Gastric ulcerogenic responses following barrier disruption in knockout mice lacking prostaglandin EP1 receptors.
Endogenous prostaglandins (PGs) are considered to play a pivotal role in maintaining the mucosal integrity of the stomach after injury. In the present study, we evaluated the mucosal ulcerogenic and mucosal blood flow (GMBF) responses in the stomach after damage by taurocholate (TC) in knockout mice lacking EP1 or EP3 receptors. Under urethane anaesthesia, a mouse stomach was mounted in an ex vivo chamber, exposed to 20 mmol/L TC for 20 min and treated with 20 mmol/L HCl before and after TC. GMBF was measured with a laser Doppler flowmeter. Mucosal exposure to TC in wild-type mice caused a marked decrease in potential difference (PD), followed by an increase in H+ loss and GMBF. The decreased PD was gradually normalized after removal of TC from the chamber, with minimal damage in the mucosa 1 h after TC treatment. This hyperaemic response was inhibited by indomethacin, resulting in severe lesions in the mucosa without any change in PD or H+ loss. None of these responses induced by TC were altered in EP3-/- mice. However, in mice lacking EP1 receptors, TC treatment did not increase GMBF, despite causing PD reduction and acid loss, and resulted in severe damage in the mucosa. These responses were closely similar to those observed in animals pretreated with ONO-8711, a EP1 receptor antagonist. Mucosal PGE2 content was significantly increased after TC, similarly in all groups of mice. These results confirm a mediator role for PGE2 in gastric hyperaemic response following mucosal exposure to TC and suggest that endogenous PGs may contribute to maintaining mucosal integrity after barrier disruption, mainly through activation of the EP1 receptor subtype.


Foot and ankle tuberculosis: A case report and review of the literature.
It is important to consider foot and ankle tuberculosis (TB) as a potential cause of cystic lesion around the ankle, especially in patients with a history of TB. Early diagnosis and treatment with a rifampin-based regimen for a duration of 12 months can lead to good functional and clinical outcomes. Skeletal TB is an uncommon accounting for 10% of extra-pulmonary TB may present slowly over an extended period of time, making a diagnosis difficult and time-consuming (Microbiology Spectr. 2017;5:5). For the best possible outcome and to reduce the risk of deformity diagnosis must be early (Foot (Edinb). 2018;37:105). For the treatment of drug-susceptible musculoskeletal illness, a rifampin-based regimen lasting 12 months is advised (Clin Infect Dis. 2016;63:e147; J Bone Joint Surg Br. 1993;75:240; Tubercle. 1986;67:243). A 33-year-old female who are working as nurse with diffuse, persistent and low in intensity ankle pain not aggravated relieved by analgesia and swelling over a period of 2 months, static not related to activity. With past medical history of partially treated pulmonary TB 1 year ago. She reported night sweats and low-grade fever during this period, and she denied any history of trauma. The right ankle was globally swollen and tender anteriorly and on the lateral malleolus. The skin over the ankle showed dark discoloration with cautery marks with no discharging sinuses. The range of motion of the right ankle was decreased. The plain x-ray of the right ankle showed three cystic lesion at the distal tibia, one cyst at the lateral malleolus and another one at the calcaneum. Surgical biopsy and expert gene test confirmed the diagnosis of tuberculous osteomyelitis. The patient was planned for surgical curettage of the lesion. After the confirmation of the diagnosis of TB with the biopsy and gene expert test, with consultation of senior chest physician the patient fitted to anti-tuberculous regimen. The patient had good functional and clinical outcome. This case report highlights the importance of considering skeletal TB as a potential cause of musculoskeletal symptoms, especially in patients with a history of TB. Early diagnosis and treatment with a rifampin-based regimen for a duration of 12 months can lead to good functional and clinical outcomes. Further research on the management and prevention of musculoskeletal TB is warranted to improve patient outcomes. The lesson behind this case is that the diagnosis TB osteomyelitis should be on the top of differential diagnosis of multiple cystic lesions around the foot and ankle especially in area where TB is endemic. Early diagnosis and early start of anti-tuberculous therapy can lead to full cure of the patient and in bad situation can minimize the complications.


Increased Free Water in the Putamen in Idiopathic REM Sleep Behavior Disorder.
It has been suggested that the loss of nigrostriatal dopaminergic axon terminals occurs before the loss of dopaminergic neurons in the substantia nigra (SN) in Parkinson's disease (PD). This study aimed to use free-water imaging to evaluate microstructural changes in the dorsoposterior putamen (DPP) of idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) patients, which is considered a prodromal stage of synucleinopathies. Free water values in the DPP, dorsoanterior putamen (DAP), and posterior SN were compared between the healthy controls (n = 48), iRBD (n = 43) and PD (n = 47) patients. In iRBD patients, the relationships between baseline and longitudinal free water values and clinical manifestations or dopamine transporter (DAT) striatal binding ratio (SBR) were analyzed. Free water values were significantly higher in the DPP and posterior substantia nigra (pSN), but not in the DAP, in the iRBD and PD groups than in controls. In iRBD patients, free water values in the DPP were progressively increased and correlated with the progression of clinical manifestations and the striatal DAT SBR. Baseline free water in the DPP was negatively correlated with striatal DAT SBR and hyposmia and positively correlated with motor deficits. This study demonstrates that free water values in the DPP are increased cross-sectionally and longitudinally and associated with clinical manifestations and the function of the dopaminergic system in the prodromal stage of synucleinopathies. Our findings indicate that free-water imaging of the DPP has the potential to be a valid marker of early diagnosis and progression of synucleinopathies. © 2023 International Parkinson and Movement Disorder Society.


Evaluation of the DNA-repair host-mediated assay. I. Induction of repairable DNA damage in E. coli cells recovered from liver, spleen, lungs, kidneys, and the blood stream of mice treated with methylating carcinogens.
The DNA-repair host-mediated assay was further calibrated by determining the genotoxic activities of 4 methylating carcinogens, namely, dimethylnitrosamine (DMNA), 1,2-dimethylhydrazine (SDMH), methyl nitrosourea (MNU) and methyl methanesulphonate (MMS) in various organs of treated mice. The ranking of the animal-mediated genotoxic activities of the compounds was compared with that obtained in DNA repair assays performed in vitro. The differential survival of strain E. coli K-12/343/113 and of its DNA-repair-deficient derivatives recA, polA and uvrB/recA, served as a measure of genotoxic potency. In the in vitro assays and at equimolar exposure concentrations, MMS and MNU are the most active chemicals, followed by DMNA, which shows a slight genotoxic effect only in the presence of mouse liver homogenate; SDMH has no activity under these conditions. In the host-mediated assays, the order of genotoxic potency of the compounds was quite different: those carcinogens which require mammalian metabolic activation, namely, DMNA and SDMH, show strong effects in liver and blood, a lesser effect in the lungs and kidneys and the least effect in the spleen. The activity of MNU, a directly acting compound, is similar in all organs investigated, but it is clearly lower than that of DMNA and SDMH. MMS, also a directly acting carcinogen, causes some (barely significant) effect at the highest dose tested. A similar order of potency was observed when the compounds were tested in intrasanguineous host-mediated assays with gene mutation as an endpoint. DMNA and SDMH induce comparable frequencies of L-valine-resistant mutants in E. coli K-12/343/113 recovered from liver and spleen of treated mice, the effect in the liver being the strongest. MNU is mutagenic only at a higher dose, while MMS shows no effect. The results are discussed with respect to the literature data on organ-specific DNA adduct formation induced by the compounds. It is concluded that qualitatively there is a good correlation between the degree of genotoxic activity found in the DNA repair host-mediated assay and DNA adduct formation in the animal's own cells. This is exemplified by the finding that the relative order of genotoxic activity of the 4 methylating agents in bacteria recovered from various organs (DMNA approximately equal to SDMH greater than MNU greater than MMS) is reflected by the same order of magnitude in DNA alkylation in corresponding mammalian organs. Quantitatively, the indirectly acting agents DMNA and SDMH seem to induce fewer genotoxic effects in bacteria present in the liver than would be expected on the basis of DNA-adduct formation data.


Smear layer removal by auxiliary chemical substances in biomechanical preparation: a scanning electron microscope study.
The aim of this study was to assess, by scanning electron microscopy analysis, the cleaning ability of irrigants and auxiliary chemical substances in biomechanical preparation. Thirty-two single-rooted human teeth were subjected to standardized root canal instrumentation with different irrigants (n = 8): group 1, 2.5% NaOCl + 17% ethylenediaminetetraacetic acid (EDTA); group 2, 2% chlorhexidine gel + 17% EDTA; group 3, Canal Plus + 2.5% NaOCl; group 4, saline + 17% EDTA. After instrumentation, the teeth were prepared for scanning electron microscopy analysis (2000x) to evaluate the cleaning of cervical, middle, and apical thirds. The area analyzed was quantified according to the percentage of open tubules, and data were statistically analyzed by analysis of variance and Tukey tests (P = .05). The results showed statistically significant difference with higher quantity of open tubules in groups 1 and 3. In all groups, the cleaning obtained on the cervical third was better than that obtained on the middle and apical thirds, with statistically significant difference in the chlorhexidine group. Irrigation with Canal Plus in combination with NaOCl and NaOCl followed by EDTA produced greater cleaning of the root canal walls.


Serum prostacyclin binding and half-life in the umbilical circulation.
Serum prostacyclin binding and half-life was measured in twenty pairs of maternal and umbilical venous samples and in twenty non-pregnant controls. When compared to non-pregnant values both umbilical and maternal samples demonstrated significantly lower albumin concentrations, percentage of prostacyclin binding and shorter prostacyclin half-life.


Synthesis and biological evaluation of novel C6-cyclo secondary amine substituted purine steroid-nucleosides analogues.
Novel C6-cyclo secondary amine substituted purine steroid-nucleoside analogues (2-9) were efficiently synthesized through displacement of the C6 chloro on the purine ring of series 1 with versatile cyclic secondary amines, including pyrrolidines, piperidine, morpholine, and piperazines. All the newly-synthesized compounds were evaluated for their anticancer activity in vitro against Hela, PC-3 and MCF-7 cell lines. Among them, compounds 5c and 6b exhibited significant cytotoxicity on PC-3 cell lines.


