Nitrogen enrichment leads to changing fatty acid composition of phytoplankton and negatively affects zooplankton in a natural lake community.
Secondary production in freshwater zooplankton is frequently limited by the food quality of phytoplankton. One important parameter of phytoplankton food quality are essential polyunsaturated fatty acids (PUFAs). Since the fatty acid composition of phytoplankton is variable and depends on the algae's nutrient supply status, inorganic nutrient supply may affect the algal PUFA composition. Therefore, an indirect transfer of the effects of nutrient availability on zooplankton by changes in algal PUFA composition is conceivable. While the phosphorus (P) supply in lakes is largely decreasing, nitrogen (N) inputs continue to increase. This paper presents data from a mesocosm field experiment in which we exposed phytoplankton communities to increasing N enrichment. As a consequence, the PUFA composition of the phytoplankton community changed. With increasing nitrogen fertilisation, we observed lower quantities of essential PUFAs, together with a decrease in the abundances of the dominant herbivorous zooplankton Daphnia sp. Their biomass was significantly correlated with phytoplankton PUFA content (C18:3 ω3, C20:5 ω3, C18:2 ω6). Our data therefore indicate that changes in nitrogen supply, together with the resultant changes in phytoplankton food quality, can negatively affect the secondary production of herbivorous zooplankton by reducing the availability of essential polyunsaturated fatty acids.


Use of dual energy CT to identify gastrointestinal anastomotic leak by assessment of percutaneous drain contents.
Anastomotic leakage is a feared complication of many different types of gastrointestinal surgery. It is important to identify patients with leaks early because sepsis may develop quickly. Suspected leaks are typically confirmed by either fluoroscopy or computed tomography with oral contrast. This article presents a novel method to confirm the presence of a gastrointestinal anastomotic leak when standard imaging and clinical presentation are ambiguous.


Prevalence of nasopharyngeal Streptococcus pneumoniae carriage and resistance to macrolides in the setting of azithromycin mass drug administration: analysis from a cluster-randomised controlled trial in Malawi, 2015-17.
Azithromycin mass drug administration (MDA) could reduce child mortality. However, macrolide resistance, which has generally been reported to develop after whole-community MDA for trachoma control, is a concern, and it has less commonly been studied in the context of treating children to reduce mortality. Here, we report on macrolide resistance after biannual azithromycin MDA at the Malawi site of the MORDOR study. In the MORDOR cluster-randomised trial in Malawi, 30 communities in Mangochi District were randomly selected. Communities were randomly assigned to receive azithromycin or placebo by simple randomisation without stratification. Children aged 1-59 months were administered azithromycin 20 mg/kg or placebo as an oral suspension biannually for a total of four treatments in 2015-17. 1200 children (40 children per community) were randomly selected for nasopharyngeal swabs at baseline, 12 months (6 months after the second treatment visit), and 24 months (6 months after the fourth treatment visit). Samples were processed to culture Streptococcus pneumoniae. The primary outcome was the proportion of S pneumoniae isolates exhibiting macrolide resistance at 12 months and 24 months, assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02048007. At baseline, 3467 (76%) of 4541 eligible children in the azithromycin group and 3107 (72%) of 4308 eligible children in the placebo group were treated. 564 nasopharyngeal swabs were taken from the azithromycin group and 563 from the placebo group, with similar numbers of swabs taken at 12 months and 24 months. In both groups at baseline, carriage of S pneumoniae was greater than 85% and the proportion of strains resistant to macrolides was 28%. At the 12-month follow-up, macrolide resistance was higher in the azithromycin group (36·9%, 95% CI 32·5-41·2) than in the placebo group (21·6%, 17·7-25·4; OR 2·26, 95% CI 1·46-3·49; p=0·0002). At 24 months, macrolide resistance remained higher in the azithromycin group (43·9%, 39·2-48·5) compared with placebo (32·8%, 28·5-37·1; OR 1·66, 1·15-2·40; p=0·0069). These findings support previous evidence from trachoma MDA programmes and suggest that monitoring of macrolide resistance should remain a key component of azithromycin interventions for reducing child mortality. Bill & Melinda Gates Foundation.


Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors.
Immune checkpoint inhibitors (ICIs) improve clinical outcomes in patients suffering from different types of cancer. Liver toxicity is one of the immune-related adverse events associated with immunotherapy; although not common, its management is challenging as it is extremely heterogeneous in terms of presentation and severity. Differences in the development and evolution of ICI-related toxicity in healthy or cirrhotic livers have not yet been elucidated. Assessing causality is key to diagnosing ICI-induced liver toxicity; liver biopsies can assist not only in the differential diagnosis but also in assessing the severity of histological liver damage. The current classification of severity overestimates the grade of liver injury and needs to be revised to reflect the views of hepatologists. Spontaneous improvements in ICI-related liver toxicity have been reported, so corticosteroid therapy should probably be individualised not systematic. The reintroduction of ICIs in a patient with previous immune-mediated hepatitis may be possible, but the risk/benefit ratio should be considered, as the risk factors for hepatitis recurrence are currently unclear. The management of these patients, requiring a balance between efficacy, toxicity and specific treatments, necessitates multidisciplinary collaboration. The incidence of immune-related liver toxicity will continue to rise based on the increasing use of ICIs for most cancers, mandating improved understanding and management of this complication.


Boys-men mean-power-frequency differences in progressive exercise to exhaustion, confounded by variability and adiposity.
Only scant research has compared children's mean power frequency (MPF) to adults', with a clear overview still lacking. A significant obstacle has been MPF's high variability, which this study aimed to overcome by elucidating the MPF characteristics distinguishing boys from men in progressive exhaustive exercise. Electromyographic (EMG) data of 20 men (23.5 ± 2.5yrs) and 17 boys (10.2 ± 1.0 yrs), who performed progressively exhausting, intermittent isometric knee extensions, were subjected to secondary MPF analysis. Participants' vastus lateralis MPF data series were transformed to third-order polynomial regressions and expressed as percentages of the peak polynomial MPF values (%MPFpeak). The resulting curves were compared at 5-% time-to-exhaustion (TTE) intervals, using repeated-measures ANOVA. Raw MPFpeak values were adiposity corrected to 0% fat and used to convert the %MPFpeak data back to absolute MPF values (Hz) for estimating muscle-level MPF. No overall interaction or group effects could be shown between the %MPFpeak plots, but pairwise comparisons revealed significantly higher men's values at 50-70%TTE and lower at 100%TTE, i.e. boys' shallower MPF rise and decline. The adiposity-corrected boys' and men's composite MPF values peaked at 125.7 ± 2.5 and 166.0 ± 2.4 Hz, respectively (110.7 ± 1.7 and 122.5 ± 2.1 Hz, uncorrected), with a significant group effect (p < 0.05) and pairwise differences at all %TTE points. The boys were lower than the men in both the observed and, more so, in the adiposity-corrected MPF values that presumably estimate muscle-level MPF. The boys' shallower MPF rise and decline conform to children's claimed type-II motor-unit activation and/or compositional deficits and their related known advantage in muscular endurance.


Vanillin and isovanillin: comparative vibrational spectroscopic studies, conformational stability and NLO properties by density functional theory calculations.
This study is a comparative analysis of FT-IR and FT-Raman spectra of vanillin (3-methoxy-4-hydroxybenzaldehyde) and isovanillin (3-hydroxy-4-methoxybenzaldehyde). The molecular structure, vibrational wavenumbers, infrared intensities, Raman scattering activities were calculated for both molecules using the B3LYP density functional theory (DFT) with the standard 6-311++G(∗∗) basis set. The computed values of frequencies are scaled using multiple scaling factors to yield good coherence with the observed values. The calculated harmonic vibrational frequencies are compared with experimental FT-IR and FT-Raman spectra. The geometrical parameters and total energies of vanillin and isovanillin were obtained for all the eight conformers (a-h) from DFT/B3LYP method with 6-311++G(∗∗) basis set. The computational results identified the most stable conformer of vanillin and isovanillin as in the "a" form. Non-linear properties such as electric dipole moment (μ), polarizability (α), and hyperpolarizability (β) values of the investigated molecules have been computed using B3LYP quantum chemical calculation. The calculated HOMO and LUMO energies show that charge transfer occurs within the molecules.


[Current concepts in diagnosis and treatment of tachyarrhythmias].
A diagnostic and therapeutic approach of supraventricular and ventricular tachyarrhythmia is always challenging. Several criteria serve to discriminate correctly between these two types of tachycardia. Cardiac arrhythmias are terminated reliably by intravenous (IV) application of antiarrhythmic drugs: adenosine for supraventricular arrhythmia, amiodarone or ajmaline for ventricular tachycardia. Furthermore, AV-nodal tachycardia, atrioventricular reciprocating tachycardia, and typical atrial flutter is treated curatively by radiofrequency ablation during an electrophysiological study. This interventional therapy is well established in patients suffering from ventricular premature contractions or tachycardia originating in the right or left ventricular outflow tract. Aside treatment with an implantable defibrillator, patients with coronary artery disease highly benefit from adjusted pharmaceutical treatment.


Robotics: self-replication from random parts.
Autonomously self-replicating machines have long caught the imagination but have yet to acquire the sophistication of biological systems, which assemble structures from disordered building blocks. Here we describe the autonomous self-replication of a reconfigurable string of parts from randomly positioned input components. Such components, if suitably miniaturized and mass-produced, could constitute self-fabricating systems whose assembly is brought about by the parts themselves.


An evaluation of prophylactic and therapeutic antibiotic prescribing in Lebanese dental practice.
To evaluate antibiotic prescribing patterns and correlates among Lebanese dentists. A descriptive observational study was conducted, from the first of April to the end of May 2017. Dentists who specialized in oral dental surgery or general dental practitioners were eligible to participate in this study. All patients who sought consultation with the selected dentists over a 1 month period were included. A total of 2323 oral and dental procedures were performed by 60 dentists; 553 antibiotic prescriptions were prescribed, representing 23.8% (52.35% for prophylactic purposes and 47.65% for curative purposes). Prophylactic indications were mainly for implant surgery (36.3%) with only 1% appropriate. Curative use was mainly for periodontal abscesses/abscesses (indeterminate) (22.8%), followed by pulpal diseases and periradicular complications (20.5%); it was appropriate in only 1.7 and 1.9% of cases respectively. Amoxicillin-clavulanic acid was the antibiotic that was mostly prescribed for both curative and prophylactic uses (57.6 and 55.9%, respectively), followed by amoxicillin for prophylactic purposes and a combination of spiramycin plus metronidazole for curative purposes. Adherence to guidelines was low for both curative and prophylactic purposes (17.4 and 21.8%, respectively), but was better in patients who were younger [adjusted odds ratio(aOR) = 0.96], male (aOR = 0.40), or had cardiac disease with moderate or high infective endocarditis risk (aOR = 21.72), and when prescribed by oral surgeons (aOR = 0.15). This study showed evidence of the overuse of antibiotics among Lebanese dentists. It can serve as a basis for future studies to optimize antibiotic use among dentists in Lebanon.


