Differing expression of insulin-like growth factor I in the developing and in the adult rat cerebellum.
Insulin-like growth factor I (IGF-I; somatomedin C) is a trophic peptide of importance for the development of several tissues and organs. In the present study we have mapped the cellular distribution and dynamic changes of IGF-I immunoreactivity in the rat cerebellum from its postnatal development to maturity. In vitro hybridization of IGF-I mRNA was used to demonstrate that the IGF-I immunoreactive material was synthesized in the cerebellum during a limited time period of cerebellar differentiation. IGF-I immunoreactivity was absent in primordial nerve cells but was present in neuroglial cells during the first two days after birth and then rapidly increased in intensity in the latter during the next few days. Proliferative nerve cells in the external granular layer did not express IGF-I immunoreactivity, while migrating and differentiating nerve cells as well as neuroglial cells showed intense labelling. Starting about 2 weeks postnatally, the IGF-I immunoreactivity declined, first in the neuroglial cells and eventually in the nerve cells. No IGF-I immunoreactivity could be demonstrated in the normal adult cerebellum. Colchicine pretreatment did, however, enable demonstration of IGF-I immunoreactivity in adult cerebellar nerve cells but not in neuroglial cells. In vitro hybridization revealed IGF-I mRNA in the developing cerebellum but only at very low levels in the adult cerebellum. It is concluded that IGF-I is likely to be a factor of importance for the development and maturation of nerve cells and neuroglial cells in the brain.(ABSTRACT TRUNCATED AT 250 WORDS)


Variable temperature neutron diffraction and X-ray charge density studies of tetraacetylethane.
Single crystal neutron diffraction data have been collected on a sample of enolized 3,4-diacetyl-2,5-hexanedione (tetraacetylethane, TAE) at five temperatures between 20 and 298 K to characterize the temperature-dependent behavior of the short, strong, intramolecular hydrogen bond. Upon decreasing the temperature from 298 K to 20 K, the O2-H1 distance decreases from 1.171(11) to 1.081(2) A and the O1...H1 distance increases from 1.327(10) to 1.416(6) A. The convergence of the C-O bond lengths from inequivalent distances at low temperature to identical values (1.285(4) A) at 298 K is consistent with a resonance-assisted hydrogen bond. However, a rigid bond analysis indicates that the structure at 298 K is disordered. The disorder vanishes at lower temperatures. Short intermolecular C-H...O contacts may be responsible for the ordering at low temperature. The intramolecular O...O distance (2.432 +/- 0.006 A) does not change with temperature. X-ray data at 20 K were measured to analyze the charge density and to gain additional insight into the nature of the strong hydrogen bond. Quantum mechanical calculations demonstrate that periodic boundary conditions provide significant enhancement over gas phase models in that superior agreement with the experimental structure is achieved when applying periodicity. One-dimensional potential energy calculations followed by quantum treatment of the proton reproduce the location of the proton nearer to the O2 site reasonably well, although they overestimate the O-H distance at low temperatures. The choice of the single-point energy calculation strategy for the proton potential is justified by the fact that the proton is preferably located nearer to O2 rather than being equally distant to O1 and O2 or evenly distributed (disordered) between them.


Respiratory Viral Infections in Children and Adolescents with Hematological Malignancies.
Despite the introduction of a polymerase chain reaction (PCR) test for the diagnosis of respiratory viral infection (RVI), guidance on the application of this test and the management of RVI in immunocompromised children is lacking. This study evaluated the clinical characteristics of RVI and established strategies for the PCR test in children and adolescents with hematological malignancies. This study included children and adolescents with underlying hematological malignancies and respiratory symptoms, in whom a multiplex PCR test was performed. Patients in whom RVI was identified and not identified were categorized into Groups I and II, respectively. Group I was sub-divided into patients with upper and lower respiratory infections. The medical records of the enrolled patients were retrospectively reviewed. A total of 93 respiratory illnesses were included. Group I included 46 (49.5%) cases of RVI, including 31 (67.4%) upper and 15 (32.6%) lower respiratory infections. Rhinovirus (37.0%) was the most common viral pathogen. Significantly more patients in Group I had community-acquired respiratory illnesses (p=0.003) and complained of rhinorrhea (p<0.001) and sputum (p=0.008) than those in Group II. In Group I, significantly more patients with lower respiratory infections had uncontrolled underlying malignancies (p=0.038) and received re-induction or palliative chemotherapy (p=0.006) than those with upper respiratory infections. A multiplex PCR test should be considered for RVI diagnosis in immunocompromised children and adolescents with respiratory symptoms, especially in those with rhinorrhea or sputum prominent over a cough. The early application of the PCR test in patients with uncontrolled underlying malignancies may improve outcomes.


Genetic risk variants as therapeutic targets for Crohn's disease.
The pathogenesis of Inflammatory bowel diseases (IBD) is multifactorial, with interactions between genetic and environmental factors. Despite the existence of genetic factors being largely demonstrated by epidemiological data and several genetic studies, only a few findings have been useful in term of disease prediction, disease progression and targeting therapy. Areas covered: This review summarizes the results of genome-wide association studies in Crohn's disease, the role of epigenetics and the recent discovery by genetic studies of new pathogenetic pathways. Furthermore, it focuses on the importance of applying genetic data to clinical practice, and more specifically how to better target therapy and predict potential drug-related toxicity. Expert opinion: Some genetic markers identified in Crohn`s disease have allowed investigators to hypothesize about, and in some cases, prove the usefulness of new specific therapeutic agents. However, the heterogeneity and complexity of this disease has so far limited the daily clinical use of genetic information. Finally, the study of the implications of genetics on therapy, either to predict efficacy or avoid toxicity, is considered still to be in its infancy.


New insights in acute heart failure.
Acute heart failure (AHF) is a clinical complex disease and a worldwide issue due to its inconsistent diagnosis and poor prognosis. The cornerstone of pathophysiology of AHF is systemic venous congestion, which is led by the underlying structural and functional cardiac condition. Systemic venous congestion is a major target for AHF management because it causes symptoms and organs dysfunction, and is associated with poor prognosis. The mainstay of decongestive therapy is diuresis with intravenous loop diuretics combined with other diuretics including thiazides when necessary, and non-invasive ventilation. The presence of unresolved congestion at discharge can lead heart failure related rehospitalization, and careful follow-up is required especially during "vulnerable phase", several months after discharge. The updated recommendation for management of AHF has been provided by latest guidelines from European Society of Cardiology and American Heart Association/American College of Cardiology/Heart Failure Society of America. Several large studies have currently demonstrated the benefits of guideline-directed oral medical therapies, and trials are ongoing on medication such as selective sodium-glucose transport proteins 2 inhibitors and protocols for congestive therapy. This review aimed to summarize the latest insights in AHF, based primarily on the most recent guidelines and large randomized controlled trials.


Proteolipid and collagen calcification, in vitro.
Initiation of in vitro calcification with insoluble type I collagen appears to be a function of tightly-bound proteolipid. The collagen preparation calcified during incubation in a metastable calcium phosphate solution before but not after lipid extraction. Calcifiability of the extracted lipid, similarly incubated, was restricted to the proteolipid fraction.


Biological indicators of cadmium exposure and toxicity.
The increasing environmental and occupational exposure of populations to cadmium creates the need for biological indicators of cadmium exposure and toxicity. The advantages and disadvantages of monitoring blood cadmium, urinary, fecal, hair, and tissue cadmium, serum creatinine, beta 2-microglobulin, alpha 1-antitrypsin and other proteins, and urinary amino acids, enzymes, total proteins, glucose, beta 2-microglobulin, retinol-binding protein, lysozyme, and metallothionein are discussed. It is concluded that urinary cadmium, metallothionein and beta 2-microglobulin may be used together to assess cadmium exposure and toxicity.


Saiga (Saiga tatarica) conservation strategy in Kazakhstan.
The saiga antelope (Saiga tatarica) is a living symbol of the Eurasian steppes. Even in the recent past, its total number exceeded a million heads. As a commercial species, it was a source of inexpensive meat and skins for suede. The natural world range of saiga in Eurasia covers the steppe and desert ecosystems of Kazakhstan, Uzbekistan, Turkmenistan, Mongolia, as well as Kalmykia and the Astrakhan region in the Russian Federation. It is divided into two subspecies: (Saiga tatarica tatarica) the nominal subspecies and (S.t.mongolica) the Mongolian saiga, which is found only in Mongolia. In 2002, the International Union for the Conservation of Nature (UICN) classified saiga as CR-critically endangered. The purpose of this work is to analyze the saiga population dynamics on the territory of Kazakhstan and characterize possible anthropogenic, genetic and environmental factors affecting their numbers, with the rationale for approaches to conserving these animals' population in Kazakhstan. The article highlights the saiga dynamics of number and distribution over the past decade, the reasons for decline in its number, also discusses specific measures to conserve the saiga in modern conditions, because the current critical situation with saiga in Kazakhstan requires implementing a strategy for its conservation as a species of mammals fauna of the republic.


Ion-Selective Electrodes with Solid Contact Based on Composite Materials: A Review.
Potentiometric sensors are the largest and most commonly used group of electrochemical sensors. Among them, ion-selective electrodes hold a prominent place. Since the end of the last century, their re-development has been observed, which is a consequence of the introduction of solid contact constructions, i.e., electrodes without an internal electrolyte solution. Research carried out in the field of potentiometric sensors primarily focuses on developing new variants of solid contact in order to obtain devices with better analytical parameters, and at the same time cheaper and easier to use, which has been made possible thanks to the achievements of material engineering. This paper presents an overview of new materials used as a solid contact in ion-selective electrodes over the past several years. These are primarily composite and hybrid materials that are a combination of carbon nanomaterials and polymers, as well as those obtained from carbon and polymer nanomaterials in combination with others, such as metal nanoparticles, metal oxides, ionic liquids and many others. Composite materials often have better mechanical, thermal, electrical, optical and chemical properties than the original components. With regard to their use in the construction of ion-selective electrodes, it is particularly important to increase the capacitance and surface area of the material, which makes them more effective in the process of charge transfer between the polymer membrane and the substrate material. This allows to obtain sensors with better analytical and operational parameters. Brief characteristics of electrodes with solid contact, their advantages and disadvantages, as well as research methods used to assess their parameters and analytical usefulness were presented. The work was divided into chapters according to the type of composite material, while the data in the table were arranged according to the type of ion. Selected basic analytical parameters of the obtained electrodes have been collected and summarized in order to better illustrate and compare the achievements that have been described till now in this field of analytical chemistry, which is potentiometry. This comprehensive review is a compendium of knowledge in the research area of functional composite materials and state-of-the-art SC-ISE construction technologies.


