Retinopathy of prematurity: A comprehensive risk analysis for prevention and prediction of disease.
Retinopathy of prematurity (ROP) is a blinding morbidity of preterm infants. Our current screening criteria have remained unchanged since their inception and lack the ability to identify those at greatest risk. We sought to comprehensively analyze numerous proposed maternal, infant, and environmental ROP risk variables in a robustly phenotyped population using logistic regression to determine the most predictive model for ROP development and severity. We further sought to determine the statistical interaction between significant ROP risk variables, which has not previously been done in the field of ROP. We hypothesize that our comprehensive analysis will allow for better identification of risk variables that independently correlate with ROP disease. Going forward, this may allow for improved infant risk stratification along a time continuum from prenatal to postnatal development, making prevention more feasible. We performed a retrospective cohort analysis of preterm infants referred for ROP screening in one neonatal intensive care unit from 2010-2015. The primary outcome measure was presence of ROP. Secondary outcome measures were ROP requiring treatment and severe ROP not clearly meeting current treatment criteria. Univariate, stepwise regression and statistical interaction analyses of 57 proposed ROP risk variables was performed to identify variables which were significantly associated with each outcome measure. We identified 457 infants meeting our inclusion criteria. Within this cohort, numerous factors showed a significant individual association with our ROP outcome measures; however, stepwise regression analysis found the most predictive model for overall ROP risk included estimated gestational age, birth weight, the need for any surgery, and maternal magnesium prophylaxis. The corresponding Area Under the Curve (AUC) for this model was 0.8641, while the traditional model of gestational age and birth weight predicted ROP disease less well with an AUC of 0.8489. Development of severe ROP was best predicted by estimated gestational age (week), the need for any surgery and increased probability of death or moderate-severe BPD at 7 days. Finally, the model most predictive for type 1 ROP included estimated gestational age (week) and the presence of severe chronic lung disease. No significant statistical interaction was found between variables. Our work is unique as we report comprehensive analysis of the greatest number of proposed ROP risk variables to date in a robustly phenotyped population. We describe novel risk models for our ROP outcome measures and demonstrate independence of these variables using statistical modeling not previously applied to ROP. This may better allow for individual infant risk stratification and importantly mitigation of future risk.


Dectin-1 Y238X polymorphism associates with susceptibility to invasive aspergillosis in hematopoietic transplantation through impairment of both recipient- and donor-dependent mechanisms of antifungal immunity.
The C-type lectin receptor Dectin-1 plays a pivotal role in antifungal immunity. In this study, the recently characterized human DECTIN1 Y238X early stop codon polymorphism leading to diminished Dectin-1 receptor activity was studied in relation to invasive aspergillosis susceptibility and severity in patients receiving hematopoietic stem cell transplantation. We found that the presence of the DECTIN1 Y238X polymorphism in either donors or recipients of hematopoietic stem cell transplantation increased susceptibility to aspergillosis, with the risk being highest when the polymorphism was present simultaneously in both donors and recipients (adjusted hazard ratio = 3.9; P = .005). Functionally, the Y238X polymorphism impaired the production of interferon-γ and interleukin-10 (IL-10), in addition to IL-1β, IL-6, and IL-17A, by human peripheral mononuclear cells and Dectin-1 on human epithelial cells contributed to fungal recognition. Mechanistically, studies on preclinical models of infection in intact or bone marrow-transplanted Dectin-1 knockout mice revealed that protection from infection requires a distinct, yet complementary, role of both donor and recipient Dectin-1. This study discloses Dectin-1 deficiency as a novel susceptibility factor for aspergillosis in high-risk patients and identifies a previously unsuspected role for Dectin-1 in antifungal immunity that is the ability to control both resistance and tolerance to the fungus contingent on hematopoietic/nonhematopoietic compartmentalization.


[A prospective study of the development of nocturnal sleep patterns in infants].
To investigate the development of nocturnal sleep pattern in infants. Fifty healthy full-term newborns born in Chongqing Maternal and Child Health Care Hospital were chosen for a prospective longitudinal study. A non-invasive sleep monitor, Actiwatch, was used to monitor infants' 12 sleep parameters on the 10th day, 28th day, the first Tuesday at the 2nd, 3rd, 4th, 5th, 6th, 9th and 12th month after birth, each monitoring time lasting 60 hours. All sleep parameters were analyzed by two-level mixed effect model. Twenty-two boys and 25 girls completed the whole follow-up study. From birth to the 12th month after birth, the nocturnal sleep onset latency (NSOL) decreased by about 48% at 3 months of age and by 83% at 6 months of age. The nocturnal sleep efficiency (NSE%) increased from 66% to 87%, the nocturnal total sleep time (NTST) increased from 416 minutes to 517 minutes, and the longest nocturnal continuous sleeping time (L-NCST) increased from 197 minutes to 327 minutes. NSE%, NTST and L-NCST increased with age (P<0.01). The 3rd to 12th month ratios of NSE%, NTST and L-NCST were 86%, 84% and 72%, respectively, and the 6th to 12th month ratios of those were 97%, 91% and 94%, respectively. The nocturnal total wake time (NTWT) and longest nocturnal continuous waking times (L-NCWT) decreased with age (P<0.01). The decline speeds in the first half year were 5-6 times of those in the second half year after birth (P<0.05). NTST, nocturnal continuous sleeping ability and NSE% in boys were lower than those in girls (P<0.05). Infantile nocturnal sleep patterns develop rapidly during the first 6 months, especially within the first 3 months after birth. Partial infantile sleep parameters are related to gender.


