Dextromethorphan and caffeine as probes for simultaneous determination of debrisoquin-oxidation and N-acetylation phenotypes in children.
The feasibility and reliability of simultaneously determining debrisoquin oxidation and N-acetylation phenotypes was assessed in children with use of two innocuous substrate probes given by mouth, 30 mg dextromethorphan (Pertussin ES) and 25 to 46 mg caffeine (Coca-Cola beverage). Twenty-six children and adolescents (aged 3 to 21 years) were studied three times, once with each substrate given alone and once with the two substrates given together. Urine was collected for 4 hours, and the molar urinary metabolic ratios for dextromethorphan:dextrorphan and for two caffeine metabolites (AFMU:1X) were determined by HPLC ultraviolet assays. The urinary metabolic ratios for both substrates were not significantly different when the substrates were given alone compared with when they were given together. There also was no difference in either the oxidation or acetylation phenotype assignments when the two substrates were given alone and when they were given together. No adverse effects were observed. We conclude that dextromethorphan and caffeine can be given together to simultaneously determine oxidation and acetylation phenotypes and can thereby provide an innocuous, noninvasive method for the assessment of polymorphic drug metabolism in various pediatric populations.


High-throughput phenotypic screen identifies a new family of potent anti-amoebic compounds.
Entamoeba histolytica is a disease-causing parasitic amoeba which affects an estimated 50 million people worldwide, particularly in socioeconomically vulnerable populations experiencing water sanitation issues. Infection with E. histolytica is referred to as amoebiasis, and can cause symptoms such as colitis, dysentery, and even death in extreme cases. Drugs exist that are capable of killing this parasite, but they are hampered by downsides such as significant adverse effects at therapeutic concentrations, issues with patient compliance, the need for additional drugs to kill the transmissible cyst stage, and potential development of resistance. Past screens of small and medium sized chemical libraries have yielded anti-amoebic candidates, thus rendering high-throughput screening a promising direction for new drug discovery in this area. In this study, we screened a curated 81,664 compound library from Janssen pharmaceuticals against E. histolytica trophozoites in vitro, and from it identified a highly potent new inhibitor compound. The best compound in this series, JNJ001, showed excellent inhibition activity against E. histolytica trophozoites with EC50 values at 0.29 μM, which is better than the current approved treatment, metronidazole. Further experimentation confirmed the activity of this compound, as well as that of several structurally related compounds, originating from both the Janssen Jump-stARter library, and from chemical vendors, thus highlighting a new structure-activity relationship (SAR). In addition, we confirmed that the compound inhibited E. histolytica survival as rapidly as the current standard of care and inhibited transmissible cysts of the related model organism Entamoeba invadens. Together these results constitute the discovery of a novel class of chemicals with favorable in vitro pharmacological properties. The discovery may lead to an improved therapy against this parasite and in all of its life stages.


Cannabinoid receptors promote chronic intermittent hypoxia-induced breast cancer metastasis via IGF-1R/AKT/GSK-3β.
The progression of breast cancer is closely related to obstructive sleep apnea-hypopnea syndrome (OSAHS). Low concentrations of cannabinoids promote tumor proliferation. However, the role of cannabinoid receptors (CBs) in chronic intermittent hypoxia (CIH)-induced breast cancer has not been reported. The migration and invasion of breast cancer cell lines (MCF-7 and T47D) were measured by scratch assay and transwell assay. Gene and protein expressions were analyzed by qPCR and western blotting. Tumor xenograft mice model were established to evaluate the function of CBs. We observed that chronic hypoxia (CH) and CIH increased CBs expression and promoted migration and invasion in breast cancer. Mice grafted with MCF-7 exhibited obvious tumor growth, angiogenesis, and lung metastasis in CIH compared with CH and control. In addition, CIH induced CBs expression, which subsequently activated insulin-like growth factor-1 receptor (IGF-1R)/AKT/glycogen synthase kinase-3β (GSK-3β) axis. Knockdown of CBs alleviated CIH-induced migration and invasion of breast cancer in vitro. Furthermore, CIH exaggerated the malignancy of breast cancer and silencing of CBs suppressed tumor growth and metastasis in vivo. Our study contributed to understanding the role of CIH in breast cancer development modulation.


Some problems with Bryden and Sprott's "statistical determination of degree of lateralization".
Bryden and Sprott (Neuropsychologia 19, 571-581, 1982) have proposed an index, lambda, of lateralization that has the same range of possible values no matter what the overall level of accuracy obtained in the experiment. It is shown by way of example that changes in lambda over the levels of the independent variable may be predictable from increases in the level of accuracy for the right and left sides. Specifically, if accuracy increases at a constant rate for the two sides, then lambda, except for some highly artificial situations, is constrained to increase or decrease. It is argued that difficulties associated with the difference between correct responses for the two sides as an index of the degree of lateralization may have been exaggerated. It is shown for hypothetical data that the difference measure may have many of the properties of lambda.


The fate of antibiotic resistance genes in cow manure composting: shaped by temperature-controlled composting stages.
Current work for animal manure processing is not up to the required standards and hence are not supposed to reflect the actual performance in antibiotic resistance control. As a result, this study carried out temperature-controlled aerobic composting, with sulfamethoxazole (SMX) as a typical antibiotic. The results of four different treatments demonstrated that temperature, water content, C/N ratio, EC, and pH showed no significant (p > 0.05) difference. Antibiotic resistance genes (ARGs) significantly decreased in the initial 10 days of the thermophilic phase, but the abundance of sul1 and sul2 increased greatly after 30 days. Moreover, ARGs were closely related with each other during the late stages of composting. A noteworthy effect of composting properties, especially temperature on bacterial community, which then had a positive effect on ARGs abundances. These findings provided evidence that the standard composting was still insufficient to control antibiotic resistance.


The location of the cementodentinal junction in single-rooted mandibular first premolars from Egyptian and Saudi patients: a histological study.
To determine the location of the cementodentinal junction (CDJ) in mandibular first premolars from Egyptian and Saudi patients. One hundred and twenty-two extracted single-rooted mandibular first premolars (68 Egyptian; 54 Saudi) were examined histologically. Half of the teeth were fixed, decalcified, embedded in paraffin, mesio-distally sectioned and stained with H&E, whilst the other half were ground with a stone prior to microscopic evaluation. Measurements of the location of the CDJ were made parallel to the long axis of the teeth from the external surface of the root apex on the mesial and distal sides of the canal. Measurements were statistically analysed using two-way anova of repeated-measure design. The CDJ in Egyptian sections ranged from 0 to 2.0 mm (mean +/- SD = 0.9 +/- 0.4 mm) on the mesial side of the canal and from 0.2 to 2.5 mm (mean +/- SD = 1.0 +/- 0.5 mm) on the distal aspect. In the Saudi sample, the CDJ ranged from 0.5 to 1.2 mm (mean +/- SD = 0.8 +/- 0.3 mm) on the mesial side and from 0.6 to 0.9 mm (mean +/- SD = 0.7 +/- 0.4 mm) on the distal side. The mesial and distal differences between Egyptian and Saudi premolars on the mesial and distal surface were statistically significant (P < 0.001). The location of the CDJ varied between the Egyptian and Saudi mandibular first premolars, indicating that this junction is not a fixed point in populations of different countries.


Morphological assessment of cartilage and osteoarthritis in clinical practice and research: Intermediate-weighted fat-suppressed sequences and beyond.
Magnetic resonance imaging (MRI) is widely regarded as the primary modality for the morphological assessment of cartilage and all other joint tissues involved in osteoarthritis. 2D fast spin echo fat-suppressed intermediate-weighted (FSE FS IW) sequences with a TE between 30 and 40ms have stood the test of time and are considered the cornerstone of MRI protocols for clinical practice and trials. These sequences offer a good balance between sensitivity and specificity and provide appropriate contrast and signal within the cartilage as well as between cartilage, articular fluid, and subchondral bone. Additionally, FS IW sequences enable the evaluation of menisci, ligaments, synovitis/effusion, and bone marrow edema-like signal changes. This review article provides a rationale for the use of FSE FS IW sequences in the morphological assessment of cartilage and osteoarthritis, along with a brief overview of other clinically available sequences for this indication. Additionally, the article highlights ongoing research efforts aimed at improving FSE FS IW sequences through 3D acquisitions with enhanced resolution, shortened examination times, and exploring the potential benefits of different magnetic field strengths. While most of the literature on cartilage imaging focuses on the knee, the concepts presented here are applicable to all joints. KEY POINTS: 1. MRI is currently considered the modality of reference for a "whole-joint" morphological assessment of osteoarthritis. 2. Fat-suppressed intermediate-weighted sequences remain the keystone of MRI protocols for the assessment of cartilage morphology, as well as other structures involved in osteoarthritis. 3. Trends for further development in the field of cartilage and joint imaging include 3D FSE imaging, faster acquisition including AI-based acceleration, and synthetic imaging providing multi-contrast sequences.


[Significance of environmental factors on the tolerated enteral feeding volumes for patients in neonatal intensive care units].
The influence of environmental factors on the tolerated feeding volumes as well as on the frequency of breathing were studied in 32 infants. During intensive neonatal care the tolerated feeding volumes were decreased and also the frequencies of breathing were influenced. The duration and intensity of light exposure was related as one of the most important factors.


The hangman effect boosts hydrogen production by a manganese terpyridine complex.
The manganese terpyridine complex 1 with a coordinated carboxylate in the axial position was obtained in situ. By virtue of a hangman effect, complex 1 catalyzes electrochemical hydrogen evolution from phenol in acetonitrile solution with a turnover frequency of 525 s-1 at a low overpotential of ca. 230 mV.


Cystic fibrosis in black African children in South Africa: a case control study.
Cystic fibrosis (CF) is described more commonly in Caucasian populations in whom p.Phe508del is the most common mutation. There is a paucity of data of CF in black African children. The aim of this study was to describe and compare the presentation and outcomes of black African children with CF to those with p.Phe508del genotype. A retrospective case-controlled study was conducted from January 2000 - March 2018 of children with CF attending two CF centres in South Africa. Presentation, genotype, nutrition and pulmonary function outcomes of black African children were compared to matched controls with the p.Phe508del mutation. Thirty-four black African children (cases) with median age of diagnosis (5.5 months, IQR 2.0-15.0) were matched to 34 controls. Among cases, 3120+1G->A CFTR mutation was most commonly identified; homozygous n=22 (64.7%) and heterozygous=7(20.5%). Compared to controls, cases at diagnosis were more malnourished and fewer presented with neonatal bowel obstruction [cases n=2 (5.9%) vs. controls n=10 (29.4%); p = 0.03]. Nutrition and pulmonary function (FEV1 in children ≥ 6 years) outcomes and changes over time from ages 3-16 years were similar in both groups; median FEV1 z-score at age 6,10 and 14 years was -0.9 (±1.5), -1.8 (±2.0) and -1.8 (±1.9) respectively for all patients. Deaths were recorded in three cases (8.8%) and one control (2.9%) (p = 0.6). Black African children with CF were more malnourished at diagnosis, and fewer presented with neonatal bowel obstruction. Cases and controls had comparable nutritional, pulmonary function and early mortality outcomes.


