Deadly Puppy Infection Caused by an MDR Escherichia coli O39 bla CTX-M-15, bla CMY-2, bla DHA-1, and aac(6)-Ib-cr - Positive in a Breeding Kennel in Central Italy.
Antimicrobial consumption in veterinary medicine has led to the spread of multi drug-resistance in clinically important bacteria, with the companion animals and their environment involved as emerging reservoirs. While CTX-M-15 and CMY-2 acquired β-lactamases have been widely detected in the bacterial population of companion and breeding animals in European area, DHA-1 enzymes have been rarely reported in veterinary medicine. The aim of the study was to characterize the Escherichia coli associated with mortality of a litter of Bulldog puppies in a breeding kennel located in Pesaro area, Central Italy. The E. coli strains O39 serotype were resistant to 3rd/4th generation cephalosporins, chloramphenicol, aminoglycosides, trimethoprim-sulfamethoxazole, and ciprofloxacin, retaining susceptibility to carbapenems, colistin, fosfomycin, and levofloxacin (by Microscan Autoscan4, EUCAST clinical breakpoints). Pulse field gel electrophoreses (PFGE-XbaI) on five E. coli strains revealed the presence of a single profile. Whole genome sequencing (WGS) analysis revealed a complex resistome, harboring bla TEM-1b, bla CTX-M-15, bla OXA-1, aph(6)-Ib, aac(6')Ib-cr, aac(3)-Ila, aph(6)-Id, aadA1, qnrB1, sul2, catA1, catB3, tetA, and dfrA14 genes located on a 302597 bp IncHI2/HI2A plasmid. Moreover, bla DHA-1, qnrB4, mph(A), sul1, and dfrA17 determinants were carried on an 83,429 bp IncFII plasmid. A bla CMY-2 determinant was carried on a 90,249 bp IncI1 plasmid. Two IncX1 and IncX4 plasmids without antimicrobial resistance genes were also detected. The presence of lpfA, iss, astA, and gad virulence factors was highlighted. This is the first report in Italy on an invasive infection in eight 2-weeks old dogs caused by the same MDR E. coli O39 bla CTX-M-15, bla CMY-2, bla DHA-1, and aac(6')-Ib-cr positive strain. The above MDR E. coli clone caused the death of the entire litter, despite amoxicillin-clavulanate and enrofloxacin administration. The tank for storage of the water used to prepare the milk-based meal for the litter was the suspected reservoir.


Apoptosis by [Pt(O,O'-acac)(γ-acac)(DMS)] requires PKC-δ mediated p53 activation in malignant pleural mesothelioma.
Mesothelioma cancer cells have epithelioid or sarcomatoid morphology. The worst prognosis is associated with sarcomatoid phenotype and resistance to therapy is affected by cells heterogeneity. We recently showed that in ZL55 mesothelioma cell line of epithelioid origin [Pt(O,O'-acac)(γ-acac)(DMS)] (Ptac2S) has an antiproliferative effect in vitro and in vivo. Aim of this work was to extend the study on the effects of Ptac2S on ZL34 cell line, representative of sarcomatoid mesothelioma. ZL34 cells were used to assay the antitumor activity of Ptac2S in a mouse xenograft model in vivo. Then, both ZL34 and ZL55 cells were used in order to assess the involvement of p53 protein in (a) the processes underlying the sensitivity to chemotherapy and (b) the activation of various transduction proteins involved in apoptosis/survival processes. Ptac2S increases ZL34 cell death in vivo compared with cisplatin and, in vitro, Ptac2S was more efficacious than cisplatin in inducing apoptosis. In Ptac2S-treated ZL34 and ZL55 cells, p53 regulated gene products of apoptotic BAX and anti-apoptotic Bcl-2 proteins via transcriptional activation. Ptac2S activated PKC-δ and PKC-ε; their inhibition by PKC-siRNA decreased the apoptotic death of cells. PKC-δ was responsible for JNK1/2 activation that has a role in p53 activation. In addition, PKC-ε activation provoked phosphorylation of p38MAPK, concurring to apoptosis. In ZL34 cells, Ptac2S also activated PKC-α thus provoking ERK1/2 activation; inhibition of PKC-α, or ERK1/2, increased Ptac2S cytotoxicity. Results confirm that Ptac2S is a promising therapeutic agent for malignant mesothelioma, giving a substantial starting point for its further validation.


[Improvement of the activity of activated sludge by low intensity ultrasound].
Aerobic activated sludge from domestic wastewater treatment plant was used as an experimental material. Oxygen Uptake Rate(OUR) was detected as the index to indicate the changes of sludge activity induced by ultrasound(US) at 35kHz in 0 - 40 min with the US intensities of 0 - 1 .2 W/cm2. The best results were achieved at a US intensity of 0.3 W/cm2 and irradiation time of 10 min. Improper US intensity and irradiation time lead to a decrease of sludge activity. Therefore, the stimulating effects of US on the sludge activity could be enhanced at an optimized US intensity and irradiation time. In addition, changes of sludge activities (within 48 hours) after US irradiation at 0.3 W/cm2 in 10 min were examined. The activity of sludge took 8 hours after irradiation to reach peak level, and the activity was as double as that of the initial level after irradiation. In 24 hours after irradiation, the enhancement effects induced by ultrasound disappeared. Therefore, to improve the treatment efficiency of biological reactor, ultrasound with intensity of 0.3W/cm2 could be employed to irradiate part of the sludge in the biological treatment system for 10 minutes every 8 hours. It also presented the hypothetical explanation of the mechanism of biological activity enhancement stimulated by ultrasound.


Validation of a new formula for mean arterial pressure calculation: the new formula is superior to the standard formula.
Mean arterial pressure (MAP) has traditionally been derived from systolic and diastolic pressures, weighted 1/3 systolic and 2/3 diastolic. No correction is made for the increasing time dominance of systole with increasing heart rates. In a previous study, we developed a new and more accurate heart rate-corrected MAP formula from central aorta pressure determinations in a large number of patients: MAP = DP + [0.33 + (HR x 0.0012)] x [PP] where SP and DP are systolic and diastolic pressure and HR is heart rate. The current study validates the new MAP formula in the same patient at increasing paced heart rates. A central aorta catheter was used to obtain computer-determined systolic, diastolic, and MAP in 12 patients. Values were obtained at baseline and then at increasing right atrial paced heart rates. The new and standard MAP formula-derived values were compared with computer-determined values. The new formula showed a much closer correlation with the computer-derived values for MAP. Standard MAP calculations for MAP can easily be improved by inclusion of a heart rate factor.


Updated Nasal Surgery for Obstructive Sleep Apnea.
Numerous studies report that difficulty breathing through the nose is associated with reduced sleep quality, increased daytime dysfunction, and increased risk of snoring and obstructive sleep apnea (OSA). Additionally, chronic nasal obstruction often complicates and limits successful medical device therapy for OSA, particularly with continuous positive airway pressure (CPAP). When medical evaluation and management of the nose is inadequate, surgical therapy to lower nasal resistance has been shown to substantially improve sleep and breathing outcome measures. Although nasal surgery in isolation does not have a consistent effect on the apnea-hypopnea index in OSA patients, it does have robust evidence on improving snoring, subjective sleep quality, daytime sleepiness, sleep-related quality of life measures, and other important OSA outcome measures. Furthermore, in OSA patients with sinonasal disease who are struggling with CPAP and other medical devices, sinonasal surgery also has the potential to lower pressure requirements and improve adherence rates. Nasal surgery plays a key adjunctive role in the management of an OSA patient population.


7 alpha-17 alpha-Dimethyl-19-nortestosterone (mibolerone) induces conformational changes in progesterone receptors distinct from those induced by ORG 2058.
Using synthetic peptides with sequences derived from specific regions of human estrogen (ER) and progesterone (PR) receptors, we have developed site-directed monoclonal and polyclonal antibodies to specific domains of these receptors. These antibodies interact specifically with the native (nondenatured) receptors and detect changes in the conformation of these proteins. Monoclonal antibody PR-AT 4.14 bound more tightly to PR-ORG 2058 complexes than to PR-7 alpha,17 alpha-dimethyl-19-nor-testosterone (7 alpha,17 alpha, DMNT; mibolerone) complexes, suggesting possible ligand-induced conformational changes in PR. In the absence of the antibody, PR-[3H]ORG 2058 complexes sedimented as 4S-5S entity on sucrose density gradients (SDG) containing 0.4 M KCl. In the presence of the antibody, PR-[3H]ORG 2058 complexes sedimented as 7-8S complexes. In contrast, at the same concentrations of antibody, PR-[3H]7 alpha,17 alpha, DMNT complexes sedimented at 4S-5S region in the absence of the antibody and as two populations in the presence of the antibody, suggesting that the antibody did not recognize all of the PR-7 alpha,17 alpha, DMNT complexes. To exclude the possibility that the inability of the antibody to recognize receptor-[3H]7 alpha,17 alpha, DMNT complexes was due to its binding to androgen receptors, unlabeled 5 alpha-dihydrotestosterone (5 alpha-DHT) (50 nM) was added to the incubation to inhibit 7 alpha,17 alpha, DMNT binding to androgen receptors. While PR-[3H]ORG 2058 complexes were immunoprecipitated in the presence of the antibody, PR-[3H]7 alpha,17 alpha, DMNT complexes were only partially immunoprecipitated, further confirming the results obtained with SDG.(ABSTRACT TRUNCATED AT 250 WORDS)


Zebrafish seizure model identifies p,p -DDE as the dominant contaminant of fetal California sea lions that accounts for synergistic activity with domoic acid.
Fetal poisoning of California sea lions (CSLs; Zalophus californianus) has been associated with exposure to the algal toxin domoic acid. These same sea lions accumulate a mixture of persistent environmental contaminants including pesticides and industrial products such as polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs). Developmental exposure to the pesticide dichlorodiphenyltrichloroethane (DDT) and its stable metabolite 1,1-bis-(4-chlorophenyl)-2,2-dichloroethene (p,p -DDE) has been shown to enhance domoic acid-induced seizures in zebrafish; however, the contribution of other co-occurring contaminants is unknown. We formulated a mixture of contaminants to include PCBs, PBDEs, hexachlorocyclohexane (HCH), and chlordane at levels matching those reported for fetal CSL blubber to determine the impact of co-occurring persistent contaminants with p,p -DDE on chemically induced seizures in zebrafish as a model for the CSLs. Embryos were exposed (6-30 hr postfertilization) to p,p -DDE in the presence or absence of a defined contaminant mixture prior to neurodevelopment via either bath exposure or embryo yolk sac microinjection. After brain maturation (7 days postfertilization), fish were exposed to a chemical convulsant, either pentylenetetrazole or domoic acid; resulting seizure behavior was then monitored and analyzed for changes, using cameras and behavioral tracking software. Induced seizure behavior did not differ significantly between subjects with embryonic exposure to a contaminant mixture and those exposed to p,p -DDE only. These studies demonstrate that p,p -DDE--in the absence of PCBs, HCH, chlordane, and PBDEs that co-occur in fetal sea lions--accounts for the synergistic activity that leads to greater sensitivity to domoic acid seizures.