Talking effect and "white coat" effect in hypertensive patients: physical effort or emotional content?
Talking has been shown to increase blood pressure instantaneously in hypertensive patients and to contribute to the white coat effect. The effects of talking were compared with those of counting aloud in 64 patients with essential hypertension who were randomly assigned to a period of stress talking and a period of counting aloud (active periods), alternating with three periods of silence (control). The same monitor was used for office measurements and 24-hour ambulatory blood pressure analysis. Systolic/diastolic blood pressures increased significantly more during talking (163/110 mmHg) than during counting aloud (152/102 mmHg, both p < .0001) in both treated and untreated patients and in sustained and clinical hypertension. Talking had a residual effect on systolic blood pressure that lasted 5.8 +/- 0.1 minutes. The emotional content seemed to be the only cause of the talking effect. Its instantaneous and residual effects on blood pressure and heart rate should be considered when measuring these variables.


Recovery from respiratory failure after decompression laparotomy for severe acute pancreatitis.
We present three cases of patients (at the age of 56 years, 49 years and 74 years respectively) with severe acute pancreatitis (SAP), complicated by intra-abdominal compartment syndrome (ACS) and respiratory insufficiency with limitations of mechanical ventilation. The respiratory situation of the patients was significantly improved after decompression laparotomy (DL) and lung protective ventilation was re-achieved. ACS was discussed followed by a short review of the literature. Our cases show that DL may help patients with SAP to recover from severe respiratory failure.


Chronic Milk-Dependent Food Protein-Induced Enterocolitis Syndrome in Children from West Pomerania Region.
Characteristics of chronic milk-dependent food protein-induced enterocolitis syndrome (FPIES) in children from the region of Western Pomerania were studied. Prospectively, 55 children were diagnosed at a median of 2.2 months. The open food challenges (OFC), morphologies, milk-specific IgE (sIgE) (FEIA method, CAP system), and skin prick tests (SPTs) were examined. Vomiting and diarrhea escalated gradually but quickly led to growth retardation. Of the infants, 49% had BMI < 10 c, 20% BMI < 3 c; 25% had anemia, and 15% had hypoalbuminemia. During the OFCs we observed acute symptoms that appeared after 2-3 h: vomiting diarrhea and pallor. A total of 42% children required intravenous hydration. Casein hydrolysates or amino acids formulae (20%) were used in treatment. In 25% of children, SPT and milk sIgE were found, in 18%-other food SPTs, and in 14% allergy to other foods. A transition to IgE-dependent milk allergy was seen in 3 children. In the twelfth month of life, 62% of children had tolerance to milk, and in the twenty-fifth month-87%. Conclusions. Chronic milk-dependent FPIES resolves in most children. By the age of 2 children are at risk of multiple food sensitization, and those who have milk sIgE are at risk to transition to IgE-mediated milk allergy. Every OFC needs to be supervised due to possible severe reactions.


Evaluation of congenital diseases of the heart.
Three different new developments have taken place in the evaluation of congenital heart diseases. First, in the fetal period, intravaginal echocardiography allows earlier diagnosis of significant cardiac abnormalities that could lead to a wanted termination of pregnancy. Second, in adults and children, MR imaging has become a standard imaging modality in complex congenital heart diseases. Moreover MR imaging has become the best noninvasive imaging method in visualization of the great vessels. Finally, in surgery, the intraoperative epicardial echocardiography could improve operation results in the future (solving the regurgitation problem). Postoperatively, MR imaging has become an important diagnostic tool that helps to reduce repeated catheterization and angiography.