Liquid-like movements in crystalline insulin.
Diffuse X-ray scattering from protein crystals provides information about molecular flexibility and packing irregularities. Here we analyse diffraction patterns from insulin crystals that show two types of scattering related to disorder: very diffuse, liquid-like diffraction, and haloes around the Bragg reflections. The haloes are due to coupled displacements of neighbouring molecules in the lattice, and the very diffuse scattering results from variations in atomic positions that are only locally correlated within each molecule. The measured intensity was digitally separated into three components: the Bragg reflections and associated haloes; the water and Compton scattering; and the scattering attributed to internal protein movements. We extend methods used to analyse disorder in membrane structures to simulate the diffuse scattering from crystalline insulin in terms of (1) the Patterson (autocorrelation) function of the ideal, ordered crystal structure, (2) the root-mean-square (r.m.s.) amplitude of the atomic movements, and (3) the mean distance over which these displacements are coupled. Movements of the atoms within the molecules, with r.m.s. amplitudes of 0.4-0.45 A, appear to be coupled over a range of approximately 6 A, as in a liquid. These locally coupled movements account for most of the disorder in the crystal. Also, the protein molecules, as a whole, jiggle in the lattice with r.m.s. amplitudes of approximately 0.25 A that appear to be significantly correlated only between nearest neighbours.


Isolation and in vitro partial characterization of hemolytic proteins from the nematocyst venom of the jellyfish Stomolophus meleagris.
Jellyfish venom contains various toxins and can cause itching, edema, muscle aches, shortness of breath, blood pressure depression, shock or even death after being stung. Hemolytic protein is one of the most hazardous components in the venom. The present study investigated the hemolytic activity of the nematocyst venom from jellyfish Stomolophus meleagris. Anion exchange chromatography, DEAE Sepharose Fast Flow, and gel filtration chromatography, Superdex200 had been employed to isolate hemolytic proteins from the nematocyst venom of jellyfish S. meleagris. Hemolysis of chicken red blood cells was used to quantify hemolytic potency of crude nematocyst venom and chromatography fractions during the purification process. Native-PAGE profile displayed one protein band in the purified hemolytic protein (SmTX); however, two protein bands with apparent molecular weights of ≈ 45 kDa and 52 kDa were observed in the reducing SDS-PAGE analysis. Approximately 70 μg/mL of SmTX caused 50% hemolysis (HU50) of the erythrocyte suspension. The hemolytic activity of SmTX was shown to be temperature and pH dependent, with the optimum temperature and pH being 37°C and pH 5.0. The present study is the first report of isolation and partial characterization of hemolytic proteins from the nematocyst venom of the jellyfish S. meleagris. The mechanism of the hemolytic activity of SmTX is not clear and deserves further investigation.


Extraforaminal lumbar disc herniations: CT demonstration of Sharpey's fibers avulsion.
Forty-seven extraforaminal lumbar disc herniations (EFLDH) accounting for 7% of all lumbar disc herniations encountered during the same period of time were reviewed. L3-L4 or L4-L5 disc was involved in 89% of the cases giving rise to a L3 or L4 nerve root compression. An abnormal motion of lateral bending with rotation of the trunk was found retrospectively in 60% of the patients. In 53% of all EFLDH a bony avulsion of the vertebral end-plate facing the herniation was demonstrated at the site of attachment of Sharpey's fibers. This study suggests that this previously undescribed bony change witnesses a special injury of the spine responsible for most EFLDH.


Substance Use in Registered Nurses: "I Heard About a Nurse Who . . ."
BACKGROUND: Estimates of substance use (SU) in nurses is on par with that of the general population: between 6% and 8%. However, collecting sensitive information such as SU is difficult based on social desirability and fears of disclosure. AIMS: Part of a larger study surrounding nurses' self-reports of SU (n = 1,478), the purpose was to explore open-ended responses of nurses (n = 373) who were invited to "Please add any additional comments related to substance or alcohol use that you have experienced or witnessed in registered nurses." METHOD: This qualitative study employed a content analysis of 373 nurses' open-ended responses collected via an online survey. RESULTS: The majority of nurses (n = 250) forwarded comments that described SU in other nurses, while 24 comments reflected the nurse's past or current SU. Content analysis revealed the following four themes: (1) differing social network proximity to SU; (2) individual process: vulnerability to adaptive/maladaptive coping resulting in positive and negative outcomes; (3) bedside, system, and organizational spaces and effects; and (4) there are no SU issues in nursing. CONCLUSIONS: Although direct reports of SU constitute approximately one quarter of the comments forwarded, nurses reported peers' struggles with SU, including observing nurses working in patient care while impaired and the use of substances to cope with work and personal stressors. Individual factors and system-related failures appear to be contributors to SU in nurses.


Children in nonparental care: health and social risks.
Approximately 2.3 million children in the United States live separately from both parents; 70-90% of those children live with a relative. Compared with children living with one or both parents, children in nonparental care are in poorer health, are at heightened risk for experiencing disruptions and instability in caregiving, and are vulnerable to other social antecedents of child health (e.g., neglect, poverty, maltreatment). Given the significant impact of adversity in childhood on health across the lifespan, which is increased among children in nonparental care, it is informative to consider the health risks of children living in nonparental care specifically. Research examining the contributions of poverty, instability, child maltreatment, and living in nonparental care, including meta-analyses of existing studies, are warranted. Longitudinal studies describing pathways into and out of nonparental care and the course of health throughout those experiences are also needed. Despite these identified gaps, there is sufficient evidence to indicate that attention to household structure is not only relevant but also essential for the clinical care of children and may aid in identifying youth at risk for developing poor health across the lifespan.


Structures of the psychrophilic Alteromonas haloplanctis alpha-amylase give insights into cold adaptation at a molecular level.
. Enzymes from psychrophilic (cold-adapted) microorganisms operate at temperatures close to 0 degreesC, where the activity of their mesophilic and thermophilic counterparts is drastically reduced. It has generally been assumed that thermophily is associated with rigid proteins, whereas psychrophilic enzymes have a tendency to be more flexible. . Insights into the cold adaptation of proteins are gained on the basis of a psychrophilic protein's molecular structure. To this end, we have determined the structure of the recombinant form of a psychrophilic alpha-amylase from Alteromonas haloplanctis at 2.4 A resolution. We have compared this with the structure of the wild-type enzyme, recently solved at 2.0 A resolution, and with available structures of their mesophilic counterparts. These comparative studies have enabled us to identify possible determinants of cold adaptation. . We propose that an increased resilience of the molecular surface and a less rigid protein core, with less interdomain interactions, are determining factors of the conformational flexibility that allows efficient enzyme catalysis in cold environments.


Cardioprotection by cariporide after prolonged hypothermic storage of the isolated working rat heart.
Inhibition of the sodium-hydrogen (Na(+)-H(+)) exchanger decreases the extent of ischemia-reperfusion injury in the myocardium. Inhibition may also improve preservation of hearts stored for transplantation. Our aim was to characterize the dose response and to determine optimal timing for administering cariporide, an Na(+)-H(+) exchange inhibitor, during prolonged hypothermic storage. We used the rat isolated working-heart model to measure cardiac function. To determine the optimal dose of cariporide, hearts received either no treatment (control) or incremental doses of cariporide (1, 3.2, 10, or 30 micromol/liter) before storage and during reperfusion. Hearts were arrested with and stored in an extracellular-based cardioplegic solution at 2 to 3 degrees C for 6 hours. To determine optimal timing, we arrested a group of hearts with and stored them in a cariporide-supplemented (10 micromol/liter) cardioplegic solution but did not pre-treat them with cariporide. Finally, we treated a separate group of hearts with 10 micromol/liter cariporide before, during, and after storage. Recovery of cardiac function in control hearts was poor. The cardioprotective effect of cariporide was dose dependent, with maximal protection observed at a concentration of 10 micromol/liter. Storing hearts in a cariporide-supplemented cardioplegic solution did not result in better recovery of cardiac function compared with cariporide given before storage and during reperfusion. Moreover, recovery of cardiac function was significantly worse in hearts that had not been pre-treated with cariporide. Sodium-hydrogen-exchange inhibition with cariporide significantly protects the hypothermic ischemic rat heart, increasing cardiac function after reperfusion. The timing of cariporide administration is an important determinant of this cardioprotection.


Monitoring daily physical activity of upper extremity in young and adolescent boys with Duchenne muscular dystrophy: A pilot study.
Accelerometry of the upper extremity (UE) potentially provides information on the extent of activities in daily life in patients with Duchenne muscular dystrophy (DMD). The objective of this study is to evaluate the validity of home measurements of UE accelerometry. This was a cross-sectional study in 16 patients with DMD (aged 7-17 years). Patients were monitored for 1 to 3 days with two accelerometers on the UE and one accelerometer on the wheelchair. The mean intensity of activity and the mean frequency of transfers of arm elevation from low to middle were approximately twofold higher in patients with a Brooke scale score of 1 or 2 than in patients with a Brooke scale score of 3 or 4. Correlations with the Performance of Upper Limb scale score were high for intensity and for the total frequency of arm elevations per hour. Intensity, percentage of time in middle orientation, and frequency of transfers of the upper arm correlated well with functional measurements.


Growth promotory potential of the cold adapted diazotroph Pseudomonas migulae S10724 against native green gram (Vigna radiata (L.) Wilczek).
It is being confirmed previously the atmospheric nitrogen fixing ability of the cold adapted Pseudomonas migulae S10724 strain at the fluctuating temperatures. Therefore, net house bioinoculation experiment was performed to determine the effectiveness of inoculation of strain S10724 on the growth enhancement of native green gram (Vigna radiata L. Wilczek). The strain significantly (p < 0.05) stimulated the growth of roots (45.3 %) and shoots (45.6 %) of green gram plants. Furthermore, other growth related parameters viz. fresh and dry weight was also found to be increased significantly. Treated plants typically showed more obvious modifications in their biochemical status also. The total chlorophyll and nitrate reductase activity was increased in S10724 inoculated plant as compared to the control one. Moreover, in vitro seed germination assay revealed that the germination was increased in S10724 strain treated seeds by 22 % at 25 °C while 25 % at 12 °C unlikely to respective controls. The results suggest that P.migulae S10724 strain is a potential plant growth promoting bacterium for legume under fluctuating temperature ranges and therefore, could be used effectively as a low cost bioinoculant in Himalayan agricultural belt successfully.


