Dysregulation of the cortisol diurnal rhythm following prenatal alcohol exposure and early life adversity.
The hypothalamic-pituitary-adrenal (HPA) axis is impacted by a multitude of pre- and postnatal factors. Developmental programming of HPA axis function by prenatal alcohol exposure (PAE) has been demonstrated in animal models and in human infants, but remains understudied in older children and adolescents. Moreover, early life adversity (ELA), which occurs at higher rates in children with PAE than in non-exposed children, may also play a role in programming the stress response system. In a cohort of children and adolescents with PAE and ELA (PAE + ELA), we evaluated HPA function through assessment of diurnal cortisol activity compared to that in typically developing controls, as well as the associations among specific ELAs, adverse outcomes, protective factors, and diurnal cortisol. Morning and evening saliva samples were taken under basal conditions from 42 children and adolescents (5-18 years) with PAE + ELA and 43 typically developing controls. High rates of ELA were shown among children with PAE, and significantly higher evening cortisol levels and a flatter diurnal slope were observed in children with PAE + ELA, compared to controls. Medication use in the PAE + ELA group was associated with lower morning cortisol levels, which were comparable to controls. Complex associations were found among diurnal cortisol patterns in the PAE + ELA group and a number of ELAs and later adverse outcomes, whereas protective factors were associated with more typical diurnal rhythms. These results complement findings from research on human infants and animal models showing dysregulated HPA function following PAE, lending weight to the suggestion that PAE and ELA may interact to sensitize the developing HPA axis. The presence of protective factors may buffer altered cortisol regulation, underscoring the importance of early assessment and interventions for children with FASD, and in particular, for the many children with FASD who also have ELA.


High doses of opioids usage for amyotrophic lateral sclerosis patients with non-invasive ventilation.
While opioids have been found to be useful in relieving suffering in amyotrophic lateral sclerosis (ALS), there is a lack of evidence concerning how and how much to use them in practice. This study was conducted to clarify how opioids were used for patients with ALS. We performed a retrospective case-based analysis at a single tertiary neurology center in Tokyo from 2010 to 2018. We enrolled patients with ALS who had died before the end of 2018. We examined the opioid dosage equivalent of morphine hydrochloride and patients' clinical backgrounds, focusing on ventilatory support. Morphine was administered in 110 patients with ALS, and 84 were followed up until their death. Of these 84 patients, 57 (69.9%) did not use mechanical ventilation until death (no-MV group), and 21 (22.9%) utilized only non-invasive ventilation (NIV group). Final morphine dosage in the NIV group was significantly higher (mean 65.7 mg [SD 54.6], range 10-200 mg) than in the no-MV group (mean 31.7 mg [SD 26.9], range 0-120 mg; p = 0.015, Welch's t-test). The NIV group needed psychotropic drugs more frequently than the no-MV group (62% [n = 13] vs. 35% [n = 20]). Patients in the NIV group used opioids for a statistically significantly longer time and at a higher dose than those in the no-MV group. Symptom control with opioids alone may be difficult, and the development of multifaceted evaluation and care is desirable.


Analysis of the effect of triclosan on gonadal differentiation of zebrafish based on metabolome.
Although the previous research confirmed that triclosan (TCS) affects the female proportion at the early stage of zebrafish (Danio rerio) and has an estrogen effect, the mechanism by which TCS affects the sex differentiation of zebrafish is not entirely clear. In this study, zebrafish embryos were exposed to different concentrations of TCS (0, 2, 10, and 50 μg/L) for 50 consecutive days. The expression of sex differentiation related genes and metabolites were then determined in larvae using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Liquid Chromatography-Mass Spectrometer (LC-MS), respectively. TCS upregulated the expression of the sox9a, dmrt1a and amh genes, down-regulating the expression of wnt4a, cyp19a1b, cyp19a1a, and vtg2 gene. The overlapped classification of Significant Differential Metabolites (SDMs) between the control group and three TCS treated groups related to gonadal differentiation was Steroids and steroid derivatives, including 24 down-regulated SDMs. The enriched pathways related to gonadal differentiation were Steroid hormone biosynthesis, Retinol metabolism, Metabolism of xenobiotics by cytochrome P450, and Cortisol synthesis and secretion. Moreover, SDMs were significantly enriched in Steroid hormone biosynthesis in the 2 μg/L TCS group, which included Dihydrotestosterone, Cortisol, 11beta-hydroxyandrost-4-ene-3, 17-dione, 21-Hydroxypregnenolone, Androsterone, Androsterone glucuronide, Estriol, Estradiol, 19-Hydroxytestosterone, Cholesterol, Testosterone, and Cortisone acetate. Results showed that TCS affects the female proportion mainly through Steroid hormone biosynthesis, in which aromatase plays a key role in zebrafish. Retinol metabolism, metabolism of xenobiotics by cytochrome P450, and cortisol synthesis and secretion may also participate in TCS-mediated sex differentiation. These findings reveal the molecular mechanisms of TCS-induced sex differentiation, and provide theoretical guidance for the maintenance of water ecological balance.


Effect of soaking and air-resting on the phytochemical, antioxidant, and antimicrobial properties of Piper guineense (Schum and Thonn) seeds.
Soaking and air-resting are processing steps in malting. This has been reported to increase metabolic and enzyme activities in rice paddy as a result of exposure of the grain to atmospheric oxygen. The present study evaluated the effect of soaking and air-resting on the phytochemical composition of Piper guineense seeds. The seed extracts were prepared by: soaking the seeds in water for 4 h; air-resting for 30, 60, 90, and 120 min; and re-soaking for another 4 h. The out-of-steep seeds were milled and an extract was formed by tissue homogenization and maceration using ethanol. The phytochemical, antioxidant, and antibacterial properties of the seed extract were determined using standard methods. The alkaloid, flavonoid, saponin, tannin, and total phenol contents were 0.126-0.268, 0.091-0.172, 0.080-0.123, 0.00-0.107, and 0.447-0.908 g kg-1 respectively. The antioxidant properties (reducing power) of the seed extracts were concentration-dependent and were in the range 1.08-3.24 g kg-1 at 8 mg mL-1 , 1.14-3.47 g kg-1 at 16 mg mL-1 , 1.30-3.35 g kg-1 at 24 mg mL-1 , 1.26-3.11 g kg-1 at 32 mg mL-1 , and 1.13-3.04 g kg-1 at 40 mg mL-1 , respectively. The antibacterial activities against Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa showed that, at 100 mg mL-1 , the inhibition zone diameters of the seed extracts were in the range 10-23 mm. Soaking and air-resting of P. guineense seeds increased the phytochemical components of the seeds. The extracts from the seeds air-rested for 30 min showed the highest phytochemical contents and had the highest antioxidant and antimicrobial properties. © 2022 Society of Chemical Industry.


Tricuspid valve endocarditis: repair with the use of artificial chordae.
We report on a patient who developed tricuspid valve endocarditis on a permanent endocardial pacemaker lead. At operation the endocardial lead was removed and accurate debridement of the tricuspid tissue was performed. Tricuspid valve reconstruction included commissural plication and the construction of artificial polytetrafluoroethylene chordae from the anterior leaflet to the anterior papillary muscle to obtain valve competence.


Noise Characterization and Performance of MODIS Thermal Emissive Bands.
The MODerate-resolution Imaging Spectroradiometer (MODIS) is a premier Earth observing sensor of the early 21st Century, flying on-board the Terra (T) and Aqua (A) spacecrafts. Both instruments far exceeded their 6 year design life and continue to operate satisfactorily for more than 15 and 13 years, respectively. The MODIS instrument is designed to make observations at nearly a 100% duty cycle covering the entire Earth in less than 2 days. The MODIS sensor characteristics include a spectral coverage from 0.41 μm - 14.4 μm, of which those wavelengths ranging from 3.7 μm - 14. 4 μm cover the thermal infrared region which is interspaced in 16 Thermal Emissive Bands (TEB). Each of the TEB contains 10 detectors which record samples at a spatial resolution of 1 km. In order to ensure a high level of accuracy for the TEB measured Top Of Atmosphere (TOA) radiances, an onboard BlackBody (BB) is used as the calibration source. This paper reports the noise characterization and performance of the TEB on various counts. First, the stability of the onboard BB is evaluated to understand the effectiveness of the calibration source. Next, key noise metrics such as the Noise Equivalent Temperature difference (NEdT) and the Noise Equivalent dn difference (NEdN) for the various TEB are determined from multiple temperature sources. These sources include the nominally controlled BB temperature of 290 K for T-MODIS and 285 K for A-MODIS, as well as a BB Warm Up - Cool Down (WUCD) cycle that is performed over a temperature range from roughly 270 K - 315 K. The Space View (SV) port that measures the background signal serves as a viable cold temperature source for measuring noise. In addition, a well characterized Earth View (EV) Target, the Dome C site located in the Antarctic plateau, is used for characterizing the stability of the sensor, indirectly providing a measure of the NEdN. Based on this rigorous characterization, a list of the noisy and inoperable detectors for the TEB for both instruments is reported to provide the science user communities quality control of the MODIS Level 1B calibrated product.


Comparison of heparin and a semi-synthetic heparin analogue, A73025. II. Some effects on platelet function.
A comparison has been made of some effects of a semi-synthetic heparin analogue, A73025, and heparin upon platelet function. In several of the in vitro tests performed, such as their potentiating effects on ADP and adrenaline induced aggregation and their effects on the aggregation of washed platelets by activated factor X, heparin proved to be more potent than A73025. Following intravenous injection of twice the quantity of A73025, an equivalent anti-factor Xa activity was obtained, in the agreement with our previous studies. However, it was found that PRP containing heparin and A73025 with comparable anti-Factor Xa acitvity responded differently to the addition of thrombin, as A73025 barely inhibited thrombin induced aggregation. Similarly, A73025 had little effect on the dilute thrombin clotting time of plasma, following intravenous injection. Heparin and A73025 were neutralized to approximately the same degree by a crude PF4 preparation.


Field evaluation of TaqMan Array Card (TAC) for the simultaneous detection of multiple respiratory viruses in children with acute respiratory infection.
Multipathogen reverse transcription real-time PCR (RT-qPCR) platforms have proven useful in surveillance for acute respiratory illness (ARI) and study of respiratory outbreaks of unknown etiology. The TaqMan(®) Array Card (TAC, Life Technologies™), can simultaneously test 7 clinical specimens for up to 21 individual pathogens (depending on arrangement of controls and use of duplicate wells) by arrayed singleplex RT-qPCR on a single assay card, using minimal amounts of clinical specimens. A previous study described the development of TAC for the detection of respiratory viral and bacterial pathogens; the assay was evaluated against well-characterized analytical materials and a limited collection of human clinical specimens. We wished to compare TAC assay performance against standard individual RT-qPCR assays for respiratory viral detection, focusing on 10 viruses (adenovirus, human metapneumovirus, human parainfluenza viruses 1-4, influenza viruses A and B, respiratory syncytial virus, and rhinovirus) from a larger collection of human specimens. We used specimens from 942 children with ARI enrolled systematically in a population-based, ARI surveillance study (New Vaccine Surveillance Network, NVSN). Compared with standard individual RT-qPCR assays, the sensitivity of TAC for the targeted viruses ranged from 54% to 95% (54%, 56%, and 75% for adenovirus, human parainfluenza viruses-1 and -2, respectively, and 82%-95% for the other viruses). Assay specificity was 99%, and coefficients of variation for virus controls ranged from 1.5% to 4.5%. The TAC assay should prove useful for multipathogen studies and rapid outbreak response.