Impact of social and clinical factors on the diagnostic delay of chronic kidney disease: an evaluation study.
This study aimed to investigate the impact of social and clinical factors on the diagnostic delay of chronic kidney disease (CKD) among Iranian patients. Our study was conducted on 350 CKD patients who were referred to Faghihi and Motahari clinics (the two largest kidney diseases referral centers in Shiraz the capital of Fars province). Data were collected via an interviewer-administered questionnaire. A multiple linear regression model was used to measure the effect of factors affecting the delay of CKD diagnosis. The medians and Interquartile ranges (IQR) of all delays, patient delay, and doctor delay were 6.5 (0-12.2), 5.1 (0-11.2), and 0.9 (0-3.1) months, respectively. The results showed that women were diagnosed 1.61 months earlier than men (p < 0.05). The duration of all delays in patients residing in the rural areas was 1.28 months longer than patients residing in the urban areas (p < 0.05). Also, patients with perceived good economic status were diagnosed 1.30 months earlier than patients who reported having very poor economic status (p < 0.05). The delay is in part due to the neglect and misinterpretation of symptoms by both patients and physicians. It is necessary to improve the awareness of CKD among general public and medical professionals.


A new antituberculosis drug that selectively kills nonmultiplying Mycobacterium tuberculosis.
An important report by Bryk et al. in this issue of Cell Host & Microbe describes the properties of a rhodanine prodrug active against nonmultiplying Mycobacterium tuberculosis (Mtb). Considering the tolerance of nonreplicating Mtb to most currently available agents, such a drug could be a major addition to our antituberculosis arsenal and would greatly benefit control of the disease.


Extensive aberrant Mongolian spot.
A 9-month-old male infant had generalized diffuse blue-gray pigmentation over most of his body, sparing the scalp, face, neck, palms, soles, periumbilical area, genital area, and nipples. Within the lesion, there were several conspicuous macules of considerably darker hue. Histologic examination revealed numerous dermal melanocytes. By 16 months of age, the child's blue-gray pigmentation had decreased substantially.


Feasibility of a Hybrid Risk-Adapted Monitoring System in Investigator-Sponsored Trials in Cancer.
We assessed the feasibility of a hybrid monitoring system (minimal on-site monitoring + strategic central monitoring) used at the academic research office at Asan Medical Center (Seoul, Korea) in monitoring investigator-sponsored oncology trials. Monitoring findings in three oncology trials conducted between 2014 and 2017 were compared. A confirmatory source data verification (SDV) was carried out in the low-risk trial and compared with the central monitoring findings. The economic advantages of central monitoring were tested by calculating the monitoring hours per patient. A total of 50, 118, 228 patients were enrolled in the high-, intermediate-, and low-risk trials, respectively. The high-risk trial was monitored through 42 on-site visits (1299 findings); the intermediate-risk trial had 79 monitorings (on-site, 24%; central, 76%; 1464 findings); the low-risk trial had 197 monitorings (on-site, 4%; central, 96%; 3364 findings). Central monitoring was more effective than on-site monitoring in revealing minor errors such as "missing case report forms" and "data outliers" (both P < 0.0001), and showed comparable results in revealing major issues such as investigational product compliance and delayed reporting of serious adverse events (both P > 0.05). Confirmatory SDV in the low-risk trial revealed more findings than central monitoring in the "inconsistent data" and "inappropriate adverse event" categories. The total monitoring hours per patient were lower in the intermediate- and low-risk trials than in the high-risk trial (8.1 and 7.3 vs. 14.3 h, respectively). Our hybrid monitoring system showed acceptable feasibility in revealing both major and minor issues in multi-center oncology investigator-sponsored trials.


Role of epidermal growth factor-induced membrane depolarization and resulting calcium influx in osteoblastic cell proliferation.
This study investigated the effects of epidermal growth factor (EGF) on the membrane potential of rat calvarial osteoblasts, in order to understand the mechanism responsible for calcium influx and the role these EGF-induced events have in osteoblastic cell proliferation. Changes in plasma membrane potential were measured using patch clamp techniques in isolated cells. EGF induced changes in plasma membrane potential only after cells had been in culture for at least 6 days. EGF induced membrane depolarization in 55% of rat calvarial osteoblasts studied after 6 to 8 days in culture. This membrane event was dependent on extracellular calcium, therefore, one or more calcium conductances were involved. Nifedipine, a voltage-activated calcium channel blocker, significantly reduced membrane depolarization, and demonstrated the existence of a nifedipine-insensitive conductance. Osteoblastic cell proliferation was measured by cell count. The EGF-dependent increase in cell proliferation was blocked by addition of 10 microM nifedipine. Therefore, it appears that the mechanism of action of EGF-induced osteoblastic cell proliferation is mediated by changes in plasma membrane potential which result in extracellular calcium influx.


Factors that affect pain management in adults diagnosed with acute appendicitis in the emergency department: A retrospective study.
Analgesic treatment, including with opioids, can safely be given to patients who are suspected of having appendicitis. The study examined factors which may influence the treatment of pain in appendicitis in the adult emergency department (ED). A secondary objective was to determine if analgesia affected clinical outcomes. This single-center retrospective study examined medical records of all adult patients with a discharge diagnosis of appendicitis. Patients were categorized based on the type of analgesia received in the ED. Variables included the day of week and staffing shift of presentation, gender, age, and triage pain scale, as well as time to ED discharge, imaging, operation, and hospital discharge. Univariable and multivariable logistic regression models were performed to determine which factors influenced treatment and affected outcomes. Records of 1839 patients were categorized into three groups - 883 (48%) did not receive analgesia, 571 (31%) received only non-opioid medications, and 385 (21%) received at least one opioid. Patients with a higher triage pain level were significantly more likely to receive analgesia (4-6: OR = 1.85; 95% CI = 1.2-2.84, 7-9: OR = 3.36; 95% CI = 2.18-5.17, 10: OR = 10.78; 95% CI = 6.38-18.23) and at least one opioid (4-6: OR = 2.88; 95% CI = 1.13-7.34, 7-9: OR = 4.36; 95% CI = 1.73-11.01, 10: OR = 6.23; 95% CI = 2.42-16.09). Male gender was associated with a significantly lower likelihood of receiving analgesia (OR = 0.74; 95% CI = 0.61-0.9), but a significantly greater likelihood of receiving at least one opioid given that they received any pain medication (OR = 1.87; 95% CI = 1.41-2.48). Patients aged 25-64 years old were significantly more likely to receive at least one opioid if they received any pain medication (25-44: OR = 1.47; 95% CI = 1.08-2.02, 45-64: OR = 1.78; 95% CI = 1.15-2.76). Presentation to the ED on Sundays was associated with lower rates of opioid treatment (OR = 0.63; 95% CI = 0.42-0.94). Regarding clinical outcomes, patients who received analgesia waited longer for imaging (+0.58 h; 95% CI = 0.31-0.85), stayed longer in the ED (+2.2 h; 95% CI = 1.60-2.79), and had a slightly longer hospitalization (+0.62d; 95% CI = 0.34-0.90). Almost half of patients with appendicitis didn't receive analgesia, with most of those treated receiving only non-opioid analgesia. Older age and Sunday presentations were associated with less opioid treatment. Patients who received analgesia waited longer for imaging, stayed longer in the ED, and had a longer hospitalization.


Bactericidal activity of normal human serum against Morganella, Proteus, and Providencia strains.
The susceptibility od Proteus, Providencia, and Morganella strains to bactericidal action of human serum was examined. The percentage of survival was determined after one and three hours incubation with 50% human serum. The susceptible strains were treated by serum preparations with blocked classical or alternative complement activation pathways as well as with lysozyme removed. Following mechanisms of the bactericidal action of serum were found: complement activated by the classical or alternative pathway with participation of lysozyme, complement activated simultaneously via both pathways-while the participation of lysozyme was necessary for killing some strains and superfluos for others and complement activated only via the classical pathway without lysozyme.


Cover and uncover: chiral switching exploiting templating and layer-by-layer grafting.
Consecutive grafting of crosslinked L-phenylalanine anilide, D-phenylalanine anilide and non-imprinted polymer layers on the surface of wide pore silica resulted in porous composite beads displaying enantiomeric discrimination reflecting the last grafted layer. This no longer holds for beads freed from silica, which instead display enantioselectivity reflecting the first grafted layer.


Electroacupuncture of 2 hz has a rewarding effect: evidence from a conditioned place preference study in rats.
Electroacupuncture (EA) has been used to suppress heroin craving in addicts and the conditioned place preference (CPP) for morphine in the rat. The question remained whether EA by itself will produce some rewarding effect. This was investigated using the CPP procedure in the present study. The results indicated that rats showed a significant preference to the 2 Hz EA-paired compartment. This rewarding effect of EA was prevented by pre-treatment with the opioid receptor antagonist naloxone [2 mg kg(-1), intraperitoneally (i.p.)], CB1 cannabinoid antagonist AM251 (3 μg per rat, intracerebroventricularly) or D1 dopamine receptor antagonist SCH23390 (0.1 mg kg(-1), i.p.), respectively. TempspacetempspaceIt is concluded that 2 Hz EA is capable of inducing CPP in the rat via the activation of the endogenous opioid-, cannabinoid- and dopamine-systems.


Comparative risk of genital infections associated with sodium-glucose co-transporter-2 inhibitors.
The extent to which sodium-glucose co-transporter-2 (SGLT2) inhibitors increase the risk of genital infections in routine clinical care, compared with other antidiabetic medications, is not clear, or whether the increased risk is consistent across gender or age subgroups, within individual SGLT2 agents, or if it is more pronounced at a particular time after treatment initiation. We conducted a retrospective cohort study using two US commercial claims databases (2013-2017). In the primary analysis, 1:1 propensity score-matched cohorts of female and male subjects with type 2 diabetes mellitus initiating SGLT2 versus dipeptidyl peptidase-4 inhibitors were created. The outcome was a composite of genital candidal infections, vaginitis or vulvovaginitis in women, and genital candidal infections, balanitis, balanoposthitis, phimosis or paraphimosis in men. Among propensity score-matched cohorts of 129 994 women and 156 074 men, the adjusted hazard ratio (HR) and excess risk per 1000 person-years for SGLT2 versus DPP-4 inhibitors was 2.81 (95% confidence interval [CI], 2.64, 2.99) and 87.4 (95% CI, 79.1, 96.2) respectively for women, and was 2.68 (95% CI, 2.31, 3.11) and 11.9 (95% CI, 9.3-15.0) for men. Findings were similar in the SGLT2 inhibitor versus GLP-1 agonist comparison, more pronounced in the subgroup of patients aged ≥60 (HR, 4.45 [95% CI, 3.83-5.17] in women and 3.30 [95% CI, 2.56-4.25] in men), and no meaningful difference across individual SGLT2 inhibitors was identified. This increase in risk was evident in the first month of treatment initiation and remained elevated throughout the course of therapy. SGLT2 inhibitors were associated with an approximately 3-fold increase in risk of genital infections.


