[Long-term results of elastic intramedullary nailing in pediatric femoral shaft fractures].
In our retrospective study, we evaluated pediatric femoral shaft fractures sustained by children of five to fifteen years of age, all of whom were treated with elastic intramedullary nailing. Between 1990 and 2000, 32 femoral fractures of 30 children, 14 (47%) polytraumatized, with an average age of 9.9 (6-14), were treated with elastic intramedullary nailing. Average follow-up was 105.3 (25-145) months. Three cases (9.3%) were re-operated due to developed angulations related to weight bearing in the early postoperative period. In three (9,3%) of our cases we diagnosed more than five degrees valgus deformity, in one (3.1%) anterior angulation and in 1 (3.1%) internal rotation. The average of absolute value of length discrepancies was determined as 9 mm (-15mm - +15mm). Elastic intramedullary fixation is a recommended method, especially for polytraumatized patients, because of facilitates of patient care, recovers social activity quickly, and causes minimal soft tissue damage. However angular or rotational deformations are also possible. Selection criteria and follow up period is important and treatment of the complications must be on time.


Genetic positioning of centromeres using half-tetrad analysis in a 4x-2x cross population of potato.
From biological and genetic standpoints, centromeres play an important role in the delivery of the chromosome complement to the daughter cells at cell division. The positions of the centromeres of potato were determined by half-tetrad analysis in a 4x-2x population where the male parent produced 2n pollen by first-division restitution (FDR). The genetic linkage groups and locations of 95 male parent-derived amplified fragment length polymorphism markers could be determined by comparing their position on a 2x-2x highly saturated linkage map of potato. Ten centromere positions were identified by 100% heterozygosity transmitted from the 2n heterozygous gametes of the paternal parent into the tetraploid offspring. The position of these centromeric marker loci was in accordance with those predicted by the saturated 2x-2x map using the level of marker clustering as a criterion. Two remaining centromere positions could be determined by extrapolation. The frequent observation of transmission of 100% heterozygosity proves that the meiotic restitution mechanism is exclusively based on FDR. Additional investigations on the position of recombination events of three chromosomes with sufficient numbers of markers showed that only one crossover occurred per chromosome arm, proving strong interference of recombination between centromere and telomere.


The Fundamental Property of Human Leg During Walking: Linearity and Nonlinearity.
Leg properties have been involved in the broad study of human walking from mechanical energy to motion prediction of robotics. However, the variable leg elasticities and their functions during gait have not been fully explored. This study presented that the fundamental leg properties during human walking comprise axial stiffness, rest leg length, tangential stiffness and force-free leg angles. We measured the axial force-leg length and tangential force-leg angle data in eight participants (mean ± s.d. age 24.6 ± 3.0 years, mass 68.2 ± 6.8 kg, height 177.5 ± 5.2 cm) at three self-selected walking speeds (slow: 1.25 ± 0.22, normal: 1.48 ± 0.28, fast: 1.75 ± 0.32 m/s) on two different contact conditions (fixed and moving). After obtaining these gait measurements, we extracted the linear and nonlinear leg elasticities during human walking by using a minimum root-mean-square fitting. We found that the axial stiffness of nonlinear elasticity (fixed condition: 7.1-8.0, moving condition: 21.3-22.6) is higher than that of the linear elasticity (fixed condition: 5.0-5.7, moving condition: 15.2-16.5). The tangential stiffness behaves different during four stance phases of gait, with the highest (linear: 2.52-3.72, nonlinear: 1.71-2.01, in moving condition) occurred at early stance and second highest at late stance, followed by two stiffnesses in mid-stance. For both linearity and nonlinearity, the axial stiffness and rest length are independent of walking speeds in both contact conditions, while the tangential stiffness and contact angles are independent of walking speeds only in moving condition. Regardless of walking speed, elasticity and contact condition, the force-free contact angle at mid-stance is maintained at average of 82.2 °. This paper first demonstrates the mechanical walking leg property from both axial and tangential aspects. The findings provide insight into the fundamental properties including linearity and nonlinearity of human leg during locomotion for stability analysis and precise motion prediction of robotics and rehabilitation exoskeletons.


Interstitial keratitis secondary to severe hidradenitis suppurativa: a case report and literature review.
To report a patient who presented with bilateral interstitial keratitis in association with severe hidradenitis suppurativa. Case report. An 18-year-old African American woman with severe active hidradenitis suppurativa of the axillae and groin presented with a 2-week history of bilateral blurry vision. On examination, best-corrected visual acuity was counting fingers in the right eye and 20/70 in the left eye. Slit-lamp examination revealed diffuse vascularization of the corneal stroma with surrounding infiltrates bilaterally. In the left eye, corneal thinning and an epithelial defect were present in an area of infiltrate. Our clinical impression at that time was bilateral interstitial keratitis with secondary bacterial keratitis in the left eye. Topical therapy, prednisolone acetate 1% in the right eye, and ofloxacin in the left eye, was instituted. A systemic workup, including antinuclear antibody, rheumatoid factor, Lyme titer, cytoplasmatic staining antineutrophil cytoplasmic antibodies, perinuclear staining antineutrophil cytoplasmic antibodies, erythrocyte sedimentation rate, Venereal Disease Research Laboratory, rapid plasma reagin, basic metabolic panel, angiotensin-converting enzyme level, and a chest x-ray was negative. Topical steroids were used in the left eye after resolution of the bacterial keratitis. The interstitial keratitis responded to topical steroids and remained in remission after steroid taper. However, bilateral interstitial keratitis recurred coincident with a severe flare of hidradenitis suppurativa within 1 month of discontinuing the topical steroids. A course of subcutaneous adalimumab injections (40 mg/mL every 2 weeks) for hidradenitis suppurativa was implemented. Both her dermatological and ocular conditions responded to this therapy and have remained in remission through 7 months of follow-up. Hidradenitis suppurativa is a rare cause of bilateral interstitial keratitis. Patients may experience simultaneous exacerbations of both dermatological and ocular manifestations. Systemic treatment with adalimumab can improve both dermatological and ocular conditions.


Caregiving and Perceived Generativity: A Positive and Protective Aspect of Providing Care?
Although a sizable body of research supports negative psychological consequences of caregiving, less is known about potential psychological benefits. This study aimed to examine whether caregiving was associated with enhanced generativity, or feeling like one makes important contributions to others. An additional aim was to examine the buffering potential of perceived generativity on adverse health outcomes associated with caregiving. Analyses utilized a subsample of participants (n = 3,815, ages 30-84 years) from the second wave of the National Survey of Midlife Development in the United States (MIDUS). Regression analyses adjusting for sociodemographic factors indicated greater negative affect and depression (p < .001) and lower levels of positive affect (p < .01), but higher self-perceptions of generativity (p < .001), in caregivers compared with non-caregivers. This association remained after adjusting for varying caregiving intensities and negative psychological outcomes. Additionally, generativity interacted with depression and negative affect (p values < .05) to lessen the likelihood of health-related cutbacks in work/household productivity among caregivers. Results suggest that greater feelings of generativity may be a positive aspect of caregiving that might help mitigate some of the adverse health and well-being consequences of care. Self-perceptions of generativity may help alleviate caregiver burden and explain why some caregivers fare better than others.


Phenotypic Consequences of the GJD2 Risk Genotype in Myopia Development.
To study the relatively high effect of the refractive error gene GJD2 in human myopia, and to assess its relationship with refractive error, ocular biometry and lifestyle in various age groups. The population-based Rotterdam Study (RS), high myopia case-control study MYopia STudy, and the birth-cohort study Generation R were included in this study. Spherical equivalent (SER), axial length (AL), axial length/corneal radius (AL/CR), vitreous depth (VD), and anterior chamber depth (ACD) were measured using standard ophthalmologic procedures. Biometric measurements were compared between GJD2 (rs524952) genotype groups; education and environmental risk score (ERS) were calculated to estimate gene-environment interaction effects, using the Synergy index (SI). RS adults carrying two risk alleles had a lower SER and longer AL, ACD and VD (AA versus TT, 0.23D vs. 0.70D; 23.79 mm vs. 23.52 mm; 2.72 mm vs. 2.65 mm; 16.12 mm vs. 15.87 mm; all P < 0.001). Children carrying two risk alleles had larger AL/CR at ages 6 and 9 years (2.88 vs. 2.87 and 3.00 vs. 2.96; all P < 0.001). Education and ERS both negatively influenced myopia and the biometric outcomes, but gene-environment interactions did not reach statistical significance (SI 1.25 [95% confidence interval {CI}, 0.85-1.85] and 1.17 [95% CI, 0.55-2.50] in adults and children). The elongation of the eye caused by the GJD2 risk genotype follows a dose-response pattern already visible at the age of 6 years. These early effects are an example of how a common myopia gene may drive myopia.


[Evaluation of an anti-influenza vaccine in a group of elderly].
To 57 individuals of the Old People's Home in Güines and Artemisa Municipalities, without vaccinal contraindications, was administered and inactivated bivalent antigrippal vaccine with the antigenic content: A/Kiev/59/79 (H1N1) and A/Filipina/2/82 (H3N2). Trough the inhibition technique of hemagglutination in pair sera, satisfactory results (seroconversion) were obtained in more of the vaccinated individuals, for both antigens. Local reactions such as erythema and papule were observed. Nine patients were detected among the vaccinated individuals by the epidemiologic surveillance carried out a year after vaccination. The serologic study performed to five of them showed a case positive to influenza A (H3N2) and another one positive to influenza B.


Biopterin analogues: novel nitric oxide synthase inhibitors with immunosuppressive action.
Tetrahydrobiopterin plays an essential role in nitric oxide synthase catalysis, not only as an allosteric modulator but also as a cofactor involved in electron flow through the enzyme. In absence of tetrahydrobiopterin, all isoforms of nitric oxide synthases are virtually inactive. The present review focuses on attempts to inhibit nitric oxide synthase by biopterin analogues, and what is known about the pharmacological effects of these compounds. While several biopterin analogues are capable of inhibiting nitric oxide synthases, the 4-amino analogue of tetrahydrobiopterin (4-amino tetrahydrobiopterin) is the compound of which pharmacological actions in animals have been described. 4-Amino tetrahydrobiopterin inhibits all three isoforms of nitric oxide synthases in micromolar concentrations. In cultured cells and in aortic strips, a surprising selectivity of inhibition of the inducible isoform of nitric oxide synthases has been observed. When applied intramuscularly, 4-amino tetrahydrobiopterin spreads throughout the body within minutes, and is cleared with a half life of about an hour. A single bolus dose applied intravenously in a rat model of septic shock, saved the animals from the lethal effects of endotoxin. When applied three times a day intramuscularly in a murine model of cardiac allograft rejection, 4-amino tetrahydrobiopterin prolongs allograft survival as efficiently as high-dose cyclosporin A treatment does. Thus, 4-amino tetrahydrobiopterin is an effective immunosuppressant. The mechanism of its action is currently under investigation.