A new standardized tool for quantification of closed-loop communication in trauma care: CAST Grid reliability study.
The CAST Grid has been developed to evaluate the use of closed-loop communication (CLC) in the trauma bay. The CAST Grid and two validated non-technical team performance assessment tools (the TEAM and T-NOTECHS grids) were completed by 2 independent reviewers based on trauma care simulation videos from a French Level 1 trauma center. Intra- and inter-rater agreements were evaluated for CLC parameters and non-technical performance, and correlations between these parameters were analyzed. The study analyzed 11 videos. The intra- and inter-rater agreement for the number of CLC per minute (CLC/min) was moderate and good, respectively, based on Lin's concordance correlation coefficient [95%CI] (0.57 [-0.40;0.94] and 0.77 [0.33;0.94]). However, the agreement was poor for the percentage of CLC (0.37 [-0.58;0.89] and -0.36 [-0.71;0.14], respectively). The study found that a lower number of CLC/min was correlated with an increased duration of the simulation (r = -0.75 [-0.93; -0.25]). The CAST Grid showed a relatively good inter-rater agreement to quantify the number of CLC/min which was inversely correlated with the duration of care. This tool opens up the possibility of quantifying CLC and allows for new analyses of team functioning and interactions.


Correction: ACPA and RF as predictors of sustained clinical remission in patients with rheumatoid arthritis: data from the Ontario Best practices Research Initiative (OBRI).
[This corrects the article DOI: 10.1136/rmdopen-2018-000738.].


Associations of prepartum body condition score with occurrence of clinical endometritis and resumption of postpartum ovarian activity in dairy cattle.
This study was performed to investigate the effect of periparturient body condition score on the occurrence of clinical endometritis and postpartum resumption of ovarian activity in dairy cows. Eighty-seven lactating Holstein cows, fed with a total mixed ration diet, were included into the study. Body condition scoring (using a 5-point scale with quarter-point divisions) was performed by the same investigator using the visual technique every 2 weeks, from 2 weeks before until 6 weeks after calving. Palpation of the reproductive tract and ultrasonographic assessment of ovaries for detection of corpus luteum using a rectal linear probe was also performed at 2, 4, and 6 weeks after calving. Cows with clinical endometritis had significantly lower body condition score (BCS) than normal cows at all weeks pre- and postcalving, and cows that did not ovulate until 45 days after calving had a significantly lower BCS pre- and postpartum. Cows that did not ovulate until 45 days after calving also lost more BCS from 2 weeks before to 4 weeks after calving. Besides, first ovulation after calving take occurred later in cows with clinical endometritis compared to normal cows (P < 0.05). In conclusion, low BCS is a risk factor for postpartum endometritis and delayed cyclicity in dairy cows. BCS loss from dry-off to early lactation and occurrence of clinical endometritis can significantly affect postpartum ovarian activity.


Enhancing Antibacterial Performance and Biocompatibility of Pure Titanium by a Two-Step Electrochemical Surface Coating.
A two-step electrochemical surface treatment has been developed to modify the CP Ti surface on commercially pure titanium grade 2 (CP Ti): (1) anodic oxidation to form TiO2 nanotube precoatings loaded with silver (Ag) and (2) microarc oxidation (MAO) to produce a porous Ca-P-Ag coating in an electrolyte containing Ag, Ca, and P. One-step MAO in the same electrolyte has also been used to produce porous Ca-P-Ag coatings without anodic oxidation and preloaded Ag as a control. Surface morphologies and alloying chemistry of the two coatings were characterized by SEM, EDS, and XPS. Biocompatibility and antimicrobial properties have been evaluated by the MTT method and co-culture of Staphylococcus aureus, respectively. It is demonstrated that porous coatings with high Ag content can be achieved on the CP Ti by the two-step treatment. The optimized MAO voltage for excellent comprehensive properties of the coating is 350 V, in which a suitable chemical equilibrium between Ag, Ca, and P contents and a Ca/P ratio of 1.67 similar to HA can be obtained, and the Ag particles are in the size of less than 100 nm and embedded into the underneath of the coating surface. After being contacted with S. aureus for 1 and 7 days, the average bactericidal rates were 99.53 and 89.27% and no cytotoxicity was detected. In comparison, the one-step MAO coatings contained less Ag, had a lower Ca/P ratio, and showed lower antimicrobial ability than the two-step treated samples.


Conformations of hydrophobic polyelectrolytes.
Recent studies on the (hypercoiled) compact conformation and the pH-induced conformational transition to the extended coil of the hydrophobic poly(acids or bases), which have been well used in industrial and medical circles, are summarized, especially on the basis of our studies on poly(alpha-alkyl acrylic acids) and maleic acid copolymers with hydrophobic aromatic monomers. The stability of the compact conformation and values of various thermodynamic parameters of the transition of the hydrophobic polyelectrolytes suggest the importance of hydrophobic interaction among the side chains to form the compact conformation. Characterization of various physicochemical methods, including 1H-NMR measurements, gives a model of the compact conformation with a more expanded structure than in globular proteins, a free-draining property of the solvent, the conformation fluctuation, etc. Also, the apparent two-state character of each segment in the transition region, a life-time in each state and the cooperative parameter for the compact form formation are discussed. A review of our conformational studies on the hydrophobic-hydrophilic polypeptides is also given. For the anion-induced conformation transition in basic homopoly(alpha-amino acids), hydrophobic characters of the anion and the side chain in the polypeptide are shown to be important, especially in terms of solvation. The difference in the induced conformation by the anion between random and alternating basic copolypeptides is explained by introducing a model which shows the importance of the sequence of hydrophobic and hydrophilic residues in the polypeptide to induce the ordered conformation of the anions. Also, we attempt to explain the difference between the induction of ordered conformation in the basic homo- or copolypeptide in reversed micelles with a large sulfonate (AOT) vs. that in aqueous AOT in terms of the hydrophobic character of the side chains in the polypeptides, AOT and the medium.


Immobilisation of lead and zinc in contaminated soil using compost derived from industrial eggshell.
This study aims to evaluate the capacity of a compost obtained by co-composting of industrial eggshell (CES) to immobilise lead (Pb) and zinc (Zn) in an acidic soil contaminated by mining activities. Mature compost without eggshell (CWES) and natural eggshell (ES) were also tested as soil amendments for comparison purposes. Three different application rates were used for each material, ensuring the same quantity in terms of neutralizing capacity. Incubation experiments were conducted under controlled conditions and CO2 emissions monitored for 94 days. The environmental availability of Pb and Zn in the amended soil was assessed and bioassays were performed at the end of the incubation period. When eggshells were present, the CES compost raised the soil pH to values higher than 6 and reduced the soil mobile fraction for both Pb and Zn, in more than 95%. Soil toxicity towards Vibrio fischeri was also suppressed and environmental risk decreased to "low level". However, the immobilisation in the acid insoluble soil component was significantly achieved only for Zn. In addition, regarding soil carbon dynamics the CO2-C emissions were enhanced, mainly in the case of the highest rate of amendment. Both first order-E and parallel first order models may adequately describe the kinetic data of CO2-C cumulative release. Without eggshells, the CWES compost revealed limited effect on heavy metals immobilisation, likely due to its small capacity to correct soil acidity, at lower application rates. Using solely eggshells, the ES waste had similar outcomes when compared with CES, but at the higher application rate, CO2 emissions were enhanced with the eggshell compost due to the contribution of biotic carbon present therein. Therefore, this study points out that CES is an effective liming material and may be used for in situ remediation of contaminated soil with Pb and Zn.


Inter-critical and critical excessive daily sleepiness in episodic migraine patients.
The objective of this study was to determine the relationship between sleepiness and migraine in the intercritical period and to evaluate the time course of critical drowsiness during the attacks. One hundred patients fulfilling IHCD 2nd (2004) criteria for migraine without aura were compared to 100 healthy subjects. Habitual excessive daily sleepiness, evaluated by means of Epworth Sleepiness Scale, was not more frequent in patients with episodic migraine than in controls (12% migraineurs vs. 8% controls, NS). The analysis of critical sleepiness by means of Stanford Sleepiness Scale (SSS) revealed a beginning of sleepiness increase before the attack onset, starting 12 h before, a peak of SSS values at the migraine attack onset and then a gradual decrease to reach baseline values only 12-24 h later. Moreover, patients responding to symptomatic drugs showed a greater and faster decrease of critical sleepiness in comparison with non-responder migraineurs; this finding allows excluding the role of medications in promoting critical somnolence and together with critical drowsiness time-course supports the hypothesis that vigilance impairment could be related to migraine pathogenesis.


Evaluation of the clinical sensitivity for the quantification of human immunodeficiency virus type 1 RNA in plasma: Comparison of the new COBAS TaqMan HIV-1 with three current HIV-RNA assays--LCx HIV RNA quantitative, VERSANT HIV-1 RNA 3.0 (bDNA) and COBAS AMPLICOR HIV-1 Monitor v1.5.
The COBAS TaqMan HIV-1 test (Roche Diagnostics) was compared with the LCx HIV RNA quantitative assay (Abbott Laboratories), the Versant HIV-1 RNA 3.0 (bDNA) assay (Bayer) and the COBAS Amplicor HIV-1 Monitor v1.5 test (Roche Diagnostics), using plasma samples of various viral load levels from HIV-1-infected individuals. In the comparison of TaqMan with LCx, TaqMan identified as positive 77.5% of the 240 samples versus 72.1% identified by LCx assay, while their overall agreement was 94.6% and the quantitative results of samples that were positive by both methods were strongly correlated (r=0.91). Similarly, in the comparison of TaqMan with bDNA 3.0, both methods identified 76.3% of the 177 samples as positive, while their overall agreement was 95.5% and the quantitative results of samples that were positive by both methods were strongly correlated (r=0.95). Finally, in the comparison of TaqMan with Monitor v1.5, TaqMan identified 79.5% of the 156 samples as positive versus 80.1% identified by Monitor v1.5, while their overall agreement was 95.5% and the quantitative results of samples that were positive by both methods were strongly correlated (r=0.96). In conclusion, the new COBAS TaqMan HIV-1 test showed excellent agreement with other widely used commercially available tests for the quantitation of HIV-1 viral load.