Epidemiological and Clinical Patterns of Newly Diagnosed Hepatocellular Carcinoma in Brazil: the Need for Liver Disease Screening Programs Based on Real-World Data.
Describe sociodemographic and clinical characteristics of patients with hepatocellular carcinoma (HCC) and establish their history in the Brazilian public health system. Retrospective observational study was conducted using the database from the Department of Informatics of the Unified Health System (DataSUS). Patients with at least one claim of HCC between July/2011 and June/2016 were included. A record linkage methodology was performed to obtain longitudinal data across different databases. Demographic and clinical data were evaluated, including the time elapsed between diagnosis of HCC risk-factors and the cancer development. Data was analyzed using descriptive statistics. A total of 28,822 HCC cases were identified between July/2011 and June/2016. Mean age was 59.7 years (SD = 14.7), and most patients were men (55.9%). The highest relative number of HCC cases was detected in the south of Brazil (> 20 cases/100,000 inhabitants). About 86.5% of the patients had diagnosis of HCC without previous liver diseases. Only 8% had diagnosis of chronic viral hepatitis and 3.5% cirrhosis. About 76% were diagnosed at an advanced stage, and only 11% of the patients had early stage HCC. Approximately 58% of patients with previous underlying liver diseases were diagnosed at early stages, compared with only 24% of patients without prior record of underlying diseases. The diagnosis of HCC in the Brazilian public health is usually made in patients with no previous diagnosis of liver disease and in advanced stages, when no curative treatment is available and survival rates are low. Public health policies are key for the screening and monitoring liver disease and, consequently, HCC.


Genetic risk factors influence nighttime blood pressure and related cardiovascular complications in patients with coronary heart disease.
Genetic predisposition of elevated nighttime blood pressure (BP) in patients with coronary heart disease is unknown. We evaluated genetic predisposition and the relationship between elevated nighttime BP and cardiovascular complications over a median of 8.6 years of observation of hypertensive subjects with coronary atherosclerosis confirmed by coronary angiography. Genetic Risk Score (GRS19) was constructed to evaluate the additive effect of single-nucleotide polymorphisms for daytime and nighttime BP. The Receiver Operating Characteristic was used for determination of cutoff points for daytime BP (systolic BP (SBP) 133 mm Hg and diastolic BP (DBP) 77 mm Hg) and nighttime BP (SBP 122 mm Hg and DBP 73 mm Hg). The curves of cumulative incidence revealed an increased risk of major advanced cardiovascular events in subjects with elevated nighttime BP compared with those without elevated nighttime BP during the follow-up period. Subjects with normal daytime and elevated nighttime BP exhibited increased GRS19 compared with those with normal daytime and nighttime BPs (8.6±3.0 vs. 7.9±3.0, P<0.01). After adjustment for cardiovascular risk factors, GRS19 determined nighttime SBP (β 0.4, 95% confidence interval (CI) 0.3-0.5, P<0.01). Our study confirmed that elevated nighttime SBP was genetically determined and related to an increased risk of major adverse coronary events in patients with confirmed coronary atherosclerosis.


Genetic characterisation of circulating fetal cells allows non-invasive prenatal diagnosis of cystic fibrosis.
Cystic fibrosis (CF) is an autosomal recessive disease due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The purpose of this study was to develop a molecular method to characterise both paternal and maternal CFTR alleles in DNA from circulating fetal cells (CFCs) isolated by ISET (isolation by size of epithelial tumour/trophoblastic cells). The molecular protocol was defined by developing the F508del mutation analysis and addressing it both to single trophoblastic cells, isolated by ISET and identified by short tandem repeats (STR) genotyping, and to pooled trophoblastic genomes, thus avoiding the risk of allele drop out (ADO). This protocol was validated in 100 leucocytes from F508del carriers and subsequently blindly applied to the blood (5 mL) of 12 pregnant women, at 11 to 13 weeks of gestation, whose offspring had a 1/4 risk of CF. Ten couples were carriers of F508del mutation, while two were carriers of unknown CFTR mutations. Results showed that one fetus was affected, seven were heterozygous carriers of a CFTR mutation, and four were healthy homozygotes. These findings were consistent with those obtained by chorionic villus sampling (CVS). Our data show that the ISET-CF approach affords reliable prenatal diagnosis (PND) of cystic fibrosis and is potentially applicable to pregnant women at risk of having an affected child, thus avoiding the risk of iatrogenic miscarriage.


The Warburg effect modulates DHODH role in ferroptosis: a review.
Ferroptosis is an iron-dependent regulated cell death that suppresses tumor growth. It is activated by extensive peroxidation of membrane phospholipids caused by oxidative stress. GPX4, an antioxidant enzyme, reduces these peroxidized membrane phospholipids thereby inhibiting ferroptosis. This enzyme has two distinct subcellular localization; the cytosol and mitochondria. Dihydroorotate dehydrogenase (DHODH) complements mitochondrial GPX4 in reducing peroxidized membrane phospholipids. It is the rate-limiting enzyme in de novo pyrimidine nucleotide biosynthesis. Its role in ferroptosis inhibition suggests that DHODH inhibitors could have two complementary mechanisms of action against tumors; inhibiting de novo pyrimidine nucleotide biosynthesis and enhancing ferroptosis. However, the link between mitochondrial function and ferroptosis, and the involvement of DHODH in the ETC suggests that its role in ferroptosis could be modulated by the Warburg effect. Therefore, we reviewed relevant literature to get an insight into the possible effect of this metabolic reprogramming on the role of DHODH in ferroptosis. Furthermore, an emerging link between DHODH and cellular GSH pool has also been highlighted. These insights could contribute to the rational design of ferroptosis-based anticancer drugs. Video Abstract.


Bioleaching of polymetallic sulphidic mining residues: influence of increasing solid concentration on microbial community dynamics and metal dissolution.
Within the European research project NEMO, a bioleaching strategy was developed for efficient metal extraction from bioleach residue currently heap-leached at Sotkamo (Finland) that still contains sulphidic minerals and valuable metals (Ni, Zn, Co, Cu). The strategy of gradually increasing the solid content with 5% steps allowed the adaptation of the consortium up to 20% (w/w) solid content, with efficient metal dissolution and same dominant bacteria. Largest proportions of Sulfobacillusthermosulfidooxidans while Eh increased suggested it to be most involved in iron oxidation. Acidithiobacilluscaldus was rather found when pH stabilized, in line with a production of protons from sulphur oxidation that maintained low pH. 'Acidithiomicrobium' P2 was favoured towards the end of the runs and at 20% (w/w) solids possibly due to its tolerance to Ni. The use of gene abundance to evaluate biomass in the pulp provided complementary results to classical cell counts in the liquid phase, and suggested a key role of bacteria associated to mineral particles in iron oxidation. Scaling-up in 21-L stirred-tank reactor at 20% (w/w) solids had no detrimental effect on bioleaching and confirmed metal extraction rates. 'Acidithiomicrobium' P2 and Sb. thermosulfidooxidans remained main actors. However, the biological activity was considerably reduced at 30% (w/w) solid concentration, which may be due to a too drastic environmental change for the bacteria to adapt to higher solid concentration. Efficient bioleaching of Sotkamo bioleaching residue at high solid concentration was demonstrated, as well as the robustness of the selected moderately thermophilic consortium, at laboratory and pilot scales.


A refined concept of the Critoniopsisbogotana species group in Colombia with two new species (Vernonieae, Asteraceae).
Critoniopsisbogotana is more precisely delimited, and two related Colombian species are described as new. The form of trichomes on the abaxial surfaces of the leaves is found to be of major importance. A short key to the Critoniopsisbogotana group is provided.


Upper extremity deep vein thrombosis following BBIBP-CorV COVID-19 vaccine (Sinopharm vaccine): A case report.
In patients with acute symptoms such as pain, swelling, and erythema of the upper extremities shortly after receiving COVID-19 vaccines, even inactivated virus vaccines, these symptoms may indicate thrombosis, which may be due to the vaccination. BBIBP-CorV COVID-19 vaccine (Sinopharm vaccine) is an inactivated whole virus vaccine to control the COVID-19 pandemic. Studies concluded that inactivated COVID-19 vaccines do not increase the risk of thrombosis. This report presents a 23-year-old man with the chief complaint of severe pain, swelling, and erythema of the right upper extremity following his second dose of the Sinopharm vaccine. Duplex ultrasound of the right upper extremity revealed upper extremity deep vein thrombosis, and treatment started with oral anticoagulation. It is probably the first upper extremity deep vein thrombosis case following inactivated COVID-19 vaccines.


Synthesis and antimalarial evaluation of artesunate-polyamine and trioxolane-polyamine conjugates.
A series of artesunate-polyamine and trioxolane-polyamine conjugates have been prepared. The conjugates were evaluated for antimalarial activity towards the K1 dual drug resistant and NF54 chloroquine-sensitive strains of Plasmodium falciparum (Pf) and for cytotoxicity towards the rat myoblast cell line L6. (Bis)-Boc-(bis)-artesunate-polyamine and (tetra)-artesunate-polyamine conjugates exhibited potent in vitro activity towards both strains of Pf, with IC50 values in the range of 0.3-1.1 nM, comparable to the parent artesunate. Cytotoxicity within this series of analogues typically increased with polyamine (PA) chain length, identifying the PA3-4-3 (spermine), and to some extent the PA3-7-3 series, as being highly selective towards the parasite. The corresponding series of (bis)-Boc-(bis)-trioxolane and (tetra)-trioxolane-polyamine conjugates were less active as antimalarials than the parent trioxolane acid, highlighting the limitation of using this warhead for drug-conjugate studies. Preliminary in vivo evaluation of two artesunate-polyamine conjugates 11 and 16 demonstrated 95.5-99.8% reduction in parasitaemia with maximal 30 day survival rates (ip delivery). Oral testing of 11 proved less efficacious, with 95.7% activity and inconsistent survival rates of 16-30 days. In contrast, trioxolane-polyamines were substantially less effective (ip delivery), exhibiting only modest reductions in parasitaemia and modest to no increase in survival rates.


ACE activity in blood and brain axis in an animal model for schizophrenia: Effects of dopaminergic manipulation with antipsychotics and psychostimulants.
Objectives: Angiotensin I-converting enzyme (ACE) was initially correlated with schizophrenia (SCZ) in studies showing a correlation of ACE increased enzyme activity with memory impairments. Possible role for ACE in SCZ was also suggested by ACE activity interaction with dopaminergic mechanisms to modulate abnormalities of sensorimotor gating. In addition, we have demonstrated higher ACE activity in blood of SCZ subjects, its implication in cognitive performance in SCZ and its power as a predictor for SCZ diagnosis.Methods: ACE activity was determined in the serum and in selected brain regions of an animal model presenting SCZ-like behaviour, before and after the treatment with typical and atypical antipsychotics, and also in the serum of animals receiving the psychostimulants amphetamine/lisdexamphetamine.Results: Dopaminergic manipulations with antipsychotics and psychostimulants influenced the ACE activity, but with no correlation with the animal blood pressure.Conclusions: The validity of measuring ACE activity in animal blood to predict activity in the CNS, as well as the lack of correlation between the activity and blood pressure, before and after the treatment with antipsychotics, were confirmed here. Correlations of the present findings with data from clinical studies also strengthen the value of this animal model for studying several aspects of SCZ.