Autobiographical memory disturbance in combat-related posttraumatic stress disorder.
Vietnam combat veterans with (n = 19) and without (n = 13) posttraumatic stress disorder (PTSD) participated in an autobiographical memory experiment in which they attempted to retrieve specific personal memories exemplifying traits denoted by positive (e.g. loyal) and negative (e.g. guilty) cue words. Veterans with PTSD exhibited difficulties retrieving specific autobiographical memories, especially in response to positive trait cue words. These deficits were especially pronounced in PTSD Ss who wore Vietnam War regalia (e.g. medals, fatigues) to the laboratory. Regalia-wearing PTSD Ss disproportionately retrieved memories from the Vietnam War, unlike other Ss who retrieved relatively recent memories. Wearing regalia in daily life may be emblematic of psychological fixation to a war fought more than two decades ago. Difficulties remembering one's past may underlie difficulties envisioning one's future, as reflected in the PTSD symptom of 'future foreshortening', and difficulties using memory specifically may also hamper efforts to solve personal problems.


Structural polymorphism of murine factor B controlled by a locus closely linked to the H-2 complex and demonstration of multiple alleles.
New alleles of murine factor B (Bf) protein were demonstrated. When ethylenediaminetetraacetic acid (EDTA)-plasmas from inbred and wild mice were analyzed by isoelectrofocusing (IEF) and immunofixation, murine Bf proteins were visualized as distinct protein bands in all mice tested. Four variants of murine Bf could be demonstrated in a large number of tested mice: Bf 1 (isoelectrofocusing point (P.I.) range of 5.8-6.1) exemplified by B10 and B10.BR, Bf 2 (P.I. range of 5.8-6.0) exemplified by B10.MOL (OHM), Bf 3 (P.I. range of 5.6-5.9) exemplified by B10.MOL (TEN2) and Mus musculus (Mus m.) subspecies Chc, Bf 4 (P.I. range of 6.0-6.3) exemplified by Mus m. subspecies Shh. The genetic linkage between S locus and Bf locus was studied with two backcross progenies--[B10.BR X (B10.BR X Mus m. subspecies Chc)F1] and [B10.BR X (B10.BR X Mus m. subspecies Shh)F1]. Totally, 256 backcross progenies were typed for Bf type and for Ss type (plasma level of the fourth complement protein regulated by S locus). The results indicated that murine Bf was controlled by a single codominant locus located close to the H-2 complex because no mouse showing recombination between Bf locus and S locus was found.


Excretion of N(1), N(12)-diacetylspermine in the urine of healthy individuals.
Urinary N(1),N(12)-diacetylspermine (DiAcSpm) is a novel tumour marker that can be used to detect early cancers. In this study, we examined whether spot urine samples could represent the daily excretion of DiAcSpm after creatinine normalization and which factors should be taken into account in determining reference values for this biomarker. We collected the following urine samples: (1) samples from seven healthy volunteers collected on each day of two 2-day sessions to examine the circadian variation of DiAcSpm excretion; (2) samples from 3952 male and 1782 female volunteers to estimate the DiAcSpm concentrations in apparently healthy adults and (3) samples from 16 female volunteers collected every morning over a 3-month period to examine the menstruation-related variation in DiAcSpm excretion. The DiAcSpm concentrations were determined by enzyme-linked immunosorbent assay or a colloidal gold aggregation procedure using DiAcSpm-specific antibodies. (1) The circadian variation of DiAcSpm in the urine was greatly diminished after creatinine normalization. (2) DiAcSpm was higher in females than in males, and the creatinine-normalized medians (95th percentile) of the urinary DiAcSpm concentrations were 149 (305) and 100 (192) nmol/g creatinine for females and males, respectively. (3) The mean concentrations of urinary DiAcSpm were lower after menstruation than before menstruation by approximately 30 nmol/g creatinine. Spot urine samples obtained at any time of a day may be used to estimate the daily excretion of DiAcSpm in nmol DiAcSpm per gram creatinine. Sex, age and menstrual condition should be considered when determining the reference values for urinary DiAcSpm.


Early increase in TNF-alpha-containing mast cells in skin lesions.
We have evaluated the numbers and immunohistochemical positivity for tumor necrosis factor (TNF) alpha of the mast cells in (a) 40 skin samples collected at autopsy from subjects who had survived for a few seconds to 1 h, (b) 10 samples of post-mortem skin lesions and (c) 10 surgical biopsies of healthy skin. Sections were treated with fluoresceinated avidin, to tag mast cell granules, followed by indirect immunohistochemistry for TNF-alpha with polyclonal primary and rhodaminated secondary antibodies. We could confirm a progressive increase in mast cell numbers, which became significant 1 h after trauma. More important, the fraction of mast cells positive for TNF-alpha increased progressively in the same time period and became significantly higher than controls in specimens collected more than 15 min after trauma. Samples from post-mortem lesions had significantly fewer mast cells and fewer TNF-alpha-positive cells than any other group of samples. The results suggest that mast cells are quickly recruited to an injured site in response to trauma and upregulate their TNF-alpha content, which can play an early role in directing tissue response to injury. The forensic pathologist can take advantage from this behavior of mast cells for the evaluation of the timing of early vital lesions.


Bacteriophage bionanowire as a carrier for both cancer-targeting peptides and photosensitizers and its use in selective cancer cell killing by photodynamic therapy.
A photosensitizer, pyropheophorbid-a (PPa), is conjugated to SKBR-3 breast cancer cell-specific biological nanowire phage, to form a novel PPa-phage complex, which is further successfully used in selectively killing SKBR-3 breast cancer cells by the mechanism of photodynamic therapy (PDT).


[Consensus statement for accreditation of multidisciplinary thyroid cancer units].
Thyroid cancer is the leading endocrine system tumor. Great advances have recently been made in understanding of the origin of these tumors and the molecular biology that makes them grow and proliferate, which have been associated to improvements in diagnostic procedures and increased availability of effective local and systemic treatments. All of the above makes thyroid cancer a paradigm of how different specialties should work together to achieve the greatest benefit for the patients. Coordination of all the procedures and patient flows should continue throughout diagnosis, treatment, and follow-up, and is essential for further optimization of resources and time. This manuscript was prepared at the request of the Working Group on Thyroid Cancer of the Spanish Society of Endocrinology and Nutrition, and is aimed to provide a consensus document on the definition, composition, requirements, structure, and operation of a multidisciplinary team for the comprehensive care of patients with thyroid cancer. For this purpose, we have included contributions by several professionals from different specialties with experience in thyroid cancer treatment at centers where multidisciplinary teams have been working for years, with the aim of developing a practical consensus applicable in clinical practice.


Relationship of lower extremity skin blood flow to the ankle brachial index in patients with peripheral arterial disease and normal volunteers.
Changes in posture of the lower extremities induce changes in skin blood flow, known as veno-arteriolar response (VAR). We investigated the relationship between ankle brachial index (ABI) and VAR in patients (ABI<0.9) with peripheral arterial disease (PAD) and age-matched normal controls (ABI>1). We measured ankle pressure, ABI at rest, and post-exercise ABI. Using laser Doppler flowmetry, skin blood flow was measured with the lower extremity in extended and flexed positions and the fractional change (extended-flexed/extended) in blood flow (VAR) was calculated. With external pressure applied serially to the lower extremity in the extended position using a sphygmomanometer, the pressure (PVAR) at which the VAR was similar to that in the flexed position was recorded. Patients and controls did not differ by age or comorbidity, except higher cigarette smoking in patients (95.8% vs. 4.3%, p=0.001). VAR and PVAR were significantly lower in patients than controls (0.42+/-0.16 vs. 0.65+/-0.11 flux/min, p=0.001 and 29+/-8 vs. 48+/-9 mm Hg, p=0.001, respectively). There was significant correlation between ABI-post and VAR (r=0.6, p=0.01) and between the VAR and PVAR (r=0.8, p=0.001). VAR<0.3 flux/min was 100% sensitive, 80% specific, and area under curve of 0.88, p=0.001 for detecting PAD as defined by ABI<0.9. Similarly, PVAR of 22 mm Hg was 100% sensitive, 85% specific, and area under curve of 0.94, p=0.001 for detecting PAD. Skin blood flow by this method correlates with the presence and severity of an abnormal ABI. This may offer a method of monitoring the effect of therapy and regression of peripheral atherosclerosis.


Provider characteristics, clinical-work processes and their relationship to discharge summary quality for sub-acute care patients.
Discharge summaries play a pivotal role in the transitional care of patients discharged to sub-acute care facilities, but the best ways to facilitate document completeness/quality remain unknown. To examine the relationship among clinical-work processes, provider characteristics, and discharge summary content to identify approaches that promote high-quality discharge documentation. Retrospective cohort study. All hip fracture and stroke patients discharged to sub-acute care facilities during 2003-2005 from a large Midwestern academic medical center (N = 489). Patients on hospice/comfort care were excluded. We abstracted 32 expert-recommended components in four categories ('patient's medical course,' 'functional/cognitive ability at discharge,' 'future plan of care,' and 'name/contact information') from the discharge summaries of sample patients. We examined predictors for the number of included components within each category using Poisson regression models. Predictors included work processes (document completion in relation to discharge day; completion time of day) and provider characteristics (training year; specialty). Historical components (i.e., 'patient's medical course' category) were included more often than components that directly inform the admission orders in the sub-acute care facility (i.e., 'future plan of care'). In this latter category, most summaries included a discharge medication list (99%), disposition (90%), and instructions for follow-up (91%), but less frequently included diet (68%), activity instructions (58%), therapy orders (56%), prognosis/diagnosis communication to patient/family (15%), code status (7%), and pending studies (6%). 'Future plan of care' components were more likely to be omitted if a discharge summary was created >24 h after discharge (incident rate ratio = 0.91, 95% confidence interval = 0.84-0.98) or if an intern created the summary (0.90, 0.83-0.97). Critical component omissions in discharge summaries were common, and were associated with delayed document creation and less experienced providers. More research is needed to understand the impact of discharge documentation quality on patient/system outcomes.


