Characteristics of tobacco-related lung diseases in Fukuoka Prefecture, Japan: A prospective, multi-institutional, observational study.
Tobacco smoking causes a variety of smoking-related diseases, death, and economic damage. Despite targeted anti-smoking campaigns, tobacco-related deaths are expected to increase in Japan. We investigated the current state of non-cancerous lung diseases such as idiopathic interstitial pneumonias (IIPs), chronic obstructive pulmonary disease (COPD), and combined pulmonary fibrosis and emphysema (CPFE), which are known to be highly related to tobacco smoking. This prospective multi-institutional observational study involved 29 major hospitals within the Fukuoka Prefecture area (Fukuoka tobacco-related lung disease registry study group). Patients diagnosed with IIPs, including CPFE and COPD, registered from September 1, 2013 to April 30, 2016 were included. Clinical background information, laboratory and pulmonary function test results, findings of imaging tests, including chest radiography and chest computed tomography, and DNA isolated from peripheral blood were collected from each patient. Follow-up surveillance involved collection of data regarding the exacerbation of disease and death until 5 years of registration. In the present study, we report the baseline characteristics of the patients registered in this surveillance study. Overall, 1016 patients (524 with IIPs, including 145 CPFE and 492 with COPD) were enrolled. Among the patients with COPD, 96.8% were current or former smokers. Among the patients with IIPs, 69.9% were current or former smokers. This study revealed the current status of lung diseases potentially related to tobacco smoking in Fukuoka Prefecture. Both COPD and CPFE were highly related to tobacco smoking, whereas 30% of patients with IIPs had never smoked.


Chemoresistant lung cancer stem cells display high DNA repair capability to remove cisplatin-induced DNA damage.
The persistence of lung cancer stem cells (LCSCs) has been proposed to be the main factor responsible for the recurrence of lung cancer as they are highly resistant to conventional chemotherapy. However, the underlying mechanisms are still unclear. We examined the cellular response of a human LCSC line to treatment with cisplatin, a DNA-damaging anticancer drug that is used extensively in the clinic. We compared the response to cisplatin of LCSCs and differentiated LCSCs (dLCSCs) by determining the viability of these cells, and their ability to accumulate cisplatin and to implement genomic and transcription-coupled DNA repair. We also investigated the transcription profiles of genes related to drug transport and DNA repair. LCSCs were found to be more stem-like, and more resistant to cisplatin-induced cytotoxicity than dLCSCs, confirming their drug resistance properties. LCSCs accumulated less cisplatin intracellularly than dLCSCs and showed less DNA damage, potentially due to their ability to down-regulate AQP2 and CTR1. The results of the transcription-coupled repair of cisplatin-DNA cross-links indicated a higher level of repair of DNA damage in LCSCs than in dLCSCs. In addition, LCSCs showed a greater ability to repair cisplatin-DNA interstrand cross-links than dLCSCs; this involved the activation of various DNA repair pathways. Our results further clarify the mechanism of cisplatin resistance in LCSCs in terms of reduced cisplatin uptake and enhanced ability to implement DNA repairs. These findings may aid in the design of the next-generation of platinum-based anticancer drugs.


Correction: The work environment pilot: An experiment to determine the optimal office design for a technology company.
[This corrects the article DOI: 10.1371/journal.pone.0232943.].


The use of remifentanil in obstetrics.
Remifentanil has been proposed as the most suitable systemic opioid for use in obstetrics. Although the onset and offset are rapid, it cannot achieve maximum effect within the time period of a single uterine contraction. Nevertheless, it provides worthwhile analgesia mainly for the first stage of labor with consistently high maternal satisfaction. Maternal oxygen desaturation limits the dose and suitable monitoring during use is advised. As an adjunct to general anesthesia, it is successful in blunting responses to airway manipulation and providing hemodynamic stability in high-risk women. Neonatal effects when used in labor are minimal, but when combined with general anesthesia neonatal depression is unpredictable and more likely with an infusion dose greater than 0.1 microg/kg/min.


Chronic BDNF deficiency permanently modifies excitatory synapses in the piriform cortex.
Brain-derived neurotrophic factor (BDNF), aside from its classic neurotrophic role in development and survival of neurons, has been shown to be involved in modification and plasticity of central synapses. In mice with BDNF gene deletion (BDNF+/-), deficits in synaptic transmission are often observed but are reversed readily by administration of BDNF, suggesting its acute effect. In support, blockade of BDNF signaling in wild-type hippocampal slices by TrkB-IgG closely reproduces synaptic alterations observed in BDNF+/- mice. We demonstrate that in BDNF+/- mice, lateral olfactory tract (LOT) synapses exhibit decreased release probability of glutamate, suggested by increased paired-pulse facilitation (PPF) of field excitatory postsynaptic potentials (fEPSPs), as well as by slower blocking rate of N-methyl-D-aspartate (NMDA) receptor-mediated excitatory postsynaptic currents (EPSCs) by MK-801 in the pyramidal neurons of the piriform cortex. The changes in PPF were not mimicked in wild-type mice by acute blockade of BDNF signaling by TkrB-IgG. These data imply that BDNF deficit during development might lead to chronic changes of excitatory transmission in LOT synapses. Modification of the LOT synapses in BDNF+/- mice was associated with altered inhibitory drive onto the mitral cells from the granule and glomerular neurons, which in turn exhibited decreased renewal rate compared to that in wild-type mice. Taken together, these data suggest that BDNF deficiency can have both acute and more permanent effects on synaptic function, particularly when BDNF signaling is compromised during the early stages of brain development. In the latter case, altered synaptic properties in BDNF+/- mice could be secondary to other complex changes in the brain, e.g., cell survival/proliferation.


Developmental and regional differences in the vulnerability of rat hippocampal slices to lack of glucose.
Field excitatory postsynaptic potentials were recorded in stratum radiatum of CA1 and CA3 in submerged hippocampal slices from adult or newborn (postnatal days 5-25) Wistar rats. In adult slices, excitatory postsynaptic potentials were depressed by glucose removal ("aglycemia") more rapidly and to a greater extent in CA1 than in CA3 [respective mean times to 50% reduction in peak amplitude were 7.5 +/- 0.83 (standard error) min and 12.5 +/- 0.27 (standard error) min]. Subsequent recovery of excitatory postsynaptic potentials in normoglycemic medium was correspondingly quicker in CA3 than in CA1. Transmission failure at the synapses was indicated by the preservation of the afferent volley, and sharp depression of synaptic input-output plots. In the early postnatal period, CA1 excitatory postsynaptic potentials were much more resistant to aglycemia, substantially persisting for as long as 75 min, with full subsequent recovery in normoglycemic medium. The higher resistance of slices from newborn rats progressively disappeared over the first two postnatal weeks.


Non-infectious orbital vasculitides.
Non-infectious vasculitides comprise a large number of diseases. Many of these diseases can cause inflammation within the orbit and a clinical presentation, which mimics numerous other processes. Orbital disease can often be the initial presentation of a systemic process and early diagnosis can help prevent long-term, potentially fatal consequences. The evaluation and treatment of non-infectious orbital vasculitides are often complicated and require a thorough understanding of the disease and underlying systemic associations. The long-term prognosis visually and systemically must be weighed against the risks and benefits of the treatment regimen. A large variety of corticosteroid formulations currently exist and are the mainstay of initial treatment. Traditional steroid-sparing immunosuppressive agents are also an important arsenal against these vasculitides. Recently, a new class of drugs called biologics, which target the various mediators of the inflammation cascade, may potentially provide more effective and less toxic treatment. This review aims to synthesize the current literature on non-infectious orbital vasculitides.


Correlates of Forced Sex Among Young Men Who Have Sex With Men in Yangon and Monywa, Myanmar.
Forced sex at an early age is associated with a variety of negative factors including increased illness, high-risk sexual and substance-use behaviors, and mental and psychological stress. These sequelae may be compounded for men who have sex with men (MSM), especially young MSM and those with feminine gender identity and expression. This survey examined the prevalence and associations of forced sex among young MSM in two cities in Myanmar. In 2013-2014, surveys using respondent-driven sampling collected data on 200 young MSM in Yangon and 200 in Monywa. One quarter of young MSM in Yangon and 21 % in Monywa reported ever experiencing forced sex. In a multivariable model, having problems with family members and having any MSM friends with many partners had higher odds of experiencing forced sex. Having maternal acceptance of same-sex attraction (compared to acceptance by both parents) and becoming aware of their same-sex attraction at or above the age of 16 had lower odds of experiencing forced sex. Focused research is needed to understand the family and other social dynamics affecting vulnerability to forced sex, as well as specific sexual risks associated with forced sex among young MSM, including HIV acquisition and transmission risks.


Spontaneous resolution of severe aplastic anemia associated with viral hepatitis A in a 6-year-old child.
Recovery from acquired aplastic anemia associated with hepatitis is rare. This case of a 6-year-old boy with severe aplastic anemia is the first reported association of this disease with a hepatitis A infection. Antibody to hepatitis A (anti-HA) was not detected on admission, but was detected three weeks later. Infection with hepatitis B virus, cytomegalovirus (CMV), and Epstein-Barr virus (EBV) were excluded. The peak titer of anti-HA was higher than would be expected for passive transfer of antibody resulting from transfusions. The persistence of antibody for more than 20 months after the last transfusion was not consistent with passive antibody, which would be expected to disappear over that time. This child had indications for allogeneic marrow transplant and a sibling donor who was histocompatible. However, the transplant was postponed because the prognosis was considered to be poor in the presence of active hepatitis. There was a spontaneous remission without the necessity of the transplantation procedure.


Enhancing the net benefits of disseminating efficacious prevention programs: a note on target efficiency with illustrative examples.
We consider the implementation, in a non-research setting, of a new prevention program that has previously been evaluated in a randomized trial. When the target population for the implementation is heterogeneous, the overall net benefits of the implementation may differ substantially from those reported in the economic evaluation of the randomized trial, and from those that would be realized if the program were implemented within a selected subgroup of the target population. This note illustrates a simple and practical approach to targeting that can combine risk-factor results from the literature with the overall cost-benefit results from the program's randomized trial to maximize the expected net benefit of implementing the program in a heterogeneous population.


Root canal debridement: an online study guide.
The Editorial Board of the Journal of Endodontics has developed a literature-based study guide of topical areas related to endodontics. This study guide is intended to give the reader a focused review of the essential endodontic literature and does not cite all possible articles related to each topic. Although citing all articles would be comprehensive, it would defeat the idea of a study guide. This section will present root canal debridement including subdivisions on canal access, canal debridement, orifice enlargement and preflaring, crown-down technique, balanced force, nickel titanium and other shape memory alloys, rotary engine-driven techniques, endodontic instruments, irrigation, electronic apex locators, sonics/ultrasonics, smear layer, and intracanal medicaments.