A correlative radioimmunoassay and immunohistochemical study of LHRH-induced LH depletion in the anterior pituitary of male and female neonatal rats in vitro.
After an exposure of 24 h to synthetic LHRH (100 ng/ml) in vitro, the anterior pituitaries of 4-day-old rats show a notable loss of immunoreactive material in most LH cells in males, but not in females. When radioimmunoassayed without incubation, the pituitary LH content of 4-day-old female rats is 2.8 times higher than that of males of the same age. LHRH treatment stimulates a higher rate of LH discharge in females than in males, but if LH release is expressed as a percentage of the initial pituitary LH content, there is no apparent difference. In both sexes, more than 70% of the initially stored LH is discharged into the medium after 24 h of LHRH stimulation. In males, this discharge produces a pronounced depletion, but in females, the pituitary still contains 78.2% of the initial LH content despite the large amount of hormone released. From these results, it is concluded that in newborn rats the LH synthetic rate in females is higher than that in males. This high synthetic activity, together with the large store of LH, may explain why prolonged LHRH treatment fails to cause LH depletion in females. At 4 days of age LHRH had no stimulatory effect on pituitary synthesis of LH in either sex.


Anesthesia management for tracheoesophageal fistula closed with a new gastrointestinal occluder device: a case report.
Tracheoesophageal fistula (TEF) is a rare but life-threatening complication after esophagectomy. A new gastrointestinal occluder device provides treatment for TEF patients. However, TEF-related pneumonia and respiratory failure increase the difficulty of anesthesia management, especially in airway management. A 64-year-old man with thoracic esophageal cancer underwent esophagectomy and gastric tube reconstruction one year ago. The patient presented with recurrent cough and sputum after surgery. Gastroscopy revealed a fistula between the esophagogastric anastomotic site and membrane of the trachea. Therefore, the patient received implantation of a new gastrointestinal occluder device under gastroscopy combined with tracheoscopy. Airway management under general anesthesia was discussed with an interdisciplinary decision, and cuffed endotracheal tube with an inner diameter of 5.5 mm was chosen. This airway management ensured adequate oxygenation during the operation and provided sufficient space for the operation of the tracheoscope in the trachea. Finally, the TEF disappeared after the operation, and the patient was administered an oral diet on the first postoperative day. The implantation of a new gastrointestinal occluder device under gastroscopy combined with tracheoscopy provides a new treatment for TEF patients. This case report suggests that it is important to select an endotracheal tube with an appropriate inner diameter that can not only meet the requirements of ventilation but also does not affect the operation of tracheoscopy in the trachea.


A successful new primary health care provider in the newborn nursery.
The mothers' acceptance of the Child Health Associate ("CHA") as a qualified health professional and the documentation of CHA's clinical abilities to provide broad-based health care for normal infants attest to their capabilities to function as primary health care providers in a newborn nursery. In "low-risk" nursery settings, where other capable health professionals may not be available, the CHA can assume primary and direct responsibility for the care of the normal newborn infant.


Aging effects on chemical transformation and metal(loid) removal by entrapped nanoscale zero-valent iron for hydraulic fracturing wastewater treatment.
In this study, alginate and polyvinyl alcohol (PVA)-alginate entrapped nanoscale zero-valent iron (nZVI) was tested for structural evolution, chemical transformation, and metals/metalloids removal (Cu(II), Cr(VI), Zn(II), and As(V)) after 1-2month passivation in model saline wastewaters from hydraulic fracturing. X-ray diffraction analysis confirmed successful prevention of Fe0 corrosion by polymeric entrapment. Increasing ionic strength (I) from 0 to 4.10M (deionized water to Day-90 fracturing wastewater (FWW)) with prolonged aging time induced chemical instability of alginate due to dissociation of carboxyl groups and competition for hydrogen bonding with nZVI, which caused high Na (7.17%) and total organic carbon (24.6%) dissolution from PVA-alginate entrapped nZVI after 2-month immersion in Day-90 FWW. Compared to freshly-made beads, 2-month aging of PVA-alginate entrapped nZVI in Day-90 FWW promoted Cu(II) and Cr(VI) uptake in terms of the highest removal efficiency (84.2% and 70.8%), pseudo-second-order surface area-normalized rate coefficient ksa (2.09×10-1Lm-2h-1 and 1.84×10-1Lm-2h-1), and Fe dissolution after 8-h reaction (13.9% and 8.45%). However, the same conditions inhibited Zn(II) and As(V) sequestration in terms of the lowest removal efficiency (31.2% and 39.8%) by PVA-alginate nZVI and ksa (4.74×10-2Lm-2h-1 and 6.15×10-2Lm-2h-1) by alginate nZVI. The X-ray spectroscopic analysis and chemical speciation modelling demonstrated that the difference in metals/metalloids removal by entrapped nZVI after aging was attributed to distinctive removal mechanisms: (i) enhanced Cu(II) and Cr(VI) removal by nZVI reduction with accelerated electron transfer after pronounced dissolution of non-conductive polymeric immobilization matrix; (ii) suppressed Zn(II) and As(V) removal by nZVI adsorption due to restrained mass transfer after blockage of surface-active micropores. Entrapped nZVI was chemically fragile and should be properly stored and regularly replaced for good performance.


A 31P NMR study of the GI tract: effect of fructose loading and measurement of transverse relaxation times.
The effect of fructose loading on high-energy phosphates in the jejunum, ileum, and large intestine of rats was studied using 31P NMR. Following fructose loading, an increase in the intensity of the PME resonance was observed in the jejunum, indicating an accumulation of fructose-1-phosphate. There were no significant changes in ATP or Pi. This demonstrates that the activity of fructokinase in the jejunum can be monitored by 31P NMR. Fructose loading had no detectable effect on metabolite levels in the ileum and large intestine. Resolution of intestinal spectra was poor due to unusually large linewidths and the presence of broad underlying signals. To study the mechanism of line broadening, the T2's of the phosphorus resonances were measured using a solenoidal coil. The T2's of the ATP, Pi, PME, and PCr resonances were much longer than the T2's, suggesting that the linewidths of these resonances are primarily due to susceptibility gradients and/or compartmentation of metabolites. Other signals, particularly in the PDE region, were homogeneously broadened and had very short T2's. Spin echoes obtained with evolution times of 1 to 4 ms suppressed these broad components, with little loss of intensity in the inhomogeneously broadened resonances; as a result, resolution was improved.


Does intraoperative neurophysiologic monitoring matter in noncomplex spine surgeries?
To determine associations between intraoperative neurophysiologic monitoring (IOM) for spinal decompressions and simple fusions with neurologic complications, length of stay, and hospitalization charges. Adult discharges in the Nationwide/National Inpatient Sample (NIS) (2007-2012) with spinal decompressions and simple spinal fusions were included. Revision surgeries, instrumentations, complicated approaches, and tumor- and trauma-related surgeries were excluded. Extracted data included patient demographics, medical comorbidities, primary spinal surgery type, and hospital characteristics. Bivariate and multiple regression analyses using NIS survey design variables correlated IOM use with neurologic complications, hospital charges, and length of stay. IOM was reported in 4.9% of an estimated 1.1 million discharges in the weighted sample. Discharges reporting IOM were more often privately insured (61% vs 57%, p < 0.001) and had slightly more comorbidities (25% vs 24% with 3+ comorbidities, p = 0.01). Spinal fusions more often reported IOM than decompressions. The IOM group had fewer neurologic complications (0.8% vs 1.4% of controls) with no difference in length of stay (3.0 days for each group), but increased hospital charges (39% greater). Multiple regression adjustment showed significant associations of IOM with fewer neurologic complications (odds ratio 0.60, 95% confidence interval [CI] 0.47, 0.76, p < 0.001), while the estimated percentage of hospital charges was sizably diminished from the unadjusted analysis (IOM effect +9%, 95% CI +4%, +13%, p < 0.001), and length of stay was reduced (IOM effect -0.26 days, 95% CI -0.42, -0.11, p < 0.001). IOM was associated with better clinical outcomes and some increased hospital charges among discharges of simple spinal fusions and laminectomies in a large, multiyear, nationally representative dataset.


Neurologic status, cough, secretions and extubation outcomes.
To determine the degree to which neurologic function, cough peak flows and quantity of endotracheal secretions affected the extubation outcomes of patients who had passed a trial of spontaneous breathing (SBT). Prospective observational study. The medical intensive care unit of a 325-bed teaching hospital. Cough peak flow (CPF), endotracheal secretions and ability to complete four simple tasks were measured just before extubation in patients who had passed a SBT. Eighty-eight patients were studied; 14 failed their first trials of extubation. The CPF of patients who failed was lower than that of those who had a successful extubation (58.1+/-4.6 l/min vs 79.7+/-4.1 l/min, p=0.03) and those with CPF 60 l/min or less were nearly five times as likely to fail extubation compared to those with CPF higher than 60 l/min (risk ratio [RR]=4.8; 95% CI=1.4-16.2). Patients with secretions of more than 2.5 ml/h were three times as likely to fail (RR=3.0; 95% CI=1.0-8.8) as those with fewer secretions. Patients who were unable to complete four simple tasks (i.e. open eyes, follow with eyes, grasp hand, stick out tongue) were more than four times as likely to fail as those who completed the four commands (RR=4.3; 95% CI=1.8-10.4). There was synergistic interaction between these risk factors. The failure rate was 100% for patients with all three risk factors compared to 3% for those with no risk factors (RR=23.2; 95% CI=3.2-167.2). The presence of any two of the above risk factors had a sensitivity of 71 and specificity of 81% in predicting extubation failure. Patients who failed a trial of extubation were 3.8 times as likely to have any two risk factors compared to those who were successful. These simple, reproducible methods may provide a clinically useful approach to guiding the extubation of patients who have passed a SBT.