Prebiotically-relevant low polyion multivalency can improve functionality of membraneless compartments.
Multivalent polyions can undergo complex coacervation, producing membraneless compartments that accumulate ribozymes and enhance catalysis, and offering a mechanism for functional prebiotic compartmentalization in the origins of life. Here, we evaluate the impact of lower, more prebiotically-relevant, polyion multivalency on the functional performance of coacervates as compartments. Positively and negatively charged homopeptides with 1-100 residues and adenosine mono-, di-, and triphosphate nucleotides are used as model polyions. Polycation/polyanion pairs are tested for coacervation, and resulting membraneless compartments are analyzed for salt resistance, ability to provide a distinct internal microenvironment (apparent local pH, RNA partitioning), and effect on RNA structure formation. We find that coacervates formed by phase separation of the shorter polyions more effectively generated distinct pH microenvironments, accumulated RNA, and preserved duplexes than those formed by longer polyions. Hence, coacervates formed by reduced multivalency polyions are not only viable as functional compartments for prebiotic chemistries, they can outperform higher molecular weight analogues.


Nonpharmacologic intervention in acute alcohol withdrawal.
The importance of nonpharmacologic and pharmacologic interventions in the treatment of alcohol withdrawal is not known. A randomized, double-blind, placebo-controlled trial was conducted with 41 patients in alcohol withdrawal in an emergency department. The patients received either supportive care (10 min of standardized assessments, reassurance, reality orientation, and nursing care an hour) with three doses of sublingual lorazepam 2 mg every 2 hr (21 patients, drug group) or supportive care with three doses of sublingual placebo every 2 hr (20 patients, no-drug group). Immediately before each drug dose, the clinical course of alcohol withdrawal was assessed hourly by the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-A). Interraters reliability in using CIWA-A was high. After each assessment, supportive care was given for 10 min before each dose. After completion of a 7-hr initial phase, patients were discharged and reassessed daily for 5 days. Thirty-seven patients (90.2%) improved in the initial phase. Treatment failures (CIWA-A greater than 10) were more common in the patients treated without drug (3/20, 15%) than in those treated with drug (1/21, 4.8%). Overall variations in intergroup CIWA-A scores during the initial phase were not significant. The rate of improvement of CIWA-A scores over the first 2 hr after drug was slightly faster in patients receiving lorazepam than in the control group. CIWA-A scores were the same during follow-up. These results indicate that most outpatients in mild to moderate alcohol withdrawal without medical complications improve without drug therapy in the emergency department setting.


Laser therapy in the management of benign and malignant tumours in the colon and rectum.
Since 1983 the Neodymium-YAG laser has been used endoscopically to treat 93 patients with inoperable colorectal carcinoma and 18 patients with benign sessile adenomas. In an additional 11 patients with colorectal cancer, photodynamic therapy (PDT) has been applied using an argon-pumped dye laser. Objective and subjective measurements of quality of life have shown the beneficial effects of the Nd-YAG laser in the relief of symptoms, and four patients have apparently been rendered disease free. Benign tumours also respond to Nd-YAG ablation but close histological supervision is necessary to detect malignant transformation at an early stage. Although PDT may offer a potential for cure in small inoperable tumours, it seems likely that Nd-YAG laser treatment will remain the laser option of choice for advanced bulky tumours.


Fasting breath hydrogen in celiac disease.
We studied the possible clinical significance of high basal levels of H2 by analyzing the breath excreted by the following fasting subjects: 50 healthy volunteers, 149 subjects with functional bowel disorders, 16 patients with small bowel bacterial overgrowth proven by bacteriology, 34 patients with untreated celiac disease, 40 patients with celiac disease on a gluten-free diet, and 40 patients with disorders of the small intestine other than celiac disease (disease controls). The fasting levels of H2 in untreated celiac patients (mean 22.5 +/- 19.3 ppm) were significantly higher than those in healthy volunteers (5.8 +/- 3.1 ppm), patients with functional bowel disorders (6.6 +/- 4.4 ppm), treated celiac patients (9.9 +/- 8.1 ppm), and disease controls (7.0 +/- 6.7 ppm). No significant difference was found between patients with untreated celiac disease and bacterial overgrowth (mean 14.7 +/- 14.0 ppm). The percentage of patients with elevated H2 fasting levels in untreated celiac disease (58.8%) was significantly higher than that in the other groups, except for the patients with bacterial overgrowth (43.7%). In 14 celiac patients, studied before and after a gluten-free diet, fasting H2 levels decreased from 26.6 +/- 18 to 11.6 +/- 10 ppm, becoming normal only in those patients with healing of intestinal lesions. Our results show that high fasting H2 levels are a frequent feature of untreated celiac disease and that the return to normal of these levels is predictive of villous regrowth.


Plenty new under the sun.
Variation at the melanocortin 1 receptor (MC1R) is very common in most non-African world populations. A range of variants predispose to skin cancer, including melanoma. What remains unclear are the mechanisms linking gene variation with sun sensitivity or tumor risk. In particular, it remains unclear whether pigmentary effects of the MC1R can account for all of the increase in cancer risk.


Protective potential of IL-6 against trimethyltin-induced neurotoxicity in vivo.
We investigated the role of cytokines in trimethyltin (TMT)-induced convulsive neurotoxicity. Evaluation of TNF-α, interferon-γ, and interleukin (IL)-6 knockout (-/-) mice showed that the IL-6(-/-) mice had the greatest susceptibility to TMT-induced seizures. In both wild-type and IL-6(-/-) mice, TMT treatment increased glutathione oxidation, lipid peroxidation, protein oxidation, and levels of reactive oxygen species in the hippocampus. These effects were more pronounced in the IL-6(-/-) mice than in wild-type controls. In addition, the ability of TMT to induce nuclear translocation of Nrf2 and upregulation of heme oxygenase-1 and γ-glutamylcysteine ligase was significantly decreased in IL-6(-/-) mice. Treatment of IL-6(-/-) mice with recombinant IL-6 protein (rIL-6) restored these effects of TMT. Treatment with rIL-6 also significantly attenuated the TMT-induced inhibition of phosphoinositol 3-kinase (PI3K)/Akt signaling, thereby increasing phosphorylation of Bad (Bcl-xL/Bcl-2-associated death promoter protein), expression of Bcl-xL and Bcl-2, and the interaction between p-Bad and 14-3-3 protein and decreasing Bax expression and caspase-3 cleavage. Furthermore, in IL-6(-/-) mice, rIL-6 provided significant protection against TMT-induced neuronal degeneration; this effect of rIL-6 was counteracted by the PI3K inhibitor LY294002. These results suggest that activation of Nrf2-dependent glutathione homeostasis and PI3K/Akt signaling is required for the neuroprotective effects of IL-6 against TMT.


Advances in biomarker development in acetaminophen toxicity.
Acetaminophen liver injury is the most common cause of acute liver injury in the United States and several other countries. Diagnosis of acetaminophen-induced acute liver injury in the clinic is challenging due to the lack of validated and specific biomarkers. The following chapter provides an overview of recent advances evaluating candidate biomarkers in development for acetaminophen acute liver injury. Relationships of biomarkers to mechanisms of acetaminophen toxicity and their potential role in confirming the diagnosis and/or predicting evolving toxicity are addressed.


High- and low-potency ligands with similar affinities for the TCR: the importance of kinetics in TCR signaling.
We have examined binding characteristics for a single TCR interacting with five of its different peptide/MHC ligands using surface plasmon resonance. We find that very small structural changes produce ligands with similar equilibrium binding affinities (K(D)) for the TCR, but vastly different potencies for T cell activation. Ligands with similar K(D)s induce similar amounts of total phospho-zeta but distinct patterns of zeta phosphorylation. Lower potency ligands induce only incomplete phosphorylation of TCR zeta and generally have faster off-rates. Therefore, the potency of TCR ligands is primarily determined by the half-life of the TCR-ligand complex and the consequent ability to induce complete phosphorylation of zeta.


Cultured gastrointestinal smooth muscle cells: cell response to contractile agonists depends on their phenotypic state.
In the digestive tract, the transit of ingested food induces a local contraction-relaxation reflex of which the smooth muscle cell (SMC) represents the functional unit. Although freshly isolated SMCs have been extensively used for in vitro studies, in specific cases cultured cells appear necessary. Because conventionally cultured SMCs lose their contractile properties, we have developed: (1) differentiated, contractile rabbit gastric SMCs (D-stim cells), cultured in a medium supplemented with insulin, and (2) proliferative, dedifferentiated rabbit gastric SMCs (P-stim cells), cultured in a medium supplemented with insulin, fetal serum, EGF and b-FGF. The proliferative index was 5 +/- 4% and 82 +/- 10%, respectively, for D-stim and P-stim cells. Expression of SM-myosin heavy chain was observed in 90% of D-stim cells, whereas it was progressively lost in P-stim cells. Carbachol (1-100 nM), glicentin (2 nM) and gastrin-17 (100 nM) induced contraction of D-stim cells cultured for 3 or 6 days, whereas they did not induce the contraction of P-stim cells; in contrast, gastrin-17 (10 nM) was able to stimulate DNA synthesis (1.86 +/- 0.09-fold increase) in P-stim cells. The coupling of muscarinic receptors to intracellular transduction pathways was evaluated in D-stim cells: at day 3, carbachol (100 nM) induced a twofold increase in the production of inositol tri-tetra-phosphates; in parallel, a phosphorylation of ERK MAP kinases occurred within 1 min of carbachol stimulation. In conclusion, cultured functional myocytes derived from mature tissue may be used for long-term studies concerning the events coupled either to proliferation or to motility regulation of differentiated SMCs due to the activation of G-protein-coupled receptors.


Oxidative stress during vitamin A-induced abnormal tail regeneration in the tadpoles of Polypedates maculatus.
Vitamin A and its derivatives inhibit normal tail regeneration in amphibians. The most remarkable effect is the development of limbs at the cut end of the tail in anurans. Prior to ectopic limb development, there is an abnormal tail regeneration in the treated tadpoles. The purpose of the present study was to compare oxidative stress condition in the regenerated tail of normal and vitamin A (10I U/ml, 72 h) treated tadpoles. The present findings show a hyper-oxidative stress condition in the regenerated tail of the vitamin A-treated tadpoles of the Indian jumping frog, Polypedates maculatus (Anura: Rhacophoridae).