System to Evaluate the Skill of Operating Hydraulic Excavators Using a Remote Controlled Excavator and Virtual Reality.
We developed a system to evaluate the skill of operating a hydraulic excavator. The system employs a remotely controlled (RC) excavator and virtual reality (VR) technology. We remodeled the RC excavator so that it can be operated in the same manner as a real excavator and proceeded to measure the excavator's state. To evaluate the skill of operating this system, we calculated several indices from the data recorded during excavation work and compared the indices obtained for expert and non-expert operators. The results revealed that it is possible to distinguish whether an expert or non-expert is operating the RC excavator. We calculated the same indices from the data recorded during excavation with a real excavator and verified that there exists a high correlation between the indices of the RC excavator and those of the real excavator. Thus, we confirmed that the indices of the real excavator and those of the simulator exhibited similar trends. This suggests that it is possible to partly evaluate the operation characteristics of a real excavator by using an RC excavator with different dynamics compared with a real excavator.


Vaginal estrogen use for genitourinary symptoms in women with a history of uterine, cervical, or ovarian carcinoma.
Menopausal symptoms may adversely affect quality of life and health in women diagnosed with a gynecologic malignancy. The aim of this study was to determine the incidence of adverse outcomes, including cancer recurrence, venous thromboembolism, and secondary malignancies, among patients with a history of endometrial, ovarian, or cervical cancer prescribed vaginal estrogen for genitourinary syndrome of menopause. A retrospective cohort study was performed including women who were diagnosed with endometrial, ovarian, or cervical cancer from January 1, 1991 to December 31, 2017 and subsequently treated with vaginal estrogen for genitourinary syndrome of menopause. Patients were included if not undergoing active cancer treatment and were disease-free based on most recent cancer surveillance visit with physical exam and/or imaging. Demographics, oncologic variables, estrogen use, and adverse outcomes were recorded. Descriptive statistics and univariate analysis were performed. Of 244 women who received vaginal estrogen, 52% (n=127) had a history of endometrial, 25.4% (n=62) cervical, 18.9% (n=46) ovarian cancer, and 3.7% (n=9) low malignant potential tumors. The mean age and body mass index were 55.5±12.5 years and 29.2±8.6 mg/kg2, respectively. With a median follow-up of 80.2 months, the incidence of recurrence for endometrial, ovarian, and cervical cancer was 7.1% (n=9), 18.2% (n=10), and 9.7% (n=6), respectively. In patients with endometrial cancer who recurred, the incidence was 2.4% (n=3) for stage I/II and 4.7% (n=6) for stage III/IV disease. Similarly, recurrence rates for ovarian cancer were 4.3% (n=2) for stage I/II and 17.4% (n=8) for stage III/IV disease. All cervical cancer recurrences were in patients with stage I/II disease. Adverse outcomes including breast cancer (1.6%, n=4), secondary malignancy (2.5%, n=6), and venous thromboembolism (2.5%, n=6) were rare. In women with a history of endometrial, ovarian, or cervical cancer prescribed vaginal estrogen use for genitourinary syndrome of menopause, adverse outcomes, including recurrence and thromboembolic events, are infrequent. Vaginal estrogen may be considered safe in gynecologic cancer survivors.


The effects of combining elastic and free weight resistance on strength and power in athletes.
This study was undertaken to determine whether combined elastic and free weight resistance (CR) provides different strength and power adaptations than free weight resistance (FWR) training alone. Forty-four young (age 20 +/- 1 years), resistance-trained (4 +/- 2 years' experience) subjects were recruited from men's basketball and wrestling teams and women's basketball and hockey teams at Cornell University. Subjects were stratified according to team, then randomly assigned to the control (C; n = 21) or experimental group (E; n = 23). Before and after 7 weeks of resistance training, subjects were tested for lean body mass, 1 repetition maximum back squat and bench press, and peak and average power. Both C and E groups performed identical workouts except that E used CR (i.e., elastic resistance) for the back squat and bench press, whereas the C group used FWR alone. CR was performed using an elastic bungee cord attached to a standard barbell loaded with plates. Elastic tension was accounted for in an attempt to equalize the total work done by each group. Statistical analyses revealed significant (P < 0.05) between-group differences after training. Compared with C, improvement for E was nearly three times greater for back squat (16.47 +/- 5.67 vs. 6.84 +/- 4.42 kg increase), two times greater for bench press (6.68 +/- 3.41 vs. 3.34 +/- 2.67 kg increase), and nearly three times greater for average power (68.55 +/- 84.35 vs. 23.66 +/- 40.56 watt increase). Training with CR may be better than FWR alone for developing lower and upper body strength, and lower body power in resistance-trained individuals. Long-term effects are unclear, but CR training makes a meaningful contribution in the short term to performance adaptations of experienced athletes.


Magnetic resonance imaging in Alzheimer's disease and mild cognitive impairment.
Research utilizing magnetic resonance imaging (MRI) has been crucial to the understanding of the neuropathological mechanisms behind and clinical identification of Alzheimer's disease (AD) and mild cognitive impairment (MCI). MRI modalities show patterns of brain damage that discriminate AD from other brain illnesses and brain abnormalities that are associated with risk of conversion to AD from MCI and other behavioural outcomes. This review discusses the application of various MRI techniques to and their clinical usefulness in AD and MCI. MRI modalities covered include structural MRI, diffusion tensor imaging (DTI), arterial spin labelling (ASL), magnetic resonance spectroscopy (MRS), and functional MRI (fMRI). There is much evidence supporting the validity of MRI as a biomarker for these disorders; however, only traditional structural imaging is currently recommended for routine use in clinical settings. Future research is needed to warrant the inclusion for more advanced MRI methodology in forthcoming revisions to diagnostic criteria for AD and MCI.


[Adrenergic innervation of the middle and internal ear in man].
Adrenergic nervous structures (ANS) in morphofunctional formations of human middle and internal ear were studied on the autopsy material obtained from 5 victims of accidents free of any ear disease. The samples were treated histochemically with glyoxylic acid. Non-varicose dilated sympathetic nerve fibers (single and in bundles, non-myelinized, intensively luminescent, twisted and direct) were detected in vertical nerve sections, in spiral and vestibular ganglia, in chorda tympani. A thick net of adrenergic nerve fibers (ANF) was noted around the labyrinthine artery. ANF were absent long along the walls of the utriculus and semicircular canals, in the modiolus vessels, spiral ligament, vascular stripe. ANF were most numerous on the osseous spiral lamina. Near the Corti's organ ANF are thicker and often varicose. On the vertical sections of m. stapedius ANF with varicose parts locate in the connective tissue perimysial layers and in the endomysium directly between the muscular cells. At the site of muscle transition into the tendon and in tendon as such no ANF were found. Two sets of ANF were noted in the middle ear mucosa: perivascular and unrelated to blood vessels.


Dixon techniques for water and fat imaging.
In 1984, Dixon published a first paper on a simple spectroscopic imaging technique for water and fat separation. The technique acquires two separate images with a modified spin echo pulse sequence. One is a conventional spin echo image with water and fat signals in-phase and the other is acquired with the readout gradient slightly shifted so that the water and fat signals are 180 degrees out-of-phase. Dixon showed that from these two images, a water-only image and a fat-only image can be generated. The water-only image by the Dixon's technique can serve the purpose of fat suppression, an important and widely used imaging option for clinical MRI. Additionally, the availability of both the water-only and fat-only images allows direct image-based water and fat quantitation. These applications, as well as the potential that the technique can be made highly insensitive to magnetic field inhomogeneity, have generated substantial research interests and efforts from many investigators. As a result, significant improvement to the original technique has been made in the last 2 decades. The following article reviews the underlying physical principles and describes some major technical aspects in the development of these Dixon techniques.


Predictive significance of arachidonate 15-lipoxygenase for eosinophilic chronic rhinosinusitis with nasal polyps.
Eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) exhibits a poorer outcome compared with non-eosinophilic chronic rhinosinusitis with nasal polyps (nonECRSwNP), so it is significant to identify effective markers to differentiate ECRSwNP in guiding the treatment strategies of these patients. Although arachidonate 15-lipoxygenase (ALOX15) is positioned as a marker of eosinophilic inflammation, its study in differentiating ECRSwNP has not been reported. The aim of this study is to assess the potential of ALOX15 in distinguishing and predicting ECRSwNP. Forty-eight patients with chronic rhinosinusitis with nasal polyps (CRSwNP), including 30 ECRSwNP and 18 nonECRSwNP patients, were enrolled. ALOX15 mRNA level was determined in polyps by real-time polymerase chain reaction (RT-PCR). The patients' baseline characteristics were evaluated and analyzed for correlations with ALOX15. Receiver operating characteristic (ROC) curve was used to assess the predictive significance of the potential predictors for ECRSwNP. ALOX15 mRNA level was significantly higher in ECRSwNP patients than in nonECRSwNP patients (P < 0.001). ALOX15 mRNA was significantly correlated with tissue and blood eosinophil percentages (r = 0.565, P < 0.001 and r = 0.395, P = 0.006), olfaction scores (r = 0.400, P = 0.005), total visual analogue scale (VAS) symptom scores (r = 0.383, P = 0.007), ethmoid/maxillary sinus (E/M) ratio (r = 0.463, P = 0.001), and endoscopy scores (r = 0.409, P = 0.004). Logistic regression analysis showed ALOX15 mRNA level and percentage of blood eosinophils to be predictive factors for ECRSwNP (P = 0.004 and P = 0.036, respectively). ROC curve indicated ALOX15 to have high predictive accuracy for ECRSwNP (area under the curve (AUC) = 0.909), which was further improved by combination of ALOX15 with percentage of blood eosinophils (AUC = 0.933). The relative ALOX15 mRNA level alone or in combination with blood eosinophils might be a reliable biomarker for predicting a diagnosis of ECRSwNP.