Differentiation of Trypanosoma cruzi and Trypanosoma rangeli of Colombia using minicircle hybridization tests.
Although Trypanosoma rangeli is harmless for humans, it is a serious problem since it may be confused with diagnosis of Trypanosoma cruzi, the etiologic agent of Chagas disease. Both parasites overlap geographically, share antigenic protein, and are able to infect the same Triatominae vector and vertebrate host, including human. Our objective was to differentiate T. cruzi and T. rangeli isolates from Colombia based on polymerase chain reaction (PCR) amplification of the minicircles followed by appropriate hybridization tests with selected DNA probes and restriction fragment length polymorphism (RFLP) analysis. We worked with highly characterized T. cruzi and T. rangeli isolates from different biologic origins and geographic areas of Colombia, and they were analyzed by RFLP and PCR amplification of variable region of minicircles and Southern blot analysis. Our results and experimental conditions demonstrate the usefulness of PCR amplification of the minicircles followed by Southern blot analysis to differentiate T. cruzi from T. rangeli, which can be highly important to improve diagnosis of Chagas disease.


Refeeding activates neurons in the dorsomedial hypothalamus to inhibit food intake and promote positive valence.
The regulation of food intake is a major research area in the study of obesity, which plays a key role in the development of metabolic syndrome. Gene targeting studies have clarified the roles of hypothalamic neurons in feeding behavior, but the deletion of a gene has a long-term effect on neurophysiology. Our understanding of short-term changes such as appetite under physiological conditions is therefore still limited. Targeted recombination in active populations (TRAP) is a newly developed method for labeling active neurons by using tamoxifen-inducible Cre recombination controlled by the promoter of activity-regulated cytoskeleton-associated protein (Arc/Arg3.1), a member of immediate early genes. Transgenic mice for TRAP were fasted overnight, re-fed with normal diet, and injected with 4-hydroxytamoxifen 1 h after the refeeding to label the active neurons. The role of labeled neurons was examined by expressing excitatory or inhibitory designer receptors exclusively activated by designer drugs (DREADDs). The labeled neurons were extracted and RNA sequencing was performed to identify genes that are specifically expressed in these neurons. Fasting-refeeding activated and labeled neurons in the compact part of the dorsomedial hypothalamus (DMH) that project to the paraventricular hypothalamic nucleus. Chemogenetic activation of the labeled DMH neurons decreased food intake and developed place preference, an indicator of positive valence. Chemogenetic activation or inhibition of these neurons had no influence on the whole-body glucose metabolism. The labeled DMH neurons expressed prodynorphin (pdyn), gastrin-releasing peptide (GRP), cholecystokinin (CCK), and thyrotropin-releasing hormone receptor (Trhr) genes. We identified a novel cell type of DMH neurons that can inhibit food intake and promote feeding-induced positive valence. Our study provides insight into the role of DMH and its molecular mechanism in the regulation of appetite and emotion.


Host-intestinal microbiota mutualism: "learning on the fly".
Given the complexity of the mammalian microbiota, there is a need for simple models to decipher the effector and regulatory mechanisms underlying host/microbiota mutualism. Approaches using Drosophila and its simple microbiota carry the potential to unravel the evolutionarily conserved mechanisms engaged in this association. Here, we review recent work carried out in this model, providing insights and exciting perspectives.


An infant with congenital heart defects and proteinuria: a case report.
Branchio-Oto-Renal (BOR) Syndrome is a rare autosomal disorder with a wide variety of clinical manifestations and a high degree of heterogeneity. Typical clinical manifestations of BOR syndrome include deafness, preauricular fistula, abnormal gill slits, and renal malformations. However, atypical phenotypes such as congenital hip dysplasia, congenital heart anomaly or facial nerve paresis are rare in BOR syndrome, and this might be easily misdiagnosed with other congenital disorders. We report a 5-month-old boy of BOR syndrome with "congenital heart defects and proteinuria" as clinical features. Initially, as this case mainly presented with symptoms of recurrent respiratory infections and was found to be with congenital heart disease and proteinuria at the local hospital, but he only was diagnosed with congenital heart disease combined with pulmonary infection and anti-infective and supportive treatment was given. Subsequently, during the physical examination at our hospital, left side preauricular pit and branchial fistulae on the right neck were found. Subsequent evaluation of auditory brainstem response and distortion product otoacoustic emission were revealed sensorineural hearing impairment. Results of renal ultrasonography showed small kidneys. Genetic analysis revealed a microdeletion at chromosome 8q13.2-q13.3 encompassing EYA1 gene, this patient was finally diagnosed with BOR syndrome. Then, this patient received transcatheter patent ductus arteriosus closure and hearing aid treatment. Proteinuria, renal function and hearing ability are monitoring by nephrologist and otologist. The patient is currently being followed up until 3 months after discharge and his condition is stable. Careful physical examination, detailed history and the implementation of diagnostic laboratory tests can reduce the incidence of misdiagnosis. Genetic sequencing analysis of patients is a key guide to the differential diagnosis of BOR syndrome.


Reversing cortical porosity: Cortical pore infilling in preclinical models of chronic kidney disease.
Chronic kidney disease (CKD) patients have a high incidence of fracture due in part to cortical porosity. The goal of this study was to study cortical pore infilling utilizing two rodent models of progressive CKD. Exp 1: Female C57Bl/6J mice (16-week-old) were given dietary adenine (0.2%) to induce CKD for 10 weeks after which calcium water supplementation (Ca-H2O; 1.5% and 3%) was given to suppress PTH for another 4 weeks. Exp 2: Male Cy/+ rats were aged to ~30 weeks with baseline porosity assessed using in vivo μCT. A second in vivo scan followed 5-weeks of Ca-H2O (3%) supplementation. Exp 1: Untreated adenine mice had elevated blood urea nitrogen (BUN), parathyroid hormone (PTH), and cortical porosity (~2.6% porosity) while Ca-H2O lowered PTH and cortical porosity (0.5-0.8% porosity). Exp 2: Male Cy/+ rats at baseline had variable porosity (0.5%-10%), but after PTH suppression via Ca-H2O, cortical porosity in all rats was lower than 0.5%. Individual pore dynamics measured via a custom MATLAB code demonstrated that 85% of pores infilled while 12% contracted in size. Ca-H2O supplementation causes net cortical pore infilling over time and imparted mechanical benefits. While calcium supplementation is not a viable clinical treatment for CKD, these data demonstrate pore infilling is possible and further research is required to examine clinically relevant therapeutics that may cause net pore infilling in CKD.


Medication use and contextual factors associated with meeting guideline-based glycemic levels in diabetes among a nationally representative sample.
Based on the long-lasting diabetes management challenges in the United States, the objective was to examine glycemic levels among a nationally representative sample of people with diabetes stratified by prescribed antihyperglycemic treatment regimens and contextual factors. This serial cross-sectional study used United States population-based data from the 2015 to March 2020 National Health and Nutrition Examination Surveys (NHANES). The study included non-pregnant adults (≥20 years old) with non-missing A1C and self-reported diabetes diagnosis from NHANES. Using A1C lab values, we dichotomized the outcome of glycemic levels into <7% versus ≥7% (meeting vs. not meeting guideline-based glycemic levels, respectively). We stratified the outcome by antihyperglycemic medication use and contextual factors (e.g., race/ethnicity, gender, chronic conditions, diet, healthcare utilization, insurance, etc.) and performed multivariable logistic regression analyses. The 2042 adults with diabetes had a mean age of 60.63 (SE = 0.50), 55.26% (95% CI = 51.39-59.09) were male, and 51.82% (95% CI = 47.11-56.51) met guideline-based glycemic levels. Contextual factors associated with meeting guideline-based glycemic levels included reporting an "excellent" versus "poor" diet (aOR = 4.21, 95% CI = 1.92-9.25) and having no family history of diabetes (aOR = 1.43, 95% CI = 1.03-1.98). Contextual factors associated with lower odds of meeting guideline-based glycemic levels included taking insulin (aOR = 0.16, 95% CI = 0.10-0.26), taking metformin (aOR = 0.66, 95% CI = 0.46-0.96), less frequent healthcare utilization [e.g., none vs. ≥4 times/year (aOR = 0.51, 95% CI = 0.27-0.96)], being uninsured (aOR = 0.51, 95% CI = 0.33-0.79), etc. Meeting guideline-based glycemic levels was associated with medication use (taking vs. not taking respective antihyperglycemic medication classes) and contextual factors. The timely, population-based estimates can inform national efforts to optimize diabetes management.


Indirect evidence for the induction of a prooxidant state by cadmium chloride in cultured mammalian cells and a possible mechanism for the induction.
The effects of scavengers of active oxygen species on cadmium chloride (CdCl2)-induced inhibition of cell growth and DNA synthesis and on the metal-induced clastogenesis were investigated to evaluate whether cadmium could induce a prooxidant state in cultured Chinese hamster V79 cells. Inhibition by CdCl2 of cell growth and [3H]thymidine incorporation into the acid-insoluble fraction of cells and the metal-induced clastogenesis were suppressed in part by the presence of the diffusible radical scavenger, butylated hydroxytoluene (BHT). The action of BHT was concentration-dependent and did not affect the intracellular level of cadmium. D-Mannitol, a hydroxyl radical scavenger, also significantly suppressed Cd-induced inhibition of cell growth and [3H]thymidine incorporation. Catalase was marginally suppressive on Cd-induced inhibition of cell growth. These results suggest that cadmium can induce a prooxidant state in cultured mammalian cells. The mechanism by which cadmium induces a prooxidant state was investigated by measuring the effect of cadmium on those enzymes which constitute a cellular defense against active oxygen and on the level of the intracellular antioxidant, glutathione (GSH). 2-h treatments with CdCl2 over a concentration range of 2-10 X 10(-5) M did not influence superoxide dismutase, catalase, GSH peroxidase or GSSG reductase. In contrast, the level of glutathione was decreased to approximately 40% by treatment with 2 X 10(-5) M cadmium. The decrease in glutathione level may be responsible for a role by active oxygen in Cd-induced inhibition of cell growth and DNA synthesis and the metal-induced clastogenesis.


The effect of old age on supra-span learning of visuo-spatial sequences under incidental and intentional encoding instructions.
Recent findings [Turcotte, Gagnon, & Poirier, 2005. The effect of old age on the learning of supra-span sequences. Psychology and Aging, 20, 251-260.] indicate that incidental learning of visuo-spatial supra-span sequences through immediate serial recall declines with old age (Hebb's paradigm). In this study, we examined whether strategies induced by awareness of the repeated sequence might explain age differences. Young (18-35 years old) and older (65-80 years old) participants underwent either incidental or intentional learning instructions. Results indicated that older adults demonstrated reduced learning of the repeated sequence under both incidental and intentional instructions. In comparison, young adults showed superior learning of the repeated sequence in both conditions but intentional instructions triggered faster and greater learning in this age group. The results strongly indicated that knowledge of the repeated sequence enhanced learning only in the group of young adults. Older adults were unable to translate the knowledge of the repetition into elaborate strategies that would increase recall of the repeated sequence. Other findings suggest that incidental learning in young adults was mediated by both non-conscious and conscious recollection processes.