[Antigenicity study of carboplatin in guinea pigs and mice].
Carboplatin and carboplatin-ovalbumin mixture were examined for their antigenicity in Hartley guinea pigs as well as BALB/c and C3H/He mice in comparison with ovalbumin (OVA) and 2,4-dinitrochlorobenzene (DNCB)-OVA conjugate. The results obtained were as follows: 1. When guinea pigs were sensitized with carboplatin or carboplatin-OVA emulsified with Freund's complete adjuvant (FCA), these animals showed negative reactions in active systemic anaphylaxis (ASA), active cutaneous anaphylaxis (ACA), passive cutaneous anaphylaxis (PCA), passive hemagglutination (PHA) and Schultz-Dale test. 2. When mice were sensitized with carboplatin or carboplatin-OVA adsorbed to alum, these animals revealed a negative reaction in PCA using rats. 3. As positive controls, guinea pigs were sensitized with OVA or DNCB-OVA emulsified with FCA, and mice with OVA or DNCB-OVA adsorbed to alum. As a result, these animals disclosed positive reactions in ASA, ACA, PCA, PHA and Schultz-Dale test. As shown above, carboplatin was considered to possess neither antigenic nor haptenic properties. In addition, the dose levels of carboplatin employed in the present experiment were confirmed not to suppress immune reactions.


Intramolecular energy transfer in a tetra-coumarin perylene system: influence of solvent and bridging unit on electronic properties.
The synthesis and characterisation of a novel coumarin donor-perylene bisimide acceptor light-harvesting system is reported, in which an energy-transfer efficiency of >99% is achieved. Comparison of the excited-state properties of the donor-acceptor system with model compounds revealed that although the photophysical properties of the perylene bisimide acceptor unit are affected considerably by the nature of the substituent at the imide positions and the solvent employed, through-bond interaction between the donor and acceptor units is negligible. Energy transfer in the present system can be described as occurring via a through-space energy-transfer mechanism. Careful consideration of the redox properties of the donor relative to the acceptor units allows for avoidance of potentially deleterious excited-state electron-transfer processes.


Hyperprolactinemia in children: clinical features and long-term results.
Hyperprolactinemia is a rare endocrine disorder in childhood, which may result from hypophyseal adenoma. We aimed to review the etiologic reasons and clinical features in hyperprolactinemia patients retrospectively. The mean age of 11 female patients at diagnosis was 14.2 ± 1.3 years. Five patients had microadenoma, four patients had macroadenoma, and two patients were diagnosed with idiopathic hyperprolactinemia. The most frequent symptoms were menstrual disorders, headache, and galactorrhea, and one-third of the patients had obesity at diagnosis. There was no anterior pituitary hormone deficiency. All patients received bromocriptine as initial therapy; only two patients with macroadenoma and one patient with microadenoma were switched to cabergoline. Transsphenoidal surgery was performed for a patient with macroadenoma, who had cavernous sinus invasion and visual field defect. Medical treatment should be the first-line treatment option in both microadenoma and macroadenoma cases without any neurological signs. Surgery should be employed with limited indications.


CKS protein overexpression renders tumors susceptible to a chemotherapeutic strategy that protects normal tissues.
The cyclin-dependent kinase-interacting proteins Cyclin-dependent Kinase Subunit 1 and 2 (CKS1 and 2) are frequently overexpressed in cancer and linked to increased aggressiveness and poor prognoses. We previously showed that CKS protein overexpression overrides the replication stress checkpoint activated by oncoproteins. Since CKS overexpression and oncoprotein activation/overexpression are often observed in the same tumors, we have hypothesized that CKS-mediated checkpoint override could enhance the ability of premalignant cells experiencing oncoprotein-induced replication stress to expand. This tumor advantage, however, could represent a vulnerability to exploit therapeutically. Here, we first show in vitro that CKS protein overexpression selectively sensitizes tumor-derived cell lines to nucleoside analog-mediated toxicity under replication stress conditions. A treatment combination of the nucleoside analog gemcitabine and an agent that induces replication stress (thymidine or methotrexate) resulted in selective targeting of CKS protein-overexpressing tumor-derived cells while protecting proliferative cells with low CKS protein levels from gemcitabine toxicity. We validated this strategy in vivo and observed that Cks2-overexpressing mammary tumors in nude mice were selectively sensitized to gemcitabine under conditions of methotrexate-induced replication stress. These results suggest that high CKS expression might be useful as a biomarker to identify subgroups of cancer patients who might benefit from the described therapeutic approach.


Von Willebrand factor and the aortic valve: Concepts that are important in the transcatheter aortic valve replacement era.
Since the approval of the first transcatheter aortic valve replacement (TAVR) device in 2011, this technology has undergone substantial enhancements and exponential growth. However, valve thrombosis and residual paravalvular leaks (PVL) are among the challenges that require further investigation. Recently, monitoring von Willebrand factor (vWF) multimers has emerged as a tool to help evaluate the severity of PVL after TAVR. Following TAVR, vWF large multimers recovery have been documented. The role of large vWF multimers recovery and their interactions with platelets, and the endothelium have not been entirely elucidated. In this review, we discuss vWF synthesis and its role in aortic stenosis. We further provide an overview of the studies that investigated changes affecting vWF multimers following TAVR and the role of HMW vWF multimers monitoring in the determination of PVL severity. We also offer potential future directions for what will be fertile ground for research in this field.


Naive CD4(+) T cells and recent thymic emigrant levels in treated individuals with HIV: clinical relevance.
An increase in the levels of naive T cells after the administration of HAART is an indicator of the quality of immune reconstitution. We investigated whether levels of naive CD4 T cells (CD4(+)/CD45RA(+)) and of recent thymic emigrants (RTEs; CD4(+)/CD45RA(+)/CD31(+)) achieved in chronically treated HIV-infected patients could predict the length of time patients could interrupt antiretroviral treatment before their CD4 counts reached values < or =350 cells/mm(3) or HIV-1 RNA levels increased to > or =100,000 copies/ml (Tibet cohort). Serial measurements revealed that the level of naive CD4 T cells among patients was extremely variable (5-95%), but the values for each patient remained stable throughout the study. We then focused on those patients who showed percentages of naive CD4 T cells above 60% or below 30%. The levels of naive T cells, RTEs, mononuclear cells containing T cell receptor excision circles (TRECs), and the strength of CD4 helper responses to HIV p24 antigen during treatment failed to predict the duration of treatment interruptions. In contrast, the median survival time of patients with a CD4 nadir > or =350 cells/mm(3) was 2-fold higher than that of patients with a CD4 nadir <350. However, the probability of restarting therapy in these two groups of patients was independent of the levels of naive T cells, RTEs, or TRECs.


Precision shooting: Sampling long transition pathways.
The kinetics of collective rearrangements in solution, such as protein folding and nanocrystal phase transitions, often involve free energy barriers that are both long and rough. Applying methods of transition path sampling to harvest simulated trajectories that exemplify such processes is typically made difficult by a very low acceptance rate for newly generated trajectories. We address this problem by introducing a new generation algorithm based on the linear short time behavior of small disturbances in phase space. Using this "precision shooting" technique, arbitrarily small disturbances can be propagated in time, and any desired acceptance ratio of shooting moves can be obtained. We demonstrate the method for a simple but computationally problematic isomerization process in a dense liquid of soft spheres. We also discuss its applicability to barrier-crossing events involving metastable intermediate states.


PABPC1-induced stabilization of IFI27 mRNA promotes angiogenesis and malignant progression in esophageal squamous cell carcinoma through exosomal miRNA-21-5p.
Emerging evidence has demonstrated that RNA-binding protein dysregulation is involved in esophageal squamous cell carcinoma (ESCC) progression. However, the role of poly (A) binding protein cytoplasmic 1 (PABPC1) in ESCC is unclear. We therefore aimed to explore the functions and potential mechanisms of PABPC1 in ESCC progression. PABPC1 expression was characterized using immunohistochemistry and qRT-PCR in ESCC tissues and cell lines. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were used to detect histone acetylation in the promoter region of PABPC1. A series of in vitro and in vivo assays were further applied to elucidate the functions and underlying molecular mechanisms of PABPC1 in ESCC angiogenesis and malignant procession. PABPC1 expression was upregulated in ESCC tissues compared with in normal esophageal epithelial tissues. Elevated PABPC1 expression was correlated with tumor cell differentiation and poor prognosis in patients. Sp1 and p300 cooperated to increase the level of H2K37ac in the PABPC1 promoter. Functionally, PABPC1 overexpression enhanced esophageal squamous cell proliferation and invasion by activating the IFN/IFI27 signaling pathway. PABPC1 interacted with eIF4G to increase the stability of IFI27 mRNA by competing with RNA exosomes in ESCC. Furthermore, PABPC1/IFI27 could increase miR-21-5p expression to enable exosomal delivery of miR-21-5p to human umbilical vein endothelial cells to increase angiogenesis via inhibiting CXCL10. PABPC1 plays a critical role in ESCC malignant progression by interacting with eIF4G to regulate IFI27 mRNA stability and promote angiogenesis via exosomal miR-21-5p/CXCL10. Taken together, our results suggest that PABPC1 is a promising therapeutic target for ESCC.


Emergent Diversity and Persistent Turnover in Evolving Microbial Cross-Feeding Networks.
A distinguishing feature of many ecological networks in the microbial realm is the diversity of substrates that could potentially serve as energy sources for microbial consumers. The microorganisms are themselves the agents of compound diversification via metabolite excretion or overflow metabolism. It has been suggested that the emerging richness of different substrates is an important condition for the immense biological diversity in microbial ecosystems. In this work, we study how complex cross-feeding networks (CFN) of microbial species may develop from a simple initial community given some elemental evolutionary mechanisms of resource-dependent speciation and extinctions using a network flow model. We report results of several numerical experiments and report an in-depth analysis of the evolutionary dynamics. We find that even in stable environments, the system is subject to persisting turnover, indicating an ongoing co-evolution. Further, we compare the impact of different parameters, such as the ratio of mineralization, as well as the metabolic versatility and variability on the evolving community structure. The results imply that high microbial and molecular diversity is an emergent property of evolution in cross-feeding networks, which affects transformation and accumulation of substrates in natural systems, such as soils and oceans, with potential relevance to biotechnological applications.