eHSCPr discriminating the cell identity involved in endothelial to hematopoietic transition.
Hematopoietic stem cells (HSCs) give rise to all blood cells and play a vital role throughout the whole lifespan through their pluripotency and self-renewal properties. Accurately identifying the stages of early HSCs is extremely important, as it may open up new prospects for extracorporeal blood research. Existing experimental techniques for identifying the early stages of HSCs development are time-consuming and expensive. Machine learning has shown its excellence in massive single-cell data processing and it is desirable to develop related computational models as good complements to experimental techniques. In this study, we presented a novel predictor called eHSCPr specifically for predicting the early stages of HSCs development. To reveal the distinct genes at each developmental stage of HSCs, we compared F-score with three state-of-art differential gene selection methods (limma, DESeq2, edgeR) and evaluated their performance. F-score captured the more critical surface markers of endothelial cells and hematopoietic cells, and the area under receiver operating characteristic curve (ROC) value was 0.987. Based on SVM, the 10-fold cross-validation accuracy of eHSCpr in the independent dataset and the training dataset reached 94.84% and 94.19%, respectively. Importantly, we performed transcription analysis on the F-score gene set, which indeed further enriched the signal markers of HSCs development stages. eHSCPr can be a powerful tool for predicting early stages of HSCs development, facilitating hypothesis-driven experimental design and providing crucial clues for the in vitro blood regeneration studies. http://bioinfor.imu.edu.cn/ehscpr. Supplementary data are available at Bioinformatics online.


Measuring aerosols in the operating theatre and beyond using a real-time sensor network.
The ability to measure and track aerosols in the vicinity of patients with suspected or confirmed COVID-19 is highly desirable. At present, there is no way to measure and track, in real time, the sizes, dispersion and dilution/disappearance of aerosols that are generated by airway manipulations such as mask ventilation; tracheal intubation; bronchoscopy; dental and gastro-intestinal endoscopy procedures; or by vigorous breathing, coughing or exercise. We deployed low-cost photoelectric sensors in five operating theatres between surgical cases. We measured and analysed dilution and exfiltration of aerosols we generated to evaluate air handling and dispersion under real-world conditions. These data were used to develop a model of aerosol persistence. We found significant variation between different operating theatres. Equipment placement near air vents affects air flows, impacting aerosol movement and elimination patterns. Despite these impediments, air exchange in operating theatres is robust and prolonged fallow time before theatre turnover may not be necessary. Significant concentrations of aerosols are not seen in adjoining areas outside of the operating theatre. These models and dispersion rates can predict aerosol persistence in operating theatres and other clinical areas and potentially facilitate quantification of risk, with obvious and far-reaching implications for designing, evaluating and confirming air handling in non-medical environments.


MicroRNA-155-5p Contributes to 5-Fluorouracil Resistance Through Down-Regulating TP53INP1 in Oral Squamous Cell Carcinoma.
The anticancer drug 5-fluorouracil (5-FU) resistance is a major obstacle to reducing the effectiveness of cancer treatment, and its detailed mechanism has not been fully elucidated. Here, in 5-FU-resistant human oral squamous cell carcinoma (OSCC) HSC3 cells (HSC3/5-FU), the levels of 21 miRNA candidates were detected using RT-PCR and miR-155-5p level increased strikingly in HSC3/5-FU cells compared to HSC3 cells. Compared with HSC3 cells, the CCK-8 assay showed that the HSC3/5-FU cells transfected with miR-155-5p inhibitors decreased 5-FU IC50. Ectopic expression of miR-155-5p in HSC3 and HSC4 cells increased 5-FU IC50 (CCK-8 assay), migration (wound-healing and transwell assays) and invasion (transwell assay) abilities. Seven miR-155-5p target candidates were discovered by miRNA prediction algorithms (miRDB, Targetscan, and miRWalk), and the RT-PCR results showed that in HSC3/5-FU cells TP53INP1 was of the lowest mRNA expression level compared with HSC3 cells. The RT-PCR and Western blotting assays showed that ectopic expression of miR-155-5p in HSC3 and HSC4 cells decreased TP53INP1 expression level. Furthermore, the luciferase reporter and RNA pull-down assays determined the interference effect of miR-155-5p on TP53INP1 expression. The enhancement of cell viability (CCK-8 assay), migration (wound-healing and transwell assays) and invasion (transwell assay) by miR-155-5p after 5-FU treatment was reversed by TP53INP1 overexpression. After treatment with 5-FU, HSC3-miR-155-5p tumor-bearing nude mice presented growing tumors, while HSC3-TP53INP1 group possessed shrinking tumors. In conclusion, these results lead to the proposal that miR-155-5p enhances 5-FU resistance by decreasing TP53INP1 expression in OSCC.