Antitumor effect of new HER2 peptide vaccination based on B cell epitope.
While the benefit of passive immunotherapy is commonly accepted, active immunization may have advantages for the patient's quality of life. We identified a new epitope of Mab CH401 against Her-2/neu extracellular domain (N: 167-175), and evaluated the effect of active immunization of the 20mer peptide containing the epitope (CH401 peptide). Epitope-mapping was performed using ELISA with Her-2/neu-related multiple antigen peptides (MAP). BALB/c mice were transplanted with Her-2/neu-expressing lymphoma cell line and immunized with the peptides. For monitoring the condition, ELISA and flow cytometry was performed. CH401 peptide induced Her-2/neu-specific IgG antibody. Tumor growth in immunized mice was suppressed and tumor-infiltrating lymphocytes comprised more CD8(+) T-cells, which secreted larger amounts of interleukin-2 after the peptide re-stimulation. The new Her-2/neu peptide contained epitopes for CD4(+) and CD8(+) T-cells, which contributes to the suppressive effect on Her-2/neu-expressing tumor cell growth.


Surgical Fixation Using Screw-Rod Construct Instrumentation for Upper Cervical Instability in Pediatric Down Syndrome Patients.
Retrospective case series. To describe the indications and outcomes of cervical fixation using modern instrumentation in a case series of pediatric Down syndrome (DS) patients. Cervical instability is the major cervical spine concern in children with DS. Although fixation techniques have advanced over the past quarter-century, the outcome of fixation with modern instrumentation for upper cervical instability in DS patients has not been thoroughly investigated. We searched the orthopedic database at our institution for patients with a diagnosis of DS who had undergone a cervical spine fusion between 2006 and 2017. Patient demographics, diagnoses, surgical indications, surgical details, and complications were recorded. Preoperative imaging was reviewed to determine atlanto-dens intervals and spinal cord signal changes. Postoperative radiographs or CT scans were reviewed to determine union. Twelve DS patients met our inclusion criteria. The mean age at surgery was 9.3 years (range 3.8-18.8 years). Patients with secondary causes of instability included 7 patients with os odontoideum and 1 patient with a pars fracture. Three patients (25%) were identified on asymptomatic screening, with none of these having cord signal changes on magnetic resonance imaging (MRI). Modern implants (screws, plates, cages) were used in every patient in our series. The mean number of levels fused was 1.9 (range 1-5). The overall complication rate was 41.7% (5/12). Four patients required repeat surgery for nonunion. All patients with adequate radiographic follow-up demonstrated union (11/11, 100%). One patient was lost to follow-up. Fixation for cervical instability is a critical component of the management of DS. A minority of patients receiving surgery were identified through asymptomatic screening. There was a high complication risk associated with surgery in our study; however, the addition of rigid fixation has lessened the complication rate compared with previous studies. Level IV.


Granulocytopenia complicating colchicine therapy for primary biliary cirrhosis.
A case is presented of a 76-yr-old woman with primary biliary cirrhosis and adult polycystic liver disease who developed bone marrow toxicity associated with chronic low-dose colchicine therapy. Two months after starting colchicine therapy (0.6 mg b.i.d. p.o.), the patient developed hematologic toxicity as evidenced by transient but profound granulocytopenia which promptly reversed 4 days after the drug was stopped. Bone marrow examination revealed moderate hypocellularity of all cell lines and striking dysplastic changes in the late myeloid and erythroid series. There was no apparent toxicity involving other organ systems. The patient fully recovered. This case is compared with previous descriptions of colchicine toxicity.


BAY K 8644, a 1,4-dihydropyridine Ca2+ channel activator: dissociation of binding and functional effects in brain synaptosomes.
K+-stimulated 45Ca2+ uptake into rat brain and guinea pig cerebral cortex synaptosomes was measured at 10 s and 90 s at K+ concentrations of 5-75 mM. Net increases in 45Ca2+ uptake were observed in rat and guinea pig brain synaptosomes. 45Ca2+ uptake under resting or depolarizing conditions was not increased by the 1,4-dihydropyridine BAY K 8644, which has been shown to activate Ca2+ channels in smooth and cardiac muscle. High-affinity [3H]nitrendipine binding in guinea pig synaptosomes (KD = 1.2 X 10(-10) M, Bmax = 0.56 pmol mg-1 protein) was competitively displaced with high affinity (IC50 2.3 X 10(-9) M) by BAY K 8644. Thus high-affinity Ca2+ channel antagonist and activator binding sites exist in synaptosome preparations, but their relationship to functional Ca2+ channels is not clear.


Quercetin inhibits hexose transport in a human diploid fibroblast.
The flavonol quercetin, a phloretin analog, inhibits transport of 2-deoxyglucose and 3-O-methylglucose in a cultured human diploid fibroblast. This inhibition is related to transport itself and not to the reported effects of flavonoids on membrane-bound ATPases. From concentration-inhibition curves at several pH's we conclude that uncharged (acid) quercetin (pK = 7.65) is the inhibitory form of the molecule (K1 = 10micron). Quercetin, unlike phloretin, is rapidly degraded in 0.1 N NaOH; the degradation products are weakly inhibitory to hexose transport.


Global cerebral vasodilatation elicited by focal electrical stimulation within the dorsal medullary reticular formation in anesthetized rat.
We examined the effects of electrical stimulation of a restricted area of the dorsal medullary reticular formation (DMRF) on regional cerebral blood flow (CBF) in anesthetized (by chloralose), paralyzed (by curare) rats. CBF was measured in tissue samples by the Kety principle, with 14C-iodoantipyrine as indicator. Stimulation of DMRF elicited a widespread, significant increase in CBF in 12 of 13 areas. The increase in flow was greatest in cerebral cortex, up to 240% of control. However, it was also substantially increased in selected regions of telencephalon, diencephalon, mesencephalon, and lower brainstem, but not cerebellum. In contrast, electrical stimulation of the midline (interstitial nucleus of the medial longitudinal fasciculus) 1 mm medial to the DMRF did not change CBF. The increase in CBF evoked by DMRF stimulation persisted after transection of the spinal cord at C1 or cervical sympathetic trunk. We conclude that excitation of neurons originating in or passing through the DMRF can elicit a potent and virtually global increase of CBF. The effect appears to be mediated by intrinsic pathways of the central nervous system.


Effect of calcium hydroxide on proinflammatory cytokines and neuropeptides.
Calcium hydroxide, a widely used intracanal medicament, is known to exert an antimicrobial effect and to degrade bacterial-derived lipopolysaccharides. However, little is known about the effect of Ca(OH)(2) on endogenous inflammatory mediators such as interleukin-1 alpha (IL-1 alpha), tumor necrosis factor-alpha (TNF-alpha), and calcitonin gene-related peptide (CGRP). This is an important gap in knowledge because these inflammatory mediators play an important role in mediating the pathogenesis of periradicular periodontitis. We tested the hypothesis that Ca(OH)(2) denatures IL-1 alpha, TNF-alpha, and CGRP. Human IL-1 alpha (0.125 ng/mL), TNF-alpha (0.2 ng/mL), and CGRP (0.25 ng/mL) were incubated with Ca(OH)(2) (0.035 mg/mL) for 1-7 days. At the end of the incubation period, the pH of the samples was neutralized, and the concentrations of the mediators were measured by immunoassays. Data were analyzed with one-way analysis of variance and Bonferroni multiple comparison tests. The results indicate that Ca(OH)(2) denatures IL-1 alpha, TNF-alpha, and CGRP by 50%-100% during the testing periods (P < .001). We concluded that denaturation of these proinflammatory mediators is a potential mechanism by which Ca(OH)(2) contributes to the resolution of periradicular periodontitis.


Total gastrectomy for benign disease.
Among 37 patients who underwent total gastrectomy for nonmalignant disease, operative mortality was 4 per cent after 27 elective operations and 10 per cent after 10 emergency operations. Three other patients died 1 to 6 months after operation. Major postoperative complications occurred in 24 per cent. Long-term follow-up of 26 patients (81 per cent of survivors) after a mean +/- SEM of 8.4 +/- 1.1 years showed that 73 per cent of patients had no or only occasional, easily controlled, mild abdominal symptoms and good enough health to enable them to work or carry out normal activities for their age. The patients lost a mean of 15 per cent of their body weight, however, and about one third of them had weakness and diarrhea. A quarter of them had anemia despite iron and vitamin B12 therapy. Our conclusion was that total gastrectomy is a reasonable operation for benign diseases. Nonetheless, in view of the substantial postoperative mortality and morbidity, the operation should be used only when less extensive operations will not suffice.


Mannosylated solid lipid nanoparticles as vectors for site-specific delivery of an anti-cancer drug.
The purpose of the present study was to investigate the tumor targeting potential of surface tailored solid lipid nanoparticles (SLNs) loaded with an anti-cancer drug doxorubicin HCl (DOX). DOX encapsulating SLNs were prepared, characterized and further mannosylated. The developed formulations were characterized by Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), particle size/polydispersity index and zeta-potential analysis. The formulations were evaluated for in vitro drug release and hemolytic toxicity. The ex vivo cytotoxicity and cellular uptake studies were performed on A549 cell lines. In vivo studies were conducted to determine pharmacokinetics, tissue distribution pattern and nephrotoxic/hepatotoxic effect of mannosylated SLNs. In vitro, the formulations exhibited a biphasic pattern characterized by initial rapid release of the drug followed by rather slow and prolonged release. Further, the in vitro studies depicted mannose-conjugated SLNs to be least hemolytic and suitable for sustained drug delivery. Mannosylated SLNs were most cytotoxic and were preferably taken up A549 tumor cells as evaluated against uncoated SLNs and plain DOX. Pharmacokinetic studies revealed improved bioavailability, half life and mean residence time of DOX upon mannose conjugation. The biodistribution pattern exhibited that mannosylated SLNs were able to deliver a higher concentration of DOX in the tumor mass. They were also proficient to circumvent damage to renal as well as hepatic tissues. It may therefore be interpreted that mannosylated SLNs are capable to ferry bioactives selectively and specifically to the tumor sites with the interception of minimal side effects, thereby suggesting their potential application in cancer chemotherapy.


Use of biomarkers of sub-clinical infection, nutrition and neonatal maturity to interpret plasma retinol in Nigerian neonates.
Using the World Health Organization criterion, the prevalence of sub-clinical vitamin A deficiency can be assessed using plasma retinol concentrations <0.7 micromol/l. However, plasma retinol can be depressed by infection; thus, the use of this criterion alone may overestimate deficiency. In the present study, we investigated the usefulness of the acute-phase proteins (APP) alpha1-antichymotrypsin (ACT) and alpha1-acid glycoprotein (AGP), plasma carotenoids and anthropometric and gestational indices to interpret plasma retinol in the blood of 192 apparently healthy Nigerian neonates collected randomly during days 1-20 postpartum. The mean weight (2.64 kg) and length (0.458 m) of the neonates and plasma concentrations (geometric mean, micromol/l) of retinol (0.54), alpha-carotene (0.072), ss-carotene (0.076) and lutein (0.080) were low. The prevalence of vitamin A deficiency was 72 %, indicating a severe public health problem. Babies who were of low birth weight (P<0.003) or premature and low birth weight (P<0.023) had significantly lower retinol concentrations than full-term normal weight babies. Thirty-two neonates had abnormal ACT and forty-four abnormal AGP concentrations. Positive correlations between retinol and ACT (r 0.186, P=0.05) and AGP (r 0.31, P=0.0001) during days 1-5 may be due to the increasing plasma retinol from maternal milk and a coincidental increasing capacity to synthesise APP. Subsequently, negative correlations between retinol and ACT (r -0.28, P=0.02) and AGP (r -0.29, P=0.018) from day 6 onwards reflected the continuing increase in plasma retinol, but no further increase in the APP. Overall, weight, ACT, lutein and age explained 30 % of the variance in retinol, but lutein was the most significant (r(2) 0.18, P<0.0001). Hence, the distribution of plasma retinol concentrations in this group of neonates was more strongly linked with nutrition (via the surrogate marker lutein) than infection.


