[The role of cervical transformational zone as an object of human papilloma virus oncogenic effect in cervical intraepithelial neoplasms and invasive cancer development].
The correlation of morphological mistakes in neoplasia grade verification from visibility of transformation zone (TZ) and patient age was studied in 503 patients with CIN and microinvasive cervical cancer. The square of ectocervix lesion was defined by LeiseCap software in colposcopic working station Leisegang 3MV. The exclusive significance of TZ in HPV-associated cancerogenesis was confirmed clinically. We've established that the neoplasia stage increases with age while lesion extension and TZ visibility decrease dramatically leading to the subsequent decrease in colposcopy sensitivity and adequacy of guided biopsy. The critical age for underdiagnosis of latent lesions seems to be 35 years. The diagnostic and therapeutic value of conization and the large loop excision of the TZ (LLETZ) as the procedures with the optimal TZ excision in patients with visibly unchanged ectocervix are confirmed in cases when CIN 2-3 and microinvasive cancer are suspected.


Preservation of human skin: a study of two media using the athymic (nude) mouse model.
This study is part of an ongoing attempt to define the optimal conditions for short-term storage of viable human skin for auto- or homotransplantation. Roswell Park Memorial Institute 1640 (RPMI) media was more convenient to use than Eagle's Minimum Essential Medium with HEPES buffer (MEM-H) but functional skin viability was not statistically different in the two media. MEM without HEPES buffer did not preserve human skin at 20 days storage. The athymic (nude) mouse provides an excellent in vivo test of stored human skin functional viability.


Aberrant static and dynamic functional network connectivity in heart failure with preserved ejection fraction.
Heart failure may lead to brain functional alterations related to cognitive impairment. This study aimed to detect alterations of static functional network connectivity (FNC) and dynamic FNC in heart failure with preserved ejection fraction (HFpEF) and to estimate the association between the altered FNC and clinical features related to HFpEF. The clinical and resting-state functional magnetic resonance imaging (fMRI) data of HFpEF patients (n = 35) and healthy controls (HCs) (n = 35) were acquired at baseline. Resting-state networks (RSNs) were established based on independent component analysis (ICA) and FNC analyses were performed. The associations between the FNC abnormalities and clinical features related to HFpEF were analysed. Compared with HCs, HFpEF patients showed decreased functional connectivity within the default mode network, left frontoparietal network, and right frontoparietal network and increased functional connectivity within the right frontoparietal network and visual network. Negative correlations were observed between decreased dynamic FNC and the left ventricular end-diastolic diameter (LVDd) (r = -0.435, P = 0.015) as well as the left ventricular end-systolic diameter (LVDs) (r = -0.443, P = 0.013). The FNC disruption and altered temporal properties of functional dynamics in HFpEF patients may reflect the neural mechanisms of brain injury after HFpEF, which may deepen our understanding of the disease.


Modeling Biologically Important NH···π Interactions Using peri-Disubstituted Naphthalenes.
For the first time, systematic studies of 8-aryl and 8-pyrrolyl derivatives of 1-aminonaphthalene as simple, synthetically available, and nicely preorganized models were conducted for a better understanding the properties of NH···π interactions involved in the stabilization of the secondary and tertiary protein structures as well as the recognition of guest molecules by biological receptors. It was shown that the NH···π binding is especially effective when the NH-donor is a positively charged group, for example, Me2NH+, and the π-donor is an electron-rich aromatic substituent, in particular, the 1-pyrrolyl or the 4-hydroxyphenyl group. Using protonated tetrafluoroborate salts, a strong counterion effect was demonstrated by means of theoretical calculations. Through several mechanisms, including short CH···F contacts, bifurcation, and long-range dispersion, the counterion promotes considerable structural changes and weakens the NH···π interactions from 12-15 kcal mol-1 in "naked" cations to 5-9 kcal mol-1 in the salts. To this end, 8-(2,5-dimethylpyrrol-1-yl)-N,N-dimethylnaphthalene-1-ammonium tetrafluoroborate, with the record linearity and shortness (2.07 Å) of the NH···π-centroid bond, was recognized as the most appropriate model with the strongest NH···π interaction ever described.


Recurring and emerging themes in prokaryotic innate immunity.
A resurgence of interest in the pathways that bacteria use to protect against their viruses (i.e. phages) has led to the discovery of dozens of new antiphage defenses. Given the sheer abundance and diversity of phages - the ever-evolving targets of immunity - it is not surprising that these newly described defenses are also remarkably diverse. However, as their mechanisms slowly come into focus, some common strategies and themes are also beginning to emerge. This review highlights recurring and emerging themes in the mechanisms of innate immunity in bacteria and archaea, with an emphasis on recently described systems that have undergone more thorough mechanistic characterization.


3D and quantum QSAR of non-benzodiazepine compounds.
A combined physicochemical and 3D technique is used to establish the QSAR of four series of non-benzodiazepines towards BzR. In physicochemical QSAR study, the semi-empirical PM3 based parameters like hardness, electronegativity, electrophilicity index, molar refractivity, heat of formation, solvent assessable surface area and logP were used as descriptors. The heat of formation (HF) and logP are recognized as the most important descriptors for binding affinity of such compounds to BzR. The 3D QSAR study reveals that beta-Carbolines of series "A" and Imidazo[1, 2-alpha]pyrimidines of series "C" show steric bulk interaction, the beta-Carbolines of series "B" and di-substituted purines of series "D" have dominance of electrostatic interaction with BzR. The CoMSIA also indicate the same trend in terms of steric and electrostatic interaction. The CoMSIA reveals that only in case of series "D", the hydrophobic field effect is important. Some possible candidates for all four series were designed and their probable activities were estimated by using different QSAR models. The activities of designed molecules are in better range and developed models might be helpful to design the potent ligands of BzR.


Effects of different surface modification and contents on municipal solid waste incineration fly ash/epoxy composites.
Incineration fly ash, a waste from municipal solid waste incineration plant can be used to replace conventional filler as reinforcing filler to enhance the mechanical strength of a composite. Surface modification was performed on the incineration fly ash before mixing into the soft polymer matrix so as to improve interfacial bond of the filler and epoxy resin. In this study, detailed characterisation of mechanical, morphological and leaching behaviours of municipal solid waste incineration (MSWI) fly ash infused composite has been carried out. Flexural and tensile test was conducted to determine the effect on mechanical properties of the composite by varying the concentration of incineration fly ash filler added into polymer matrix and surface modification of incineration fly ash filler using silane coupling agent and colloidal mesoporous silica (CMS). The results indicated that composite infused with incineration fly ash filler surface treated with CMS shown improvement on the tensile and flexural strengths. In addition, SEM images showed that surface modification of incineration fly ash with colloidal mesoporous silica enhanced the interfacial bonding with polymer resin which explained the improvement of mechanical strength. Leaching test showed result of toxic metals such as Pb, Zn, Fe, Cu, Cr, Cd and Rb immobilised in the polymer matrix of the composite. Hence, the use of MSWI fly ash as reinforcing filler in the composite appears green and sustainable because this approach is a promising opportunity to substitute valuable raw material with MSWI fly ash.


N2 gas egress from patients' airways during LN2 spray cryotherapy.
Spray cryotherapy using liquid nitrogen (LN2) is a general surgical tool used to ablate benign or malignant lesions. Adequate egress of the gaseous nitrogen (N2) generated during this process must be provided for safe use when LN2 is used within the body rather than topically. When delivered to either the gastrointestinal tract (requiring active venting via a suction tube) or body cavities open to room barometric pressure (such as lung airways) allowing for passive venting, the N2 gas generated from the boiling process must be evacuated. This work will examine the egress of N2 during procedures requiring passive venting from human airways undergoing liquid nitrogen spray cryotherapy. Venting characteristics for safe N2 egress will be presented and discussed based on analytical modeling using fluid mechanics simulations and experimental studies of N2 venting with laboratory and porcine models.


6-aminoalkyloxazolo[4,5-b]pyridin-2(3H)-ones: synthesis and evaluation of antinoceptive activity.
Series of 6-aminoalkyloxazolo[4,5-b]pyridin-2(3H)-ones incorporating structural modifications both in the alkyl chain and basic amino moiety were tested for their analgesic efficacy and safety in mice and rats. Two of the synthesised compounds, 4a (3-methyl-6-[(4-phenyl-1-piperazinyl)methyl]oxazolo[4,5-b]pyridin-2(3H)-one) and 12a (3-methyl-6¿1-[2-(4-phenyl-1-piperazinyl)ethan-1-ol]¿oxazolo[4,5-b]pyridin- 2(3H)-one) were found to be more potent than aspirin with ED50 values of 26 (16.1-42.4) and 15.5 (11.4-21.2) mg/kg po (mouse, phenylquinone writhing test) respectively and 6 (3.1-9.8) and 5.5 (3.5-8.8) mg/kg po (rat, acetic acid writhing test). Compounds 4a and 12a proved to be potent nonopioid nonantiinflammatory analgesics but unfortunately have sedative properties at relatively low doses (respectively 64 and 16 mg/kg po, mice).


Transplantation of kidneys from uncontrolled donation after circulatory determination of death: comparison with brain death donors with or without extended criteria and impact of normothermic regional perfusion.
The aim of this study was to compare the outcomes of kidney transplants from uncontrolled DCD (uDCD) with kidney transplants from extended (ECD) and standard criteria donors (SCD). In this multicenter study, we included recipients from uDCD (n = 50), and from ECD (n = 57) and SCD (n = 102) who could be eligible for a uDCD program. We compared patient and graft survival, and kidney function between groups. To address the impact of preservation procedures in uDCD, we compared in situ cold perfusion (ICP) with normothermic regional perfusion (NRP). Patient and graft survival rates were similar between the uDCD and ECD groups, but were lower than the SCD group (P < 0.01). Although delayed graft function (DGF) was more frequent in the uDCD group (66%) than in the ECD (40%) and SCD (27%) groups (P = 0.08 and P < 0.001), graft function was comparable between the uDCD and ECD groups at 3 months onwards post-transplantation. The use of NRP in the uDCD group (n = 19) was associated with a lower risk of DGF, and with a better graft function at 2 years post-transplantation, compared to ICP-uDCD (n = 31) and ECD. In conclusion, the use of uDCD kidneys was associated with post-transplantation results comparable to those of ECD kidneys. NRP preservation may improve the results of uDCD transplantation.