Photoinduced electron transfer across lipid bilayers containing magnesium octaethylporphyrin.
Both photoinitiated (thermodynamically downhill) and photodriven (thermodynamically uphill) electron transfer reactions across lipid bilayers are sensitized by magnesium octaethyl porphyrin (MgOEP). It is shown that the reaction mechanism is via reduction of photoexcited MgOEP at the reducing (ascorbate) side of the bilayer and the charge carrier is likely the neutral protonated MgOEP anion. The MgOEP cation (or its neutral form) does not contribute to charge passage across the bilayer even though it is readily formed at the acceptor (ferricyanide or methyl viologen) side of the membrane. Photoelectric measurements on planar bilayers show that the time constant for reduction of excited MgOEP is about 10 microseconds with 10 mM ascorbate. The membrane transport of the mediator appears to be rate limiting when the reaction is photoinitiated and the interfacial reaction appears to be limiting when the reaction is photodriven. The quantum yield of the process is about 0.1 in the latter case and about 0.02 in the former. The former yield is increased to about 0.15 in the presence of a redox mediator, duroquinone. In these systems, the magnesium porphyrin is both sensitizer and trans membrane redox mediator.


Enhanced lithium storage performance of V2O5 with oxygen vacancy.
Orthorhombic phase V2O5 nanosheets with a high V4+ content (V-V2O5) have been fabricated via a facile sol-gel method and freeze-drying technology followed with a vacuum annealing process. XPS tests demonstrated that the content of V4+ in the as-prepared V-V2O5 sample was 7.4%, much higher than that (4.7%) in the V2O5 sample annealed in air. Compared with the V2O5 annealed in air, the V-V2O5 sample exhibited better cycling stability, higher lithium storage activity, and smaller electrochemical reaction resistance when evaluated as a cathode active material for lithium ion batteries. For example, the specific capacity of the V-V2O5 and V2O5 electrodes after 100 cycles at 200 mA g-1 are 224.7 and 199.2 mA h g-1, respectively; after 200 cycles at 3 A g-1 are 150 and 136.7 mA h g-1, respectively.


PSCA promotes prostate cancer proliferation and cell-cycle progression by up-regulating c-Myc.
The Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol (GPI)-anchored protein. Increasing evidence has indicated PSCA plays an important role in tumorigenesis. However, its function and the underlying molecular mechanisms in prostate cancer (PCa) are still not fully elucidated. In this study, we aimed to explore the effect of PSCA on cell cycle of PCa cells and its mechanism research. Immunohistochemistry, quantitative reverse transcription-PCR (qRT-PCR) and Western blotting were used to quantify PSCA expression pattern in PCa tissues and cell lines. The association of PSCA expression with the biochemical recurrence (BCR)-free survival and overall survival (OS) of PCa patients were analyzed using Kaplan-Meier method. The roles of PSCA in PCa were confirmed based on both in vitro and in vivo systems. Immunohistochemistry results showed that PSCA was upregulated in PCa tissue. PSCA overexpression were significantly associated with high Gleason score (GS) (P = 0.028), positive BCR (P = 0.002), and poor OS (P = 0.032) and high c-Myc expression (P = 0.019). PSCA promoted PCa cell cycle progression and tumor growth via increased c-Myc expression. Additional, PI3K/AKT signaling pathways was involved in PSCA-mediated c-Myc expression and cell proliferation. PSCA is a novel cell cycle regulator with a key role in mediating c-Myc-induced proliferation. PSCA may be a potential diagnostic marker and therapeutic target for patients with PCa.


Plasmid multimerization is dependent on RAD52 activity in Saccharomyces cerevisiae.
A mutant plasmid, pX, derived from the 1453 base pair small plasmid, YARp1 (or TRP1 RI circle), consists of 849 base pairs of DNA bearing the TRP1 gene and the ARS1 sequence of Saccharomyces cerevisiae and, unlike YARp1 and other commonly used yeast plasmids, highly multimerizes in a S. cerevisiae host. The multimerization of pX was dependent on RAD52, which is known to be necessary for homologous recombination in S. cerevisiae. Based upon this observation, a regulated system of multimerization of pX with GAL1 promoter-driven RAD52 has been developed. We conclude that the regulated multimerization of pX could provide a useful model system to study genetic recombination in the eukaryotic cell, in particular to investigate recombination intermediates and the effects of various trans-acting mutations on the multimerization and recombination of plasmids.


Long-Term Outcomes in Percutaneous Radiofrequency Ablation for Histologically Proven Colorectal Lung Metastasis.
To evaluate the long-term outcome of image-guided radiofrequency ablation (RFA) when treating histologically confirmed colorectal lung metastasis in terms of overall survival (OS), progression-free survival (PFS) and local tumour control (LTC). Retrospective single-centre study. Consecutive RFA treatments of histologically proven lung colorectal metastases between 01/01/2008 and 31/12/14. The primary outcome was patient survival (OS and PFS). Secondary outcomes were local tumour progression (LTP) and complications. Prognostic factors associated with OS/ PFS were determined by univariate and multivariate analyses. Sixty patients (39 males: 21 females; median age 69 years) and 125 colorectal lung metastases were treated. Eighty percent (n = 48) also underwent lung surgery for lung metastases. Mean metastasis size (cm) was 1.4 ± 0.6 (range 0.3-4.0). Median number of RFA sessions was 1 (1-4). During follow-up (median 45.5 months), 45 patients died (75%). The estimated OS and PFS survival rates at 1, 3, 5, 7, 9 years were 96.7%, 74.7%, 44.1%, 27.5%, 16.3% (median OS, 52 months) and 66.7%, 31.2%, 25.9%, 21.2% and 5.9% (median PFS, 19 months). The LTC rate was 90% with 6 patients developing LTP with 1-, 2-, 3- and 4-year LTP rates of 3.3%, 8.3%, 10.0% and 10.0%. Progression-free interval < 1 year (P = 0.002, HR = 0.375) and total number of pulmonary metastases (≥ 3) treated (P = 0.037, HR = 0.480) were independent negative prognostic factors. Thirty-day mortality rate was 0% with no intra-procedural deaths. The long-term OS and PFS following RFA for the treatment of histologically confirmed colorectal lung metastases demonstrate comparable oncological durability to surgery.


A Highly Sensitive Pan-Cancer Test for Microsatellite Instability.
Microsatellite instability (MSI) is an evolving biomarker for cancer detection and treatment. MSI was first used to identify patients with Lynch syndrome, a hereditary form of colorectal cancer (CRC), but has recently become indispensable in predicting patient response to immunotherapy. To address the need for pan-cancer MSI detection, a new multiplex assay was developed that uses novel long mononucleotide repeat (LMR) markers to improve sensitivity. A total of 469 tumor samples from 20 different cancer types, including 319 from patients with Lynch syndrome, were tested for MSI using the new LMR MSI Analysis System. Results were validated by using deficient mismatch repair (dMMR) status according to immunohistochemistry as the reference standard and compared versus the Promega pentaplex MSI panel. The sensitivity of the LMR panel for detection of dMMR status by immunohistochemistry was 99% for CRC and 96% for non-CRC. The overall percent agreement between the LMR and Promega pentaplex panels was 99% for CRC and 89% for non-CRC tumors. An increased number of unstable markers and the larger size shifts observed in dMMR tumors using the LMR panel increased confidence in MSI determinations. The LMR MSI Analysis System expands the spectrum of cancer types in which MSI can be accurately detected.


A genetically engineered vaccine against the alpha-toxin of Clostridium perfringens protects mice against experimental gas gangrene.
Fragments of the alpha-toxin of Clostridium perfringens have been produced using genetic manipulation techniques. Antibody which cross-reacted with the alpha-toxin was induced after immunization with fragments representing the N- (Cpa1-249) and C-terminal (Cpa247-370) domains of the toxin. Smaller fragments of the alpha-toxin did not induce cross-reacting antibody. Anti-Cpa1-249 serum neutralized phospholipase C activity but not haemolytic activity of the toxin. Anti-Cpa247-370 serum neutralized both the phospholipase C and haemolytic activities. Only immunization with Cpa247-370 induced protection against the lethal effects of the toxin. Immunization with Cpa247-370 also provided protection in a mouse model against at least 10 LD100 doses of C. perfringens type A. This result confirms the essential role of this toxin in the pathogenesis of gas gangrene.


Single versus multiple treatment sessions of argon laser panretinal photocoagulation for proliferative diabetic retinopathy.
A prospective, randomized study was performed to demonstrate whether there was a difference in the beneficial or adverse effects of argon laser photocoagulation for proliferative diabetic retinopathy depending on whether treatment was administered in a single session as compared with multiple sessions spaced over time. Results show no major differences between groups in the effect of treatment on visual acuity, visual field scores, or retinopathy risk factors. Exudative retinal detachment, choroidal detachment, and angle closure occurred more commonly in single session treatment group eyes, but these effects were transient, and no long-term difference between treatment groups was found.


Inorganic molecule (O2, NO) adsorption on nitrogen- and phosphorus-doped MoS2 monolayer using first principle calculations.
We performed a systematic study of the adsorption behaviors of O2 and NO gas molecules on pristine MoS2, N-doped, and P-doped MoS2 monolayers via first principle calculations. Our adsorption energy calculations and charge analysis showed that the interactions between the NO and O2 molecules and P-MoS2 system are stronger than that of pristine and N-MoS2. The spin of the absorbed molecule couples differently depending on the type of gas molecule adsorbed on the P- and N-substituted MoS2 monolayer. Meanwhile, the adsorption of O2 molecules leaves N- and P-MoS2 a magnetic semiconductor, whereas the adsorption of an NO molecule turns this system into a nonmagnetic semiconductor, which may provide some helpful information for designing new N- and P-substituted MoS2-based nanoelectronic devices. Therefore, P- and N-MoS2 can be used to distinguish O2 and NO gases using magnetic properties, and P-MoS2-based gas sensors are predicted to be more sensitive to detect NO molecules rather than pristine and N-MoS2 systems.