Reappraisal of Perforasomes of the Superficial Femoral, Descending Genicular, and Saphenous Arteries and Clinical Applications to Locoregional Reconstruction.
The superficial femoral artery and medial thigh region has been an underused donor site for perforator flaps. This study evaluated perforasomes of the superficial femoral artery and its principal branches to review the clinical applications for locoregional reconstruction. Twenty-six fresh cadaveric lower extremities were dissected. Perforator size and anatomical course from the superficial femoral artery, descending genicular artery, and saphenous artery branch were documented. Perforators were selectively injected with iodinated contrast to assess vascular territories using computed tomography. A retrospective chart review was conducted on consecutive patients (2014 to 2015). One hundred thirty perforators were mapped in the medial thigh region. Eleven extended medial thigh perforator flaps and 15 hemicircumferential flaps were harvested. The mean distance from the joint line was 16.7 ± 7.3 cm. Perforators arose from the superficial femoral artery (62 percent), saphenous artery branch (23 percent), and descending genicular artery (15 percent). Superficial femoral artery perforators were located around the mid and proximal thigh region (p < 0.001). The median perforasome surface area was 244 cm, representing 36 percent in hemithigh flaps with preferential filling in the anteromedial region. Proximal perforasomes were the smallest. Perforasome areas based on vessel origin were comparable; however, saphenous artery perforators had a broader perforasome compared with descending genicular (p = 0.01) and superficial femoral artery perforators (p = 0.04). Six clinical case examples were presented for knee, thigh, and lower leg reconstruction. The superficial femoral artery or its branches can provide nontraditional reconstructive perforator flap options in regional reconstruction. They can be simple to harvest using a free-style approach, do not require preoperative imaging, offer a one-stage reconstructive method with low morbidity, and obviate the need for microsurgery or muscle flaps.


School screening in remote aboriginal communities--results of an evaluation.
As part of ongoing quality assurance, the effectiveness of the school screening program in meeting the health needs of Aboriginal children in a rural district in the Northern Territory Top End was evaluated. The major health problems of Aboriginal children were analysed for their suitability for screening programs. A prospective cross-sectional study used routinely collected field data from the school screening program in 1993. To ascertain follow-up, children who had failed screening tests had their clinic notes reviewed. A total of 774 children from 11 remote communities were screened. The results confirmed high level of disease, with rates for anaemia, malnutrition and trachoma reaching 39%, 22% and 26% respectively. Nearly one-third failed the hearing screening, urinalysis was abnormal in 19%, 3% failed visual acuity and 6% were considered to have abnormal heart auscultation. Many of the major health problems did not meet the recommended criteria for screening programs and others would be better dealt with by ongoing surveillance rather than a single screening. Some abnormalities found on screening were inadequately investigated and/or treated. This evaluation has demonstrated a limited role for school screening in identifying and meeting the health needs of Aboriginal children living in remote areas. In collaboration with the NT Department of Education, a school-age child health policy, including a new school-age child health surveillance program, is being developed. This promotes greater participation by communities, families and schools with the aim of improving the health and learning outcomes for all school-age children in the NT.


Patient satisfaction in musculoskeletal medicine.
This is a literature review of the measurement of patient satisfaction in musculoskeletal medicine. Its purpose is to better understand the motivation for such measurements, the potential confounders, and the potential physician behaviors that may modulate such measures. There have been studies documenting that physician conveyance of empathy, the extent to which patients' expectations for pain control and timeliness of care are met, as well as patient demographics and health status all affect the current measures of patient satisfaction. In the mission to affect patient-centered care are met, musculoskeletal providers will be measured by their patients' satisfaction. There is much yet to be understood regarding patients' expectations of care; the science behind case-mix adjustment in this sphere is in its infancy, but there are some compelling reasons for musculoskeletal providers to attempt to optimize their patients' satisfaction.


Fluorescence resonance energy transfer between a quantum dot donor and a dye acceptor attached to DNA.
We show that direct coupling of a dye-labelled DNA (acceptor) to a quantum dot (QD) donor significantly reduces the donor-acceptor distance and improves the FRET efficiency: a highly efficient FRET (approximately 88%) at a low acceptor-to-donor ratio of 2 has been achieved at the single-molecule level.


Splenic artery pseudoaneurysm resulting from gastric ulcer presenting acute upper gastrointestinal bleeding.
Splenic artery pseudoaneurysm (SAP) is a rare entity, which occurs when the arterial wall is composed only of the intima and media mainly caused by pancreatitis, or abdominal trauma. Regardless of size, SAP is a high mortality disease that carries a high risk of rupture, causing abdominal pain and severe pancreatic and gastrointestinal bleeding. Here, we describe a rare case of SAP rupture caused by a large gastric ulcer due to Helicobacter pylori infection and NSAIDs use. Understanding the characteristic enhanced CT images of SAP, the complications of splenic infarction, and the therapeutic efficacy of arterial embolization is essential for the clinician to properly diagnose and treat SAP.


Quitline Promotion to Medicaid Members Who Smoke: Effects of COVID-19-Specific Messaging and a Free Patch Offer.
People who smoke are at increased risk of serious COVID-19-related disease but have had reduced access to cessation treatment during the pandemic. This study tested 2 approaches to promoting quitline services to Medicaid members who smoke at high rates: using COVID-19-specific messaging and offering free nicotine patches. The hypotheses were that both would increase enrollment. A California Medicaid mailing from October 2020 to January 2021 (N=7,489,093) included 4 versions of a flyer following a 2 × 2 design comparing generic with COVID-19-specific messaging and a no-patch with free-patch offer. The main outcome measure was quitline enrollments. Quit outcomes (attempted quitting, quit ≥7 days, quit ≥30 days) were assessed at 2 months. A subsequent free-patch offer was sent to all members (N=7,577,198) from April 2021 to June 2021. Data were collected in 2020-2021 and analyzed in 2022. The first mailing generated 1,753 enrollments. Response rates were 0.023% and 0.024% for generic and COVID-19-specific messaging, respectively (p=0.538), and 0.006% and 0.041% for no-patch and free-patch offers, respectively, the latter being 6.7 times more effective than the former (p<0.0001). Quit outcomes were comparable across conditions. The subsequent free-patch offer generated 3,546 enrollments at $40.28 per enrollee. In a Medicaid mailing during COVID-19, offering free patches generated more than 6 times as many quitline enrollments as offering generic help. COVID-19-specific messaging was no more effective than generic messaging. Offering free patches was highly cost-effective. Medicaid programs partnering with quitlines should consider using similar strategies, especially during a pandemic when regular health care is disrupted.


Elevated vascular resistance after labetalol during resection of a pheochromocytoma (brief report).
To report a case of pheochromocytoma exhibiting an increase in systemic vascular resistance index (SVRI) and decreased cardiac index (CI) after use of labetalol. A 36-yr-old male underwent adrenectomy for pheochromocytoma. Midazolam 5 mg, fentanyl 100 microg and labetalol 20 mg were administrated intravenously for premedication upon arrival in the operating theatre. After induction of anesthesia with fentanyl, thiopental and atracurium, 30 mg iv labetalol was administered. The blood pressure gradually rose to 178/101 mmHg with mildly increased SVRI (1958 dn-sec(-1).m(2).cm(5)) and stable CI (3.8 L.min(-1).m(2) ). The blood pressure reached 247/150 mmHg after intubation with an increase in SVRI (3458 dn-sec(-1).m(2).cm(5)) and a decrease in CI (3.6 L.min(-1).m(2)). The SVRI increased further to 4986 dn-sec(-1).m(2).cm(5) and CI declined to 2.4 L.min(-1).m(2) after the administration of additional labetalol 20 mg. Sodium nitroprusside was administered and the blood pressure declined immediately to 108/72 mmHg, with a decreased SVRI (2526 dn-sec(-1).m(2).cm(5)) and stable CI (2.3 L.min(-1).m(2)). The elevated SVRI with low CI was considered to result from increased alpha-adrenergic activity secondary to ss-adrenergic blockade with labetalol. Clinicians should be aware of the possibility of a hypertensive crisis after iv labetalol. We suggest that labetalol should be replaced promptly with alpha-adrenergic blockers or other vasodilators when such a condition arises.


Activities of some enzymes of phospholipid metabolism in cultured rat ventricular myocytes in normoxic and hypoxic conditions.
Phospholipid catabolism is thought to be one of the critical events in membrane injury during heart ischemia. In this work, the enzymes involved in phospholipid metabolism were studied in purified cultured ventricular myocytes in normoxic and hypoxic conditions. Purified ventricular myocytes exhibited an alkaline phospholipase A activity which had sn-2 specificity and which was calcium dependent, and an acid phospholipase A activity with sn-1 specificity. These cells also exhibited lysophospholipase and acyl-CoA/lysophosphatidylcholine acyltransferase activities. Oxygen deprivation of the myocardial cells for 4 h resulted in a sharp reduction of both phospholipase A2 and A1 activities. The activities of the other lipolytic enzymes were unaffected by hypoxia. Although hypoxia resulted in a marked increase of lactate dehydrogenase leakage in the bathing fluid, no additional release of the lipolytic enzymes and mitochondrial enzyme was observed. However, we noted an important alkaline phospholipase A2 leakage during normoxia. It is suggested that ventricular myocytes, under hypoxia, tend to prevent phospholipid degradation by reducing their phospholipase A activities.


[Effects of inorganic arsenicals on the methylation of p16 gene CpG islands and the expression of p16 gene in BEP2D cells].
To study the effects of inorganic arsenicals on the methylation of p16 gene CpG islands and the expression of p16 gene in BEP2D cells. The methylation of p16 gene CpG islands and the expression of p16 gene in BEP2D cells were measured by methylation-specific PCR (MSP) and RT-PCR methods. (1) The exposure of the BEP2D cells to sodium arsenite (0.016 approximately 2 micromol/L) or high-density sodium arsenate (80 approximately 160 micromol/L), but not low-density sodium arsenate (20 approximately 40 micromol/L), produced significant hypermethylation of p16 gene CpG islands in BEP2D cells. (2) The expressions of p16 gene in the groups of sodium arsenite and sodium arsenate at the test were lower than that of the control group, especially in the groups of sodium arsenite. Inorganic arsenicals alter the methylation patterns and the expression of p16 gene in BEP2D cells, which suggests that the hypermethylation of p16 gene CpG islands may be one of the mechanisms of carcinogenesis of inorganic arsenicals.


How have evolutions in strategies for the treatment of relapsed/refractory multiple myeloma translated into improved outcomes for patients?
Although multiple myeloma (MM) remains incurable, the introduction of novel agents has improved clinical outcomes dramatically over the past 15 years. Response rates have risen from ∼30% with single agents to up to 90% with combination therapies. The immunomodulatory drugs (IMiDs) thalidomide and lenalidomide, and the proteasome inhibitor bortezomib, form the foundations for treatment of relapsed and/or refractory MM (RRMM). Newer agents, such as the IMiD pomalidomide, the histone deacetylase inhibitor panobinostat and the proteasome inhibitors carfilzomib and ixazomib, as well as the monoclonal antibodies daratumumab and elotuzumab, have further improved overall response rates in these patients. Importantly, increased response rates have been observed in heavily pretreated patients. The availability of highly effective and tolerable drugs may offer alternative treatment strategies to those who are unsuitable for treatment with thalidomide, lenalidomide or bortezomib. Improving tolerability of treatment regimens and lengthening progression-free intervals has been shown to significantly improve health-related quality of life for patients living with RRMM.