Comparative nutritional compositions and proteomics analysis of transgenic Xa21 rice seeds compared to conventional rice.
Transgenic rice expressing the Xa21 gene have enhanced resistant to most devastating bacterial blight diseases caused by Xanthomonas oryzae pv. oryzae (Xoo). However, identification of unintended modifications, owing to the genetic modification, is an important aspect of transgenic crop safety assessment. In this study, the nutritional compositions of seeds from transgenic rice plants expressing the Xa21 gene were compared against non-transgenic rice seeds. In addition, to detect any changes in protein translation levels as a result of Xa21 gene expression, rice seed proteome analyses were also performed by two-dimensional gel electrophoresis. No significant differences were found in the nutritional compositions (proximate components, amino acids, minerals, vitamins and anti-nutrients) of the transgenic and non-transgenic rice seeds. Although gel electrophoresis identified 11 proteins that were differentially expressed between the transgenic and non-transgenic seed, only one of these (with a 20-fold up-regulation in the transgenic seed) shows nutrient reservoir activity. No new toxins or allergens were detected in the transgenic seeds.


Assessment of nociceptive system in vegetative and minimally conscious state by using laser evoked potentials.
The aim of this study is to assess if laser evoked potentials (LEPs) examination should be considered as an objective evidence of potential or residual pain perception capacity in vegetative (VS) and minimally conscious state (MCS) patients and if it could be a feasible methodology in order to differentiate these two clinical entities. This is a cross-sectional observational study focusing on the role of LEP examination, which is an easy and objective neurophysiological approach of the nociceptive system. Thirteen VS and 10 MCS patients were enrolled. All subjects were evaluated clinically by using validated behavioural scales and underwent to upper and lower limbs LEP recording. Intra-group LEPs analysis in VS patients highlighted significant differences for N2P2 latency (p = 0.036) and amplitude (p = 0.018). Inter-group LEPs analysis showed significant differences in post-anoxic condition for N2P2 latency (p = 0.034), amplitude (p = 0.034) and a trend in N2P2 latency in brain trauma (p = 0.07). Interestingly, correlation analysis showed a significant relationship between N2P2 amplitude and Coma Recovery Scale-Revised scoring in the post-traumatic VS (r = 0.823, p = 0.044). The findings lead to detection of potential markers of conscious pain perception in patients with DOC, with important impact on therapeutic and rehabilitative management, and provide new information that may allow a better differential diagnosis.


Women heterozygous for deficiency of the (p21 leads to pter) region of the X chromosome are fertile.
A woman balanced carrier of a X/15 translocation gave birth to a balanced infertile son and three unbalanced Xp--fertile daughters. This family and the other eleven cases of Xp--fertile women found in the literature demonstrate that loss of the p21 leads to pter region of the X chromosome is compatible with fertility, probably because it leaves on Xp the region which is never inactivated.


A review of infrared thermography as applied to human sexual psychophysiology.
Infrared thermography (IRT) is a non-contact technique that permits mapping and analysis of the temperature of the body's skin surface. This method has been applied to sexual psychophysiology since the 1980s and its use has been expanding ever since, mainly because it provides several advantages over existing genital response measures. This article presents a review of experimental studies employing IRT to investigate human sexual arousal, with the aim of summarizing the available procedures and evidence so far and to identify important caveats in the literature. The studies reviewed support the feasibility and validity of IRT as a real-time physiological measure of sexual arousal but varied substantially regarding methodology and procedures. The results of this review underscore the value and validity of IRT in sexual psychophysiology and point at the critical need for the standardization of IRT protocols to accommodate the specific needs of applying this methodology to sexual physiology.


Angiotensin II drives the production of tumor-promoting macrophages.
Macrophages frequently infiltrate tumors and can enhance cancer growth, yet the origins of the macrophage response are not well understood. Here we address molecular mechanisms of macrophage production in a conditional mouse model of lung adenocarcinoma. We report that overproduction of the peptide hormone Angiotensin II (AngII) in tumor-bearing mice amplifies self-renewing hematopoietic stem cells (HSCs) and macrophage progenitors. The process occurred in the spleen but not the bone marrow, and was independent of hemodynamic changes. The effects of AngII required direct hormone ligation on HSCs, depended on S1P(1) signaling, and allowed the extramedullary tissue to supply new tumor-associated macrophages throughout cancer progression. Conversely, blocking AngII production prevented cancer-induced HSC and macrophage progenitor amplification and thus restrained the macrophage response at its source. These findings indicate that AngII acts upstream of a potent macrophage amplification program and that tumors can remotely exploit the hormone's pathway to stimulate cancer-promoting immunity.


[Escherichia coli O157:H7 strains carrying Shiga toxin 2 variant slt2vha were isolated from Xuzhou City of Jiangsu Province].
To monitor the changes of predominant Shiga toxin types of Escherichia coli O157:H7 in Xuzhou City, Jiangsu Province. PCR typing with slt2-specific primer pairs (slt2cslt2, slt2v1slt2v2), hybridization of chromosome DNA digested by PstI, and DNA sequencing of PCR products. with slt2-specific primer pairs (slt2cslt2d; slt2eslt2f) were conducted on 14 strains of E. coli isolated from diarrhea patients and dung beetles in 1999 and 2000. The 5 strains of E. coli isolated from diarrhea patients in 1999 carried slt1 and slt2. The 1 strains of E. coli O157:H7 isolated from diarrhea patients and the 5 strains isolated from dung beetles in 2000 only carried slt2vha, a variance of Shiga toxin 2. The predominant Shiga toxin types of E. coli O157:H7 in Xuzhou changed 1999 - 2000, which may be related to the changes of epidemiological features of E. coli O157:H7 infection in Xuzhou. A genotyping method based on restriction fragment length polymorphism (RFLP) analysis of a B-subunit-encoding DNA fragment obtained by PCR described in this study is a useful tool to identify slt2 gene and slt2 variant gene in epidemiological studies with O157:H7 strains.


Ubbelohde effect within weak C-H···π hydrogen bonds: the rotational spectrum of benzene-DCF3.
The Fourier transform microwave investigation of C6H6-DCF3 outlines a shortening of the distance between the two constituent molecules of about 0.0044(2) Å upon H → D substitution of the hydrogen atom involved in the C-H···π hydrogen bond. This proves that the Ubbelohde effect takes place also within weak hydrogen bonding. The measure of the spectra of several (13)C isotopologues in natural abundance has been useful to obtain structural information.


Discourses of culture and illness in South African mental health care and indigenous healing, Part I: Western psychiatric power.
This discourse analytic study explores constructions of culture and illness in the talk of psychiatrists, psychologists and indigenous healers as they discuss possibilities for collaboration in South African mental health care. Versions of 'culture', and disputes over what constitutes 'disorder', are an important site for the negotiation of power relations between mental health practitioners and indigenous healers. The results of this study are presented in two parts. Part I explores discourses about western psychiatric/psychological professionalism, tensions in diagnosis between cultural relativism and psychiatric universalism, and how assertion of 'cultural differences' may be used to resist psychiatric power. Part II explores how discursive constructions of 'African culture' and 'African madness' work to marginalize indigenous healing in South African mental health care, despite repeated calls for collaboration.


Synthesis of nano-sized Eu³⁺-imprinted polymer and its application for indirect voltammetric determination of europium.
Europium(III)-imprinted polymer nanoparticles were synthesized using suspension polymerization in silicon oil. Vinyl pyridine and methacrylic acid were used either as the complexing ligand or functional monomer. Divinyl benzene was applied as cross-linker agent. Carbon paste electrodes, impregnated with the ion imprinted polymer (IIP), were incubated in the solutions containing Cu(2+) and different kinds of lanthanide ions. The oxidative stripping differential pulse voltammetry method was then utilized to measure the signal of adsorbed Cu(2+), after removal of the electrodes from the first solutions and immersion of them in the electrochemical cell. The response of the IIP-modified electrode to Cu(2+) decreased in the solution containing both Cu(2+) and Eu(3+); but, it was not influenced in the solutions of Cu(2+) and other lanthanides. This suggested that Eu(3+) could compete against Cu(2+) to capture the selective sites of the IIP; whereas, other lanthanide ions were not capable of replacement with Cu(2+) in the IIP sites. However, In the case of non-imprinted polymer (NIP)-modified electrode, no considerable signal difference was found between the pure Cu(2+) solution and the solution containing both Cu(2+) and Eu(3+). This indicated that the selective sites of the IIP were responsible for the observed phenomenon. The decrease in the response of IIP-based electrode to Cu(2+) was found to be reasonably proportional to Eu(3+) concentration. This finding was utilized for the indirect voltammetric determination of Eu(3+). The effect of different factors on the method was then investigated and the optimum conditions were chosen. The electrode showed high selectivity for Eu(3+), even in the presence of other lanthanide ions. The developed method exhibited concentration linear range of 5 × 10(-7)-3 × 10(-5)mol L(-1) and detection limit of 1.5 × 10(-7)mol L(-1) (signal/noise, S/N). Relative standard error percent of 5 separate determinations was found to be 2.91%. The developed method was successfully applied for the determination of Eu(3+) in the synthetic and spiked real samples.


Intranasal Spray Characteristics for Best Drug Delivery in Patients With Chronic Rhinosinusitis.
To determine parameter combinations for effective drug delivery of intranasal spray steroids to the ostiomeatal complex (OMC) and maxillary sinus (MS) in patients with chronic rhinosinusitis (CRS). Each patient's sinonasal cavity was reconstructed from computed tomography scans. Intranasal airflow and drug particle transport were simulated using computational fluid dynamic modeling. Airflow simulations were performed at 15 Pascal inhalation pressure. Intranasal spray particles of 1-100 μm were simulated at release speeds of 1, 5, and 10 m/s from 6 release locations (Bottom, Center, Top, Lateral, Lateral-Bottom, and Lateral-Top) at a nozzle insertion depth of 15 mm. Drug delivery simulations were performed in the head tilted forward position. Maximal OMC deposition was 0.78%-12.44%, while maximal MS deposition was 0.02%-1.03% across all simulations. In general, particles between 6 and 10 μm had the best OMC (at 1 m/s particle velocity) and MS (at 10 m/s particle velocity) deposition. Particles ranging from 21 to 30 μm also had superior OMC deposition. The lateral and lateral-top spray release locations produced maximum OMC deposition, but no one release location demonstrated an increase in MS deposition. This preliminary study suggests that it is challenging to determine a common set of intranasal spray parameter combinations for effective drug delivery to the OMC and MSs. Although drug particle size and spray particle velocity seem to impact particle deposition patterns, spray release location appears to vary with anatomical differences between subjects, particularly when the MS is the target location for particle deposition. Laryngoscope, 133:1036-1043, 2023.