Effects of two different lipid emulsions on morbidities and oxidant stress statuses in preterm infants: an observational study.
We examined the morbidities and oxidative stress statuses in preterms receiving either SMOFlipid or ClinOleic. This observational study was performed in Etlik Zubeyde Hanim Hospital, Turkey. Infants received SMOFlipid (5 months) or ClinOleic (7 months). Two hundred and twenty seven infants (SMOFlipid: 93, ClinOleic: 134) very low birth weighted infants were included. The oxidative stress status was evaluated in infants at low risk of oxidative stress by total antioxidant capacity (TAC) and total oxidant status (TOS) and oxidative stress index (OSI; TAC/TOS/100) at baseline, first week and third week. Parenteral nutrition was given for a median of 7 days in both groups. There were statistically insignificantly higher rates of retinopathy of prematurity (9.4 versus 11.7%) and chronic lung disease (4.7 versus 6.7%) in ClinOleic group compared with SMOFlipid group. The TAC, TOS and OSI decreased significantly in ClinOleic group after 1 week, and although the results were not statistically significant, the TAC increased while the TOS and OSI decreased in SMOFlipid group. In both groups, the TAC, TOS and OSI were lower than baseline after 3 weeks. SMOFlipid and ClinOleic result in similar oxidative stress statuses after they were stopped, and we detected no statistically significant differences in morbidity rates.


Structural analysis of arabinose-5-phosphate isomerase from Bacteroides fragilis and functional implications.
The crystal structure of arabinose-5-phosphate isomerase (API) from Bacteroides fragilis (bfAPI) was determined at 1.7 Å resolution and was found to be a tetramer of a single-domain sugar isomerase (SIS) with an endogenous ligand, CMP-Kdo (cytidine 5'-monophosphate-3-deoxy-D-manno-oct-2-ulosonate), bound at the active site. API catalyzes the reversible isomerization of D-ribulose 5-phosphate to D-arabinose 5-phosphate in the first step of the Kdo biosynthetic pathway. Interestingly, the bound CMP-Kdo is neither the substrate nor the product of the reaction catalyzed by API, but corresponds to the end product in the Kdo biosynthetic pathway and presumably acts as a feedback inhibitor for bfAPI. The active site of each monomer is located in a surface cleft at the tetramer interface between three monomers and consists of His79 and His186 from two different adjacent monomers and a Ser/Thr-rich region, all of which are highly conserved across APIs. Structure and sequence analyses indicate that His79 and His186 may play important catalytic roles in the isomerization reaction. CMP-Kdo mimetics could therefore serve as potent and specific inhibitors of API and provide broad protection against many different bacterial infections.


Treatment of the psychostimulant-sensitized animal model of schizophrenia.
Behavioral sensitization to psychostimulants in rodents is associated with the alteration of dopaminergic neurotransmission, and has been proposed as a useful model of schizophrenia due to its progressively intensifying, easily relapsing, and long-lasting features. Pharmacological treatments that reverse the established sensitization may have potential therapeutic values for schizophrenia. The present aim is to review pharmacological treatments that induce the reversal of established sensitization to psychostimulants. In addition, we discuss possible mechanisms for the reversal of sensitization. Reversal of sensitization is induced by chronic dopamine D1 receptor agonism, D2 or D1/D2 receptor agonism combined with mild N-methyl-D-aspartate (NMDA) receptor antagonism or serotonin (5-HT(2A) or 5-HT(3) ) receptor antagonism, 5-HT(1A) receptor agonism, and 5-HT(2A) or 5-HT(3) receptor antagonism. Chronic treatments with these drugs likely adjust altered dopaminergic neurotransmission in sensitized animals. Especially, chronic dopamine D1 receptor agonism, which may adjust mesolimbic hyperdopaminergic and mesocortical hypodopaminergic functions in sensitized animals, is an attractive therapeutic approach for schizophrenia.


[Deoxycholate induces apoptosis in cultured normal human esophageal mucosal epithelial cells].
To study the effect of deoxycholate in inducing apoptosis of human normal esophageal mucosal epithelial cells in vitro and investigate the molecular mechanism. Cultured normal human esophageal mucosal epithelial cells were treated with deoxycholate, and the cell apoptosis were evaluated with TUNEL, DNA ladder, flow cytometry with PI-staining, Annexin V-FITC conjugated with PI staining, and Western blotting. Flow cytometry, TUNEL and DNA ladder demonstrated that deoxycholate could induce apoptosis in normal human esophageal mucosal epithelial cells in a dose- and time-dependent manner. A percentage of 21.3% of the cell population treated with deoxycholate at 500 micromol/L for 30 min exhibited detectable caspase-3 activity shown by flow cytometry, which was significantly higher than the control level (1.5%, P<0.01). Western blotting suggested that deoxycholate down-regulated Bcl-2 protein expression and up-regulated Bax expression, but Fas was negative in the cells before and after deoxycholate treatment. Deoxycholate could induce apoptosis in cultured human esophageal mucosal epithelial cells. Aaspase-3 activation, Bcl-2 protein down-regulation and Bax up-regulation are involved in deoxycholate-induced apoptosis, which does not involve Fas-L/Fas.


Human chorionic gonadotropin and relaxin concentrations in early ectopic and normal pregnancies.
The present study was performed to investigate whether determination of serum relaxin concentrations would allow assessment of the gestation further than that provided by determination of hCG. Serum relaxin concentrations were quantified in women with resorbing ectopic gestations (as documented by declining titers of beta-hCG). The control group consisted of individuals with intrauterine pregnancies. As an additional control, we studied pregnancies conceived through ovulation induction, which usually have an increased volume of relaxin-secreting luteal tissue. On days 39-70 of gestation, the mean serum relaxin concentrations were significantly lower in ten resorbing ectopic gestations (P less than .001, permutation test) than in the normal control group of 13 intrauterine pregnancies. The median serum relaxin concentrations in patients who had ovulation induction with Pergonal were substantially higher than the median for all normal controls; values in clomiphene citrate-treated patients were within the normal range. These data suggest that relaxin secretion correlates with luteal function in both normal and abnormal gestations and reflects the status of the pregnancy. Thus, relaxin may serve as a useful clinical marker.


Silver nanoparticle aggregates on copper foil for reliable quantitative SERS analysis of polycyclic aromatic hydrocarbons with a portable Raman spectrometer.
Silver nanoparticle aggregates were synthesized on copper foil, which was used for the surface-enhanced Raman spectroscopy (SERS) detection of polycyclic aromatic hydrocarbons (PAHs) with a portable Raman spectrometer. Silver nanoparticle aggregates were prepared by immersing copper foil in the solution of Sn(2+) and AgNO(3) in a cyclic fashion. A four-cycle process was selected for the following experiments due to its high enhancement and relatively convenient experimental procedure. The substrate has greater temporal stability under continuous laser radiation, good uniformity and reproducibility, which indicated that the substrate could provide reliable measurements. The relationship between SERS intensity and concentrations of PAHs was studied. Quantitative analysis of PAHs in aqueous solution was further performed based on the prepared substrate. The log-log plot of normalized SERS intensity to PAHs concentration exhibited a good linear relationship, with the detection limits in the range of 5-500 μg L(-1). Thus, due to the stability, reproducibility and quantitative results, the prepared substrate could be used as a potential SERS sensor for the analysis of environmental pollutants.


The components of shoulder and elbow movements as goals of primary reconstructive operation in obstetric brachial plexus lesions.
Most of the cases of obstetric brachial plexus lesions (OBPL) show satisfactory improvement with conservative management, but in about 25% some surgical treatment is indicated. The present paper analyzes the effects of primary reconstructive surgeries in aspect of achieving delineated intraoperatively goals. Children operated before the age of 18 months with follow-up period longer than 1 year were selected. Therapeutic goals established during the operation were identified by analysis of initial clinical status and operative protocols. The elementary movement components in shoulder and elbow joints were classified by assessing range of motion, score in Active Movement Scale and modified British Medical Research Council scale of muscle strength. The effect was considered satisfactory when some antigravity movement was possible, and good when strength exceeded M3 or antigravity movement exceeded half of range of passive movement. In 13 of 19 patients most of established goals were achieved at good level, in 2 at satisfactory level. Remaining 4 patients showed improvement only in some aspects of extremity function. In 2 patients improvement in some movements was accompanied by worsening of other movements. The analysis of results separated into individual components of movements showed that goals were achieved in most of the cases, simultaneously clearly indicating which damaged structures failed to provide satisfactory function despite being addressed intraoperatively. The good results were obtained mainly by regeneration through grafts implanted after resection of neuroma in continuity, which proves that this technique is safe in spite of unavoidable temporary regression of function postoperatively.


Intravenous contrast-enhanced cone beam computed tomography (IVCBCT) of intrahepatic tumors and vessels.
Liver tumors are challenging to visualize on cone beam computed tomography (CBCT) without intravenous (IV) contrast. Image guidance for liver cancer stereotactic body ablative radiation therapy (SABR) could be improved with the direct visualization of hepatic tumors and vasculature. This study investigated the feasibility of the use of IV contrast-enhanced CBCT (IV-CBCT) as a means to improve liver target visualization. Patients on a liver SABR protocol underwent IV-CBCT before 1 or more treatment fractions in addition to a noncontrast CBCT. Image acquisition was initiated 0 to 30 seconds following injection and acquired over 60 to 120 seconds. "Stop and go" exhale breath-hold CBCT scans were used whenever feasible. Changes in mean CT number in regions of interest within visible vasculature, tumor, and adjacent liver were quantified between CBCT and IV-CBCT. Twelve pairs of contrast and noncontrast CBCTs were obtained in 7 patients. Intravenous-CBCT improved hepatic tumor visibility in breath-hold scans only for 3 patients (2 metastases, 1 hepatocellular carcinoma). Visible tumors ranged in volume from 124 to 564 mL. Small tumors in free-breathing patients did not show enhancement on IVCBT. Intravenous-CBCT may enhance the visibility of hepatic vessels and tumor in CBCT scans obtained during breath hold. Optimization of IV contrast timing and reduction of artifacts to improve tumor visualization warrant further investigation.


Wishful thinking and source monitoring.
Memory distortions sometimes serve a purpose: It may be in our interest to misremember some details of an event or to forget others altogether. The present work examines whether a similar phenomenon occurs for source attribution. Given that the source of a memory provides information about the accuracy of its content, people may be biased toward source attributions that are consistent with desired accuracy. In Experiment 1, participants read desirable and undesirable predictions made by sources differing in their a priori reliability and showed a wishful thinking bias--that is, a bias to attribute desirable predictions to the reliable source and undesirable predictions to the unreliable source. Experiment 2 showed that this wishful thinking effect depends on retrieval processes. Experiment 3 showed that under some circumstances, wishes concerning one event can produce systematic source memory errors for others.