Surgical management of familial polyposis and Gardner's syndrome.
Twenty-six patients with documented familial polyposis or Gardner's syndrome were followed up to twenty-eight years after total colectomy with ileorectal anastomosis. All patients were followed a minimum of five years. Patients were subjected to periodic proctosigmoidoscopies, and rectal polyps were electrocoagulated when found. In no patient in this series did an adenocarcinoma of the rectum develop during the follow-up period. Total abdominal colectomy with ileorectal anastomosis is the treatment of choice in patients with familial polyposis and Gardner's syndrome, provided adequate follow-up is assured and polyps are destroyed when encountered.


Dermatitis due to orthopaedic implants. A review of the literature and report of three cases.
The cases of three patients who had dermatosis that was caused by an orthopaedic implant are reported. The main clinical pattern was localized or generalized eczema or urticaria. The diagnostic criteria that have been proposed by various authors are reviewed. Removal of the implant did not always result in rapid disappearance of the dermatosis, presumably because a few particles of metal remained in the area of the implant.


Real-time fiber-optic recording of acute-ischemic-stroke signatures.
We present an experimental framework and methodology for in vivo studies on rat stroke models that enable a real-time fiber-optic recording of stroke-induced hydrogen peroxide and pH transients in ischemia-affected brain areas. Arrays of reconnectable implantable fiber probes combined with advanced optogenetic fluorescent protein sensors are shown to enable a quantitative multisite time-resolved study of oxidative-stress and acidosis buildup dynamics as the key markers, correlates and possible drivers of ischemic stroke. The fiber probes designed for this work provide a wavelength-multiplex forward-propagation channel for a spatially localized, dual-pathway excitation of genetically encoded fluorescence-protein sensors along with a back-propagation channel for the fluorescence return from optically driven fluorescence sensors. We show that the spectral analysis of the fiber-probe-collected fluorescence return provides means for a high-fidelity autofluorescence background subtraction, thus enhancing the sensitivity of real-time detection of stroke-induced transients and significantly reducing measurement uncertainties in in vivo acute-stroke studies as inherently statistical experiments operating with outcomes of multiply repeated measurements on large populations of individually variable animal stroke models.


Fatty acid-binding protein 3 regulates differentiation of IgM-producing plasma cells.
Plasma cells (PCs), which aim to protect host health, produce various subsets of immunoglobulin (Ig) in response to extracellular pathogens. Blimp-1 (encoded by Prdm1)-a protein that is highly expressed by PCs-is important for PC functions, including the generation of Igs. Fatty acid-binding protein 3 (FABP3) is a carrier protein of polyunsaturated fatty acids (PUFAs) and participates in multiple cellular functions. Although the functions of FABP3 in neurons and cardiac myocytes are well-noted, their roles in immune cells remain to be fully elucidated. In this study, we demonstrate that FABP3 is expressed in activated B cells and that FABP3 promotes PC development and IgM secretion. Moreover, we provide the first evidence that FABP3 is necessary for Blimp-1 expression, by regulating the histone modification of its promoter region. Taken together, our findings reveal that FABP3 acts as a positive regulator of B-cell activation by controlling histone acetylation of the Blimp-1 gene, thereby playing a role in host defense against pathogens.


Development and implementation of a population-based breast cancer quality index in Queensland, Australia.
While quality indicators (QI) are relatively commonplace, QIs focusing on breast cancer treatment and outcomes have not been previously developed in Australia. We describe the development and implementation of the Queensland Breast Cancer Quality Index (BCQI) and report on trends in performance indicators over time. Development of the BCQI was overseen by a clinician-led quality assurance committee covering several clinical disciplines. Using a population-based dataset of female patients diagnosed with breast cancer from 2007 to 2016 (n = 27,541) we examined trends in indicators over time. The BCQI includes two quality dimensions (Effective and Accessible) and 14 indicators for public and private cancer services. Rates of re-excision following breast conservation surgery (BCS) and conversion of BCS to mastectomy reduced over time (p < 0.001 and p = 0.005, respectively). BCS was less common for women living outside a major city (p < 0.001), who had their surgery in a public (p < 0.001) or low volume hospital (p < 0.001). Application of the BCQI at a population-level demonstrated our results are comparable to, and in some cases superior to other jurisdictions. We identified some areas where improvement over time has occurred, while also identifying some outcomes requiring further investigation. The BCQI is a well-established and valuable tool for measuring and monitoring breast cancer care. Practice indicators provide useful information to assist with identifying services performing well as well as those that may benefit from improvement.


Factors affecting stomatal uptake of ozone by different canopies and a comparison between dose and exposure.
Measured ozone (O(3)) and carbon dioxide (CO(2)) concentrations and fluxes over five different canopies (mixed coniferous-deciduous forest, deciduous forest, corn, soybean and pasture) in the eastern USA were analyzed to investigate the stomatal uptake of O(3). It was found that the ambient O(3) concentration levels had little effect on stomatal conductance. However, the accumulated stomatal uptake of O(3), upon reaching a threshold value on any given day, appears to reduce the rate of further O(3) uptake substantially. This may explain why the maximum O(3) deposition velocity often appeared in the early morning hours over some forest canopies. Substantially reduced CO(2) fluxes over wet canopies compared to dry canopies suggest that stomata were likely partially or totally blocked by water droplets or films when canopies were wet. By using a big-leaf dry deposition model, measured O(3) fluxes were separated into stomatal and non-stomatal portions. It was estimated that stomatal uptake contributed 55-75% of the total daytime O(3) fluxes and 40-60% of the total daytime plus nighttime fluxes, depending on canopy type. This suggests that about half of the total O(3) flux occurred through the non-stomatal pathway. At three locations (deciduous forest, corn and soybean sites), O(3) concentrations of 30-60 ppb and of 60-85 ppb contributed equally to the accumulated stomatal fluxes, while at the other two locations (mixed coniferous-deciduous forest and pasture sites), concentrations of 30-60 ppb contributed twice as much as those from 60 to 85 ppb.


Disparity in Adiposity among Adults with Normal Body Mass Index and Waist-to-Height Ratio.
Body mass index (BMI) is commonly used to define obesity. However, concerns about its accuracy in predicting adiposity have been raised. The feasibility of using BMI as well as waist-height ratio (WHtR) in assessing adiposity was examined in relation to a more direct measurement of percent body fat (%BF). We analyzed the relation between dual-energy X-ray absorptiometry (DXA)-measured fat mass and BMI and WHtR using the US 1999-2004 National Health and Nutrition Examination Survey (NHANES) data. A considerable proportion of subjects in the healthy BMI range 20-25 were found to have excess adiposity, including 33.1% of males and 51.9% of females. The use of WHtR also supports the notion of normal-weight central obesity (NWCO), which increases with age. These findings have important implications not only for clinical practice but also for many comparative studies where control subjects are usually selected based on age, sex, and BMI.


Supradural inflammatory soup in awake and freely moving rats induces facial allodynia that is blocked by putative immune modulators.
Facial allodynia is a migraine symptom that is generally considered to represent a pivotal point in migraine progression. Treatment before development of facial allodynia tends to be more successful than treatment afterwards. As such, understanding the underlying mechanisms of facial allodynia may lead to a better understanding of the mechanisms underlying migraine. Migraine facial allodynia is modeled by applying inflammatory soup (histamine, bradykinin, serotonin, prostaglandin E2) over the dura. Whether glial and/or immune activation contributes to such pain is unknown. Here we tested if trigeminal nucleus caudalis (Sp5C) glial and/or immune cells are activated following supradural inflammatory soup, and if putative glial/immune inhibitors suppress the consequent facial allodynia. Inflammatory soup was administered via bilateral indwelling supradural catheters in freely moving rats, inducing robust and reliable facial allodynia. Gene expression for microglial/macrophage activation markers, interleukin-1β, and tumor necrosis factor-α increased following inflammatory soup along with robust expression of facial allodynia. This provided the basis for pursuing studies of the behavioral effects of 3 diverse immunomodulatory drugs on facial allodynia. Pretreatment with either of two compounds broadly used as putative glial/immune inhibitors (minocycline, ibudilast) prevented the development of facial allodynia, as did treatment after supradural inflammatory soup but prior to the expression of facial allodynia. Lastly, the toll-like receptor 4 (TLR4) antagonist (+)-naltrexone likewise blocked development of facial allodynia after supradural inflammatory soup. Taken together, these exploratory data support that activated glia and/or immune cells may drive the development of facial allodynia in response to supradural inflammatory soup in unanesthetized male rats.


Bifidobacterial carbohydrate/nucleoside metabolism enhances oxidative phosphorylation in white adipose tissue to protect against diet-induced obesity.
Comparisons of the gut microbiome of lean and obese humans have revealed that obesity is associated with the gut microbiome plus changes in numerous environmental factors, including high-fat diet (HFD). Here, we report that two species of Bifidobacterium are crucial to controlling metabolic parameters in the Korean population. Based on gut microbial analysis from 99 Korean individuals, we observed the abundance of Bifidobacterium longum and Bifidobacterium bifidum was markedly reduced in individuals with increased visceral adipose tissue (VAT), body mass index (BMI), blood triglyceride (TG), and fatty liver. Bacterial transcriptomic analysis revealed that carbohydrate/nucleoside metabolic processes of Bifidobacterium longum and Bifidobacterium bifidum were associated with protecting against diet-induced obesity. Oral treatment of specific commercial Bifidobacterium longum and Bifidobacterium bifidum enhanced bile acid signaling contributing to potentiate oxidative phosphorylation (OXPHOS) in adipose tissues, leading to reduction of body weight gain and improvement in hepatic steatosis and glucose homeostasis. Bifidobacterium longum or Bifidobacterium bifidum manipulated intestinal sterol biosynthetic processes to protect against diet-induced obesity in germ-free mice. Our findings support the notion that treatment of carbohydrate/nucleoside metabolic processes-enriched Bifidobacterium longum and Bifidobacterium bifidum would be a novel therapeutic strategy for reprograming the host metabolic homeostasis to protect against metabolic syndromes, including diet-induced obesity. Video Abstract.