An investigation of content and media images in gay men's magazines.
This study provides an analysis of gay men's magazines, examining both the content and advertisements. Four magazine titles were selected, including The Advocate, Genre, Instinct, and Out, each targeting gay men as its target audience. These magazines were coded for both article content and advertisement content. In the advertisement analysis, both the type of advertisement and characteristics of the men depicted within the advertisement when present. The results mirror previous research findings relating to the portrayal of women, including the objectification of specific body parts and the high community standards set by the images depicted. These findings were reinforced by both the advertisements and content analyzed to include a high degree of importance being placed on having the right body type. Implications for further research are discussed.


Assessment of Bracket Surface Morphology and Dimensional Change.
The objective of this study was to compare the surface morphology and dimensional stability of the bracket slot at the onset of treatment and after 12 months of intraoral exposure. The study also compared the amount of calcium at the bracket base which indicates enamel loss among the three orthodontic brackets following debonding after 12 months of intraoral exposure. The sample consisted of 60 (0.022" MBT) canine brackets. They were divided into three groups: self-ligating, ceramic bracket with metal slot, and stainless steel (SS) brackets. The slot dimensions, micromorphologic characteristics of as-received and retrieved brackets were measured with a stereomicroscope and scanning electron microscope (SEM), respectively. The amount of calcium at the bracket base which indicates enamel damage was quantified using energy-dispersive X-ray spectrometry (EDX). The results showed statistically significant alterations (P < 0.05) in the right vertical dimension, internal tie wing width (cervical), right and left depth of the slot (Kruskal-Wallis test). Multiple comparison using Mann-Whitney test showed that ceramic brackets underwent (P < 0.05) minimal alterations in the right vertical dimension, internal tie wing width (cervical), right and left depth of the slot (0.01 mm, -0.003 mm, 0.006 mm, -0.002 mm, respectively) when compared with the changes seen in SS and self-ligating brackets. SEM analysis revealed an increase in the surface roughness of ceramic with metal slot brackets and self-ligating bracket showed the least irregularity. The presence of calcium was noted on all evaluated brackets under EDX, but ceramic with metal slot brackets showed a significantly greater amount of enamel loss (P = 0.001). Ceramic brackets were found to be dimensionally stable when compared to SS and self-ligating. Self-ligating bracket showed minimal surface irregularity. Ceramic with metal slot brackets showed a greater amount of enamel loss following debonding.


Functional recovery after dantrolene-supplementation of cold stored hearts using an ex vivo isolated working rat heart model.
The ryanodine receptor antagonist dantrolene inhibits calcium release from the sarcoplasmic reticulum and reduces cardiac ischaemia-reperfusion injury (IRI) in global warm ischaemia models however the cardioprotective potential of dantrolene under hypothermic conditions is unknown. This study addresses whether the addition of dantrolene during cardioplegia and hypothermic storage of the donor heart can improve functional recovery and reduce IRI. Using an ex vivo isolated working heart model, Wistar rat (3 month and 12 month) hearts were perfused to acquire baseline haemodynamic measurements of aortic flow, coronary flow, cardiac output, pulse pressure and heart rate. Hearts were arrested and stored in Celsior preservation solution supplemented with 0.2-40 μM dantrolene for 6 hours at 4°C, then reperfused (15 min Langendorff, 30 min working mode). In 3-month hearts, supplementation with 1 μM dantrolene significantly improved aortic flow and cardiac output compared to unsupplemented controls however lactate dehydrogenase (LDH) release and contraction bands were comparable. In contrast, 40 μM dantrolene-supplementation yielded poor cardiac recovery, increased post-reperfusion LDH but reduced contraction bands. All 3-month hearts stored in dantrolene displayed significantly reduced cleaved-caspase 3 intensities compared to controls. Analysis of cardioprotective signalling pathways showed no changes in AMPKα however dantrolene increased STAT3 and ERK1/2 signaling in a manner unrelated to functional recovery and AKT activity was reduced in 1 μM dantrolene-stored hearts. In contrast to 3-month hearts, no significant improvements were observed in the functional recovery of 12-month hearts following prolonged storage in 1 μM dantrolene. Dantrolene supplementation at 1 μM during hypothermic heart preservation improved functional recovery of young, but not older (12 month) hearts. Although the molecular mechanisms responsible for dantrolene-mediated cardioprotection are unclear, our studies show no correlation between improved functional recovery and SAFE and RISK pathway activation.


Transcriptome-microRNA analysis of Sarcoptes scabiei and host immune response.
Scabies is a parasitic disease, caused by the mite Sarcoptes scabiei, and is considered one of the top 50 epidemic diseases and one the most common human skin disease, worldwide. Allergic dermatitis, including an intense itch, is a common symptom, however diagnosis is difficult and there is currently no effective vaccine. The goal of this study was to examine the immune interaction mechanism of both S. scabiei and infected hosts. mRNA-seq and microRNA-seq were conducted on the S. scabiei mite and on infected and uninfected hosts. We focused on differential expression of unigenes and microRNAs, as well as the real targets of unigenes in enriched immune signaling pathways. S. scabiei enhanced host immune function and decreased metabolism after infection, while the immune response of the host inhibited S. scabiei proliferation and metabolism signaling pathways. Differentially expressed unigenes of S. scabiei were enriched in the JAK-STAT signaling pathway and the Toll-like receptor signaling pathway. The differential expression analysis indicated that microRNAs of S. scabiei and hosts have major roles in regulating immune interactions between parasites and hosts.


Ulk1-mediated autophagy plays an essential role in mitochondrial remodeling and functional regeneration of skeletal muscle.
Autophagy is a conserved cellular process for degrading aggregate proteins and dysfunctional organelle. It is still debatable if autophagy and mitophagy (a specific process of autophagy of mitochondria) play important roles in myogenic differentiation and functional regeneration of skeletal muscle. We tested the hypothesis that autophagy is critical for functional regeneration of skeletal muscle. We first observed time-dependent increases (3- to 6-fold) of autophagy-related proteins (Atgs), including Ulk1, Beclin1, and LC3, along with reduced p62 expression during C2C12 differentiation, suggesting increased autophagy capacity and flux during myogenic differentiation. We then used cardiotoxin (Ctx) or ischemia-reperfusion (I/R) to induce muscle injury and regeneration and observed increases in Atgs between days 2 and 7 in adult skeletal muscle followed by increased autophagy flux after day 7 Since Ulk1 has been shown to be essential for mitophagy, we asked if Ulk1 is critical for functional regeneration in skeletal muscle. We subjected skeletal muscle-specific Ulk1 knockout mice (MKO) to Ctx or I/R. MKO mice had significantly impaired recovery of muscle strength and mitochondrial protein content post-Ctx or I/R. Imaging analysis showed that MKO mice have significantly attenuated recovery of mitochondrial network at 7 and 14 days post-Ctx. These findings suggest that increased autophagy protein and flux occur during muscle regeneration and Ulk1-mediated mitophagy is critical for recovery for the mitochondrial network and hence functional regeneration.


Thermally adaptive tradeoffs in closely related marine bacterial strains.
Time series studies have shown that some bacterial taxa occur only at specific times of the year while others are ubiquitous in spite of seasonal shifts in environmental variables. Here, we ask if these ubiquitous clades are generalists that grow over a wide range of environmental conditions, or clusters of strain-level environmental specialists. To answer this question, vibrio strains isolated at a coastal time series were phylogenetically and physiologically characterized revealing three dominant strategies within the vibrio: mesophiles, psychrophiles and apparently generalist broad thermal range clades. Thermal performance curves from laboratory growth rate experiments help explain field observations of relative abundances: the mesophilic clade grows optimally at temperatures 16°C higher than the psychrophilic clade. Strains in the broad thermal range clade all have similar optimal growth temperatures but also exhibit temperature-related tradeoffs with faster growth rates for warm temperature strains and broader growth ranges for strains from cool temperatures. Moreover, the mechanisms of thermal adaptation apparently differ based on evolutionary time scales: shifts in the temperature of maximal growth occur between deeply branching clades but thermal performance curve shape changes on shorter time scales. Thus, apparently ubiquitous clades are likely not generalists, but contain subclusters with distinct environmental preferences.


Axoplasmic transport with velocities induced by pargyline.
The axoplasmic transport of proteins in spinal motor neurons is altered by pargyline, a drug that causes increased release of monoamines. Two new peaks of transported protein were detected in the sciatic nerves of rats treated with pargyline (75 mg/kg/day ip for three days). These peaks moved with velocities of 595 mm/day (peak I) and 1,230 mm/day (peak II). The bulk of labeled protein was still transported at the control rate of 362 mm/day. Electrophoresis of transported polypeptides labeled with [35S] methionine showed that peak I material was qualitatively similar to material transported at the normal rate in controls, but peak Ii material contained fewer labeled polypeptides. Both peak I and peak II differed from controls in the relative intensity of labeling of various polypeptides. Fast axoplasmic transport in sensory neurons was unaffected by pargyline. Intraspinal injection of pargyline (50 microgram/day for three days) caused changes in axoplasmic transport similar to those induced by intraperitoneal pargyline. These results show that transport of certain proteins along a peripheral nerve can be accelerated by a mechanism initiated in the region of the nerve cell bodies.


Bispecific Antibody Detection Using Antigen-Conjugated Synthetic Nucleic Acid Strands.
We report here the development of two different sensing strategies based on the use of antigen-conjugated nucleic acid strands for the detection of a bispecific antibody against the tumor-related proteins Mucin1 and epidermal growth factor receptor. Both approaches work well in serum samples (nanomolar sensitivity), show high specificity against the two monospecific antibodies, and are rapid. The results presented here demonstrate the versatility of DNA-based platforms for the detection of bispecific antibodies and could represent a versatile alternative to other more reagent-intensive and time-consuming analytical approaches.