Proteins mediating DNA loops effectively block transcription.
Loops are ubiquitous topological elements formed when proteins simultaneously bind to two noncontiguous DNA sites. While a loop-mediating protein may regulate initiation at a promoter, the presence of the protein at the other site may be an obstacle for RNA polymerases (RNAP) transcribing a different gene. To test whether a DNA loop alters the extent to which a protein blocks transcription, the lac repressor (LacI) was used. The outcome of in vitro transcription along templates containing two LacI operators separated by 400 bp in the presence of LacI concentrations that produced both looped and unlooped molecules was visualized with scanning force microscopy (SFM). An analysis of transcription elongation complexes, moving for 60 s at an average of 10 nt/s on unlooped DNA templates, revealed that they more often surpassed LacI bound to the lower affinity O2 operator than to the highest affinity Os operator. However, this difference was abrogated in looped DNA molecules where LacI became a strong roadblock independently of the affinity of the operator. Recordings of transcription elongation complexes, using magnetic tweezers, confirmed that they halted for several minutes upon encountering a LacI bound to a single operator. The average pause lifetime is compatible with RNAP waiting for LacI dissociation, however, the LacI open conformation visualized in the SFM images also suggests that LacI could straddle RNAP to let it pass. Independently of the mechanism by which RNAP bypasses the LacI roadblock, the data indicate that an obstacle with looped topology more effectively interferes with transcription.


Depression in Intimate Partner Violence Victims in Slovenia: A Crippling Pattern of Factors Identified in Family Practice Attendees.
This multi-centre cross-sectional study explored associations between prevalence of depression and exposure to intimate partner violence (IPV) at any time in patients' adult life in 471 participants of a previous IPV study. In 2016, 174 interviews were performed, using the Short Form Domestic Violence Exposure Questionnaire, the Zung Scale and questions about behavioural patterns of exposure to IPV. Family doctors reviewed patients' medical charts for period from 2012 to 2016, using the Domestic Violence Exposure Medical Chart Check List, for conditions which persisted for at least three years. Depression was found to be associated with any exposure to IPV in adult life and was more likely to affect women. In multivariable logistic regression modelling, factors associated with self-rated depression were identified (p < 0.05). Exposure to emotional and physical violence was identified as a risk factor in the first model, explaining 23% of the variance. The second model explained 66% of the variance; past divorce, dysfunctional family relationships and a history of incapacity to work increased the likelihood of depression in patients. Family doctors should consider IPV exposure when detecting depression, since lifetime IPV exposure was found to be 40.4% and 36.9% of depressed revealed it.


HIV-1 variants from a perinatal transmission pair demonstrate similar genetic and replicative properties in tonsillar tissues and peripheral blood mononuclear cells.
Human immunodeficiency virus type 1 (HIV-1) can be acquired through oropharyngeal tissues in breastfeeding infants. Efforts to better understand the determinants of breast milk transmission are hampered by the lack of a relevant oral human mucosa model and well-defined breast milk-derived viruses. This study used human ex vivo palatine tonsil tissues and peripheral blood mononuclear cells (PBMCs) to characterize the genetic, biological, and replicative properties of HIV-1 variants obtained from a perinatal transmission pair. Unique viral populations from maternal breast milk and infant blood were identified by gp120 V1-V2- and V3-specific heteroduplex tracking assays (HTAs). Full-length infectious recombinant viruses, containing a common HIV-1 NL4-3 genetic background, were generated with V1-V3 gp120 fragments from maternal and infant isolates representing the major viral populations identified in the HTAs. The resulting recombinant viruses used the CCR5 coreceptor, were nonsyncytium forming, and demonstrated replication properties similar to those of parental and control viruses in PBMCs and tonsillar explants. These findings indicate that viruses from breast milk cells and infant blood can infect PBMCs and tonsil tissues. The maternal and infant HIV-1 viruses detailed here will provide useful tools for defining the viral and host factors that contribute to HIV breastfeeding transmission.


[Immunohistologic findings in paragangliomas in the area of the head and neck].
30 patients with paraganglioma of the head and neck region were subjected to surgery at the Department of Otorhinolaryngology during 1978-1985. Histological classification of the obtained specimens was performed using also immunocytochemical methods to detect more details. The site of origin of the tumours was the glomus tympanicum in 18 cases, 7 times the glomus caroticum and 5 times the glomus jugulare. Antibodies against neuronal components (S-100 protein), endothelial cells (UEAI) and endocrine activity (NSE) were used for subtyping by PAP-method (Figs. 1-3). Immunocytochemistry provided for an easy subtyping of the tumours and showed an increase in severe progress forms in adenomatous variants of paragangliomas.


Pre-existing inflammatory state compromises heat tolerance in rats exposed to heat stress.
This study investigated the roles of endotoxemia and heat-induced tissue damage in the pathology of heat stroke. In groups of eight, male Wistar rats were treated with heat exposure only (HE), or heat exposure with turpentine (T+HE), dexamethasone (D+HE), and turpentine and dexamethasone combined (TD+HE). The rats remained sedated for 2 h after receiving the respective treatments, followed by heat exposure until the core temperature (T(c)) was 42 degrees C for 15 min; control rats received turpentine (T), dexamethasone (D), and turpentine and dexamethasone (TD) without heat stress. Blood samples were collected before treatment (baseline I), after 2 h of passive rest (baseline II), at T(c) 40 degrees C (T40), and 15 min after achieving T(c) 42 degrees C (T42). No rats died in the nonheat-stressed groups. Survival rate was lowest in the TD+HE rats (37.5%), followed by the HE (62.5%), T+HE (75%), and D+HE (100%) rats (P < 0.05). The duration of survival at T42 degrees C was shortest in the TD+HE rats (9.9 +/- 6.2 min) (P < 0.01), followed by the T+HE (11.3 +/- 6.1 min) and the HE (12.2 +/- 4 min) (P < 0.05) rats. The increase in plasma IL-6 concentrations was highest in the T+HE (352%) and HE (178%) rats (P < 0.05). D+HE treatment suppressed the increases in plasma aspartate transaminase, alanine aminotransferase, and IL-6 and LPS concentrations during severe heat stress. Heat stroke can be triggered by endotoxemia or heat-induced tissue damage, and preexisting inflammation compromises heat tolerance, whereas blocking endotoxemia increases heat tolerance.


Pre-etching vs. grinding in promotion of adhesion to intact enamel using self-etch adhesives.
This study was aimed to determine the effectiveness of grinding and pre-etching in promotion of adhesion to human intact enamel using the self-etch adhesive (SEA) Adper Easy Bond (3M ESPE). Etch-and-rinse adhesive Adper Single Bond (3M ESPE) served as control. Composite cylinders (AP-X Kuraray) were built and after 24 h micro-shear bond strengths (MSBS) were measured. Bonding interfaces were evaluated under scanning electron microscope (SEM). For evaluation of average roughness (Ra) and morphological analysis, treated enamel surfaces were observed under SEM and confocal laser scanning microscope (CLSM) with 3D surface profiling. Highest bond strengths were obtained by pre-etching and grinding showed a less significant role. Phosphoric acid (PA) etching compare to grinding created significantly rougher surface (Ra: 0.72 and 0.43 µm respectively). Therefore, this study recommends pre-etching the intact enamel prior to application of the adhesive instead of grinding.


The SIV-infected rhesus monkey model for HIV-associated dementia and implications for neurological diseases.
The neuropathogenesis of human immunodeficiency virus (HIV)-associated dementia has remained elusive, despite identification of HIV as the causal agent. Although a number of contributing factors have been identified, the series of events that culminate in motor and cognitive impairments after HIV infection of the central nervous system (CNS) are still not known. Rhesus monkeys infected with simian immunodeficiency virus (SIV) manifest immunosuppression and CNS disease that is pathologically [L. R. Sharer et al. (1991) J. Med. Primatol. 20, 211-217] and behaviorally [E. A. Murray et al. (1992) Science 255, 1246-1249] similar to humans. The SIV model of HIV-associated dementia (HAD) is widely recognized as a highly relevant model in which to investigate neuropathogenesis. With better understanding of neuropathogenesis comes the opportunity to interrupt progression and to design better treatments for HAD. This becomes increasingly important as patients live longer yet still harbor HIV-infected cells in the CNS. The use of the SIV model has allowed the identification of neurochemical markers of neuropathogenesis important not only for HAD, but also for other inflammatory neurological diseases.


Maximum likelihood fitting of single channel NMDA activity with a mechanism composed of independent dimers of subunits.
Steady-state single channel activity from NMDA receptors was recorded at a range of concentrations of both glutamate and glycine. The results were fitted with several plausible mechanisms that describe both binding and gating. The mechanisms we have tested were based on our present understanding of receptor structure, or based on previously proposed mechanisms for these receptors. The steady-state channel properties appear to have virtually no dependence on the concentration of either ligand, other than the frequency of channel activations. This limited the ability to discriminate detail in the mechanism, and, along with the persistence of open-shut correlations in high agonist concentrations, suggests that NMDA channels, unlike other neurotransmitter receptors, cannot open unless all binding sites are occupied. As usual for analyses of NMDA channels, the applicability of our results to physiological observations is limited by uncertainties in synaptic zinc and hydrogen ion concentrations, both of these being known to affect the receptor. The mechanism that we propose, on the basis of steady-state single channel recordings, predicts with fair accuracy the apparent open and shut-time distributions in different concentrations of agonists, correlations between open and shut times, and both the rising and falling phases of the macroscopic response to concentration jumps, and can therefore account for the main features of synaptic currents.


Measuring specific interaction of transcription factor ZmDREB1A with its DNA responsive element at the molecular level.
Specific interactions between transcription factors and DNA responsive elements are of fundamental importance in understanding how genetic regulatory proteins control gene transcription. Here we have developed a new method of using atomic force microscopy (AFM) to quantitatively study the single molecular specific interaction between ZmDREB1A, a transcription factor from maize, and its DNA responsive element, dehydration-responsive element (DRE) with core sequence A/GCCGAC. It was found that ZmDREB1A bound to both DRE ACCGAC and GCCGAC efficiently. The single molecular interaction forces of ZmDREB1A with DRE A/GCCGAC were determined to be 101 +/- 5 and 108 +/- 3 pN, respectively. The point mutation of ZmDREB1A in its DNA-binding domain or single base substitution of the DRE core sequence greatly reduced the binding affinity, demonstrating the high sensitivity of the AFM measurements. AFM is expected to be a simple, quick, sensitive and reliable method that offers valuable information for the characterization of transcription factors and the identification of their potential DNA responsive elements in functional genomics research.