Logarithmic curves depicting initial level and rise of serum beta human chorionic gonadotropin and live delivery outcomes with in vitro fertilization: an analysis of 6021 pregnancies.
To correlate the live delivery rate with the initial level and rise of serum beta-hCG. Retrospective cohort analysis. Large private academic center for assisted reproductive technologies and infertility. Records of all patients from 1999 to 2005 undergoing IVF with detectable early serum beta-hCG after ET. None. Live delivery rate. Data from 6021 pregnancies were analyzed. Initial beta-hCG was predictive for delivery rate for all patients and for each age group. After controlling for the first beta-hCG, there were higher loss rates as age increased. Percent rise in second beta-hCG drawn 2 days later added predictive value. A decline in beta-hCG almost always resulted in a failure to deliver. There was a progressive increase in delivery rate as the percent rise in beta-hCG went from 0 to 100%; however, there was no further enhancement in delivery rates beyond the 100% rise point. While a better rise in beta-hCG was a good prognostic factor in all age groups, the differences in outcomes for the different age groups remained, even after controlling for first beta-hCG and percent rise. Initial level and rise in beta-hCG predicts live delivery rate, with oocyte age providing additional predictive value. The established logarithmic curves should provide convenient reference tools for tracking outcomes and counseling patients.


Exposure and Health Effects of Fungi on Humans.
Fungi are ubiquitous microorganisms that are present in outdoor and indoor environments. Previous research has found relationships between environmental fungal exposures and human health effects. We reviewed recent articles focused on fungal exposure and dampness as risk factors for respiratory disease development, symptoms, and hypersensitivity. In particular, we reviewed the evidence suggesting that early exposure to dampness or fungi is associated with the development of asthma and increased asthma morbidity. Although outdoor exposure to high concentrations of spores can cause health effects such as asthma attacks in association with thunderstorms, most people appear to be relatively unaffected unless they are sensitized to specific genera. Indoor exposure and dampness, however, appears to be associated with an increased risk of developing asthma in young children and asthma morbidity in individuals who have asthma. These are important issues because they provide a rationale for interventions that might be considered for homes and buildings in which there is increased fungal exposure. In addition to rhinitis and asthma, fungus exposure is associated with a number of other illnesses including allergic bronchopulmonary mycoses, allergic fungal sinusitis, and hypersensitivity pneumonitis. Additional research is necessary to establish causality and evaluate interventions for fungal- and dampness-related health effects.


Clinical characteristics of primary Fallopian tube carcinoma: A single-institution retrospective study of 57 cases.
To analyze the clinical profile and prognosis of primary Fallopian tube cancer (PFTC) in order to improve earlier diagnosis. In this retrospective study, 57 women with PFTC were assessed from 2006 to 2016. Pathology, clinical index, recurrence, and survival were analyzed. Mean age was 57.35 ± 9.01 years, and 73% (19/26) of the patients with early-stage PFTC (I/II) were aged less than 60 years. Of patients who presented with abnormal vaginal bleeding, 75% (9/12) were at an early stage and their condition was often misdiagnosed as endometrial carcinoma preoperatively. In patients with Stages I/II and Stages III/IV PFTC, 59.09% (13/22) and 96.43% (27/28), respectively, had adnexal masses on color Doppler ultrasonography. The 5-year overall survival (OS) and disease-free survival rates were 69.23% and 44.23%, respectively, and univariate analysis showed that tumor stage and residual tumor size significantly affected the two survival rates. Primary Fallopian tube cancer is more likely to be misdiagnosed in patients aged less than 60 years or those presenting with vaginal bleeding at the premenopausal stage. Magnetic resonance imaging, cervical smear, and endometrial brush may be helpful for early PFTC diagnosis. Satisfactory cytoreductive surgery is critical because tumor stage and residual tumor size are significantly associated with the OS rate.


Seasonal changes in luteinizing hormone-releasing hormone concentrations in microdissected brain regions of male rough-skinned newts (Taricha granulosa).
Luteinizing hormone-releasing hormone (LHRH) concentrations were measured in specific brain areas of male rough-skinned newts collected from a single population throughout the reproductive cycle. Plasma androgen and corticosterone (B) concentrations were also measured. Androgen concentrations were highest during the breeding season (winter) and lowest during the summer. In contrast, plasma B was lowest during the breeding season and highest in the summer. Concentrations of LHRH in the infundibulum (I) and rostral hypothalamus (RH) were positively correlated throughout the reproductive cycle; LHRH was always higher in the I than in the RH. Concentrations of LHRH in the ventral preoptic area (POA) fluctuated independently of concentrations of LHRH in the I and RH. However, LHRH concentrations decreased to undetectable levels in all three brain areas in March and April, which was before the end of the breeding season and before plasma androgen concentrations had decreased. An injection of LHRH into postbreeding males resulted in a significant increase in plasma androgen concentrations, indicating that the pituitary-gonad axis was still functional at the end of the breeding season. These results support the hypothesis that an abrupt decline in LHRH secretion is the initial endocrine event that signals the end of the breeding season in this amphibian.


Enhanced reductive dechlorination of trichloroethylene by sulfidated nanoscale zerovalent iron.
Direct injection of reactive nanoscale zerovalent iron particles (NZVI) is considered to be a promising approach for remediation of aquifers contaminated by chlorinated organic pollutants. In this study we show that the extent of sulfidation of NZVI enhances the rate of dechlorination of trichloroethylene (TCE) compared to that by unamended NZVI, and the enhancement depends on the Fe/S molar ratio. Experiments where TCE was reacted with NZVI sulfidated to different extents (Fe/S molar ratios 0.62-66) showed that the surface-area normalized first-order TCE degradation rate constant increased up to 40 folds compared to non-sulfidated NZVI. Fe/S ratios in the range of 12-25 provided the highest TCE dechlorination rates, and rates decreased at both higher and lower Fe/S. In contrast, sulfidated NZVI exposed to water in the absence of TCE showed significantly lower hydrogen evolution rate (2.75 μmol L(-1) h(-1)) compared to that by an unamended NZVI (6.92 μmol L(-1) h(-1)), indicating that sulfidation of NZVI suppressed corrosion reactions with water. Sulfide (HS(-)) ions reacted rapidly with NZVI and X-ray photoelectron spectroscopy analyses showed formation of a surface layer of FeS and FeS2. We propose that more electrons are preferentially conducted from sulfidated NZVI than from unamended NZVI to TCE, likely because of greater binding of TCE on the reactive sites of the iron sulfide outer layer. Resuspending sulfidated NZVI in sulfide-free or sulfide containing solutions altered the TCE degradation rate constants because of changes in the FeS layer thickness. Sulfidated NZVI maintained its high reactivity in the presence of multiple mono and divalent ions and with polyelectrolyte coatings. Thus, sulfide ions in groundwater can significantly alter NZVI reactivity.


Exemplifying guidelines for preparation of recombinant DNA products in phase I trials in cancer: preparation of a genetically engineered anti-CEA single chain Fv antibody.
Products of recombinant DNA technology have potential for the diagnosis or treatment of cancer. There is a need to investigate whether they function by the intended mechanism in small phase I clinical trials before their suitability for more extensive studies can be assessed. Quality and safety of these products should be assured prior to their use in humans in a way which is appropriate to the preliminary nature of the trials but not inhibitory to progress. The Cancer Research Campaign control recommendations for products derived from recombinant DNA technology (Begent RHJ and associates. Eur J Cancer 1993, 29A, 13, 1907-1910) provide guidelines for the production of new biotechnology products in academic research units within a relatively short time, while ensuring appropriate quality and safety. The practical application of the guidelines requires that solutions are found for the quality and safety issues during the production of recombinant products. We describe an approach to the relevant quality and safety issues during and after the production and purification of a genetically engineered anti-carcinoembryonic antigen (CEA) single chain Fv (scFv) antibody for a phase I trial of radioimmunoguided surgery with the intention of providing a model for other products.


A histochemical study on the innervation of the cerebral blood vessels in the carp.
Adrenergic and cholinergic innervation of the cerebral blood vessels were studied in the carp using fluorescence and cholinesterase histochemistry. Most of the major cerebral and pial arteries were densely innervated with both nerves. Moreover, both nerves, being probably of central origin, were observed frequently on the walls of parenchymal arterioles and capillaries in the sections of the inferior lobe but were only rarely found in the other brain sections.


Immunochemical characterization of the new platelet alloantigen system Bra/Brb.
We report the immunochemical characterization of the new platelet-specific alloantigens Bra and Brb. Bra antibodies were from mothers of children with neonatal alloimmune thrombocytopenia (NAIT), and anti-Brb was found in the serum of a polytransfused patient. By radioimmunoprecipitation, anti-Bra and anti-Brb precipitated two proteins with apparent relative molecular masses in sodium dodecyl sulphate-polyacrylamide gel electrophoresis of 155,000 and 130,000 under non-reduced conditions, and of 165,000 and 148,000 under reduced conditions. In two-dimensional polyacrylamide gel electrophoresis, the two bands moved with isoelectric points ranging from 5.2 to 5.4 and from 4.5 to 4.7, respectively. These features fulfil previously defined criteria for platelet membrane glycoproteins (GP) Ia and IIa. The results were supported by data obtained by an assay employing monoclonal antibody (mab)-specific immobilization of platelet antigens (MAIPA). By this technique, Bra and Brb antigens could be immobilized by mabs specific for the GP Ia/IIa complex (mab Gi 14) or a mab specific for the very late antigen-2 (mab 12 F1), but not by a mab specific for GP IIb/IIIa complex (mab Gi3). Furthermore, platelets from a thrombasthenic patient with complete absence of GP IIb/IIIa expressed the Brb antigen normally as shown in MAIPA; this antigen could be immunoprecipitated with anti-Brb and was identical to that of normal platelets. This confirms that the antigens of the Br system are not associated with the GP IIb/IIIa complex. By direct binding studies using mabs Gi3 and Gi14, we calculated that 51,500 +/- 3900 molecules of anti-GP IIb/IIIa and 6,470 +/- 500 molecules of anti-GP Ia/IIa were bound per platelet at saturation. Our results provide evidence for the first platelet-specific alloantigen system residing on the GP Ia. The difficulty in detecting anti-Bra and anti-Brb by direct binding assays may be related to the small number of GP Ia/IIa complexes on platelets.