Endogenous aldosterone is involved in vascular calcification in rat.
Aldosterone (Aldo) is an important active hormone in the renin-angiotensin-aldosterone system and plays a vital role in the development of hypertension, heart failure and other cardiovascular diseases. We aimed to explore the role of endogenous Aldo in aortic calcification in rats. We induced arterial calcification in rats by intramuscular administration of vitamin D(3) plus oral nicotine (VDN) and determined calcium content, (45)Ca(2+) accumulation and activity of alkaline phosphatase (ALP). The mRNA level of osteopontin (OPN) was measured by semi-quantitative reverse transcriptase polymerase chain reaction. Deposition of collagen in the aorta wall was measured by Sirius red staining. The content of angiotensin II (Ang II) and Aldo in plasma and myocardial and vascular tissue was determined by radioimmunoassay. In rats with VDN treatment, von Kossa staining showed calcification in vascular smooth muscle cells and extracellular matrix, and the content of calcium in calcified arteries was 5.8-fold of that in control arteries (P < 0.01). The accumulation of (45)Ca(2+) and activity of ALP in calcified aortic tissue was three- and 2.5-fold, respectively, that in control tissue (P < 0.01). The mRNA expression of OPN was significantly higher, by 58%, in calcified than control tissue (P < 0.01). Vascular fibrosis was greater in rats with calcified tissue than in control rats. The level of Ang II and Aldo was 58% and 80% higher, respectively, in calcified than control tissue (both P < 0.01). The changes could be significantly improved by treatment with captopril, an angiotensin-converting enzyme inhibitor, and the Aldo receptor antagonist spironolactone. These results suggest that Aldo is an endogenous bioactive factor involved in vascular calcification.


Feline asthma syndrome: a retrospective study of the clinical presentation in 29 cats.
Feline asthma syndrome (FAS) is a clinical condition characterised by recurrent bouts of coughing, wheezing and, or, dyspnoea. While the aetiology is unproven, the condition is believed to involve a type I immediate hypersensitivity reaction to inhaled allergens. In this paper the clinical data from 29 cats, where a diagnosis of FAS was made, are assessed retrospectively. The most common clinical presentation was recurrent bouts of coughing (n = 26) and dyspnoea (n = 21). Radiographic changes were noted in 24 cats, which included increased bronchial (n = 5), interstitial (n = 7) and mixed (n = 12) (bronchial and interstitial) patterns. Right middle lung lobe collapse was noted in two cats. Abnormal bronchial cytology was present in 16 cats. A predominant eosinophilic sample was collected in only three cats. There were minimal changes in differential white cell counts, and mild eosinophilia was found in only five cats. Prednisolone alone was the most effective therapy, although avoidance of putative aeroallergens and antibacterial therapy was effective in some. On the basis of the data from these cases it would appear that the diagnosis of FAS depends largely on the clinical presentation and radiographic findings. The value of ancillary tests in the diagnosis of FAS appears to be limited.


The Vulnerability of the Developing Brain: Analysis of Highly Expressed Genes in Infant C57BL/6 Mouse Hippocampus in Relation to Phenotypic Annotation Derived From Mutational Studies.
The hippocampus has been shown to have a major role in learning and memory, but also to participate in the regulation of emotions. However, its specific role(s) in memory is still unclear. Hippocampal damage or dysfunction mainly results in memory issues, especially in the declarative memory but, in animal studies, has also shown to lead to hyperactivity and difficulty in inhibiting responses previously taught. The brain structure is affected in neuropathological disorders, such as Alzheimer's, epilepsy, and schizophrenia, and also by depression and stress. The hippocampus structure is far from mature at birth and undergoes substantial development throughout infant and juvenile life. The aim of this study was to survey genes highly expressed throughout the postnatal period in mouse hippocampus and which have also been linked to an abnormal phenotype through mutational studies to achieve a greater understanding about hippocampal functions during postnatal development. Publicly available gene expression data from C57BL/6 mouse hippocampus was analyzed; from a total of 5 time points (at postnatal day 1, 10, 15, 21, and 30), 547 genes highly expressed in all of these time points were selected for analysis. Highly expressed genes are considered to be of potential biological importance and appear to be multifunctional, and hence any dysfunction in such a gene will most likely have a large impact on the development of abilities during the postnatal and juvenile period. Phenotypic annotation data downloaded from Mouse Genomic Informatics database were analyzed for these genes, and the results showed that many of them are important for proper embryo development and infant survival, proper growth, and increase in body size, as well as for voluntary movement functions, motor coordination, and balance. The results also indicated an association with seizures that have primarily been characterized by uncontrolled motor activity and the development of proper grooming abilities. The complete list of genes and their phenotypic annotation data have been compiled in a file for easy access.


Comparison on functional assays for Gq-coupled GPCRs by measuring inositol monophospate-1 and intracellular calcium in 1536-well plate format.
Cell-based functional assays used for compound screening and lead optimization play an important role in drug discovery for G-protein coupled receptors (GPCRs). Cell-based assays can define the role of a compound as an agonist, antagonist or inverse agonist and can provide detailed information about the potency and efficacy of a compound. In addition, cell-based screens can be used to identify allosteric modulators that interact with sites other than the binding site of the endogenous ligand. Intracellular calcium assays which use a fluorescent calcium binding dye (such as Fluo-3, Fluo-4 or Fura-2) have been used in compound screening campaigns to measure the activity of Gq-coupled GPCRs. However, such screening methodologies require a special instrumentation to record the rapid change in intracellular free calcium concentration over time. The radioactive inositol 1,4,5- triphosphate (IP(3)) assay measures (3)H-inositol incorporation and is another traditional assay for the assessment of Gq-coupled GPCR activity, but it is not suitable for screening of large size compound collections because it requires a cell wash step and generates radioactive waste. To avoid these limitations, we have optimized and miniaturized a TR-FRET based IP-One assay that measures inositol monophosphate in a 1536-well plate format. This assay is homogenous, non-radioactive and does not require a kinetic readout. It has been tested with the cell lines expressing M(1) acetylcholine, FFAR1, vasopressin V1b, or Neuropeptide S receptors. The activities of antagonists determined in the IP-One assay correlated well with these measured in the intracellular calcium assay while the correlation of agonist activities might vary from cell line to cell line. This IP-One assay offers an alternative method for high throughput screening of Gq-coupled GPCRs without using costly kinetic plate readers.


Resource planning strategies for healthcare systems during a pandemic.
We study resource planning strategies, including the integrated healthcare resources' allocation and sharing as well as patients' transfer, to improve the response of health systems to massive increases in demand during epidemics and pandemics. Our study considers various types of patients and resources to provide access to patient care with minimum capacity extension. Adding new resources takes time that most patients don't have during pandemics. The number of patients requiring scarce healthcare resources is uncertain and dependent on the speed of the pandemic's transmission through a region. We develop a multi-stage stochastic program to optimize various strategies for planning limited and necessary healthcare resources. We simulate uncertain parameters by deploying an agent-based continuous-time stochastic model, and then capture the uncertainty by a forward scenario tree construction approach. Finally, we propose a data-driven rolling horizon procedure to facilitate decision-making in real-time, which mitigates some critical limitations of stochastic programming approaches and makes the resulting strategies implementable in practice. We use two different case studies related to COVID-19 to examine our optimization and simulation tools by extensive computational results. The results highlight these strategies can significantly improve patient access to care during pandemics; their significance will vary under different situations. Our methodology is not limited to the presented setting and can be employed in other service industries where urgent access matters.


Impact of PIP2 Lipids, Force Field Parameters, and Mutational Analysis on the Binding of the Osh4's α6-α7 Domain.
All-atom molecular dynamics simulations are used with the highly mobile membrane mimetic method to study the α6-α7 peptide of the critical yeast Osh4 peripheral membrane protein. This research focuses on the impact of 1-palmitoyl-2-oleoyl-sn-glycero-phosphatidylinoside 4,5-bisphosphate (PIP2) lipids and 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-l-serine on the protein's ability to bind to the membrane. Details of the binding mechanism are described qualitatively and quantitatively by measuring the position of the deepest residues, angle of the peptide during binding, root mean square deviation of the atomic positions within the peptide, and interaction energy, while changing variables, such as the force field used and the presence of the PIP2 lipids. The negatively charged PIP2 has a large head group that is a few Ångstroms above the main membrane phosphates enabling the PIP2 lipids to interact with the peptide before it binds deeper into the membrane. The PIP2 lipids can alter the position of the peptide during binding by recruiting charged residues on the α7 helix, such as R344 and R347. Residues R347 and R344 are unusual because they are slightly out of the reach of the main membrane phosphates but optimally positioned to interact with the PIP2 lipids. The salt-bridge interactions can also typically occur between cationic peptide residues such as R314, K325, and K336. The force field interaction effect on peptide binding was also investigated by changing the standard CHARMM36m to an improved description between some amino acids and lipid moieties (Phys. Chem. Chem. Phys. 20, 8432-8449). This resulted in the total number of salt bridges and hydrogen bonds being drastically reduced, the interaction energy was also reduced, and there was more balance between electrostatic and nonpolar interactions, but the general bound structure is maintained. This work is an important initial step to understand the effect of the Osh4 protein on the membrane binding and to quantify the effect of PIP2 lipids on this domain.


Empagliflozin prevents oxidative stress in human coronary artery endothelial cells via the NHE/PKC/NOX axis.
Empagliflozin (EMPA) ameliorates reactive oxygen species (ROS) generation in human endothelial cells (ECs) exposed to 10 % stretch, but the underlying mechanisms are still unclear. Pathological stretch is supposed to stimulate protein kinase C (PKC) by increasing intracellular calcium (Ca2+), therefore activating nicotinamide adenine dinucleotide phosphate oxidase (NOX) and promoting ROS production in human ECs. We hypothesized that EMPA inhibits stretch-induced NOX activation and ROS generation through preventing PKC activation. Human coronary artery endothelial cells (HCAECs) were pre-incubated for 2 h before exposure to cyclic stretch (5 % or 10 %) with either vehicle, EMPA or the PKC inhibitor LY-333531 or PKC siRNA. PKC activity, NOX activity and ROS production were detected after 24 h. Furthermore, the Ca2+ chelator BAPTA-AM, NCX inhibitor ORM-10962 or NCX siRNA, sodium/potassium pump inhibitor ouabain and sodium hydrogen exchanger (NHE) inhibitor cariporide were applied to explore the involvement of the NHE/Na+/NCX/Ca2+ in the ROS inhibitory capacity of EMPA. Compared to 5 % stretch, 10 % significantly increased PKC activity, which was reduced by EMPA and PKC inhibitor LY-333531. EMPA and LY-333531 showed a similar inhibitory capacity on NOX activity and ROS generation induced by 10 % stretch, which was not augmented by combined treatment with both drugs. PKC-β knockdown inhibits the NOX activation induced by Ca2+ and 10 % stretch. BAPTA, pharmacologic or genetic NCX inhibition and cariporide reduced Ca2+ in static HCAECs and prevented the activation of PKC and NOX in 10%-stretched cells. Ouabain increased ROS generation in cells exposed to 5 % stretch. EMPA reduced NOX activity via attenuation of the NHE/Na+/NCX/Ca2+/PKC axis, leading to less ROS generation in HCAECs exposed to 10 % stretch.