Virulence characteristics and phylogenetic background of ciprofloxacin resistant Escherichia coli in the urine samples from Korean women with acute uncomplicated cystitis.
To clarify the characteristics of the virulence factors (VFs) of ciprofloxacin resistant Escherichia coli (CFRE) with acute uncomplicated cystitis (AUC), we determined the VFs and the phylogenetic background of all 54 CFRE strains and the 55 randomly selected ciprofloxacin sensitive E. coli strains (CFSE) from patients with AUC in 22 Korean hospitals. The prevalence of the VFs was as follows: fimA, papEF, papGIII, sfaI, dafaBC, cnf1, and hlyA were presented in 96%, 54%, 68%, 91%, 49%, 72%, and 29% of the samples, respectively. The expressions of papEF, cnf1, and hlyA were significantly more prevalent in the CFSE. Moreover, the expressions of cnf, and papEF significantly reduced the risk of ciprofloxacin resistance. The CFSE was also marginally associated with the group B2 (P=0.05). Although the presence of pyuria and a previous cystitis history were not related with the phylotyping and the expressions of VFs, group B2, and fimA and papEF were more expressed in the younger age patients (P<0.05). In conclusion, the CFRE exhibits a selective loss of VFs and the non-B2 phylotype in Korean AUC patients. The group B2 and the presence of fimA and papEF are associated with a younger age of AUC patients.


Spectrum of GABAA receptor variants in epilepsy.
Recent publications point to an increasingly important role of variants in genes encoding GABAA receptor subunits associated with both common and rare forms of epilepsies. The aim of this review is to give an overview of the current clinical phenotypes, genetic findings and pathophysiological mechanisms related to GABAA receptor variants. Early work showed that inherited variants in GABRG2 and GABRA1 cause relatively mild forms of monogenic epilepsies in large families. More recent studies have revealed that de novo variants in several GABAA receptor genes cause severe developmental and epileptic encephalopathies, inherited variants cause remarkably variable phenotypes within the same pedigrees ranging from asymptomatic carriers to developmental and epileptic encephalopathies, and variants in all GABAA receptor genes are enriched in common forms of epilepsy, namely rolandic epilepsy and genetic generalized epilepsy. Analyses from cellular expression systems and mouse models suggest that all variants cause a loss of GABAA receptor function resulting in GABAergic disinhibition. Genetic studies have revealed a crucial role of the GABAergic system in the underlying pathogenesis of various forms of common and rare epilepsies. Our understanding of functional consequences of GABAA receptor variants provide an opportunity to develop precision-based therapeutic strategies that are hopefully free from the side-effect burden seen with currently available GABAergic drugs.


Interactions Between Structural Remodeling and Hypertrophy in the Right Ventricle in Response to Pulmonary Arterial Hypertension.
Pulmonary arterial hypertension (PAH) exerts substantial pressure overload on the right ventricle (RV), inducing RV remodeling and myocardial tissue adaptation often leading to right heart failure. The associated RV free wall (RVFW) adaptation involves myocardial hypertrophy, augmented intrinsic contractility, collagen fibrosis, and structural remodeling in an attempt to cope with pressure overload. If RVFW adaptation cannot maintain the RV stroke volume (SV), RV dilation will prevail as an exit mechanism, which usually decompensates RV function, leading to RV failure. Our knowledge of the factors determining the transition from the upper limit of RVFW adaptation to RV decompensation and the role of fiber remodeling events such as extracellular fibrosis and fiber reorientation in this transition remains very limited. Computational heart models that connect the growth and remodeling (G&R) events at the fiber and tissue levels with alterations in the organ-level function are essential to predict the temporal order and the compensatory level of the underlying mechanisms. In this work, building upon our recently developed rodent heart models (RHM) of PAH, we integrated mathematical models that describe volumetric growth of the RV and structural remodeling of the RVFW. The time-evolution of RV remodeling from control and post-PAH time points was simulated. The results suggest that the augmentation of the intrinsic contractility of myofibers, accompanied by an increase in passive stiffness of RVFW, is among the first remodeling events through which the RV strives to maintain the cardiac output. Interestingly, we found that the observed reorientation of the myofibers toward the longitudinal (apex-to-base) direction was a maladaptive mechanism that impaired the RVFW contractile pattern and advanced along with RV dilation at later stages of PAH. In fact, although individual fibers were more contractile post-PAH, the disruption in the optimal transmural fiber architecture compromised the effective contractile function of the RVFW, contributing to the depressed ejection fraction (EF) of the RV. Our findings clearly demonstrate the critical need for developing multiscale approaches that can model and delineate relationships between pathological alterations in cardiac function and underlying remodeling events across fiber, cellular, and molecular levels.


Pediatric Calcaneal Tuberosity Avulsion Fracture: A Case Report and Literature Review.
Calcaneus fractures are rare in the pediatric population, and avulsion fracture of the calcaneal tuberosity is even less common. In adults, those fractures are usually associated with poor bone quality, however, this is not the case in children. It is a fracture that requires emergent intervention to prevent devastating skin and soft-tissue-related complications. We report a case of a 9-year-old female who had a displaced calcaneal tuberosity fracture with heel skin impending compromise, after a fall at an indoor gymnastic facility. The child had a history of acute lymphoblastic leukemia, diagnosed at age 4, she was in remission at the time of injury. In the present report, besides reporting a rare injury among the pediatric population, we also describe the operative management, the post-operative course, and we review the literature. Pediatric calcaneal tuberosity fractures, although rare, can lead to devastating complications if not addressed promptly, and should be treated in an expedited fashion.


The Role of Nurse Leaders in the Well-being of Clinicians.
This column reviews the concept of humanism in leadership. After surviving a year perceived by many healthcare professionals as the most challenging of a generation, the author reflects on leadership essentials for rebuilding our nursing workforce.


Hemi- or homozygosity: a requirement for some but not other p53 mutant proteins to accumulate and exert a pathogenetic effect.
Activating mutations within the p53 gene cause stabilization and therefore increased steady-state levels of the p53 protein; some, but not all, also result in the generation of an epitope recognized by the antibody pAB240. We have shown here that in 70% of Burkitt lymphoma cell lines, but not in normal EBV transformed B cell lines, p53 protein is readily detectable by Western blot analysis using either an antibody directed against the 240 epitope or an antibody against wild-type p53. Genomic analysis of these BL cell lines demonstrated the presence of mutations within the p53 gene in all cell lines with detectable p53 protein. We have also shown that in the cell lines ST486, Raji, and TE 110, which are heterozygous for a neutral sequence codon polymorphism (Arg/Pro) that causes altered migration of an otherwise normal protein and also contain a heterozygous mutation, only the protein derived from the mutated allele is stabilized. Thus the dominant effect of the mutations present in these cell lines apparently does not result from sequestering of the normal protein by the abnormal protein, and therefore presumably is a consequence of a gain-of-function resulting from the mutation. Although all cell lines with stabilized p53 also contained p53 mutations, three lymphoid tumors (two cell lines and one fresh B-CLL) with a heterozygous mutation at codon 248 did not express elevated levels of p53. In contrast, p53 was readily detectable in Western blot analysis from cell lines KK124, Namalwa, and CA46, which had homo- or hemizygous mutations at codon 248, and from PP1084, a cell line with a codon 273 mutation and a carboxyl-terminal truncation in the other allele. These results suggest that mutations at codon 248, unlike those in cell lines ST486 and TE110, are stabilizing only in the absence of the wild-type p53. Heterozygous mutations at codons 248 have been described in the germline of individuals belonging to cancer-prone families described by Li and Fraumeni (see ref 18), but tumors detected in such individuals are homozygous, i.e., contain only mutated p53. This is consistent with the possibility that such mutations exert a pathogenetic effect only in the absence of the wild-type protein, and are coupled to our findings that stabilization of p53 is a necessary component of the oncogenic pathways relevant to p53. However, whereas some mutations are stabilizing in the presence of the normal p53 protein, others are stabilizing only in the homozygous state.


Holocene Selection for Variants Associated With General Cognitive Ability: Comparing Ancient and Modern Genomes.
Human populations living during the Holocene underwent considerable microevolutionary change. It has been theorized that the transition of Holocene populations into agrarianism and urbanization brought about culture-gene co-evolution that favored via directional selection genetic variants associated with higher general cognitive ability (GCA). To examine whether GCA might have risen during the Holocene, we compare a sample of 99 ancient Eurasian genomes (ranging from 4.56 to 1.21 kyr BP) with a sample of 503 modern European genomes (Fst = 0.013), using three different cognitive polygenic scores (130 SNP, 9 SNP and 11 SNP). Significant differences favoring the modern genomes were found for all three polygenic scores (odds ratios = 0.92, p = 001; .81, p = 037; and .81, p = .02 respectively). These polygenic scores also outperformed the majority of scores assembled from random SNPs generated via a Monte Carlo model (between 76.4% and 84.6%). Furthermore, an indication of increasing positive allele count over 3.25 kyr was found using a subsample of 66 ancient genomes (r = 0.22, pone-tailed = .04). These observations are consistent with the expectation that GCA rose during the Holocene.


X monosomy in female systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, predominantly occurring in women of childbearing age. SLE, like several other autoimmune diseases, is characterized by a striking female predominance and, although sex hormone influences have been suggested as an explanation for this phenomenon, definitive data are still unavailable. Our group recently reported an increased X monosomy in lymphocytes of women, affected with primary biliary cirrhosis (PBC), systemic sclerosis (SSc), and autoimmune thyroiditis (AITD) in comparison to healthy women, thus suggesting the involvement of this chromosome in female predominance and in the deregulation of the immune system that characterizes autoimmunity. We have now evaluated X monosomy rates in SLE using fluorescence in situ hybridization (FISH) on peripheral mononuclear white blood cells (PBMCs) from female patients compared to healthy age-matched controls. In addition, because of a previous finding of microchimerism as a pathogenetic cause of a number of autoimmune diseases, we investigated the presence of cells carrying the Y chromosome. We did not identify an increased X monosomy in women with SLE compared to controls (P = 0.3960, SLE vs. HCs, Student's t-test), thus suggesting that a different mechanism of immune deregulation might be predominant in the female population of patients with SLE.