Childhood obesity and its physical and psychological co-morbidities: a systematic review of Australian children and adolescents.
Australia is predicted to have the highest overweight/obesity rate in the world by 2022 outranking the USA and UK. The purpose of this systematic review was to evaluate the associations between childhood obesity and physical and psychological health co-morbidities. Therefore, a systematic literature search was conducted from six databases (2004-2014). Studies were included if they investigated obesity-related co-morbidities with participants residing in Australia aged 0-18 years. Forty-seven studies fulfilled selection criteria. Evidence suggests that overweight/obese Australian children and adolescents, compared to normal-weight peers, had more cardio-metabolic risk factors and higher risk factors of non-alcohol fatty liver disease and were experiencing more negative psychological outcomes (depression, low self-esteem and lower scores of health-related quality of life). Many other health consequences have either not been investigated in Australia, or as frequently as in other countries. Given Australia's current overweight/obesity prevalence and trajectory, Australia-based studies are needed to identify the suspected co-morbidities, understand the range of individual, social and environmental mechanisms driving obesity, and help identify policies, interventions and strategies that will change the future trajectory and 'disease burden' both in Australia and internationally. • Trend analyses have shown that obesity prevalence in Australia is increasing and will outrank UK and the USA by 2022. • Every third Australian child/adolescent between 5 and 19 years old is predicted to be classified as overweight or obese by 2025. • Childhood obesity is associated with multiple immediate physical and psychological health co-morbidities as well as co-morbidities in adulthood. These have often been identified and examined individually. What is New: • This paper presents a holistic picture of childhood obesity and the associated multiple co-morbidities in Australia. • The extensive health-related outcomes from childhood obesity and those requiring further research are identified. • The findings of this paper will influence the development of local/regional, state and national strategies to change Australia's future trajectory.


Divergent effects of phenothiazines on Leydig tumor cell steroidogenesis and adenylate cyclase activity.
The dose and temporal (1-24 h) effects of two phenothiazines, chlorpromazine and trifluoperazine, on steroidogenesis and adenylate cyclase activity of gonadotropin-responsive Leydig tumor cells (M5480A) in primary culture were examined. At low doses (e.g. 0.1-1 microM) these antipsychotic drugs were slightly inhibitory (trifluoperazine) or without effect (chlorpromazine), while at 25 microM each drug was weakly stimulatory to basal testosterone production. Trifluoperazine was, in general, inhibitory to HCG-stimulated testosterone production, but chlorpromazine exhibited paradoxical effects. At 5 and 10 microM this neuroleptic agent increased HCG-stimulated steroidogenesis, while at 25 microM testosterone production was inhibited. In a particulate fraction prepared from the tumor the activity of adenylate cyclase was stimulated 3.4-fold in the presence of 10 microM 5'-guanylimidodiphosphate and 5-fold in the presence of HCG plus the non-hydrolyzable GTP analogue. Between doses of 1-100 microM neither drug altered the basal activity of adenylate cyclase. Trifluoperazine at doses of 1-100 microM inhibited 5'-guanylimidodiphosphate-stimulated adenylate cyclase activity both with and without added gonadotropin. At doses of 1-10 microM chlorpromazine had no effect on adenylate cyclase activity, but it stimulated activity in the dose range of 20-100 microM. Interestingly, in the presence of 5'-guanylimidodiphosphate this drug did not alter the stimulated enzymic activity achieved with a maximal dose of HCG. Therefore, these phenothiazines exhibit quite divergent dose-dependent effects and their actions must occur at multiple loci. Also, it seems unlikely that the effects of these agents on steroidogenesis and adenylate cyclase activity can be reconciled solely in terms of calmodulin-mediated processes.


Non-thermal atmospheric pressure plasma increased mRNA expression of growth factors in human gingival fibroblasts.
The aim of this in vitro study was to investigate the effects of a non-thermal atmospheric pressure plasma jet (NTAPPJ) on the cellular activity of human gingival fibroblasts (HGF) for possible non-surgical application of it during gingival wound healing. HGF cells were exposed with NTAPPJ for 1, 2, and 4 min and were investigated for cellular attachment, cell viability, morphology of attached cells, proliferation rate, and messenger ribonucleic acid (mRNA) expression of various growth factors. Also, scavengers for chemicals produced by NTAPPJ were used to identify the chemical species responsible for the effects. There was no significant change in the number of HGF cells attached or their proliferation following NTAPPJ exposure. Also, high cell viability resulted from exposure of all of HGF cells to NTAPPJ for 1, 2, and 4 min. However, cells were more stretched while the mRNA expressions of transforming growth factor and vascular endothelial growth factor were significantly increased following NTAPPJ exposure. Additionally, the scavenger test showed that nitric oxide is likely to be the chemical responsible for an increase of cellular activity. The results demonstrated that the NTAPPJ increased mRNA expressions of growth factors in human gingival fibroblasts. Application of NTAPPJ would be useful in gingival wound healing in clinics though additional studies confirming the effects would be needed.


Treatment Goals in Schizophrenia: A Real-World Survey of Patients, Psychiatrists, and Caregivers in the United States, with an Analysis of Current Treatment (Long-Acting Injectable vs Oral Antipsychotics) and Goal Selection.
To understand similarities and differences in patient treatment goals as selected by US psychiatrists, adult patients with schizophrenia, and their caregivers in a real-world setting in the United States, including stratification by current medication and age. Data were drawn from the Adelphi Schizophrenia Disease Specific Programme™, a point-in-time survey of psychiatrists and their consulting adult patients with schizophrenia, conducted from June to October 2019. Psychiatrists completed record forms for their next 8 consecutive outpatients and (where possible) 2 inpatients matching inclusion criteria. Participating psychiatrists, patients, and caregivers completed treatment goal questionnaires as part of the survey. Psychiatrists (n = 124) provided data on 1204 patients with schizophrenia, including 1135 on drug treatment (207 inpatients [18%] and 928 outpatients [82%]); questionnaires were completed by 555 patients and 135 caregivers. Decrease in disease symptoms was identified as the most important patient treatment goal by patients (64%), psychiatrists (selecting for 63% of patients), and caregivers (selecting for 68% of patients). Patients, psychiatrists, and caregivers similarly rated the least important goals (less sexual problems and less weight gain). Patients indicated their current medication helped to reach their most important goals: decrease in disease symptoms (68%) and thinking more clearly (39%). Findings based on analysis of treatment goals by treatment and age were similar to overall trends. These findings, including identification of a primary consensus goal of decrease in disease symptoms, may help with discussions between patients with schizophrenia, psychiatrists, and caregivers to inform effective management strategies and encourage shared decision-making.


Systemic lupus erythematosus: A new autoimmune disorder in Kabuki syndrome.
We report a case of a 17-year-old Caucasian girl with syndromic features of clinically unrecognized Kabuki syndrome (KS), who developed systemic lupus erythematosus (SLE). Diagnosis of KS was established after whole exome sequencing (WES) and detection of de novo frameshift 1bp deletion in histone-lysine N-methyltransferase 2D gene (KMT2D). The pathogenic variant in exon 34 (c.8626delC: 55 reads C, 56 reads delC), has not been described previously and is predicted to truncate the protein (p.Gln2876Serfs*34) resulting in KMT2D loss of function. Notwithstanding that patients with KS have a substantial susceptibility to various autoimmune diseases, to the best of our knowledge this is the first report of an SLE and KS association. The exact relationship between the two conditions in our patient is difficult to determine with certainty, as a number of clinical features, including positive antiphospholipid antibodies, persistent hypogammaglobulinemia and the episode of convulsions may occur in both conditions, suggesting potential overlap of KS and SLE. The combination of a high susceptibility towards infections and an autoimmune disorder present a great challenge when trying to achieve the optimum therapy which will enable the patient to stay on the thin line of remission. This case report emphasizes the value of WES as a powerful tool for the diagnosis of rare disorders and/or unusual disease presentations of possible genetic cause.


Effects of indapamide, a thiazide-like diuretic, on structure of cerebral arterioles in hypertensive rats.
We examined the effects of indapamide, a thiazide-like diuretic, on cerebral arterioles in spontaneously hypertensive rats (SHR). The structure and mechanics of cerebral arterioles were examined in untreated Wistar Kyoto rats (WKY) and SHR that were untreated or treated for 3 months with a low (1 mg/kg per day) or a high (10 mg/kg per day) dose of indapamide. We measured pressure, diameter, and cross-sectional area of the vessel wall (CSA) in maximally-dilated (EDTA) cerebral arterioles. Treatment of SHR with the high dose of indapamide normalized cerebral arteriolar mean pressure (62+/-4 [mean+/-SEM] versus 59+/-3 mm Hg in WKY and 88+/-6 mm Hg in untreated SHR; P<0.05), pulse pressure (13+/-1 versus 10+/-1 mm Hg in WKY and 20+/-1 mm Hg in untreated SHR; P<0.05), and CSA (1080+/-91 versus 1100+/-48 microm2 in WKY and 1439+/-40 microm2 in untreated SHR; P<0.05). In contrast, treatment of SHR with the low dose of indapamide did not normalize arteriolar mean (72+/-3) and pulse pressure (20+/-1 mm Hg), but did normalize CSA (1091+/-52 microm2). Treatment with either dose of indapamide failed to increase external diameter in cerebral arterioles of SHR (89+/-4 and 92+/-4 microm, respectively, versus 103+/-6 microm in WKY and 87+/-4 microm in untreated SHR). Finally, treatment with indapamide attenuated the rightward shift of the stress-strain curve in SHR, suggesting that treatment with indapamide attenuated increases in distensibility of cerebral arterioles in SHR. These findings suggest that, whereas thiazide-like diuretics may not attenuate eutrophic inward remodeling of cerebral arterioles in SHR, they may attenuate hypertrophic inward remodeling via a mechanism unrelated to their pressor effects.


Dosage optimization of voriconazole in children with haematological malignancies based on population pharmacokinetics.
Voriconazole has a complex pharmacokinetic profile and exhibits different pharmacokinetic characteristics in adults and children. Nevertheless, few studies have been conducted on the population pharmacokinetics (PPK) of voriconazole in children with haematological malignancies. This study aims to build a PPK model and propose a suitable voriconazole treatment scheme for children with haematological malignancies. We retrospectively collected 146 samples from 67 children aged from 1.08 to 17.92 years. The PPK model was established using nonlinear mixed effects modelling (NONMEM). Dosage simulations were conducted on the basis of the final model's covariates. Data were fully characterized by a one-compartment model with first-order absorption and elimination. The weight (WT), CYP2C19 phenotype, and Albumin (ALB) were notable covariates for clearance (CL). The typical values of CL, the volume of distribution (V), and oral bioavailability (F) were 2.29 L/h, 76 L, and 0.902, respectively. The proposed doses for different CYP2C19 genotypes were presented in this ranking: EM (extensive metabolizer) > IM (intermediate metabolizer) > PM (poor metabolizer). Furthermore, higher dosages for light WT patients were recommended while lower ALB levels required lower doses. The probability of achieving the target (PTA) for the recommended doses ranged from 72.2% to 99%. We successfully built a voriconazole PPK model for children with hematologic malignancies. Dosing regimens were developed for different patients based on the final model, which could enhance the rational use of voriconazole in children with haematological malignancies.