Impact of low flow on the outcome of high-risk patients undergoing transcatheter aortic valve replacement.
This study sought to assess the impact of baseline left ventricular (LV) outflow, LV ejection fraction (LVEF), and transvalvular gradient on outcomes following transcatheter aortic valve replacement (TAVR) in patients with severe aortic stenosis (AS). Low flow (i.e., reduced stroke volume index [SVi]) can occur with both reduced and preserved LVEF. Low flow is often associated with low gradient despite severe stenosis and with worse outcomes following surgical aortic valve replacement. However, there are few data about the impact of low flow on outcomes following TAVR. We retrospectively analyzed the clinical, Doppler-echocardiographic, and outcome data prospectively collected in 639 patients who underwent TAVR for symptomatic severe AS in 2 Canadian centers. In this cohort, 334 (52.3%) patients had a low flow (SVi <35 ml/m(2)) and these patients had increased 30-day mortality (11.4 vs. 5.9%, p = 0.01), 2-year all-cause mortality (35.3 vs. 30.9%, p = 0.005), and 2-year cardiovascular mortality (25.7 vs. 16.8%, p = 0.01) compared with patients with normal flow. Reduced flow was an independent predictor of 30-day mortality (odds ratio: 1.94, p = 0.026), cumulative all-cause mortality (hazard ratio: 1.27 per 10 ml/m(2) SVi decrease, p = 0.016), and cumulative cardiovascular mortality (hazard ratio: 1.29 per 10 ml/m(2) decrease, p = 0.04). Despite significant association in univariable analyses, low LVEF and low mean gradient were not found to be independent predictors of outcomes in multivariable analyses. Low flow but not low LVEF or low gradient is an independent predictor of early and late mortality following TAVR in high-risk patients with severe AS. SVi should be integrated in the risk stratification process of these patients.


Gene replacement method for determining conditions in which Bacillus subtilis genes are essential or dispensable for cell viability.
We describe a method for determining conditions in which Bacillus subtilis genes are essential or dispensable for cell viability. This method utilizes a chloramphenicol-resistant plasmid containing a temperature-sensitive (ts) replication origin. In this method, the target gene is first cloned into the ts vector and the recombinant plasmid is used to transform wild-type B. subtilis. The second step involves transformation of the resulting strain with a linear DNA fragment containing a second antibiotic resistance marker (tet) that disrupts the gene of interest. Selection for tetracycline resistance forces a double crossover between the chromosomal and fragment-borne copies of the gene, thereby replacing the wild-type gene in the chromosome with the disrupted allele. Cells survive even if the gene is essential by virtue of the complementing plasmid. Transformants are then grown at the non-permissive temperature for plasmid replication under various growth conditions. Isolation of chloramphenicol-sensitive colonies indicates that the gene is dispensable, whereas the inability to isolate chloramphenicol-sensitive colonies indicates that the gene is essential. The general utility of this method is demonstrated by allowing disruption of mtrA and trpE under conditions that render each gene non-essential, but not under growth conditions in which each gene is essential.


Hypothalamic norepinephrine: circadian rhythms and the control of feeding behavior.
The time of day is a decisive determinant of the effects of l-norepinephrine on feeding behavior. During the dark, direct application of l-norepinephrine to the hypothalamus of rats suppressed feeding behavior. During the light, treatment with the same dose of l-norepinephrine facilitated feeding behavior. Thus, l-norepinephrine has dual and opposite effects on feeding behavior. A hypothalamic substrate that fluctuates in a circadian rhythm could account for both actions of l-norepinephrine.


[Estrogens of vegetable origin].
In recent years, estrogens of vegetable origin have acquired some importance that justify the presentation of the available data. The compounds that have estrogenic effect when ingested as food through vegetables include isoflavones, lignines and lactones. The review comprises their chemical structure, metabolism and excretion as well as their effect on plasmatic levels of estrogens FSH, LH and SHBG as well as their activity over lipoproteins and, naturally, their action on menopause symptoms and breast cancer.


Ebola virus glycoprotein directly triggers T lymphocyte death despite of the lack of infection.
Fatal outcomes of Ebola virus (EBOV) infections are typically preceded by a 'sepsis-like' syndrome and lymphopenia despite T cells being resistant to Ebola infection. The mechanisms that lead to T lymphocytes death remain largely unknown; however, the degree of lymphopenia is highly correlative with fatalities. Here we investigated whether the addition of EBOV or its envelope glycoprotein (GP) to isolated primary human CD4+ T cells induced cell death. We observed a significant decrease in cell viability in a GP-dependent manner, which is suggestive of a direct role of GP in T cell death. Using immunoprecipitation assays and flow cytometry, we demonstrate that EBOV directly binds to CD4+ T cells through interaction of GP with TLR4. Transcriptome analysis revealed that the addition of EBOV to CD4+ T cells results in the significant upregulation of pathways associated with interferon signaling, pattern recognition receptors and intracellular activation of NFκB signaling pathway. Both transcriptome analysis and specific inhibitors allowed identification of apoptosis and necrosis as mechanisms associated with the observed T cell death following exposure to EBOV. The addition of the TLR4 inhibitor CLI-095 significantly reduced CD4+ T cell death induced by GP. EBOV stimulation of primary CD4+ T cells resulted in a significant increase in secreted TNFα; inhibition of TNFα-mediated signaling events significantly reduced T cell death while inhibitors of both necrosis and apoptosis similarly reduced EBOV-induced T cell death. Lastly, we show that stimulation with EBOV or GP augments monocyte maturation as determined by an overall increase in expression levels of markers of differentiation. Subsequently, the increased rates of cellular differentiation resulted in higher rates of infection further contributing to T cell death. These results demonstrate that GP directly subverts the host's immune response by increasing the susceptibility of monocytes to EBOV infection and triggering lymphopenia through direct and indirect mechanisms.


Activity of the multikinase inhibitor sorafenib in combination with cytarabine in acute myeloid leukemia.
Acute myeloid leukemia (AML) is a genetically heterogeneous cancer that frequently exhibits aberrant kinase signaling. We investigated a treatment strategy combining sorafenib, a multikinase inhibitor with limited single-agent activity in AML, and cytarabine, a key component of AML chemotherapy. Using 10 human AML cell lines, we determined the effects of sorafenib (10 μM) on antileukemic activity by measuring cell viability, proliferation, ERK1/2 signaling, and apoptosis. We also investigated the effects of sorafenib treatment on the accumulation of cytarabine and phosphorylated metabolites in vitro. A human equivalent dose of sorafenib in nontumor-bearing NOD-SCID-IL2Rγ(null) mice was determined by pharmacokinetic studies using high performance liquid chromatography with tandem mass spectrometric detection, and steady-state concentrations were estimated by the fit of a one-compartment pharmacokinetic model to concentration-time data. The antitumor activity of sorafenib alone (60 mg/kg) twice daily, cytarabine alone (6.25 mg/kg administered intraperitoneally), or sorafenib once or twice daily plus cytarabine was evaluated in NOD-SCID-IL2Rγ(null) mice bearing AML xenografts. Sorafenib at 10 μM inhibited cell viability, proliferation and ERK1/2 signaling, and induced apoptosis in all cell lines studied. Sorafenib also increased the cellular accumulation of cytarabine and metabolites resulting in additive to synergistic antileukemic activity. A dose of 60 mg/kg in mice produced a human equivalent sorafenib steady-state plasma exposure of 10 μM. The more dose-intensive twice-daily sorafenib plus cytarabine (n = 15) statistically significantly prolonged median survival in an AML xenograft model compared with sorafenib once daily plus cytarabine (n = 12), cytarabine alone (n = 26), or controls (n = 27) (sorafenib twice daily plus cytarabine, median survival = 46 days; sorafenib once daily plus cytarabine, median survival = 40 days; cytarabine alone, median survival = 36 days; control, median survival = 19 days; P < .001 for combination twice daily vs all other treatments listed). Sorafenib in combination with cytarabine resulted in strong anti-AML activity in vitro and in vivo. These results warrant clinical evaluation of sorafenib with cytarabine-based regimens in molecularly heterogeneous AML.


Production of monoclonal antibodies with a controlled N-glycosylation pattern in seeds of Arabidopsis thaliana.
Seed-specific expression is an appealing alternative technology for the production of recombinant proteins in transgenic plants. Whereas attractive yields of recombinant proteins have been achieved by this method, little attention has been paid to the intracellular deposition and the quality of such products. Here, we demonstrate a comparative study of two antiviral monoclonal antibodies (mAbs) (HA78 against Hepatitis A virus; 2G12 against HIV) expressed in seeds of Arabidopsis wild-type (wt) plants and glycosylation mutants lacking plant specific N-glycan residues. We demonstrate that 2G12 is produced with complex N-glycans at great uniformity in the wt as well as in the glycosylation mutant, carrying a single dominant glycosylation species, GnGnXF and GnGn, respectively. HA78 in contrast, contains additionally to complex N-glycans significant amounts of oligo-mannosidic structures, which are typical for endoplasmic reticulum (ER)-retained proteins. A detailed subcellular localization study demonstrated the deposition of both antibodies virtually exclusively in the extracellular space, illustrating their efficient secretion. In addition, although a KDEL-tagged version of 2G12 exhibited an ER-typical N-glycosylation pattern, it was surprisingly detected in protein storage vacuoles. The different antibody variants showed different levels of degradation with hardly any degradation products detectable for HA78 carrying GnGnXF glycans. Finally, we demonstrate functional integrity of the HA78 and 2G12 glycoforms using viral inhibition assays. Our data therefore demonstrate the usability of transgenic seeds for the generation of mAbs with a controlled N-glycosylation pattern, thus expanding the possibilities for the production of optimally glycosylated proteins with enhanced biological activities for the use as human therapeutics.