Hydromermis contorta (Kohn) and Hydromermis pseudocontorta n. sp. from chironomids of Lake Itasca and Long Lake, Minnesota.
Hydromermis contorta (Kohn) and Hydromermis pseudocontorta n. sp. are described from chironomids in Lake Itasca and Long Lake, Minnesota, respectively. The former was recovered from adult females of Glyptotendipes paripes (Edwards) and the latter from fourth-instar larvae of Chironomus sp. Hydromermis pseudocontorta n. sp. resembles H. contorta in cephalic structures, overall size, and the presence of a restricted trophosome in the female. The terminal mouth, long uterine and vulvar limbs of the vagina, and the strongly chitinized brownish spicule of H. contorta contrast with the subventral mouth, short vaginal limbs, and the light yellow spicule of H. pseudocontorta n. sp. Both nematode species emerge from the host as sexually mature adults and both species give evidence of mating while in the host. The H. contorta described by Welch is designated as a new species, Hydromermis albionis n. sp.


Regulatory Expansion in Mammals of Multivalent hnRNP Assemblies that Globally Control Alternative Splicing.
Alternative splicing (AS) patterns have diverged rapidly during vertebrate evolution, yet the functions of most species- and lineage-specific splicing events are not known. We observe that mammalian-specific AS events are enriched in transcript sequences encoding intrinsically disordered regions (IDRs) of proteins, in particular those containing glycine/tyrosine repeats that mediate formation of higher-order protein assemblies implicated in gene regulation and human disease. These evolutionary changes impact nearly all members of the hnRNP A and D families of RNA binding proteins. Regulation of these events requires formation of unusual, long-range mammalian-specific RNA duplexes. Differential inclusion of the alternative exons controls the formation of tyrosine-dependent multivalent hnRNP assemblies that, in turn, function to globally regulate splicing. Together, our results demonstrate that AS control of IDR-mediated interactions between hnRNPs represents an important and recurring mechanism underlying splicing regulation. Furthermore, this mechanism has expanded the regulatory capacity of mammalian cells.


Practice of CYP450 genotyping and phenotyping in children in a real-life setting.
Pharmacokinetics varies widely between children. Many factors play an important role in this variability, such as ontogeny, pharmacogenetics, gender, comorbidities, and drug-drug interactions. Significant work has already been done in adults to understand the impact of genetic polymorphisms on drug-metabolizing enzyme activity and drug response. Data remain poor in children due to ontogeny that impacts genotyping-phenotyping correlation and the difficulty enrolling children in prospective studies. Our study aimed to describe the use of cytochromes P450 (CYP) phenotyping and/or genotyping tests in children in a real-life setting and assess the correlation between the genotype and the phenotype. We reviewed the results of tests performed between January 2005 and December 2020. Fifty-two children were genotyped and/or phenotyped. Four patients were excluded from the present analysis as they only underwent ABCB1 genotyping, without CYP testing. Of the remainder, 18 underwent simultaneous CYP genotyping and phenotyping, while 17 underwent CYP genotyping only, and 13 underwent CYP phenotyping only. In all cases, investigations were performed after the following situations: insufficient clinical response to treatment, low plasma concentrations, and adverse drug reactions (ADR). The vast majority of cases were related to immunosuppressive or antipsychotic therapy. Genotyping and/or phenotyping explained or contributed to the aforementioned clinical events in 56% of cases. The correlation between the genotype and the phenotype showed variability depending on the assessed cytochrome. In several cases, the phenotype did not correspond to the genotype because of comedications. In conclusion, there is clearly value in guiding drug based on CYP activity in children.


Optimal Body Size and Limb Length Ratios Associated with 100-m Personal-Best Swim Speeds.
This study aims to identify optimal body size and limb segment length ratios associated with 100-m personal-best (PB) swim speeds in children and adolescents. Fifty national-standard youth swimmers (21 males and 29 females age 11-16 yr; mean ± SD age, 13.5 ± 1.5 yr) participated in the study. Anthropometry comprised stature; body mass; skinfolds; maturity offset; upper arm, lower arm, and hand lengths; and upper leg, lower leg, and foot lengths. Swimming performance was taken as the PB time recorded in competition for the 100-m freestyle swim. To identify the optimal body size and body composition components associated with 100-m PB swim speeds (having controlled for age and maturity offset), we adopted a multiplicative allometric log-linear regression model, which was refined using backward elimination. Lean body mass was the singularly most important whole-body characteristic. Stature and body mass did not contribute to the model, suggesting that the advantage of longer levers was limb-specific rather than a general whole-body advantage. The allometric model also identified that having greater limb segment length ratios [i.e., arm ratio = (low arm)/(upper arm); foot-to-leg ratio = (foot)/(lower leg)] was key to PB swim speeds. It is only by adopting multiplicative allometric models that the above mentioned ratios could have been derived. The advantage of having a greater lower arm is clear; however, having a shorter upper arm (achieved by adopting a closer elbow angle technique or by possessing a naturally endowed shorter upper arm), at the same time, is a new insight into swimming performance. A greater foot-to-lower-leg ratio suggests that a combination of larger feet and shorter lower leg length may also benefit PB swim speeds.


Obesity and renal disease: Benefits of bariatric surgery.
The prevalence of obesity, a preventable and reversible condition with a high impact on health, continues to rise, especially after the COVID-19 pandemic. Severe overweight is well recognized as a risk factor for diabetes and hypertension, among other conditions, that may increase cardiovascular risk. Obesity has grown simultaneously with a rise in the prevalence of chronic kidney disease, and a pathophysiological link has been established, which explains its role in generating the conditions to facilitate the emergence and maximize the impact of the risk factors of chronic kidney disease and its progression to more advanced stages. Knowing the mechanisms involved and having different tools to reverse the overweight and its consequences, bariatric surgery has arisen as a useful and efficient method, complementary or alternative to others, such as lifestyle changes and/or pharmacotherapy. In a detailed review, the mechanisms involved in the renal consequences of obesity, the impact on risk factors, and the potential benefit of bariatric surgery at different stages of the disease and its progression are exposed and analyzed. Although the observational evidence supports the value of bariatric surgery as a renoprotective measure in individuals with obesity, diabetic or not, randomized studies are expected to establish evidence-based recommendations that demonstrate its positive risk-benefit balance as a complementary or alternative therapeutic tool.


A new mechanism for aging: chemical "age spots" in immortal DNA strands in distributed stem cells.
The existence of immortal DNA strands (IDSs) in distributed stem cells (DSCs) of adult human tissues was first inferred by Cairns. Cairns deduced the existence of IDSs by connecting two seemingly disparate observations - one his own and the other belonging to Lark. Cairns noted a mathematical discrepancy between predicted human tissue cell mutation rates and human cancer incidence. He integrated this insight with Lark's earlier discovery of non-random mitotic chromosome segregation in both plant root tip cells and mouse fetal fibroblast cultures to predict the existence of IDSs as the essential elements of a mutation-defense mechanism in DSCs. Since Cairns' seminal prediction, several laboratories have identified IDSs in diverse mammalian cells with DSC properties. Past studies focused on the potential roles of IDSs as originally envisioned in DSC genetic fidelity or in the maintenance of the DSC phenotype. Another possible consequence of IDSs, aging, has received little attention. Herein, the potential for cumulative chemical modifications and decompositions (i.e., "age spots") of IDSs in DSCs to act as a major determinant of human aging is considered. If accrued chemical alterations of IDSs prove to be essential determinants of aging, then a means to restore IDSs may yield new strategies for tissue rejuvenation.


Induction of cationic chicken liver-expressed antimicrobial peptide 2 in response to Salmonella enterica infection.
Cationic antimicrobial peptides constitute part of the innate immune system and provide an essential role in the defense against infection. At present there is a paucity of information regarding the antimicrobial profile of the chicken (Gallus gallus). Using in silico studies, an expressed sequence tag (EST) clone was identified which encodes a novel cationic antimicrobial peptide, chicken liver-expressed antimicrobial peptide 2 (cLEAP-2). The predicted amino acid sequence composed a prepropeptide, and the active peptide contained four conserved cysteine amino acids. The gene was localized to chromosome 13, and analysis of the genome revealed three exons separated by two introns. The cLEAP-2 gene was expressed in a number of chicken epithelial tissues including the small intestine, liver, lung, and kidney. Northern analysis identified liver-specific cLEAP-2 splice variants, suggesting some degree of tissue-specific regulation. To investigate whether cLEAP-2 expression was constitutive or induced in response to microbial infection, 4-day-old birds were orally infected with Salmonella. Analyses of cLEAP-2 expression by semiquantitative reverse transcription-PCR indicated that cLEAP-2 mRNA was upregulated significantly in the small intestinal tissues and the liver, indicative of direct and systemic responses. The antimicrobial activity of cLEAP-2 against Salmonella was analyzed in vitro with a time-kill assay and recombinant cLEAP-2. Interestingly Salmonella enterica serovar Typhimurium SL1344 showed increased susceptibility to the active cationic peptide (amino acids 37 to 76) compared to S. enterica serovar Typhimurium C5 and Salmonella enteritidis. Taken together, these data suggest that cationic cLEAP-2 is part of the innate host defense mechanisms of the chicken.


[Molecular mechanism of geniposide in regulating GLUT2 glycosylation in pancreatic β cells].
Type 2 diabetes mellitus( T2 DM) is a common chronic metabolic disease characterized by persistent hyperglycemia and insulin resistance. In pancreatic β-cells,glucose-stimulated insulin secretion( GSIS) plays a pivotal role in maintaining the balance of blood glucose level. Previous studies have shown that geniposide,one of the active components of Gardenia jasminoides,could quickly regulate the absorption and metabolism of glucose,and affect glucose-stimulated insulin secretion in pancreatic β cells,but the specific mechanism needs to be further explored. Emerging evidence indicated that glycosylation of glucose transporter( GLUT) has played a key role in sensing cell microenvironmental changes and regulating glucose homeostasis in eucaryotic cells. In this study,we studied the effects of geniposide on the key molecules of GLUT2 glycosylation in pancreatic β cells. The results showed that geniposide could significantly up-regulate the mRNA and protein levels of Glc NAc T-Ⅳa glycosyltransferase( Gn T-Ⅳa) and galectin-9 but had no signi-ficant effect on the expression of clathrin,and geniposide could distinctively regulate the protein level of Gn T-Ⅳa in a short time( 1 h) under the conditions of low and medium glucose concentrations,but had no significant effect on the protein level of galectin-9. In addition,geniposide could also remarkably affect the protein level of glycosylated GLUT2 in a short-time treatment. The above results suggested that geniposide could quickly regulate the protein level of Gn T-Ⅳa,a key molecule of protein glycosylation in INS-1 rat pancreatic βcells and affect the glycosylation of GLUT2. These findings suggested that the regulation of geniposide on glucose absorption,metabolism and glucose-stimulated insulin secretion might be associated with its efficacy in regulating GLUT2 glycosylation and affecting its distribution on the cell membrane and cytoplasm in pancreatic β cells.