3D Dielectric Layer Enabled Highly Sensitive Capacitive Pressure Sensors for Wearable Electronics.
Flexible capacitance sensors play a key role in wearable devices, soft robots, and the Internet of things (IoT). To realize these feasible applications, subtle pressure detection under various conditions is required, and it is often limited by low sensitivity. Herein, we demonstrate a capacitive touch sensor with excellent sensing capabilities enabled by a three-dimensional (3D) network dielectric layer, combining a natural viscoelastic property material of thermoplastic polyurethane (TPU) nanofibers wrapped with electrically conductive materials of Ag nanowires (AgNWs). Taking advantage of the large deformation and the increase of effective permittivity under the action of compression force, the device has the characteristics of high sensitivity, fast response time, and low detection limit. The enhanced sensing mechanism of the 3D structures and the conductive filler have been discussed in detail. These superior functions enable us to monitor a variety of subtle pressure changes (pulse, airflow, and Morse code). By detecting the pressure of fingers, a smart piano glove integrated with 10 circuits of finger joints is made, which realizes the real-time performance of the piano and provides the possibility for the application of intelligent wearable electronic products such as virtual reality and human-machine interface in the future.


3D printed pedicle screw guides reduce the rate of intraoperative screw revision in adolescent idiopathic scoliosis surgery.
Pedicle screw fixation has become common in the treatment of adolescent idiopathic scoliosis (AIS). Malpositioned pedicle screws have significant complications and identifying surgical techniques to optimize screw placement accuracy is imperative. To compare the rate of intraoperative revision, replacement, or removal of pedicle screws placed utilizing 3D printed guides compared with pedicle screws placed utilizing a freehand technique. Retrospective cohort study/single academic center. Thirty-two patients aged 10 to 18 with AIS. Revision rate of pedicle screws and operative time between groups. A retrospective study was performed on patients 10 to 18 years of age who underwent posterior spinal instrumented fusion for AIS from February 2021 to July 2022. The study received an IRB exemption. Patient demographics, intraoperative measures, and outcome variables were recorded. Intraoperatively, all patients underwent a 3-dimensional fluoroscopic "check scan," which included axial, sagittal, and coronal images, to assess for screw accuracy. A secondary outcome of operative time was compared between groups. The p-values <.05 were considered significant. A total of 32 patients were included in this study. There were 17 cases in the 3D guided and 15 cases in fluoroscopy-guided freehand cohort. There was a total of 254 pedicle screws using 3D guides and 402 screws using freehand technique. Between cohorts, there were no significant differences in a number of levels fused (p=.54) or length of surgery (p=.36). The total revision rate of 3D guided screw placement was 5.5% and that of the freehand technique was 8.5%. The freehand screw placement group had significantly higher revision rates per vertebral level compared with 3D guided (p=.0096). Notably, 3D printed guides had fewer screws that were removed/revised for being too anterior (7.1%) compared with freehand (23.5%). Surgical time was not significantly different between the 3D guided and freehand cohort (p=.35). 3D printed guides reduce intraoperative revision rate compared with freehand techniques. Total operative time is comparable to freehand technique.


Development and validation of an IL-6 immuno-receptor assay based on surface plasmon resonance.
Interleukin-6 (IL-6) is a pleiotropic cytokine which interacts with the specific IL-6 receptor at the surface of the T lymphocytes. A combined immuno- and receptor-assay has been developed and validated to characterize the biological activity of recombinant IL-6 (rIL-6). This assay is based on Surface Plasmon Resonance (SPR) technology. From each experiment two successive interactions were monitored: anti-IL-6 antibody/rIL-6 and rIL-6/IL-6 soluble Receptor (sIL-6R). Based on the first interaction an immuno-assay for rIL-6 was optimized and validated. Based on the second interaction a receptor-assay for rIL-6 biological activity was optimized and validated. The assays were validated by performing three different assays on three different days. The intra- and inter-day precisions (%CV) for the immuno-assay were respectively 0.9% and 1.7%. The overall recovery of the immuno-assay was 98.9 +/- 1.6. Intra- and inter-day precisions for the receptor-assay were respectively 1.1% and 1.4%. The overall recovery of the receptor-assay was 99.4% +/- 1.1. This immuno-receptor assay has allowed to compare the rIL-6 stability after storage at different temperatures. The results did not show significant difference between the three lower storage temperatures (-70, -20 and 5 degrees C). However, results obtained for the aliquot stored at 25 degrees C have shown a drastic denaturation of the rIL-6. These results illustrate the advantage of this method combining the evaluation of the immunological and biological integrity of the drug and high reproducibility and precision of the biosensor based technology.


Uridine treatment improves nerve regeneration and functional recovery in a rat model of sciatic nerve injury.
Peripheral nerve regeneration remains an issue, and novel therapeutic approaches are required for functional recovery. This study investigated the regenerative potential and long-term functional effects of Uridine treatment in a rat model of sciatic nerve injury. Male Sprague-Dawley rats were randomized to receive sham surgery plus saline (Sham group), right sciatic nerve transection and primary repair plus saline (Control group), right sciatic nerve transection, and primary repair plus 500 mg/kg Uridine (Uridine group). Saline or Uridine was injected intraperitoneally (i.p.) for seven days, and the rats were monitored for 12 weeks after surgery. We evaluated electrophysiological and functional recovery using electromyography (EMG) and sciatic functional index (SFI) at six and 12 weeks, respectively. At 12 weeks, rats were decapitated and their right sciatic nerves were examined in macroscopic and histomorphologic manners. Functional evaluation by SFI and sciatic nerve conduction velocity analyzed by EMG both decreased in the Control group but recovered in the Uridine group 12 weeks after surgery. Additionally, upon experiment completion, Uridine treatment was observed to enhance nerve adherence, separability scores, and the number of myelinated axons. These results reveal that short-term Uridine treatment provides morphological and electrophysiological benefits, which are represented by long-term functional improvement in a rat model of sciatic nerve injury. These findings validate and extend our knowledge on Uridine's regenerative effects in peripheral nerve injuries.


[Total proteins levels and embryonic development of eggs of sea urchins (Lytechinus variegatus) treated with YbCl3].
Total proteins levels and the embryonic development of sea urchin (Lytechinus variegatus) eggs treated with 25 micrograms/ml of YbCl3 in sea water for one hour were studied. After the treatment, eggs were let to develop for 24 hours when the total proteins levels were determined and morphological changes as well as the synchronism of the embryonic development have been checked.


Placental transfer and vascular effects of pharmaceutical drugs in the human placenta ex vivo: A review.
At least 80% of pregnant woman in Europe use at least one medication during their pregnancy. The majority of these drugs are prescribed off-label. A better understanding of drug transport and effects in the placenta can provide an improved pharmacological basis to rationalize drug and dose selection for prescription. Here we provide a narrative review of studies that used the ex vivo placenta perfusion model to study placental drug transport and vascular effects of pharmaceuticals. For studies on placental transfer, we found that the methodology used varied substantially between studies as well as the way in which data was reported. Across the different therapeutic groups, ex vivo measurements of transfer generally corresponded well to in vivo findings. Still, further standardization of the perfusion technique would facilitate a broader use of perfusion data, e.g. in the context of quantitative systems pharmacology models as has been explored in recent years. Only few studies investigated the effects of drugs on the vascular tone using the ex vivo dual-side perfusion model. The model was particularly applied to study vasodilatory effects of pharmaceuticals in the fetoplacental circulation. In conclusion, the ex vivo dually perfused human cotyledon provides a relevant system to gain insights in placental drug disposition and study effects on the fetoplacental vasculature.


Improved detection rate of structural abnormalities in the first trimester using an extended examination protocol.
To assess the potential of first-trimester sonography in the detection of fetal abnormalities using an extended protocol that is achievable with reasonable resources of time, personnel and ultrasound equipment. This was a prospective two-center 2-year study of 5472 consecutive unselected pregnant women examined at 12 to 13 + 6 gestational weeks. Women were examined using an extended morphogenetic ultrasound protocol that, in addition to the basic evaluation, involved a color Doppler cardiac sweep and identification of early contingent markers for major abnormalities. The prevalence of lethal and severe malformations was 1.39%. The first-trimester scan identified 40.6% of the cases detected overall and 76.3% of major structural defects. The first-trimester detection rate (DR) for major congenital heart disease (either isolated or associated with extracardiac abnormalities) was 90% and that for major central nervous system anomalies was 69.5%. In fetuses with increased nuchal translucency (NT), the first-trimester DR for major anomalies was 96%, and in fetuses with normal NT it was 66.7%. Most (67.1%) cases with major abnormalities presented with normal NT. A detailed first-trimester anomaly scan using an extended protocol is an efficient screening method to detect major fetal structural abnormalities in low-risk pregnancies. It is feasible at 12 to 13 + 6 weeks with ultrasound equipment and personnel already used for routine first-trimester screening. Rate of detection of severe malformations is greater in early- than in mid-pregnancy and on postnatal evaluation. Early heart investigation could be improved by an extended protocol involving use of color Doppler.


Direct parabrachial nuclear projections to the pharyngeal motoneurons in the rat: an anterograde and retrograde double-labeling study.
The parabrachial nucleus consists of several subnuclei which contains autonomic, gustatory, visceral sensory, nociceptive, and respiratory related neurons. We have investigated the direct projections from the rat parabrachial region, including the K olliker-Fuse nucleus, to the pharyngeal motoneurons with an anterograde and retrograde double-tracing technique. The cholera toxin subunit-B was injected into the lower pharynx or the esophagus after injection of biotinylated dextran amine into the ventrolateral parabrachial nuclear region, including the external medial, the external lateral, and the crescent area of the central lateral parabrachial nuclei and into the Kölliker-Fuse nucleus. The anterogradely dextran amine-labeled fibers from these nuclei projected to the semicompact, loose and external formations besides the compact formation of the nucleus ambiguus. Many anterogradely labeled fibers and terminals were found to contact retrogradely cholera toxin-labeled pharyngeal neuronal soma and dendrites in the semicompact formation of the nucleus ambiguus. The medial half of the parabrachial nucleus, including the medial and the medial part of the central lateral parabrachial nuclei, sent a few fibers to the reticular formation just dorsal to the esophageal motoneurons but no fibers to either the pharyngeal or to the esophageal motoneurons. These results suggested that the visceral sensory, gustatory, nociceptive or respiratory related neurons in the parabrachial nucleus project directly to the pharyngeal motoneurons, but there are no parabrachial projections to the esophageal motoneurons in the nucleus ambiguus.