[The prevalence of chronic disease in a group of elderly Brazilian people and their nutritional status].
Evaluating the prevalence of chronic disease in a group of elderly people living in the city of João Pessoa, PB, Brazil and their nutritional status. 117 subjects aged 60 to 89 attending local Reference and Citizenship Centres were evaluated. The research instrument used was a questionnaire addressing socio-demographic, socioeconomic and anthropometric variables and health-related behaviour. The data so collected was organised using SPSS statistical software and presented via descriptive statistics (mean and standard deviation, and absolute and percentage frequencies). 4.3% and 9.4% of the subjects admitted using tobacco and alcohol, respectively. 56.4% did not engage in any physical activity. As many as 78.6% used medications and 82.1% admitted to suffering from some non-transmissible chronic disease, the most frequent being hypertension (56.4%), dyslipidaemia (33.3%) and diabetes mellitus (20.5%). According to body mass index (BMI) classification, 46.2% were overweight and 40.2% presented degree I obesity. Regarding the waist-to-hip ratio (WHR), abdominal obesity was diagnosed in 97.4% of the elderly in the study. The prevalence of chronic disease, especially hypertension, was high in the studied population. Most institutionalised elderly were classified as suffering from abdominal obesity, representing an extremely high risk of developing cardiovascular disease.


Proton storage in the periphery of zirconium(IV) porphyrinogen.
The reaction of zirconium(IV) porphyrinogen with water yields a dinuclear complex in which one mu-oxo ligand bridges two Zr(IV) centres, and two protons are bound to the alpha carbons of two porphyrinogen pyrroles. The reaction establishes the utility of the porphyrinogen macrocycle as a storage site for protons as well as electrons.


Development of a novel europium complex-based luminescent probe for time-gated luminescence imaging of hypochlorous acid in living samples.
Luminescent lanthanide complexes are key reagents used in the time-gated luminescence bioassay technique, but functional lanthanide complexes that can act as luminescent probes for specifically responding to analytes are very limited. In this work, we designed and synthesized a novel Eu3+ complex-based luminescence probe for hypochlorous acid (HOCl), NPPTTA-Eu3+, by using terpyridine polyacid-Eu3+, dinitrophenyl, and hydrazine as luminophore, quencher and HOCl-recognizer moieties, respectively. In the absence of HOCl, the probe is non-luminescent due to the strong luminescence quenching of the dinitrophenyl group in the complex. However, upon reaction with HOCl, the dinitrophenyl moiety is rapidly cleaved from the probe, which affords a strongly luminescent Eu3+ complex CPTTA-Eu3+, accompanied by a ∼900-fold luminescence enhancement with a long luminescence lifetime of 1.41 ms. This unique luminescence response of NPPTTA-Eu3+ to HOCl allowed NPPTTA-Eu3+ to be conveniently used as a probe for highly selective and sensitive detection of HOCl under the time-gated luminescence mode. In addition, by loading NPPTTA-Eu3+ into RAW 264.7 macrophage cells and Daphnia magna, the generation of endogenous HOCl in RAW 264.7 cells and the uptake of exogenous HOCl by Daphnia magna were successfully imaged on a true-color time-gated luminescence microscope. The results demonstrated the practical applicability of NPPTTA-Eu3+ as an efficient probe for time-gated luminescence imaging of HOCl in living cells and organisms.


Efficacy of Celecoxib for Early Postoperative Pain Management in Hip Arthroscopy: A Prospective Randomized Placebo-Controlled Study.
To determine whether 400 mg of celecoxib administered 1 hour before hip arthroscopy surgery would reduce pain, provide reduction in overall narcotic consumption, and lead to more rapid discharge from recovery rooms. Ninety-eight patients were randomized to either the celecoxib group (n = 50) or the placebo group (n = 48). An a priori power analysis was done set to detect a difference of 0.50 on the visual analog scale (VAS), based on the senior author's preference. The number of patients planned for recruitment was rounded up to 100 to allow for flexibility in the study. Inclusion criteria were any patient at least 18 years old who underwent hip arthroscopy surgery performed by the senior author. All patients had less than Tönnis grade 2 arthritis. Exclusion criteria were allergy to sulfa-based drugs, prior adverse reaction to celecoxib, or patients who were on chronic narcotics for whom alternative pain management regimens were arranged before surgery. Randomization was performed on a 1:1 basis in blocks of 10 using sealed envelopes stating celecoxib or placebo. One hour before surgery, all patients received either 400 mg celecoxib or placebo. Patients were evaluated using a VAS preoperatively, immediately postoperatively, and at 1 and 2 hours postoperatively. Time from the operating room to "ready for discharge" and number of morphine equivalents of narcotic medication required in the postanesthesia care unit were recorded. Age and preoperative VAS were similar between the celecoxib and placebo control group, with average ages of 34.2 ± 11.9 and 35.8 ± 11.6 (P = .27) and preoperative VAS of 2.1 ± 2.06 and 2.3 ± 1.98 (P = .29), respectively. The celecoxib group had 26 females and 24 males, whereas the placebo group had 29 females and 19 males (P = .42). The most common surgical procedures were labral repair (31 patients in the celecoxib group and 29 patients in the placebo group), and labral repair with acetabular osteoplasty (13 patients in the celecoxib group and 11 patients in the placebo group). There were no significant differences in procedures performed between the 2 groups (P > .05). At 1 hour postoperatively, patients who received celecoxib had a lower pain score that was statistically significant compared with the placebo group (4.6 vs 5.4, P = .03). There was a significant difference in discharge time between patients who received celecoxib and the control group (152.9 minutes vs 172.9 minutes, P = .04). There was no significant difference found in morphine equivalents consumed in the postanesthesia care unit between the 2 groups (15.3 vs 15.4, P = .48). A preoperative dose of 400 mg of celecoxib led to statistically significantly reduced patient-reported pain on the VAS in the acute postoperative period after hip arthroscopy surgery, though the difference is not likely clinically significant. There was a significantly shorter time to discharge in patients who received celecoxib versus placebo. Level I, randomized controlled trial.


Meta-analysis of the efficacy of liraglutide in patients with type 2 diabetes accompanied by incipient nephropathy.
The efficacy of liraglutide in patients with type 2 diabetes accompanied by early-stage nephropathy has remained to be fully elucidated. The present meta-analysis was performed to determine the clinical outcomes associated with liraglutide treatment. The PubMed, Ovid, Cochrane Library, Chinese National Knowledge Infrastructure and Wanfang databases were searched in October 2018 to identify randomized controlled trials of liraglutide for diabetes patients with early-stage nephropathy. The treatment effect was estimated by calculating the mean difference (MD). Heterogeneity was assessed using χ2 and I2 tests. In addition, risk of bias graphs and summaries were used to assess the quality of the trials included. A total of 13 randomized controlled trials were included in the present meta-analysis. In subjects with stage I-II diabetic nephropathy (DN), liraglutide had obvious advantages in lowering the urinary albumin-to-creatinine ratio [UACR; MD=-90.96, 95% confidence interval (CI)=-94.12 to -87.80, P<0.00001], urinary albumin excretion rate (UAER; MD=-64.86, 95% CI=-66.63 to -63.08, P<0.00001), serum creatinine (Scr; MD=-13.67, 95% CI=-17.88 to -9.46, P<0.00001). In subjects with stage-III DN, liraglutide had favorable effects on renal function (UACR: MD=-11.23, 95% CI=-13.14 to -9.32, P<0.00001; UAER: MD=-14.06; 95% CI=-6.93 to -11.18; P<0.00001; Scr: MD=-9.17, 95% CI=-14.61 to -3.72, P=0.0010) and exhibited anti-inflammatory effects (transforming growth factor-β1: P<0.00001; tumor necrosis factor-α: P=0.006; interleukin-6: P<0.00001). Furthermore, liraglutide also reduced the blood lipid levels, body mass index and post-prandial blood glucose. The most common adverse effects of liraglutide were gastrointestinal tract reactions and hypoglycemia, but these symptoms resolved quickly. Liraglutide appears to be effective in reducing proteinuria, improving renal function, producing an anti-inflammatory effect and ameliorating glucose and lipid metabolism in diabetic patients with early-stage nephropathy.


Effects of a free-choice high-fat high-sugar diet on brain PER2 and BMAL1 protein expression in mice.
The suprachiasmatic nucleus (SCN) times the daily rhythms of behavioral processes including feeding. Beyond the SCN, the hypothalamic arcuate nucleus (ARC), involved in feeding regulation and metabolism, and the epithalamic lateral habenula (LHb), implicated in reward processing, show circadian rhythmic activity. These brain oscillators are functionally coupled to coordinate the daily rhythm of food intake. In rats, a free choice high-fat high-sugar (fcHFHS) diet leads to a rapid increase of calorie intake and body weight gain. Interestingly, under a fcHFHS condition, rats ingest a similar amount of sugar during day time (rest phase) as during night time (active phase), but keep the rhythmic intake of regular chow-food. The out of phase between feeding patterns of regular (chow) and highly rewarding food (sugar) may involve alterations of brain circadian oscillators regulating feeding. Here, we report that the fcHFHS diet is a successful model to induce calorie intake, body weight gain and fat tissue accumulation in mice, extending its effectiveness as previously reported in rats. Moreover, we observed that whereas in the SCN the day-night difference in the PER2 clock protein expression was similar between chow-fed and fcHFHS-fed animals, in the LHb, this day-night difference was altered in fcHFHS-exposed animals compared to control chow mice. These findings confirm previous observations in rats showing disrupted daily patterns of feeding behavior under a fcHFHS diet exposure, and extend our insights on the effects of the diet on circadian gene expression in brain clocks.


Topical vitamin A, or its derivatives, for treating and preventing napkin dermatitis in infants.
Napkin dermatitis (nappy or diaper rash) is a non-specific term used to describe inflammatory eruptions (rashes) in the napkin area. Most infants develop napkin dermatitis at least once during their infancy. Topical vitamin A has been suggested as a treatment for napkin dermatitis. To determine if treatment with topical vitamin A is successful in either preventing napkin dermatitis, or producing resolution or decreasing the severity of napkin dermatitis. We searched the Cochrane Skin Group Specialised Register (May 2005); Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2005); Ovid MEDLINE from 1966 to August 2005; EMBASE (2003 to May 2005); Ovid OLDMEDLINE (1950 to 1965); and CINAHL (1982 to August 2005). We also searched reference lists of articles. Randomised controlled trials, where the topical application of medication containing vitamin A (or its derivatives) was compared with either placebo, no treatment or other topical medication, for the prevention or treatment of napkin dermatitis in infants aged from zero to two years. Two authors (AJD and MWD) identified and checked titles and abstracts obtained from the searches, and reviewed the full text where necessary. They decided which trials met the inclusion criteria, and recorded their methodological quality. They assessed studies as either adequate, unclear or inadequate using the following key criteria: (a) randomisation (method of generation and concealment of allocation); (b) blinding; (c) loss to follow-up. We did not find any studies for the treatment of napkin dermatitis. We found only one study comparing the use of topical application of medication containing vitamin A, with another topical medication or placebo, to prevent napkin dermatitis. This included study, of 114 newborn infants, reported no significant differences between groups with regard to the severity or duration of napkin dermatitis. For the treatment of napkin dermatitis there is no evidence to support or refute the use of topical vitamin A preparations. For the prevention of napkin dermatitis there is no evidence to suggest that topical vitamin A alters the development of napkin dermatitis. Further RCTs are required to determine whether topical vitamin A is efficacious in treating or preventing napkin dermatitis.