Early tumor dissemination, but late metastasis: insights into tumor dormancy.
The classical model of metastasis is that tumor cell dissemination occurs late in tumor development, after the primary tumor has grown, and that only then will tumor cells invade the local tissue, enter the blood or lymphatic vessels, and colonize new sites to cause metastases. However, evidence increasingly indicates that single tumor cells spread to distant sites much earlier than previously believed. In this issue of the JCI, Eyles and colleagues provide new insight into the mechanisms underlying early tumor cell dissemination, formation of metastases, and tumor immunosurveillance using transgenic mice that spontaneously develop melanomas of the uvea. The authors provide striking evidence that tumor cells start to disseminate during the initial steps of tumor development, that late appearing metastases arise from these early disseminated tumor cells, and that CD8+ T cells inhibit the growth of disseminated tumor cells, surprisingly, not by cytotoxic effects, but through cytostatic effects.


Controlled positioning of nanoparticles on graphene by noninvasive AFM lithography.
Atomic force microscopy is shown to be an excellent lithographic technique to directly deposit nanoparticles on graphene by capillary transport without any previous functionalization of neither the nanoparticles nor the graphene surface while preserving its integrity and conductivity properties. Moreover this technique allows for (sub)micrometric control on the positioning thanks to a new three-step protocol that has been designed with this aim. With this methodology the exact target coordinates are registered by scanning the tip over the predetermined area previous to its coating with the ink and deposition. As a proof-of-concept, this strategy has successfully allowed the controlled deposition of few nanoparticles on 1 μm(2) preselected sites of a graphene surface with high accuracy.


Use of microsatellite instability and immunohistochemistry testing for the identification of individuals at risk for Lynch syndrome.
It is now generally recognized that a specific subset of those patients clinically defined as having hereditary non polyposis colon cancer (HNPCC) have germline mutations in any one of several genes involved in DNA mismatch repair (MMR). This important subset of HNPCC families is now defined as having Lynch syndrome. A considerable amount of data has shown that tumors from patients with Lynch syndrome have characteristic features resulting from the underlying molecular involvement of defective MMR, that is, the presence of microsatellite instability (MSI) and the absence of MMR protein expression by immunohistochemistry (IHC). As a result, identifying patients with Lynch syndrome can now be accomplished by testing tumors for these tumor-related changes. Together, MSI and IHC are powerful tools that help identify individuals at risk for having Lynch syndrome and to distinguish these cases from HNPCC cases with other hereditary gene defects. Furthermore, IHC analysis provides valuable clues as to which MMR gene is mutated, allowing for comprehensive mutational analyses of that gene. Here, we discuss the current and historical perspectives regarding MSI and IHC analyses in tumors from sporadic colon cancer and from patients with Lynch syndrome. Given this background, we also provide a testing strategy for the identification of patients at risk for Lynch syndrome and subsequent gene testing.


Consequences of inducing intrinsic disorder in a high-affinity protein-protein interaction.
The kinetic and thermodynamic consequences of intrinsic disorder in protein-protein recognition are controversial. We address this by inducing one partner of the high-affinity colicin E3 rRNase domain-Im3 complex (K(d) ≈ 10(-12) M) to become an intrinsically disordered protein (IDP). Through a variety of biophysical measurements, we show that a single alanine mutation at Tyr507 within the hydrophobic core of the isolated colicin E3 rRNase domain causes the enzyme to become an IDP (E3 rRNase(IDP)). E3 rRNase(IDP) binds stoichiometrically to Im3 and forms a structure that is essentially identical to the wild-type complex. However, binding of E3 rRNase(IDP) to Im3 is 4 orders of magnitude weaker than that of the folded rRNase, with thermodynamic parameters reflecting the disorder-to-order transition on forming the complex. Critically, pre-steady-state kinetic analysis of the E3 rRNase(IDP)-Im3 complex demonstrates that the decrease in affinity is mostly accounted for by a drop in the electrostatically steered association rate. Our study shows that, notwithstanding the advantages intrinsic disorder brings to biological systems, this can come at severe kinetic and thermodynamic cost.


Evaluation of auto bi-level algorithm to treat pressure intolerance in obstructive sleep apnea.
The objective of this study was to evaluate whether a new auto-adjusting bi-level algorithm was comparable to a standard method for prescribing bi-level therapy. This study was a prospective randomized, double-blinded crossover evaluation of the equivalency of the auto-adjusting bi-level mode (VAuto™) compared to standard bi-level mode, using a pre-determined difference in Apnea-Hypopnea Index (AHI) of five events per hour. Data were obtained during sleep studies performed on two separate nights. Twenty-two subjects met the entry criteria and were enrolled in the study at four investigational sites in the USA. Mean AHI for the auto-adjusting bi-level mode was 6.2 ± 5.4 events per hour and for the standard bi-level mode 8.3 ± 5.8 events per hour. The AHI for the two modes were clinically equivalent. The difference in median pressure between these two modes was -3.8 cm H(2)O ± 3.6 (p = 0.0008) in favor of the auto-adjusting bi-level mode. In addition, the maximum pressure was significantly higher in the auto-adjusting bi-level mode (16.0 cm H(2)O vs. 14.1 cm H(2)O, p = 0.02). Our results demonstrated that the auto-adjusting bi-level mode normalized AHI comparable to the standard bi-level mode. The results of this study have several significant implications for the clinical management of sleep apnea. Obstructive sleep apnea (OSA) is a common condition and is associated with untoward complications. Non-compliance with positive airway pressure (PAP) limits the efficacy of the PAP therapy. The auto-adjusting bi-level mode provides a potentially reliable alternative for sleep clinicians faced with prescribing bi-level PAP for non-compliant patients. This study documents that this type of auto-adjusting device provides effective treatment of OSA.


The SENSOR Study: Protocol for a Mixed-Methods Study of Self-Management Checks to Predict Exacerbations of Pseudomonas Aeruginosa in Patients with Long-Term Respiratory Conditions.
There are an estimated three million people in the United Kingdom with chronic obstructive pulmonary disease (COPD), and the incidence of bronchiectasis is estimated at around 0.1% but is more common in COPD and severe asthma. Both COPD and bronchiectasis are characterized by exacerbations in which bacteria play a central role. Pseudomonas aeruginosa is isolated from sputum samples from 4% to 15% of adults with COPD and is more likely to be isolated from patients with severe disease. Earlier detection of exacerbations may improve morbidity and mortality by expediting treatment. Aseptika Ltd has developed a system for patients to self-monitor important physiological measurements including levels of physical activity, peak flow, forced expiratory volume (FEV1), and biomarkers for P aeruginosa in sputum. We aim to test this system in 20 participants with P aeruginosa colonization and 10 controls with Haemophilus influenzae. We plan to recruit 30 adult participants with COPD or non-CF bronchiectasis who have cultured P aeruginosa or H influenzae during an exacerbation in the last 6 months. They must produce sputum on most days and should have been stable for 4 weeks prior to entry. Daily data collected will include symptoms, health care usage, medication, weight, FEV1, physical activity level, blood pressure, oxygen saturation, and temperature. Sputum and urine samples will be provided daily. These data will be analyzed to assess predictive value in detecting upcoming exacerbations. Qualitative data will be gathered through self-administered questionnaires and semistructured interviews to gather information on participant coping and their use of the technology involved. Recruitment has been completed and results from the study should be available at the end of 2017. The SENSOR study aims to test a home-monitoring system in people with chronic airway infection and is currently underway.


Plasma-derived exosome characterization reveals a distinct microRNA signature in long duration Type 1 diabetes.
Type 1 diabetes mellitus (T1DM) results from an autoimmune attack against the insulin-producing ß cells which leads to chronic hyperglycemia. Exosomes are lipid vesicles derived from cellular multivesicular bodies that are enriched in specific miRNAs, potentially providing a disease-specific diagnostic signature. To assess the value of exosome miRNAs as biomarkers for T1DM, miRNA expression in plasma-derived exosomes was measured. Nanoparticle tracking analysis and transmission electron microscopy confirmed the presence of plasma-derived exosomes (EXOs) isolated by differential centrifugation. Total RNA extracted from plasma-derived EXOs of 12 T1DM and 12 control subjects was hybridized onto Nanostring human v2 miRNA microarray array and expression data were analyzed on nSolver analysis software. We found 7 different miRNAs (1 up-regulated and 6 down-regulated), that were differentially expressed in T1DM. The selected candidate miRNAs were validated by qRT-PCR analysis of cohorts of 24 T1DM and 24 control subjects. Most of the deregulated miRNAs are involved in progression of T1DM. These findings highlight the potential of EXOs miRNA profiling in the diagnosis as well as new insights into the molecular mechanisms involved in T1DM.


HER2 Ile655Val Single Nucleotide Polymorphism in Patients with Ovarian Cancer.
The association between HER2 Ile655Val single nucleotide polymorphism and cancer is controversial. The aim of our study was to investigate this polymorphism in patients with ovarian cancer. Genomic DNA was extracted from peripheral blood leukocytes of 107 patients and 130 healthy women. HER2 gene polymorphism was assessed by PCR-RFLP. No significant difference was observed in genotype and allele frequency between patient and control groups according to HER2 Ile655Val polymorphism. The disease stage, age, and histological type were also not associated with the polymorphism. Our data showed that HER2 Ile655Val single nucleotide polymorphism was not significantly associated with onset, histological type, age, and stage of ovarian cancer in Iranian patients.


Nitrogen-doped carbon capsules via poly(ionic liquid)-based layer-by-layer assembly.
Layer-by-layer (LbL) assembly technique is applied for the first time for the preparation of nitrogen-doped carbon capsules. This approach uses colloid silica as template and two polymeric deposition components, that is, poly(ammonium acrylate) and a poly (ionic liquid) poly(3-cyanomethyl-1-vinylimidazolium bromide), which acts as both the carbon precursor and nitrogen source. Nitrogen-doped carbon capsules are prepared successfully by polymer wrapping, subsequent carbonization and template removal. The as-synthesized carbon capsules contain ≈7 wt% of nitrogen and have a structured specific surface area of 423 m(2) g(-1). Their application as supercapacitor has been briefly introduced. This work proves that LbL assembly methodology is available for preparing carbon structures of complex morphology.