Crossed immunoelectrophoretic and crossed radioimmunoelectrophoretic studies employing a model allergen from codfish.
A standard reference pattern in crossed immunoelectrophoresis (CIE) of the parvalbumin fraction of a cod white muscle extract was established. Crossed line immunoelectrophoresis (CLIE), tandem CIE and crossed radioimmunoelectrophoresis (CRIE) were used to identify the major allergens, thereby establishing a basis for future work employing quantitative immunoelectrophoretic techniques in the study of codfish allergens. Rocket immunoelectrophoresis and rocket-line immunoelectrophoresis were used to demonstrate antigenic determinants on polypeptide fragments of the major allergen, Allergen M. The results show the usefulness of these techniques in studies of antigenic determinants on non-precipitating polypeptides. CRIE with 8 patients's sera showed radiostaining indicating IgE binding corresponding to at least 7 precipitates in the crude extract CIE preparations. The purified DS 22 fraction was shown to contain 2 CRIE-positive (IgE-binding) precipitates. When using Allergen M, these precipitates were also demonstrated, one of them in trace amounts only.


Modulatory effect of MgATP on smooth muscle myosin phosphatase activity.
To deepen our understanding of the regulatory mechanism of smooth muscle contraction, we examined properties of smooth muscle myosin phosphatase (SMMP) which was purified from chicken gizzard according to the method of Alessi et al. with slight modifications. The SMMP was a heterotrimer of 130, 37 and 20 kDa subunits as reported. Because the enzymatic activity was strongly dependent on the ionic strength, all experiments were carried out at a constant ionic strength of 0.15 M. The Vmax and K(m) of the enzyme toward bovine stomach phosphorylated myosin was 25.2 mumol/mg protein/min and 0.45 microM at 25 degrees C, respectively, which implied that the rate of dephosphorylation by SMMP in smooth muscle cells should be comparable to that of phosphorylation by the myosin light chain kinase in the presence of a saturating Ca2+ concentration. ATP dose-dependently decreased the SMMP activity to one-fifth. The IC50 for ATP was 0.6 microM in the presence of 5 mM MgCl2, whereas it increased to 10 microM in the absence of Mg2+ with the addition of 1 mM EDTA. ADP, AMP, GTP and ITP showed no or only weak effect. The finding that ATP gamma S was ineffective indicates that phosphorylation of the 130 kDa subunit cannot be the underlying mechanism. This modulation was observed with myosin from bovine stomach, but not from chicken gizzard. The difference in conformation of myosin molecules in the presence of MgATP may be critical in its modulatory effect.


Design, synthesis and structure-activity relationship studies of novel partial FXR agonists for the treatment of fatty liver.
Nonalcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease, while there is still no medicine available. Farnesoid X receptor (FXR) is considered as a potential target for the treatment of NAFLD, and there are several FXR agonists reached in clinical trials. Based on better safety, industry and academia are pursuing development of the partial FXR agonists. To extend the chemical space of existing partial FXR agonists, we performed a structure-activity relationship study based on previously reported partial agonist 1 by using bioisosteric strategy. All of these efforts resulted in the identification of novel partial FXR agonist 13, which revealed the best agonistic activity in this series. Notably, compound 13 significantly alleviated the hepatic steatosis and hepatic function index in methionine-choline deficient (MCD) induced db/db mice, a classical nonalcoholic steatohepatitis (NASH) model widely used in preclinical evaluation. These results suggested that partial FXR agonist 13 might be a promising lead compound worthy further researches.


Inflammation-induced shift in the valence of spinal GABA-A receptor-mediated modulation of nociception in the adult rat.
The objective of this study was to assess the impact of persistent inflammation on spinal gamma-aminobutyric acid-A (GABA-A) receptor-mediated modulation of evoked nociceptive behavior in the adult rat. Nocifensive threshold was assessed with von Frey filaments applied to the dorsal surface of the hind paw. The GABA-A receptor agonist muscimol, the antagonist gabazine, the benzodiazepine receptor agonist midazolam, and antagonists PK11195 and flumazenil were administered spinally in the presence and absence of complete Freund's adjuvant (CFA)-induced inflammation. In naive rats, muscimol increased and gabazine decreased nociceptive threshold. After CFA, the effects of these compounds were reversed: Low doses of muscimol exacerbated the inflammation-induced decrease in nociceptive threshold and gabazine increased nociceptive threshold. Midazolam increased nociceptive threshold both in the presence and absence of inflammation. Flumazenil but not PK11195 blocked the analgesic effects of midazolam. These findings indicate that inflammation-induced changes in GABA-A signaling are complex and are likely to involve several distinct mechanisms. Rectifying the changes in GABA-A signaling may provide effective relief from hypersensitivity observed in the presence of inflammation. An inflammation-induced shift in spinal GABA-A receptor signaling from inhibition to excitation appears to underlie inflammatory pain and hypersensitivity. Use of GABA-A receptor selective general anesthetics in association with therapeutic interventions may be contraindicated. More importantly, rectifying the changes in GABA-A signaling may provide effective relief from inflammatory hypersensitivity.


Biological properties and clinical application of propolis. VI. Investigation of the influence of ethanol extracts of propolis (EEP) on cartilaginous tissue regeneration.
Dressing of artificially formed losses of the cartilaginous tissue with the preparation containing ethanol extract of propolis (EEP) caused acceleration of regenerating processes in the lesioned cartilage. EEP inserted into the joint is well tolerated.


Investigation of Self-Interaction Corrections for an Exactly Solvable Model System: Orbital Dependence and Electron Localization.
A systematic investigation of two approximate self-interaction corrections (SICs), Perdew-Zunger SIC and Lundin-Eriksson SIC, and the local-density approximation (LDA) is performed for a model Hamiltonian whose exact many-body solution and exact LDA are known. Both SICs as well as LDA are applied in the calculation of ground-state energies, ground-state densities, energy gaps, and impurity densities of one-dimensional Hubbard chains differing in size, particle number, and interaction strength. The orbital-dependent potentials arising from either SIC are treated within the optimized-effective potential method, which we reformulate for the Hubbard model. The delocalization tendency of LDA is confronted with the localization tendency of SIC. A statistical analysis of the resulting data set sheds light on the role of SIC for weakly and strongly interacting particles and allows one to assess the performance of each methodology.


Proteomic study of in vitro osteogenic differentiation of mesenchymal stem cells in high glucose condition.
Patients with diabetes have been widely reported to be at an increased risk of secondary osteoporosis. Osteoporosis is caused by an imbalance in bone remodeling due to increased bone resorption and/or decreased osteoblast-dependent bone formation. In this study, mesenchymal stem cells (MSCs) were used as a disease model to determine the effects of high glucose levels on MSC-osteoblast development. The results indicated that under high glucose conditions, MSCs had reduced cell viability and increased number of β-galactosidase-positive cells. Furthermore, in vitro osteogenesis was shown to be reduced in MSCs cultured in osteogenic differentiation medium at 10, 25, and 40 mM glucose as demonstrated by Alizarin red S staining and alkaline phosphatase activity assay. Moreover, a proteomic study was performed in MSCs cultured with 25 and 40 mM glucose. The proteomic results demonstrated that 12 proteins were up- and downregulated in bone marrow-derived mesenchymal stem cells cultured with high glucose in a dose-dependent manner. The findings presented here contribute to our understanding of the mechanism of diabetes mellitus responsible for bone loss. However, the exact mechanism of action of hyperglycemia on bone deformability requires additional studies.


Nighttime sleep duration, daytime napping, and metabolic syndrome: findings from the China Health and Retirement Longitudinal Study.
This study aimed to assess the association between nighttime sleep, daytime napping, and metabolic syndrome (MetS) in an elderly Chinese population. A cross-sectional study was conducted using data from the 2011 China Health and Retirement Longitudinal Study (CHARLS) to examine the association between nighttime sleep, daytime napping, and MetS (defined according to the Chinese Diabetes Society criteria). Sleep duration was assessed by a self-reported questionnaire. Binary logistic regression models were used to estimate odds ratios and 95% confidence intervals of the associations adjusting for covariates. Among 4785 elderly Chinese aged over 65 years old, there was no association between short-time sleep duration (< 7 h/day) and MetS. However, long-time sleep duration (> 8 h/day) decreased the odds of MetS by 53% (aOR= 0.47; 95% CI 0.23-0.96) compared to normal sleep duration (7-8 h/day). Compared to no daytime napping, short-time napping (≤ 30 min/day) was associated with increased odds of MetS (aOR = 1.55, 95% CI 1.02-2.36) and long-time napping (> 30 min/day) was associated with even higher odds of MetS (aOR = 1.77, 95%CI 1.24-2.53). Individuals who were over 75 years old, with elementary school education, and good health status had lower odds of MetS, while women, individuals living in rural areas, and those who reported poor health status had higher odds of MetS. Long-time sleep duration decreased and daytime napping increased the risk of MetS among the elderly Chinese population. We speculate that increasing nighttime sleep duration and decreasing daytime napping may help reduce the risk of MetS.


Statistical considerations for stopping systemic lupus erythematosus clinical trials earlier.
Group sequential designs are used to potentially shorten randomized clinical trials and thereby reduce subject burden, improve safety, and save time and resources. Clinical trials comparing treatments for systemic lupus erythematosus (SLE) might adopt such designs if the ordinal outcome scales for SLE, such as the Systemic Lupus Activity Measure and Systemic Lupus Erythematosus Disease Activity Index, were more like continuous outcome scales with interval properties. After describing the basic features of sequential trials and highlighting some major issues in their design, we propose approaches that mitigate these issues. In particular, high-speed computing has accelerated advances in sequential design, making available a variety of designs that can be implemented with minimal technical support. The challenge now is to understand the concepts behind such flexible designs and then to apply them to improve studies of SLE.


