesicles derived from human induced pluripotent stem cells.
Extracellular vesicles that are derived from stem cells play an important role in the treatment of disease. To obtain high-quality small extracellular vesicles (sEVs), we optimized the culture conditions of human induced pluripotent stem cells (hiPSCs), the supernatant collection time, and sEVs extraction methods. Firstly, hiPSCs were cultured in extracellular vesicles-production medium (EVs-PM) containing different concentrations (0%, 0.25%, 0.5%, 2%, 5%, and 20%) of extracellular vesicle-depleted knockout serum replacement (ED-KSR), and the culture supernatants were collected continuously for 5 days. Then, the sEVs were isolated, followed by an evaluation of their characteristics. The survival rates of the hiPSCs lines that were cultured in EVs-PM containing 0.5% to 20% ED-KSR were not significantly different (P > 0.05). The survival rates of the hiPSCs in 0.5% ED-KSR after the culture supernatants were continuously collected for day 1, day 3, and day 5 were not statistically significant (P > 0.05). After 5 days of continuous collection of the supernatant, the hiPSCs expressed some pluripotent markers, while SSEA4 and TRA-1-60 expression changed gradually. The sEVs that were extracted by the two methods were all 50-200 nm, double-layered and oval or round cellular vesicles and expressed the marker proteins CD63, TSG101, and HSP70. The characteristics of sEVs extracted on day 1, day 3, and day 5 were almost identical on morphology, size and the relative quantity of annexin V-positive subpopulations. The PKH67 staining showed that the sEVs could be endocytosed by HepG2 cells and aggregated in the cytoplasm. The proliferation experiments showed that the sEVs can promote cell proliferation. In Conclusion, the 0.5% ED-KSR is the optimal concentration, and that the hiPSCs culture supernatant can be continuously collected for 5 days while maintaining high cell viability and some pluripotent characteristics. Both of the methods extraction can be used to obtain biologically active sEVs.


Extracorporeal blood oxygenation and ozonation (EBOO): a controlled trial in patients with peripheral artery disease.
Since 1990 our group has been using extracorporeal circulation to ozonate blood by an original method, known as extracorporeal blood oxygenation and ozonation (EBOO), with the aim of amplifying the results observed with ozone autohemotherapy. To verify the hypothesis that EBOO improves the skin lesions typical of peripheral artery disease (PAD) patients. Twenty-eight patients with PAD were randomized to receive EBOO or intravenous prostacyclin in a controlled clinical trial. The primary efficacy parameters were regression of skin lesions and pain,and improvement in quality of life and vascularisation. Patients treated with EBOO showed highly significant regression of skin lesions with respect to patients treated with prostacyclin. Other parameters that were significantly different in the two groups of patients were pain,pruritus, heavy legs and well-being. No significant differences in vascularisation of the lower limbs before and after treatment were found in either group. No side effects or complications were recorded during the 210 EBOO treatments. EBOO was much more effective than prostacyclin for treating skin lesions in PAD patients and also had a positive effect on patient general condition without any apparent change in arterial circulation. This suggests other mechanisms of action of EBOO.


Genome-wide long noncoding RNA and mRNA expression profiles demonstrate associations between exposure to inorganic elements and the risk of developing hepatocellular carcinoma.
Long noncoding RNAs (lncRNAs) are closely associated with the development of hepatocellular carcinoma (HCC). The present study conducted a genome-wide microarray analysis and qPCR validation to obtain comprehensive insights into this issue. Thirty male HCC patients with chronic HBV infection were included in the present study. Primary HCC tissue and normal tissue were collected. Double-stranded complementary DNA synthesized from 10 pairs of samples was labeled and hybridized to a microarray chip. Further analyses, such as hierarchical clustering, gene ontology (GO) and pathway analyses, were performed. In addition, qPCR validation was performed on tissue samples and additional serum samples. The microarray analysis identified 946 upregulated and 571 downregulated lncRNAs and 1720 upregulated and 1106 downregulated mRNAs. Among these RNAs, ENST00000583827.1 (fold change: 21) and uc010isf.1 (fold change: 18) were the most over- and underexpressed lncRNAs in the HCC tissues, respectively. For the mRNAs, KIF20A (fold change: 26) and HEPACAM (fold change: 50) were the most over- and underexpressed in the HCC tissues, respectively. The GO analysis demonstrated that the most differentially expressed mRNAs were related to the response of metal ions. The pathway analysis also suggested that the most enriched pathway was mineral absorption. The subsequent qPCR validation exhibited high consistency with the microarray analysis, except for three lncRNAs. The qPCR analysis also demonstrated that TCONS_00008984 had a 767-fold overexpression level in HCC tissues when compared with normal tissues, and this finding was confirmed in the serum samples; therefore, TCONS_00008984 has the potential to serve as a diagnostic marker or prognostic indicator. The GO and pathway analyses indicated that exposure to inorganic elements may be involved in HCC risk.