Anxiety level and body weight changes in rats living in overpopulated cages.
Behavioral indicators of anxiety and body weight dynamics were compared in rats kept under standard conditions (4-5 animals per cage) and in overpopulated cages (17 rats per cage). The behavior of rats exposed to overcrowding for a short and long period was evaluated in the open field, light-darkness, and elevated plus-maze tests. The anxiety parameters of animals increased only in the light-darkness test during the acute period of overcrowding and in all tests during chronic overcrowding. Behavioral tests had a negative impact on body weight gain in controls and rats living in overpopulated cages. If the behavioral tests were carried out at the beginning of the experiment, body weight ceased to increase in animals exposed to overcrowding and continued to increase in the controls. Overcrowding without behavioral tests had no effects on the body weight dynamics. The model of chronic (but not acute) overcrowding may be used for evaluation of anxiolytic effects of drugs.


Pain management and coping strategies for primary dysmenorrhea: A qualitative study among female nursing students.
Primary dysmenorrhea is a problem that affects both young and adult women, with a significant impact on their daily lives. This pain is primarily managed through the consumption of non-steroidal anti-inflammatories and non-pharmacological approaches such as exercise, acupressure and heat. The present study aimed to describe how Spanish university students manage dysmenorrhea. Qualitative case study. Nursing students (N = 33) from the region of Andalusia (Spain) participated in focus groups. A purposive sampling method was used, and the data were collected through videoconferencing and subsequently analysed thematically. The guidelines for conducting qualitative studies established by the consolidated criteria for reporting qualitative research (COREQ) and the standards for reporting qualitative research (SRQR) were followed. Four principal themes were identified: (a) Strategies for pain management; (b) using painkillers; (c) choosing the ideal treatment; (d) non-pharmacological interventions. The nursing students experienced difficulties in managing primary dysmenorrhea, they self-medicated, expressed reluctance to seek professional medical advice, used non-pharmacological strategies and seeked advice from other women within their family/social circle.


Use of a novel GFP reporter cell line to examine replication capacity of CXCR4- and CCR5-tropic HIV-1 by flow cytometry.
The rate of HIV-1 disease progression correlates strongly with plasma viral load and is likely to be influenced by both host and viral determinants. Though interest in the impact of viral replication capacity during HIV-1 infection has been increasing, especially with respect to drug resistance mutations, its influence on disease course remains poorly understood. This is due in part to significant drawbacks in conventional means of measuring HIV-1 growth in vitro (i.e. expense, inconvenience, and experimental variability). A FACS-based method is described here to measure HIV-1 replication sensitively and a modification of this method can be used to determine viral titer accurately. Importantly, the target cells used are permissive to CXCR4- and CCR5-tropic HIV-1 strains. In pilot experiments, the growth kinetics of laboratory-adapted strains NL4-3 and IIIB were examined carefully. Using this method, differences were observed in growth kinetics between three laboratory strains and seven primary isolates, indicating the potential for a broad range of in vitro replication capacities among individual isolates. In conclusion, this FACS-based method provides a sensitive approach to measure the replication capacity of HIV-1 and may prove useful in studies examining the impact of viral fitness on disease progression.


Reinforcement schedules and extrapolations to humans from animals in behavioral pharmacology.
Behavior controlled by various schedules of reinforcement is useful for characterizing drugs as well as for analyzing the mechanisms of action of their effects on behavior. Conditioned avoidance techniques have been useful for studying neuroleptics and for predicting their clinical antipsychotic acitivity; the possible involvement of dopaminergic mechanisms in the effect of neurolpetics on avoidance behavior is discussed. Tricyclic antidepressant agents have been studied in assays involving interactions with other agents, such as cocaine, amphetamine and tetrabenazine. One type of operant behavior, Sidman avoidance, has been used as particularly sensitive assay for such drug interactions. Another schedule, in which "observing" responses in pigeons are measured. seems to provide a method for studying antidepressants without involving drug interaction phenomena. For tricyclic compounds, facilitation of observing responses and weak potency of conditioned avoidance inhibition constitute a pharmacological profile that seems to have some predictive value for clinical imipramine-like antidepressant activity. "Conflict (punishment) schedules have been useful for predicting antianxiety activity in man. Although the degree of anticonflict effect observed is consistent with Dew's rate dependency hypothesis, this principle does not fully account for the observed drug effects. In the conflict model, the actions of benzodiazepines differ in drug-naive versus drug-experienced animals. Experiments with parachlorophenylalnine have not yet provided clear support for the postulated role of serotonin in related phenomena.


Lactic acid induces fibroblast growth factor 23 (FGF23) production in UMR106 osteoblast-like cells.
Endocrine and paracrine fibroblast growth factor 23 (FGF23) is a protein predominantly produced by bone cells with strong impact on phosphate and vitamin D metabolism by targeting the kidney. Plasma FGF23 concentration early rises in kidney and cardiovascular diseases correlating with progression and outcome. Lactic acid is generated in anaerobic glycolysis. Lactic acidosis is the consequence of various physiological and pathological conditions and may be fatal. Since FGF23 production is stimulated by inflammation and lactic acid induces pro-inflammatory signaling, we investigated whether and how lactic acid influences FGF23. Experiments were performed in UMR106 osteoblast-like cells, Fgf23 mRNA levels estimated from quantitative real-time polymerase chain reaction, and FGF23 protein determined by enzyme-linked immunosorbent assay. Lactic acid dose-dependently induced Fgf23 gene expression and up-regulated FGF23 synthesis. Also, Na+-lactate as well as formic acid and acetic acid up-regulated Fgf23. The lactic acid effect was significantly attenuated by nuclear factor kappa-light-chain enhancer of activated B-cells (NFκB) inhibitors wogonin and withaferin A. Lactic acid induces FGF23 production, an effect at least in part mediated by NFκB. Lactic acidosis may, therefore, be paralleled by a surge in plasma FGF23.


Paroxysmal spike and wave activity in drowsiness in young children: its relationship to febrile convulsions.
Paroxysmal rhythmic theta waves appearing during early stages of sleep have long been recognized in the EEGs of normal children. A similar pattern with intermixed spikes appears to have a different correlation. We called this pattern 'hypnagogic paroxysmal spike wave activity' or 'hypnagogic PSW.' This investigation was designed to test whether there exists a relationship between hypnagogic PSW, febrile convulsions (FC) and age. We selected 3 cohorts of children: G-1 or normal control consisted of 94 children selected with the following criteria: complete normal neurodevelopmental examination and no personal or family history of FC, epilepsy, or other neurological disorder. They all had one EEG obtained without drug induction showing a clear sequence of awake-drowsy-sleep-arousal-awake states. G-2 or pathological control group consisted of 126 children selected at random, referred to the Division of Neurophysiology at the Children's Hospital Medical Center for any problem excluding FC. At least one EEG met the criteria mentioned above. G-3 or FC group consisted of 375 children in whom the very first seizure was associated with fever without evidence of other causes for the convulsion. All met the same EEG criteria of G-1 and G-2. The medical record of 169 children of this group (40 with hypnagogic PSW and 129 without hypnagogic PSW) were reviewed.(ABSTRACT TRUNCATED AT 250 WORDS)


Heterodimer formation of the myeloid zinc finger 1 SCAN domain and association with promyelocytic leukemia nuclear bodies.
Myeloid zinc finger 1 (MZF1) is a transcription factor that plays an important role in blood cell development. Previous reports indicate MZF1 is an essential factor whose abnormal expression results in cancer. However, the molecular mechanisms by which MZF1 functions in development and contributes to cancer progression remain unknown. MZF1 is a member of the SCAN domain family of zinc finger proteins (SCAN-ZFP) that form dimers via their highly conserved SCAN motif. To better understand the molecular mechanism of MZF1 function, we sought to characterize the cellular localization pattern of MZF1 in the context of SCAN dimerization. Here we provide evidence that MZF1 is a constituent of promyelocytic leukemia nuclear bodies (PML-NBs) and that the SCAN domain is necessary for association with these intranuclear structures. In addition, the SCAN-ZFP member ZNF24 was identified as a novel heterodimeric partner of MZF1 that also associates with PML-NBs in a unique ring-type pattern. Finally, we provide support that MZF1 protein may be modified by SUMOylation, which provides further support for localization of MZF1 protein complexes to PML-NBs. Altogether, these data suggest that MZF1 is recruited to PML-NBs and that the SCAN domain may play an integral role in regulating the localization of heterodimeric protein complexes to these intranuclear structures.


AFLP markers and cytotaxonomic analysis reveal hybridisation in the genus Schoenus (Cyperaceae).
Molecular, cytological, and morphological data support the existence of a hybrid population between Schoenus nigricans and Schoenus ferrugineus. This population was found in northeastern Italy, where S. nigricans is central with respect to its natural range and S. ferrugineus is marginal, being most common in the Alps and in central and northern Europe. Molecular marker data show that the putative hybrid population is genetically intermediate between nearby populations of the parent species. Cytological evidence confirmed the hybrid nature of this population, as does the almost complete sterility of plants within the population. Although no seeds were produced by the hybrid population, some possibly fertile pollen grains were produced; this suggests that the possibility of introgression between the two species through the hybrids cannot completely be excluded.


Control of massive hemoptysis via a "back-door" approach through the pulmonary artery.
Bronchial artery embolization is an effective nonsurgical therapy for massive hemoptysis. Routine selection of the bronchial arteries from the aorta usually enables the interventionalist full interrogation and embolization of the culprit vascular abnormality. In problematic cases where bronchial artery access is difficult, a systemic-to-pulmonary arterial shunt can be exploited as a retrograde means of vascular intervention. A case is presented where inaccessibility of a tortuous left bronchial artery was circumvented by accessing the left pulmonary artery, leading to successful embolization and control of hemoptysis.


Effect of hydraulic retention time on microbial community in biochemical passive reactors during treatment of acid mine drainage.
The effect of hydraulic retention time (HRT) on the microbial community during acid mine drainage (AMD) treatment was investigated. Physicochemical and molecular (illumina and qPCR) analyses were performed on reactive mixtures collected from seven bioreactors in three-operation period (8, 17 and 36weeks). Long HRT (4day) favored the relative abundance of SRB, causing the increase of residual sulfides and short HRT (1day) affected the anaerobic conditions of the bioreactors and favored the presence the acidophilic chemolithotrophic microorganisms. Besides qPCR indicated that genes related to cellulose degradation were present in low copy numbers and were affected by the HRT. Finally, environmental factors (pH, organic source, metal sulfides, and sulfate concentrations) had significant impact on relative abundance of the phylogenetic lineages, rather than the types of lineages present in the reactive mixture. The findings of this study indicate that HRT affects the stability of passive bioreactors and their microbial communities.