Reticular fibers in the stroma of the thymus.
There were investigated thymic biopsies taken from 14 children deceased of intercurrent diseases. After routine paraffin procedures, slides were stained with hematoxylin-eosin, Gordon-Sweet, Wilder and Laidlaw methods. Reticular fibers are described in the stroma and parenchyma of the thymus. Their number and thickness are higher in connective septa, perivascular sheaths, at the cortico-medullary junction and around Hassall's bodies. Their involvement in a basal membrane like structure located between epithelio-reticular cells and thymocytes is discussed.


Gingival crevicular fluid protein content and alkaline phosphatase activity in relation to pubertal growth phase.
To evaluate gingival crevicular fluid (GCF) protein content and alkaline phosphatase (ALP) activity in growing subjects in relation to stages of skeletal maturation, ie, the growth phase, as prepubertal, pubertal, and postpubertal. Fifty healthy growing subjects (31 girls and 19 boys; age range, 7.8-17.7 years) were enrolled in this study that followed a double-blind, prospective, cross-sectional design. Collection of GCF was performed at the mesial and distal sites of both central incisors, for the maxilla and mandible. Growth phase was assessed through the cervical vertebral maturation method. GCF parameters were expressed as total protein content, total ALP activity, and normalized ALP activity. The total GCF protein content was similar between the different growth phases. On the contrary, the total ALP activity showed a peak for the pubertal growth phase. The normalized GCF ALP activity was only poorly associated with growth phase. No differences were seen between the maxillary and mandibular sites, or between the sexes, for any GCF parameter. The total GCF protein content is not sensitive to the growth phase. However, GCF ALP activity has potential as a diagnostic aid for identification of the pubertal growth phase in individual subjects when expressed as total, but not normalized, values.


Moon Illusion: An Observation.
Size comparisons of the moon are made from different locations by direct viewing (as opposed to comparisons by instrumental techniques). Under the proper conditions, the illusion is seen while the moon's position remains essentially unaltered. By this means, evidence is adduced in favor of Ptolemy's apparent-distance hypothesis.


Mercapturic acids (N-acetylcysteine S-conjugates) as endogenous substrates for the renal organic anion transporter-1.
Mercapturic acids are N-acetyl-L-cysteine S-conjugates that are formed from a range of endogenous and exogenous chemicals. Although the kidney is a major site for elimination of mercapturic acids, the transport mechanisms involved have not been identified. The present study examined whether mercapturic acids are substrates for the renal basolateral organic anion transporter-1 (Oat1) from rat kidney. This carrier mediates uptake of organic anions from the bloodstream in exchange for intracellular alpha-ketoglutarate. Uptake of [(3)H]p-aminohippuric acid (PAH) in Oat1-expressing Xenopus laevis oocytes was strongly inhibited by S-(2,4-dinitrophenyl)-N-acetyl-L-cysteine (DNP-NAC) and by all other mercapturic acids tested, including the endogenous mercapturic acid N-acetyl-leukotriene E(4). Inhibition by the mercapturic acids was competitive, which is consistent with the hypothesis that these compounds are substrates for Oat1. This conclusion was supported by the direct demonstration of saturable [(35)S]DNP-NAC uptake in Oat1-expressing oocytes. [(35)S]DNP-NAC uptake was inhibited by PAH and other mercapturic acids and was stimulated in oocytes preloaded with glutarate. The apparent K(m) value for DNP-NAC uptake was only 2 microM, indicating that this mercapturic acid is a high affinity substrate for Oat1. Together, these data indicate that clearance of endogenous mercapturic acids is an important function of the renal organic anion transporter.


Enhancing Thermal Transport in Layered Nanomaterials.
A comprehensive rational thermal material design paradigm requires the ability to reduce and enhance the thermal conductivities of nanomaterials. In contrast to the existing ability to reduce the thermal conductivity, methods that allow to enhance heat conduction are currently limited. Enhancing the nanoscale thermal conductivity could bring radical improvements in the performance of electronics, optoelectronics, and photovoltaic systems. Here, we show that enhanced thermal conductivities can be achieved in semiconductor nanostructures by rationally engineering phonon spectral coupling between materials. By embedding a germanium film between silicon layers, we show that its thermal conductivity can be increased by more than 100% at room temperature in contrast to a free standing thin-film. The injection of phonons from the cladding silicon layers creates the observed enhancement in thermal conductivity. We study the key factors underlying the phonon injection mechanism and find that the surface conditions and layer thicknesses play a determining role. The findings presented here will allow for the creation of nanomaterials with an increased thermal conductivity.


Forced convective heating for low-temperature sterilization.
A novel impermeable sterile pouch is developed to allow the forced convective heating mechanism for improving the sterilization cycle. The heating process is parametrically investigated to obtain an optimized condition in which a sterilization load is heated from 20 to 45 °C within 2 min, and the forced convection is experimentally and numerically analyzed to find that the convection coefficient is dramatically increased to 450 W/m2 K when compared with the conventional natural convection coefficient of 80 W/m2 K. The optimized heating process is applied to a sterilization cycle using the impermeable pouch, and the overall sterilization cycle is found to be completed within 7.5 min whose performance is validated by using a process challenge device.


Dual anode single-photon avalanche diode for high-speed and low-noise Geiger-mode operation.
The after-pulsing effect is a common problem in high-speed and low-noise single-photon detection based on single-photon avalanche diodes (SPADs). This article presents a dual anode InGaAs/InP SPAD (DA-SPAD) with two separate anode output ports that can be utilized for discriminating relatively weak avalanche signals, providing a simple and robust configuration of the SPAD-based single-photon detection system. Weak avalanche signals with amplitudes below the amplitude of the parasitic capacitive response of the SPAD were easily detected by the DA-SPAD and a simple subtraction circuit. The gated Geiger-mode performance of the DA-SPAD was also investigated. At a gating frequency of 1 GHz, the detection efficiency was 20.4% with an after-pulse probability of 3.5% at a temperature of -20 °C.


Revealing the dynamic landscape of drug-drug interactions through network analysis.
Introduction: The landscape of drug-drug interactions (DDIs) has evolved significantly over the past 60 years, necessitating a retrospective analysis to identify research trends and under-explored areas. While methodologies like bibliometric analysis provide valuable quantitative perspectives on DDI research, they have not successfully delineated the complex interrelations between drugs. Understanding these intricate relationships is essential for deciphering the evolving architecture and progressive transformation of DDI research structures over time. We utilize network analysis to unearth the multifaceted relationships between drugs, offering a richer, more nuanced comprehension of shifts in research focus within the DDI landscape. Methods: This groundbreaking investigation employs natural language processing, techniques, specifically Named Entity Recognition (NER) via ScispaCy, and the information extraction model, SciFive, to extract pharmacokinetic (PK) and pharmacodynamic (PD) DDI evidence from PubMed articles spanning January 1962 to July 2023. It reveals key trends and patterns through an innovative network analysis approach. Static network analysis is deployed to discern structural patterns in DDI research, while evolving network analysis is employed to monitor changes in the DDI research trend structures over time. Results: Our compelling results shed light on the scale-free characteristics of pharmacokinetic, pharmacodynamic, and their combined networks, exhibiting power law exponent values of 2.5, 2.82, and 2.46, respectively. In these networks, a select few drugs serve as central hubs, engaging in extensive interactions with a multitude of other drugs. Interestingly, the networks conform to a densification power law, illustrating that the number of DDIs grows exponentially as new drugs are added to the DDI network. Notably, we discovered that drugs connected in PK and PD networks predominantly belong to the same categories defined by the Anatomical Therapeutic Chemical (ATC) classification system, with fewer interactions observed between drugs from different categories. Discussion: The finding suggests that PK and PD DDIs between drugs from different ATC categories have not been studied as extensively as those between drugs within the same categories. By unearthing these hidden patterns, our study paves the way for a deeper understanding of the DDI landscape, providing valuable information for future DDI research, clinical practice, and drug development focus areas.


Preoperative Hemoglobin Level, Oxygen Saturation and Postoperative Outcomes in Children With Cyanotic Congenital Heart Disease: A Propensity-Score Matching Analysis.
The optimal preoperative hemoglobin (Hb) level is difficult to define in children with cyanotic congenital heart disease (CHD) due to hypoxemia-induced secondary erythrocytosis. This retrospective study integrated preoperative Hb and pulse oxygen saturation (SpO2) using the product of Hb × SpO2 to predict postoperative outcomes in children with cyanotic CHD. Children aged <18 years undergoing cardiac surgery with cyanotic CHD were included. The cutoff value of Hb × SpO2 was the age-adjusted lower limit of normal Hb (aaHb) in healthy children. The main outcomes were in-hospital death and the composite outcome of severe postoperative events. Multivariate logistic regression analysis and propensity score matching analysis were used to adjust for important confounders. The presence of preoperative Hb × SpO2 < aaHb was observed in 21.6% of cyanotic children (n = 777). Children with Hb × SpO2 < aaHb had higher in-hospital mortality (12.5% vs. 4.6%, P < 0.001) and composite outcome incidence (69.6% vs. 32.3%, P < 0.001) than those with Hb × SpO2 ≥ aaHb. After propensity score matching, 141 pairs of children were successfully matched. Multivariate analysis showed that preoperative Hb × SpO2 < aaHb was significantly associated with the composite outcome in the entire population (odds ratio = 4.092, 95% confidence interval = 2.748-6.095, P < 0.001) and the matched cohorts (odds ratio = 2.277, 95% confidence interval = 1.366-3.795, P = 0.002). Our results suggest that a preoperative Hb × SpO2 value below the lower limit of normal hemoglobin is a prognostic factor in cyanotic children undergoing cardiac surgery and is a potential criterion to evaluate preoperative anemia in this population.