Transfer of orbital angular momentum in a multimode parametric oscillator.
We investigate the transfer of orbital angular momentum (OAM) in a type-II optical parametric oscillator (OPO). We produce different kinds of transverse modes on the downconverted beams by pumping the OPO with a first-order Laguerre-Gaussian beam well above threshold. Different operation regimes are attained showing a rich variety of transverse modes bearing OAM.


Cryoballoon Pulmonary Vein Isolation and Roof and Posterior Wall Debulking Using Navik 3D™: A New Technique for Atrial Fibrillation Ablation.
The success rates of traditional endocardial ablation techniques for managing atrial fibrillation remain modest. Recently, the performance of posterior wall ablation in conjunction with pulmonary vein (PV) isolation (PVI) has been reported to increase the chance of success following endocardial ablation. We report a systematic approach for the isolation of the PVs and ablation of the left atrial roof and posterior wall using a cryoballoon guided by the novel Navik 3D™ mapping system (APN Health LLC, Waukesha, WI, USA) and offer preliminary data including procedure, fluoroscopy, and cryoablation times for review. Patients (n = 52) aged 63 years ± 10 years with paroxysmal (n = 42), persistent (n = 11), or chronic (n = 2) atrial fibrillation underwent cryoballoon ablation for PVI and/or the left atrial roof, posterior wall, anterior ganglion plexi (GP), or mitral isthmus line. Lesions were accurately delivered to the PVs, left atrial roof, posterior wall, anterior GP, or mitral isthmus line as appropriate. Acute PVI was achieved in 98% of all patients, and eight (15%) required direct current cardioversion to restore sinus rhythm at the end of the procedure. The mean ± standard deviation procedure, fluoroscopy, and cryoballoon ablation times were 149 minutes ± 39 minutes, 33 minutes ± 30 minutes, and 41 minutes ± 14 minutes, respectively. The Navik 3D™ mapping system is believed to be the only available mapping system that allows for the visualization and location of the cryoballoon in three dimensions, enabling the operator to deliver contiguous, overlapping lesions on the roof and posterior wall of the left atrium. It also facilitates precise measurement of the distance between the esophageal temperature probe and the cryoballoon, thereby helping to avoid freezing damage to the esophagus.


Introducing RAPTOR: RevMan Parsing Tool for Reviewers.
Much effort is made to ensure Cochrane reviews are based on reliably extracted data. There is a commitment to wide access to these data-for novel processing and/or reuse-but delivering this access is problematic. To describe a proof-of-concept programme to extract, curate and structure data from Cochrane reviews. One student of Applied Sciences (16 weeks full time), access to pre-publication review files and use of 'Eclipse' to create an open-access tool (RAPTOR) using the programming language Java. The final software batch processes hundreds of reviews in seconds, extracting all study data and automatically tidying and unifying presentation of data for return into the source review, reuse, or export for novel analyses. This software, despite being limited, illustrates how the efforts of reviewers meticulously extracting study data can be improved, disseminated and reused with little additional effort.


[Effects of different amounts of phosphate fertilizers on copper, zinc transfer in red soil under the application of KH2PO4].
In order to study the effects of different phosphate addition amounts on migration and transformation of heavy metals (Cu, Zn) in soil, an indoor leaching experiment using soil columns was carry out to study the leaching behavior of Cu and Zn. The KH2PO4 was chosen as the fertilizer application at the doses of 5 mg.kg-1, 15 mg.kg-1 and 25 mg.kg-1. The results showed that KH2PO4, could reduce the leachate pH, but different phosphate amounts had little effect on leachate pH, pH in leachate kept rising in the whole leaching process. With the application of KH2PO4, Cu migration was mainly in the surface layer while Zn migrated into deeper soil. Concentrations of Cu, Zn in deep soil leachate were low indicating that it was harmless to the shallow groundwater. After leaching, heavy metals mainly existed in the residual form in soil, the proportion of residual form of Cu was around 60% and the proportion of residual form of Zn was around 40%. High concentration of KH2PO4 helps the transformation of Zn from residual organic combination state to exchange state.


The role of plasma transferrin in iron absorption in the rat.
The question of whether plasma transferrin acts as a carrier of iron from intestinal mucosal cells to the blood plasma was investigated in a series of experiments in the tat. By thoracic duct cannulation and collection of lymph during absorption it was confirmed that nearly all absorbed iron passes directly to portal blood. The total rate of transcapillary exchange of transferrin and the rate of passage of plasma transferrin into the extravascular compartment of the intestinal mucosa were then measured in separate groups of rats. The rate of exchange were insufficient for transferrin to act as the carrier of iron at the rate at which it passes from intestinal cells to portal plasma after ingesting a dose of inorganic iron. Some specific binding of transferrin and cellular uptake of iron by intestinal mucosa was observed after the intravenous injection of transferrin labelled with 59Fe and 125I. It is concluded from these experiments that absorbed iron passes from intestinal cells to portal plasma largely in a low molecular weight form. The passage of plasma transferrin into the interstitial fluid of the intestinal mucosa and binding to mucosal cells probably functions primarily to supply iron to the cells and not to act as a carrier of iron from the cells.


Arginine Is a Critical Substrate for the Pathogenesis of Pseudomonas aeruginosa in Burn Wound Infections.
Environmental conditions affect bacterial behavior and can greatly influence the course of an infection. However, the environmental cues that elicit bacterial responses in specific infection sites are relatively unknown. Pseudomonas aeruginosa is ubiquitous in nature and typically innocuous. However, it is also one of the most prevalent causes of fatal sepsis in burn wound patients. The aim of this study was to determine the impact of environmental factors, specifically the availability of arginine, on the pathogenesis of P. aeruginosa in burn wound infections. Comparison of burned versus noninjured tissue revealed that l-arginine (l-Arg) was significantly depleted in burn wounds as a consequence of elevated arginase produced by myeloid-derived suppressor cells. We also observed that l-Arg was a potent chemoattractant for P. aeruginosa, and while low concentrations of l-Arg increased P. aeruginosa's swimming motility, high concentrations resulted in diminished swimming. Based on these observations, we tested whether the administration of exogenous l-Arg into the burn wound could attenuate the virulence of P. aeruginosa in thermally injured mice. Administration of l-Arg resulted in decreased P. aeruginosa spread and sepsis and increased animal survival. Taken together, these data demonstrate that the availability of environmental arginine greatly influences the virulence of P. aeruginosa in vivo and may represent a promising phenotype-modulating tool for future therapeutic avenues.IMPORTANCE Despite our growing understanding of the pathophysiology of burn wounds and the evolution of techniques and practices to manage infections, sepsis remains a significant medical concern for burn patients. P. aeruginosa continues to be a leader among all causes of bacteremic infections due to its tendency to cause complications in immunocompromised patients and its ubiquitous presence in the hospital setting. With the unforgiving emergence of multidrug-resistant strains, it is critical that alternative strategies to control or prevent septic infections in burn patients be developed in parallel with novel antimicrobial agents. In this study, we observed that administration of l-Arg significantly reduced bacterial spread and sepsis in burned mice infected with P. aeruginosa Given the safety of l-Arg in high doses and its potential wound-healing benefits, this conditionally essential amino acid may represent a useful tool to modulate bacterial behavior in vivo and prevent sepsis in burn patients.


Unconventional Spin Pumping and Magnetic Damping in an Insulating Compensated Ferrimagnet.
Recently, the interest in spin pumping (SP) has escalated from ferromagnets into antiferromagnetic systems, potentially enabling fundamental physics and magnonic applications. Compensated ferrimagnets are considered alternative platforms for bridging ferro- and antiferromagnets, but their SP and the associated magnetic damping have been largely overlooked so far despite their seminal importance for magnonics. Herein, an unconventional SP together with magnetic damping in an insulating compensated ferrimagnet Gd3 Fe5 O12 (GdIG) is reported. Remarkably, the divergence of the nonlocal effective magnetic damping induced by SP close to the compensation temperature in GdIG/Cu/Pt heterostructures is identified unambiguously. Furthermore, the coherent and incoherent spin currents, generated by SP and the spin Seebeck effect, respectively, undergo a distinct direction change with the variation of temperature. The physical mechanisms underlying these observations are self-consistently clarified by the ferrimagnetic counterpart of SP and the handedness-related spin-wave spectra. The findings broaden the conventional paradigm of the ferromagnetic SP model and open new opportunities for exploring the ferrimagnetic magnonic devices.


Infertility and Psychological and Social Health of Iranian Infertile Women: A Systematic Review.
Objective: Infertility influences various emotional, psychological, social, and relational aspects of women's lives. By employing a systematic review on the papers published in this field, this study aimed to identify the consequences of infertility on psychological and social health of women in Iran. Method : This was a descriptive study, conducted through a systematic review according to the directions denoted by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) in 2018. To investigate the entirety of the published studies on the sociopsychological consequences of women's infertility in Iran, various databases, including Comprehensive Human Science Portal, Scientific Information Databases (SID), Magiran, National Library and Archives of I. R. IRAN, Noormags, MEDLIB, Science Direct, Google Scholar, Medline, and ProQuest, were explored for the studies published between 1991 and 2018. The selected papers were evaluated according to the content analysis method. Results: Out of the 53 papers investigated, 27 were published in domestic journals (51%), while the remaining 26 papers were published in international journals and were in English (49%). The results revealed that sociopsychological consequences of women's infertility are categorized in 6 main categories: (1) quality of life, (2) depression, (3) anxiety, (4) social support, (5) violence, and (6) sexual function. Conclusion: The results of this study can be used to design psychocognitive interventions and assist women in decreasing the emerging psychological pain and pressure.