Adrenergic and VIP-ergic relaxatory mechanisms of the feline extrahepatic biliary tree.
Relaxatory mechanisms of the extrahepatic biliary tree were investigated in anesthetized cats allowing separate recordings of the sphincter of Oddi, gallbladder and duodenal wall. Regional intra-arterial administration of vasoactive intestinal peptide (VIP) elicited dose-dependent relaxatory motor responses, which were not influenced by blockade of cholino- or beta-adrenoceptors, but were most probably due to activation of VIP receptors at the smooth muscle membrane. Efferent electrical vagal nerve stimulation unmasked relaxatory motor responses after previous blockade of muscarinic cholinoceptors. The neural transmission did not involve beta-adrenoceptors but was effectively antagonized after additional blockade with hexamethonium. Since both nerve terminals and ganglion cells with VIP-like immunoreactivity were abundant in the feline sphincter of Oddi, VIP is one possible transmitter candidate of the postganglionic inhibitory neurons. Non-selective activation of beta-adrenoceptors by isoprenaline or selective activation of beta 2-adrenoceptors by terbutaline also induced a dose-dependent relaxation of these regions. On a molar basis, relaxation via beta-adrenoceptors was 40-50 times less potent than via VIP. Both types of beta-adrenergic relaxation were antagonized by propranolol. The terbutaline-induced responses were selectively antagonized by beta 2-adrenoceptor blockade. To evaluate the role of beta 1-adrenoceptors, non-selective stimulation with isoprenaline was given; this relaxation was little influenced by blockade of beta 2-adrenoceptors but was completely antagonized by propranolol. In all experiments using beta-adrenoceptor antagonists these drugs each increased the basal tone of the preparation suggesting release of tonic inhibition exerted via beta-adrenoceptors.


Thymus size and its relationship to the respiratory distress syndrome.
Thymic size can be affected by both exogenous and endogenous glucocorticoids. The risk of respiratory distress syndrome is reduced after maternal steroid administration. To find whether fetal lung maturity correlates with size of the thymus, the cardiothymic:thoracic ratio was measured in 167 newborn infants with and without RDS. Mean CT/T was significantly greater (0.40 vs 0.35; P less than 0.001) in those babies with RDS. This relation was independent of gestational age, although an increase in CT/T with advancing gestational age was shown. Prepartum maternal steroid administration did not result in significant involution of the cardiothymic shadow when compared with control infants with and without RDS. The CT/T may be of use in predicting which premature babies are more likely to develop RDS.


Inhibition of telomerase RNA decay rescues telomerase deficiency caused by dyskerin or PARN defects.
Mutations in the human telomerase RNA component (hTR), the telomerase ribonucleoprotein component dyskerin (DKC1) and the poly(A) RNase (PARN) can lead to reduced levels of hTR and to dyskeratosis congenita (DC). However, the enzymes and mechanisms responsible for hTR degradation are unknown. We demonstrate that defects in dyskerin binding lead to hTR degradation by PAPD5-mediated oligoadenylation, which promotes 3'-to-5' degradation by EXOSC10, as well as decapping and 5'-to-3' decay by the cytoplasmic DCP2 and XRN1 enzymes. PARN increased hTR levels by deadenylating hTR, thereby limiting its degradation by EXOSC10. Telomerase activity and proper hTR localization in dyskerin- or PARN-deficient cells were rescued by knockdown of DCP2 and/or EXOSC10. Prevention of hTR RNA decay also led to a rescue of localization of DC-associated hTR mutants. These results suggest that inhibition of RNA decay pathways might be a useful therapy for some telomere pathologies.


The interaction between the mu opioid receptor and filamin A.
Our laboratory embarked on research to discover proteins the interaction of which with the mu opioid receptor (MOPr) is required for its function and regulation. We performed yeast two-hybrid screens, using the carboxy tail of the human MOPr as bait and a human brain library. This yielded a number of proteins that seemed to bind to the MOPr C-tail. The one we chose to study in detail was filamin A (FLNA). Evidence was obtained that there was indeed protein-protein binding between the C-tail of MOPr and FLNA. A human melanoma cell line (M2) lacking the gene for FLNA and a control cell line (A7) which differed from M2 only in having been transfected with the gene for FLNA and expressing the FLNA protein were made available to us. We transfected these cell lines with the gene for MOPr and used them in our studies. The absence of FLNA strongly reduced MOPr downregulation as well as desensitization of adenylyl cyclase inhibition and G protein activation. A recent finding, published here for the first time, is that FLNA is required for the activation by mu opioid agonists of the MAP kinase p38. Deletion studies indicated that the MOPr binding site on FLNA is in the 24th repeat, close to its C-terminal. It was further found that FLNA lacking the N-terminal actin binding domain is as capable as full length FLNA to restore cells to control status, suggesting that actin binding is not required. A surprising finding was that upregulation of MOPr by morphine and some agonist analogs occurs in M2 cells lacking FLNA, whereas normal receptor downregulation takes place in A7 cells.


A comparison of antiasthma drugs between acute and chronic ovalbumin-challenged guinea-pig models of asthma.
Pre-clinical evaluation of asthma therapies requires animal models of chronic airways inflammation, airway hyperresponsiveness (AHR) and lung remodelling that accurately predict drug effectiveness in human asthma. However, most animal models focus on acute allergen challenges where chronic inflammation and airway remodelling are absent. Chronic allergen challenge models have been developed in mice but few studies use guinea-pigs which may be more relevant to humans. We tested the hypothesis that a chronic rather than acute pulmonary inflammation model would best predict clinical outcome for asthma treatments. Guinea-pigs sensitized with ovalbumin (OVA) received single (acute) or nine OVA inhalation challenges at 48 h intervals (chronic). Airways function was recorded as specific airways conductance (sG(aw)) in conscious animals for 12 h after OVA challenge. AHR to inhaled histamine, inflammatory cell influx and lung histology were determined 24 h after the single or 9th OVA exposure. The inhaled corticosteroid, fluticasone propionate (FP), the phosphodiesterase 4 inhibitor, roflumilast, and the inducible nitric oxide synthase (iNOS) inhibitor, GW274150, orally, were administered 24 and 0.5 h before and 6 h after the single or final chronic OVA exposure. Both models displayed early (EAR) and late (LAR) asthmatic responses to OVA challenge, as falls in sG(aw), AHR, as increased histamine-induced bronchoconstriction, and inflammatory cell influx. Tissue remodelling, seen as increased collagen and goblet cell hyperplasia, occurred after multiple OVA challenge. Treatment with FP and roflumilast inhibited the LAR, cell influx and AHR in both models, and the remodelling in the chronic model. GW274150 also inhibited the LAR, AHR and eosinophil influx in the acute model, but not, together with the remodelling, in the chronic model. In the clinical setting, inhaled corticosteroids and phosphodiesterase 4 inhibitors are relatively effective against most features of asthma whereas the iNOS inhibitor GW274150 was ineffective. Thus, while there remain certain differences between our data and clinical effectiveness of these antiasthma drugs, a chronic pulmonary inflammation guinea-pig model does appear to be a better pre-clinical predictor of potential asthma therapeutics than an acute model.


Diastereoselection of chiral acids in a cylindrical capsule.
The cylindrical dimeric capsule binds two chiral carboxylic acids with modest selectivity for homochiral or heterochiral pairs.


Design and performance study of a novel immobilized hollow fiber membrane bioreactor.
A dual-layer coaxial hollow fiber (DLHF) bioreactor for cell immobilization developed to overcome nutrients transport limitation is presented. Cells were contained in the annular space between two coaxial hollow fibers, and nutrients were supplied by a forced convective transport from the shell side through the annular space to the lumen side. With judicious selection of the membrane materials, a low operating transmembrane pressure of 50 kPa, and using E. coli as the model organism, a high cell density of 10(11) cells/mL annular space volume and a high cell viability of (up to 80%) were obtained.


Appetite ratings and ghrelin concentrations in young adults after administration of a balanced meal. Does sex matter?
Sex-based differences in appetite ratings have been observed previously. Ghrelin is the only known orexigenic peptide hormone. Sex differences in postprandial ghrelin responses may underlie different perceptions of hunger and satiety, but results are conflicting. We conducted a parallel study to evaluate sex differences in postprandial appetite ratings and ghrelin concentration after administration of a physiological meal among students of University of Milan. Twenty-four healthy, normal weight volunteers (12 men and 12 women) aged 18-35 years were recruited. A balanced mixed meal meeting 40% of the estimated daily energy expenditure and providing 60% of calories from carbohydrates, 25% from lipids and 15% from protein was administrated. Sex differences in appetite ratings (satiety, hunger, fullness and desire to eat) and magnitude of ghrelin suppression during postprandial period (up to 180 min) were determined. In the fasting state, men and women did not differ in appetite ratings and ghrelin concentrations. After feeding, women tended to reach peak of satiety earlier than men, who in turn reached the nadir of hunger later than women (median: 30 min, interquartile range (IQR): 1; 120 vs. 1 min, IQR 1; 1, p = 0.007). Ghrelin suppression was greater in women (median decremental AUC - 95, IQR - 122; - 66) than in men (median decremental AUC - 47, IQR - 87; - 31, p = 0.041). These findings suggest sex differences in the postprandial appetite regulation that might be important for nutritional strategy to prevent and treat obesity and eating disorders.


Genetic polymorphisms influencing response to lithium in early-onset Bipolar disorder from south India.
Early-onset Bipolar disorder (EOBD), has a more malignant course with high recurrence risk and there is a need for population-specific pharmaco-genomic study. This study is a prospective and retrospective observational study. Both newly diagnosed patients and those on follow-up with a diagnosis of bipolar I disorder with onset before 18 years of age and on lithium prophylaxis as part of treatment-as-usual were recruited for the study. Response to treatment was assessed at the end of two years follow up using ALDA scale. Ten single nucleotide polymorphisms associated with treatment response based on previous studies were chosen for analysis. Of 162 who had EOBD, sixty-four fulfilled inclusion criteria and fifty-seven completed the study. TT and TG genotypes of rs75222709 on AL157359.3 gene were found to be significantly different between non-responders(N = 43) and healthy controls (N = 220). The frequency of the GA genotype of the single nucleotide polymorphism rs17204573 of the RORA (Retinoic Acid related orphan receptor alpha) gene was significantly lower among subjects (27.3%, N = 54) as compared to controls (42.9%, OR:0.5, CI: 0.26-0.96, p value 0.035). However, the significance of both disappeared after Bonferroni correction. Among clinical factors female gender was significantly associated with lithium non-response. Although conducting pharmaco-genomic studies with large sample size is a challenge for low and middle-income countries, future studies can help improve the long-term outcome of youth with EOBD.