CO2 excretion and postcapillary pH equilibration in blood-perfused turtle lungs
Turtles possess a significant postcapillary CO2 partial pressure (PCO2) disequilibrium between arterial blood and alveolar gas. There are several possible explanations for this blood disequilibrium including a slow rate of erythrocyte physiological anion shift (Cl-/HCO3- exchange) or inaccessibility of plasma HCO3- to red blood cell or pulmonary carbonic anhydrase. The present study characterized the contribution of erythrocyte anion exchange and pulmonary and erythrocyte carbonic anhydrase to CO2 excretion and, hence, to postcapillary CO2-HCO3--H+ equilibration in blood-perfused turtle (Pseudemys scripta) lungs. Turtle lungs perfused in situ with red cell suspensions containing inhibitors of erythrocyte anion exchange and/or pulmonary and red cell carbonic anhydrase produced significant postcapillary blood PCO2 and pH disequilibria, while no disequilibria were measured when lungs were perfused with control red cell suspensions. Erythrocyte anion exchange and pulmonary intravascular carbonic anhydrase contributed 11 % and 9 %, respectively, to CO2 excretion during single-pass perfusion, whereas red cell and pulmonary carbonic anhydrase contributed 32 % to the measured CO2 excretion. The lack of a measurable PCO2 disequilibrium during perfusion with control erythrocyte suspensions in this study suggests that alternative mechanisms may be responsible for the arterial-lung PCO2 disequilibrium measured during breathing or diving episodes in turtles.


Productivity and Welfare Effects of Nigeria's e-Voucher-Based Input Subsidy Program.
In an attempt to go beyond the so called "smart" subsidies, Nigeria has embarked on a potentially innovative mobile phone-based input subsidy program that provides fertilizer and improved seed subsidies through electronic vouchers. In this article, we examined the productivity and welfare effects of the program using household-level data from rural Nigeria. The article employed instrumental variable regression approach to control for the potential endogeneity of the input subsidy program. Our results suggest that the program is effective in improving productivity and welfare outcomes of beneficiary smallholders. The size of the estimated effects suggests a large improvement in productivity and welfare outcomes. Moreover, the distributional effects of the program suggest no heterogeneity effects based on gender and farm land size. These results are robust to using alternative measurements of program participation. The benefit-cost ratio of 1.11 suggests that the program is marginally cost-effective. Overall, our results suggest that while improving average productivity is a good outcome for improving food security, improving the distributional outcome of the program by targeting the most disadvantaged groups would maximize the program's contribution to food security and poverty reduction.


Facilitatory transmitter causes a selective and prolonged increase in adenosine 3':5'-monophosphate in sensory neurons mediating the gill and siphon withdrawal reflex in Aplysia.
Sensitization of the gill and siphon withdrawal reflex in the marine mollusc, Aplysia california, is a simple form of learning Underlying this behavioral changes is a cascade of biochemical events. The first step in this cascade is postulated to be an increase in cAMP within the sensory neurons of the abdominal ganglion. We have developed a labeling protocol with 32Pi which permits us to measure the synthesis of cAMP within a single sensory neurons. Application of serotonin for 5 min was found to triple the content of [32P]cAMP in sensory neurons. The response is specific to serotonin: dopamine, a transmitter that does not produce sensitization, did not increase cAMP. Physiological stimulation of facilitator neurons also resulted in a 3.5-fold increase of cAMP in sensory neurons but not in other cells of the ganglion. We studied the time course of the increase of cAMP in sensory cells stimulated with serotonin and found that it parallels closely the time course of the short term form of presynaptic facilitation. We also have determined the effects of transmitters on the synthesis of cAMP in other identified neurons of the ganglion. The bag cells responded specifically to serotonin. R15, which has been shown to be hyperpolarized both the serotonin and by dopamine, responded to both transmitters by increased synthesis synthesis of cAMP. Thus, the dopamine- and serotonin-sensitive cyclase can be localized to both the same and different cells. Other cells did not respond to serotonin or to dopamine, indicating that a transmitter-sensitive adenylate cyclase is a specific property and is not present in all neurons.


Risk factor analysis and management strategies of operating room-related infections after coronary artery bypass grafting.
To investigate and analyze the risk factors of operating room-related infections after coronary artery bypass grafting (CABG), to propose corresponding infection control management strategies, and to verify and evaluate the effectiveness of the strategy implementation. Patients with coronary heart disease who underwent CABG in a hospital from January 2015 to December 2016 were selected for inclusion in this study. The following patient variables were documented: demographics, history of underlying diseases (hypertension and diabetes), preoperative American Society of Anesthesiologists (ASA) score, skin preparation method, perioperative use of antibiotics, operation duration, intraoperative hypothermia, intraoperative blood loss, intraoperative blood transfusion, presence of visitors in the operating room, consecutive use of the same operating room, qualification of the surgeon, and surgical site infection. The infection diagnosis was confirmed using the Diagnostic Criteria for Nosocomial Infections (Trial) issued by the Ministry of Health in 2001. Univariate chi-square tests and multivariate logistic regression analysis were used to analyze the risk factors for infection in patients undergoing CABG, and infection control management strategies were proposed. The proposed infection control strategies were applied to patients who underwent CABG in the hospital in 2017. The effectiveness of the strategy implementation was evaluated. We analyzed in 139 patients (417 coronary artery bypass grafts from January 2015 to December 2016) and identified 4 surgical site infections. The incidence of infection was 2.88%. According to the univariate analysis, the following factors were related to the high incidence of surgical site infections: advanced age, history of underlying diseases (hypertension and diabetes), obesity, ASA score (class II or above), conventional skin preparation method, irrational perioperative antibiotic use, operation duration >4 hours, presence of visitors in the operating room, and consecutive use of the same operating room (P<0.05 for all variables). Multivariate logistic regression analysis showed that advanced age, history of underlying diseases (hypertension and diabetes), irrational perioperative antibiotic use, operation duration >4 hours, and presence of visitors in the operating room were high risk factors for surgical site infection after CABG. From January 2017 to December 2017, after applying the proposed infection control measures to patients undergoing CABG, the surgical site infection rate was 1.13% (3/266), which was significantly different from that of the previous period (P<0.05). The following are high risk factors for surgical site infection after CABG: advanced age, history of underlying diseases (hypertension and diabetes), irrational antibiotic use during the perioperative period, operation duration >4 hours, and presence of visitors in the operating room. Medical providers should fully understand these risk factors and optimize the adjustable factors during the perioperative period to minimize the incidence of infections after CABG.


Venous gangrene of the hand.
Thrombosis of the subclavian and axillary vein is a rare entity. Venous gangrene of the upper extremity is even more rare. A case of a 71-year-old man with poorly differentiated squamous cell carcinoma who developed venous gangrene of the right hand has been presented.


Functional imaging of human crossmodal identification and object recognition.
The perception of objects is a cognitive function of prime importance. In everyday life, object perception benefits from the coordinated interplay of vision, audition, and touch. The different sensory modalities provide both complementary and redundant information about objects, which may improve recognition speed and accuracy in many circumstances. We review crossmodal studies of object recognition in humans that mainly employed functional magnetic resonance imaging (fMRI). These studies show that visual, tactile, and auditory information about objects can activate cortical association areas that were once believed to be modality-specific. Processing converges either in multisensory zones or via direct crossmodal interaction of modality-specific cortices without relay through multisensory regions. We integrate these findings with existing theories about semantic processing and propose a general mechanism for crossmodal object recognition: The recruitment and location of multisensory convergence zones varies depending on the information content and the dominant modality.


Extraction of motion information from peripheral processes.
This paper is mainly concerned with low-level processes in machine perception of motion. A motion analysis system should exploit information contained in ``early warning signals'' during the intensity based peripheral phase of motion perception. We show that intensity based difference pictures contain motion information about objects in a dynamic scene, and present methods for the extraction of motion information in the peripheral phase. Some experiments with laboratory generated and real world scenes demonstrate the potential of the technique.


Effect of Statins on Patients and Graft Survival in Kidney Transplant Recipients: a Survival Meta-analysis.
Modifying cardiovascular risk factors is very important for the patients after kidney transplantation. Statins are a potentially beneficial intervention for kidney transplant patients, and the effect of statins on cardiovascular outcomes in patients with chronic kidney disease varies according to the stages. This systematic review summarizes the potential beneficial effects of statins on kidney allograft outcome. A systematic review and meta-analysis was conducted by literature search using the PubMed, Science Direct, Scopus, ISI Web of Knowledge, and Google Scholar. Articles published after 2000 reporting hazard ratios (HRs) for the effect of statins on patient and graft survival of kidney transplant patients were included. Seven articles were included in the systematic review, involving 1870 kidney transplant patients that received statins and 3339 kidney transplant patients as the control group. Statins has no protective effect on transplant rejection, graft survival or patient survival after kidney transplantation. The effect of statins on graft survival, however, was significant when adjusted for factors such as age, sex, and serum creatinine level (HR, 0.80; 95% CI, 0.69 to 0.92; P = .003). Similarly, patient survival was significantly better with statin use (adjusted HR, 0.75; 95% CI, 0.63 to 0.88; P = .003). The present study may provide valuable information on the potential beneficial effects of statins in kidney allograft recipients. Meta-analysis showed that the use of statins correlated independently with improved patient and graft survival after kidney transplantation.


Influence of Different Cooking Methods on Fillet Steak Physicochemical Characteristics.
Meat is a source of protein widely consumed by the population in many countries due mainly to the nutritional aspects, sensory characteristics, and cultural aspects. The meat cooking preparation can promote significant changes in the meat's chemical composition and physical characteristics. Such transformations can impact both the acceptance of the product and consumers' health. Due to the different thermal processes altering the physical-chemical characteristics of meat, the present study aimed to evaluate the physicochemical characteristics of fillet steak submitted to different cooking methods: pan-frying with and without oil and air fryer. We performed the analysis to evaluate the physicochemical characteristics considering moisture, lipid, protein, ash, sodium, and potassium content, cooking loss index and colorimetry in three degrees of doneness of the meat, rare, medium, and well done. The fillet steak prepared by pan-frying with oil lost higher moisture and weight than the other samples. The air fryer method presented the highest moisture content. There was a significant difference in lipid content in which the pan-frying with oil fillet steak showed the highest amount of lipids. The pan-frying with oil steak fillet also presented more changes in the colorimetric parameters evaluated compared to the other samples. The pan-frying with oil cooking method promoted more pronounced changes in the steak fillet, and the cooking air fryer, the changes in meat quality are less pronounced. Therefore, the air fryer can be considered a good alternative for cooking meat.