The role of arginine residues in the function of D-glyceraldehyde-3-phosphate dehydrogenase.
Inactivation of apo-glyceraldehyde-3-phosphate dehydrogenase from rat skeletal muscle in the presence of butanedione is the result of modification of one arginyl residue per subunit of the tetrameric enzyme molecule. The loss of activity follows pseudo-first-order kinetics. NAD+ increases the apparent first-order rate constant of inactivation. The effect of NAD+ on the enzyme inactivation is cooperative (Hill coefficient = 2.3--3.2). Glyceraldehyde 3-phosphate protected the holoenzyme against inactivation, decreasing the rate constant of the reaction. At saturating concentrations of substrate the protection was complete. The Hill plot demonstrates that the effect is cooperative. This suggests that subunit interactions in the tetrameric holoenzyme molecule may affect the reactivity of the essential arginyl residues. In contrast, glyceraldehyde 3-phosphate had no effect on the rate of inactivation of the apoenzyme in the presence of butanedione. 100 mM inorganic phosphate protected both the apoenzyme and holoenzyme against inactivation. The involvement of the microenvironment of the arginyl residues in the functionally important conformational changes of the enzyme is discussed.


Vitamin B3 and sirtuin function.
Sirtuins are NAD(+)-dependent protein deacetylases that are involved in transcriptional regulation, metabolism, apoptosis, differentiation and ageing. These unique enzymes are inhibited by nicotinamide, which is a form of vitamin B3. Recent studies have uncovered the molecular basis for nicotinamide inhibition, and provided the framework to understand the physiological processes mediated by sirtuins and to develop strategies to modulate their cellular activity.


Inhibition of cathepsin L-induced degradation of epidermal growth factor receptors by c-Ha-ras gene products.
The inhibitory activities of c-Ha-ras gene products (p21s) toward several cysteine proteinases have been investigated. The activity of cathepsin L was inhibited by p21s most effectively while those of cathepsin B and papain were slightly inhibited by p21s. p21s did not show any inhibitory activity toward cathepsin H. In order to connect the protease-inhibitor activity of p21s with cell growth, the degradation of epidermal growth factor receptors (EGF-receptors) was investigated. EGF-receptors were preferentially cleaved by cathepsin L but not by cathepsin B or H. The cleavage of EGF-receptors by cathepsin L was inhibited by p21s dose-dependently. These results raise the possibility that p21s can suppress the degradation of growth-related proteins such as EGF-receptors and thereby affect cell growth.


Proteoglycan-lymphocyte association in the development of hypertrophic scars.
Parallel histological stains and immunohistological stains were made of hypertrophic scars and normal scars in order to identify the type of cells and associated proteoglycans present in perivascular cuffs in hypertropic scars. Tissue sections were treated with monoclonal antibodies which specifically recognize T-cells and unsulphated, 4-sulphated and 6-sulphated chondroitin proteoglycans. There was a striking association between the perivascular lymphocytic infiltration and chondroitin-4-sulphate, which may be an important contributory factor in the development of hypertrophic scars.


Targeting and tinkering with interaction networks.
Biological interaction networks have been in the scientific limelight for nearly a decade. Increasingly, the concept of network biology and its various applications are becoming more commonplace in the community. Recent years have seen networks move from pretty pictures with limited application to solid concepts that are increasingly used to understand the fundamentals of biology. They are no longer merely results of postgenome analysis projects, but are now the starting point of many of the most exciting new scientific developments. We discuss here recent progress in identifying and understanding interaction networks, new tools that use them in predictive ways in exciting areas of biology, and how they have become the focus of many efforts to study, design and tinker with biological systems, with applications in biomedicine, bioengineering, ecology and beyond.


An unusual foreign body in the urinary bladder mimicking a parasitic worm.
We report an unusual case of a foreign body removed from the urinary bladder of a 63-year-old male which mimicked a parasitic worm. The foreign body was identified as an artificial fishing worm by morphological comparison to a similar commercially produced product and by infrared spectrum analysis.


Pulmonary thromboembolism from a large hemangioma in a 4-week-old infant.
A female infant with an extensive congenital hemangioma of the left knee region was treated medically for consumption coagulopathy; the hemangioma began to shrink, the coagulopathy improved, and the infant was clinically well when she died suddenly at the age of 4 weeks. The cause of death was a saddle pulmonary thromboembolus which had originated in the hemangioma. This is the first documented case of fatal thromboembolism complicating a conservatively managed extensive neonatal hemangioma. Causes of neonatal thromboembolism are reviewed.


Hydranencephaly: Clinical Features and Survivorship in a Retrospective Cohort.
Hydranencephaly is a congenital central nervous system disorder characterized by the complete or near-complete absence of the cerebral cortex and basal ganglia. Because of its rarity, data on the clinical features and survivorship remain sparse. We aim to determine the clinical features and survivorship of a cohort of patients with hydranencephaly. We performed a retrospective cohort study of all patients diagnosed with hydranencephaly at our institution from 2008 to 2018. Data on demographics, clinical features, presence of comorbidities, surgical operations performed, and status on last follow-up were collected. Survival curves were generated using Kaplan-Meier analysis. Fifty patients were included in the cohort, who had a median age at diagnosis of 4 months and a female predilection. The most common clinical manifestations were macrocephaly (92%) and seizures or myoclonic movements. Infection was present in 36% of cases, endocrinopathies in 22%, dysmorphisms in 20%, and cardiac disease in 8%. Twenty patients underwent shunt insertion, with half developing a postoperative complication at a mean follow-up of 14.9 months. The median survival of the cohort was not reached at 7.5 years. Among the patients with follow-up, characteristics were similar between the surgical and nonsurgical groups, except for the greater incidence of infections in the nonsurgical group. The survival curves among the groups were significantly different, with a hazard ratio of 3.731 in the nonsurgical group. In this large single-center retrospective cohort of patients with hydranencephaly, novel findings are presented regarding the clinical manifestations and survivorship of this condition.


Synthesis of new pentacyclic chromophores through a highly regio- and diastereoselective cascade process.
A new family of pentacyclic compounds incorporating a central 1,2-dihydropyridine core is obtained through a pseudo three-component reaction. Four new bonds and two stereocenters with trans relationship are produced during the cascade process under palladium catalysis.


[Computerized axial tomography. Technical principles, clinical application, organizational aspects].
The technical principles, clinical application and organisational problems associated with computerised axial tomography are discussed. Numerous examples of pictures obtained on the brain and the whole body and in the normal subjects and various diseases are presented.


Canonical correlation between LFP network and spike network during working memory task in rat.
Working memory refers to a system to temporary holding and manipulation of information. Previous studies suggested that local field potentials (LFPs) and spikes as well as their coordination provide potential mechanism of working memory. Popular methods for LFP-spike coordination only focus on the two modality signals, isolating each channel from multi-channel data, ignoring the entirety of the networked brain. Therefore, we investigated the coordination between the LFP network and spike network to achieve a better understanding of working memory. Multi-channel LFPs and spikes were simultaneously recorded in rat prefrontal cortex via microelectrode array during a Y-maze working memory task. Functional connectivity in the LFP network and spike network was respectively estimated by the directed transfer function (DTF) and maximum likelihood estimation (MLE). Then the coordination between the two networks was quantified via canonical correlation analysis (CCA). The results show that the canonical correlation (CC) varied during the working memory task. The CC-curve peaked before the choice point, describing the coordination between LFP network and spike network enhanced greatly. The CC value in working memory showed a significant higher level than inter-trial interval. Our results indicate that the enhanced canonical correlation between the LFP network and spike network may provide a potential network integration mechanism for working memory.


Biochemical profiles of two thermostable and organic solvent-tolerant esterases derived from a compost metagenome.
Owing to the functional versatility and potential applications in industry, interest in lipolytic enzymes tolerant to organic solvents is increasing. In this study, functional screening of a compost soil metagenome resulted in identification of two lipolytic genes, est1 and est2, encoding 270 and 389 amino acids, respectively. The two genes were heterologously expressed and characterized. Est1 and Est2 are thermostable enzymes with optimal enzyme activities at 80 and 70 °C, respectively. A second-order rotatable design, which allows establishing the relationship between multiple variables with the obtained responses, was used to explore the combined effects of temperature and pH on esterase stability. The response curve indicated that Est1, and particularly Est2, retained high stability within a broad range of temperature and pH values. Furthermore, the effects of organic solvents on Est1 and Est2 activities and stabilities were assessed. Notably, Est2 activity was significantly enhanced (two- to tenfold) in the presence of ethanol, methanol, isopropanol, and 1-propanol over a concentration range between 6 and 30% (v/v). For the short-term stability (2 h of incubation), Est2 exhibited high tolerance against 60% (v/v) of ethanol, methanol, isopropanol, DMSO, and acetone, while Est1 activity resisted these solvents only at lower concentrations (below 30%, v/v). Est2 also displayed high stability towards some water-immiscible organic solvents, such as ethyl acetate, diethyl ether, and toluene. With respect to long-term stability, Est2 retained most of its activity after 26 days of incubation in the presence of 30% (v/v) ethanol, methanol, isopropanol, DMSO, or acetone. All of these features indicate that Est1 and Est2 possess application potential.


Understanding the effect of environmental history on bilayer tablet interfacial shear strength.
To understand the effect of post production environmental conditions on the interfacial strength of bilayer tablets. Bilayer tablets of microcrystalline cellulose/dicalcium phosphate were exposed to several humidity conditions higher/lower than production conditions and tested in shear to assess interfacial strength. Specific failure mechanisms were observed using x-ray microtomography and scanning electron microscopy. Transients in moisture diffusion of bilayer tablets with significant differential moisture absorption characteristics are responsible for the reduction of strength in both high and low moisture environments. X-ray microtomography and SEM experiments have shown that two different mechanisms of interfacial crack formation are present. For low moisture exposure, interfacial cracks close to the surface were produced, whereas at high moisture conditions, internal interfacial cracks were created. In both cases the fracture modes are consistent with the tensile stresses that develop locally due to the volumetric strains induced by moisture absorption. The insight gained from this work will be useful for material selection and packaging of bilayer tablet systems. While additional work is needed to develop specific guidelines for the optimization of bilayer strength, the results presented here provide a rational basis upon which such work can be conducted.