Inhibition by fibrin coagulation of lung cancer cell destruction by human interleukin-2-activated killer cells.
We examined the effect of fibrin coagulation on tumor cytotoxicity mediated by human lymphokine (IL-2)-activated killer (LAK) cells. LAK cells were induced from peripheral blood mononuclear cells (MNC) by culture with recombinant IL-2 for 4 or 5 days, and LAK cell-mediated cytotoxicity against tumor cells was assessed by 51Cr release assay in the presence or absence of plasma from normal subjects and lung cancer patients. Plasma did not affect the phase of induction of LAK activity by IL-2, but dose-dependently inhibited the effector phase of LAK cell-mediated cytotoxicity against Daudi cells. Similar inhibition of LAK cell-mediated cytotoxicity was observed on pretreatment of Daudi cells and human lung cancer cell lines with human fibrinogen plus thrombin. A parallel relationship was found between the amount of fibrinogen in plasma of lung cancer patients and inhibition of LAK cytotoxicity. This inhibition was reduced by addition of anticoagulants (heparin or argatroban). These findings suggest that fibrin coagulation on tumor cells protects them from LAK cell-mediated tumor cytotoxicity in malignant lesions and that a combination of an anticoagulant drug and IL-2/LAK therapy may be effective for treatment of lung cancer patients.


Prevalence of inflammatory bowel disease in the Australian general practice population: A cross-sectional study.
The burden of inflammatory bowel disease (IBD) in Australia is increasing but national data about the current prevalence are limited. We aimed to estimate the prevalence of IBD (including Crohn's disease, ulcerative colitis and unspecified IBD) as well as Crohn's disease and ulcerative colitis separately in a general practice population in Australia. We also assessed risk factors associated with Crohn's disease and ulcerative colitis. We conducted a cross-sectional study using data from MedicineInsight, a national database of general practice electronic health records, from 1 July 2017 to 30 June 2019. The prevalence of IBD was calculated and stratified by sociodemographic characteristics. Logistic regression analysis was conducted to assess risk factors associated with Crohn's disease and ulcerative colitis. The study comprised 2,428,461 regular patients from 481 practices. The estimated crude prevalence of IBD was 653 per 100,000 patients; Crohn's disease was 306 per 100,000 and ulcerative colitis was 334 per 100,000. Males were independently associated with a lower risk of Crohn's disease (OR: 0.86; 95% CI: 0.81, 0.90) but a greater risk of ulcerative colitis (OR: 1.12; 95% CI: 1.06, 1.17) than females. Compared to non-smokers, patients who were current smokers were associated with a greater risk of Crohn's disease (OR: 1.13; 95% CI: 1.04, 1.23) but a lower risk of ulcerative colitis (OR: 0.52; 95% CI: 0.47, 0.57). Other factors positively associated with both Crohn's disease and ulcerative colitis were age (≥ 25 years), non-Indigenous status and socioeconomic advantage. Our findings provide a current estimate of the prevalence of IBD, Crohn's disease and ulcerative colitis in a large national general practice population in Australia and an assessment of the factors associated with Crohn's disease and ulcerative colitis. These data can assist in estimating the health burden and costs, and planning for health services.