Evaluation of the antibody-dependent cytotoxic capabilities of individual human monocytes. Role of Fc gamma RI and Fc gamma RII and the effects of cytokines at the single cell level.
In this report we present evidence that not all human peripheral blood monocytes mediate antibody-dependent cellular cytotoxicity (ADCC), and that this function may be determined on an individual cell by both the type and level of expression of FcR, and by the state of cellular activation and/or differentiation. Although the diverse range of effector and regulatory functions performed by human monocytes suggests the possibility of distinct subsets, it is not clear whether observed functional heterogeneity reflects the presence of true monocyte subpopulations, or whether this diversity represents a continuum of maturational states present in the peripheral circulation. In an attempt to address this question, we investigated the ability of human monocytes to carry out ADCC at the single cell level, with emphasis on the role of the three FcR for IgG (Fc gamma RI, Fc gamma RII, and Fc gamma RIII) in mediating cytotoxicity. Using a modified plaque assay, 58.3% +/- 4.9 of freshly isolated monocytes mediated ADCC, as evidenced by the formation of lytic plaques in monolayers of ox erythrocyte (oxE) target cells. Significant increases in the number of plaque-forming cells were observed after positive selection by flow microfluorimetry for those monocytes expressing high levels of Fc gamma RI and Rc gamma RII, but not Fc gamma RIII. Bispecific antibodies composed of Fab fragments of anti-oxE antibody covalently coupled to Fab fragments of anti-Fc gamma R antibodies were used to independently evaluate the ability of Fc gamma RI, Fc gamma RII, and Fc gamma RIII to mediate single cell cytotoxicity. Significant increases in the number of plaque-forming cells were observed in the presence of anti-Fc gamma RI x anti-oxE and anti-Fc gamma RII x anti-oxE bispecific antibodies, confirming the efficiency of Fc gamma RI and Fc gamma RII as cytotoxic trigger molecules on human monocytes. Incubation of monocytes with purified rIFN-gamma and granulocyte macrophage-CSF, but not IL-2, IL-3, IL-4, IL-6, or TNF-alpha, also resulted in significant increases in the number of monocytes mediating cytotoxicity, suggesting that cytotoxic ability at the single cell level may be influenced by factors which effect monocyte activation and differentiation, respectively. Overall, these studies demonstrate that freshly isolated human monocytes are heterogeneous in their ability to mediate ADCC, and suggest that this functional diversity arises not from discrete subpopulations of cells, but from a continuum of maturational/activational states present within the peripheral circulation.


The great transition.
As China's economy grows and opens further, the opportunity it presents to multinationals is changing. Foreign companies are moving to country development and new strategic choices. Now, foreign firms can actually go after the Chinese domestic market, and it's worth going after. Improvements in China's infrastructure, workforce, and regulatory environment are making it possible for companies to lower their costs to reap new competitive advantages. Multifaceted and often-shifting risks accompany this shifting opportunity. The reforms required for admission into the WTO will be politically difficult for China to implement, and its progress will be slowed by the scarcity of resources for the country's shaky banking system, the inadequacy of the social safety net, environmental problems, and local governments' cash shortage. China's breathtaking 9% average annual GDP growth rests on an unsteady foundation of overcapitalized state-owned enterprises, which have oversupplied many markets, and fiercely protectionist regional government officials pursuing growth-at-almost-all-costs policies. Frequent changes in regulations, bureaucracies, and reporting relationships will continue to make planning difficult, and, as the SARS epidemic demonstrated, there is always the potential for serious disruptions. But for at least the next ten years, multinationals should be the biggest winners in China. To reap the benefits, a multinational must properly nest its effort into its overall organization, show "one face to China" at the national level but also tailor local strategies, be wary of joint ventures, and mitigate risk, in particular the theft of intellectual property. China is a major opportunity for companies that forthrightly face its complexities. It will remain largely inscrutable--and unprofitable--for the rest.


Next generation sequencing panel target genes: possible diagnostic tool for ectodermal dysplasia related diseases.
Ectodermal dysplasias (EDs) are a large and complex group of disorders affecting the ectoderm-derived organs; the clinical and genetic heterogeneity of these conditions renders an accurate diagnosis more challenging. The aim of this study is to demonstrate the clinical utility of a targeted resequencing panel through enhancing the molecular and clinical diagnosis of EDs. Given the recent developments in gene and protein-based therapies for X-linked hypohidrotic ectodermal dysplasia, there is a re-emerging interest in identifying the genetic basis of EDs and the respective phenotypic presentations, in an aim to facilitate potential treatments for affected families. We assessed seventeen individuals, from three unrelated families, who presented with diverse phenotypes suggestive of ED. An extensive multidisciplinary clinical evaluation was performed followed by a targeted exome resequencing panel (including genes that are known to cause EDs). MiSeqTM data software was used, variants with Qscore >30 were accepted. Three different previously reported hemizygous EDA mutations were found in the families. However, a complete genotype-phenotype correlation could not be established, neither in our patients nor in the previously reported patients. Targeted exome resequencing can provide a rapid and accurate diagnosis of EDs, while further contributing to the existing ED genetic data. Moreover, the identification of the disease-causing mutation in an affected family is crucial for proper genetic counseling and the establishment of a genotype-phenotype correlation which will subsequently provide the affected individuals with a more suitable treatment plan.


Attitudes among dermatologists regarding actinic keratosis treatment options.
Actinic keratosis (AK) is considered a precancerous lesion that can develop into invasive squamous cell carcinoma. Its prevalence is increasing, and it is estimated that it affects between 1% and 44% of the adult population worldwide. Advanced age, fair skin phototypes, and cumulative sun exposure are the main risk factors for AK. Therapies for AK consists of lesion-directed treatment (i.e., cryotherapy, curettage, electrocoagulation, and laser therapy) or field therapy [i.e., photodynamic therapy (PDT), 5-fluorouracil (5-FU), diclofenac sodium (DIC), imiquimod (IMQ), and ingenol mebutate (Ing Meb)]. The type of therapy chosen is determined by the number and location of AKs, the patient's condition, and the patient's tolerability and compliance. In this survey, we collected information from 110 Italian dermatologists about their knowledge and attitudes toward various AK therapeutic approaches. In our study, we discovered that cryotherapy and PDT are the most used treatments for AK, while surgery and laser therapy are the least commonly used. The most commonly used topical therapies are DIC and IMQ 3.75 percent cream, followed by IMQ 5 percent cream, Ing Meb, and 5-FU. The correct treatment for AK can be difficult to choose, but adherence to therapy is critical for good results. Given the high and continuing rise in the incidence of AK, dermatologists' knowledge of various therapeutic approaches is critical.


[Evaluation of FIVNAT 1992].
FIVNAT registry collected information on 21,960 individual assisted reproductive technology (ART) cycles in 1992. The present analysis concerns 15,557 cycles arrived on time to be incorporated, 97.9% being in vitro fertilization (IVF) cycles. The transfer rate was 80.9% and the clinical pregnancy rate was 19.2% per oocyte recovery cycle and 23.7% per transfer. The mean oocyte number slightly increased compared to 1991 (8.5 +/- 5.6 vs 8.2 +/- 5.6, p < 0.001) whereas the mean number of embryos obtained was not modified and the mean number of transferred oocytes slightly decreased. The mean fertilization rate slightly increased (53.0% +/- 30.2% vs 48.3% +/- 32.7%, p < 0.001). Infertility of tubal origin represented 59.1% of infertilities, and cycles realised with donor semen were associated to the highest pregnancy rate. GnRH analogues were widely used (87.5%), but those using a short blocking period tended to decrease, replaced by protocols without GnRH analogues. Stimulation regimen using a long blockage phase were associated to a higher pregnancy rate than the others (19.8% per recovery). The proportion of transfers involving 4 or more embryos decreased in 1991 to 22.9%. The analysis of 7,960 pregnancy forms resulting of recoveries realised from 1987 to 1991 showed a preterm birth rate of 9.2% for singleton, but a still high rate for twins and multiple pregnancies. For singleton pregnancies, in utero mortality concerned 6.9/1000 of the children, and the neonatal mortality rate (< 7 days) was 6.7/1000. The overall malformation rate was 2.8%.


D1 dopamine receptors are not expressed in human melanoma.
D1 dopamine receptor mRNA has been demonstrated in mouse melanoma cells, and the expression of these G-protein-coupled receptors in human melanoma was therefore presumed when dopamine receptor binding radiopharmaceuticals were found to be useful for the detection of metastases in whole-body scintigraphy. The aim of this study was thus to investigate if D1 dopamine receptor mRNA or protein could be directly demonstrated in melanoma cells. The presence of D1 dopamine receptor mRNA was investigated in six human melanoma cell lines from metastases using reverse transcriptase-polymerase chain reaction (RT-PCR). In addition, in vitro binding assays with the D1 dopamine receptor agonist 125I-Sch 23982 were performed in 19 melanoma metastases. No D1 dopamine receptor mRNA could be detected by RT-PCR. All melanotic metastases were found to accumulate 125I-Sch 23982, with the presence of binding sites and intensity of 125I-Sch 23982 labelling correlating to the amount of melanin present in the metastases. Two amelanotic melanomas did not accumulate 125I-Sch 23982. D1 dopamine receptors could not be detected by means of RT-PCR or in vitro binding assays in human melanomas. Detection of antagonists is best explained by non-specific binding to melanin.


Innominate artery compression of the trachea in patients with neurological or neuromuscular disorders.
The purpose of this study was to review and assess our surgical management of innominate artery compression of the trachea (IACT) in patients with neurological or neuromuscular disorders (NMDs). Thirty patients with NMD who underwent surgical treatment for IACT at Kobe Children's Hospital and Kobe University Hospital from 2002 to 2012, were enrolled in this retrospective study. The clinical outcomes of preventive elective surgery for IACT (Group A, n=20) were assessed and compared with those of emergent surgery (Group B, n=10). A total of 27 patients underwent innominate artery transection (17 in Group A and 10 in Group B), and 3 patients in Group A underwent innominate artery reimplantation using prosthetic graft interposition. No operative or early death occurred. There were no cases of postoperative mediastinitis or neurological complications. The operative benefits in Group A included a smaller skin incision, more limited sternotomy, less blood loss, shorter operative time and shorter hospital stay, compared with Group B. No blood transfusion was required in Group A. The number of patients in whom cerebral circulation was assessed before surgery in Group A was significantly higher than those in Group B. Preventive elective surgery for IACT provides many advantages, including minimally invasive procedures and successful postoperative outcomes without neurological complications in patients with NMD. Because this surgical management can prevent the tragic occurrence of a tracheo-innominate artery fistula or an exacerbation of tracheomalacia, it would be an optimal surgical treatment for IACT to improve the quality of life in patients with NMD.