Rules for nuclear localization sequence recognition by karyopherin beta 2.
Karyopherinbeta (Kapbeta) proteins bind nuclear localization and export signals (NLSs and NESs) to mediate nucleocytoplasmic trafficking, a process regulated by Ran GTPase through its nucleotide cycle. Diversity and complexity of signals recognized by Kap betas have prevented prediction of new Kap beta substrates. The structure of Kap beta 2 (also known as Transportin) bound to one of its substrates, the NLS of hnRNP A1, that we report here explains the mechanism of substrate displacement by Ran GTPase. Further analyses reveal three rules for NLS recognition by Kap beta 2: NLSs are structurally disordered in free substrates, have overall basic character, and possess a central hydrophobic or basic motif followed by a C-terminal R/H/KX(2-5)PY consensus sequence. We demonstrate the predictive nature of these rules by identifying NLSs in seven previously known Kap beta 2 substrates and uncovering 81 new candidate substrates, confirming five experimentally. These studies define and validate a new NLS that could not be predicted by primary sequence analysis alone.


Hidden Hypergraphs, Error-Correcting Codes, and Critical Learning in Hopfield Networks.
In 1943, McCulloch and Pitts introduced a discrete recurrent neural network as a model for computation in brains. The work inspired breakthroughs such as the first computer design and the theory of finite automata. We focus on learning in Hopfield networks, a special case with symmetric weights and fixed-point attractor dynamics. Specifically, we explore minimum energy flow (MEF) as a scalable convex objective for determining network parameters. We catalog various properties of MEF, such as biological plausibility, and then compare to classical approaches in the theory of learning. Trained Hopfield networks can perform unsupervised clustering and define novel error-correcting coding schemes. They also efficiently find hidden structures (cliques) in graph theory. We extend this known connection from graphs to hypergraphs and discover n-node networks with robust storage of 2Ω(n1-ϵ) memories for any ϵ>0. In the case of graphs, we also determine a critical ratio of training samples at which networks generalize completely.


Aquaporin 4 deficiency eliminates the beneficial effects of voluntary exercise in a mouse model of Alzheimer's disease.
Regular exercise has been shown to reduce the risk of Alzheimer's disease (AD). Our previous study showed that the protein aquaporin 4 (AQP4), which is specifically expressed on the paravascular processes of astrocytes, is necessary for glymphatic clearance of extracellular amyloid beta (Aβ) from the brain, which can delay the progression of Alzheimer's disease. However, it is not known whether AQP4-regulated glymphatic clearance of extracellular Aβ is involved in beneficial effects of exercise in AD patients. Our results showed that after 2 months of voluntary wheel exercise, APP/PS1 mice that were 3 months old at the start of the intervention exhibited a decrease in Aβ burden, glial activation, perivascular AQP4 mislocalization, impaired glymphatic transport, synapse protein loss, and learning and memory defects compared with mice not subjected to the exercise intervention. In contrast, APP/PS1 mice that were 7 months old at the start of the intervention exhibited impaired AQP4 polarity and reduced glymphatic clearance of extracellular Aβ, and the above-mentioned impairments were not alleviated after the 2-month exercise intervention. Compared with age-matched APP/PS1 mice, AQP4 knockout APP/PS1 mice had more serious defects in glymphatic function, Aβ plaque deposition, and cognitive impairment, which could not be alleviated after the exercise intervention. These findings suggest that AQP4-dependent glymphatic transport is the neurobiological basis for the beneficial effects of voluntary exercises that protect against the onset of AD.


Rehabilitation of geriatric patients.
To describe the role of geriatric rehabilitation, the methods of practice, and the mechanisms underlying integrated care in rehabilitation medicine. We reviewed the rehabilitation-related medical literature and outlined an approach to the evaluation of impairment in older patients and subsequent rehabilitation planning. For optimal rehabilitation of geriatric patients, knowledge of general principles of rehabilitation and key areas affecting the elderly population is important. A rehabilitation program will be most successful if a team approach--including a physician, rehabilitation nurse, physical therapist, occupational therapist, psychologist, medical social worker, and recreational therapist--is used. Attention should be paid to special considerations in older patients (such as the presence of comorbid conditions) and potential barriers to care in order to maximize benefit. Rehabilitation of elderly patients can assist in preserving functional independence and improving the quality of life. Assessment and management in an individual patient are best performed by a team approach.


Coenzyme Q10 analytical determination in biological matrices and pharmaceuticals.
In recent years, the analytical determination of coenzyme Q10 (CoQ10) has gained importance in clinical diagnosis and in pharmaceutical quality control. CoQ10 is an important cofactor in the mitochondrial respiratory chain and a potent endogenous antioxidant. CoQ10 deficiency is often associated with numerous diseases and patients with these conditions may benefit from administration of supplements of CoQ10. In this regard, it has been observed that the best benefits are obtained when CoQ10 deficiency is diagnosed and treated early. Therefore, it is of great value to develop analytical methods for the detection and quantification of CoQ10 in this type of disease. The methods above mentioned should be simple enough to be used in routine clinical laboratories as well as in quality control of pharmaceutical formulations containing CoQ10. Here, we discuss the advantages and disadvantages of different methods of CoQ10 analysis.