Silurana Chromosomal Evolution: A New Piece to the Puzzle.
The African clawed frogs of the subgenus Silurana comprise both diploid and tetraploid species. The root of the polyploidization event leading to the extant Xenopus calcaratus, X. mellotropicalis, and X. epitropicalis is not fully understood so far. In X. mellotropicalis, we previously proposed 2 evolutionary scenarios encompassing complete (scenario A) or incomplete (scenario B) translocation of a heterochromatic block from chromosome 9 to 2 in a diploid ancestor. To resolve this puzzle, we performed FISH coupled with tyramide signal amplification (FISH-TSA) using 5 X. tropicalis and X. mellotropicalis single copy gene probes (gyg2, cept1, fn1, ndufs1, and sf3b1) reflecting borders of the heterochromatic blocks in X. tropicalis chromosome 9 (XTR 9) and X. mellotropicalis chromosome 9b (XME 9b) and XME 2a. cDNA sequencing recognized both homoeologous genes in X. mellotropicalis. Comparison of gene physical mapping between X. tropicalis and X. mellotropicalis clearly confirmed complete rather than incomplete translocation t(9;2) of the heterochromatic block in the diploid predecessor and thus favored scenario A regarding the formation of an ancestral allotetraploid karyotype.


Temporal distinctions in the synthesis and accumulation of proteins by oocytes and cumulus cells during maturation in vitro of bovine oocytes.
Successful in vitro maturation (IVM) of bovine oocytes requires continual and/or episodic protein synthesis by cumulus-oocyte complexes. This study was designed to expose time-dependent changes in protein synthesis and accumulation by bovine oocytes and cumulus cells during routine IVM. Silver staining after sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) demonstrated little if any change in protein species present or their relative contents in oocytes during IVM; one notable exception, however, was the gradual accumulation of a 39-kDa polypeptide between 4-24 hr of maturation culture. Cumulus cells, on the other hand, exhibited no qualitative differences during the period examined, but total protein content did increase during IVM. Metabolic labeling with [35S]-methionine, however, demonstrated changes in protein synthesis, both quantitative and qualitative, by both cell types. Oocytes exhibited a steady or slightly increasing rate of synthesis during the first 12 hr of IVM; thereafter, protein synthesis declined to about 10% of the initial rate by 40 hr in culture. In contrast, protein synthesis in cumulus cells was relatively constant during the first 24 hr. Of greater interest is the demonstration that the synthesis of at least seven oocyte-specific and five cumulus-specific proteins was stage-dependent during maturation. These results indicate that maturation of bovine oocytes is associated with the synthesis of several distinct and temporally expressed proteins which may play roles in the highly ordered sequence of events that culminates in oocyte maturation.


Derivation and External Validation of Machine Learning-Based Model for Detection of Pancreatic Cancer.
There is currently no widely accepted approach to screening for pancreatic cancer (PC). We aimed to develop and validate a risk prediction model for pancreatic ductal adenocarcinoma (PDAC), the most common form of PC, across 2 health systems using electronic health records. This retrospective cohort study consisted of patients aged 50-84 years having at least 1 clinic-based visit over a 10-year study period at Kaiser Permanente Southern California (model training, internal validation) and the Veterans Affairs (VA, external testing). Random survival forests models were built to identify the most relevant predictors from >500 variables and to predict risk of PDAC within 18 months of cohort entry. The Kaiser Permanente Southern California cohort consisted of 1.8 million patients (mean age 61.6) with 1,792 PDAC cases. The 18-month incidence rate of PDAC was 0.77 (95% confidence interval 0.73-0.80)/1,000 person-years. The final main model contained age, abdominal pain, weight change, HbA1c, and alanine transaminase change (c-index: mean = 0.77, SD = 0.02; calibration test: P value 0.4, SD 0.3). The final early detection model comprised the same features as those selected by the main model except for abdominal pain (c-index: 0.77 and SD 0.4; calibration test: P value 0.3 and SD 0.3). The VA testing cohort consisted of 2.7 million patients (mean age 66.1) with an 18-month incidence rate of 1.27 (1.23-1.30)/1,000 person-years. The recalibrated main and early detection models based on VA testing data sets achieved a mean c-index of 0.71 (SD 0.002) and 0.68 (SD 0.003), respectively. Using widely available parameters in electronic health records, we developed and externally validated parsimonious machine learning-based models for detection of PC. These models may be suitable for real-time clinical application.


Fully Customizable, Low-Cost, Multi-Contact Nerve Cuffs for Spatially Selective Neuromodulation.
Selective neuromodulation of peripheral nerves is an emerging treatment for neurological diseases that are resistant to traditional drug therapy. While nerve cuffs with multichannel stimulation can be made by many varied methods, they usually require specialized microfabrication or additive manufacturing equipment. A truly low-cost and effective method of creating a custom cuff has not been accessible to researchers to prototype new methodologies and therapies in acute studies. Here, we present an inexpensive, highly repeatable method to create multi-contact nerve cuffs that require a simple postproduction PEDOT:PSS coating to improve the tissue/electrode interface. We demonstrate spatially selective neuromodulation with the proposed cuff design on the rat sciatic by preferentially activating the tibialis anterior (TA) and the lateral gastrocnemius (LG) in longitudinal and transverse stimulation patterns. This demonstrates that the proposed cuff fabrication method was not only effective for selective neuromodulation, but it is also significantly lower in cost, fully-customizable, and easily manufactured for future selective neuromodulation studies.


A big gene linked to small eyes encodes multiple Mitf isoforms: many promoters make light work.
Among more than 80 different loci related to mouse coat color, microphthalmia-associated transcription factor (Mitf) encoded at the mouse microphthalmia locus is one of the most exciting molecules that regulates the development and survival of many cell types, including melanocyte, retinal pigment epithelium (RPE), and mast cells. Mitf and its human homolog MITF consist of at least three isoforms, referred to as Mitf-A/MITF-A, the heart-type Mitf-H/MITF-H, and the melanocyte lineage-specific Mitf-M/MITF-M, respectively. These isoforms differ in the amino-terminal domains but share a transactivation domain and a basic helix-loop-helix and leucine-zipper structure that is required for DNA binding and dimerization. MITF-M is exclusively expressed in melanocytes and melanoma cells, but not in other cell types, including RPE cells. In contrast, MITF-A mRNA is widely expressed in many cell types. These three isoform mRNAs are possibly generated by differential usage of the gene promoters and by alternative splicing. We predict that the entire MITF gene spans about 200 kb of DNA. Like MITF-M, MITF-A is able to activate the two melanogenesis gene promoters, tyrosinase and tyrosinase-related protein 1. These results suggest that melanogenesis may be regulated by different MITF isoforms in melanocyte and RPE. Possible implications of the multiplicity in Mitf/MITF isoforms are discussed.


Targeting HSP 90 induces apoptosis and inhibits critical survival and proliferation pathways in multiple myeloma.
The second most commonly diagnosed hematologic malignancy, multiple myeloma, affects predominantly older patients (>60s) and is characterized by paraprotein in the serum or urine. Clinical manifestations include anemia, hypercalcaemia, progressive renal impairment, and osteolytic bone destruction. Despite promising new therapies, multiple myeloma eventually relapses in almost all patients. HSP are ubiquitous and highly conserved in prokaryotes and eukaryote organisms. Exposure to a broad range of stimuli results in increased HSP protein expression. These chaperone proteins are involved in protein transportation, prevent protein aggregation, and ensure correct folding of nascent and stress-accumulated misfolded proteins. In cancer, HSP expression is dysregulated, resulting in elevated expression, which promotes cancer by preventing programmed cell death and supporting autonomous cells growth, ultimately leading to resistance to heat, chemotherapy, and other stresses. Client proteins of HSP90 such as AKT, p53, MEK, STAT3, and Bcr-Abl are vital in tumor progression, including multiple myeloma, and their maturation and stability is dependent on HSP90. Therefore, inhibition of HSP90 via a HSP90 inhibitor (such as NVP-HSP990) should interrupt multiple signaling pathways essential for oncogenesis and growth in multiple myeloma. Our study showed that NVP-HSP990 triggered apoptosis in a panel of human multiple myeloma cells, induced cell-cycle arrest, PARP cleavage, downregulation of client proteins, the inability to reactivate phospho-STAT3 following exogenous IL-6 stimulation, and it synergized with azacytidine and bortezomib in cell lines and primary multiple myeloma samples. The mechanism of HSP90 inhibition in multiple myeloma warrants further evaluation.


Current status of hypertensive disease treatment: results from the Evaluation and Interventions for Systolic Blood pressure Elevation: Regional and Global (EISBERG) project.
Conclusive evidence has shown the benefits of antihypertensive treatment The systematic review of end-point trials has indicated that for a reduction of 10-12 mmHg in systolic blood pressure or 5-6 mmHg in diastolic blood pressure, the incidence of stroke is reduced by 38% and ischaemic heart disease by 16%. Despite this, studies on the effectiveness of treatment - carried out both in specialist hypertension clinics and in the community - have all shown that patients receiving treatment for hypertension continue to be at increased risk of cardiovascular disease. Failure to control blood pressure to recommended guidelines contributes substantially to this excess risk. Some reasons for this failure are outlined below. Socioeconomic factors and lack of professional and patient compliance appear to be of considerable importance in the failure to control blood pressure. The Evaluation and Interventions for Systolic Blood pressure Elevation: Regional and Global (EISBERG) project investigated both the quantitative and qualitative aspects of the current treatment of hypertension internationally. The quantitative study indicated major shortcomings in blood pressure control, and in particular, poor control of elevated systolic pressure, which accounted for 90% of treatment failures. The qualitative research was based upon semi-structured interviews with professionals, patients and their care-givers. These interviews indicated that there were misconceptions among physicians regarding the relative importance of systolic and diastolic blood pressure, the need for more aggressive treatment in the elderly, and the need for improved physician-patient interactions. If the therapeutic advances emerging from medical research are to be translated into clinical benefits, both the understanding and communication of the need for effective blood pressure control must be improved.