Mediation of the vasoactive properties of diadenosine tetraphosphate via various purinoceptors.
The vasoactive properties of P1,P4-diadenosine tetraphosphate (Ap4A) were studied by measuring the effects of perfusion pressure of a rat isolated perfused kidney. The vasoconstrictive response to Ap4A was mediated to a large extent to a P2X receptor which could be shown by inhibition with pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid tetrasodium. The remaining vasoconstriction of Ap4A could be blocked by a 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective A1 receptor antagonist In raised tone preparation Ap4A evoked vasodilation when P2 receptors were blocked by suramin. The dilation was not mediated by a P2Y receptor as the effect could not be blocked by suramin. Ap4A induces vasoconstriction via A1 and P2X receptors and vasodilatation via an unidentified receptor which is not a P2Y receptor. Ap4A may play an important role in kidney perfusion and, thus, in blood-pressure control.


Early Effects of Ticagrelor Versus Clopidogrel on Peripheral Endothelial Function After Non-ST-Elevation Acute Coronary Syndrome and Assessment of Its Relationship With Coronary Microvascular Function.
Peripheral endothelial dysfunction is an independent predictor of adverse long-term prognosis after acute coronary syndrome. Data are lacking on the effects of oral P2Y12-inhibitors on peripheral endothelial function in non-ST-elevation acute coronary syndrome (NSTEACS). Furthermore, the relation between peripheral endothelial function and invasive indexes of coronary microvascular function in NSTEACS is unclear. Between March 2018 and July 2020, hospitalized patients with NSTEACS were randomized (1:1) to ticagrelor or clopidogrel. Peripheral endothelial function was assessed with brachial artery flow-mediated vasodilation (FMD). Invasive indexes of coronary microvascular function were obtained using an intracoronary pressure-temperature sensor-tipped wire. In 70 patients included, mean age was 58.6 years, 78.6% (n = 55) were male and 20% (n = 14) had diabetes mellitus. Compared with clopidogrel, ticagrelor significantly improved FMD (14.2 ± 5.4% vs 8.9 ± 5.3%, p <0.001) after a median treatment time of 41.2 hours. The FMD was significantly correlated with the index of microcirculatory resistance (IMR) measured in the infarct-related artery (r = -0.38, p = 0.001), with a stronger correlation found in those who did not have percutaneous coronary intervention (r = -0.52, p = 0.03). Using receiver operating characteristic curve analysis, an FMD of 8.2% identified an IMR of >34 as the threshold, with 77.6% sensitivity and 52.4% specificity. In patients who did not have a percutaneous coronary intervention, an FMD of 11.49% identified an IMR of >34 with 84.6% sensitivity and 80% specificity. In conclusion, ticagrelor significantly improved peripheral endothelial function compared with clopidogrel in patients with NSTEACS. There was a significant correlation between brachial artery FMD and IMR of the infarct-related artery.


Comprehensive search for topological materials using symmetry indicators.
Over the past decade, topological materials-in which the topology of electron bands in the bulk material leads to robust, unconventional surface states and electromagnetism-have attracted much attention. Although several theoretically proposed topological materials have been experimentally confirmed, extensive experimental exploration of topological properties, as well as applications in realistic devices, has been restricted by the lack of topological materials in which interference from trivial Fermi surface states is minimized. Here we apply our method of symmetry indicators to all suitable nonmagnetic compounds in all 230 possible space groups. A database search reveals thousands of candidate topological materials, of which we highlight 241 topological insulators and 142 topological crystalline insulators that have either noticeable full bandgaps or a considerable direct gap together with small trivial Fermi pockets. Furthermore, we list 692 topological semimetals that have band crossing points located near the Fermi level. These candidate materials open up the possibility of using topological materials in next-generation electronic devices.


Liver metastases of oat cell carcinoma of lung detected on 99mTc-diphosphonate bone scan.
Colon carcinoma, cholangiocarcinoma, malignant melanoma and liver metastases detected on bone imaging have been reported with different bone seeking radiopharmaceuticals. This report is concerned with an interesting case of oat cell carcinoma with hepatic metatases visualized on 99mTc-diphosphonate bone imaging. This has not been previously reported.


Phytochemicals for the treatment of metabolic diseases: Evidence from clinical studies.
With the continuous improvement of people's living standard, the incidence of metabolic diseases is gradually increasing in recent years. There is growing interest in finding drugs to treat metabolic diseases from natural compounds due to their good efficacy and limited side effects. Over the past few decades, many phytochemicals derived from natural plants, such as berberine, curcumin, quercetin, resveratrol, rutin, and hesperidin, have been shown to have good pharmacological activity against metabolic diseases in preclinical studies. More importantly, clinical trials using these phytochemicals to treat metabolic diseases have been increasing. This review comprehensively summarizes the clinical progress of phytochemicals derived from natural plants in the treatment of several metabolic diseases, including type 2 diabetes mellitus (T2DM), obesity and non-alcoholic fatty liver disease (NAFLD). Accumulating clinical evidence shows that a total of 18 phytochemicals have good therapeutic effects on the three metabolic diseases by lowering blood glucose and lipid levels, reducing insulin resistance, enhancing insulin sensitivity, increasing energy expenditure, improving liver function, and relieving inflammation and oxidative stress. The information will help us better understand the medicinal value of these phytochemicals and promote their clinical application in the treatment of metabolic diseases.


Development of SNP and InDel markers by genome resequencing and transcriptome sequencing in radish (Raphanus sativus L.).
Single nucleotide polymorphisms (SNPs) and insertions/deletions (InDels) are the most abundant genetic variations and widely distribute across the genomes in plant. Development of SNP and InDel markers is a valuable tool for genetics and genomic research in radish (Raphanus sativus L.). In this study, a total of 366,679 single nucleotide polymorphisms (SNPs) and 97,973 insertion-deletion (InDel) markers were identified based on genome resequencing between 'YZH' and 'XHT'. In all, 53,343 SNPs and 4,257 InDels were detected in two cultivars by transcriptome sequencing. Among the InDel variations, 85 genomic and 15 transcriptomic InDels were newly developed and validated PCR. The 100 polymorphic InDels markers generated 207 alleles among 200 Chinese radish germplasm, with an average 2.07 of the number of alleles (Na) and with an average 0.33 of the polymorphism information content (PIC). Population structure and phylogenetic relationship revealed that the radish cultivars from northern China were clustered together and the southwest China cultivars were clustered together. RNA-Seq analysis revealed that 11,003 differentially expressed genes (DEGs) were identified between the two cultivars, of which 5,020 were upregulated and 5,983 were downregulated. In total, 145 flowering time-related DGEs were detected, most of which were involved in flowering time integrator, circadian clock/photoperiod autonomous, and vernalization pathways. In flowering time-related DGEs region, 150 transcriptomic SNPs and 9 InDels were obtained. The large amount of SNPs and InDels identified in this study will provide a valuable marker resource for radish genetic and genomic studies. The SNPs and InDels within flowering time-related DGEs provide fundamental insight into for dissecting molecular mechanism of bolting and flowering in radish.


In vivo detecting mouse persistent hyperplastic primary vitreous by Spectralis Optical Coherence Tomography.
To identify imaging characteristics of mouse persistent hyperplastic primary vitreous (PHPV) by Spectralis Optical Coherence Tomography (OCT), as well as to assess and compare the sensitivity and precision of OCT with color photography (CP) and Fundus Fluorescein Angiography (FFA) imaging in detecting mouse PHPV. Notch4-/- C57BL/6J mice (224 eyes) aged from 3 months to 7 months were examined in this study. CP, FFA and OCT imaging were utilized to examine vitreous cavity and retina of mouse eyes. Horizontal and radial OCT scan volume was centered on the optic nerve head. Hematoxylin and eosin (H&E) staining was performed to validate PHPV. For color photography and FFA imaging, retrolental irregular fibrovascular membrane-like tissues were found in 33 eyes with/without blood vessels in vitreous cavity. Among them, 31 eyes were visualized with lateral and oblique linear hyperreflective opacities in vitreous cavity using Spectralis OCT. Position of PHPV in posterior segment of eyes was also measured via OCT. Mouse PHPV was validated by H&E staining. Typical hyperreflective opacities in vitreous cavity were detected in PHPV mouse using Spectralis OCT. Spectralis OCT imaging can effectively detect mouse PHPV as color photography and FFA.


Phosphorylase b kinase deficiency in man: a review.
Phosphorylase b kinase is involved in the activation of glycogen phosphorylase and is thus involved in the breakdown of glycogen. The enzyme exists as several tissue specific isoenzymes of which the muscle enzyme (rabbit) has been most characterized. It is a multimeric protein composed of four subunits, alpha, beta, gamma and delta. The four subunits are coded on different chromosomes, the alpha, beta and gamma subunit genes being on the X, 16 and 17 chromosomes respectively. The delta subunit is a calmodulin and confers calcium sensitivity on phosphorylase b kinase. Tissue specificity of the enzyme is conferred, at least in some cases, by variation in the gamma subunit. Seven different clinical types of phosphorylase b kinase deficiency have been described. The most common type is X-linked and affects the liver only; other types affect liver, muscle and liver, muscle or heart and have an autosomal recessive mode of inheritance, while in some types the mode of inheritance is not clear. Diagnosis based on the study of erythrocytes or leukocytes can be misleading due to the tissue specific nature of the enzyme, and liver or muscle biopsies may be required.


The UV-absorption spectrum of human iridal melanosomes: a new perspective on the relative absorption of eumelanin and pheomelanin and its consequences.
Photoemission electron microscopy is used to measure the absorption coefficients, εc, of intact iridal stroma melanosomes isolated from dark brown and blue-green human irides for the spectral range λ=244-310 nm. These iridal stroma melanosomes were chosen because different colored irides produce organelles of varying eumelanin:pheomelanin ratios with similar size and morphology. Similar absorption spectra are found for the two types of melanosomes. The experimental spectra measured within are compared with both the extinction coefficient spectra obtained on soluble synthetic model systems and the monomeric precursors to each pigment.


The impact of photoreceptor noise on retinal gain controls.
Multiple retinal mechanisms preserve visual sensitivity as the properties of the light inputs change. Rapid gain controls match the effective signaling range of retinal neurons to the local image statistics. Such gain controls trade an increased sensitivity for some aspects of the inputs for a decreased sensitivity to others. Rapid, local gain control comes at another cost: noise in the signal controlling gain (e.g. from the photoreceptors) will cause gain itself to vary even when the statistics of the light input are constant. Recent advances in identifying retinal pathways and the sites and mechanisms of mean and contrast adaptation have begun to clarify the tradeoffs associated with different gain control locations and how these tradeoffs differ for rod and cone vision.