Ciprofloxacin: mammalian DNA topoisomerase type II poison in vivo.
Ciprofloxacin (CF), a fluoroquinolone widely used as a potent antimicrobial drug, was evaluated in vivo in mouse bone marrow cells for its ability to induce clastogenicity and DNA damage in terms of increased sister-chromatid exchange (SCE) frequencies. Doses of 0.6, 6 and 20 mg/kg body weight of CF given intraperitoneally induced a positive dose-dependent significant clastogenicity (trend test alpha < or = 0.05), though the effects were not specific for specific phases of the cell cycle. The DNA-damaging effect observed as increased SCE frequencies using doses of 0.15, 0.30, 0.60, 1.2 and 6 mg/kg body weight showed a significant dose-dependent increase (trend test alpha < or = 0.05; lowest effective concentration 1.2 mg/kg of body weight). Compared to a potent eukaryotic DNA topoisomerase type II poison, etoposide (VP-16, 0.5, 1 and 5 mg/kg body weight, given intraperitoneally), ciprofloxacin produced comparable dose-dependent SCE frequency increases. Ciprofloxacin was postulated to be specific for the target DNA gyrase, the prokaryotic homologue of DNA topoisomerase type II enzyme. The present paper along with the existing earlier data strongly suggest that topoisomerase type II and DNA gyrase are physiological targets for the drug action. In view of the present significant in vivo mammalian DNA topoisomerase type II-mediated genotoxicity and clastogenicity data, ciprofloxacin should be administered with caution.


Treatment of endoscopic ultrasound-guided coil deployment for isolated gastric varices using 0.035-inch hydrocoil: Experience of three cases.
Endoscopic ultrasound (EUS)-guided coil deployment (EUS-coiling) has been newly developed for treating isolated gastric varices (iGV). This report describes three cases of EUS-coiling for iGV using a 0.035-inch hydrocoil (Azur; Terumo Corp., Tokyo, Japan). When used for EUS-coiling, this hydrocoil provides the following benefits: Its electrically detachable system allows pull back. It has smooth and dense deployment. Moreover, it has a strong blood-flow blocking effect because of its long length and large diameter with internal swelling functions of the hydrogel. Technical success of coiling was achieved in all cases. After coiling, additional treatments such as cyanoacrylate and sclerosant injection were performed as deemed appropriate. All iGVs were obliterated successfully. No adverse event occurred during the procedure or during the mean follow-up of six months. Our findings indicate that this 0.035-inch hydrocoil can be used to treat iGV safely and effectively.


Levels and predictors of airborne and internal exposure to manganese and iron among welders.
We investigated airborne and internal exposure to manganese (Mn) and iron (Fe) among welders. Personal sampling of welding fumes was carried out in 241 welders during a shift. Metals were determined by inductively coupled plasma mass spectrometry. Mn in blood (MnB) was analyzed by graphite furnace atom absorption spectrometry. Determinants of exposure levels were estimated with multiple regression models. Respirable Mn was measured with a median of 62 (inter-quartile range (IQR) 8.4-320) μg/m(3) and correlated with Fe (r=0.92, 95% CI 0.90-0.94). Inhalable Mn was measured with similar concentrations (IQR 10-340 μg/m(3)). About 70% of the variance of Mn and Fe could be explained, mainly by the welding process. Ventilation decreased exposure to Fe and Mn significantly. Median concentrations of MnB and serum ferritin (SF) were 10.30 μg/l (IQR 8.33-13.15 μg/l) and 131 μg/l (IQR 76-240 μg/l), respectively. Few welders were presented with low iron stores, and MnB and SF were not correlated (r=0.07, 95% CI -0.05 to 0.20). Regression models revealed a significant association of the parent metal with MnB and SF, but a low fraction of variance was explained by exposure-related factors. Mn is mainly respirable in welding fumes. Airborne Mn and Fe influenced MnB and SF, respectively, in welders. This indicates an effect on the biological regulation of both metals. Mn and Fe were strongly correlated, whereas MnB and SF were not, likely due to higher iron stores among welders.


YY2/PHGDH axis suppresses tumorigenesis by inhibiting tumor cell de novo serine biosynthesis.
Metabolic reprogramming is one of the key features of tumors facilitating their rapid proliferation and adaptation to harsh microenvironments. Yin Yang 2 (YY2) has recently been reported as a tumor suppressor downregulated in various types of tumors; however, the molecular mechanisms underlying its tumor-suppressive activity remain poorly understood. Furthermore, the involvement of YY2 in tumor cell metabolic reprogramming remains unclear. Herein, we aimed to elucidate the novel regulatory mechanism of YY2 in the suppression of tumorigenesis. Using transcriptomic analysis, we uncovered an unprecedented link between YY2 and tumor cell serine metabolism. YY2 alteration could negatively regulate the expression level of phosphoglycerate dehydrogenase (PHGDH), the first enzyme in the serine biosynthesis pathway, and consequently, tumor cell de novo serine biosynthesis. Mechanistically, we revealed that YY2 binds to the PHGDH promoter and suppresses its transcriptional activity. This, in turn, leads to decreased production of serine, nucleotides, and cellular reductants NADH and NADPH, which subsequently suppresses tumorigenic potential. These findings reveal a novel function of YY2 as a regulator of the serine metabolic pathway in tumor cells and provide new insights into its tumor suppressor activity. Furthermore, our findings suggest the potential of YY2 as a target for metabolic-based antitumor therapeutic strategies.


Characterization of human T-lymphocyte clones (TLCs) specific for HLA-region gene products.
Clones of lymphocytes, primed in vitro to HLA-DR1;Dw1, were tested for allospecific proliferation on a panel of thirty-one HLA-phenotyped stimulating cells. No clone was restimulated exclusively by cells sharing the DR1;Dw1 priming antigens and most clones were restimulated by subsets of cells bearing DR1;Dw1. Generally, positive responses were at least 20-fold higher than autologous negative controls. Peak proliferative responses occurred around 72 h and varied, depending on the stimulating cell as well as the responding clone. Selected clones were induced to proliferate only by cells incapable of forming rosettes with sheep erythrocytes. Specific proliferation by TLCs was blocked by monoclonal DR-specific antibodies, but not by monoclonal anti-Thy 1.2. Genetic studies demonstrated that TLCs detected some cell-surface determinants that are encoded by genes in linkage disequilibrium with HLA and others that may not be linked to the human major histocompatibility complex.


Organisation and expression of a cluster of yolk protein genes in the Australian sheep blowfly, Lucilia cuprina.
The Australian sheep blowfly Lucilia cuprina is a major pest for the Australian and New Zealand sheep industries. With the long-term aim of making a strain of L. cuprina suitable for a genetic control program, we previously developed a tetracycline-repressible female lethal genetic system in Drosophila. A key part of this system is a female-specific promoter from a yolk protein (yp) gene controlling expression of the tetracycline-dependent transactivator (tTA). Here we report the sequence of a 14.2 kb genomic clone from L. cuprina that contains a cluster of three complete yp genes and one partial yp gene. The Lcyp genes are specifically expressed in females that have received a protein meal. A bioinformatic analysis of the promoter of one of the yp genes (LcypA) identified several putative binding sites for DSX, a known regulator of yp gene expression in other Diptera. A transgenic strain of L. cuprina was made that contained the LcypA promoter driving the expression of the Escherichia coli lacZ reporter gene. Transgenic females express high levels of β-galactosidase after a protein meal. Thus the LcypA promoter could be used to obtain female-specific expression of tTA in transgenic L. cuprina.


Blood pressure via telemetry during social confrontations in rats: effects of clonidine.
Male Long-Evans rats were implanted with blood pressure transmitters and introduced as intruders for 60 min into the home cage of a reproductively active resident male rat. Physical interaction ended after 3-5 min when the intruder displayed clear submissive behaviors. A protective wire cage was placed over the intruder until the animal was returned to its home cage. Systolic (+29.3 +/- 3.6 mmHg) and diastolic (+25.7 +/- 3.7 mmHg) blood pressures, pulse pressure (+7.3 +/- 2.0 mmHg), and heart rate (+129.0 +/- 12.6 BPM) peaked in the intruder rats during the defeat and did not fully return to control levels until return to the home cage. These acute changes as well as the heart rate and blood pressure baselines did not change when the confrontations were repeated on alternating days for a maximum of three trials per week. Pretreatment with clonidine (0.01, 0.03, 0.06, and 0.1 mg/kg) led to a dose-dependent decrease in the heart rate response but blood pressure was reduced similarly for all doses. We conclude that acute "defeat" can lead to an abrupt, large increase in blood pressure and heart rate in normotensive, Long-Evans rats that is sustained even in the absence of physical contact with the threatening resident. This response is diminished but not prevented by administration of clonidine.


Decline in somatomedin-C (insulin-like growth factor-1) with experimentally induced zinc deficiency in human subjects.
Six healthy volunteers (5 males and 1 female) participated in this study which was designed so that each subject served as his/her own control. During a 4-week stabilisation period subjects consumed a zinc-deficient diet (1.28 mg Zn/day) and zinc supplement (Zn-acetate in capsules) so that their daily intake of zinc was equivalent to their daily habitual intake prior to study period. The stabilisation period was followed by a 12-week zinc-depletion period where subjects consumed the zinc-deficient diet with no zinc supplement. Levels of energy, protein and all other nutrients were kept constant throughout the study period and matched their intake prior to the initiation of the study. Body weight and parametric measurements of zinc status indicated that zinc deficiency has been produced in these subjects. Plasma somatomedin-C/insulin-like growth factor 1 (IGF-1) dropped significantly (p < 0.05) at the first month of zinc-depletion and continued to decline throughout the second and third month (p < 0.001). The pattern of decline in plasma IGF-1 was comparable to the decline in body weight and plasma zinc concentration. The present study suggests that IGF-1 is zinc-dependent and could be used as a valid parameter for diagnosing zinc-deficiency. I suggest that the present finding should be considered in the interpretation of studies dealing with growth retardation associated with zinc deficiency in humans.


Naringenin accords hepatoprotection from streptozotocin induced diabetes in vivo by modulating mitochondrial dysfunction and apoptotic signaling cascade.
Diabetic complications cause noticeable liver damage, which finally progresses to diabetic hepatopathy. Nutritive antioxidants not only reduce the liver damage, but also prevent it by modulating the release of various proteins involved in apoptotic signaling cascades. This study explores the molecular mechanisms underlying diabetes-induced liver damage and its modulation by naringenin. Antioxidant status, liver & kidney biomarker enzymes, reactive oxygen species (ROS) generation, mitochondrial membrane potential, expression of apoptotic proteins like Bax (bcl-2 associated X), Bcl-2 (b-cell Lymhoma-2), Caspase-3, Caspase-9, AIF (Apoptosis inducing factor) and Endo-G (Endonuclease-G) were studied in streptozotocin induced diabetic rats. Significant hyperglycemia, disturbed antioxidant status, altered carbohydrate metabolizing enzymes, increased ROS and lipid peroxidation; decreased mitochondrial membrane potential and enhanced release of AIF and Endo-G were observed. Hyperglycemia also affected apoptosis and its related genes at both transcriptional and translational level (Caspase-3 & 9, Bax and Bcl-2) in the liver of diabetic rats. Naringenin, a flavonone, exerted anti-hyperglycemic effect and was able to prevent oxidative stress and resultant apoptotic events caused due to diabetes-induced hepatotoxicity. Thus, our study shows, a protective effect of naringenin against diabetes induced liver damage and redox imbalance, which could further be exploited for the management of diabetic hepatopathy.