Knocking out histone methyltransferase PRMT1 leads to stalled tadpole development and lethality in Xenopus tropicalis.
Asymmetric arginine dimethylation of histone H4R3 to H4R3me2a by protein arginine methyltransferase 1 (PRMT1) has been implicated to play a key role in gene activation throughout vertebrates. PRMT1 knockout in mouse leads to embryonic lethality. This and the uterus-enclosed nature of the mouse embryo make it difficult to determine the development role of PRMT1 in mammals. We took advantage of the external development of the diploid anuran Xenopus tropicalis and adapted the TALEN genome editing technology to knock out PRMT1 in order to investigate how PRMT1 participates in vertebrate development. We observed that PRMT1 knockout had no apparent effect on embryogenesis because normally feeding tadpoles were formed, despite the reduced asymmetric H4R3 di-methylation (H4R3me2a) due to the knockout. However, PRMT1 knockout tadpoles had severely reduced growth even with normal growth hormone gene expression. These tadpoles were also stalled in development shortly after feeding began at stages 44/45 and died within 2 weeks, well before the onset of metamorphosis. In situ analyses revealed broad cessation or drastic reduction in cell proliferation in diverse organs including the eye, brain, spinal cord, liver, and intestine. Our findings suggest that PRMT1 is not required for embryogenesis but is a key regulator for normal progression of vertebrate development and growth. The similarities and differences between PRMT1 knockout Xenopus tropicalis and mouse suggest that two distinct phases of vertebrate development: early embryogenesis and subsequent growth/organ maturation, have different but evolutionally conserved requirement for epigenetic modifications.


Alkyl substituted aminal derivatives of HCV NS5A inhibitor MK-8742.
HCV NS5A inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed dose combination regimen for the treatment of HCV infection. Herein we describe our continued research efforts around the alkyl "Z group" modification of the tetracyclic indole-based NS5A inhibitor MK-8742, which led to the discovery of a series of potent NS5A inhibitors. Compounds 10 and 19 are of particular interests since they are as potent as our previous leads and have much improved rat pharmacokinetic profiles.


Facial Feminization Surgery Changes Perception of Patient Gender.
The goal of facial feminization surgery (FFS) is to feminize the sexually dimorphic characteristics of the face and enable transwomen to be correctly gendered as female. Studies have demonstrated high patient satisfaction with FFS. However, the correct gendering of patients after FFS has never been objectively studied. The aim of this study was to determine if FFS changed the perceived gender of patients in the public eye. An online survey platform with control photographs of cis-gender males and cis-gender females as well as preoperative and postoperative FFS patients was created. Respondents were asked to identify patients as "male" or "female" and to assign a confidence score ranging from -10 (masculine) to +10 (feminine) (n = 802). Cis-gender male and female controls were gendered correctly 99% and 99.38% of the time and with a confidence metric (CM) of -8.96 and 8.93, respectively. Preoperative FFS patients were gendered as female 57.31% of the time with a CM of 1.41 despite hormone therapy, makeup, and hairstyle. Postoperative FFS patients were gendered as female 94.27% of the time with a CM of 7.78. Ninety-five percent of patients showed a significant improvement in CM after FFS. This study illustrates that FFS changes the social perception of a patient's gender. Patients after FFS are more likely to be identified as female and with greater confidence than before surgery. This is despite preoperative female hormone therapy, and nonsurgical methods that patients use to feminize their appearance.


An investigation into the risk of population bias in deep learning autocontouring.
To date, data used in the development of Deep Learning-based automatic contouring (DLC) algorithms have been largely sourced from single geographic populations. This study aimed to evaluate the risk of population-based bias by determining whether the performance of an autocontouring system is impacted by geographic population. 80 Head Neck CT deidentified scans were collected from four clinics in Europe (n = 2) and Asia (n = 2). A single observer manually delineated 16 organs-at-risk in each. Subsequently, the data was contoured using a DLC solution, and trained using single institution (European) data. Autocontours were compared to manual delineations using quantitative measures. A Kruskal-Wallis test was used to test for any difference between populations. Clinical acceptability of automatic and manual contours to observers from each participating institution was assessed using a blinded subjective evaluation. Seven organs showed a significant difference in volume between groups. Four organs showed statistical differences in quantitative similarity measures. The qualitative test showed greater variation in acceptance of contouring between observers than between data from different origins, with greater acceptance by the South Korean observers. Much of the statistical difference in quantitative performance could be explained by the difference in organ volume impacting the contour similarity measures and the small sample size. However, the qualitative assessment suggests that observer perception bias has a greater impact on the apparent clinical acceptability than quantitatively observed differences. This investigation of potential geographic bias should extend to more patients, populations, and anatomical regions in the future.


The treatment of internal fistulae that complicate diverticular disease of the sigmoid colon by laparoscopically assisted colectomy.
Seven patients with internal fistulae complicating colonic diverticular disease were treated by laparoscopic assisted colectomy over a 24-month period. Prospective review of these patients was carried out to ascertain efficacy of the treatment. No intraoperative complications were encountered and return of gastrointestinal function was apparent within two days in all cases. Postoperative hospital stay was limited to an average of 4.7 days. No long-term complication or fistula recurrence has been noted in the mean 11-month follow-up period. This study indicates laparoscopic assisted colectomy is an effective means of treatment for diverticular fistulae.


Effect of disease-modifying agents and their association with mortality in multi-morbid patients with heart failure with reduced ejection fraction.
An increasing proportion of patients with heart failure with reduced ejection fraction (HFrEF) have co-morbidities. The effect of these co-morbidities on modes of death and the effect of disease-modifying agents in multi-morbid patients is unknown. We performed a prospective cohort study of ambulatory patients with HFrEF to assess predictors of outcomes. We identified four key co-morbidities-ischaemic aetiology of heart failure, diabetes mellitus, chronic obstructive pulmonary disease (COPD), and chronic kidney disease (CKD)-that were highly prevalent and associated with an increased risk of all-cause mortality. We used these data to explore modes of death and the utilization of disease-modifying agents in patients with and without these co-morbidities. The cohort included 1789 consecutively recruited patients who had an average age of 69.6 ± 12.5 years, and 1307 (73%) were male. Ischaemic aetiology of heart failure was the most common co-morbidity, occurring in 1061 (59%) patients; 503 (28%) patients had diabetes mellitus, 283 (16%) had COPD, and 140 (8%) had CKD stage IV/V. During mean follow-up of 3.8 ± 1.6 years, 737 (41.5%) patients died, classified as progressive heart failure (n = 227, 32%), sudden (n = 112, 16%), and non-cardiovascular deaths (n = 314, 44%). Multi-morbid patients were older (P < 0.001), more likely to be male (P < 0.001), and had higher New York Heart Association class (P < 0.001), despite having higher left ventricular (LV) ejection fraction (P = 0.001) and lower LV end-diastolic diameter (P = 0.001). Multi-morbid patients were prescribed lower doses of disease-modifying agents, especially patients with COPD who received lower doses of beta-adrenoceptor antagonists (2.7 ± 3.0 vs. 4.1 ± 3.4 mg, P < 0.001) and were less likely to be implanted with internal cardioverter defibrillators (7% vs. 13%, P < 0.001). In multivariate analysis, COPD and diabetes mellitus conferred a >2.5-fold and 1.5-fold increased risk of sudden death, whilst higher doses of beta-adrenoceptor antagonists were protective (hazard ratio per milligram 0.92, 95% confidence interval 0.86-0.98, P = 0.009). Each milligram of bisoprolol-equivalent beta-adrenoceptor antagonist was associated with 9% (P = 0.001) and 11% (P = 0.023) reduction of sudden deaths in patients with <2 and ≥2 co-morbidities, respectively. Higher doses of beta-adrenoceptor antagonist are associated with greater protection from sudden death, most evident in multi-morbid patients. Patients with COPD who appear to be at the highest risk of sudden death are prescribed the lowest doses and less likely to be implanted with implantable cardioverter defibrillators, which might represent a missed opportunity to optimize safe and proven therapies for these patients.


Food insecurity and adult weight abnormality risk: a systematic review and meta-analysis.
Research into the relationship between food insecurity and weight abnormality has yielded varied and contradictory results. Therefore, a systematic review and meta-analysis were carried out to examine the association between food insecurity and weight abnormality in adults. Pertinent studies were identified by searching PubMed and Scopus databases, up to February 2018. Data were available from 31 studies. These studies were conducted in 14 different countries. The odds ratio of 115,993 individuals in these studies was pooled for the meta-analysis. The present meta-analysis showed that adults in food-insecure households are more at risk of obesity (OR 1.15, 95% CI 1.06-1.23). Subgroup analysis by gender also revealed that women had a higher risk of obesity compared to men in food-insecure households (OR 1.26, 95% CI 1.05-1.46). Furthermore, subgroup analysis by food insecurity level implied that a severe level of household food insecurity may be associated with a higher risk of underweight (49%) than overweight (37%) or obesity (29%) among adults. In addition, subgroup analysis revealed that with lower levels of national economic development, the risk of weight abnormality shifted from obesity to underweight. It seems that adults in food-insecure households, especially women, are at higher risk of obesity. The weight abnormality risk may increase with the intensification of the level of food insecurity. Also, the level of economic development is an important factor in the effects of food insecurity on weight status. However, due to the high heterogeneity among studies, the results should be interpreted with caution.