Expert knowledge sourcing for public health surveillance: national tsetse mapping in Uganda.
In much of sub-Saharan Africa, availability of standardized and reliable public health data is poor or negligible. Despite continued calls for the prioritization of improved health datasets in poor regions, public health surveillance remains a significant global health challenge. Alternate approaches to surveillance and collection of public health data have thus garnered increasing interest, though there remains relatively limited research evaluating these approaches for public health. Herein, we present a case study applying and evaluating the use of expert knowledge sources for public health dataset development, using the case of vector distributions of Human African Trypanosomiasis (HAT) in Uganda. Specific objectives include: 1) Review the use of expert knowledge sourcing methods for public health surveillance, 2) Review current knowledge on tsetse vector distributions of public health importance in Uganda and the methods used for tsetse mapping in Africa; 3) Quantify confidence of the presence or absence of tsetse flies in Uganda based on expert informant reports, and 4) Assess the reliability and potential utility of expert knowledge sourcing as an alternative or complimentary method for public health surveillance in general and tsetse mapping in particular. Information on tsetse presence or absence, and associated confidence, was collected through interviews with District Entomologist and Veterinary Officers to develop a database of tsetse distributions for 952 sub-counties in Uganda. Results show high consistency with existing maps, indicating potential reliability of modeling approaches, though failing to provide evidence for successful tsetse control in past decades. Expert-sourcing methods provide a novel, low-cost and rapid complimentary approach for triangulating data from prediction modeling where field-based validation is not feasible. Data quality is dependent, however, on the level of expertise and documentation to support confidence levels for data reporting. Results highlight the need for increased evaluation of alternate approaches and methods to data collection.


Effects of quinoa flour (Chenopodium Quinoa Willd) substitution on wheat flour characteristics.
Quinoa is a pseudo-cereal with great nutritional and functional qualities, serving as an excellent substitution to develop quinoa-containing foods. This study aimed to explore the influence of quinoa flour substitution on quality characteristics of wheat flour (WF). WF was substituted with different level of quinoa core flour, ground quinoa whole flour and recombined quinoa whole flour. Increasing levels of quinoa flour in WF declined dough swelling index, while increased falling number of composite flours. Besides, quinoa flour substitution considerably decreased the chemical forces of gluten in composite flours. The proportions α-helix and β-sheets reduced, while the random coil proportion increased in gluten secondary structure. SEM images revealed that the gluten network structure was severely damaged. Our findings indicated that substitution of WF with quinoa flours was promising to be developed as an ingredient for food products.


Within host RNA virus persistence: mechanisms and consequences.
In a prototypical response to an acute viral infection it would be expected that the adaptive immune response would eliminate all virally infected cells within a few weeks of infection. However many (non-retrovirus) RNA viruses can establish 'within host' persistent infections that occasionally lead to chronic or reactivated disease. Despite the importance of 'within host' persistent RNA virus infections, much has still to be learnt about the molecular mechanisms by which RNA viruses establish persistent infections, why innate and adaptive immune responses fail to rapidly clear these infections, and the epidemiological and potential disease consequences of such infections.


The mitogenicity for murine splenocytes of specific surface components of the oral periodontopathic bacterium, Actinomyces viscosus.
Many characterized fractions obtained from A. viscosus were examined to identify the macromolecules responsible for mitogenicity for lymphocytes. Spleen-cell suspensions of CBA/J mice were cultured with 50-200 micrograms dry weight of A. viscosus strains T14V and T14AV cellular components. Lipopolysaccharide (LPS) (Escherichia coli) was used as a positive control. Mechanical disruption with a French pressure cell or sonication produced preparations with a stimulation of 69,082 and 45,183 counts above background (CAB), respectively. Mitogenic activity was also present in the culture supernatant (38,000 CAB). Other poorly mitogenic fractions included the peptidoglycan, cell-wall fractions, muramidase digests of cell walls, and the microcapsule extracted from whole cells with 0.5 M MgNO3. The results suggest that mitogenic activity is not associated with the isolated cell-wall structure. The activity was released from the cell surface by physical shearing forces, as well as released into the medium growth.


Parental psychological control and adolescent social problems: The mediating effect of emotion regulation.
This study aimed to investigate relationships among parental psychological control, adolescent emotion regulation, and social problems in China. In total, 1,145 adolescents aged 12-15 years participated in the study, which used the Parental Psychological Control Scale, Adolescent Problem Behavior Scale, and Emotion Regulation Scale. The results indicated the following: (1) Compared with only-child teens, adolescents in multi-child families had significant social problems; (2) parental psychological control significantly predicted adolescents' social problems; (3) there was a partially mediating effect of adolescents' emotion regulation between parental psychological control and adolescents' social problems.


Referral of elderly cancer patients to specialists: action proposals for general practitioners.
Many studies have identified advanced age as a barrier to accessing specialized oncological care. To identify elements from the literature influencing general practitioners (GPs) in their decisions to refer elderly patients with cancer to oncology teams, and propose focused actions to improve referral processes. Eligible articles published up to July 2010 identifying factors associated with referral decisions for elderly cancer patients were selected. A quality assessment of each article was performed. All factors identified were considered for possible interventions classified by the Effective Practice and Organisation of Care (EPOC) taxonomy and development of recommendations for referral of elderly patients. Thirty eligible articles were found with only 18 articles specifically exploring factors influencing physicians in the referral of their patients with cancer. Twelve focused on delay to treatment and only two uniquely on elderly patients. Patient age was the main factor associated with referral decisions, but this factor can influence GP's differently depending on the type of cancer. The small size of these studies, heterogeneity of study populations, and diversity of outcome measures used meant that compilation of guidelines based on high-quality evidence was not possible. However, organizational factors hindering decisions to refer are identified and highlighted as crucial for inclusion in intervention programs, specifically to reach GPs in smaller locations or with less experience in collaborating with specialists. For patient-related factors, professional and organizational interventions are necessary, aimed at both GPs and patients to update knowledge of the non-linear relationship between chronological age and a patient's ability to tolerate treatment. First and foremost, this article highlights the scarcity of literature specific to elderly patients with cancer. It also identifies the public health need for better knowledge of the factors for referral of elderly patients. Focussed action proposals are presented to improve knowledge and consequently, optimize the referral process.


Adult embryonal rhabdomyosarcoma in the nasal cavity; a case report with a review of the literature.
Rhabdomyosarcoma (RMS) is a primitive malignant soft tissue tumor arising from premature mesenchymal cells. The current study presents a rare case of embryonal rhabdomyosarcoma in the nasal cavity of an adult patient. An 18-year-old female presented with right nasal obstruction for five months. Examination showed a pale soft, painless mass in the right nasal cavity with attachment to the nasal septum at the osteocartilaginous junction. The patient was falsely suspected for bacterial infection, but later histological examination showed undifferentiated small round blue cell tumor with extensive necrosis. Immunohistochemistry confirmed the diagnosis of embryonal RMS. The patient was operated on for endoscopic sinus surgery to remove the mass with additional cleaning of surrounding sinuses. Embryonal RMS is a rare type of malignant tumor that mostly affects the head and neck area in children while usually occur in the extremities of adults. Encountering an adult ERMS of the nasal chambers represents a small portion of head and neck cases that lack specific presentations. Adult embryonal RMS of the nasal cavity is exceedingly rare and presents a diagnostic and management challenge, with immunohistochemistry being the only definitive diagnostic method.


Antibiotic uptake by bacteria as measured by partition in polymer aqueous phase systems.
Polyethyleneglycol/dextran and polyethyleneglycol/salt two-phase systems are used to measure the entry of antibiotics into Escherichia coli and Staphylococcus aureus cells. Aminoglycosides, macrolides, a quinolone, and a cycline were assayed. The method is simple and rapid and eliminates the problems encountered with filters, especially nonspecific binding; it allows rapid uptake kinetics to be measured.


Beta-Blocker Use and Heart Failure Outcomes in Mildly Reduced and Preserved Ejection Fraction.
Although studies consistently show that beta-blockers reduce morbidity and mortality in patients with reduced ejection fraction (EF), data are inconsistent in patients with heart failure with mildly reduced ejection fraction (HFmrEF) and suggest potential negative effects in heart failure with preserved ejection fraction (HFpEF). The purpose of this study was to examine the association of beta-blockers with heart failure (HF) hospitalization and death in patients with HF and EF ≥40% METHODS: Beta-blocker use was assessed at first encounter in outpatients ≥65 years of age with HFmrEF and HFpEF in the U.S. PINNACLE Registry (2013-2017). The associations of beta-blockers with HF hospitalization, death, and the composite of HF hospitalization/death were assessed using propensity-score adjusted multivariable Cox regression models, including interactions of EF × beta-blocker use. Among 435,897 patients with HF and EF ≥40% (HFmrEF, n = 75,674; HFpEF = 360,223), 289,377 (66.4%) were using a beta-blocker at first encounter; more commonly in patients with HFmrEF vs HFpEF (77.7% vs 64.0%; P < 0.001). There were significant interactions between EF × beta-blocker use for HF hospitalization, death, and composite of HF hospitalization/death (P < 0.001 for all), with higher risk with beta-blocker use as EF increased. Beta-blockers were associated with decreased risk of HF hospitalization and death in patients with HFmrEF but a lack of survival benefit and a higher risk of HF hospitalization in patients with HFpEF, particularly when EF was >60%. In a large, real-world, propensity score-adjusted cohort of older outpatients with HF and EF ≥40%, beta-blocker use was associated with a higher risk of HF hospitalization as EF increased, with potential benefit in patients with HFmrEF and potential risk in patients with higher EF (particularly >60%). Further studies are needed to understand the appropriateness of beta-blocker use in patients with HFpEF in the absence of compelling indications.


Recent advances in the bile acid based conjugates/derivatives towards their gelation applications.
Bile acids have contributed immensely to hydrogel research due to their peculiar physicochemical properties and biocompatibility. The wide accessibility of bile acids and their straightforward derivatization methods make them attractive building blocks for the design of novel hydrogels systems to deliver biomolecules, drugs, and vaccines. This review conceptualizes recent developments in bile acid-based hydrogels and their applications. These bile-based hydrogels have the ability to absorb carbon dioxide efficiently and may potentially work as alternative materials for carbon dioxide capture and storage. The hydrogels hold great potential in medicine and biology applications as drug carriers and models for fundamental self-assembly in pathological conditions. Herein, we have summarized the efforts that have been made for the development of molecular hydrogels in terms of biocompatibility, therapeutic applications, and challenges associated with existing molecular hydrogels.