Isolation of caprine arthritis-encephalitis virus from a goat.
Caprine arthritis-encephalitis-virus (CAEV) was isolated from the carpal joint of an Anglo-Nubian yearling goat with chronic progressive pneumonia and subclinical carpal arthritis. Anti-CAEV antibody was detected in this goat and in nine of 69 goat sera tested from two herds.


The Job Rotation of Nursing Staff and Its Effects on Nurses' Satisfaction and Occupational Engagement.
Job rotation in nursing staff involves moving workers from one department to another to increase their qualities in all areas. Investigating the effects of job rotation of nursing staff on employee satisfaction and occupational engagement. A total of 211 nurses took part in the study. A structured questionnaire with closed-ended questions was used to collect the data. The questions used were based on previous research tools. The data analysis was performed with the SPSS statistical package v.24.0. Τhe results regarding the correlation of job rotation, job satisfaction, and occupational engagement show that job rotation is positively related to occupational engagement and job satisfaction of nurses. The overall attitude of nursing staff toward job rotation is neutral, and they express moderate to neutral professional satisfaction, moderate degree of vigor and absorption, and moderate-to-high degree of dedication. Regarding the correlation of job rotation, job satisfaction, and occupational engagement with the demographic characteristics of nurses, it was found that the gender and years of work of nurses are not the factors that affect job satisfaction, occupational engagement, and job rotation. On the contrary, it was found that the age of nurses is a factor that only affects their work satisfaction, nursing education is a factor that only affects nurses' occupational engagement, and job position is a factor that affects nurses' occupational engagement and job rotation. The results highlight the importance of job rotation of nursing staff in their professional satisfaction and occupational engagement.


Progress of orthopaedic research in China over the last decade.
To summarize the representative scientific achievements in the past decade, and discuss the future challenges and directions for orthopaedic research in China. In this review, we used the data provided by National Natural Science Foundation of China (NSFC) for analysis. Over the last decade, NSFC has initiated various research programs with a total funding of over 1149 million RMB to support orthopaedic exploration. Under the strong support of NSFC, great progresses have been made in basic research, talent training, platform construction and the clinical translation in the field of orthopaedics in China. In general, since the establishment of the Department of Health Sciences of NSFC 10 years ago, both the amount of funding and the scale of researchers in the field of orthopaedic research have increased substantially. Despite of several shortcomings in orthopaedic research, with continuous support from NSFC both in funding and in policy, we believe that the orthopaedic research in China will surely make steady and significant progress. This article summarizes the representative scientific achievements in the past decade and puts forward the future challenges and directions for orthopaedic research in China.


Atrioventricular Wenckebach periodicity in athletes: influence of increased vagal tone on the occurrence of atypical periods.
In 37 athletes with atrioventricular (AV) Wenckebach periodicity, the relationship between PP and RR intervals was investigated. In most athletes, when PP intervals gradually lengthened, RR as well as PR intervals usually also gradually lengthened until a blocked P wave occurred, resulting in the occurrence of an atypical Wenckebach period with prolongation of the last RR interval (variant I). In 20 athletes, sudden marked prolongation of a PR interval occasionally occurred, which was usually followed by a blocked P wave (variant II). In five athletes, once sudden marked prolongation of a PR interval occurred, markedly long PR intervals were maintained for some time, and then a PR interval suddenly shortened without a blocked P wave (variant III). It appeared that the above findings were caused by spontaneous variations in vagal tone. It was suggested that longitudinal dissociation and concealed reentry in the AV node occurred in atypical Wenckebach periods of variants II and III, but not in the other periods.


Irradiation as a method for decontaminating food. A review.
Despite substantial efforts in avoidance of contamination, an upward trend in the number of outbreaks of foodborne illnesses caused by nonsporeforming pathogenic bacteria are reported in many countries. Good hygienic practices can reduce the level of contamination but the most important pathogens cannot presently be eliminated from most farms nor is it possible to eliminate them by primary processing, particularly from those foods which are sold raw. Several decontamination methods exist but the most versatile treatment among them is the processing with ionizing radiation. Decontamination of food by ionizing radiation is a safe, efficient, environmentally clean and energy efficient process. Irradiation is particularly valuable as an endproduct decontamination procedure. Radiation treatment at doses of 2-7 kGy--depending on condition of irradiation and the food--can effectively eliminate potentially pathogenic nonsporeforming bacteria including both long-time recognized pathogens such as Salmonella and Staphylococcus aureus as well as emerging or "new" pathogens such as Campylobacter, Listeria monocytogenes or Escherichia coli O157:H7 from suspected food products without affecting sensory, nutritional and technical qualities. Candidates of radiation decontamination are mainly poultry and red meat, egg products, and fishery products. It is a unique feature of radiation decontamination that it can also be performed when the food is in a frozen state. With today's demand for high-quality convenience foods, irradiation in combination with other processes holds a promise for enhancing the safety of many minimally processed foods. Radiation decontamination of dry ingredients, herbs and enzyme preparations with doses of 3-10 kGy proved to be a viable alternative to fumigation with microbicidal gases. Radiation treatment at doses of 0.15-0.7 kGy under specific conditions appears to be feasible also for control of many foodborne parasites, thereby making infested foods safe for human consumption. Microorganisms surviving low- and medium-dose radiation treatment are more sensitive to environmental stresses or subsequent food processing treatments than the microflora of unirradiated products. Radiation treatment is an emerging technology in an increasing number of countries and more-and-more clearances on radiation decontaminated foods are issued or expected to be granted in the near future.


Plasma tPA-Activity and Progression of Cerebral White Matter Hyperintensities in Lacunar Stroke Patients.
Tissue plasminogen activator (tPA)-activity and plasminogen activator inhibitor type 1 (PAI-1) antigen are considered to be haemostasis-related markers of endothelial activation and relate to presence of cerebral white matter hyperintensities (WMH) as was earlier shown in a cross-sectional study. We investigated whether tPA-activity and PAI-1 levels are associated with WMH progression in a longitudinal study. In 127 first-ever lacunar stroke patients in whom baseline brain MRI and plasma levels of tPA-activity and PAI-1-antigen were available, we obtained a 2-year follow-up MRI. We assessed WMH progression by a visual WMH change scale. We determined the relationship between levels of tPA-activity and PAI-1 and WMH progression, by logistic regression analysis. Plasma tPA-activity was associated with periventricular WMH progression (OR 2.36, 95% CI 1.01-5.49, with correction for age and sex and baseline presence of WMH), but not with deep or any (periventricular and/or deep) WMH progression. PAI-1 levels were lower in patients with WMH progression, but these results were not significant. We found a relationship between plasma tPA-activity and progression of periventricular WMH. More research is needed to determine whether there is a (direct) role of tPA in the development and progression of WMH.


Cysteine mediated multimerization of a recombinant dengue E fragment fused to the P64k protein following immobilized metal ion affinity chromatography.
A fragment of the Envelope protein of Dengue 2 virus encoding the amino acid (aa) 286-426 was fused to the P64k protein from Neisseria meningitidis. The hybrid gene (PD5) was expressed in Escherichia coli. The influence of using immobilized metal ion affinity chromatography (IMAC) in the purification process of PD5 was examined. After the elution, PD5 protein formed aggregates of high molecular weight depending on disulfide-bonds. The study of different conditions affecting the redox potential in the system revealed the influence of the copper ions on the multimerization of the protein, whereas metals with minor redox potential-for instance, zinc or nickel ions-did not cause this effect. It was also demonstrated that cysteines involved in this process belonged to the P64k protein. Finally, a PD5 purification process was established reaching a 85% of purity using the Zn(2+) as metal ion in the IMAC. This is a very useful finding due to the wide use of P64k as a carrier protein and the advantages of the IMAC as a chromatographic process.


Placebo effects in allergen immunotherapy: an experts' opinion.
Placebo effects are common in medicine. Randomised clinical trials help us to understand their magnitude in different therapies. There are particular problems with placebo effects in allergen immunotherapy (AIT) as it is difficult to blind the active treatment and the endpoints are largely subjective. This may explain why large placebo effects are often found in AIT trials. Patients receiving open label AIT get the benefit of the active and placebo components but it can be difficult to say how much benefit is due to the active component. The use of active placebos has been proposed but brings its own problems (ethical and scientific). An EAACI Task Force has been established to address these issues. Here we review the current literature on the placebo effect in general, with a special focus on AIT trials, and indicate what we believe to be important considerations and unmet needs in AIT trial design.


MGMT promoter methylation and glioblastoma prognosis: a systematic review and meta-analysis.
We undertook this study to comprehensively summarize the associations between MGMT promoter methylation and prognosis of glioblastoma (GBM). We searched PubMed, EMBASE and Cochrane databases (from January 2003 to November 1, 2011) and the references of the relevant articles in English with hazard ratios (HRs) and 95% confidence intervals (95% CIs). Two reviewers independently extracted data using a standardized form. Discrepancies were adjudicated by discussion. Twenty four studies met the inclusion criteria. There were 22 studies reporting on the relationship between MGMT methylation and overall survival (OS) of GBM and 12 studies on the association between MGMT methylation and progression-free survival (PFS) of GBM. Patients with a methylated status of MGMT had significant OS and PFS advantage (HR = 0.48, 95% CI: 0.35-0.65; I² = 79.78 for OS; HR = 0.43, 95% CI: 0.32-0.56; I² = 50.38 for PFS). Pooled HRs remained significant in further subgroup analysis based on the year of publication and continents of studies. Patients with MGMT promoter methylation had significant OS and PFS advantage than those without methylated status.