Thrombus formation, hemostasis, adhesiveness of leukocytes and morphological abnormalities in the microcirculation of adjuvant arthritic rats.
Microcirculatory alterations which may be responsible for the chronicity of adjuvant-induced arthritis in the rat were investigated. Thrombus formation in the mesenteric microcirculation was investigated by laser-technique. In arthritic rats thrombus formation for a given stimulus was increased significantly and a correlation was found between the intensity of the arthritic changes and this thrombotic reaction. Adherence of leukocytes to the venous endothelium was studied by an in vivo technique. The number of "rolling" and "sticking" leukocytes was greatly increased in the mesenteric venules of arthritic rats. Acute treatment of severely arthritic rats with aspirin greatly reduced the increased adhesiveness of granulocytes. By the use of an atraumatic technique for vital microscopy of the microcirculation of skin of arthritic rats, striking morphologic changes with stasis of erythrocytes were observed. Morphological aberrations were also found in the mesenteric microvessels of diseased animals.


Assessment of levothyroxine sodium bioavailability: recommendations for an improved methodology based on the pooled analysis of eight identically designed trials with 396 drug exposures.
Assessment of dosage form performance in delivering endogenous compounds, such as hormones, in vivo requires a specific approach. Assessment of relative bioavailability of levothyroxine sodium (L-T4) from eight solid preparations, compared with a liquid formulation, by using pharmacological doses, and critical evaluation of trial methodology based on the pooled analysis of individual data. Eight open-label, randomised, single-dose, crossover phase I studies using eight solid L-T4 dosage forms (25, 50, 75, 100, 125, 150, 175, 200 microg per tablet; administered total doses 600, 625 or 700 microg) and a liquid formulation; assessment of relative bioavailability by 90% confidence intervals for the relative area under the concentration-time curve (AUC) of total thyroxine (TT4), i.e. protein-bound plus free thyroxine, calculated by using the recommended log AUC four-way analysis of variance models for crossover designs. For the pooled analysis, general linear models were applied to assess the validity of model assumptions, to identify potential sources of effect modification, to discuss alternative modelling approaches with respect to endogenous hormone secretion and to give recommendations for future designs and sample sizes. One hundred and sixty-nine healthy males; 29 of these individuals participating in two studies. Single oral doses of L-T4 tablets and the liquid formulation administered after fasting, separated by at least 6 weeks; a total of 396 drug exposures. TT4 AUC from 0 to 48 hours and peak plasma concentration with and without baseline correction. Each study demonstrated equivalence of the tablets to the drinking solution, independent of the chosen analysis model. Sequence effects that could devalidate the chosen crossover approach were not found. Period effects with changing directions that could best be explained by seasonal variation were detected. While the pre-specified method of baseline correction of simply subtracting individual time-zero TT4 values was disadvantageous, the analysis of total AUC could be improved considerably by covariate adjustment for baseline TT4. With this approach, sample sizes could have been substantially reduced or, alternatively, the recommended equivalence ranges could be reduced to +/-6%. Using a single pharmacological dose of L-T4 in two-period crossover designs is a safe and reliable procedure to assess L-T4 dosage form performance. With an adequate statistical modelling approach, the design is efficient and allows general conclusions with moderate sample sizes.


Safety assessment of the Polypodium feei root extract: Acute and subchronic studies.
This study was performed to assess the safety of the oral acute and subchronic administration of Polypodium feei root extract through acute and subchronic studies in mice and rats, respectively. In the acute toxicity treatment, mice were grouped according to the dose (1000, 2000, 4000 and 5000 mg/kg, b.w) and were observed for mortality and toxicity signs for 14 days. In the subchronic treatment, there were six groups of rats (female and male), a control group, three test groups (100, 400, and 800 mg/kg, b.w), and two satellite groups (control satellite and satellite 800 mg/kg groups). The three test groups received the extract orally once daily for 90 days. No animals in the acute and subchronic treatment groups showed mortality and any signs of toxicity, with no significant difference in the body weight and organ index compared to the control. The LD50 of the extract was estimated to be higher than 5000 mg/kg, therefore regarded as practically non-toxic. The haematological profiles did not significantly change on exposure to the extract for 90 days, except the platelet count in the female animals which significantly decreased in animals treated with 400 and 800 mg/kg, returning to normal after 28 days of recovery. The 800 mg/kg dose significantly increased the urea concentration and induced lesions in the stomachs of female animals. However, this undesirable effect on the kidney was not strong, as the creatinine concentration remained in the normal limits, and the histopathological observations showed no alteration in the kidney tissues. No significant morphological alterations in organs were observed, only minor lesions in the liver. These results indicate that the P. feei root extract is safe for use as herbal medicine and recommended at doses lower than 400 mg/kg.