Dietary factors affecting the urinary mutagenicity assay system. I. Detection of mutagenic activity in human urine following a fried beef meal.
Studies have been conducted to determine whether the mutagens in fried beef ingested by human subjects are excreted in the urine. Urine samples were collected from individuals on liquid or regular diets before and after a fried beef meal. The mutagenic activity of the samples was tested in the Ames Salmonella/microsome assay system. The results showed that in individuals on liquid diets, most of the urinary mutagenic activity is recovered within 2-6 h after consuming a fried beef meal. In one individual tested, mutagenic activity was found in urine samples obtained 6-15 h after the fried beef meal. No mutagenic activity was detected in any of the urine samples obtained 15-24 h following the meal. In individuals on a regular diet, however, mutagenic activity was frequently observed in urine samples obtained 16-24 h following the fried beef meal, although the mutagenic activity was not as great as that in the preceding 16 h. It appears that the mutagenic agents generated by the frying of beef are ingested, absorbed, and excreted by the human body in biologically detectable quantities. These results suggest that subjects should abstain from fried beef at least one day prior to and during urine mutagenicity screening.


Selecting the minimum prediction base of historical data to perform 5-year predictions of the cancer burden: The GoF-optimal method.
Predicting the future burden of cancer is a key issue for health services planning, where a method for selecting the predictive model and the prediction base is a challenge. A method, named here Goodness-of-Fit optimal (GoF-optimal), is presented to determine the minimum prediction base of historical data to perform 5-year predictions of the number of new cancer cases or deaths. An empirical ex-post evaluation exercise for cancer mortality data in Spain and cancer incidence in Finland using simple linear and log-linear Poisson models was performed. Prediction bases were considered within the time periods 1951-2006 in Spain and 1975-2007 in Finland, and then predictions were made for 37 and 33 single years in these periods, respectively. The performance of three fixed different prediction bases (last 5, 10, and 20 years of historical data) was compared to that of the prediction base determined by the GoF-optimal method. The coverage (COV) of the 95% prediction interval and the discrepancy ratio (DR) were calculated to assess the success of the prediction. The results showed that (i) models using the prediction base selected through GoF-optimal method reached the highest COV and the lowest DR and (ii) the best alternative strategy to GoF-optimal was the one using the base of prediction of 5-years. The GoF-optimal approach can be used as a selection criterion in order to find an adequate base of prediction.


Intestinal ischemia secondary to thromboangiitis obliterans.
A 38-year-old woman presented with a 10-month history of postprandial abdominal pain and weight loss. She smoked two packs of cigarettes a day, but her history did not indicate diabetes mellitus, hyperlipidemia, or hypercoagulability. A lateral aortogram documented complete occlusion of all three mesenteric arteries but showed no evidence of atherosclerosis, arteritis, or medial fibroplasia. Two retrograde aortomesenteric grafts, one to the superior mesenteric artery and another to the meandering mesenteric artery, utilizing the greater saphenous vein were placed. Pathologic examination of the inferior mesenteric artery demonstrated changes that were considered diagnostic of thromboangiitis obliterans. We found only 10 confirmed cases of thromboangiitis obliterans involving the mesenteric vessels in the English language literature. The present case appears to be the first involving a woman and the only one in which the main trunk of all three mesenteric vessels was involved.


Cerebral microvascular amyloid beta protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid beta precursor protein.
Cerebral vascular amyloid beta-protein (Abeta) deposition, also known as cerebral amyloid angiopathy, is a common pathological feature of Alzheimer's disease. Additionally, several familial forms of cerebral amyloid angiopathy exist including the Dutch (E22Q) and Iowa (D23N) mutations of Abeta. Increasing evidence has associated cerebral microvascular amyloid deposition with neuroinflammation and dementia in these disorders. We recently established a transgenic mouse model (Tg-SwDI) that expresses human vasculotropic Dutch/Iowa mutant amyloid beta-protein precursor in brain. Tg-SwDI mice were shown to develop early-onset deposition of Abeta exhibiting high association with cerebral microvessels. Here we present quantitative temporal analysis showing robust and progressive accumulation of cerebral microvascular fibrillar Abeta accompanied by decreased cerebral vascular densities, the presence of apoptotic cerebral vascular cells, and cerebral vascular cell loss in Tg-SwDI mice. Abundant neuroinflammatory reactive astrocytes and activated microglia strongly associated with the cerebral microvascular fibrillar Abeta deposits. In addition, Tg-SwDI mouse brain exhibited elevated levels of the inflammatory cytokines interleukin-1beta and -6. Together, these studies identify the Tg-SwDI mouse as a unique model to investigate selective accumulation of cerebral microvascular amyloid and the associated neuroinflammation.


Prognostic factors and the necessity of chemotherapy for stage II gastric cancer: a model based on multicenter retrospective study.
This study aimed to construct a prognostic model for prognosis prediction and assess the response to adjuvant chemotherapy (ACT) of stage II gastric cancer (GC) patients on high and low survival risk stratifications. We retrospectively reviewed 547 stage II gastric cancer patients who underwent D2 radical gastrectomy from January 2009 to May 2017 in Sixth Affiliated Hospital of Sun Yat-Sen University (SAH-SYSU), the Fujian Medical University Union Hospital (FJUUH), and the Sun Yat-Sen University Cancer Center (SYSUCC).The propensity score matching (PSM) of all variables was performed to balance selective bias between ACT and surgery alone (SA) groups. Kaplan-Meier survival and multivariate Cox regression analyses were carried out to identify independent prognostic factors. Independent factors selected by the Cox regression were integrated into the nomogram. The nomogram points stratified patients into high-risk and low-risk groups by the optimal cut-off value. 278 patients were selected after PSM. Age, tumor site, T stage and lymph-nodes-examined (LNE) selected by Cox regression as independent prognostic factors were integrated into the nomogram. The nomogram performed well with a C-index of 0.76 and with C-indexes of 0.73 in and 0.71 in two validate cohorts. AUCs of the 3 year and 5 year ROC curves were 0.81 and 0.78. High- and low-risk groups stratified by the cut-off value demonstrated different responses to ACT. The nomogram performed well in prognosis prediction. Patients in high- and low-risk groups demonstrated different responses to ACT, and high-risk patients might need ACT.


Mammographic density estimation: one-to-one comparison of digital mammography and digital breast tomosynthesis using fully automated software.
To compare breast density on digital mammography and digital breast tomosynthesis using fully automated software. Following institutional approval and written informed consent from all participating women, both digital breast tomosynthesis (DBT) and full-field digital mammography (FFDM) were obtained. Breast percentage density was calculated with software on DBT and FFDM. Fifty consecutive patients (mean age, 51 years; range, 35-83 years) underwent both FFDM and DBT. Using a method based on the integral curve, breast density showed higher results on FFDM (68.1 ± 12.1 for FFDM and 51.9 ± 6.5 for DBT). FFDM overestimated breast density in 16.2% (P < 0.0001). Using a method based on maximum entropy thresholding, breast density showed higher results on FFDM (68.1 ± 12.1 for FFDM and 51.9 ± 6.5 for DBT). FFDM overestimated breast density in 11.4% (P < 0.0001). There was a good correlation among BI-RADS categories on a four-grade scale and the density evaluated with DBT and FFDM (r = 0.54, P < 0.01 and r = 0.44, P < 0.01). Breast density appeared to be significantly underestimated on digital breast tomosynthesis. Breast density is considered to be an independent risk factor for cancer Density can be assessed on full-field digital mammography and digital breast tomosynthesis Objective automated estimation of breast density eliminates subjectivity Automated estimation is more accurate than BI-RADS quantitative evaluation Breast density may be significantly underestimated on digital breast tomosynthesis.


The water proton spin-lattice relaxation times in virus-infected cells.
The water proton spin-lattice relaxation times in HEp-2 cell cultures were determined immediately after 1 h of polio-virus adsorption. The shortening of the water T1 was closely related to the multiplicity of infection, allowing direct inspections of the virus--cell interaction since the first steps of the infectious cycle. Virus-induced structural and conformational changes of cell constituents were suggested to be detectable by NMR investigation of cell water.


[Reconstruction of elbow defect by perforator propeller flap of the brachial region--clinical observation].
The elbow defects can raise problem to plastic surgeon. Indeed, this region is characterized by thin and mobile tissues; its reconstruction must be long-lasting, resistant to movements, to shear forces and to external support. Perforator propeller flaps beings appear an interesting option in the reconstruction of elbow defects. In this report, we describe a patient having benefited from the excision of a melanoma of the region of the elbow. After multidisciplinary meeting and resection of new margins, a reconstruction by perforator propeller flap was realized. A perforator pedicle of the lateral brachial region was located and used. The postoperative result in term of cover and function was considered very satisfactory. The perforator propeller flaps appear a reliable and interesting solution in the coverage of elbow defect.


Dihydropyrimidinone-derived selenoesters efficacy and safety in an in vivo model of Aβ aggregation.
In a previous in vitro study, dihydropyrimidinone-derived selenoesteres demonstrated antioxidant properties, metal chelators and inhibitory acetylcholinesterase (AChE) activity, making these compounds promising candidates for Alzheimer's Disease (AD) treatment. However, these effects have yet to be demonstrated in an in vivo animal model; therefore, this study aimed to evaluate the safety and efficacy of eight selenoester compounds in a Caenorhabditis elegans model using transgenic strains for amyloid-beta peptide (Aβ) aggregation. The L1 stage worms were acutely exposed (30 min) to the compounds at concentrations ranging from 5 to 200 μM and after 48 h the maintenance temperature was increased to 25 ° C for Aβ expression and aggregation. After 48 h, several parameters related to phenotypic manifestations of Aβ toxicity and mechanistic elucidation were analyzed. At the concentrations tested no significant toxicity of the compounds was found. The selenoester compound FA90 significantly reduced the rate of paralyzed worms and increased the number of swimming movements compared to the untreated worms. In addition, FA90 and FA130 improved egg-laying induced by levamisole and positively modulated HSP-6 and HSP-4 expression, thereby increasing reticular and mitochondrial protein folding response in C. elegans, which could attenuate Aβ aggregation in early exposure. Therefore, our initial screening using an alternative model demonstrated that FA90, among the eight selenoesters evaluated, was the most promising compound for AD evaluation screening in more complex animals.


Minor iridoid glycosides from the fruits of Cornus officinalis Sieb. et Zucc. and their anti-diabetic bioactivities.
Fifteen previously undescribed minor iridoid glycosides, including four monomers and eleven dimers, were isolated from the fruits of Cornus officinalis Sieb. et Zucc. Their chemical structures were determined on the basis of spectroscopic data and chemical evidence. All of the isolated compounds were evaluated for their effects of the glucose consumption on the insulin resistant HepG2 cells, and four compounds, named cornuofficinalisides F, H, L, and O, increased the glucose consumption significantly at 10 μM, the EC50 values of them were determined to be 0.898, 1.625, 0.923, and 8.589 μM, respectively. Moreover, the four compounds could improve the ability of glucose uptake significantly in insulin resistant HepG2 cells.