The mitogenic response of T cells to interleukin-2 requires Raf-1.
The product of the c-raf-1 proto-oncogene, Raf-1, is known to encode a 74-kDa ubiquitously expressed cytoplasmic serine/threonine kinase. Various growth factors such as epidermal growth factor, acidic fibroblast growth factor, platelet-derived growth factor, insulin, granulocyte-macrophage colony-stimulating factor, interleukin (IL)-2, IL-3 and erythropoietin have been shown to induce phosphorylation of Raf-1, thereby activating Raf-1 kinase. Raf-1 is, thus, believed to play a role in coupling growth factor receptors to proliferation. We have examined the role of Raf-1 in the mitogenic response of human peripheral blood-derived IL-2 receptor expressing T cells to human recombinant IL-2 employing c-raf antisense (AS) oligodeoxyribonucleotide. Uptake studies of oligonucleotides indicated that incorporation of oligomers was maximal at 4 h and oligodeoxynucleotides remained stable in these cells for up to 24 h. Treatment of T cells with the AS oligodeoxyribonucleotide in intracellular duplex formation followed by efficient translation blockade of c-raf-1. In contrast, sense (S) and nonsense (NS) oligodeoxynucleotides failed to form intracellular duplexes and did not interfere with translation of c-raf-1, suggesting specific elimination of c-raf-1 by the AS oligomer. Proliferation of T cells ([3H]thymidine incorporation) following exposure to IL-2 was substantially reduced when the c-raf-1 AS oligodeoxyribonucleotide was added to cultures, while the mitogenic response to this factor remained almost unaffected in the presence of S and NS oligodeoxyribonucleotides.


Motor state changes escape behavior of crickets.
Animals change their behavior depending on external circumstances, internal factors, and their interactions. Locomotion state is a crucial internal factor that profoundly affects sensory perception and behavior. However, studying the behavioral impacts of locomotion state in free-moving animals has been challenging due to difficulty in reproducing quantitatively identical stimuli in freely moving animals. We utilized a closed-loop controlled servosphere treadmill system, enabling unrestricted confinement and orientation of small animals, and investigated wind-induced escape behavior in freely moving crickets. When stimulated during locomotion, the crickets quickly stopped before initiating escape behavior. Moving crickets exhibited a higher probability of escape response compared to stationary crickets. The threshold for pausing response in moving crickets was also much lower than the escape response threshold. Moving crickets had delayed reaction times for escape and greater variance in movement direction compared to stationary crickets. The locomotion-related response delay may be compensated by an elevated sensitivity to airflow.


Incidence and predictors for chronicity of headache in patients with episodic migraine.
The authors followed 532 consecutive patients with episodic migraine (<15 days/month) for 1 year. Sixty-four patients (14%) developed chronic headache (>/=15 days/month). The odds ratios for developing CH were 20.1 (95% CI 5.7 to 71.5) comparing patients with a "critical" (10 to 14 days/month) vs "low" (0 to 4 days/month) and 6.2 (95% CI 1.7 to 26.6) in patients with an "intermediate" (6 to 9 days/month) vs "low" headache frequency and 19.4 (95% CI 8.7 to 43.2) comparing patients with and without medication overuse.


Large-scale analysis of acquired chromosomal alterations in non-tumor samples from patients with cancer.
Mosaicism, the presence of subpopulations of cells bearing somatic mutations, is associated with disease and aging and has been detected in diverse tissues, including apparently normal cells adjacent to tumors. To analyze mosaicism on a large scale, we surveyed haplotype-specific somatic copy number alterations (sCNAs) in 1,708 normal-appearing adjacent-to-tumor (NAT) tissue samples from 27 cancer sites and in 7,149 blood samples from The Cancer Genome Atlas. We find substantial variation across tissues in the rate, burden and types of sCNAs, including those spanning entire chromosome arms. We document matching sCNAs in the NAT tissue and the adjacent tumor, suggesting a shared clonal origin, as well as instances in which both NAT tissue and tumor tissue harbor a gain of the same oncogene arising in parallel from distinct parental haplotypes. These results shed light on pan-tissue mutations characteristic of field cancerization, the presence of oncogenic processes adjacent to cancer cells.


Electrochemical synthesis of ZnO branched submicrorods on carbon fibers and their feasibility for environmental applications.
We investigated the structural and optical properties of the hierarchically integrated zinc oxide (ZnO) branched submicrorods on carbon fibers (ZOCF) by scanning/transmission electron microscopy, X-ray diffraction, and photoluminescence (PL) measurements. The ZnO submicrorods were facilely synthesized by an electrochemical deposition method on polyacrylonitrile-based carbon fiber sheets used as a substrate. After coating the ZnO seed layer on the surface of the carbon fibers, ZnO submicrorods were densely grown on the nuclei sites of the seed layer. The prepared ZOCF samples exhibited high crystallinity and good PL properties. A feasibility for environmental application in Pb(II) removal from aqueous solutions was also studied. The ZOCF adsorbent exhibited an excellent maximum adsorption capacity of 245.07 mg g-1, which could be practically used in Pb(II) removal from water. These fabricated ZOCFs are potentially useful for multifunctional and environmental devices.


Quantitative structure-activity/ecotoxicity relationships (QSAR/QEcoSAR) of a series of phosphonates.
In this paper the structure-toxicity relationship studies were performed for a series of 60 phosphonates. The toxicity of the compounds was determined by two ways: by quantifying the measured toxicity values, Mlog(1/MRIC50) collected by literature, for rodents species; second by using EcoSAR software version 1.11, for calculating the toxicity for fish species, considered as dependent variables and they were related to structural features obtained by molecular and quantum mechanics calculations. The QSAR/QEcoSAR was validated by multiple linear regression (MLR), although the purpose of this work was not to validate the model proposed, but rather to test the influence of structural parameters of the proposed model QSAR/QEcoSAR. The obtained models showed that the toxicity of phosphonates was influenced by steric and molecular geometry which cause inhibition of cholinesterase activity.


An efficient isoelectric focusing of microcolumn array chip for screening of adult Beta-Thalassemia.
Traditional capillary isoelectric focusing (cIEF), liquid chromatography (LC) and capillary zone electrophoresis (CZE) still suffered from low resolution for hemoglobinopathy screening. Herein, a 30-mm pH 5.2-7.8 microcolumn IEF (mIEF) array chip was developed for hemoglobinopathy screening. As a proof of concept, adult beta-thalassemia was chosen as a model disease. In the method, blood samples were hemolyzed via hemolysin solution and loaded into the microcolumn. The experiments showed that (i) the species of Hb A, F, A2 and variants were clearly separated in the chip, and the resolution was greatly higher than the ones of LC/CZE/cIEF; (ii) up to 24 samples could be simultaneously analyzed in 12-min run; (iii) the intraday and interday RSDs were respectively 3.32-4.91 % and 4.07-5.33 %. The assays of mIEF to total 634 samples were compared with the ones of LC (n = 327) and PCR (n = 307). The cutoff of 3.5 % HbA2 led to the sensitivity of 100 % and specificity of 89.1 % for the mIEF-based screening; and there was 96.7 % coincidence between the methods of mIEF and PCR if refer Hb A2 and F. The method had the merits of facility, efficiency, specificity and sensitivity in contrast to the currently-used methods, implying its potential to screening of beta-thalassemia and hemoglobinopathies.


Effects of reductions in hemoglobin-oxygen affinity and hematocrit level on oxygen consumption and acid-base state in fetal lambs.
To determine whether the high oxygen affinity of fetal blood, compared with that of the adult, is advantageous to the fetus during fetal anemia we studied 16 chronically catheterized fetal lambs. Half of the lambs had hemoglobin-oxygen affinity reduced acutely by isovolemic exchange transfusion with fresh adult whole blood; the other half served as controls. In both groups of fetuses, we measured fetal oxygen delivery, oxygen consumption, and acid-base state at normal fetal hematocrit levels and during reductions in the hematocrit level of 30% (moderate anemia) and 60% (severe anemia) produced by isovolemic exchange transfusions with plasma. At normal fetal hematocrit levels, reductions in hemoglobin-oxygen affinity had no effect on fetal oxygen consumption or acid-base state. During moderate anemia, fetal oxygen delivery decreased in both series of fetuses, but oxygen consumption and base excess fell only in those fetuses whose circulations contained adult hemoglobin. During severe anemia, oxygen consumption and base excess decreased in both groups of fetuses, although these changes were more pronounced in fetuses with adult hemoglobin than in those with fetal hemoglobin. Our data indicate that, even though a high hemoglobin-oxygen affinity may not be essential to a healthy fetus, it is critical for normal metabolism in a fetus subjected to a hypoxic stress such as anemia.


Parenteral nutrition associated liver disease.
Liver disease is relatively common during parenteral nutrition (PN). Cholestasis predominates in infants, and ranges in severity from mild increases in plasma conjugated bilirubin to progressive liver failure that results in death of the patient. Severity of liver disease depends primarily on the magnitude of the underlying intestinal problem that indicated PN. Transient ileus resulting from a non-intestinal disorder usually results in trivial, self-limited liver injury. Removal of a large segment of the intestinal tract because of necrotizing enterocolitis or a congenital malformation predicts a more prolonged course with a guarded prognosis, particularly when initially complicated by sepsis. Pathogenesis of PN-associated liver disease is not completely understood. There is no proven treatment short of ending PN through adaptation of remnant intestine or intestinal transplantation, with or without a concurrent liver graft. Effective interventions that are less radical than transplantation are needed. Research that includes prospective trials of novel therapies in PN-associated liver disease is the key to improving outcome.


Roflumilast: an oral, once-daily selective PDE-4 inhibitor for the management of COPD and asthma.
Roflumilast is a selective phosphodiesterase-4 inhibitor with a broad range of anti-inflammatory actions. Studies in asthma and chronic obstructive pulmonary disease (COPD) have demonstrated that it can improve lung function and reduce inflammation. To review the clinical data on roflumilast in COPD and asthma. A PubMed search using the term roflumilast was used to identify articles, and the bibliographies of the identified articles were reviewed to identify other relevant reports. All roflumilast abstracts from the 2006 and 2007 International Meetings of the American College of Chest Physicians, American Thoracic Society and European Respiratory Society were also reviewed. The preliminary studies of roflumilast in COPD and asthma have only shown modest clinical benefits and may be associated with gastrointestinal side effects. Further studies are required to clarify the role of roflumilast in the management of COPD and asthma.


Distance-dependent visual fluorescence immunoassay on CdTe quantum dot-impregnated paper through silver ion-exchange reaction.
A paper-based visual fluorescence immunoassay is presented for the detection of matrix metalloproteinase-7 (MMP7) that is related to renal cancer. The method is based on the distance-dependent fluorescence quenching of CdTe quantum dots (QDs) on a nitrocellulose membrane by Ag+ following a sandwich-type immunoreaction on microtiter wells using silver nanoparticle (AgNP)-labeled secondary antibody- and primary antibody-coated microtiter wells. The silver nanoparticles captured in the well are dissolved with HNO3, while the quenching effect of QDs is based on silver ion-exchange reaction under 365-nm excitation light irradiation. Increasing concentration of released Ag+, thus higher concentration of the protein, leads to an increased distance of quenching on the nitrocellulose membrane. The paper-based immunoassay by combination of AgNP-assisted ion-exchange reaction with QD gives good distance-dependent responses and allows the detection of MMP7 at a concentration as low as 7.3 pg mL-1. The coefficients of variation are less than 6.9% and 12.4% for intra-assay and inter-assay, respectively. High specificity and long-term stability are achieved during the assay. Importantly, the testing of human serum samples using our strategy shows well-matched results with commercial human MMP7 ELISA kits. Graphical abstract A distance-dependent visual immunoassay is developed for the determination of serum matrix metalloproteinase-7 on CdTe quantum dot-impregnated paper with silver ion-exchange reaction.