An assessment of health status and health behaviours in adolescents: main points and methods of the SOPKARD-Junior programme.
The study involved preparing and implementation a model of complex screening programme for adolescents and comparison of anthropometric examinations between the population of the SOPKARD-Junior programme and representative sample of Polish children in the same age. The screening programme in 14-15 year old pupils (n = 282) included: anthropometric, blood pressure, echocardiographic, electrocardiographic, carotid arteries, kidney and thyroid ultrasound examinations, as well as respiratory, dental and masticatory system, orthopaedic, psychological and psychiatric assessment. Blood and urine tests were also performed. The results of anthropometric examinations from the SOPKARD-Junior and OLAF programmes were used for comparative analysis. Statistically significant (p < 0.001) differences between young people from Sopot and their peers in the general Polish population were found in height (+3.61 cm for boys), body mass (+5.19 kg for boys and +3.99 kg for girls), body mass index (+0.99 kg/m2 for boys and +1.33 kg/m2 for girls), waist circumference (+4.52 cm for boys and +4.52 cm for girls) and hip circumference (+2.51 cm for boys). The highest attendance rate was achieved for examinations performed in school (e.g. anthropometric and blood pressure measurements - n = 268; 95%) and the lowest for the echocardiograpy performed in local hospital (n = 133; 47%). The mean score of the programme quality (scale 1-6) assessed by children was 4.63. The SOPKARD-Junior programme represents an attempt to develop a model of screening assessments for teenagers in Poland. Preliminary results of the SOPKARD-Junior programme indicate small differences in the biological development of Sopot youth in comparison with their peers from Polish population of the OLAF programme. The high attendance rate on research conducted at the school indicate that proposed health examinations in adolescents are acceptable and feasible.


Randomized comparative study of intravenous infusion of three different fixed doses of milrinone in pediatric patients with pulmonary hypertension undergoing open heart surgery.
Pulmonary hypertension secondary to congenital heart disease is a common problem in pediatric patients presenting for open heart surgery. Milrinone has been shown to reduce pulmonary vascular resistance and pulmonary artery pressure in pediatric patients and neonates postcardiac surgery. We aimed to evaluate the postoperative outcome in such patients with three different fixed maintenance doses of milrinone. Patients were randomized into three groups. All patients received fixed bolus dose of milrinone 50 μg/kg on pump during rewarming. Following this, patients in low-dose group received infusion of milrinone at the rate of 0.375 μg/kg/min, medium-dose group received 0.5 μg/kg/min, and high-dose group received 0.75 μg/kg/min over 24 h. Heart rate, mean arterial pressure (MAP), mean airway pressure (MaP), oxygenation index (OI), and central venous pressure (CVP) were compared at baseline and 24 h postoperatively. Dose of inotropic requirement, duration of ventilatory support and Intensive Care Unit (ICU) stay were noted. MAP, MaP, OI, and CVP were comparable in all three groups postoperatively. All patients in the low-dose group required low inotropic support while 70% of patients in the high-dose group needed high inotropic support to manage episodes of hypotension (P = 0.000). Duration of ventilatory support and ICU stay in all three groups was comparable (P = 0.412, P = 0.165). Low-dose infusions while having a clinical impact were more beneficial in avoiding adverse events and decreasing inotropic requirement without affecting duration of ventilatory support and duration of ICU stay.


Usefulness of portal vein pressure for predicting the effects of tolvaptan in cirrhotic patients.
To elucidate influencing factors of treatment response, then tolvaptan has been approved in Japan for liquid retention. We herein conducted this study to clarify the influencing factors in 40 patients with decompensated liver cirrhosis complicated by liquid retention. Tolvaptan was administered at a dosage of 7.5 mg once a day for patients with conventional diuretic-resistant hepatic edema for 7 d. At the initiation of tolvaptan, the estimated hepatic venous pressure gradient (HVPG) value which was estimated portal vein pressure was measured using hepatic venous catheterization. We analyzed the effects of tolvaptan and influencing factors associated with treatment response. Subjects comprised patients with a median age of 65 (range, 40-82) years. According to the Child-Pugh classification, class A was 3 patients, class B was 19, and class C was 18. Changes from the baseline in body weight were -1.0 kg (P = 2.04 × 10(-6)) and -1.3 kg (P = 1.83 × 10(-5)), respectively. The median HVPG value was 240 (range, 105-580) mmH2O. HVPG was only significant influencing factor of the weight loss effect. When patients with body weight loss of 2 kg or greater from the baseline was defined as responders, receiver operating characteristic curve analysis showed that the optimal HVPG cutoff value was 190 mmH2O in predicting treatment response. The response rate was 87.5% (7/8) in patients with HVPG of 190 mmH2O or less, whereas it was only 12.5% (2/16) in those with HVPG of greater than 190 mmH2O (P = 7.46 × 10(-4)). We compared each characteristics factors between responders and non-responders. As a result, HVPG (P = 0.045) and serum hyaluronic acid (P = 0.017) were detected as useful factors. The present study suggests that tolvaptan in the treatment of liquid retention could be more effective for patients with lower portal vein pressure.


Mindfulness training and exercise differentially impact fear extinction neurocircuitry.
The ability to extinguish a maladaptive conditioned fear response is crucial for healthy emotional processing and resiliency to aversive experiences. Therefore, enhancing fear extinction learning has immense potential emotional and health benefits. Mindfulness training enhances both fear conditioning and recall of extinguished fear; however, its effects on fear extinction learning are unknown. Here we investigated the impact of mindfulness training on brain mechanisms associated with fear-extinction learning, compared to an exercise-based program. We investigated BOLD activations in response to a previously learned fear-inducing cue during an extinction paradigm, before and after an 8-week mindfulness-based stress reduction program (MBSR, n = 49) or exercise-based stress management education program (n = 27). The groups exhibited similar reductions in stress, but the MBSR group was uniquely associated with enhanced activation of salience network nodes and increased hippocampal engagement. Our results suggest that mindfulness training increases attention to anticipatory aversive stimuli, which in turn facilitates decreased aversive subjective responses and enhanced reappraisal of the memory.


Recent progress on bioinformatics, functional genomics, and metabolomics research of cytochrome P450 and its impact on drug discovery.
The cytochrome P450 superfamily is responsible primarily for human drug metabolism, which is of critical importance for the drug discovery and development. Rapid advancement of bioinformatics, functional genomics and metabolomics has been made over the last decade. These disciplines are essential in target identification, lead discovery and optimization. In this review, we summarize the recent progress on cytochrome P450 and its role on drug metabolism in the context of bioinformatics, functional genomics and metabolomics. Data are integrated into various databases and web-based platforms on cytochrome P450. These research tools and resources are playing an increasingly important role in drug discovery, and are helping in achieving the ultimate goal of personalized medicine, that is, to prescribe personalized drugs according to each person's genetic makeup, metabolic level, and drug disposition.


Self-Other Agreement and Metaperception Accuracy Across the Big Five: Examining the Roles of Depression and Self-Esteem.
The ability to judge other people's personality characteristics and to know how we are viewed by others are important aspects of social cognition. The present study tested the impact of depressive symptoms and low self-esteem on self-other agreement and the accuracy of metaperception (i.e., how we believe others view us) across the Big Five dimensions of personality. Participants who varied in depressive symptoms engaged in a 10-minute "getting to know you" interaction in dyads. Ratings on the Big Five personality dimensions, depression, and self-esteem were completed prior to the interaction. After the interaction, participants rated the personality of their partner and rated how they believed their partner would rate them (metaperception). Self-other agreement was only found on Extraversion, whereas there was significant meta-accuracy on Agreeableness, Conscientiousness, and Extraversion. Depressive symptoms and low self-esteem negatively biased metaperceptions of Agreeableness, Conscientiousness, and Neuroticism. Depression and low self-esteem function to negatively bias how we believe we are seen by others in new acquaintanceships and therefore may play an important role in the development of interpersonal relationships.


Lead contamination of chicken eggs and tissues from a small farm flock.
Twenty mixed-breed adult laying hens from a small farm flock in Iowa were clinically normal but had been exposed to chips of lead-based paint in their environment. These chickens were brought to the Iowa State University Veterinary Diagnostic Laboratory, Ames, Iowa, where the concentration of lead in blood, eggs (yolk, albumen, and shell), and tissues (liver, kidney, muscle, and ovary) from 5 selected chickens was determined over a period of 9 days. Blood lead levels ranged from less than 50 to 760 ppb. Lead contamination of the yolks varied from less than 20 to 400 ppb, and shells were found to contain up to 450 ppb lead. Albumen contained no detectable amount. Lead content of the egg yolks strongly correlated with blood lead levels. Deposition of lead in the shells did not correlate well with blood lead levels. Mean tissue lead accumulation was highest in kidneys (1,360 ppb), with livers ranking second (500 ppb) and ovarian tissue third (320 ppb). Muscle contained the lowest level of lead (280 ppb). Lead contamination of egg yolks and edible chicken tissues represents a potential public health hazard, especially to children repeatedly consuming eggs from contaminated family-owned flocks.


A comparison of the effect of bile salts on maximal hepatic excretion of certain organic anions in the rabbit under urethane and pentobarbitone.
The influence of two different anaesthetics, sodium pentobarbitone and ethyl urethane, on the enhancement of maximal bilirubin and bromosulphthalein (BSP) excretion induced by bile salts was investigated in rabbits. Two micelle-forming (glycodeoxycholate and taurocholate) and one non-micelle-forming (dehydrocholate) bile salts were used. Under urethane anaesthesia the bile flow was lower than with pentobarbitone, and this could be attributed to a smaller bile salt non-dependent fraction of secretion. The effect of bile salts on the maximal excretion of the two organic anions appeared more clearly related to some kind of micelle interaction in rabbits anaesthetized with urethane than in pentobarbitone-anaesthetized animals. Thus, under urethane, infusions of glycodeoxycholate substantially increased the maximal excretion of bilirubin and BSP, taurocholate exerted an intermediate and dehydrocholate only a small effect. Under pentobarbitone, however, the augmenting action of all three bile salts was similar. The influence of bile salts on the endogenous excretion of bile pigments in experiments in which the test anion was BSP showed corresponding differences dependent upon the anaesthetic used. Possible explanations for those results are discussed.


Estimating the basic reproduction rate of HFMD using the time series SIR model in Guangdong, China.
Hand, foot, and mouth disease (HFMD) has caused a substantial burden of disease in China, especially in Guangdong Province. Based on notifiable cases, we use the time series Susceptible-Infected-Recovered model to estimate the basic reproduction rate (R0) and the herd immunity threshold, understanding the transmission and persistence of HFMD more completely for efficient intervention in this province. The standardized difference between the reported and fitted time series of HFMD was 0.009 (<0.2). The median basic reproduction rate of total, enterovirus 71, and coxsackievirus 16 cases in Guangdong were 4.621 (IQR: 3.907-5.823), 3.023 (IQR: 2.289-4.292) and 7.767 (IQR: 6.903-10.353), respectively. The heatmap of R0 showed semiannual peaks of activity, including a major peak in spring and early summer (about the 12th week) followed by a smaller peak in autumn (about the 36th week). The county-level model showed that Longchuan (R0 = 33), Gaozhou (R0 = 24), Huazhou (R0 = 23) and Qingxin (R0 = 19) counties have higher basic reproduction rate than other counties in the province. The epidemic of HFMD in Guangdong Province is still grim, and strategies like the World Health Organization's expanded program on immunization need to be implemented. An elimination of HFMD in Guangdong might need a Herd Immunity Threshold of 78%.