Degradation kinetics, byproducts formation and estimated toxicity of metronidazole (MNZ) during chlor(am)ination.
The residues of pharmaceuticals and personal care products (PPCPs) in environmental waters have been widespread concerned. Metronidazole (MNZ), normally employed to treat inflammation and infection, was chosen as one model PPCP. The degradation of MNZ by chlorination could be fitted by pseudo-first-order kinetics as the observed pseudo-first-order rate constants increasing from 0.0302 min-1 to 0.2872 min-1. However, the kinetics during chloramination of MNZ followed pseudo-second-order reaction, whose estimated half-live was approximately 6-8 times longer than chlorination. The chlor(am)ination of MNZ especially formed chloroform (CF), dicholoacetamide (DCAcAm), tricholoacetamide (TCAcAm) and dichloroacetonitrile (DCAN), and their yields were overall lower under chloramination than chlorination. During chlorination, the yield of CF was increased from 0.35 ± 0.02% to 2.06 ± 0.12% with 1-20 chlorine/MNZ molar ratio, whereas the formations of DCAcAm, TCAcAm and DCAN increased firstly and then decreased. Increasing chloramine dosage promoted the concentrations of scheduled disinfection byproducts (DBPs). CF and TCAcAm kept continuous generation in chlor(am)ination versus reaction time. Compared with the chlorination, the chloramination of MNZ was more dependent on pH value due to the self-degradation of chloramine. Faintly acidic condition favored N-DBPs' formation in MNZ when it was subjected to chlor(am)ination. The chloramination of MNZ produced cytotoxicity and genotoxicity by 10-15 folds lower than chlorination, and DCAN formed during chloramination dominated both DBPs' yields and toxicity contribution. Opposite to chlorination, the integrated toxicity of MNZ during chloramination varied linearly versus N-DBPs' yields.


A new and efficient procedure for the synthesis of hexahydropyrimidine-fused 1,4-naphthoquinones.
A new and efficient method for the synthesis of hexahydropyrimidine-fused 1,4-naphthoquinones in one step with high yields from the reaction of lawsone with 1,3,5-triazinanes was developed.


Immunoporosis: Role of Innate Immune Cells in Osteoporosis.
Osteoporosis or porous bone disorder is the result of an imbalance in an otherwise highly balanced physiological process known as 'bone remodeling'. The immune system is intricately involved in bone physiology as well as pathologies. Inflammatory diseases are often correlated with osteoporosis. Inflammatory mediators such as reactive oxygen species (ROS), and pro-inflammatory cytokines and chemokines directly or indirectly act on the bone cells and play a role in the pathogenesis of osteoporosis. Recently, Srivastava et al. (Srivastava RK, Dar HY, Mishra PK. Immunoporosis: Immunology of Osteoporosis-Role of T Cells. Frontiers in immunology. 2018;9:657) have coined the term "immunoporosis" to emphasize the role of immune cells in the pathology of osteoporosis. Accumulated pieces of evidence suggest both innate and adaptive immune cells contribute to osteoporosis. However, innate cells are the major effectors of inflammation. They sense various triggers to inflammation such as pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), cellular stress, etc., thus producing pro-inflammatory mediators that play a critical role in the pathogenesis of osteoporosis. In this review, we have discussed the role of the innate immune cells in great detail and divided these cells into different sections in a systemic manner. In the beginning, we talked about cells of the myeloid lineage, including macrophages, monocytes, and dendritic cells. This group of cells explicitly influences the skeletal system by the action of production of pro-inflammatory cytokines and can transdifferentiate into osteoclast. Other cells of the myeloid lineage, such as neutrophils, eosinophils, and mast cells, largely impact osteoporosis via the production of pro-inflammatory cytokines. Further, we talked about the cells of the lymphoid lineage, including natural killer cells and innate lymphoid cells, which share innate-like properties and play a role in osteoporosis. In addition to various innate immune cells, we also discussed the impact of classical pro-inflammatory cytokines on osteoporosis. We also highlighted the studies regarding the impact of physiological and metabolic changes in the body, which results in chronic inflammatory conditions such as ageing, ultimately triggering osteoporosis.


Large eddy simulations of blood dynamics in abdominal aortic aneurysms.
We study the effects of transition to turbulence in abdominal aortic aneurysms (AAA). The presence of transitional effects in such districts is related to the heart pulsatility and the sudden change of diameter of the vessels, and has been recorded by means of clinical measures as well as of computational studies. Here we propose, for the first time, the use of a large eddy simulation (LES) model to accurately describe transition to turbulence in realistic scenarios of AAA obtained from radiological images. To this aim, we post-process the obtained numerical solutions to assess significant quantities, such as the ensemble-averaged velocity and wall shear stress, the standard deviation of the fluctuating velocity field, and vortical structures educed via the so-called Q-criterion. The results demonstrate the suitability of the considered LES model and show the presence of significant transitional effects around the impingement region during the mid-deceleration phase.


A practical approach to perimenopausal and postmenopausal urinary incontinence.
This article provides a logical approach to the evaluation and management of urinary incontinence in the perimenopausal and postmenopausal woman. The impact of the climacteric on normal anatomy and physiology of the female continence mechanism is addressed. Primary office evaluation and guidelines for referrals are provided. The surgical and nonsurgical treatments of incontinence are discussed with illustrative cases.


Malpositioning of a pacemaker lead to the left ventricle accompanied by posterior mitral leaflet injury.
There have been several reports of a malpositioned pacemaker lead as a complication in pacemaker implantation. Herein we report a rare case of a malpositioned pacemaker lead in the left ventricle, which could occur in patients with cardiac structural abnormalities. A 70-year-old woman, who had undergone implantation of a pacemaker at the left subclavian position for complete atrioventricular block five years previously, was evaluated because of dyspnea and low grade fever. Echocardiography revealed a congenital atrial septal defect through which the lead was placed into the left ventricle. Whereas percuteneous lead removal seemed to be full of risk with concerns of thromboembolic events and infective endocarditis, the patient was referred to our hospital for surgical removal of the wire and closure of the defect. The lead was a screw-in type and removed and was extracted in the theatre using radiography. Intraoperatively it was found that the lead was positioned in the left ventricle apex after perforating the posterior mitral leaflet. Repair of the mitral valve perforation and closure of the septal defect and epicardial pacemaker lead implantation was performed. This case demonstrated the possibility of malposition of the pacemaker lead to the left ventricle in a transvenous pacemaker implantation procedure, which may lead to thromboembolic complication or infective endocarditis, and the pre-eminent role of echocardiography in the diagnosis of cardiac structural abnormalities. A malpositioned pacemaker lead in the left ventricle is a rare complication that can occur in patients with cardiac structural abnormalities. Lateral chest roentgenogram and echocardiography is efficient in preventing this complication. The removal of the lead in concerns of thromboembolic events and infection is preferable.


Asthma Is Associated With Subsequent Development of Inflammatory Bowel Disease: A Population-based Case-Control Study.
Asthma and the inflammatory bowel diseases (IBD) each arise through complex interactions between genetic and environmental factors, and share many environmental risk factors. We examined the association between asthma and Crohn's disease or ulcerative colitis. We performed a population-based case-control study using health administrative data from the province of Alberta, Canada. The odds of a diagnosis of asthma preceding the diagnosis of either Crohn's disease (N = 3087) or ulcerative colitis (N = 2377) were compared with the odds of diagnosis of asthma among persons without IBD (N = 402,800) using logistic regression. Effect measure modification by age at diagnosis of IBD (16 years or less, 17-40 years, or older than 40 years) was tested using a likelihood ratio test. A diagnosis of asthma was associated with increased odds of incident Crohn's disease (adjusted odds ratio [OR], 1.45; 95% confidence interval [CI], 1.31-1.60). No effect measure modification was observed for age at diagnosis for Crohn's disease (P = .42). However, we observed effect measure modification by age at diagnosis for ulcerative colitis (P = .0103), with an adjusted OR of 1.49 (95% CI, 1.08-2.07) among individuals diagnosed at an age of 16 years or less (OR) and an adjusted OR of 1.57 (95% CI, 1.31-1.89) among individuals diagnosed at an age older than 40 years. However, there was no association between asthma and ulcerative colitis among individuals diagnosed between ages 17 and 40 (adjusted OR, 1.05; 95% CI, 0.86-1.26). In a population-based case-control study, we associated asthma with Crohn's disease, and with early and late-onset ulcerative colitis.


Lumbar root stimulation for restoring leg function: stimulator and measurement of muscle actions.
We are studying the feasibility of restoring lower limb functions to paraplegics by stimulating their lumbar anterior roots (L2-S2). The potential advantages of placing electrodes at the roots, at the cauda equina, were set out by Rushton (1), and our results so far are in a companion paper by Rushton et al. In this paper, we describe briefly the stimulator system and a special apparatus we call the multimoment chair. The stimulator is a development from an earlier design of an implantable peripheral nerve stimulator (2) and has features that make it easier to use. The multimoment chair enables us to gather simultaneously isometric joint moments for 14 axes of the legs during stimulation while the body is fixed in a posture between sitting and full extension. Such rapid data collection is essential to discover the effects of multiple-root stimulation and its functional possibilities.


Cost-efficacy of acceleration partial-breast irradiation compared with whole-breast irradiation.
The purpose of this study was to analyze the cost-efficacy of multiple accelerated partial-breast irradiation (APBI) techniques compared with whole breast irradiation (WBI) delivered utilizing 3-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiation therapy (IMRT). A previously reported matched-pair analysis consisting of 199 patients receiving WBI and 199 patients receiving interstitial APBI formed the basis of this analysis. Cost analyses included a cost minimization analysis, incremental cost- effectiveness ratio (ICER) analysis, and cost per quality adjusted life year (QALY) analysis. Per 1,000 patients treated, the cost savings with the utilization of APBI compared to WBI IMRT is $14.9 million, $10.9 million, $8.8 million, $5.0 million, and $9.7 million for APBI 3D-CRT, APBI IMRT, APBI single-lumen (SL), APBI multi-lumen (ML), and APBI interstitial, respectively. Per 1,000 patients treated, the cost savings with the utilization of APBI compared to WBI 3D-CRT is $6.0 million, $2.0 million, and $0.7 million for APBI 3D-CRT, APBI IMRT, and APBI interstitial, respectively. The cost per QALY for APBI SL, APBI ML, and APBI interstitial compared with APBI 3D-CRT are $12,273, $66,032, and $546, respectively. When incorporating non-medical costs and cost of recurrences the cost per QALY was $54,698 and $49,009 for APBI ML compared with APBI 3D-CRT. When compared to WBI IMRT, all APBI techniques are cost-effective based on cost minimization, ICER, and QALY analyses. When compared to WBI 3D-CRT, external beam APBI techniques represent a more cost-effective approach based on cost minimization with brachytherapy representing a cost-effective approach based on cost per QALY.