Global and National Declines in Life Expectancy: An End-of-2021 Assessment.
Timely, high-quality mortality data have allowed for assessments of the impact of the novel coronavirus disease 2019 (COVID-19) on life expectancies in upper-middle- and high-income countries. Extant data, though imperfect, suggest that the bulk of the pandemic-induced mortality might have occurred elsewhere. This article reports on changes in life expectancies around the world as far as they can be estimated from the evidence available at the end of 2021. The global life expectancy appears to have declined by 0.92 years between 2019 and 2020 and by another 0.72 years between 2020 and 2021, but the decline seems to have ended during the last quarter of 2021. Uncertainty about its exact size aside, this represents the first decline in global life expectancy since 1950, the first year for which a global estimate is available from the United Nations. Annual declines in life expectancy (from a 12-month period to the next) appear to have exceeded two years at some point before the end of 2021 in at least 50 countries. Since 1950, annual declines of that magnitude had only been observed on rare occasions, such as Cambodia in the 1970s, Rwanda in the 1990s, and possibly some sub-Saharan African nations at the peak of the acquired immunodeficiency syndrome (AIDS) pandemic.


Nondestructive Transfer Strategy for High-Efficiency Flexible Perovskite Solar Cells.
Flexible perovskite solar cells (F-PSCs) have been developing fast with the power conversion efficiency (PCE) exceeding 19%. However, aiming at the high-efficiency F-PSCs, to get a desired perovskite morphology before and after glass-supportive device transfer is still a challenge. Herein, we thoroughly investigated the effect of adhesive materials of substrates on the perovskite film and the solar cell performance and developed a nondestructive F-PSC transfer method by introducing a double-side tape/protective film/epoxy binder. This nondestructive transfer strategy leads to a uniform morphology of perovskites, even after transfer process, yielding an enhanced PCE up to 16.55%.


Anti-inflammatory and cytotoxic carbazole alkaloids from Murraya kwangsiensis.
Chemical investigation of the traditional Chinese medicine, Murraya kwangsiensis, led to the isolation of 16 undescribed biscarbazole alkaloids, kwangsines A-M, two undescribed natural products, (+/-)-bispyrayafoline C, and 19 known monomeric analogues. (±)-Bispyrayafoline C and (±)-kwangsines A-C are four pairs of biscarbazole atropisomers, and they were separated by chiral HPLC to obtain the optically pure compounds. The structures of the undescribed compounds were elucidated on the basis of HRESIMS and NMR data analysis. Their absolute configurations were assigned via comparison of the specific rotation, ECD exciton coupling method, as well as comparison of experimental and calculated ECD data. A compound showed significant inhibition on NO production in lipopolysaccharide-stimulated BV-2 microglial cells, and four compounds exhibited moderate cytotoxicities against HepG2 cells, with IC50 values less than 20 μM.


Mechanism of endothelial cell shape change in oxidant injury.
Changes in endothelial cell morphology induced by neutrophil-generated hydrogen peroxide (H2O2) may account for the capillary leak of the adult respiratory distress syndrome (ARDS). The relationship of H2O2 effects on the concentration of intracellular Ca2+ [( Ca2+]i) and ATP to changes in microfilaments and microtubules, important determinants of cell shape, was examined. Bovine pulmonary artery endothelial cells were injured over a 2-hr time course with a range of H2O2 doses (0-20 mM). The higher concentrations of H2O2 consistently produced contraction and rounding of greater than 50-75% of cells by 1-2 hr. The range of 1-20 mM H2O2 produced rapid, significant reductions in endothelial ATP levels over the time course of injury. Although there were significant increases in mean endothelial [Ca2+]i in response to 5, 10, and 20 mM H2O2, 1 mM H2O2 did not affect the [Ca2+]i. Fluorescence microscopy revealed that microfilament disruption occurred as ATP levels fell and preceded depolymerization of microtubules which developed after [Ca2+]i approached 1 X 10(-6) M. H2O2 at 1 mM injury caused microfilament disruption but did not depolymerize microtubules. Microfilament disruption occurred without oxidant exposure, when ATP levels were reduced by glucose depletion and mitochondrial inhibition with oligomycin (650 nM). If a Ca2+ ionophore, ionomycin (5 microM), was then added, [Ca2+]i rose to greater than 1 X 10(-6) M, microtubules fragmented and depolymerized, and cell contraction and rounding very similar to that induced by H2O2 occurred. These results suggest that endothelial cell dysfunction and capillary leak in ARDS may be due to H2O2-mediated changes in cellular ATP and [Ca2+]i.


Metabolism of the carcinogen 1,2-dimethylhydrazine by isolated human colon microsomes and human colon tumor cells in culture.
Human colon microsomes catalyze the metabolism of the model colon carcinogen 1,2-dimethylhydrazine. Activity appears to be distributed in a gradient towards the lower end of the colon. Highest activities were observed for microsomes prepared from the descending segment of the colon with the transverse segment exhibiting lower activities, while the ascending segment showed the lowest rate of metabolism. Dimethylhydrazine metabolism in each segment is inhibited significantly by inhibitors of the cytochrome P-450-dependent mixed function oxidase system. Microsomes prepared from a human colon tumor cell also catalyze the metabolism of 1,2-dimethylhydrazine. Metabolic activity in the cell line can be induced two-fold by treatment of cells with phenobarbital and three-fold by treatment of the cells with phenobarbital plus hydrocortisone. These results show that human colon activates 1,2-dimethylhydrazine and suggest that the human colon may be capable of activating other carcinogens in situ.


The careers of women graduates from St Mary's Hospital Medical School, London, 1961--72.
The careers of women doctors who qualified from St Mary's Hospital Medical School between 1961 and 1972 inclusive have been studied. Thirty-eight per cent were in full-time work, 47% were working part-time, and 15% were not practising medicine at the time of the survey. Those working full-time were predominantly single women and married women with no children. With the birth of children most women stopped working for a time, and 38% of those whose children were all under school age were not working. However, 90% returned to medicine, usually to part-time jobs that were compatible with family responsibilities. Eighty-six per cent of the respondents held one or more postgraduate qualifications. More of those with higher qualifications were in full-time work than was the case for women with a basic medical degree only, and fewer were not practising medicine. An equal proportion of single and married women intended to make their career in general practice. Fewer married women than single women chose a hospital career, because the possibilities of part-time work in this field were seen as limited.


Ventricular arrhythmias after coronary artery bypass graft surgery: incidence, risk factors and long-term prognosis.
The incidence, risk factors and long-term prognosis of complex ventricular arrhythmias after coronary artery bypass graft surgery are not known. Complex ventricular arrhythmias are defined as Lown grades 4a (couplets), 4b (ventricular tachycardia) and 5 (R on T phenomenon). Ninety-two patients with normal left ventricular function who underwent elective coronary artery bypass graft surgery were prospectively evaluated. Ventricular arrhythmias were documented by predischarge 24 hour ambulatory electrocardiographic monitoring; 43% of patients had no or simple ventricular arrhythmias (Lown grades 1 to 3) and 57% had complex ventricular arrhythmias. Risk factors analyzed included age, sex, diabetes, hypertension, smoking, preoperative digoxin or propranolol therapy, cardiopulmonary bypass time, aortic cross-clamp time, number of vessels bypassed, peak creatine kinase (CK) elevation and pericarditis. No risk factor identified patients at higher risk for complex ventricular arrhythmias. Patients were followed up for 6 to 24 months (mean 16). Patients with complex ventricular arrhythmias did not have a higher incidence of sudden death, cardiac death, syncope, angina, myocardial infarction or cerebrovascular accident. It was concluded that: Complex ventricular arrhythmias are common after coronary artery bypass graft surgery. None of the risk factors considered identify high risk patients. Complex ventricular arrhythmias after coronary artery bypass graft surgery do not indicate a poor prognosis in patients with normal left ventricular function.


Proximity Enforced Agostic Interactions Involving Closed-Shell Coinage Metal Ions.
A proximity enforcing diarylsilane ligand is reported, which gives rise to unusual Si-H···M interactions with the d10 metal ions Cu+ and Ag+ upon complexation. These interactions are studied in detail both experimentally and computationally and can be classified to be weakly agostic in nature for the Si-H···Cu interaction. The Si-H···Ag interaction has more signatures of an electrostatic contact.


Biopsy rates vary with patient profile across different physicians in an academic dermatology practice.
Current healthcare trends promote data-driven "benchmarking" to decrease cost and increase quality. Dermatologists perform 79% of skin biopsies and biopsy rate is an easily measured benchmark. To reduce the risk of a misguided "one size fits all" benchmark for biopsies, it will help to document the factors driving divergent biopsy rates.This letter compares biopsy rates and high-risk patient ratios for 1000 sequential patients from two academic dermatologists. Elevated biopsy rates (0.55 vs 0.42, p < 0.001) were associated with elevated ratios of high-risk patients (.52 versus .30, p< 0.001). Although limited by small sample size, this research takes a first step toward future efforts to improve accuracy of biopsy benchmarking.


Rigorous intensity and phase-shift manipulation in optical frequency conversion.
A simple method is employed to investigate the nonlinear frequency conversion in optical superlattices (OSL) with pump depletion. Four rigorous phase-matching conditions for different purposes are obtained directly from the nonlinear coupled equations, and the resulting OSL domain structures are generally aperiodic rather than periodic. With this method, not only the intensity but also the phase-shift of the harmonic waves can be manipulated at will. The second-harmonic generation of Gaussian beam is further investigated. This work may provide a guidance for the practical applications of designing nonlinear optical devices with high conversion efficiency.


Studies of ethylene-forming system in rat liver extract.
Evidence of enzymatic formation of ethylene from methionine by rat liver extracts is presented. The ethylene production is closely associated with growth of the animal. The conversion of L-methionine to ehtylene is oxygen dependent. Substrate analogue studies show that the ethylene-forming system is structurally specific and requires in the center of the molecule alpha-CH2-CH2- with one end attached to an unencumbered sulfur atom from a thioether moiety and the other end attached to a carboxyl group. Sylfhydryl agents are found to be very effective inhibitors of the ethylene-forming system. The finding of alpha-keto-4-methylthiobutyric acid to be a more efficient precursor of ethylene production suggests the possibility that alpha-keto-4-methylthiobutyric acid may be an intermediate in the biosynthesis of ethylene from methionine in mammalian tissues.