[Analysis of the cellular tropism of JC virus with archetypal regulatory region].
JC virus (JCV) with an archetypal regulatory region (archetype) has been cloned from urines of a healthy individual. It has been suggested that the regulatory region of prototype JC virus (PML type) isolated from brain of PML patient was derived from that of the archetype by deletion and duplication. Biological characteristics of archetypal JCV, however, have not been fully studied. In the present study we examined the infectivity of archetypal JCV (CY), PML-type JCV (Mad-1) and Chimera JCV (Mad-1/CR-CY), in which the regulatory region is composed of CY and the other region Mad-1. DNAs from the three JCV types were transfected into COS-7 (monkey kidney cells transformed with SV40 T) and IMR-32 (human neuroblastoma cell). COS-7 was permissive for all three types, but IMR-32 was only infected with Mad-1. Infected DNAs were confirmed by Southern blotting, and the constancy of the regulatory regions before and after transmission was verified by DNA sequencing. The results showed that the viral regulatory region was related to viral cell tropism and that PML type regulatory region would be necessary for IMR-32 to propagate. The fact that COS-7 was susceptible for all three types may be explained by the function of SV40 T protein. In addition, we first succeeded in the propagation of CY in COS-7, which would provide a useful system to analyze the mechanism of persistent infection of archetypal JCV.


Homogeneous nucleation rate measurements of 1-propanol in helium: the effect of carrier gas pressure.
Kinetics of homogeneous nucleation in supersaturated vapor of 1-propanol was studied using an upward thermal diffusion cloud chamber. Helium was used as a noncondensable carrier gas and the influence of its pressure on observed nucleation rates was investigated. The isothermal nucleation rates were determined by a photographic method that is independent on any nucleation theory. In this method, the trajectories of growing droplets are recorded using a charge coupled device camera and the distribution of local nucleation rates is determined by image analysis. The nucleation rate measurements of 1-propanol were carried out at four isotherms 260, 270, 280, and 290 K. In addition, the pressure dependence was investigated on the isotherms 290 K (50, 120, and 180 kPa) and 280 K (50 and 120 kPa). The isotherm 270 K was measured at 25 kPa and the isotherm 260 K at 20 kPa. The experiments confirm the earlier observations from several thermal diffusion chamber investigations that the homogeneous nucleation rate of 1-propanol tends to increase with decreasing total pressure in the chamber. In order to reduce the possibility that the observed phenomenon is an experimental artifact, connected with the generally used one-dimensional description of transfer processes in the chamber, a recently developed two-dimensional model of coupled heat, mass, and momentum transfer inside the chamber was used and results of both models were compared. It can be concluded that the implementation of the two-dimensional model does not explain the observed effect. Furthermore the obtained results were compared both to the predictions of the classical theory and to the results of other investigators using different experimental devices. Plotting the experimental data on the so-called Hale plot shows that our data seem to be consistent both internally and also with the data of others. Using the nucleation theorem the critical cluster sizes were obtained from the slopes of the individual isotherms and compared with the Kelvin prediction. The influence of total pressure on the observed isothermal nucleation rate was studied in another experiment, where not only temperature but also supersaturation was kept constant as the total pressure was changed. It was shown that the dependence of the nucleation rate on pressure gets stronger as pressure decreases.


Efficacy of transpupillary thermotherapy (TTT) in the treatment of occult subfoveal choroidal neovascularization in age-related macular degeneration.
To determine the efficacy of transpupillary thermotherapy (TTT) in the treatment of occult subfoveal choroidal neovascularization in patients with age-related macular degeneration (ARMD). We conducted a retrospective review of patients with ARMD treated with TTT from June, 1999 through July, 2000 at a retina referral practice. TTT was delivered through a slit-lamp using a modified diode laser at 810 nm wavelength and a spot size of 3 mm delivered at one location for a minimum of 60 seconds duration. Re-treatment was performed at 2-month intervals if indicated. 81 eyes of 77 patients were included in the study. Vision improved greater than one line Snellen in 18 eyes (22%), vision was stable within one line Snellen in 38 (47%), and worsened greater than one line Snellen in 25 (31%). Patients had a mean follow-up of 9 months. The average number of treatments was 1.37 (range 1 to 4). Pretreatment vision was less than or equal to 20/200 in 54% of eyes. Transpupillary thermotherapy may stabilize visual acuity in a majority of patients with occult subfoveal choroidal neovascularization secondary to ARMD. Proof of therapeutic benefit is best determined by a randomized clinical trial that is currently underway (TTT4CNV).