Is the Association Between Fruits and Vegetables and Preeclampsia Due to Higher Dietary Vitamin C and Carotenoid Intakes?
Diets dense in fruits and vegetables are associated with a reduced risk of preeclampsia, but pathways underlying this relationship are unclear. Dietary antioxidants may contribute to the protective effect. We determined the extent to which the effect of dietary fruit and vegetable density on preeclampsia is because of high intakes of dietary vitamin C and carotenoids. We used data from 7572 participants in the Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be (8 United States medical centers, 2010‒2013). Usual daily periconceptional intake of total fruits and total vegetables was estimated from a food frequency questionnaire. We estimated the indirect effect of ≥2.5 cups/1000 kcal of fruits and vegetables through vitamin C and carotenoid on the risk of preeclampsia. We estimated these effects using targeted maximum likelihood estimation and an ensemble of machine learning algorithms, adjusting for confounders, including other dietary components, health behaviors, and psychological, neighborhood, and sociodemographic factors. Participants who consumed ≥2.5 cups of fruits and vegetables per 1000 kcal were less likely than those who consumed <2.5 cups/1000 kcal to develop preeclampsia (6.4% compared with 8.6%). After confounder adjustment, we observed that higher fruit and vegetable density was associated with 2 fewer cases of preeclampsia (risk difference: -2.0; 95% CI: -3.9, -0.1)/100 pregnancies compared with lower density diets. High dietary vitamin C and carotenoid intake was not associated with preeclampsia. The protective effect of high fruit and vegetable density on the risk of preeclampsia and late-onset preeclampsia was not mediated through dietary vitamin C and carotenoids. Evaluating other nutrients and bioactives in fruits and vegetables and their synergy is worthwhile, along with characterizing the effect of individual fruits or vegetables on preeclampsia risk.


Prevalence and radiological outcomes of lung nodules in alpha 1-antitrypsin deficiency.
Pulmonary nodules are a frequent incidental finding on computed tomography (CT) imaging. This study sought to investigate the prevalence and radiological outcomes of lung nodules in patients with alpha 1-antitrypsin deficiency (AATD), and determine any association with systemic inflammation and disease progression. A retrospective study was conducted using thoracic CT imaging from 494 patients on the AATD U.K. registry. Patients were categorised according to radiological and clinical outcome, and comparisons made with respect to baseline demographics, lung function and high-sensitivity CRP (hs-CRP). Sixty-four patients (13%) had a nodule present on baseline imaging, and in total 132 patients (27%) had a nodule on at least one scan, of which 2 were malignant. The presence of a lung nodule was associated with significantly lower baseline percent predicted forced expiratory volume in 1 s (FEV1 % predicted) (p = 0.037) and percent predicted transfer coefficient of the lung for carbon monoxide (Kco % predicted, p = 0.001). Patients with self-resolving nodules had higher baseline hs-CRP concentrations (p < 0.01) and more rapid decline in Kco (p = 0.03) compared to patients in whom no nodules were observed. The prevalence of 'incidental' pulmonary nodules on CT imaging in patients with AATD was 13%. Self-resolving pulmonary nodules were associated with increased systemic inflammation and progression of emphysema and may therefore reflect an important component of emphysema pathogenesis or a marker of emphysema.


Involvement of circadian rhythm in response to ultrashort photoperiods in blackheaded bunting, Emberiza melanocephala.
Groups of photosensitive adult female blackheaded buntings were exposed to various ultrashort days photoperiodic regimes for 60 days in which a fixed 3 h photophase was coupled with dark phases in cycles of 22 to 32 hours duration. One group of buntings was kept in long days (15L:9D) as control. Significant increase in ovarian weight and circulating plasma estradiol concentration was marked in the cycles of 30 h (3L:27D), and 32 h (3L:29D) photoperiodic schedules as well as in control group (15L:9D), whereas there was no response in the cycles of 22 h (3L:19D) and 24 h (3L:21D). It seems that the response to ultrashort day cycles is due to a phase advance or delay in photosensitivity of the response system repeatedly shows coincidence of the external photophase (3 h) with the photoinducible phase of an endogenous circadian rhythm. Therefore, the present result appears to be consistent with Bünning hypothesis suggesting the involvement of an endogenous circadian component in the female blackheaded bunting.


AIEE active sensors for fluorescence enhancement based detection of Ni2+ in living cells: Mechanofluorochromic and photochromic properties with reversible sensing of acid and base.
Stimuli responsive sensors QI 1 and QI 2 were rationally developed which exhibited diverse features of mutable mechanofluorochromism, reversible photochromism, solvatochromism, aggregation induced emission enhancement (AIEE), and metal ion sensing. After observing the exceptional structural property relationship, sensors were applied for reversible colorimetric and fluorometric determination of Ni2+ with low detection limits of 12 and 17 nM, respectively. Fluorescence emission enhancement based Ni2+ sensing was induced by chelation enhanced fluorescence (CHEF) mechanism. CHEF is triggered by the inhibition of excited state intramolecular proton transfer (ESIPT) and -C=N isomerization. The proposed Ni2+ sensing mechanism was investigated through 1H NMR, FT-IR titration, theoretical studies, and Jobs plots. Further, the developed sensors successfully demonstrated the selective acid-base induced absorption/emission switching through reversible ring-opening/closing and keto-enol tautomerization, evidenced by 1H NMR titration experiments. Additionally, the sensitivity of the sensor QI 1 towards Ni2+ was effectively mimicked in live MCF-7 cells and industrial effluents. Furthermore, monitoring of Ni2+ ions was also accessed through inexpensive and portable sensors' coated fluorescent films. Finally, an INHIBIT logic gate was fabricated imputing Ni2+ and EDTA as input signals to electronically scrutinize the targeted Ni2+.


Metagenomic next-generation sequencing technology for detection of pathogens in blood of critically ill patients.
To explore the applicability of metagenomic next-generation sequencing (mNGS) technology for the detection of blood pathogens in intensive care unit patients. The clinical data of 63 critically ill patients who could not be diagnosed with blood culture (BC) and who underwent mNGS blood sample testing were retrospectively analyzed. The diagnostic efficacy of mNGS was compared with that of traditional detection methods; the distribution of the pathogens identified by mNGS was analyzed; and the differences in laboratory tests, comorbidities, treatment, and prognosis between the mNGS-positive and mNGS-negative groups were compared. The positive rate of mNGS was 41.3% (26/63), and 16 patients were found to have mixed infections. However, the positive rate of BCs performed simultaneously with mNGS was only 7.9% (5/63). The results of univariate analysis showed that the average length of intensive care unit stay (β, -8.689 [95% CI, -16.176, -1.202]; P = 0.026) and the time from onset to sequencing (β, -5.816 [95% CI,-9.936, -1.696]; P = 0.007) of the mNGS-positive group were significantly shorter than those of the mNGS-negative group. More patients in the positive group were adjusted for anti-infective treatment after mNGS (OR, 3.789 [95% CI,1.176, 12.211]; P < 0.001). Detection of blood pathogens by mNGS has good applicability for critically ill patients who cannot be diagnosed by BC in the early stages of infection, and mNGS should be performed as early as possible to obtain higher pathogen detection rates.


Objective evaluation of facial features in Congolese newborns by facial measurements. The need for population-specific measurements.
The evaluation of dysmorphism is often subjective because many continuous traits are not easily measured or lack normal values. Because many common morphologic profiles vary between populations, population-specific reference ranges of relevant traits are needed. We aim to evaluate the objective assessment of facial dysmorphism in 553 Congolese newborns based on facial measurements. Measurements taken with a ruler were on average larger compared to those with a caliper, but the bias did not depend on the size of the measurement. We therefore introduced a correction factor that allows to use both techniques for facial measurements interchangeably in future studies. The outer canthal distance, palpebral fissure length, and mouth width were significantly larger in Congolese newborns (respectively mean 6.59 [SD 0.48]; mean 2.20 [SD 0.24]; mean 2.78 [SD 0.26]) when compared to references based on European newborns (respectively mean 3.59 [SD 1.76]; mean 4.20 [SD 2.26]; mean 0.47 [SD 1.21]), while the rest of measurements were significantly smaller. The interpupillary distance (IPD) calculated from inner canthal distance and outer canthal distance was not significantly different. We observed a poor agreement between clinical evaluation and measured features (kappa of 0.432). Clinicians were more likely to recognize a face as having wide-spaced eyes when it had been recognized as such during the clinical examination, more than if the child had a high interpupillary distance. This suggests that the measured IPD is not precisely reflecting what is clinically evaluated as wide-spaced eyes.


Juvenile dermatomyositis.
Juvenile dermatomyositis (JDM) is a systemic, inflammatory, idiopathic disease, mainly affecting the skin and the muscles, starting before the age of 16, with an incidence around one case per 1 million children. Some patients display typical features of JDM without skin involvement, or even without muscle involvement; however, both tissues are affected over time in most cases. Diagnosis criteria were established by Bohan and Peter 35 years ago, based on the presence of typical skin rash and proximal muscle involvement. Other conditions have to be ruled out before making a diagnosis of JDM, such as other connective tissue diseases, polymyositis, infectious/postinfectious myositis, genetic diseases, or metabolic or drug-induced myopathies. Unlike adult-onset dermatomyositis, JDM is exceptionally associated with a malignant disease. JDM may also affect several organs, including the lungs and the digestive tract. In a subset of patients, glucose intolerance, lipodystrophia and/or calcinosis develop. Delay in treatment initiation or inadequate treatment may favor diffuse, debilitating calcinosis. JDM patients have to be referred to reference pediatric centers to properly assess disease activity and disease-related damage (including low bone density in most cases), and to define the best treatment. Long-lasting corticosteroid therapy remains the gold standard, together with physiotherapy. Ongoing clinical trials are assessing the effect of several immunosuppressive and immunomodulatory drugs, which may help to control the disease and possibly demonstrate a corticosteroid-sparing effect. Most patients respond to treatment; relapses are frequent but a complete disease remission is achieved in most cases before adulthood.


Co-expression of protease and pectinase in Bacillus subtilis using the herbal saponin extract as substrate.
This study armed to determine the expression of protease and pectinase in Bacillus subtilis using the herbal saponin extract as the fermentation substrates and then characterize the fermentation broths. The saponin concentration in the crude extract from four herbs reached to 25% under the extraction conditions of 60 °C, with a pH 9 for 3 h at a solid-liquid ratio of 1:18. In direct fermentation of Bacillus subtilis in the saponin extract, the maximum activities of protease and pectinase in the cell supernatant reached 3984 and 227 U/ml, respectively. Correspondingly, when 5% glucose was added to this extract for the fermentation, the two maximum activities were up to 2451 and 1390 U/ml, respectively. When characterization of the two abovementioned fermentation broths was carried out, it was observed that the luminousness values were increased to 26.9 and 39.2% from 9.7% of the initial value after 32 h of fermentation, respectively, and there was no significant change in the saponin concentration during the fermentation processes. The evaluation values of washing performance were remarkably improved by 8.2 and 21.7%, respectively.