Blood culture quality assurance: what Australasian laboratories are measuring and opportunities for improvement.
Blood cultures are among the most important specimen types received and processed by the microbiology laboratory. Several publications list which variables should be measured to ensure quality. We undertook a qualitative structured questionnaire of Australian and New Zealand clinical microbiology laboratories to document current blood culture practices and to determine whether expected quality standards are being met. Questions included a wide range of pre-analytical, analytical, and post-analytical aspects of blood cultures from adults. The responses from 71 laboratories were analysed. Compliance was high for use of a biological safety cabinet (90%), incubating for 5 days (86%), and commenting on likely contaminants (85%). While Gram stains were reported within 2 hours during normal hours (93%), reporting was slower after hours (59%), p<0.001. The volume of blood collected for a clinical episode was poorly monitored with only 11% (n=8) of laboratories regularly auditing the number of blood culture sets and 3% (n=2) monitoring adequacy of fill. Most laboratories received blood cultures from off-site with just 34% (n=21) meeting guidance for loading bottles onto the analyser within 4 hours. More laboratories met standards for loading bottles onto the analyser during working hours than after hours: 87% vs 56%, p<0.001. Most laboratories did not monitor the contamination rate, 56% (n=40), and only 27% (n=19) knew their rate was below the guidance threshold of less than -3%. Considerable opportunities exist to improve quality assurance of blood culture practice in Australia and New Zealand, especially for the most critical aspect affecting culture sensitivity, the volume of blood collected.


Reducing Information Gap and Increasing Market Orientation in the Agribusiness Sector: Some Evidences from Apulia Region.
Market orientation plays a crucial role in reinforcing firm's competitive advantage; nevertheless, marketing myopia can negatively affect a clear perception of the market. An organization that defines itself by product rather than by market terms is probably affected by marketing myopia, a narrowness of mind towards any newness - newness respect to firms' convincement and routines - coming from the external environment. In that context some scientific relevant developments that comes from recent patents have been considered. This paper explores the determinants of marketing myopia in the Apulia wine business (South Italy). The aim of this paper is to describe how experiential research based on Consumer Science research tools, can facilitate a better market knowledge. Experimental sessions carried out in 2013 in Apulia with a group of professionals from the oil and wine sectors clearly demonstrate how country of origin effect can improve marketing myopia. Through a protocol based on an "academicians - practitioners" model, professionals can be facilitated in their strategy formulation.


Survival of Stem Cells and Progenitors in the Intestine Is Regulated by LPA5-Dependent Signaling.
Regeneration of the epithelium by stem cells in the intestine is supported by intrinsic and extrinsic factors. Lysophosphatidic acid (LPA), a bioactive lipid mediator, regulates many cellular functions, including cell proliferation, survival, and cytokine secretion. Here, we identify LPA5 receptor as a potent regulator of the survival of stem cells and transit-amplifying cells in the intestine. We have used genetic mouse models of conditional deletion of Lpar5, Lpar5f/f;Rosa-CreERT (Lpar5KO), and intestinal epithelial cell-specific Lpar5f/f;AhCre (Lpar5IECKO) mice. Mice were treated with tamoxifen or β-naphthoflavone to delete Lpar5 expression. Enteroids derived from these mice were used to determine the effect of Lpar5 loss on the apoptosis and proliferation of crypt epithelial cells. Conditional loss of Lpar5 induced ablation of the intestinal mucosa, which increased morbidity of Lpar5KO mice. Epithelial regeneration was compromised with increased apoptosis and decreased proliferation of crypt epithelial cells by Lpar5 loss. Interestingly, intestinal epithelial cell-specific Lpar5 loss did not cause similar phenotypic defects in vivo. Lpar5 loss reduced intestinal stem cell marker gene expression and reduced lineage tracing from Lgr5+ ISCs. Lpar5 loss induced CXCL10 expression which exerts cytotoxic effects on intestinal stem cells and progenitors in the intestinal crypts. By co-culturing Lpar5KO enteroids with wild-type or Lpar5KO splenocytes, we demonstrated that lymphocytes protect the intestinal crypts via a LPA5-dependent suppression of CXCL10. LPA5 is essential for the regeneration of intestinal epithelium. Our findings reveal a new finding that LPA5 regulates survival of stem cells and transit-amplifying cells in the intestine.


Alterations in RNA-binding activities of IRES-regulatory proteins as a mechanism for physiological variability and pathological dysregulation of IGF-IR translational control in human breast tumor cells.
The type I insulin-like growth factor receptor (IGF-IR) is integrally involved in the control of cellular proliferation and survival. An internal ribosomal entry site (IRES) within the 1,038 nucleotide 5'-untranslated region of the human IGF-IR mRNA helps to provide the tight control of IGF-IR expression necessary for maintenance of normal cellular and tissue homeostasis. The IRES maps to a discrete sequence of 85 nucleotides positioned just upstream of the IGF-IR initiation codon, allowing the ribosome to bypass the highly structured regions of the 5'-UTR as well as the upstream open reading frame. The authenticity of the IGF-IR IRES has been confirmed by its sensitivity to deletion of the promoter from a bicistronic reporter construct, and its resistance in a monocistronic reporter construct to co-expression of a viral 2A protease. We previously characterized HuR as a potent repressor of IGF-IR translation. Here we demonstrate that hnRNP C competes with HuR for binding the IGF-IR 5'-UTR and enhances IRES-mediated translation initiation in a concentration-dependent manner. We observed changes in binding of hnRNP C versus HuR to the IGF-IR 5'-UTR in response to physiological alterations in cellular environment or proliferative status. Furthermore, we have found distinct alterations in the pattern of protein binding to the IGF-IR 5'-UTR in human breast tumor cells in which IGF-IR IRES activity and relative translational efficiency are aberrantly increased. These results suggest that dysregulation of the IGF-IR IRES through changes in the activities of RNA-binding translation-regulatory proteins could be responsible for IGF-IR overexpression in a proportion of human breast tumors.


Prevalence of fall and associated risk factors among the elderly living in a rural area of Kolar.
Falls in elderly persons are one of the leading causes of death. Falls are responsible for 10-15% of all emergency department visits among elderly. The study was conducted to determine the prevalence of falls in rural areas and to assess the various socio-demographic factors associated with falls. It was a community-based, cross-sectional study conducted in Rural Health Training Centre (RHTC), Devarayanasamudra, Department of Community Medicine, among the elderly persons aged ≥ 60 years. The total sample size was 511, calculated using a previous study using OpenEpi software. The data were collected using a pretested semi-structured questionnaire. The period prevalence of falls was assessed by asking for history of falls in the past 12 months. Chi-square and regression analysis were performed with statistically significant P value defined as less than 0.05. Out of 511 elderly persons aged ≥60 years, females accounted for about 54.8% and most of them were of 60-69 years age-group. The majority of the study subjects were illiterates (77.3%), and most of them were married (77.2%). The prevalence of falls in elderly persons was 46.8%. The elderly aged ≥70 years, females, chronic diseases, and use of walking aid were observed to have a statistically significant association with falls (p < 0.005). Elderly falls are very common. The primary healthcare providers in rural areas play an important role in prevention of falls in elderly. Caregivers, along with elderly, should be given more detailed health education related to fall prevention.


Development of a CRISPR-Cas12a rapid diagnostic for human cytomegalovirus.
Despite decades of research, human cytomegalovirus (CMV) continues to contribute to significant morbidity and mortality in transplant settings and remains the leading cause of viral congenital infections. Clinical diagnosis of CMV infection and/or reactivation under these settings is completed using real time quantitative polymerase chain reaction (RT-qPCR). This assay performs well but is hampered by poor sensitivity and a lack of standardization among testing facilities. A point-of-care rapid diagnostic to determine CMV viremia could address these issues and improve patient care. In this manuscript, we introduce clustered regularly interspaced short palindromic repeats (CRISPR)-Cas12a technology to design and validate a rapid diagnostic for CMV. This system was tested using CMV spiked human saliva and urine samples. Sensitivity of the assay was ∼10 infectious units (IU)/mL. Specificity of the assay was robust and failed to detect other herpesviruses. Collectively, we have designed and validated a rapid diagnostic for CMV that overcomes limitations of the current standard diagnostic. This assay has the potential to be used as a point-of-care screening tool in transplant and neonatal settings.


Pharmacophore modeling, virtual screening and 3D-QSAR studies of 5-tetrahydroquinolinylidine aminoguanidine derivatives as sodium hydrogen exchanger inhibitors.
Sodium hydrogen exchanger (SHE) inhibitor is one of the most important targets in treatment of myocardial ischemia. In the course of our research into new types of non-acylguanidine, SHE inhibitory activities of 5-tetrahydroquinolinylidine aminoguanidine derivatives were used to build pharmacophore and 3D-QSAR models. Genetic Algorithm Similarity Program (GASP) was used to derive a 3D pharmacophore model which was used in effective alignment of data set. Eight molecules were selected on the basis of structure diversity to build 10 different pharmacophore models. Model 1 was considered as the best model as it has highest fitness score compared to other nine models. The obtained model contained two acceptor sites, two donor atoms and one hydrophobic region. Pharmacophore modeling was followed by substructure searching and virtual screening. The best CoMFA model, representing steric and electrostatic fields, obtained for 30 training set molecules was statistically significant with cross-validated coefficient (q(2)) of 0.673 and conventional coefficient (r(2)) of 0.988. In addition to steric and electrostatic fields observed in CoMFA, CoMSIA also represents hydrophobic, hydrogen bond donor and hydrogen bond acceptor fields. CoMSIA model was also significant with cross-validated coefficient (q(2)) and conventional coefficient (r(2)) of 0.636 and 0.986, respectively. Both models were validated by an external test set of eight compounds and gave satisfactory prediction (r(pred)(2)) of 0.772 and 0.701 for CoMFA and CoMSIA models, respectively. This pharmacophore based 3D-QSAR approach provides significant insights that can be used to design novel, potent and selective SHE inhibitors.


Stereochemistry of flavonoidal alkaloids from Dracocephalum rupestre.
Phytochemical studies on the aerial parts of Dracocephalum rupestre led to the isolation of four groups of flavonoidal alkaloids, dracocephins A-D. They were elucidated as conjugates of flavanone with pyrrolidin-2-one on the basis of extensive spectroscopic analysis. The two stereogenic centers rendered each group of the dracocephins as two pairs of enantiomers simultaneously. All of the sixteen isomers were separated successfully by chiral HPLC and their stereochemical features were determined by their CD data and single-crystal X-ray diffraction analysis of one stereoisomer. The additive relation of the chiroptical contributions resulting from the two stereogenic centers was generalized. The CD contribution of the chiral carbon in the pyrrolidin-2-one ring was proposed by subtraction of their respective contributions.


Alterations of globin chain synthesis and of red cell membrane proteins in congenital dyserythropoietic anemia I and II.
Red cell membrane proteins were investigated in two unrelated children with congenital dyserythropoietic anemia (CDA) I and two siblings with CDA II. The CDA I patients displayed globin chain synthesis imbalance, with reduction of the non alpha/alpha ratio. One of the CDA II patients presented the reverse alteration. Whenever globin chain synthesis was unbalanced, the membrane p-nitrophenylphosphatase had an abnormally biphasic kinetics, consistent with substrate excess inhibition, as is observed in alpha- or beta-thalassemic syndromes. One CDA I patient displayed a decrease of electrophoretic band 4.1 along with an ectopic phosphorylated protein at the level of band 4.2. In CDA II and, to a lesser extent, in CDA I, the in vitro endogenous phosphorylation of band 2 + 2.1 was sharply reduced.