Uniaxial cyclic strain stimulates cell proliferation and secretion of interleukin-6 and vascular endothelial growth factor of human dermal fibroblasts seeded on chitosan scaffolds.
Human dermal fibroblasts were inoculated into chitosan sponge scaffolds coated with type I collagen and it might be developed as a dermal substitute and/or dressing material. The application of 14% uniaxial cyclic strain to the cellular scaffolds affected the characteristics of the seeded human dermal fibroblasts. Cyclic strain enhanced cellular proliferation, the activity of metalloproteinase-2, and the expression of extracellular matrix proteins such as fibronectin. Moreover, cyclic strain increased the expression of vascular endothelial growth factor (VEGF) and interleukin (IL)-6, which are critical to wound healing. Even under static culture (strain, 0%) following 14% cyclic strain, the expression of VEGF and IL-6, which had increased under 14% strain, was amplified or maintained for at least 3 days. Uniaxial cyclic strain may enhance the wound-healing potential of human dermal fibroblasts seeded on chitosan scaffolds through the changes in the cellular characteristics of the fibroblasts when the cellular scaffold is transplanted into skin wounds, especially chronic wounds such as diabetic wounds.


Lysosomal trafficking mediated by Arl8b and BORC promotes invasion of cancer cells that survive radiation.
Enhanced invasiveness, a critical determinant of metastasis and poor prognosis, has been observed in cancer cells that survive cancer therapy, including radiotherapy. Here, we show that invasiveness in radiation-surviving cancer cells is associated with alterations in lysosomal exocytosis caused by the enhanced activation of Arl8b, a small GTPase that regulates lysosomal trafficking. The binding of Arl8b with its effector, SKIP, is increased after radiation through regulation of BORC-subunits. Knockdown of Arl8b or BORC-subunits decreases lysosomal exocytosis and the invasiveness of radiation-surviving cells. Notably, high expression of ARL8B and BORC-subunit genes is significantly correlated with poor prognosis in breast cancer patients. Sp1, an ATM-regulated transcription factor, is found to increase BORC-subunit genes expression after radiation. In vivo experiments show that ablation of Arl8b decreases IR-induced invasive tumor growth and distant metastasis. These findings suggest that BORC-Arl8b-mediated lysosomal trafficking is a target for improving radiotherapy by inhibiting invasive tumor growth and metastasis.


Surface Integrity and Friction Performance of Brass H62 Textured by One-Dimensional Ultrasonic Vibration-Assisted Turning.
The processing method, one-dimensional ultrasonic vibration-assisted turning (1D UVAT), is a potential and efficient way for fabricating a micro-textured surface. This paper aims at exploring the surface integrity and friction performance of brass H62 textured by the 1D UVAT. Four micro-textured surfaces with a specific distribution, size, and shape of dimples were fabricated by optimizing processing parameters, and the corresponding surface topography, subsurface microstructure, and surface roughness were observed and analyzed. A series of friction tests were carried out under oil-lubricating conditions to research the friction performance of micro-textured surfaces. The results show that the reason for the deviation between theoretical and experimental values of dimple depth was further revealed by observing the corresponding subsurface microstructure. The surface roughness of the micro-textured surfaces prepared is related to the number of micro-dimples per unit area and dimple size, which is greater than the surface generated by conventional turning. Compared with the polished surface and micro-grooved surface, the micro-textured surfaces have better friction performance with a lower frictional coefficient (COF) and wear degree. For the micro-textured surface fabricated by 1D UVAT, the number of micro-dimples per unit area has a great effect on the friction performance, and choosing a larger number is more conducive to improving the friction performance under the oil-lubricating condition. Consequently, this study proves that the proposed 1D UVAT can be a feasible candidate for preparing a micro-textured surface with better tribological property.


Antiretroviral Therapy Outcomes in Patients with Severe Mental Illness.
A retrospective cohort analysis was performed to describe outcomes and retention in care on antiretroviral therapy (ART) of 53 patients with severe mental illness (SMI). Diagnoses were psychosis secondary to HIV (24 patients), psychosis not otherwise specified (12), mania with or without psychosis (9), depression with psychotic features (4), and schizophrenia and bipolar mood disorder (2 each). The median baseline CD4 count was 66/mm(3) and viral load was 5.4 log10 copies/mL. Thirteen (25%) patients were lost to follow-up (10 within 6 months), 3 were transferred out, and 3 died. By week 96, 29 (85%) of 34 (64%) patients still in care had a viral load <400 copies/mL and 26 (76%) a viral load <25 copies/mL. Median CD4 count increased to 307/mm(3). Twenty-seven of 34 patients discontinued antipsychotic medication. Patients with SMI and advanced HIV infection responded well to ART. The first 6 months was important for retention in care.