Computerized evaluation of mammographic image quality using phantom images.
A simple, quick and computerized method for quantitatively evaluating the image quality of mammography phantom images has been developed. Images of the American College of Radiology (ACR) mammographic accreditation phantoms were acquired under different X-ray techniques, scored and ranked subjectively by five expert readers, and digitized for quantitative analysis. The contrast and signal-to-noise (contrast-to-noise) ratios of the main nodule and microcalcification group were obtained accurately and reproducibly using an image processing protocol. The contrast values were successful at discriminating differences in image quality due to variations in scatter conditions (as a result of different kVp's, and the presence or absence of an acrylic scatterer and/or a moving Bucky grid). They were more precise, reproducible and sensitive than the ACR score. In particular, the contrast of the main nodule was highly correlated (r(s) = 0.988: p<0.001) with the ranking of image quality by our panel of expert readers.


ECG-gated cardiac scan and echocardiographic assessments of left ventricular hypertrophy: reversal by 6-month treatment with diltiazem.
Serial changes of left ventricular (LV) mass and LV function were evaluated in nine patients with essential hypertension and LV hypertrophy (LVH) after administration of diltiazem (180 mg/day). LV mass and LV function were determined at baseline and at 6 months of therapy by electrocardiogram-gated cardiac CT (ECG-gated CCT) scanning and two-dimensional-guided M-mode echocardiography. At baseline measurements, ECG-gated cardiac scanning clearly showed LVH in two patients in whom no LVH was observed by echocardiography. The systolic and diastolic blood pressures were reduced significantly after 6 months of drug therapy (189-156 mm Hg; p less than 0.01, 111-96 mm Hg; p less than 0.01, respectively). Sequential ECG-gated cardiac scanning revealed a marked reduction in thickness of the interventricular septum (IVS), LV anterior wall (AW), and LV posterior wall (PW) (15.0-12.1 mm; p less than 0.01, 12.5-9.7 mm; p less than 0.01, 10.7-8.3 mm; p less than 0.05, respectively). Simultaneous echocardiographic measurements revealed a reduction in LV mass in six of these patients and a significant reduction in thickness of the IVS (12.1-11.0 mm; p less than 0.05). ECG-gated cardiac scanning demonstrated significant reductions in the thickness of the LVAW, which are difficult to detect by echocardiography. Diltiazem had no effect on the ejection fraction (EF) measured by both methods. In conclusion, ECG-gated cardiac scanning allowed more accurate diagnosis and quantitation of LVH than conventional echocardiography, and LVH in patients with essential hypertension could be reversed by the administration of diltiazem.


Penicillin-derived inhibitors that simultaneously target both metallo- and serine-beta-lactamases.
The synthesis and beta-lactamase inhibitory activity of four 6-(mercaptomethyl)penicillinates and the four corresponding 6-(hydroxymethyl)penicillinates are described. These penicillins include both C6 stereoisomers as well as the sulfide and sulfone oxidation states of the penam thiazolidine sulfur. All compounds were evaluated as inhibitors of representative metallo- and serine-beta-lactamases enzymes. Selected (mercaptomethyl)penicillinates are shown to inactivate both metallo- and serine-beta-lactamases and to display synergism with piperacillin against beta-lactamase producing strains.


Efficacy and safety of anti-interleukin-5 therapy in patients with asthma: A pairwise and Bayesian network meta-analysis.
Anti-interleukin-5 therapy has been proposed as a novel and promising treatment option in asthma treatment. However, the optimum monoclonal antibodies for asthma treatment remain uncertain. We searched the PubMed, EMBASE and Cochrane databases from their inceptions to June 2018 for randomized controlled trials that reported pulmonary function, adverse events, Asthma Quality of Life Questionnaire (AQLQ) scores, and asthmatic exacerbations resulting from anti-interleukin-5 therapy in asthma patients. Extracted data were analyzed by pairwise and network meta-analysis. Twenty-one randomized studies were identified for this analysis. By pairwise meta-analysis using a placebo as the reference, patients treated with monoclonal antibodies were associated with significantly improved forced expiratory volume (FEV1) values (standard mean difference [SMD], 0.18; 95% confidence interval [CI], 0.12-0.23; P < 0.001), lower rates of adverse events (risk ratio [RR], 0.93; 95% CI, 0.90-0.97; P < 0.001) and significant improvements in the AQLQ scores (SMD, 0.20; 95% CI, 0.13-0.26; P < 0.001). There were no significant differences in exacerbations risks (RR, 0.68; 95% CI, 0.11-4.14; P = 0.097). According to network meta-analysis, adverse events-related benefits were seen only with reslizumab, while AQLQ scores benefits, and pulmonary function benefits were still seen with all three monoclonal antibodies. The assessment of rank probabilities indicated that reslizumab presented the greatest likelihood of having benefits for pulmonary function, reducing adverse events and improving AQLQ scores when compared with the placebo, and mepolizumab presented the best benefits for reducing asthmatic exacerbations. Anti-interleukin-5 therapy appears to be a safe and effective treatment for asthma patients with respect to pulmonary lung function, adverse events and AQLQ scores, and do not increase asthmatic exacerbations. Our network meta-analysis in patients with asthma suggests that reducing adverse events benefits due to reslizumab, and pulmonary lung function benefits as well as good AQLQ scores are seen with respect to the three antibodies. Network meta-analysis indicates the probability that the best anti-interlukin-5 therapy for asthma patients might be reslizumab, but further trials are required to determine the most effective asthma treatment drug.


Comprehensive analyses reveal the carcinogenic and immunological roles of ANLN in human cancers.
Anillin (ANLN) is an actin-binding protein that is essential for cell division and contributes to cell growth and migration. Although previous studies have shown that ANLN is related to carcinogenesis, no pan-cancer analyses of ANLN have been reported. Accordingly, in this study, we evaluated the carcinogenic roles of ANLN in various cancer types using online databases. We evaluated the potential carcinogenic roles of ANLN using TIMER2 and Gene Expression Omnibus databases with 33 types of cancers. We further investigated the associations of ANLN with patient prognosis, genetic alterations, phosphorylation levels, and immune infiltration in multiple cancers using GEPIA2, cBioPortal, UACLAN, and TIMER2 databases. Additionally, the potential functions of ANLN were explored using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Reverse transcription quantitative polymerase chain reaction and immunohistochemistry were used to determine ANLN mRNA and protein expression in colorectal cancer (CRC), gastric cancer (GC), and hepatocellular carcinoma (HCC) cell lines. ANLN was overexpressed in various tumor tissues compared with corresponding normal tissues, and significant correlations between ANLN expression and patient prognosis, genetic alterations, phosphorylation levels, and immune infiltration were noted. Moreover, enrichment analysis suggested that ANLN functionally affected endocytosis, regulation of actin cytoskeleton, and oxytocin signaling pathways. Importantly, ANLN mRNA and protein expression levels were upregulated in gastrointestinal cancers, including CRC, GC, and HCC. Our findings suggested that ANLN participated in tumorigenesis and cancer progression and may have applications as a promising biomarker of immune infiltration and prognosis in various cancers.


Influenza vaccination in elderly residents in nursing homes: immune response to trivalent and monovalent inactivated influenza virus vaccine in the season 1986-87.
Immune responses to trivalent inactivated whole virus and monovalent subunit influenza vaccines, used in the season 1986-87, were analyzed in elderly residents in nursing homes. Higher levels of induced antibody were found in the group receiving two doses of trivalent vaccine. This suggests that high risk aged patients should receive a booster dose of vaccine annually. The antibody response to administration of supplemental vaccination, using monovalent subunit preparation, did not reach the high level of antibodies found following trivalent influenza vaccine.


Time-frequency filtering of MEG signals with matching pursuit.
Time-frequency signal analysis based on various decomposition techniques is widely used in biomedical applications. Matching Pursuit is a new adaptive approach for time-frequency decomposition of such biomedical signals. Its advantage is that it creates a concise signal approximation with the help of a small set of Gabor atoms chosen iteratively from a large and redundant set. In this paper, the usage of Matching Pursuit for time-frequency filtering of biomagnetic signals is proposed. The technique was validated on artificial signals and its performance was tested for varying signal-to-noise ratios using both simulated and real MEG somatic evoked magnetic field data.


Web support for the more efficient discovery of kinase inhibitors.
Kinases have a crucial role in cell signaling and are important drug targets, given that aberrant kinase activity has been linked to most disease areas. Therefore, kinase inhibitors (KIs) have significant potential as new therapeutics. In recent years, an increasing amount of computational resources have been developed to design ideal scaffold and selective KIs more efficiently. Thus, in this review, we systematically examine the computational tools used in KI research, and discuss and compare the characteristics and limitations of these resources. Such a discussion will facilitate the design of new KIs and provide a learning platform for nonspecialists.


RPLC-RPLC-MS/MS for Proteoform Identification.
Top-down proteomics methods have a distinct advantage over bottom-up methods in that they analyze intact proteins rather than digested peptides which can result in loss of information regarding the intact protein. However, the analysis of intact proteins using top-down proteomics methods has been impeded by the low resolution of typical separation approaches applied in bottom-up proteomics studies. To increase the coverage of intact proteomes, orthogonal, two-dimensional separation techniques have been developed to improve the separation efficiency; in this chapter, we describe a two-dimensional HPLC separation technique that utilizes a high-pH mobile phase in the first dimension followed by a low-pH mobile phase in the second dimension. This two-dimensional pH-based HPLC approach demonstrates increased separation efficiency of intact proteins and increased proteome coverage when compared to one-dimensional HPLC in the analysis of larger and lower abundance proteoforms.


Abdominal magnetic resonance imaging in small rodents using a clinical 1.5 T MR scanner.
Because of superior soft-tissue contrast compared to other imaging techniques, non-invasive abdominal magnetic resonance imaging (MRI) is ideal for monitoring organ regeneration, tissue repair, cancer stage, and treatment effects in a wide variety of experimental animal models. Currently, sophisticated MR protocols, including technically demanding procedures for motion artefact compensation, achieve an MRI resolution limit of < 100 microm under ideal conditions. However, such a high spatial resolution is not required for most experimental rodent studies. This article describes both a detailed imaging protocol for MR data acquisition in a ubiquitously and commercially available 1.5 T MR unit and 3-dimensional volumetry of organs, tissue components, or tumors. Future developments in MR technology will allow in vivo investigation of physiological and pathological processes at the cellular and even the molecular levels. Experimental MRI is crucial for non-invasive monitoring of a broad range of biological processes and will further our general understanding of physiology and disease.