The effects of paroxetine on rat isolated vas deferens.
The aim of the present study is to evaluate whether paroxetine (a selective serotonin re-uptake inhibitor) can modify the contractile responses of isolated vas deferens. Some contractile agents, potassium chloride (KCl), adenosine 5'-triphosphate (ATP), noradrenaline (NA), and electrical field stimulation (EFS) caused contractions both in epididymal and prostatic portions of vas deferens. Paroxetine (PX) in concentrations 10(-7) and 10(-6)M potentiated the contractions to KCl and ATP only in epididymal portion but in higher concentrations (10(-5) and 10(-4)M) inhibited the responses in both portions. NA responses were inhibited by PX in all concentrations used, both in prostatic and epididymal portions. Prazosin (PR), an alpha adrenergic receptor blocking agent, inhibited PX-induced potentiation observed for higher concentrations of KCl. PR also inhibited PX-induced potentiation on the responses to ATP in epididymal portion. Pretreatment with PX (10(-7) to 10(-6)M) increased the contractions to EFS but in 10(-5) and 10(-4)M concentrations inhibited them. Even though the preparations were washed out, the inhibited responses of contractile agents could not be restored. After a washout period for PX, when Bay K 8644 (calcium channel activator) was added to the bath medium, the contractile responses to KCl were partially restored. In calcium-free medium, KCl caused contractions in concentrations higher than 80 mM with lower amplitudes which were not affected by PX. Reserpinization did not change the inhibitory pattern of PX's effect on exogenously applied NA in all concentrations tested. In reserpinized rats, the potentiation caused by PX in exogenously applied ATP responses was not observed. In conclusion, we can say that PX has two different effects: inhibition and potentiation of contractions to various agonists. The inhibitory effect of the drug can be explained by a calcium channel blocking activity. The potentiating effect of the drug is mainly related to its presynaptic action, such as NA re-uptake inhibitory effect.


Flexural strengths, failure load, and hardness of glass-ceramics for dental applications.
Glass-ceramics are often selected for use in dental restorations based upon advertised flexural strengths obtained from standardized tests on prefabricated specimens (bars and disks); these may not accurately reflect their performance in dental applications. The purpose of this in vitro study was to determine and compare 4-point flexural strength, biaxial flexural strength, hardness, and crown failure loads for 3 commercially available glass-ceramics. Specimens were pressed and prepared from 3 brands of glass-ceramics: Celtra (CEL), IPS e.max (EMA), and Lisi (LIS). Rectangular bars, circular disks, and fully contoured crowns were created (n=15 specimens per glass-ceramic, 45 specimens per geometry, totaling 135 specimens). Disks were tested for biaxial flexural strength by using a piston-on-3-ball (POB) test, while bars were tested for 4-point flexural strength by using 4-point bending (4PB) and Vickers hardness (VH) tests. Crown failure loads were assessed in "crunch-the-crown" (CTC) tests. The results were analyzed by using general linear modeling, the Pearson correlation coefficient, and Weibull analysis. The general linear modeling revealed significant differences (P<.05) in the failure load for crown specimens (EMA>LIS>CEL), the 4-point flexural strength (EMA>LIS>CEL), and the biaxial flexural strength (EMA>LIS=CEL). The disk specimens had higher flexural strengths than the bar specimens for CEL and EMA materials. LIS had a higher Weibull modulus than EMA and CEL for bar and crown specimens. CEL had a higher Weibull modulus than LIS and EMA for disk specimens. There was no correlation among the VH (R2=0.86 and P=.24), biaxial flexural strength (R2=0.84 and P=.26), and crown failure load. However, there was a high correlation between the failure load (crown specimens) and 4-point flexural strength (bar specimens) (R2=0.99 and P=.03). The 4-point flexural strength correlated significantly with crown failure load.


Brain Tumor Segmentation for Multi-Modal MRI with Missing Information.
Deep convolutional neural networks (DCNNs) have shown promise in brain tumor segmentation from multi-modal MRI sequences, accommodating heterogeneity in tumor shape and appearance. The fusion of multiple MRI sequences allows networks to explore complementary tumor information for segmentation. However, developing a network that maintains clinical relevance in situations where certain MRI sequence(s) might be unavailable or unusual poses a significant challenge. While one solution is to train multiple models with different MRI sequence combinations, it is impractical to train every model from all possible sequence combinations. In this paper, we propose a DCNN-based brain tumor segmentation framework incorporating a novel sequence dropout technique in which networks are trained to be robust to missing MRI sequences while employing all other available sequences. Experiments were performed on the RSNA-ASNR-MICCAI BraTS 2021 Challenge dataset. When all MRI sequences were available, there were no significant differences in performance of the model with and without dropout for enhanced tumor (ET), tumor (TC), and whole tumor (WT) (p-values 1.000, 1.000, 0.799, respectively), demonstrating that the addition of dropout improves robustness without hindering overall performance. When key sequences were unavailable, the network with sequence dropout performed significantly better. For example, when tested on only T1, T2, and FLAIR sequences together, DSC for ET, TC, and WT increased from 0.143 to 0.486, 0.431 to 0.680, and 0.854 to 0.901, respectively. Sequence dropout represents a relatively simple yet effective approach for brain tumor segmentation with missing MRI sequences.


Extended Szabo (anchor-wire) technique concept for stent implantation in congenital heart lesions.
We report the usefulness of the Szabo (anchor-wire) technique and two modifications of such based on the same concept for stent implantation in congenital heart lesions. The modifications of the original technique are related to the localization of the cell of the stent through which the anchor wire, which stops the stent advancement, is introduced: proximal in the original technique and central or distal in the reported modifications. These techniques were performed in six patients: in two to maintain permeability of the ductus arteriosus, in three to achieve a fenestration of the interatrial septum, and in one to implant a stent in a right ventricle-to-pulmonary artery conduit close to the bifurcation. We describe the technique as well as the most important difficulties and complications encountered. The Szabo or anchor-wire technique concept is a new tool for stent implantation that can provide more accurate stent positioning compared with conventional angiographically guided implantation in different congenital heart defects. As with any new tool, this technique demands a learning curve and knowledge of potential complications.


Anaemia in systemic lupus erythematosus: from pathophysiology to clinical assessment.
Haematological abnormalities are common in systemic lupus erythematosus. Anaemia is found in about 50% of patients, with anaemia of chronic disease being the most common form. Impaired erythropoietin response and presence of antibodies against erythropoietin may contribute to the pathogenesis of this type of anaemia. Patients with autoimmune haemolytic anaemia usually belong to a distinct category, which is associated with anticardiolipin antibodies, thrombosis, thrombocytopenia, and renal disease, often in the context of secondary antiphospholipid syndrome. Autoantibodies, T lymphocytes, and deregulation of the cytokine network can affect bone marrow erythropoiesis, leading to anaemia.


Effect of humic substances aggregation on the determination of fluoride in water using an ion selective electrode.
The control of drinking water quality is critical in preventing fluorosis. In this study humic substances (HS) are considered as representative of natural organic matter (NOM) in water. We show that when HS aggregate the response of fluoride ion selective electrodes (ISE) may be perturbed. Dynamic light scattering (DLS) results of both synthetic solutions and natural water sample suggest that low pH and high ionic strength induce HS aggregation. In the presence of HS aggregates, fluoride concentration measured by ISE has a reduction up to 19%. A new "open cage" concept has been developed to explain this reversible phenomenon. The interference of HS aggregation on fluoride measurement can be effectively removed by centrifugation pretreatment.


Boron nitride colloidal solutions, ultralight aerogels and freestanding membranes through one-step exfoliation and functionalization.
Manufacturing of aerogels and membranes from hexagonal boron nitride (h-BN) is much more difficult than from graphene or graphene oxides because of the poor dispersibility of h-BN in water, which limits its exfoliation and preparation of colloidal solutions. Here, a simple, one-step mechano-chemical process to exfoliate and functionalize h-BN into highly water-dispersible, few-layer h-BN containing amino groups is presented. The colloidal solutions of few-layer h-BN can have unprecedentedly high concentrations, up to 30 mg ml(-1), and are stable for up to several months. They can be used to produce ultralight aerogels with a density of 1.4 mg cm(-3), which is ∼1,500 times less than bulk h-BN, and freestanding membranes simply by cryodrying and filtration, respectively. The material shows strong blue light emission under ultraviolet excitation, in both dispersed and dry state.


Remnant lipoproteinemia predicts cardiovascular events in patients with type 2 diabetes and chronic kidney disease.
Patients having type 2 diabetes mellitus (DM) and chronic kidney disease (CKD) are at high risk of cardiovascular events. Triglyceride-rich lipoprotein levels are synergistically increased in patients with DM and CKD. This study examined the predictive value of remnant lipoprotein levels for cardiovascular events in patients with DM and CKD. Three hundred and sixty-five patients with type 2 DM and CKD were enrolled. Serum levels of remnant lipoproteins (remnant-like lipoprotein particles cholesterol; RLP-C) were measured by an immunoseparation method. All patients were followed prospectively for a period of 45±23 months or until occurrence of one of the following events: cardiac death, non-fatal myocardial infarction, unstable angina requiring unplanned coronary revascularization, or ischemic stroke. During the follow-up period, 59 patients had cardiovascular events. Multivariate Cox analysis revealed that high levels of RLP-C (≥4.3mg/dL; median value) were a significant risk factor for cardiovascular events, independent of traditional risk factors (HR: 1.30; 95% CI: 1.04-1.63; p=0.02). The addition of high levels of RLP-C to traditional risk factors improved net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI 0.36, p=0.01; and IDI 0.03, p=0.02). RLP-C is useful for risk assessment of future cardiovascular events in patients having type 2 DM and CKD.


Have we been hebbing down the wrong path?
In this issue of Neuron, Stepanyants, Hof, and Chklovskii derive a simple mathematical formula to calculate, from measurable anatomical parameters, the capacity for neuronal wiring plasticity involving local synaptic rearrangements. Their work provides a deeper understanding of the potential contribution of structural plasticity to learning and memory.