VEGF stimulation enhances Livin protein synthesis through mTOR signaling.
Livin is a member of inhibitors of apoptosis proteins (IAPs) and overexpressed in transformed cells and several cancers. Although strategies to decrease Livin levels have been conducted for rational cancer therapy, the molecular mechanism controlling Livin expression in tumors has not been completely elucidated. Here, we show that vascular endothelial growth factor (VEGF) stimulation can increase Livin expression in HeLa cells or SK-MEL-28 cells. This response is independent of de novo gene transcription or changes in mRNA expression but occurs at protein expression levels. VEGF stimulation results in mTOR signaling activation which changes the phosphorylation status of 4E-BP1, the downstream of mTOR signaling, and ultimately contributes to the translation initiation of Livin protein. Livin silencing, Rapamycin alone or in combination with cytotoxic agent can reduce Livin protein levels, and decrease cells viability. Thus, ablation of Livin translation contributes to remove an anti-apoptotic mechanism potentially contributing to aggressive tumor behavior. Pharmacologic inhibition of VEGF/mTOR/Livin signaling may provide a novel strategy for cancer treatment.


P21-Activated Kinase 1: Emerging biological functions and potential therapeutic targets in Cancer.
The p21-Activated kinase 1 (PAK1), a member of serine-threonine kinases family, was initially identified as an interactor of the Rho GTPases RAC1 and CDC42, which affect a wide range of processes associated with cell motility, survival, metabolism, cell cycle, proliferation, transformation, stress, inflammation, and gene expression. Recently, the PAK1 has emerged as a potential therapeutic target in cancer due to its role in many oncogenic signaling pathways. Many PAK1 inhibitors have been developed as potential preclinical agents for cancer therapy. Here, we provide an overview of essential roles that PAK1 plays in cancer, including its structure and autoactivation mechanism, its crucial function from onset to progression to metastasis, metabolism, immune escape and even drug resistance in cancer; endogenous regulators; and cancer-related pathways. We also summarize the reported PAK1 small-molecule inhibitors based on their structure types and their potential application in cancer. In addition, we provide overviews on current progress and future challenges of PAK1 in cancer, hoping to provide new ideas for the diagnosis and treatment of cancer.


Evaluation of Vertical Bone Regeneration Using Block and Particulate Forms of Bio-Oss Bone Graft: A Histologic Study in the Rabbit Mandible.
The aim of the present study was to evaluate histologically vertical bone regeneration outcomes after using bovine bone graft material in block and granular forms. The buccal bony plates of the outer mandibles of 10 New Zealand rabbits received Bio-Oss blocks that were immobilized using orthopedic mini-plates, and another 10 received granular forms that were gently packed and stabilized into the custom-made perforated metallic cubes. The mean graft area (GA), new bone area (NBA), bone-to-graft contact (BGC), and maximum vertical height reached by the new bone development (MVH) were histometrically evaluated and showed no significant differences between 2 graft types. The new bone was observed mostly close to the basal bone and developed penetrating the trabecular scaffold in the form of seams that covered the intralumen surfaces of the block type graft, while in the granular graft type the new bone was observed to grow between the graft particles usually interconnecting them. Either form of Bio-Oss was capable of providing considerable vertical bone augmentation.


The potential role of sirtuins regarding the effects of exercise on aging- related diseases.
Habitual physical activity and exercise are associated with the mortality rate and significantly contribute to the prevention and/or amelioration of aging-related diseases including metabolic disorders, atherosclerosis, cancer, and dementia. Sirtuins are NAD+-dependent histone deacetylases that have emerged as key regulators of many functions including metabolism, cell growth and apoptosis, as well as control of the aging process. Recent studies have demonstrated that some types of exercise affect the expression and activity of sirtuins in several tissues. This review focuses on the effects of exercise on sirtuins and also their putative role with regard to the effects of exercise on preventing aging- related diseases.


A scale for detection of negative attitudes towards medication among relatives of schizophrenic patients.
The validity of a questionnaire developed to assess negative attitudes towards drug therapy by relatives of schizophrenic patients is examined. The questionnaire items are tested against the statement: "Patients should not take drugs, they can only be helped by good advice". The prejudice of relatives of schizophrenics against drug therapy may have an effect on the patients' compliance to maintenance therapy and, subsequently, on their relapse rate. A number of factors, social and psychological, were examined as possible determinants of the negative attitudes of relatives. These factors include age, sex, profession, education, positive family history, and use of drugs among the relatives; mental state, residence, duration of illness, relapse rate and clinical features in the patients. Poor education of relatives correlated to negative attitudes towards drug therapy.