Molecular haplotype determination using allele-specific PCR and pyrosequencing technology.
Haplotyping of single-nucleotide polymorphisms (SNPs) is usually performed statistically by computational analysis or by time-consuming cloning techniques. Here we present a simple molecular approach for reliable haplotype determination on individual samples. The procedure is based on allele-specific PCR (AS-PCR) in combination with Pyrosequencing analysis. AS-PCR primers for each allelic variant of the investigated SNPs were used. A mismatch introduced at the second base from the 3' end dramatically improved allele specificity. Analysis of multiple SNPs on amplified fragments using Pyrosequencing technology allowed determination of haplotypes. Genotyping of heterozygote samples after AS-PCR gave a typical monoallelic pattern at each SNP, in which the identity of the present allele depended on the allele-specific initial amplification. Haplotype determination by the described procedure proved to be highly reliable. The results obtained by Pyrosequencing technology have the benefit of being truly quantitative, enabling detection of any nonspecific allele amplification.


eConsulting.
eConsulting, in all its contexts, can promote and improve the amount and quality of services and knowledge transferred to and among the community of health care providers and consumers. It can also improve the efficiency and effectiveness of the specialist and generalist workforce and accessibility to the services provided. This chapter defines eConsulting, provides the context, and introduces a conceptual framework to describe its current practice and future possibilities. A clinical scenario of a patient with a breast lump is used to ground the molecular, clinical, organizational, and social, legal, and ethical issues in real world practice. The approach/method used is based on the clinical process, evidence-based practice, and appraising the quality, validity, relevance, and usefulness of the information. The practicalities and utility of current eConsulting tools are discussed with a view to future ubiquitous use. Working through this chapter should assist readers to understand and describe (1) how eConsultations can link and translate scientific research into clinical practice, (2) the current implications of eConsultations, (3) the future potential of eConsultations.


Modeling gaseous emissions and dispersion of two major greenhouse gases from landfill sites in arid hot environment.
As waste production exponentially increases, landfill continues to be the common method of waste disposal. Landfills represent significant anthropogenic sources of methane (CH4) and carbon dioxide (CO2); the main constituents of greenhouse gases (GHGs) resultant from microbial decomposition of organic waste. In the present study, ISC-AERMOD dispersion model was employed to estimate the release and dispersion rates of CH4 and CO2 from major landfill sites across Kuwait under different seasonal conditions. Results revealed that dispersions of CH4 and CO2 were influenced by the dominant northwestern and southeastern wind directions and thus, the dispersion of CH4 and CO2 extended predominantly toward northeastern direction. In terms of seasonal variation, the maximum concentrations of CH4 and CO2 were detected in winter and spring seasons, close to the landfill zone, and the dispersion of CH4 and CO2 fluxes during winter and spring seasons was longer than that during summer and fall seasons. Consequently, residential areas close to the disposal sites were exposed to higher concentrations of CH4 and CO2 gases during winter and spring. The findings of this study can serve as the basis for selecting suitable landfill locations under desert climatic conditions as determined by the distances over which gaseous emissions can diffuse.


A comment on: "Conventional and Microwave Hydrothermal Synthesis and Application of Functional Materials: A Review".
In the recent paper published in Materials (Yang et al., 2019), there is a mistake in the explanation of crystal growth mechanism of the hydrothermal method. The error in this article is discussed in this short communication.


Control of homozygous beta-thalassemia by carrier screening and antenatal diagnosis in Sardinians.
This paper reports the present results of an ongoing program aimed at preventing homozygous beta-thalassemia by means of heterozygote screening and antenatal diagnosis in the Sardinian population. Screening based on the knowledge of carrier frequency and types of thalassemia prevalent in this population was designed to discover all heterozygotes except the few silent beta-thalassemia carriers. Most of the couples at risk were informed and accepted testing. Information was conveyed by mass media, midwives and marriage registry offices. Antenatal diagnosis was accepted by the majority of the couples counselled. The results of antenatal testing were very accurate. There was only one misdiagnosis out of 949 pregnancies tested. This risk of fetal loss was 7.5%. The program was highly effective, as shown by the decline of the incidence of the homozygous state from 1:205 live births in 1976 to 1:557 in 1981.


Childhood depression.
The spectrum of depressive disorders found in children and adolescents presents diagnostic and treatment challenges for the physician. The increasing scientific rigor of child and adolescent mental disorder research has explicated the importance of clinical diagnoses. Distinctions have to be made between depressive symptoms that are transient and situational specific and the constellation of depressive symptoms that represent clinical disorders such as bipolar disorder, cyclothymia, major depressive disorder, or dysthymia. The clinically sensitive physician attuned to the diagnostic criteria of these disorders has the opportunity to promote effective treatment and to reduce the morbidity associated with these conditions. The established severity and persistence of these disorders over time suggests the need for definitive medical management of these conditions. The recognition of childhood depression as a medical entity of varying severity, persistence, and prognosis represents the first step in effective treatment.


[The development of the early genital anlage and its significance for the development of the large intestine--studies of rat embryos].
The morphology of infraumbilical malformations suggests that the development of the genital anlage is of great importance for the embryology of the cloaca. In rat embryos the development of the genital anlage is documented using scanning electron microscopy. This documentation suggests that the genital anlage develops in three phases. Of these, the development of the unpaired glandular hillock seems to be especially important. The genital anlage affects the development of the cloaca in two ways: firstly its ventral growth causes a ventral shifting of the greater part of the cloaca into the region of the genitalia and secondly the cloaca gains its definite position through the development and growth of the glandular hillock.


Combined pre- and post-capillary pulmonary hypertension in left heart disease.
Patients with heart failure (HF) often have pulmonary hypertension (PH), which is mainly post-capillary; however, some of them also develop a pre-capillary component. The exact mechanisms leading to combined pre- and post-capillary PH are not yet clear, but the phenomenon seems to start from a passive transmission of increased pressure from the left heart to the lungs, and then continues with the remodeling of both the alveolar and vascular components through different pathways. More importantly, it is not yet clear which patients are predisposed to develop the disease. These patients have some characteristics similar to those with idiopathic pulmonary arterial hypertension (e.g., young age and frequent incidence in female gender), but they share cardiovascular risk factors with patients with HF (e.g., obesity and diabetes), with both reduced and preserved ejection fraction. Thanks to echocardiography parameters and newly introduced scores, more tools are available to distinguish between idiopathic pulmonary arterial hypertension and combined PH and to guide patients' management. It may be hypothesized to treat patients in whom the pre-capillary component is predominant with specific therapies such as those for idiopathic pulmonary arterial hypertension; however, no adequately powered trials of PH-specific treatment are available in combined PH. Early evidence of clinical benefit has been proven in some trials on phosphodiesterase type 5 inhibitors, while data on prostacyclin analogues, endothelin-1 receptor antagonists, and soluble guanylate cyclase stimulators are still controversial.


Abdominal Bracing Increases Ground Reaction Forces and Reduces Knee and Hip Flexion During Landing.
Controlled laboratory study. Abdominal bracing (AB) is a widely advocated method of increasing spine stability, yet the influence of AB on the execution of sporting movements has not been quantified. Landing is a common task during sporting endeavors; therefore, investigating the effect of performing AB during a drop-landing task is relevant. To quantify the effect of AB on kinematics (ankle, knee, hip, and regional lumbar spine peak flexion angles) and peak vertical ground reaction force (vGRF) during a drop-landing task. Sixteen healthy adults (7 female, 9 male; mean ± SD age, 27 ± 7 years; height, 170.6 ± 8.1 cm; mass, 68.0 ± 11.3 kg) were assessed using 3-D motion analysis, electromyography (EMG), and a force platform while performing a drop-landing task with and without AB. Abdominal bracing was achieved with the assistance of real-time internal oblique EMG feedback. Lower-limb and regional lumbar spine kinematics, peak vGRF, and normalized EMG of the left and right internal obliques and lumbar multifidus were quantified. Paired-samples t tests were used to compare variables between the AB and no-AB conditions. Abdominal bracing resulted in significantly reduced knee and hip flexion and increased peak vGRF during landing. No differences in lumbar multifidus EMG or lumbar spine kinematics were observed. Abdominal bracing reduces impact attenuation during landing. These altered biomechanics may have implications for lower-limb and spinal injury risk during dynamic tasks.


Effect of different physical states of phospholipid substrates on partially purified platelet phospholipase A2 activity.
Partial purification of alkaline phospholipase A2 (EC 188.8.131.52) from rabbit platelets was carried out and the effect of different physical states of the substrate phosphatidylcholine on the activity was investigated. (1) The enzyme was purified about 1020-fold by means of Sephadex gel chromatography after extraction from a particulate fraction of rabbit platelets, followed by CM-cellulose chromatography, and had a molecular weight of approx. 12 000 as determined by gel chromatography. (2) The activity of the purified enzyme was enhanced by the addition of detergents. Sodium deoxycholate and sodium cholate markedly stimulated the activity, and the effect of these substances was observed well below the critical micelle concentrations. Triton X-100 stimulated the activity moderately, and the activation was observed only above the critical micelle concentration. (3) The addition of negatively charged phospholipids to the substrate egg phosphatidylcholine induced a moderate activation of hydrolysis. (4) The addition of long-chain cation to the substrate induced an inhibition of the activity, whereas the addition of long-chain anion activated the hydrolysis of egg phosphatidylcholine, but did not activate the hydrolysis of phosphatidylcholine in the total lipid extract of rabbit platelets. (5) Hydrolysis of dimyristoyl phosphatidylcholine increased in the temperature region of the phase transition of the substrate. Addition of cholesterol at the concentration of 20 mol% diminished the effect of phase transition. (6) Release of [1-14C]arachidonic acid from an equimolar mixture of egg phosphatidylcholine with dipalmitoyl or distearoyl phosphatidylcholine was activated at the temperature of 0 degrees C or 20 degrees C, respectively. From these results, we suggest that platelet phospholipase A2 can be activated to release fatty acids from the platelet phospholipids at the domains within membranes, where exist the structural irregularities and/or accumulation of negative charge within the bilayers.