Smoking during pregnancy according to obstetric complications and parity: results of the EUROPOP study.
This study aimed to analyse the relationship between smoking and preterm birth (22-36 weeks) according to the main obstetric complications leading to the preterm birth, both overall and by parity. The EUROPOP study is a case-control study carried out between 1994 and 1997; 3,787 preterm and 5,602 full-term births were included, from maternity units in 10 countries, using the same protocol. Social, demographic and medical information was collected after delivery, from obstetric records and interviews with the mothers. Cases were classified according to the main obstetric complication (hypertension, haemorrhage, preterm premature rupture of membranes (PPROM), idiopathic spontaneous preterm labour, intrauterine growth retardation, all other causes). Multiple logistic regression analysis was used to control for confounders. Twenty four percent of cases and 20% of controls were smokers. Smoking during pregnancy, heavy smoking (>or=10 cigarettes per day) in particular, was a risk factor for preterm birth (aOR = 1.39, 95% CI:1.20-1.60). Smoking increased the risk of preterm delivery due to all obstetric complications other than hypertension. For these complications, the risk of preterm delivery associated with smoking was higher for multiparae (aOR = 1.46, 95% CI:1.24-1.71) than for primiparae (aOR = 1.18, 95% CI:1.00-1.38). In conclusion, smoking during pregnancy increases the risk of preterm birth among women with all obstetric complications except hypertension. This association is stronger in multiparae than in primiparae and the risk is higher for heavy smokers.


Comparison of new versus reused Harmonic scalpel performance in laparoscopic appendectomy in patients with acute appendicitis-a randomized clinical trial.
The aim of this study was to compare lateral thermal damage of the appendix and clinical outcomes after laparoscopic appendectomy using new versus reused Harmonic scalpels. A total of 100 consecutive patients with acute appendicitis who underwent laparoscopic appendectomy were enrolled in the two-center, randomized clinical trial. Using a computer random number generator, patients were allocated to new or reused group. Histopathological measurement of lateral thermal damage of the appendiceal base and mesoappendix, speed of transection of the appendiceal base, duration of surgery, subjective rating of device functionality, length of hospital stay, and complications were compared within groups. The median lateral thermal damage on the appendiceal base in the new group (N = 49) was 0.2 mm (IQR 0.1-0.2) and 0.1 mm (IQR 0.1-0.3) in the reused group (N = 51) (P = 0.644), while on the mesoappendix for both groups, thermal damage was 0.1 mm (IQR 0.1-0.2) (P = 0.418). The median time required for base transection in both groups was 8 s (IQR 7-9) (P = 0.776). The median duration of surgery was also comparable between the groups (22 min, IQR 20-30 vs 25 min, IQR 21-35; P = 0.233). Two postoperative complications in the new group and one in the reused group were recorded (4% vs 2%; P = 0.536). Surgeons' subjective assessment of the instrument did not reveal significant difference between the groups in all of the investigated categories. The results of our study support the reuse of Harmonic scalpels especially in the settings where economic constraints might hamper access to minimally invasive surgery to a larger number of patients. The results obtained on laparoscopic appendectomy might not be reproducible to other more demanding surgical procedures. ClinicalTrials.gov registry under identifier NCT04226482.


Metabolites of gentamicin-producing Micromonospora species I. Isolation and identification of metabolites.
From the cultural broth of a Micromonospora species 25 aminocyclitol antibiotics were isolated by repeated ion-exchange chromatographic processes. The main components of the metabolites were identified as gentamicin C1, C2, and C1a. The other previously reported gentamicin type antibiotics and some other degradation products including gentamicin A, B, B1, X2, sisomicin, garamine, gentamines etc., were identified by chemical, PMR, and mass spectroscopic studies. Besides these, seven new gentamicin type antibiotics were isolated and characterized.


Inverse Association Between Myocardial B-Type Natriuretic Peptide Release and Functional Capacity in Healthy Humans.
B-type natriuretic peptide (BNP) has been found to be inversely related to peak oxygen consumption (peak VO2) in various patient populations. However, in these studies, circulating plasma BNP, i.e. the net effect of release and elimination, rather than cardiac BNP release has been measured. We assessed the relationship between the transcardiac BNP gradient [ΔBNPCS-A, i.e. the difference between BNP in coronary sinus (BNPCS) and arterial (BNPA) plasma] and peak VO2 in healthy subjects with a view to better understanding the regulation of cardiac BNP release in humans. We studied 10 asymptomatic subjects (age 64±11 years, two females) with preserved left ventricular function (left ventricular ejection fraction 62±5%, averaged early diastolic mitral annular velocity 9±3cm/s) and low BNP (BNP in venous plasma [BNPV] <100ng/l). Subjects underwent measurement of BNPA and BNPCS for the calculation of ΔBNPCS-A, maximal cardiopulmonary exercise testing, echocardiography and resting and submaximal exercise right heart catheterisation. The median (range) BNPV, BNPA, BNPCS, and ΔBNPCS-A were 62 (14, 82), 60 (13, 79), 110 (25, 157), and 44 (1, 103) ng/l. The median peak VO2 during cardiopulmonary exercise testing was 21.5 (18, 54) ml/min/kg. There was an inverse correlation between higher ΔBNPCS-A and lower peak VO2 (r=-0.84; p=0.002) and oxygen pulse (r=-0.64, p=0.049). There was a trend towards an inverse correlation between ΔBNPCS-A and the exercise arteriovenous oxygen content difference (r=-0.58; p=0.08). In healthy humans, there is an inverse association between myocardial BNP release and peak VO2, which may be due to cardiac and non-cardiac mechanisms.


Maize Homologs of Hydroxycinnamoyltransferase, a Key Enzyme in Lignin Biosynthesis, Bind the Nucleotide Binding Leucine-Rich Repeat Rp1 Proteins to Modulate the Defense Response.
In plants, most disease resistance genes encode nucleotide binding Leu-rich repeat (NLR) proteins that trigger a rapid localized cell death called a hypersensitive response (HR) upon pathogen recognition. The maize (Zea mays) NLR protein Rp1-D21 derives from an intragenic recombination between two NLRs, Rp1-D and Rp1-dp2, and confers an autoactive HR in the absence of pathogen infection. From a previous quantitative trait loci and genome-wide association study, we identified a single-nucleotide polymorphism locus highly associated with variation in the severity of Rp1-D21-induced HR. Two maize genes encoding hydroxycinnamoyltransferase (HCT; a key enzyme involved in lignin biosynthesis) homologs, termed HCT1806 and HCT4918, were adjacent to this single-nucleotide polymorphism. Here, we show that both HCT1806 and HCT4918 physically interact with and suppress the HR conferred by Rp1-D21 but not other autoactive NLRs when transiently coexpressed in Nicotiana benthamiana. Other maize HCT homologs are unable to confer the same level of suppression on Rp1-D21-induced HR. The metabolic activity of HCT1806 and HCT4918 is unlikely to be necessary for their role in suppressing HR. We show that the lignin pathway is activated by Rp1-D21 at both the transcriptional and metabolic levels. We derive a model to explain the roles of HCT1806 and HCT4918 in Rp1-mediated disease resistance.


A case of unexpected gallium-67 uptake by sternum in non-Hodgkin's lymphoma with pleuritis.
A case of non-Hodgkin's lymphoma with pleural effusion was presented. Pleural effusion is not a common manifestation of this disease and 67Ga-citrate scintigraphy gave the clue for the diagnosis. The possibility of malignant lymphoma should be considered in cases with pleural effusion, and we showed that 67Ga-citrate scintigraphy can be useful in a case with pleural effusion of undetermined cause.


Glucagon-like Peptide-1 Receptor Agonists and Cardioprotective Benefit in Patients with Type 2 Diabetes Without Baseline Metformin: A Systematic Review and Update Meta-analysis.
Sodium Glucose Co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RAs) were associated with a reduction in cardiovascular disease events in cardiovascular outcomes trials (CVOTs) in type 2 diabetes. Most of the patients included in these trials received metformin as background therapy. To evaluate the effect of glucagon-like peptide 1 receptor agonists on major cardiovascular events (MACE) and mortality in metformin-naïve patients with type 2 diabetes. A systematic review and meta-analysis of randomized controlled clinical trials of GLP-1RAs on type 2 diabetes population was performed, after searching the PubMed/MEDLINE, Embase, Scielo, Google Scholar and Cochrane Controlled Trials databases. The primary endpoint was MACE. The secondary endpoints were cardiovascular death and all-cause mortality. A meta-analysis of time-to-event outcomes was performed. This meta-analysis was registered in PROSPERO (CRD42021260040) RESULTS: Seven trials, including 11510 patients, were identified and considered eligible for the analyses. GLP-1RAs were associated with a significant reduction in MACE incidence (HR: 0.86, 95% confidence interval: 0.79-0.94; I2: 0%). The secondary endpoints analysis showed a non-significant reduction in all-cause mortality (HR: 0.86, 95% confidence interval: 0.73-1.00 I2: 0%) and cardiovascular mortality (HR: 0.81, 95% confidence interval: 0.63-1.05; I2: 0%). In this meta-analysis, GLP-1RAs reduced the incidence of MACE in patients with type 2 diabetes without metformin at baseline, without significant reduction in all-cause mortality and cardiovascular mortality. These results support the fact that when a GLP-1RAs is administered, the benefit on cardiovascular outcomes is independent of the use of metformin.


Second messenger signaling in the regulation of cytosolic pH and DNA synthesis by parathyroid hormone (PTH) and PTH-related peptide in osteoblastic osteosarcoma cells: role of Na+/H+ exchange.
The present study was performed to investigate the regulation of cytosolic pH (pHi) and DNA synthesis by parathyroid hormone(PTH) and PTH-related peptide (PTHrP) in osteoblasts, using osteoblastic osteosarcoma cells, UMR-106 which possessed PTH-responsive dual signal transduction systems (cAMP-dependent protein kinase (PKA) and calcium/protein kinase C [Ca/PKC]) and amiloride-inhibitable Na+/H+ exchange system. Both human (h)PTH-(1-34) and hPTHrP-(1-34) caused a progressive decrease in pHi and the inhibition of [3H]thymidine incorporation (TdR) to the same degree in a dose-dependent manner with a minimal effective dose of 10(-10) M. Dibutyryl cAMP (10(-4) M and Sp-cAMPS (10(-4) M), a direct stimulator of PKA also caused a progressive decrease in pHi, and calcium ionophores (A23187 and ionomycin, 10(-6) M) caused a transient decrease in pHi. Pretreatment with amiloride (0.3 mM) mostly blocked dbcAMP- and Sp-cAMPS-induced decrease in pHi but did not affect calcium ionophore-induced decrease in pHi. In the presence of amiloride, PTH and PTHrP caused a transient decrease in pHi, which was similar to the pattern of calcium ionophore-induced change in pHi. Amiloride did not affect the inhibition of TdR by PTH or PTHrP as well as that by cAMP analogues or calcium ionophores. The present study indicated that PTH and PTHrP caused cytosolic acidification through PKA-inhibited Na+/H+ exchange and increased cytosolic calcium-induced pathway and that the regulation of DNA synthesis by PTH and PTHrP was not via Na+/H+ exchange system.