The Association with Dietary Patterns and Risk of Anemia in Japanese Elderly.
Anemia is a risk factor for frailty. Although various factors can reduce the risk of anemia, information on dietary contributions is limited. This study aimed to evaluate the association between anemia and eating patterns in Japanese elderly. Our study included 6,864 elderly individuals, aged ≥65 y, whose data were obtained from the 2010-2015 National Health and Nutritional Survey, Japan. Anemia was defined as whole blood hemoglobin concentrations <13 g/dL in men, and <12 g/dL in women. We classified eating patterns into 33 food groups, using food items obtained from dietary records, and identified three dietary patterns using principal component analysis method. Participants were assigned and divided into quartiles according to pattern-specific factor scores. We calculated adjusted odds ratios (ORs) for anemia using multivariate logistic regression, and assigned the first quartile (minimum) as the reference. The overall prevalence of anemia was 17.1%. The meats and vegetables eating pattern was characterized by red meat and other vegetables, the Japanese eating pattern by rice and salted or pickled vegetables, and the fruits and vegetables eating pattern by fruits and green-yellow vegetables. Participants in the highest meats and vegetables eating pattern quartile had a 20% lower risk of anemia than those in the lowest quartile (OR 0.81; 95% confidence interval (CI) 0.66-1.00); the Japanese eating pattern participants had a 20% higher risk of anemia (OR 1.28; 95% CI 1.06-1.53). The fruits and vegetables eating pattern participants had no significant change in their risk of anemia. This study may indicate that consuming a high red meat diet prevents anemia in elderly Japanese individuals.


Synthesis, Characterization, and Pickering Emulsifier Performance of Anisotropic Cross-Linked Block Copolymer Worms: Effect of Aspect Ratio on Emulsion Stability in the Presence of Surfactant.
Reversible addition-fragmentation chain transfer (RAFT) aqueous dispersion polymerization is used to prepare epoxy-functional PGMA-P(HPMA- stat-GlyMA) diblock copolymer worms, where GMA, HPMA, and GlyMA denote glycerol monomethacrylate, 2-hydroxypropyl methacrylate, and glycidyl methacrylate, respectively. The epoxy groups on the GlyMA residues were ring-opened using 3-aminopropyltriethoxysilane (APTES) in order to cross-link the worm cores via a series of hydrolysis-condensation reactions. Importantly, the worm aspect ratio can be adjusted depending on the precise conditions selected for covalent stabilization. Relatively long cross-linked worms are obtained by reaction with APTES at 20 °C, whereas much shorter worms with essentially the same copolymer composition are formed by cooling the linear worms from 20 to 4 °C prior to APTES addition. Small-angle X-ray scattering (SAXS) studies confirmed that the mean aspect ratio for the long worms is approximately eight times greater than that for the short worms. Aqueous electrophoresis studies indicated that both types of cross-linked worms acquired weak cationic surface charge at low pH as a result of protonation of APTES-derived secondary amine groups within the nanoparticle cores. These cross-linked worms were evaluated as emulsifiers for the stabilization of n-dodecane-in-water emulsions via high-shear homogenization at 20 °C and pH 8. Increasing the copolymer concentration led to a reduction in mean droplet diameter, indicating that APTES cross-linking was sufficient to allow the nanoparticles to adsorb intact at the oil/water interface and hence produce genuine Pickering emulsions, rather than undergo in situ dissociation to form surface-active diblock copolymer chains. In surfactant challenge studies, the relatively long worms required a thirty-fold higher concentration of a nonionic surfactant (Tween 80) to be displaced from the n-dodecane-water interface compared to the short worms. This suggests that the former nanoparticles are much more strongly adsorbed than the latter, indicating that significantly greater Pickering emulsion stability can be achieved by using highly anisotropic worms. In contrast, colloidosomes prepared by reacting the hydroxyl-functional adsorbed worms with an oil-soluble polymeric diisocyanate remained intact when exposed to high concentrations of Tween 80.


Epigenetic mechanisms of age-dependent KIR2DL4 expression in T cells.
Killer Ig-like receptor (KIR) expression is mostly restricted to NK cells controlling their activation. With increasing age, KIRs are expressed on T cells and contribute to age-related diseases. We examined epigenetic mechanisms that determine the competency of T cells to transcribe KIR2DL4. Compared with Jurkat cells and CD4(+)CD28(+) T cells from young individuals, DNA methyltransferase (DNMT) inhibition was strikingly more effective in T cells from elderly adults and the CD4(+)CD28(-) T cell line HUT78 to induce KIR2DL4 transcription. In these susceptible cells, the KIR2DL4 promoter was partially demethylated, and dimethylated H3-Lys 4 was increased, and all other histone modifications were characteristic for an inactive promoter. In comparison, NK cells had a fully demethylated KIR2DL4 promoter and the full spectrum of histone modifications indicative of active transcription with H3 and H4 acetylation, di- and trimethylated H3-Lys 4, and reduced, dimethylated H3-Lys 9. These results suggest that an increased competency of T cells to express KIR2DL4 with aging is conferred by a selective increase in H3-Lys 4 dimethylation and limited DNA demethylation. The partially accessible promoter is sensitive to DNMT inhibition, which is sufficient to induce full transcription without further histone acetylation and methylation.


Incorporation of Biochar to Improve Mechanical, Thermal and Electrical Properties of Polymer Composites.
The strive for utilization of green fillers in polymer composite has increased focus on application of natural biomass-based fillers. Biochar has garnered a lot of attention as a filler material and has the potential to replace conventionally used inorganic mineral fillers. Biochar is a carbon rich product obtained from thermochemical conversion of biomass in nitrogen environment. In this review, current studies dealing with incorporation of biochar in polymer matrices as a reinforcement and conductive filler were addressed. Each study mentioned here is nuanced, while addressing the same goal of utilization of biochar as a filler. In this review paper, an in-depth analysis of biochar and its structure is presented. The paper explored the various methods employed in fabrication of the biocomposites. A thorough review on the effect of addition of biochar on the overall composite properties showed immense promise in improving the overall composite properties. An analysis of the possible knowledge gaps was also done, and improvements were suggested. Through this study we tried to present the status of application of biochar as a filler material and its potential future applications.


The ethics of care: role obligations and moderate partiality in health care.
This article contends that an ethics of care has a particular moral ontology that makes it suitable to argue for the normative significance of relational responsibilities within professional health care. This ontology is relational. It means that moral choices always have to account for the web of relationships, the relational networks and responsibilities that are an essential part of particular moral circumstances. Given this ontology, the article investigates the conditions for health care professionals to be partial and to act on the basis of particular responsibilities to their patients. We will argue that priorities could be partial in three ways: first, because there may be exceptional circumstances that allow for giving priority to one patient over another; second, because the integrity of the patient and a health care worker may be connected in special ways; and, finally, even if impartiality is essential, the institutional basis of health care must always give ample space for an ethically qualified individual and personal care for patients. Even if difficult priorities may be necessary, the conditions of institutional health care should always seek to create the prerequisites for nurses and doctors to administer proper care.


Thrombomodulin with the Asp468Tyr mutation is expressed on the cell surface with normal cofactor activity for protein C activation.
Thrombomodulin (TM) is an endothelial cell glycoprotein that acts as an anticoagulant. Mutation in the TM gene is a potential risk factor for thrombosis. The first TM mutation identified was a heterozygous substitution of T for G at nucleotide position 1456, which predicted Asp468 with Tyr in a Ser/Thr-rich domain. To evaluate the reported TM gene mutation as a possible cause of thrombosis, we transiently tranfected a vector for TM gene carrying the mutation to mammalian COS7 cells. TM antigen levels in lysates of cells transfected with variant TM were comparable to those in preparations of normal TM. The TM cofactor activity for protein C (PC) activation on the variant TM-expressing cells was similar to that of the control. The Michaelis constant Km and Vmax. of variant TM for PC activation were shown to be similar compared to those of normal TM. The affinity of each TM for thrombin in PC activation was also similar. We obtained several stable cell lines expressing normal and variant TM. Lysate of the cell lines with normal and variant TM genes had a similar expression level of TM antigen. Pulse-chase analysis showed that normal and variant TM were glycosylated and resistant to endoglycosidase H, indicating that the variant TM was expressed on the cell surface in a mature form. Variant TM protein is apparently expressed on the cell surface with normal cofactor activity for PC activation. It is unlikely that the TM variant directly causes thrombosis by mechanism of reduced expression or impaired cofactor activity for PC activation, which comprises a major anticoagulant activity of TM.


Association between posttraumatic stress and depressive symptoms and functional outcomes in adolescents followed up longitudinally after injury hospitalization.
To assess the association between early posttraumatic stress disorder (PTSD) and depressive symptoms and functional and quality-of-life outcomes among injured youth. Prospective cohort study. Combined pediatric-adult level I trauma center. Randomly sampled adolescent injury survivors aged 12 to 18 years (N = 108) were recruited from surgical inpatient units. Posttraumatic stress disorder and depressive symptom levels in the days and weeks immediately following injury. We also collected relevant adolescent demographic, injury, and clinical characteristics. Multiple domains of adolescent functional impairment were assessed with the 87-item Child Health Questionnaire (CHQ-87) at 2, 5, and 12 months after injury. The investigation attained greater than 80% adolescent follow-up at each assessment after injury. Mixed-model regression was used to assess the association between baseline levels of PTSD and depressive symptoms and subsequent functional outcomes longitudinally. High baseline PTSD symptom levels were associated with significant impairments in CHQ-87 Role/Social Behavioral, Role/Social Physical, Bodily Pain, General Behavior, Mental Health, and General Health Perceptions subscales. High baseline depressive symptoms were associated with significant impairments in CHQ-87 Physical Function, Role/Social Emotional, Bodily Pain, Mental Health, Self-esteem, and Family Cohesion subscales. Early PTSD and depressive symptoms are associated with a broad spectrum of adolescent functional impairment during the year after physical injury. Coordinated investigative and policy efforts that refine mental health screening and intervention procedures have the potential to improve the functioning and well-being of injured youth treated in the acute care medical setting.


The Longitudinal Influence of Coparenting Conflict on Parental Negativity and Adolescent Maladjustment.
This study addresses two limitations of coparenting research: first, little research on coparenting has been conducted with families of adolescents, and second, there is little understanding regarding the child and family contexts in which coparenting is most salient. The longitudinal relation of coparenting conflict to parenting and adolescent maladjustment across 3 years was investigated among 516 2-parent, 2-adolescent families. Coparenting conflict predicted as much or more unique variance in parenting and adolescent adjustment as did marital quality and disagreement together. After controlling for stability, coparenting conflict predicted mothers' and fathers' negativity and adolescent antisocial behavior (but not depression). Importantly, the influence of coparenting conflict in all cases varied as a function of family type, adolescent gender, or initial level of antisocial behavior, or all. The implications of these results for family processes in different relational and developmental contexts are discussed.