Significance of the zebrafish model in the discovery of bioactive molecules from nature.
Natural products have immense therapeutic potential not only due to their structural variation and complexity but also due to their range of biological activities. Research based on natural products has led to the discovery of molecules with biomedical and pharmaceutical applications in different therapeutic areas like cancer, inflammation responses, diabetes, and infectious diseases. There are still several challenges to be overcome in natural product drug discovery research programs and the challenge of high throughput screening of natural substances is one of them. Bioactivity screening is an integral part of the drug discovery process and several in vitro and in vivo biological models are now available for this purpose. Among other well-reported biological models, the zebrafish (Danio rerio) is emerging as an important in vivo model for preclinical studies of synthetic molecules in different therapeutic areas. Zebrafish embryos have a short reproductive cycle, show ease of maintenance at high densities in the laboratory and administration of drugs is a straightforward procedure. The embryos are optically transparent, allowing for the visualization of drug effects on internal organs during the embryogenesis process. In this review, we illustrate the importance of using zebrafish as an important biological model in the discovery of bioactive drugs from natural sources.


Identification of Patients With Localized Ewing Sarcoma at Higher Risk for Local Failure: A Report From the Children's Oncology Group.
To identify clinical and treatment variables associated with a higher risk of local failure in Ewing sarcoma patients treated on recent Children's Oncology Group protocols. Data for 956 patients treated with ifosfamide and etoposide-based chemotherapy on INT-0091, INT-0154, and AEWS0031 were analyzed. Local treatment modalities were defined as surgery, definitive radiation therapy (RT), or surgery plus radiation (S+RT). Five-year cumulative incidence of local failure was determined. The local failure rate for the entire cohort was 7.3%, with a 3.9% rate for surgery, 15.3% for RT (P<.01), and 6.6% for S+RT (P=.12). The local failure incidence was 5.4% for extremity tumors, 13.2% for pelvis tumors (P<.01), 5.3% for axial non-spine tumors (P=.90), 9.1% for extraskeletal tumors (P=.08), and 3.6% for spine tumors (P=.49). The incidence of local failure was 14.8% for extremity tumors and 22.4% for pelvis tumors treated with RT, compared with 3.7% for extremity tumors and 3.9% for pelvis tumors treated with surgery (P≤.01). There was no difference in local failure incidence by local treatment modality for axial non-spine, spine, and extraskeletal tumors. The local failure incidence was 11.9% in patients aged ≥18 years versus 6.7% in patients aged <18 years (P=.02). Age ≥18 years (hazard ratio 1.9, P=.04) and treatment with RT (hazard ratio 2.40, P<.01) remained independent prognostic factors for higher local failure incidence on multivariate analysis. Tumor size (</≥ 8 cm) was available in 40% of patients and did not correlate with local failure incidence. Local tumor control is excellent and similar between surgery and RT for axial non-spine, spine, and extraskeletal tumors. Age ≥18 years and use of RT, primarily for pelvis and extremity tumors, are associated with the highest risk of local failure. Further efforts should focus on improving outcomes for these patients.


Hepatobiliary and Pancreatic Adverse Events.
The expanded approval of immune checkpoint inhibitors (ICIs) for the treatment of multiple cancer types has offered patients more opportunities in treatment selection and survival.Hepatotoxicity is a well-recognized immune-related adverse event (irAE) associated with treatment with ICI. It is considered a type of drug-induced liver injury (DILI). Depending on the specific ICI and whether the patient receives single- or dual-drug therapy, the incidence of hepatotoxicity in general could be as high as 30%. As more patients receive treatment with ICI, more cases of hepatotoxicity are expected to occur. Clinicians must exercise close pharmacovigilance to recognize liver-related irAEs early.ICI-mediated hepatobiliary toxicity (or "IMH") generally presents as asymptomatic elevations of alanine transaminase and aspartate transaminase, with or without alkaline phosphatase elevation. Some patients may present with jaundice, fever, or malaise. Rarely, it may cause liver failure and death. The diagnosis of IMH is made after careful exclusion of other causes of acute hepatitis based on medical history, laboratory evaluation, imaging, and liver histological findings. In clinically significant cases of IMH, the management involves discontinuation of ICI followed by close monitoring and the initiation of immunosuppression. Current society guidelines, which are not based on robust evidence, specify treatment recommendations depending on the grade of liver injury, according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. However, our clinical experience suggests possible alternatives, including lower corticosteroid dosing with adjunct therapies. Whereas current guidelines endorse permanent cessation of future ICI treatment in patients diagnosed with grades 3-4 IMH, published clinical experience suggests potential for flexibility when assessing for candidacy of resuming ICI.Because histologic bile duct injury has been observed in cases ascribed to IMH, ICI-mediated cholangiopathic disease probably exists on a spectrum within IMH. Even extrahepatic bile duct involvement has been observed. This phenotype warrants special considerations in treatment and surveillance.ICI-related cholecystitis has been rarely reported in the literature. Management follows current standards of care for typical cases of cholecystitis. No relationship with ICI-mediated cholangiopathic disease has been observed.Assessing for and managing ICI-associated pancreatic injury remain challenging to the clinician. Many cases of asymptomatic serum lipase elevation are detected on routine labs without clinical signs or symptoms of typical acute pancreatitis. However, symptomatic patients should be initially managed like traditional cases of acute pancreatitis requiring hospitalization for evaluation and inpatient management.


Estimation of plasma triglycerides with correction for free glycerol by orlistat inhibition of lipoprotein lipase activity.
This report presents a modification of the enzymatic method (lipoprotein lipase/glycerol kinase/glycerol-3-phosphate oxidase/peroxidase) for determination of plasma triglyceride levels in order to achieve correction for the free glycerol content. The strategy is based on elimination of lipoprotein lipase activity from the single "multienzyme reagent" by use of orlistat, thereby allowing formation of quinoneimine chromophore from free glycerol. Orlistat was found to abolish the lipoprotein lipase activity (triolein was used as substrate) without any impact on the glycerol-driven rate of quinoneimine generation. Conditions were standardized for estimation of both triglyceride and glycerol content of mice plasma using a microplate reader.


Longitudinal study of proteins in plasma and dialysate during continuous ambulatory peritoneal dialysis (CAPD).
The aim was to evaluate plasma proteins during continuous ambulatory peritoneal dialysis (CAPD) in relation to dialysis losses, membrane permeability, renal insufficiency, and time on CAPD. Ten male patients, established on CAPD for at least 14 months, were studied every 8 weeks for 56 weeks. Blood and dialysate from the morning exchange were analysed for urea, creatinine, and 7 proteins, and used to calculate dialysate to plasma concentration ratios (D/P). These ratios were not significantly changed suggesting that permeability remained constant. However, there was a trend for beta 2-microglobulin, creatinine, and urea to increase progressively. After 56 weeks, beta 2-microglobulin had increased from 27.9 to 31.3 mg/L (p less than 0.05) and creatinine 1006 to 1099 mumoL/L (p less than 0.05) and both correlated with time on CAPD (p less than 0.001). Plasma alpha 1-acid glycoprotein, albumin, transferrin, IgG, IgA, and complement C3 were not significantly changed, although IgA and complement C3 were each negatively correlated with time on CAPD (r = -0.70 and -0.67, respectively), creatinine (r = 0.51 and -0.54), and urea (r = -0.61 and -0.61) (p less than 0.001 for all). It is concluded that increases in beta 2-microglobulin, creatinine, and urea are not due to loss of membrane permeability but reflect a slight increase in uraemia. Long-term decreases in immunological proteins may be caused by uraemia or progressive depletion.


Sedimentology and geochemistry of mud volcanoes in the Anaximander Mountain Region from the Eastern Mediterranean Sea.
Investigations carried out on surface sediments collected from the Anaximander mud volcanoes in the Eastern Mediterranean Sea to determine sedimentary and geochemical properties. The sediment grain size distribution and geochemical contents were determined by grain size analysis, organic carbon, carbonate contents and element analysis. The results of element contents were compared to background levels of Earth's crust. The factors that affect element distribution in sediments were calculated by the nine push core samples taken from the surface of mud volcanoes by the E/V Nautilus. The grain size of the samples varies from sand to sandy silt. Enrichment and Contamination factor analysis showed that these analyses can also be used to evaluate of deep sea environmental and source parameters. It is concluded that the biological and cold seep effects are the main drivers of surface sediment characteristics from the Anaximander mud volcanoes.


Differential diagnosis of intraocular neoplasms with ultrasonography.
In the past five years A- and B-mode echography were used in the differential diagnosis of intraocular tumours (174 patients) and numerous cases with mimicking lesions. By using the 7200 A-scan equipment and distinct investigation techniques and giving attention to all aspects (quantitative, kinetic, and topographic) of the obtained echogram, the detection of the tumours involved in this study (choroidal melanoma, choroidal hemangioma, choroidal metastases, and retinoblastoma), is almost 99%. The accuracy in the differentiation of these tumours appears to be over 90%. Most of the false positives occur in the differentiation between choroidal melanomas and choroidal metastases.


Advance of echocardiography in cardiac amyloidosis.
Cardiac amyloidosis (CA) occurs when the insoluble fibrils formed by misfolded precursor proteins deposit in cardiac tissues. The early clinical manifestations of CA are not evident, but it is easy to progress to refractory heart failure with an inferior prognosis. Echocardiography is the most commonly adopted non-invasive modality of imaging to visualize cardiac structures and functions, and the preferred modality in the evaluation of patients with cardiac symptoms and suspected CA, which plays a vital role in the diagnosis, prognosis, and long-term management of CA. The present review summarizes the echocardiographic manifestations of CA, new echocardiographic techniques, and the application of multi-parametric echocardiographic models in CA diagnosis.