Delay in the diagnosis of dementia in urban India: Role of dementia subtype and age at onset.
Early diagnosis of dementia is crucial for timely intervention. However, frequently, there is a substantial delay in diagnosis. Therefore, it is essential to recognise and address the barriers to early diagnosis. These have not been systematically studied in India. We at a specialist memory clinic in India investigated the time from symptom onset to diagnosis of dementia and factors contributing to the delay. In this cross-sectional study, consecutive patients with dementia (n = 855) seen at a private hospital underwent a standard clinical assessment and investigations. The primary outcome variable was time from symptom onset to diagnosis (TTD). The association of age, education, gender, dementia subtype, and age of onset on TTD were examined using a univariate analysis of covariance. The median TTD was 24 months; 43% were diagnosed after 24 months. There was a significant association between TTD and age at onset (young onset-median 36 months vs. late onset-24 months) and dementia subtype. Patients with vascular dementia were diagnosed significantly earlier as compared to patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) [median 18, 24, and 30 months, respectively]. There was no effect of gender or education on the TTD. About 40% of patients with dementia were diagnosed more than 2 years after symptom onset, particularly young onset dementias and FTD. Our study findings highlight the gaps in diagnosing patients with dementia in urban India and have significant implications for developing and implementing multifaceted interventions to improve the early diagnosis of dementia.


Development of clinical immunosuppression for organ transplantation.
The progress in the understanding of allograft rejection since the first modern kidney transplantation is enormous. The concept of the histocompatibility complex (HLA system) was born and the loci for the related genes are now identified. The actual structure of HLA antigens and the molecules (lymphokines) released by them are being understood. A population of lymphocytes (suppressor cells) which reduces the host immune response to tissue allografts has also been identified. With advanced understanding, ideas and methods for immunosuppression have been developed. Hyperacute rejection due to presensitization (secondary to preformed HLA antibody) ought to be avoided or attenuated, if it were to happen. The significance of previous blood transfusion or multiple pregnancies were clarified in this regard. The tests to determine such immunological reactivity were devised. Steroids, azathioprine and cyclosporine which are presently in use for immunosuppression were reviewed as to their actions, effects and side-effects. Total lymphoid irradiation presently appears as a potential effective immunosuppressive procedure and is currently being tried in certain transplant centers. The superiority of monoclonal antibodies against polyclonal antilymphocyte antibodies has been confirmed, although the latter also has various useful actions. Finally, the need and possible means to facilitate donor specific unresponsiveness are mentioned in perspectives for the future management of clinical organ transplantation.


The effect of selected lactic acid bacterial strains on the technological and microbiological quality of mechanically separated poultry meat cured with a reduced amount of sodium nitrite.
The aim of the research was to estimate the effect of selected lactic acid bacterial strains on the technological quality and microbiological stability of mechanically separated poultry meat (MSPM) cured with a reduced amount of sodium nitrite. The 5 different treatments of MSPM batters were prepared: C150 - control cured with sodium nitrite at 150 mg/kg, C50 - control cured with sodium nitrite at 50 mg/kg, PL1 - cured with sodium nitrite at 50 mg/kg and inoculated Lactobacillus plantarum SCH1 at about 107 cfu/g, PL2 - cured with sodium nitrite at 50 mg/kg and inoculated Lactobacillus brevis KL5 at about 107 cfu/g, and PL3 - cured sodium nitrite at 50 mg/kg and inoculated L. plantarum S21 at about 107 cfu/g. The MSPM batters were tested at 1, 4 and 7 d of being in refrigerated storage. The scope of the research was as follows - physicochemical determinations: pH and redox, nitrates and nitrites as well as nitrosyl pigments levels, color estimation with a Comission Internationale de l'Eclairage Lab system and microbiological determinations: the total viable counts, the mesophilic lactic acid bacteria counts, Escherichia coli and Enterobacteriaceae counts. The inhibitory effect of L. plantarum SCH1 isolated from the ecological raw fermented meat product on E. coli in cured MSPM batters during refrigerated storage was proved (P < 0.05). The use of lactic acid bacterial strains in cured batters that were prepared and based on mechanically separated poultry meat did not have a negative effect on their technological quality. The positive effect of L. brevis KL5 on the level of nitrosyl pigments in the cured MSPM batters was observed (P < 0.05). The conducted research suggested the possibility of using the selected bacterial strains of the Lactobacillus genus to improve the microbiological quality of MSPM cured with a reduced amount of sodium nitrite.


Burden of rare earth elements and trace elements in feathers of magellanic penguins (Spheniscus magellanicus) from the southern Chilean Patagonia.
Patagonia is one of the last pristine regions on the southern hemisphere. The impact of rare earth element (REEs) and trace elements (TEs) in this region have received little attention. The main goal was to assess REEs burden in feathers of adult magellanic penguins (Spheniscus magellanicus). Sampling was performed at Magdalena Island of the Chilean Patagonia during the austral summer of 2011. Multi-elemental determination of 16 REEs and 24 TEs was performed with ICP-MS. The levels of REEs, TEs, and stable isotopes (δ15N, δ13C, and δ34S) were measured to assess the factors that condition the avian exposure to environmental contaminants. The results showed an increase of the levels of REEs and TEs from the calamus to the feather's tip. In the whole feather, the highest levels corresponded to Ce, which exhibited more than two order of magnitude than Lu and Tm levels. Similar to other penguin species, magellanic penguins can be vectors of REEs and metals in remote regions. Stable isotopes revealed that trophic ecology may influence some of the element concentrations in feathers of magellanic penguins, an issue that requires deeper attention.


Predictors of survival in a series of clinically diagnosed progressive supranuclear palsy patients.
Investigations into prognostic factors in progressive supranuclear palsy have shown conflicting results. We performed a retrospective study in order to identify clinical predictors of survival in clinically diagnosed progressive supranuclear palsy patients referred to our centre. Data on medical history, survival and five clinical disability milestones (inability to walk unassisted, unintelligible speech, severe dysphagia, dementia and institutionalization) were collected from outpatients' medical records and by a telephone interview to caregivers. Patients were subdivided into Richardson's syndrome and PSP-Parkinsonism according to symptoms during the first 2 years of disease. Survival was analyzed by the Kaplan-Meier method and Cox regression analysis. Forty-three consecutive patients were enrolled (86% Richardson's syndrome). Motor disturbances were the most frequent symptoms of onset. During the follow-up, 60.5% of patients died after a median survival of 7.1 years (2.2-18). Older age at onset (>63) (HR 2.8; 95% CI: 1.3-5.7; p = 0.007), early dysphagia (HR 2.3; 95% CI: 1-5.3; p = 0.05) and early cognitive deficits (HR 3.6; 95% CI: 1.6-8.2; p = 0.002) were predictors of shorter survival. Compared to PSP-Parkinsonism patients, Richardson's syndrome patients had shorter survival and higher mortality risk although not statistically significant (HR 3 95% CI: 0.9-9.9; p = 0.07). Seventy-seven percent of patients developed severe disability during follow-up: shorter time to the first clinical disability milestone predicted shorter survival (HR 7.8; 95% CI: 2.3-26; p = 0.0008). early dysphagia, cognitive impairment, older age at onset, and time to disability were predictors of shorter survival; Richardson's syndrome had a less favorable course than PSP-Parkinsonism. Clinical milestones should be considered as possible endpoints in future clinical trials.


Toward Modular and Flexible Open RAN Implementations in 6G Networks: Traffic Steering Use Case and O-RAN xApps.
The development of cellular wireless systems has entered the phase when 5G networks are being deployed and the foundations of 6G solutions are being identified. However, in parallel to this, another technological breakthrough is observed, as the concept of open radio access networks is coming into play. Together with advancing network virtualization and programmability, this may reshape the way the functionalities and services related to radio access are designed, leading to modular and flexible implementations. This paper overviews the idea of open radio access networks and presents ongoing O-RAN Alliance standardization activities in this context. The whole analysis is supported by a study of the traffic steering use case implemented in a modular way, following the open networking approach.


Can I Use Marijuana Safely? An Examination of Distal Antecedents, Marijuana Protective Behavioral Strategies, and Marijuana Outcomes.
Given the high prevalence of marijuana use among college students, it is imperative to determine the factors that may reduce risk of problematic marijuana use and/or the development of cannabis use disorder. We examined marijuana protective behavioral strategies (PBS) as a proximal predictor of marijuana-related outcomes and a mediator of the associations between other known risk/protective factors and marijuana-related outcomes. Using data from a sample of 2,129 past-month marijuana users, collected from 11 universities in the United States, we examined marijuana PBS use as a mediator of the effects of sex, age at first use, impulsivity-like traits, and marijuana use motives on marijuana use frequency and marijuana related consequences. Marijuana PBS was identified as a robust negative predictor of marijuana use frequency and marijuana-related consequences. Further, Marijuana PBS use fully or partially mediated the effects of sex, premeditation, perseverance, coping motives, enhancement motives, conformity motives, and expansion motives on marijuana outcomes. Our results suggest that marijuana PBS use is a good candidate to be considered as a mechanism by which marijuana users moderate their marijuana use and attenuate their risk of experiencing marijuana-related consequences.


The origins of the cell membrane, the progenote, and the universal ancestor (LUCA).
I analyse the consequences that the diversity of cell membranes present in bacteria and archaea would have for the stage reached by the evolution of cellularity in the Last Universal Common Ancestor (LUCA). Regardless of how the bacterial and archaeal membranes were distributed in the LUCA, the conclusion that would seem to emerge is always the same. That is to say, it is more likely that LUCA was a progenote rather than a genote. Indeed, if LUCA hosted both types of membranes then this would have been a transitional condition which would imply, in itself, that LUCA was a progenote. In other words, the two types of membranes evidently had to segregate in that of bacteria and that of archaea, and this segregation would imply enormous changes not expected for a cellular stage but the norm for that of progenote. Instead, in the case in which LUCA hosted only one type of membrane, for example that of archaea, then the evolution of the other type of membrane - presumably in the ancestor of bacteria - would imply a progenotic LUCA precisely because such a late origin would seem be an expression, at that time, of a still rapid and progressive evolution because it involves a fundamental and profound genetic trait, and should therefore reflect the progenotic stage. Finally, in the event that LUCA had been devoid of a membrane, then the late origin of the two types of membranes - in the ancestor of archaea and in that of bacteria - would seem to be a clear expression of a rapid and progressive evolution typical of progenote. Indeed, this would imply, for example, that all mechanisms and functions associated with the two cell membranes still had to evolve which would express the progenotic stage precisely because it would seem to be an evolution still in progress, and therefore typical of the stage of progenote. Therefore, LUCA was most likely a progenote also because there would be no strong arguments in favour of the hypothesis that LUCA had instead reached the evolutionary stage of cellularity.