[Semicircular, transurethral bladder neck resection in therapy of the overcorrected bladder neck].
We report 4 cases of severe urinary obstruction after abdominal stress incontinence procedures in women. The operative procedure consisted in transurethral resection of the obstructive, overcorrected dorsal bladder neck. After resection of the highly elevated bladder neck between the 3- and 9-o'clock position in the dorsal lithotomy position, the patients were able to regain a normal micturition without residual urine. There was no recurrence of stress incontinence.


Vasodilatory Efficacy and Impact of Papaverine on Endothelium in Radial Artery Predilatation for CABG Surgery: in Search for Optimal Concentration.
The aim of this study was to compare the efficacy of two different papaverine concentrations (0.5 mg/ml and 2 mg/ml) for vasospasm prevention and their impact on endothelium integrity. We have studied distal segments of radial arteries obtained by no-touch technique from coronary artery bypass graft (CABG) patients (n=10). The vasodilatory effect of papaverine (concentrations of 0.5 mg/ml and 2 mg/ml) was assessed in vitro, in isometric tension studies using ex vivo myography (organ bath technique) and arterial rings precontracted with potassium chloride (KCl) and phenylephrine. The impact of papaverine on endothelial integrity was studied by measurement of the percentage of vessel's circumference revealing CD34 endothelial marker. 2 mg/ml papaverine concentration showed stronger vasodilatatory effect than 0.5 mg/ml, but it caused significantly higher endothelial damage. Response to KCl was 7.35±3.33 mN for vessels protected with papaverine 0.5 mg/ml and 2.66±1.96 mN when papaverine in concentration of 2 mg/ml was used. The histological examination revealed a significant difference in the presence of undamaged endothelium between vessels incubated in papaverine 0.5 mg/ml (72.86±9.3%) and 2 mg/ml (50.23±13.42%), P=0.002. Papaverine 2 mg/ml caused the higher endothelial damage. Concentration of 0.5 mg/ml caused better preservation of the endothelial lining.


Abscisic acid is involved in root cell wall phosphorus remobilization independent of nitric oxide and ethylene in rice (Oryza sativa).
Abscisic acid (ABA) is a well-studied phytohormone demonstrated to be involved in sub-sets of stress responses in plants, such as iron (Fe) deficiency and phosphorus (P) deficiency in Arabidopsis. However, whether ABA is involved in P deficiency in rice has not been frequently studied. The present study was undertaken to investigate the mechanism underlying ABA-aggravated P deficiency in rice (Oryza sativa). P deficiency decreased ABA accumulation rapidly (within 1 h) in the roots. Exogenous ABA negatively regulated root and shoot soluble P contents by decreasing pectin content, inhibiting P deficiency-induced increases in pectin methylesterase activity and expression of the phosphate transporter gene-OsPT6, thereby decreasing the re-utilization of P from the cell wall and its translocation to the shoot. Moreover, neither the nitric oxide (NO) donor sodium nitroprusside nor ethylene precursor 1-aminocyclopropane-1-carboxylic acid had any effect on ABA accumulation, and application of ABA or the ABA inhibitor fluridone also had no effect on NO production and ethylene emission. Under P deficiency, NO levels increase as quickly as ABA levels decrease, to inhibit both the ABA-induced reduction of pectin contents for the re-utilization of cell wall P and the ABA-induced down-regulation of OsPT6 for the translocation of P from roots to shoots. Overall, our results provide novel information indicating that the reduction of ABA under P deficiency is a very important pathway in the re-utilization of cell wall P in rice under P-deficient conditions, which should be a very effective mechanism for plant survival under P deficiency stress for common agronomic practice.


Repeated electroconvulsive shock: effect on sodium dependency and regional distribution of opioid-binding sites.
The effects of single and repeated electroconvulsive shock (ECS) on the binding of [3H]diprenorphine to rat brain membranes was studied. Repeated but not single ECS significantly increased the Bmax of [3H]diprenorphine binding when measured in the absence but not in the presence of NaCl. On a regional basis the effect of ECS was greatest in the olfactory bulb, nucleus accumbens, and striatum. More modest increases were found in the hippocampus, amygdala, septum, hypothalamus, and pyriform cortex. No significant effect was found in the brainstem and frontal cortex. Although the regional rank order of receptor increase does not match the receptor distribution of brain enkephalins, the receptor increase does parallel the regional increases in brain enkephalins following ECS.


Expression of enterotoxin-coding genes in methicillin-resistant Staphylococcus aureus strains isolated from Mexican haemodialysis patients.
Methicillin-resistant Staphylococcus aureus (MRSA) causes severe catheter-related infections in haemodialysis patients ranging from local-site infections and septic thrombophlebitis to bacteraemia but the associated virulence factors and exotoxins remain unclear. We employed an in vitro infection model using reconstituted human epithelium (RHE) to analyse the expression profiles of 4 virulence genes and 12 exotoxin-coding virulence genes in 21 MRSA strains isolated from catheter-related infections in 21 Mexican patients undergoing haemodialysis. All 21 strains (100%) expressed the seg, seh, sei, eta, etb, or hla genes coding staphylococcal toxins. Eleven MRSA strains (52.3%) expressed the sea gene coding staphylococcal enterotoxin A, and two strains (9.5%) expressed the v8 gene coding serine protease. The tst, chp, and arcA genes coding toxic shock syndrome toxin 1, chemotaxis inhibitory protein, and arginine deiminase, respectively, were expressed in separate single strains (4.7%). The most frequent expression profile (42.8% of the strains) comprised seg, seh, sei, eta, etb, and hla. It is likely that the SEG, SEH, SEI, ETA, ETB, and Hla toxins may play a role in MRSA catheter-related infections. Consideration of these toxins in the development of a vaccine or as targets for monoclonal antibody therapy could provide an improved therapeutic strategy for the treatment of catheter-related infections in haemodialysis patients.


Smooth coronal surface, resin restoration and microleakage.
The space between the resin and the cavity walls has always become interesting to search. The aim of this study was to evaluate any differences on leakage values of Class 5 type resin restorations prepared on surrounding surfaces of the tooth crown. Ninety human teeth were prepared as Class 5 cavities on buccal, lingual, mesial and distal surfaces and were randomly divided into groups for bevelling, groove preparation and as control. The subgroups were arranged as fluoride gel and/or sealant applications. Fluoride gel was applied following the cavity preparations. Sealant was applied over composite resin restorations. Treated teeth were thermocycled and immersed into dye solution for 96 hours. The restorations were evaluated in a stereo-microscope following the sectioning. Bevelling of the cavosurfaces and/or preparation of a groove addition to cavity procedures did not make any difference on the microleakage scores of the restorations done on either surfaces statistically.


Association between Fluorescent Advanced Glycation End-Products and Vascular Complications in Type 2 Diabetic Patients.
Diabetes is a major health problem associated with hyperglycemia and chronically increased oxidative stress and enhanced formation of advanced glycation end-products (AGEs). The aim of this study was to determine whether oxidative plasma biomarkers in diabetic patients could be evidenced and associated with vascular complications. Oxidative stress biomarkers such as thiols, ischemia-modified albumin (IMA), glycated albumin (GA), fructosamine, and AGEs were measured in 75 patients with poorly controlled type 2 diabetes (HbA1c > 7.5%) with (44) or without (31) vascular disease and in 31 nondiabetic controls. Most biomarkers of oxidation and glycation were significantly increased in diabetic patients in comparison with nondiabetics. Fructosamines, GA, IMA, and AGEs were positively correlated and levels of fluorescent AGEs were significantly increased in the plasma from patients presenting vascular complication. These results bring new evidence for the potential interest of glycated albumin, oxidative stress, and glycoxidation parameters in the monitoring of type 2 diabetic patients. Furthermore, it emphasizes fluorescent AGEs as a putative indicator for vascular event prediction in diabetic patients.


Associations Between the Differential Definitions of Elder Mistreatment and Suicidal Ideation Outcomes in U.S. Chinese Older Adults: Do the Definitions Matter?
Elder mistreatment (EM) prevalence varies greatly according to definitional criteria. However, little is known regarding the significance of different EM definitions with respect to health outcome. This paper explores the association between different definitions of EM and their subtypes and suicidal ideation (SI) in an U.S. Chinese aging population. The Population Study of ChINese Elderly in Chicago Study was conducted from 2011 to 2013 of 3157 community-dwelling Chinese older adults aged 60 years. Psychological, physical mistreatment (PM), caregiver neglect (CN), financial exploitation (FE), and overall EM were measured by different definitional approaches varying in the strictness. SI in the past 2 weeks and 12 months were assessed. After adjusting for confounders, the least restrictive EM definition (odds ratio [OR], 2.10 [1.34-3.28]; OR, 2.43 [1.66-3.55]), moderately restrictive EM definition (OR, 2.87 [1.80-4.56]; OR, 2.71 [1.82-4.04]), and most restrictive EM definition (OR, 2.24 [1.36-3.66]; OR, 2.34 [1.54-3.56]) were associated with increased risk for 2-week and 12-month SI. For subtypes of EM, psychological mistreatment (the least and most restrictive definitions, 2-week SI: OR, 2.83 [1.71-4.68]; OR, 3.13 [1.10-8.91]; 12-month SI: OR, 2.43 [1.56-3.78]; OR, 2.88 [1.10-7.54]), PM (2-week SI: OR, 5.12 [1.83-14.29]; 12-month SI: OR, 3.45 [1.30-9.13]), and FE was not associated with 2-week SI, only the broadly defined FE (OR, 1.73 [1.01-2.96]) was associated with higher odds of reporting 12-month SI. CN was only associated with higher odds of reporting 12-month SI (OR, 2.17 [1.19-3.96]; OR, 1.94 [1.24-3.04]) but not 2-week SI. EM and its subtypes were significantly associated with SI; some associations varied by definitions and subtypes.


Super-Resolution Microscopy and Tracking of DNA-Binding Proteins in Bacterial Cells.
The ability to detect individual fluorescent molecules inside living cells has enabled a range of powerful microscopy techniques that resolve biological processes on the molecular scale. These methods have also transformed the study of bacterial cell biology, which was previously obstructed by the limited spatial resolution of conventional microscopy. In the case of DNA-binding proteins, super-resolution microscopy can visualize the detailed spatial organization of DNA replication, transcription, and repair processes by reconstructing a map of single-molecule localizations. Furthermore, DNA-binding activities can be observed directly by tracking protein movement in real time. This allows identifying subpopulations of DNA-bound and diffusing proteins, and can be used to measure DNA-binding times in vivo. This chapter provides a detailed protocol for super-resolution microscopy and tracking of DNA-binding proteins in Escherichia coli cells. The protocol covers the construction of cell strains and describes data acquisition and analysis procedures, such as super-resolution image reconstruction, mapping single-molecule tracks, computing diffusion coefficients to identify molecular subpopulations with different mobility, and analysis of DNA-binding kinetics. While the focus is on the study of bacterial chromosome biology, these approaches are generally applicable to other molecular processes and cell types.