Dissociated optic nerve fiber layer appearance after internal limiting membrane peeling for idiopathic macular holes.
To investigate the characteristics and incidence of a dissociated optic nerve fiber layer (DONFL) appearance in eyes after idiopathic macular hole surgery. Retrospective, nonrandomized, comparative interventional case series. Ninety-one eyes with idiopathic macular holes that were closed after 1 pars plana vitrectomy were studied. Among these, 67 eyes had the internal limiting membrane (ILM) peeled (ILM-peeled), and 24 did not have the ILM peeled (ILM-unpeeled). All patients received a complete ophthalmologic examination and color fundus photography preoperatively and postoperatively. Twenty ILM-peeled eyes and 9 ILM-unpeeled eyes were also examined by optical coherence tomography (OCT3), microperimetry by scanning laser ophthalmoscope (SLO), and macular sensitivity measurements by Humphrey visual field testing more than 4 months after the vitrectomy. Development of a DONFL on fundus photographs and OCT3, and the functional evaluation of a DONFL by best-corrected visual acuity, SLO-microperimetry, and Humphrey visual field testing. In 67 ILM-peeled eyes, a DONFL appearance was found in 36 eyes (54%) in color fundus photographs. A DONFL appearance was not detected in any of the 24 ILM-unpeeled eyes. Focal dehiscence of the optic nerve fiber layer was found in all 20 examined eyes by OCT3. No scotoma was found corresponding to the DONFL by SLO microperimetry. The best-corrected visual acuity and macular sensitivity were not significantly different in eyes with and without a DONFL appearance (P>0.05). A DONFL appearance was not detected in all 20 eyes examined within 1 month after surgery, was detected in all 16 eyes examined between 1 and 3 months, and no new cases were detected after 3 months. The DONFL appearance became more distinct until about 6 months after first detection and seemed not to change subsequently. The DONFL appearance in about half of the eyes with ILM peeling and none in eyes without ILM peeling strongly suggest that the DONFL appearance is related to ILM peeling. The OCT findings in eyes with no functional abnormality by SLO microperimetry suggested that the DONFL is due to a dehiscence of the optic nerve fiber layer and not a true nerve fiber layer defect.


Leukocytospermia in late adolescents: possible clinical interpretations.
No data are currently available on the implication of amicrobial leukocytospermia in male adolescents. Therefore, the primary aim of this study was to evaluate the prevalence of amicrobial leukocytospermia among non-smoker late adolescents who were exposed to other risky lifestyles for the andrological health. The main andrological clinical features of adolescents with leukocytospermia were also reported. This is a cross-sectional study carried out in 80 boys. Each adolescent underwent a physical examination, and to the assessment of sperm conventional parameters, seminal leukocytes concentration and immature germ cell evaluation. A possible correlation between seminal leukocytes and immature germ cells and testicular volume (TV) was tested. The adolescents enrolled in this study had 18.0 ± 0.4 (range 18.1-18.9) years. Unprotected sexual intercourse was referred by 38% of them. Sexual dysfunctions were found in 25% and isolated hypoactive sexual desire in 12.5% of boys. Low TV and penile length in flaccidity were found in 44% and 30% of them, respectively. Only 41% had normozoospermia at the sperm analysis, whereas 19% had isolated oligozoospermia, 15% oligo-asthenozoospermia, and 25% oligo-astheno-teratozoospermia. Leukocytospermia occurred in 25% (20 out of 80) of adolescents. No seminal infection was detected in 19% (15 out of 80) of them. Adolescents with leukocytospermia had lower progressive sperm motility, percentage of normal forms, TV, and a higher percentage of immature germ cells compared to those without leukocytospermia. Semen leukocyte concentration correlated negatively with TV and positively with the percentage of immature germ cells in the ejaculate. Leukocytospermia, increased immature germ cell number, and low TV identify a distinct phenotype suggestive of testicular tubulopathy. Primary prevention of male infertility and the counselling for andrological risky lifestyles is mandatory and should be started as early as possible.


Cardiorespiratory effects induced by acetazolamide on the ventromedullary surface of the cat.
1. Inhibition of carbonic anhydrase by acetazolamide in alpha-chloralose-anaesthetized cats, in a region of the brain stem co-extensive with the glycine-sensitive area, intermediate chemosensitive area, and probably C1 catecholaminergic neurones produces hypotension, bradycardia and depression of the central respiratory drive. 2. These responses are concentration dependent, and can still be observed when the enzyme substrate (CO2) is elevated. Therefore, in both the hypercapnic and the normocapnic condition, similar responses in arterial blood pressure, heart rate and respiratory rate are observed when acetazolamide is topically applied to the glycine-sensitive area. 3. To investigate further the contribution of peripheral baro-, chemo- and cardiopulmonary receptors to these responses, acetazolamide was topically applied to the glycine-sensitive area under three different conditions: intact gallamine-paralysed (5 mg kg-1 h-1) and artificially ventilated (A), sinoaortic denervated (B), and sinoaortic denervated plus bilaterally vagotomized cats (C). Under all conditions, similar responses were observed. The fall in arterial blood pressure was 75 +/- 11 (A), 90 +/- 13 (B), and 75 +/- 9 mmHg (C). Changes in heart rate during acetazolamide application were -23 +/- 6, -20 +/- 8, and -26 +/- 6 beats min-1, respectively. The decreases in respiratory rate were 9 +/- 2 (A), 11 +/- 2 (B), and 11 +/- 2 breaths min-1 (C). 4. The data indicate that the responses to topical application of acetazolamide are mainly due to its central action at the glycine-sensitive area and are not influenced by peripheral baroreceptor and chemoreceptor inputs.


Insight into the formation of polyhalogenated carbazoles during seawater chlorination.
Although polyhalogenated carbazoles (PHCZs) have been widely detected in the marine environment, their origin is far from clear. In this study, the formation of PHCZs in the chlorination of seawater containing carbazole and its derivatives was investigated. A total of 14 PHCZs including six commonly found and eight unknown congeners were identified in the chlorination of seawater with carbazole. In addition, this study for the first time demonstrated the production of common PHCZs from the chlorination of seawater with 3-methyl carbazole and 3-formyl carbazole, especially 1,8-dibromo-3,6-dichlorocarbazole from 3-methyl carbazole. The formation of PHCZs in the reaction resulted from the halogenation of carbazole by reactive chlorine species (RCS) and mainly reactive bromine species (RBS), forming from the oxidation of bromide by RCS. Results also indicated that the reaction followed a successive halogenation pattern. A higher content of free chlorine and bromide facilitated the generation of RBS, while a higher concentration of DOC exhibited an inhibitory effect. The effects of free chlorine, bromide, DOC, and temperature on the formation of PHCZs were congener-specific. Given the widespread use of chlorination in seawater disinfection, seawater chlorination might be a potential source of PHCZs in the marine environment.


Enzyme assay for protein kinase using micellar electrokinetic chromatography with laser-induced fluorescence detection.
Micellar electrokinetic chromatography (MEKC) with laser-induced fluorescence (LIF) detection has been developed for a protein kinase assay. This protein kinase assay could readily determine the phosphorylation activity of substrate peptide kemptide using cAMP-dependent protein kinase (PKA) as a model enzyme. Kemptide and phosphorylated kemptide could be reacted with 7-fluoro-4-nitrobenzo-2-oxa-1,3-diazole (NBD-F) as a fluorescence derivatization reagent for LIF detection by directly adding NBD-F into the PKA enzymatic reaction mixture. These derivatives of substrate and product were separated and detected within the analysis time of 5 min by micellar electrokinetic mode using a mixture of sodium dodecylsulfate and methanol as a running buffer. Good linearity of the peak response of the phosphorylated kemptide was obtained over the range of 1-20 mU/tube of PKA in the assay. The relative standard deviation of the peak areas of the phosphorylated kemptide using 2, 5 and 10 mU/tube of PKA were calculated to <10.4%, indicating that the assay was reproducible. Also, IC(50) values of six PKA inhibitors, the K(i) value and the inhibition pattern of one inhibitor, which were calculated to estimate by the variation of the peak area of the phosphorylated kemptide using 5 mU/tube of PKA, were consistent with the published data. The sensitivity of the assay was higher than that of enzyme-linked immunosorbent assay (ELISA) for PKA phosphorylation activity, as IC(50) values, K(i) value, and the inhibition mechanism of inhibitors could be estimated using one-tenth amounts of PKA, compared with that of ELISA. The MEKC-LIF is expected to be very useful for protein kinase assay and its application to the estimation of inhibitors because this method does not entail experimentally troublesome procedures such as the preparation of antibody or fluorescence-labeled substrate.


Integrating model explanations and hybrid priors into deep stacked networks for the "safe zone" prediction of acetabular cup.
Existing state-of-the-art "safe zone" prediction methods are statistics-based methods, image-matching techniques, and machine learning methods. Yet, those methods bring a tension between accuracy and interpretability. To explore the model explanations and estimator consensus for "safe zone" prediction. We collected the pelvic datasets from Orthopaedic Hospital, and a novel acetabular cup detection method is proposed for automatic ROI segmentation. Hybrid priors comprising both specific priors from data and general priors from experts are constructed. Specifically, specific priors are constructed based on the fine-tuned ResNet-101 convolutional neural networks (CNN) model, and general priors are constructed based on expert knowledge. Our method considers the model explanations and dynamic consensus through appending a SHapley Additive exPlanations (SHAP) module and a dynamic estimator stacking. The proposed method achieves an accuracy of 99.40% and an area under the curve of 0.9998. Experimental results show that our model achieves superior results to the state-of-the-art conventional ensemble classifiers and deep CNN models. This new screening model provides a new option for the "safe zone" prediction of acetabular cup.


A review on phytochemistry and pharmacological uses of Tecoma stans (L.) Juss. ex Kunth.
Tecoma stans (L.) Juss. ex Kunth (Bignoniaceae) is an attractive evergreen plant known as kusi urakame, koyawari, Palo amarillo, tronadora, yellow-elder, yellow trumpet bush, trumpet-flower, yellow-bells, trumpet bush, ginger-Thomas, esperanza, and timboco. It is widely used in traditional Mexican medicine, to treat hyperglycemia, gastrointestinal and urinary tract disorders, jaundice, toothaches, headaches, colds, skin infections, and scorpion, snake, and rat bites. Current research focusses on evaluating its bioactive components and therapeutic potential. The current article reviewed the information available on Tecoma stans ethnopharmacology, geographical distribution, chemical composition, phytochemistry, therapeutic effects, and toxicology. Information of botanical description, distribution, traditional uses, chemical composition, bioactive components, and therapeutic investigations was gathered from a comprehensive literature search of electronic databases such as Science Direct, PubMed, Web of Science, Wiley, ACS, Springer, Taylor and Francis, Google Scholar, and SCOPUS until 2020 for publications (peer-reviewed articles, eBooks, short communications, reports from international organizations, and case letters). Information was also included from books, conference proceedings, and thesis. Primary keywords for data collection were "Tecoma stans," and "Ethnopharmacology," followed by secondary keywords such as "Constituents," "Therapeutic effect," and "Toxicity." An exhaustive comparative study of the accessible sources of Tecoma stans confirmed its origin, ethnopharmacological and therapeutic uses. More than 120 chemical compounds have been isolated, and the main active principles are alkaloids, phenolic acids, flavonoids, and fatty acids. The plant possesses vast therapeutic benefits, such as lowering elevated blood sugar levels, anti-inflammatory, anti-cancer, anti-bacterial, anti-fungal, anti-oxidant, hepatoprotective, and wound healing actions. Comprehensive literature analysis exhibits that many populations have utilized Tecoma stans around the globe with specific reference to different parts of Mexico. The above information shows that the plant holds many hidden potentials and can, therefore, be studied extensively for its phytoconstituents and therapeutic effects. However, while going through the literature, it was observed that incomplete data is reported on in vivo trials, especially concerning its dosage, positive and negative control groups, intervention time, and toxicity studies. Additionally, there is a lack of information on its complete nutritional and phytochemical profiling. We trust that this review will help lay the groundwork for encouraging pharmacological and pharmaceutical studies. It will also direct us to understand the clinical relevance and applications of bioactive compounds from Tecoma stans in the prevention and treatment of diseases.