A Bead-Based Proximity Assay for BRD4 Ligand Discovery.
Bromodomain-containing proteins have emerged as desirable targets for anti-neoplastic and anti-inflammatory drug discovery. Toward the development of selective inhibitors of the BET family of bromodomains, we optimized bead-based assays to detect interactions between bromodomains and poly-acetylated histone peptides. Donor and acceptor beads bound to target and ligand are brought into proximity by this protein-protein interaction. After laser illumination, singlet oxygen evolved from donor beads travels to the spatially close acceptor beads, resulting in chemiluminesence. This AlphaScreen assay has proven amendable to high-throughput screening, secondary validation, and specificity profiling during lead discovery and optimization. Here we report our protocol for assay development to measure inhibition of ligand binding to bromodomain-containing protein 4 (BRD4). We discuss the discovery of an appropriate probe, optimization of bead, probe, and protein concentrations, and the derivation of protein-probe inhibition curves. Finally, we explore the implementation of this technology for high-throughput screening of potential BRD4 inhibitors.


Neiella litorisoli sp. nov., an alginate lyase: producing bacterium from South China Sea, and proposal of Echinimonadaceae fam. nov. in the order Alteromonadales.
A Gram-stain-negative, rod-shaped bacterium, designated HB171785T, was isolated from soil sample collected from Qishui Bay, Hainan, China. The strain grew optimally at pH 7-8, 37-40 °C and with NaCl 3-4%. The predominant isoprenoid quinone was found to be Q-8 and the major fatty acids were C16:0, C16:1 ω7c/C16:1 ω6c, C18:1 ω7c/C18:1 ω6c and C12:0 3OH. The polar lipids contained diphosphatidylglycerol, phosphatidylglycerol, and phosphatidylethanolamine. The size of the draft genome was 4.32 Mbp with G + C content 49.7%. Phylogenetic analysis of 16S rRNA gene sequence indicated that the closest phylogenetically related species were Neiella marina j221T, "Neiella holothuriorum" 126 and Echinimonas agarilytica KMM 6351T with the similarities of 98.2, 96.0 and 95.0%, respectively. The phylogenetic tree based on 16S rRNA gene and phylogenomic tree based on core genome showed that strain HB171785T clustered together with N. marina j221T, with the highest values of average nucleotide identity (82.9%) and digital DNA-DNA hybridization (25.4%). The combined phylogenetic relatedness, phenotypic and genotypic features supported the conclusion that strain HB171785T represents a novel species of the genus Neiella, for which the name Neiella litorisoli sp. nov. is proposed. The type strain is HB171785T (= MCCC 1K04625T = KCTC 82319T). In addition, Echinimonadaceae fam. nov. in the order Alteromonadales was proposed.


Lathyrus cicera copper amine oxidase reactions with tryptamine.
Lathyrus cicera copper amine oxidase (LCAO) rapidly formed the typical Cu(I)-TPQ semiquinone UV-visible spectrum, identical to that formed by other substrates, upon O(2) exhaustion by turnover with excess tryptamine. A new band at 630 nm formed more slowly, with intensity dependent on aldehyde and H(2)O(2) concentrations. On prolonged incubation, all bands decayed in parallel, together with loss of enzymatic activity. The blue color disappeared on addition of KCN, a Cu(I) stabilizing agent, while the intensity of the radical visible bands increased. This shows that the 630 nm absorbing species is a Cu(II) derivative, as confirmed by the unchanged intensity of the EPR spectrum of the frozen blue solution from that of the native protein. Rapid kinetics experiments showed that this species derives from a reduced form of the protein, plus aldehyde and H(2)O(2) and that it is not in dynamic equilibrium with the radical. Given the similar population of the semiquinone radical with all substrates, it is possible that the reaction with aldehyde and H(2)O(2) occurs in all cases although substrates lacking the indole group only produce the Cu(I)-semiquinone band. The radical participation to the catalytic activity is demonstrated by the observation that its relative population (controlled by the pH) parallels changes in the reoxidation rate constant, while the 630 nm absorbing species is implied in the inactivation process, which depends on H(2)O(2) and aldehyde concentration. The results of the paper are consistent with half-of-the-site reactivity, i.e. the two subunits of LCAO are kinetically and spectroscopically distinct from each other.


Endoplasmic reticulum Ca2+ depletion activates XBP1 and controls terminal differentiation in keratinocytes and epidermis.
Endoplasmic reticulum (ER) Ca(2+) depletion, previously shown to signal pathological stress responses, has more recently been found also to trigger homeostatic physiological processes such as differentiation. In keratinocytes and epidermis, terminal differentiation and barrier repair require physiological apoptosis and differentiation, as evidenced by protein synthesis, caspase 14 expression, lipid secretion and stratum corneum (SC) formation. To investigate the role of Ca(2+) depletion-induced ER stress in keratinocyte differentiation and barrier repair in vivo and in cell culture. The SERCA2 Ca(2+) pump inhibitor thapsigargin (TG) was used to deplete ER calcium both in cultured keratinocytes and in mice. Levels of the ER stress factor XBP1, loricrin, caspase 14, lipid synthesis and intracellular Ca(2+) were compared after both TG treatment and barrier abrogation. We showed that these components of terminal differentiation and barrier repair were signalled by physiological ER stress, via release of stratum granulosum (SG) ER Ca(2+) stores. We first found that keratinocyte and epidermal ER Ca(2+) depletion activated the ER-stress-induced transcription factor XBP1. Next, we demonstrated that external barrier perturbation resulted in both intracellular Ca(2+) emptying and XBP1 activation. Finally, we showed that TG treatment of intact skin did not perturb the permeability barrier, yet stimulated and mimicked the physiological processes of barrier recovery. This report is the first to quantify and localize ER Ca(2+) loss after barrier perturbation and show that homeostatic processes that restore barrier function in vivo can be reproduced solely by releasing ER Ca(2+), via induction of physiological ER stress.


Characterization and genomic structure of Dnah9, and its roles in nodal signaling pathways in the Japanese flounder (Paralichthys olivaceus).
The nodal signaling pathway has been shown to play crucial roles in inducing and patterning the mesoderm and endoderm, as well as in regulating neurogenesis and left-right axis asymmetry. Here, we present the first complete cDNA and genomic sequences as well as the promoter predication of the Dnah9 gene in the Japanese flounder. The 15,558-bp-long cDNA is divided into 96 exons and spread over 138 kb of genomic DNA. Protein sequence comparison showed that it shares higher identity with other vertebrate orthologs, with an ATP binding dynein motor, AAA domain and microtubule binding stalk of dynein motor. Dnah9 exhibited maternal and ubiquitous expression in all cells of the early development stages, but became concentrated in the head at 1 DAH, as identified by qRT-PCR and in situ hybridization methods. Furthermore, after nodal signaling was inhibited, the level of Southpaw did not change significantly at early development stage (50 % epiboly) but increased significantly at late stages (27-somite stages and 1 DAH), as well as the expression of Lefty, an inhibitor of nodal signaling, increased continuously. On the other hand, the expression level of Dnah9 decreased. The transcription factor binding site of FAST-1 (SMAD interacting protein) was identified in the transcription region of Dnah9 by the promoter analysis, which might format the complexes of SMADs, FAST-1 and the transcription region of Dnah9 served as a bridge of Dnah9 and nodal signaling. All evidences indicated that Dnah9 might be downstream of nodal during the early development stages, and an indirect function through SMADs for nodal signaling pathway.


Acute puerperal uterine inversion: two-step management with a beta-mimetic and a prostaglandin.
Sequential administration of a beta 2-mimetic and a prostaglandin, the latter preferably injected into the uterus, is a simple and highly effective method for managing acute puerperal uterine inversion.


Role of supportive care in improving the quality of life and reducing unscheduled hospital care in patients with metastatic breast cancer.
Metastatic breast cancer (MBC) patients experience long survival and report poorer quality of life than localized breast cancer patients. Comprehensive supportive care (CSC) has been shown to improve the quality of life (QoL) of MBC. The respective part of each support care has not been fully examined, and little is known about whether meeting patients' needs is accompanied by decreased unscheduled hospital care (UHC). This prospective monocentric study included women who started a new treatment line for MBC between January 2018 and December 2018. The endpoints were factors associated with UHC and QoL (SF36) at month 12. 100 patients were offered CSC, 78 were included (21 refusals, 1 no MBC). CSC was provided to 60 patients: pain (43%), psychological (37%), kinesitherapy (30%), social assistance (22%), esthetic (18%), nutrition (18%), massage (13%), and none (10%). CSC rate was not statistically different among patients with (58%) and without UHD (49%). Factors associated with a decrease of UHC were age > 65 years (p = 0.01), no previous treatment for MBC (p = 0.0001) with a trend for the lack of CSC (p = 0.054). Among the 8 domains of the SF36 scale, only health change perception was improved (p = 0.01) and its predictive factors were treatment carried out as planned (p = 0.0004), pain care (p = 0.003), and lack of MBC progression (p = 0.0035). CSC can improve QoL in MBC. Painful patients might benefit more from CSC. UHC did not decrease for patients receiving CSC as expected possibly because of their important needs for clinical care.


Safety and efficacy of the eCLIPs bifurcation remodelling system for the treatment of wide necked bifurcation aneurysms: 1 year results from the European eCLIPs Safety, Feasibility, and Efficacy Study (EESIS).
The eCLIPs bifurcation remodelling system is a non-circumferential implant that bridges the neck from outside of a bifurcation aneurysm. The goal of the multicenter, post-marketing European eCLIPs Safety, FeasIbility, and Efficacy Study (EESIS), was to present the efficacy and safety results of the eCLIPs device after 365 days of follow-up. All patients were to receive an eCLIPs in conjunction with coils. The study was conducted according to good clinical practices and included independent adjudication of safety and efficacy outcomes. Twenty patients were enrolled at four European centers. Mean age was 60 years (range 41-74) and aneurysms were located at the basilar tip (n=19) and carotid tip (n=1). Average aneurysm dome height was 6.0 mm (range 2.0-15.0). Mean neck length was 5.1 mm (range 2.6-8.5). The technical success rate was 90% (18 of 20). No major territorial strokes or deaths occurred between the index procedure and after 365 days of follow-up. Complete occlusion was achieved in 60% of patients (12 of 20 patients) and 67% of patients with an eCLIPs device (12 of 18) after 365 days of follow-up. Adequate occlusion (complete occlusion and neck remnant) was achieved in 80% of patients (16 of 20 patients) and 89% of patients with an eCLIPs device (16 of 18 patients) after 365 days of follow-up. In this small series, treatment with eCLIPs was feasible, safe, and efficacious, considering the challenging nature of the aneurysms. ClinicalTrials.gov NCT02607501.