Biliary bile acids in uncomplicated pregnancy and in cholestasis of pregnancy.
Conjugated and sulfated bile acids were determined by gas-liquid chromatography and by high-pressure liquid chromatography in gallbladder bile samples of four pregnant women at term and of two patients with cholestasis of pregnancy. In healthy pregnant women the mean ratio of cholyl/chenodeoxycholyl/deoxycholyl glycine was 3.7 : 1 : 0.23 and that of taurine conjugates 3.0 : 1 : 0.25, respectively. In gallbladder bile pool of non-pregnant females these ratios were 1.0 : 1 : 0.00 and 1.0 1 : 0.70, respectively. Thus cholic acid predominated in pregnancy bile. In patients with cholestasis of pregnancy, cholid acid comprised 90% of total biliary bile acids, the proportion of chenodeoxycholic acid was greatly decreased and nonsulfated deoxycholic acid was not detected. The proportion of sulfated bile acids of total biliary bile acids was between 0.4 and 1.2% in uncomplicated pregnancy and 0.3 and 0.5% in cholestasis patients.


Effect of nitrogen supply on growth, allocation and gas exchange characteristics of two perennial grasses from inland dunes.
We studied the effects of nitrogen supply on growth, allocation, and gas exchange characteristics of two perennial grasses of dry, nutrient-poor inland dunes: Corynephorus canescens (L.) Beauv. and Agrostis vinealis Schreber. C. canescens invests more biomass in leaves and less in roots, but has less leaf area and more root length per unit plant weight than A. vinealis. A. vinealis invests more nitrogen per unit leaf weight, but less per unit leaf area, despite a similar relative nitrogen investment in leaves and plant nitrogen concentration. Between-species differences in the rate of net photosynthesis, transpiration and shoot respiration are positively related to leaf nitrogen content per unit leaf area. The rate of net photosynthesis per unit plant weight is higher for A. vinealis at both levels of nitrogen supply, due to differences in leaf area ratio (LAR), and despite the reverse differences in the rate of net photosynthesis per unit leaf area. The water use efficiency of the two species is similar and increases significantly with an increase in nitrogen supply. The photosynthetic nitrogen use efficiency on the other hand is not affected by nitrogen supply, while at both low and high nitrogen supply A. vinealis has a 10% higher photosynthetic nitrogen use efficiency than C. canescens.


Transplacental cancerization by Rous sarcoma virus.
Experimental data obtained in the mouse are presented, pointing to the possibility of transplacental transmission of the genetic information contained in the genome of Rous sarcoma virus(RSV), by either intact RSV virions or nucleic acids extracted from infectant suspensions of tumors induced by the Carr(Ziber) on Bryan RSV strains.


Engineering endostatin-expressing cartilaginous constructs using injectable biopolymer hydrogels.
The release of an anti-angiogenic agent, such as type XVIII/endostatin, from an implantable scaffold may be of benefit in the repair of articular cartilage. The objectives of this study are to develop an injectable mesenchymal stem cell (MSC)-incorporating collagen-based hydrogel capable of undergoing covalent cross-linking in vivo and overexpressing endostatin using nonviral transfection, and to investigate methods for the retention of the endostatin protein within the scaffolds. The effects of different cross-linking agents (genipin, transglutaminase-2, and microbial transglutaminase) and different binding molecules for endostatin retention (heparin, heparan sulfate, and chondroitin sulfate) are evaluated. Cartilaginous constructs that overexpress endostatin for 3 weeks are successfully engineered. Most of the endostatin is released into the surrounding media and is not retained within the constructs. The presence of two common basement membrane molecules, laminin and type IV collagen, which have been reported in developing and mature articular cartilage and are generally associated with type XVIII collagen in vivo, is also observed in the engineered cartilaginous constructs. Endostatin-producing cartilaginous constructs can be formulated by growing nonvirally transfected mesenchymal stem cells in collagen gels covalently cross-linked using genipin, transglutaminase-2, and microbial transglutaminase. These constructs warrant further investigation for cartilage repair procedures. The novel finding of laminin and type IV collagen in the engineered cartilage constructs may be of importance for future work toward understanding the role of basement membrane molecules in chondrogenesis and in the physiology and pathology of articular cartilage.


Protease-activated receptor 2 expression in trigeminal neurons innervating the rat nasal mucosa.
Protease-activated receptor 2 (PAR2) is activated by trypsin and mast cell tryptase to induce widespread inflammation by unknown mechanisms. Trypsin and tryptase were shown to activate sensory neurons to release substance-P and related peptides to mediate neurogenic inflammation. In the present study, the expression of PAR2 and tachykinins were investigated in rat trigeminal neurons that were identified by retrograde labeling with rhodamine dye from the nasal mucosa by using neuronal tracing in combination with immunohistochemistry. We found that large subpopulation of all trigeminal neurons (43.5+/-2.6%) identified by the pan-neuronal marker PGP 9.5 were stained with PAR2-immunoreactivity. Of all trigeminal neurons, 7.5+/-2.1% were immunoreactive for tachykinins and PAR2, and only 3.9+/-1.7% of all trigeminal neurons expressed tachykinins, but not PAR2-immunoreactivity. The present study also found that a large number trigeminal neurons innervating the nasal mucosa expressed PAR2-immunoreactivity. Of the rhodamine-labeled trigeminal neurons, 52.5+/-1.8% were immunoreactive for only PAR2 expression, 7.3+/-1.9% contained tachykinins and PAR2, and 3.1+/-0.4 of the rhodamine-labeled trigeminal neurons were non-immunoreactive PAR2, but were positive for tachykinins-immunoreactivity. In conclusion, based on the co-localization of PAR2 and tachykinins in trigeminal sensory neurons innervating the nasal mucosa, the present study suggests that, following an activation of PAR2 receptor in tachykinergic neurons by trypsin and mast cell tryptase, there may be a triggering of tachykinin-mediated phenomena such as neurogenic inflammation in allergic or non-allergic rhinitis.


Synthesis and Spectroscopic Studies of Phenanthroimidazole-Imine Derivatives and Evaluation of Their Antioxidant Activity.
The phenanthroimidazole derivatives are used in the drug industry in large scale. In this study four new phenanthroimidazole-imine derivatives were synthesized and their spectroscopic studies as well as their antioxidant behaviors were examined. Structural analyses were made by FT-IR, 1H-NMR, 13C-NMR, LC-MS spectroscopy techniques. UV-vis absorption and emission spectroscopy techniques have been used to determine the photophysical characteristics of four newly synthesized phenanthroimidazoles. The maximum absorption and emission wavelengths, molar extinction coefficients (ε), singlet energy levels (Es), Stokes' shift values (Δλ) of phenanthroimidazole-imine derivatives are given. Additionally, the antioxidant behavior of all compounds were investigated which the ascorbic acid used as standard molecule in present study.


Changes in chromosome patterns of murine lymphosarcoma LS/BL cells during long-term continuous irradiation in vivo.
The chromosome pattern of murine lymphosarcoma LS/BL and its changes during continuous exposure to ionizing radiation in vivo were studied. Absorbed dose rates (60Co) were 10 and 50 mGy/h. The hypodiploid sets with 39 chromosomes (73%) predominated in the control, unirradiated line. The continuously irradiated LS/BL-CI line exhibited insignificant changes in the modal chromosome number. The number of structural aberrations and sister chromatid exchanges was increased.


An audit of ventilation and perfusion SPECT reporting for the diagnosis of pulmonary embolism in a tertiary cardiothoracic centre.
The aim of the study was to identify reporting patterns of ventilation and perfusion single-photon emission computed tomography (V/Q SPECT) scans done in our department over 3 months in 2016. Factors impacting on reporting and patient groups that would most benefit from the addition of low-dose computed tomography (CT) to V/Q SPECT were analysed. Among 178 patients, 173 (97.2%) had a definitive (positive/negative) report and 2.8% had an equivocal report. As the majority of the equivocal reports were seen in patients aged ≥70 years, we believe that addition of low-dose CT with V/Q SPECT to this patient group will reduce the non-diagnostic rate.


The effect of postintensive care syndrome on the quality of life of intensive care unit survivors: A secondary analysis.
Despite increasing interest in postintensive care syndrome and the quality of life of intensive care unit survivors, the empirical literature on the relationship between these two variables is limited. This study aimed to examine whether postintensive care syndrome predicts the quality of life of intensive care unit survivors. We analysed secondary data, which were collected as part of a larger cross-sectional study. The participants were recruited from six health institutions in Korea. The data of 496 survivors who had been admitted to an intensive care unit for at least 48 h during the past year were analysed. They responded to measures of postintensive care syndrome and quality of life. The participants' mean physical and mental component summary scores (quality of life) were 40.08 ± 8.99 and 40.24 ± 11.19, respectively. Physical impairment (β = -0.48, p < 0.001), unemployment (β = -0.19, p < 0.001), low income (β = -0.11, p = 0.004), older age (β = -0.08, p = 0.039), and cognitive impairment (β = -0.11, p = 0.045) predicted lower physical component summary scores. Mental (β = -0.49, p < 0.001) and cognitive impairment (β = -0.14, p = 0.005) and low income (β = -0.09, p = 0.014) predicted mental component summary scores. The participants reported poor physical and mental health-related quality of life. Postintensive care syndrome, unemployment, low income, and older age were the main predictors of poor quality of life. In addition, postintensive care syndrome was a stronger risk factor for poor quality of life than demographic characteristics and intensive care unit treatment factors.


Sanitation and marriage markets in India: Evidence from the Total Sanitation Campaign.
This paper measures the additional value of sanitation within the marriage arrangement. We use data from the Indian human development household survey (IHDS) to model the marital decisions of men and women in rural India and to estimate the marital surplus (the gains from being married). We use the model to demonstrate that the government's Total Sanitation Campaign (TSC) increased marital surplus and changed marriage market outcomes for men and women. Decomposition reveals (i) that sanitation makes it more attractive to be in a marriage for both gender, and (ii) that TSC exposure led to a decrease in the wife's surplus share, implying a redistribution of gains within the marriage.


Inorganic mercury dissociates preassembled Fas/CD95 receptor oligomers in T lymphocytes.
Genetically susceptible rodents exposed to low burdens of inorganic mercury (Hg2+) develop autoimmune disease. Previous studies have shown that low, noncytotoxic levels of Hg2+ inhibit Fas-mediated apoptosis in T cells. These results suggest that inhibition of the Fas death receptor pathway potentially contributes to autoimmune disease after Hg2+ exposure, as a consequence of disruption of peripheral tolerance. The formation of active death inducing signaling complexes (DISC) following CD95/Fas receptor oligomerization is a primary step in the Fas-mediated apoptotic pathway. Other recent studies have shown that Hg2+ at concentrations that inhibit apoptosis also inhibit formation of active DISC, suggesting that inhibition of DISC is the mechanism responsible for Hg2+-mediated inhibition of apotosis. Preassociated Fas receptors have been implicated as key elements necessary for the production of functional DISC. We present evidence in this study showing that low and nontoxic concentrations of Hg2+ induce the dissociation of preassembled Fas receptor complexes in Jurkat T cells. Thus, this Hg2+-induced event should subsequently decrease the amount of preassembled Fas available for DISC formation, potentially resulting in the attenuation of Fas-mediated apoptosis in T lymphocytes.