Phosphoprotein phosphatase activity at the outer surface of intact normal and transformed 3T3 fibroblasts.
Using 32P-labeled phosphocasein or phosphohistones as exogenous substrates it was possible to detect a phosphoprotein phosphatase activity on the outer surface of intact normal and transformed 3T3 fibroblasts. Incubation of monolayers of intact cells in buffered salt solution with the radioactively labeled substrate resulted in the release of alkali-labile 32P counts into the surrounding medium. The reaction was: (a) linear with time (at least up to 20 min); (b) proportional to the cell density; (c) dependent on the temperature and pH of the incubation medium; (d) stimulated by K+; and (e) inhibited by sodium fluoride, inorganic pyrophosphate, zinc chloride and relatively impermeant sulfhydryl reagents. Less than 2% of the externally located phosphoprotein phosphatase activity was detectable in pooled cell-free washings of the intact cell monolayer. Phosphocasein did not cause any detectable leakage of intracellular lactate dehydrogenase or soluble phosphoprotein phosphatase activity into the external medium; incubation of the cells with phosphohistones, on the other hand, resulted in appreciable leakage of both these cytoplasmic activities. Neoplastic transformation was associated with a nearly two-fold decrease in the activity of the surface phosphoprotein phosphatase. Addition of serum to either non-transformed 3T3 or spontaneously transformed 3T6 cells resulted in a rapid and remarkeable drop in the cell surface dephosphorylating activity. Acrylamide gel electrophoresis of the dephosphorylated casein or histone substrate revealed no proteolytic degradation or change in electrophoretic mobility. The intact cells showed no damage upon microscopic examination as a result of exposure to phosphocasein or phosphohistones.


Injection Site Reactions in the Federal Adverse Event Reporting System (FAERS) Post-Marketing Database Vary Among Biologics Approved to Treat Moderate-To-Severe Psoriasis.
Biologics used to treat moderate-to-severe plaque psoriasis may cause injection site reactions (ISRs) characterized by erythema, edema, itch, and sometimes pain. The Federal Adverse Event Reporting System (FAERS) is a repository of spontaneous post-marketing reports of adverse events (AEs) that are reported to the US Food and Drug Administration (FDA). Our objective was to perform a pharmacovigilance analysis of FAERS reports of ISRs associated with the use of subcutaneously administered biologic products approved to treat moderate-to-severe plaque psoriasis. The products included in our assessment were adalimumab, etanercept, ixekizumab, secukinumab, and ustekinumab. Reports from the date of US approval for each biologic as treatment for plaque psoriasis through 2 years were included using the search term "injection site." The results show that the FAERS database contained reports of ISRs for all of the included biologics during the 2 years following FDA approval. The most common reports on ISRs were on pain, irritation, and erythema for adalimumab; reaction, pain, and erythema for etanercept; erythema, pain, and reaction for ixekizumab; bruising, pain, hemorrhage for secukinumab; and pain, induration, and swelling for ustekinumab. FAERS does not include data on total patient exposure; therefore, ISR rates could not be calculated. Specific ISRs varied among the biologic therapies assessed. The findings presented could be helpful when patients consider switching therapies due to ISRs. Eli Lilly and Company.


Whole genome microarray expression analysis in blood identifies pathways linked to signs and symptoms of a patient with hypercalprotectinaemia and hyperzincaemia.
A child, 2 years with the 'hypercalprotectinaemia with hyperzincaemia' clinical syndrome, presented with atypical symptoms and signs, notably persistent fever of approximately 38°C, thrombocythaemia of > 700 × 109 /l and a predominance of persistent intestinal symptoms. In an effort to find a cure by identifying the dysregulated pathways we analysed whole-genome mRNA expression by the Affymetrix HG U133 Plus 2·0 array in blood on three occasions 3-5 months apart. Major up-regulation was demonstrated for the Janus kinase/signal transducer and activators of transcription (JAK/STAT) pathway including, in particular, CD177, S100A8, S100A9 and S100A12, accounting for the thrombocytosis; a large number of interleukins, their receptors and activators, accounting for the febrile apathic state; and the high mobility group box 1 (HMBG1) gene, possibly accounting for part of the intestinal symptoms. These results show that gene expression array technology may assist the clinician in the diagnostic work-up of individual patients with suspected syndromal states of unknown origin, and the expression data can guide the selection of optimal treatment directed at the identified target pathways.


Monitoring pathways of β-glucan degradation by enzyme mixtures in situ.
The degradation of β-glucans from cereal cell walls is related to health benefits of whole grain foodstuffs and is a prominent cost in the production of bioethanol and in improving the filterability of malt-based beverages. Detailed assays of β-glucan degradation pathways by enzyme mixtures therefore promise to support the analysis of physiological and the optimization of technological processes. Physiological and biotechnological processes tend to occur in complex mixtures of catalysts and substrates and the development of advanced methodologies for mixture analysis has been attracting a great deal of attention. In situ detection of processes that involve carbohydrate synthesis and degradation encompasses the challenge of detecting monomer identities and linkage patterns, as well as enzymatic stereochemistry and specificity while resolving chemically similar reactants, challenges that are complicated in the additional detection of intermediate degradation steps. In the current study, we show that nuclear magnetic resonance (NMR) spectroscopy near the highest available spectrometer fields permits detailed real-time assays of the degradation of polymeric barley (1→3),(1→4)-β-glucan by commercial enzyme mixtures. Up to six different intermediates can be resolved and structurally assigned within a 0.07 ppm chemical shift range using the anomeric 1H chemical signal in β-(1→3) glycosidic linkages as a structural reporter. More than 16 different glucopyranosyl spin systems are assigned to structural motifs in degradation fragments. The time course of intermediate emergence permits deciphering cleavage pathways and stereochemistry for up to four different enzyme catalyzed steps in situ.


Assessment of clinical and radiologic differences between small and large adrenal pheochromocytomas.
To evaluate differences in clinical and radiologic features of small and large pheochromocytomas. This study included 39 patients with adrenal pheochromocytomas. Several clinical and radiologic features were statistically analyzed and compared between small and large pheochromocytomas. No significant differences were found in clinical features between them. Small pheochromocytomas had more relatively homogeneous attenuation although large pheochromocytomas had more cystic or necrotic changes. Pheochromocytomas tend to have different CT imaging features mimicking other tumors according to the size of the tumors. However, clinical features, CT imaging characteristics, and radioisotope activity are not different between small and large pheochromocytomas.


Ketamine induces EEG oscillations that may aid anesthetic state but not dissociation monitoring.
Ketamine is an anesthetic drug associated with dissociation. Decreased electroencephalogram alpha (8-13 Hz) and low-beta (13-20 Hz) oscillation power have been associated with ketamine-induced dissociation. We aimed to characterize surface electroencephalogram signatures that may serve as biomarkers for dissociation. We analyzed data from a single-site, open-label, high-density surface electroencephalogram study of ketamine anesthesia (2 mg/kg, n = 15). We assessed dissociation longitudinally using the Clinician Administered Dissociation States Scale (CADSS) and administered midazolam to attenuate dissociation and enable causal inference. We analyzed electroencephalogram power and global coherence with multitaper spectral methods. Mixed effects models were used to assess whether power and global coherence signatures of ketamine could be developed into dissociation-specific biomarkers. Compared to baseline, ketamine unresponsiveness was associated with increased frontal power between 0.5 to 9.3 Hz, 12.2 to 16.6 Hz, and 24.4 to 50 Hz. As subjects transitioned into a responsive but dissociated state (mean CADSS ± SD, 22.1 ± 17), there was a decrease in power between 0.5 to 10.3 Hz and 11.7 to 50 Hz. Midazolam reduced dissociation scores (14.3 ± 11.6), decreased power between 4.4 to 11.7 Hz and increased power between 14.2 to 50 Hz. Our mixed-effects model demonstrated a quadratic relationship between time and CADSS scores. When models (frontal power, occipital power, global coherence) were reanalyzed with midazolam and electroencephalogram features as covariates, only midazolam was retained. Ketamine is associated with structured electroencephalogram power and global coherence signatures that may enable principled anesthetic state but not dissociation monitoring. A neurophysiological biomarker for dissociation may lead to a better understanding of neuropsychiatric disorders.


Shexiang Baoxin Pill (MUSKARDIA) reduces major adverse cardiovascular events in women with stable coronary artery disease: A subgroup analysis of a phase IV randomized clinical trial.
A previous phase IV trial revealed sex as a potential effect modifier of MUSKARDIA efficacy in stable coronary artery disease (CAD). To assess the clinical effect of MUSKARDIA as a supplemental treatment to optimal medical therapy (OMT) in stable CAD cases. This study was a subgroup analysis of a multicenter, randomized, double-blinded, placebo-controlled phase IV clinical study. Eligible individuals underwent randomization to the oral MUSKARDIA and placebo groups and were treated for 24 months. All participants received OMT according to existing guidelines. The primary composite outcome was the major adverse cardiovascular event (MACE), included cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal stroke. The secondary composite outcome encompassed all-cause mortality, non-fatal MI, non-fatal stroke, hospitalization for unstable angina and/or heart failure, and undergoing coronary procedure/surgery during treatment. Safety signals, especially cardiovascular adverse events (AEs), were analyzed. The female subgroup included 776 participants (384 and 392 in the MUSKARDIA and placebo groups, respectively). The occurrence of the primary composite outcome was lower in the MUSKARDIA group compared with placebo-treated individuals (HR = 0.27, 95%CI: 0.09-0.83; P = 0.02), but the secondary composite outcome showed no significant difference (HR = 0.77, 95%CI: 0.47-1.25; P = 0.29). The MUSKARDIA group had reduced incidence of cardiovascular AEs compared with placebo-treated cases (2.9% vs. 5.6%). As a supplemental treatment to OMT, 24-month administration of MUSKARDIA is effective and safe in female stable CAD cases. [https://clinicaltrials.gov/], identifier [NCT01897805].