Mathematical means to allow computer calculation of stereotaxic settings.
Stereotaxic instruments have wide use in neuroscience research. In certain of these machines the electrode can be introduced at an angle as well as perpendicularly. Computation of instrument settings to place the electrode in the desired location is the problem this paper addresses. Mathematical formulae are presented that allow a computer to calculate instrument settings given coordinates and angles read from a stereotaxic atlas.


Is chemical neurotransmission altered specifically during methylmercury-induced cerebellar dysfunction?
Methylmercury (MeHg) is an important environmental neurotoxicant that is present in seafood and affects the developing and mature nervous system. The neurotoxicity induced by MeHg is a concern, particularly for fish-eating populations and pregnant or nursing women. During MeHg-induced neurotoxicity, degeneration of the granule cell layer in the cerebellum occurs, which leads to deficits in motor function. I suggest that the action of MeHg on specific neurotransmitter receptors contributes to the selective vulnerability of granule cells. MeHg appears to stimulate M(3) muscarinic acetylcholine receptors and to inhibit GABA(A) receptor subtypes preferentially on cerebellar granule cells. This could lead to the loss of tonic inhibition of granule cells as a result of antagonism of GABA(A) receptors, and a M(3)-receptor-mediated increase in the intracellular concentration of Ca(2+) and block of a K(+)-dependent leak current. The net result would be increased spontaneous release of glutamate, which, coupled with a MeHg-induced impairment of glutamate uptake by astrocytes, could cause Ca(2+)-mediated cytotoxicity.


[Usefulness of brain natriuretic propeptide in the diagnosis and management of patent ductus arteriosus].
Patent ductus arteriosus (PDA) is a prevalent condition in preterm infants, and may be related to increased morbidity and mortality in the most immature newborns. Recent studies have examined the usefulness of brain natriuretic propeptide (proBNP) in the diagnosis of this pathology. The aim of the study was to evaluate the diagnostic efficacy of proBNP as a marker of hemodynamic overload in PDA. A retrospective study was conducted on preterm infants less than 32 weeks of gestation and/or weight less than 1500 grams. Echocardiogram and determination of proBNP levels were performed on all patients. Comparison was made by subgroups according to the presence of PDA and their haemodynamic characteristics. Of the 60 patients enrolled, 71.7% had PDA, of which 86% had haemodynamically significant patent ductus arteriosus (HS-PDA). All of them, but one, received medical treatment with ibuprofen or acetaminophen. Surgical closure was required in 29.7% of HS-PDA. Higher values of proBNP were found in patients with HS-PDA (33338±34494.47pg/mL; p=.000) compared with patients with closed or non-haemodynamically significant ductus arteriosus. Higher values were also found in patients who required surgical closure of PDA (30596.8±14910.9; p=.004). A greater decrease inproBNP levels was found in the group of patients which duct closure after pharmacological treatment (68±24.69% vs -12.22±99.4%; p=.030). ProBNP cutoff-level for HS-PDA was calculated by ROC curve and it was 9321.5pg/mL (Specificity: 100%, Sensitivity: 94.6%). ProBNP levels are related to the presence or absence of haemodynamically significant patent ductus arteriosus; and its variations with treatment response. High values are also related to the need for surgical closure of PDA.


[Interdisciplinary limits of jurisdiction and responsibility from a legal viewpoint (author's transl)].
In the interdisciplinary cooperation between the surgeon and the anesthetist, the following factors are in effect: the principle of strict division of labor; each brings the functions of his specialty and carries complete responsibility for them; the principle of trust: each can depend on the meticulousness of the other, as long as no obvious qualification deficiencies are apparent; obligation for coordination: each must accommodate himself to the requirements of the other specialty.


Benchmarking small-variant genotyping in polyploids.
Genotyping from sequencing is the basis of emerging strategies in the molecular breeding of polyploid plants. However, compared with the situation for diploids, in which genotyping accuracies are confidently determined with comprehensive benchmarks, polyploids have been neglected; there are no benchmarks measuring genotyping error rates for small variants using real sequencing reads. We previously introduced a variant calling method, Octopus, that accurately calls germline variants in diploids and somatic mutations in tumors. Here, we evaluate Octopus and other popular tools on whole-genome tetraploid and hexaploid data sets created using in silico mixtures of diploid Genome in a Bottle (GIAB) samples. We find that genotyping errors are abundant for typical sequencing depths but that Octopus makes 25% fewer errors than other methods on average. We supplement our benchmarks with concordance analysis in real autotriploid banana data sets.


Combined administration routes of marine yeasts enhanced immune-related genes and protection of white shrimp (Penaeus vannamei) against Vibrio parahaemolyticus.
Antibiotic usage to control infectious diseases in shrimp aquaculture has led to serious problems on antimicrobial resistance. An alternative to mitigate this issue is the use of probiotics, which can be easily administered by feed and water. This study examines immunomodulatory and protective effects of the marine yeasts Debaryomyces hansenii CBS8339 (Dh) and Yarrowia lipolytica Yl-N6 (Yl) -alone and mixed-in white shrimp Penaeus vannamei post-larvae. Administration routes (fed and water alone or in combination), supplementation frequency and time elapsed after the last dietary supplement were tested on growth and gene expression of penaeidin, lectin, lysozyme, superoxide dismutase, catalase, and peroxidase, as well as survival upon Vibrio parahaemolyticus IPNGS16 challenge. Penaeidin and lectin genes were upregulated in post-larvae fed orally with Yl or combined Dh + Yl. Higher growth and survival for yeast supplementation treatments were observed compared to the control group, mainly when yeasts (Dh + Yl) and administration routes (feed and water) were combined. In conclusion, mixed yeast and combined administration routes improved growth and immunity against V. parahaemolyticus.


Outcomes in patients who underwent a concomitant tricuspid valve procedure during left ventricular assist device implantation.
Study findings have been inconsistent regarding whether a concomitant tricuspid valve replacement or repair performed concurrently with continuous-flow left ventricular assist device (CF-LVAD) implantation has additive clinical benefit in patients with severe tricuspid valve regurgitation (TR). To determine the effect of performing a concomitant tricuspid valve procedure (TVP) at the time of CF-LVAD implantation on patient outcomes. We retrospectively reviewed our single-institution experience in 526 patients who underwent primary implantation of a CF-LVAD between November 2003 and March 2016. We identified 59 (11.2%) patients who had severe TR at the time of implantation and analyzed the effect of performing a concomitant TVP at the time of CF-LVAD implantation on the rate of survival, incidence of postoperative right heart failure (RHF), recurrence of TR, and incidence of 30-day readmission. We did not observe a significant difference in the overall survival rate (P = .51), incidence of postoperative RHF (P = .26), or recurrence of TR (P = .73) between patients with severe TR who underwent a TVP and those who did not at the time of CF-LVAD implantation. However, the incidence of 30-day readmission was significantly lower in patients who underwent a TVP than in those who did not (P = .002). Performing a concomitant TVP at the time of CF-LVAD implantation did not improve patient outcomes but reduced the incidence of 30-day readmission.


A large conserved family of small-molecule carboxyl methyltransferases identified from microorganisms.
Small-molecule carboxyl methyltransferases (CbMTs) constitute a small proportion of the reported methyltransferases, but they have received extensive attention due to their important physiological functions. Most of the small-molecule CbMTs isolated to date originate from plants and are members of the SABATH family. In this study, we identified a type of CbMT (OPCMT) from a group of Mycobacteria, which has a distinct catalytic mechanism from the SABATH methyltransferases. The enzyme contains a large hydrophobic substrate-binding pocket (~400 Å3) and utilizes two conserved residues, Thr20 and Try194, to retain the substrate in a favorable orientation for catalytic transmethylation. The OPCMT_like MTs have a broad substrate scope and can accept diverse carboxylic acids enabling efficient production of methyl esters. They are widely (more than 10,000) distributed in microorganisms, including several well-known pathogens, whereas no related genes are found in humans. In vivo experiments implied that the OPCMT_like MTs was indispensable for M. neoaurum, suggesting that these proteins have important physiological functions.


Condensation of the β-cell secretory granule luminal cargoes pro/insulin and ICA512 RESP18 homology domain.
ICA512/PTPRN is a receptor tyrosine-like phosphatase implicated in the biogenesis and turnover of the insulin secretory granules (SGs) in pancreatic islet beta cells. Previously we found biophysical evidence that its luminal RESP18 homology domain (RESP18HD) forms a biomolecular condensate and interacts with insulin in vitro at close-to-neutral pH, that is, in conditions resembling those present in the early secretory pathway. Here we provide further evidence for the relevance of these findings by showing that at pH 6.8 RESP18HD interacts also with proinsulin-the physiological insulin precursor found in the early secretory pathway and the major luminal cargo of β-cell nascent SGs. Our light scattering analyses indicate that RESP18HD and proinsulin, but also insulin, populate nanocondensates ranging in size from 15 to 300 nm and 10e2 to 10e6 molecules. Co-condensation of RESP18HD with proinsulin/insulin transforms the initial nanocondensates into microcondensates (size >1 μm). The intrinsic tendency of proinsulin to self-condensate implies that, in the ER, a chaperoning mechanism must arrest its spontaneous intermolecular condensation to allow for proper intramolecular folding. These data further suggest that proinsulin is an early driver of insulin SG biogenesis, in a process in which its co-condensation with RESP18HD participates in their phase separation from other secretory proteins in transit through the same compartments but destined to other routes. Through the cytosolic tail of ICA512, proinsulin co-condensation with RESP18HD may further orchestrate the recruitment of cytosolic factors involved in membrane budding and fission of transport vesicles and nascent SGs.


Application of a novel drug-tolerant target assay for measuring target engagement when only one epitope remains after therapeutic antibodies bind their targets.
The measurement of proteins with a limited number of available non-overlapping epitopes recognizable by antibodies represents a common challenge for the development of drug-tolerant clinical biomarker assays. For target proteins with two dominant epitopes, only one epitope remains when the other is occupied by the therapeutic antibody. Alternative strategies for overcoming this obstacle have been described in the literature; however, these methods have potential limitations. We have developed a novel method for measuring target engagement when only one epitope remains after therapeutic antibodies bind their analytes. The method combines Affinity Capture Elution (ACE) followed by simultaneous capture and detection of the protein of interest. This novel method has been named ACE-Sandwich. The application of this method is not dependent on the immunoglobulin G subclass of the therapeutic antibody, nor does this method require sample pretreatment. Furthermore, the ACE-Sandwich method is highly sensitive, reproducible, and tolerant to high concentrations of therapeutic antibody.