Zinc Ions Affect Siderophore Production by Fungi Isolated from the Panax ginseng Rhizosphere.
Although siderophore compounds are mainly biosynthesized as a response to iron deficiency in the environment, they also bind with other metals. A few studies have been conducted on the impact of heavy metals on the siderophore-mediated iron uptake by microbiome. Here, we investigated siderophore production by a variety of rhizosphere fungi under different concentrations of Zn²⁺ ion. These strains were specifically isolated from the rhizosphere of Panax ginseng (Korean ginseng). The siderophore production of isolated fungi was investigated with chrome azurol S (CAS) assay liquid media amended with different concentrations of Zn²⁺ (50 to 250 μg/ml). The percentage of siderophore units was quantified using the ultra-violet (UV) irradiation method. The results indicated that high concentrations of Zn²⁺ ion increase the production of siderophore in iron-limited cultures. Maximum siderophore production by the fungal strains was detected at Zn²⁺ ion concentration of 150 μg/ml except for Mortierella sp., which had the highest siderophore production at 200 μg/ml. One potent siderophore-producing strain (Penicillium sp. JJHO) was strongly influenced by the presence of Zn²⁺ ions and showed high identity to P. commune (100% using 18S-rRNA sequencing). The purified siderophores of the Penicillium sp. JJHO strain were chemically identified using UV, Fourier-transform infrared spectroscopy (FTIR), and matrix-assisted laser desorption/ionization time-of-flight mass spectrometer (MALDI-TOF-MS) spectra.


Supercoiling-mediated feedback rapidly couples and tunes transcription.
Transcription induces a wave of DNA supercoiling, altering the binding affinity of RNA polymerases and reshaping the biochemical landscape of gene regulation. As supercoiling rapidly diffuses, transcription dynamically reshapes the regulation of proximal genes, forming a complex feedback loop. However, a theoretical framework is needed to integrate biophysical regulation with biochemical transcriptional regulation. To investigate the role of supercoiling-mediated feedback within multi-gene systems, we model transcriptional regulation under the influence of supercoiling-mediated polymerase dynamics, allowing us to identify patterns of expression that result from physical inter-gene coupling. We find that gene syntax-the relative ordering and orientation of genes-defines the expression profiles, variance, burst dynamics, and inter-gene correlation of two-gene systems. Furthermore, supercoiling can enhance or weaken biochemical regulation. Our results suggest that supercoiling couples behavior between neighboring genes, providing a regulatory mechanism that tunes transcriptional variance in engineered gene networks and explains the behavior of co-localized native circuits.


Do beta blockers differ in their effects on hepatic microsomal enzymes and liver blood flow?
The effects of three beta blockers on liver blood flow and hepatic enzyme activity were investigated. Eight healthy subjects received placebo, 100 mg metoprolol, 40 mg nadolol, and 60 mg propranolol orally three times a day for four days in a randomized block design. On the fourth day of each treatment, beta blockade was measured by inhibition of exercise-induced tachycardia and apparent liver blood flow was measured by indocyanine green clearance. Plasma concentrations of the beta blockers were measured 2 hours after the early morning dose. Metoprolol produced the greatest inhibition of exercise tachycardia. All three drugs appeared to reduce liver blood flow, but this was only statistically significant in the case of propranolol. Enzyme inhibition occurred but to a varying extent. Propranolol produced a 36 per cent fall in antipyrine clearance (P less than 0.1) while metoprolol and nadolol both caused a 12 per cent reduction (P less than 0.05 and P = 0.06, respectively). Wide interindividual variation in the plasma concentrations of the drugs limit interpretation, but the results suggest that at the doses used, metoprolol and nadolol may be less likely to cause significant drug interaction by enzyme inhibition than propranolol.


Recent Advances in Asialoglycoprotein Receptor and Glycyrrhetinic Acid Receptor-Mediated and/or pH-Responsive Hepatocellular Carcinoma- Targeted Drug Delivery.
Hepatocellular carcinoma (HCC) seriously affects human health, especially, it easily develops multi-drug resistance (MDR) which results in treatment failure. There is an urgent need to develop highly effective and low-toxicity therapeutic agents to treat HCC and to overcome its MDR. Targeted drug delivery systems (DDS) for cancer therapy, including nanoparticles, lipids, micelles and liposomes, have been studied for decades. Recently, more attention has been paid to multifunctional DDS containing various ligands such as polymer moieties, targeting moieties, and acid-labile linkages. The polymer moieties such as poly(ethylene glycol) (PEG), chitosan (CTS), hyaluronic acid, pullulan, poly(ethylene oxide) (PEO), poly(propylene oxide) (PPO) protect DDS from degradation. Asialoglycoprotein receptor (ASGPR) and glycyrrhetinic acid receptor (GAR) are most often used as the targeting moieties, which are overexpressed on hepatocytes. Acid-labile linkage, catering for the pH difference between tumor cells and normal tissue, has been utilized to release drugs at tumor tissue. This review provides a summary of the recent progress in ASGPR and GAR-mediated and/or pH-responsive HCC-targeted drug delivery. The multifunctional DDS may prolong systemic circulation, continuously release drugs, increase the accumulation of drugs at the targeted site, enhance the anticancer effect, and reduce side effects both in vitro and in vivo. But it is rarely used to investigate MDR of HCC; therefore, it needs to be further studied before going into clinical trials.


Integrating background knowledge from internet databases into predictive toxicology models.
While data integration for data analysis has been investigated extensively in biological applications, it has not yet been so much the focus in computational chemistry and quantitative structure-activity relationship (QSAR) research. With the availability and growing number of chemical databases on the web, such data integration efforts become an intriguing possibility (and, in fact, a necessity). In this paper, we take a first step towards the following vision and scenario for predictive toxicology applications. Given a new structure to be predicted, the first step would be to gather (integrate) all relevant information from internet databases for the structure itself, and all structures with available information for the endpoint of interest. In a second step, the collected information is combined statistically into a prediction of the new structure. We simulate this scenario with three endpoints (data sets) from the DSSTox database and collect information from three public chemical databases: PubChem, ChemBank and Sigma-Aldrich. In the experiments, we investigate whether the addition of background knowledge from the three databases can improve predictive performance (over using chemical structure alone) in a statistically significant way. For this purpose, we define groups of features (belonging together from an application point of view) from the three databases, and perform a variant of forward selection to include these feature groups in a prediction model. Our experiments show that the integration of background knowledge from internet databases can significantly improve prediction performance, especially for regression tasks.


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Since ancient times, the study of cognitive deterioration has been a medical and philosophical constant. Unitl the 18th century, this study took place alongside that of other mental illnesses, for which reason it could not be separated, except in certain special cases, from other processes that were genuinely psychiatric. This century has witnessed a Mental Revolution as a consequence of the divorce between neuropsychiatry on the one hand, and philosophy and religious ideas on the other, of the spread of the ideas of Cullen, Chiarugi and Pinel, the emergence of the Enlightenment and Vitalism. At the end of the 19th century there were three anatomoclinical and etiopathogenic schools of thought regarding dementia in the senile period (presbyophrenic vascular and senile dementia). Alzheimer's description of the illness which now bears his name marked a break with the earlier schools of thought and began a controversy in the different neurological schools which lasted until the second half of the twentieth century, with the publication of cases similar to that of Alzheimer (Bonfiglio, 1908; Sarteschi, 1909; Perusini, 1910) and, in particular, the dissemination of the case that came about when Kraepelin named the phenomenon Alzheimer's disease in 1910. This term was not readily accepted, and the illness was categorised in several other ways: atypical senile dementia, presenile dementia, atypical presbyophrenic dementia and so on. Given that the problem of the use of term Alzheimer's disease lay not only in the unspecific nature of clinical data, but also in the fact that it affected the most important anatomopathological discoveries, the decision to use the term was left to the discretion of the different neurological schools of thought. Kraepelin's personal opinion played a very relevant role from the first; his scientific prestige and authority decisively contributed to its denomination as Alzheimer's disease.


Normal weight obesity and the risk of diabetes in Chinese people: a 9-year population-based cohort study.
We evaluated the risk of developing diabetes in Chinese individuals with normal weight obesity (NWO). This 9-year population-based cohort study was based on the China National Diabetes and Metabolic Disorders Survey. A total of 1128 subjects without diabetes were included. Body fat percentage (BF%) was assessed by electrical bioimpedance. NWO was defined as subjects with a normal BMI (< 24 kg/m2) and an excess BF% (≥ 24% in men; ≥ 33% in women). Of 1128 individuals, 528 individuals were normal weight non-obese (NWNO), 118 (10.5%) were normal weight obese (NWO), 63 were overweight non-obese (OWNO), and 419 were overweight obese (OWO). During a follow-up of 9.0 years (interquartile range: 8.9-9.3), 113 (10.0%) individuals developed diabetes. The incidence rates of diabetes in NWNO, NWO, OWNO and OWO people were 5.69 (27 cases), 11.30 (12 cases), 3.53 (2 cases) and 19.09 (72 cases) per 1000 person-years, respectively. Cox regression analyses indicated multivariate-adjusted hazard ratios of diabetes in NWO, OWNO and OWO people were 2.110 (95% CI 1.026-4.337, p = 0.025), 0.441 (95% CI 0.101-1.928, p = 0.232) and 3.465 (95% CI 2.163-5.551, p < 0.001), respectively, relative to NWNO people. Chinese people with NWO are at increased risk of developing diabetes. We strongly suggest the incorporation of BF% measurement into the regular physical examination in Chinese medical practice.


Cytotoxic Nitrogenous Terpenoids from Two South China Sea Nudibranchs Phyllidiella pustulosa, Phyllidia coelestis, and Their Sponge-Prey Acanthella cavernosa.
A detailed chemical investigation of two South China Sea nudibranchs Phyllidiella pustulosa and Phyllidia coelestis, as well as their possible sponge-prey Acanthella cavernosa, led to the isolation of one new nitrogenous cadinane-type sesquiterpenoid xidaoisocyanate A (1), one new naturally occurring nitrogen-containing kalihinane-type diterpenoid bisformamidokalihinol A (16), along with 17 known nitrogenous terpenoids (2⁻15, 17⁻19). The structures of all the isolates were elucidated by detailed spectroscopic analysis and by the comparison of their spectroscopic data with those reported in the literature. In addition, the absolute stereochemistry of the previously reported axiriabiline A (5) was determined by X-ray diffraction (XRD) analysis. In a bioassay, the bisabolane-type sesquiterpenoids 8, 10, and 11 exhibited cytotoxicity against several human cancer cell lines.