Stress training for the surgical resident.
Much effort in surgical education is placed on the development of clinical judgment and technical proficiency. However, little focus is placed on the management of stress associated with surgical performance. The inability to manage stress may lead to poor patient care, attrition from residency, and surgeon burnout. A blinded, matched, comparison group study to evaluate the efficacy of an educational program designed to improve surgical resident performance during stressful scenarios was conducted. The experimental group (n = 11) participated in stress training sessions, whereas the control group (n = 15) did not. Both groups then completed a simulation during which stress was evaluated using objective and subjective measures, and resident performance was graded using a standardized checklist. Performance checklist scores were 5% higher in the experimental group than the control group (P = .54). No change existed in anxiety state according to the State Trait Anxiety Inventory (P = .34) or in heart rate under stress (P = .17) between groups. There was a trend toward improved performance scoring but no difference in anxiety levels after stress training. However, 91% of residents rated the stress training as valuable.


Microscopic pulmonary tumor embolism from adenocarcinoma of the prostate.
Microscopic pulmonary tumor embolisms from prostate cancer are extremely rare. In this case of prostate cancer, microscopic pulmonary tumor embolism developed during androgen deprivation therapy. A 56-year-old man was diagnosed with prostate cancer and underwent androgen deprivation therapy. Three months after starting treatment, he noticed shortness of breath and developed acute progressive dyspnea. He was diagnosed with pulmonary hypertension; however, the cause was not found. His dyspnea was progressive and he died 40 days after the onset of symptoms. Autopsy proved that the cause of pulmonary hypertension was microscopic pulmonary tumor emboli from prostate cancer. Furthermore, histology revealed differences in the androgen receptors in the prostate and emboli, with significantly greater Ki-67 expression in the emboli than in the prostate. Prostate cancer proliferated in the pulmonary artery after hematogenous metastasis, caused vascular occlusion, and formed microscopic pulmonary tumor embolisms.


Mitochondrial Metabolism, Contact Sites and Cellular Calcium Signaling: Implications for Tumorigenesis.
Mitochondria are organelles that are mainly involved in the generation of ATP by cellular respiration. In addition, they modulate several intracellular functions, ranging from cell proliferation and differentiation to cell death. Importantly, mitochondria are social and can interact with other organelles, such as the Endoplasmic Reticulum, lysosomes and peroxisomes. This symbiotic relationship gives advantages to both partners in regulating some of their functions related to several aspects of cell survival, metabolism, sensitivity to cell death and metastasis, which can all finally contribute to tumorigenesis. Moreover, growing evidence indicates that modulation of the length and/or numbers of these contacts, as well as of the distance between the two engaged organelles, impacts both on their function as well as on cellular signaling. In this review, we discuss recent advances in the field of contacts and communication between mitochondria and other intracellular organelles, focusing on how the tuning of mitochondrial function might impact on both the interaction with other organelles as well as on intracellular signaling in cancer development and progression, with a special focus on calcium signaling.


Plasma metabolomics reveals lower carnitine concentrations in overweight Labrador Retriever dogs.
The prevalence of overweight is increasing in dogs, but the metabolic events related to this condition are still poorly understood. The purpose of the study was to investigate the postprandial response of plasma metabolites using a meal-challenge test and to identify metabolic variations related to spontaneous overweightness in privately owned dogs. Twenty-eight healthy male intact Labrador Retriever dogs were included, 12 of which were classified as lean (body condition score (BCS) 4-5 on a 9-point scale) and 16 as overweight (BCS 6-8). After an overnight fast (14-17 h), blood samples were collected and dogs were thereafter fed a high-fat meal. Postprandial blood samples were collected hourly four times. Plasma metabolites were identified by nuclear magnetic resonance. Postprandial metabolomes differed from the fasting metabolome in multivariate discriminant analysis (PLS-DA: Q2Y = 0.31-0.63, cross-validated ANOVA: P ≤ 0.00014) Eleven metabolites, all amino acids, contributed to the separations. Carnitine was identified as a metabolite related to overweight (stepwise logistic regression analysis P ≤ 0.03) and overweight dogs had overall lower carnitine response (mixed model repeated measures analysis P = 0.005) than lean dogs. Notably, mean fasting carnitine concentration in overweight dogs (9.4 ± 4.2 µM) was close to a proposed reference limit for carnitine insufficiency. A postprandial amino acid response was detected but no time-dependent variations with regards to body condition groups were found. Lower carnitine concentrations were found in overweight compared to lean dogs. The latter finding could indicate a carnitine insufficiency related to spontaneous adiposity and altered lipid metabolism in overweight dogs in this cohort of otherwise healthy Labrador Retrievers.


Melatonin upregulates DNA-PKcs to suppress apoptosis of human umbilical vein endothelial cells via inhibiting miR-101 under H2O2-induced oxidative stress.
Melatonin has been implicated in inhibiting oxidative stress-induced apoptosis of endothelial cells. However, the underlying mechanism remains poorly understood. In this study, we examined the effect of melatonin on apoptosis of human umbilical vein endothelial cells (HUVECs) induced by H2O2 and explored the underlying mechanisms. Our results demonstrated that DNA-dependent protein kinase catalytic subunit (DNA-PKcs) upregulation contributed to the protective role of melatonin in HUVECs under oxidative stress with H2O2. Further study showed that melatonin treatment led to a decreased level of miRNA-101, which could be responsible for DNA-PKcs upregulation and DNA-PKcs-mediated apoptosis inhibition in HUVECs under oxidative stress with H2O2. Our results also showed that melatonin increased the activity of PI3K/AKT and DNA-PKcs knockdown in melatonin-treated HUVECs that lead to inactivation of PI3K/AKT signaling under oxidative stress with H2O2. Furthermore, blockade of PI3K/AKT signal with LY294002 significantly reduced melatonin-induced apoptosis inhibition in H2O2-treated HUVECs. Taken together, our findings identify a miR-101/DNA-PKcs/PI3K/AKT signaling pathway in melatonin-induced endothelial cell apoptosis inhibition under oxidative stress with H2O2.


Genotoxicity kinetics in murine normoblasts as an approach for the in vivo action of difluorodeoxycytidine.
This study analyzed the kinetics of in vivo micronucleus induction in normoblasts by determining the kinetics of difluorodeoxycytidine (dFdC)-induced micronucleated polychromatic erythrocytes (MN-PCEs) in the peripheral blood of mice. The kinetic indexes of MN-PCE induction of dFdC were correlated with the previously reported mechanisms DNA damage induction by this compound. In general, this study aimed to establish an in vivo approach for discerning the processes underlying micronucleus induction by antineoplastic agents or mutagens in general. The frequencies of PCEs and MN-PCEs in the peripheral blood of mice were determined prior to treatment and after treatment using dFdC at doses of 95, 190, or 380 µmol/kg at 8 h intervals throughout a 72 h post-treatment. The area beneath the curve (ABC) for MN-PCE induction as a function of time, which is an index of the total effect, indicated that the dose response was directly proportional and that the effect of dFdC on micronucleus induction was reduced compared with that of aneuploidogens and monofunctional and bifunctional alkylating agents but increased compared with that of promutagens, which is consistent with our previous results. The ABC showed a single peak with a small broadness index, which indicates that dFdC has a single mechanism or concomitant mechanisms for inducing DNA breaks. The time of the relative maximal induction (T rmi) indicated that dFdC requires more time to achieve MN-PCE induction compared with aneugens and monofunctional and bifunctional alkylating agents, although it requires a similar time to achieve MN-PCE induction as azacytidine, which is consistent with evidence showing that both agents must be incorporated into DNA for their action to be realized. The timing of maximal cytotoxicity observed with the lowest dFdC dose was correlated with the timing of the main genotoxic effect. However, early and late cytotoxic effects were detected, and these effects were independent of the genotoxic response. A correlation analysis indicated that dFdC appears to induce MN-PCEs through only one mechanism or mechanisms that occur concomitantly, which could be explained by the previously reported concurrent inhibitory effects of dFdC on DNA polymerase alpha, polymerase epsilon, and/or topoisomerase. The timing of maximal cytotoxicity was correlated with the timing of maximal genotoxicity; however, an early cytotoxic effect that appeared to occur prior to the incorporation of dFdC into DNA was likely related to a previously reported inhibitory effect of dFdC on thymidylate synthase and/or ribonucleotide reductase.


Treadmill training regulates β-catenin signaling through phosphorylation of GSK-3β in lumbar vertebrae of ovariectomized rats.
Postmenopausal osteoporosis is associated with high level of adipogenesis within the bone marrow at the expense of osteoblast population. The mechanical effect on β-catenin through phosphorylation of glycogen synthase kinase-3β (GSK-3β) is critical for inhibition of adipogenesis in mesenchymal stem cells in vitro. In present study, we hypothesized that treadmill training could regulate the β-catenin signaling through phosphorylation of GSK-3β in the lumbar vertebrae of ovariectomized (OVX) rats. 3-month-old female Sprague-Dawley rats were divided randomly into the following four groups: (a) Sham, (b) OVX, (c) OVX exercised (EX), and (d) OVX estrogen replacement (E(2)). At the end of the experiment, the serum levels of estradiol (E(2)) and luteinizing hormone (LH), the ultimate lumbar vertebra strength, as well as the protein expression for peroxisome proliferators-activated receptor γ (PPARγ), β-catenin, P-GSK-3β, and osterix (Osx) in lumbar vertebrae were analyzed. Moreover, the protein expression for β-catenin and P-GSK-3β were also examined in the uterus. The EX group had lower protein level of PPARγ, higher ultimate lumbar vertebral strength, and higher protein levels of β-catenin, and P-GSK-3β in lumbar vertebral bodies compared with sedentary OVX group. The effects of EX treatment on the protein levels of β-catenin and P-GSK-3β in bones were not reproducible in the uterus. Moreover, exercise treatment produced no estrogenic effect as evidenced by serum level of LH. In conclusion, this study suggested that treadmill training could activate the GSK-3β/β-catenin signaling and inhibit the production of PPARγ in lumbar vertebrae of OVX rats, which may contribute to the prevention of bone loss in OVX rats.