Benefits and harms of endoscopic screening for gastric cancer.
Gastric cancer has remained a serious burden worldwide, particularly in East Asian countries. However, nationwide prevention and screening programs for gastric cancer have not yet been established in most countries except in South Korea and Japan. Although evidence regarding the effectiveness of endoscopic screening for gastric cancer has been increasingly accumulated, such evidence remains weak because it is based on results from studies other than randomized controlled trials. Specifically, evidence was mostly based on the results of cohort and case-control studies mainly conducted in South Korea and Japan. However, the consistent positive results from these studies suggest promising evidence of mortality reduction from gastric cancer by endoscopic screening. The major harms of endoscopic screening include infection, adverse effects, false-positive results, and overdiagnosis. Despite the possible harms of endoscopic screening, information regarding these harms remains insufficient. To provide appropriate cancer screening, a balance of benefits and harms should always be considered when cancer screening is introduced as a public policy. Quality assurance is very important for the implementation of cancer screening to provide high-quality and safe screening and minimize harms. Endoscopic screening for gastric cancer has shown promising results, and thus deserves further evaluation to reliably establish its effectiveness and optimal use.


Unleashing the importance of creativity, experience and intellectual capital in the adaptation of export marketing strategy and competitive position.
Export marketing strategy has become an exciting research topic in strategic management literature because of its momentous role in sustainable competitive advantage and performance of firms. However, it is not yet recognized what factors enable top management team in adaptation of the export marketing strategy. This research aims to unleash how the intangible skills; creativity, business experience and intellectual capital facilitate marketing managers in adaptation of the expert marketing strategy (product, price, promotion and distribution) that can spur sustainable competitive performance. We collected data from 293 SMEs and used structural equation modeling for testing the hypotheses. The results indicate that the intangible skills; creativity, experience and intellectual capital do not directly contribute to sustainable competitive performance. However, creativity has a significant influence on product, price, promotion and distribution strategy, experience has a significant influence on product, price and promotion strategy and intellectual capital is only a significant predictor of product strategy. In the dimensions of export marketing strategy, product, price and distribution significantly while promotion does not significantly contribute to sustainable competitive performance. Moreover, export marketing strategy adaptation fully mediates the relationship between creativity and sustainable competitive performance as well as between experience and sustainable competitive performance while it does not mediate the path between intellectual capital and sustainable competitive performance. The findings recommend SMEs to emphasize highly skilled marketing staff who have competencies (experience, creative and intellectual) in order to build an effective export marketing strategy-resulting sustainable competitive performance. Further implications are discussed.


[Secondary biological recurrence after radical prostatectomy: multivariate analysis of prognostic clinical, biological, and histologic factors].
To define the clinical, laboratory and histological variables associated with secondary elevation, after an undetectable phase, of PSA after radical prostatectomy. This was a prospective study of 83 consecutive patients undergoing retropubic radical prostatectomy with an undetectable postoperative PSA at 3 months. The predictive value of five preoperative criteria (age, total PSA, Gleason score on biopsies, positive apical biopsies, clinical stage) and four postoperative criteria (pathological stage, Gleason score on the operative specimen, positive margins, follow-up) for secondary laboratory progression was studied by univariate and multivariate analysis. With a median follow-up of 36 months, the laboratory recurrence rate was 19%. Laboratory recurrence was associated with a biopsy Gleason score greater than or equal to 7 (p = 0.04), a high pathological stage (p = 0.03), a high histological score (Gleason > or = 7) (p < 0.01) and positive margins (p = 0.04). Logistic regression identified a Gleason score on the operative specimen greater than or equal to 7 to be the only element predictive of secondary laboratory progression. The concept of positive margins or high pathological stage is insufficient to identify the risk of laboratory progression after radical prostatectomy. The Gleason score, which evaluates tumour aggressiveness, the risk of micrometastases or periprostatic extension, therefore appears to be more useful.


Myosin-X is a molecular motor that functions in filopodia formation.
Despite recent progress in understanding lamellipodia extension, the molecular mechanisms regulating filopodia formation remain largely unknown. Myo10 is a MyTH4-FERM myosin that localizes to the tips of filopodia and is hypothesized to function in filopodia formation. To determine whether endogenous Myo10 is required for filopodia formation, we have used scanning EM to assay the numerous filopodia normally present on the dorsal surfaces of HeLa cells. We show here that siRNA-mediated knockdown of Myo10 in HeLa cells leads to a dramatic loss of dorsal filopodia. Overexpressing the coiled coil region from Myo10 as a dominant- negative also leads to a loss of dorsal filopodia, thus providing independent evidence that Myo10 functions in filopodia formation. We also show that expressing Myo10 in COS-7 cells, a cell line that normally lacks dorsal filopodia, leads to a massive induction of dorsal filopodia. Because the dorsal filopodia induced by Myo10 are not attached to the substrate, Myo10 can promote filopodia by a mechanism that is independent of substrate attachment. Consistent with this observation, a Myo10 construct that lacks the FERM domain, the region that binds to integrin, retains the ability to induce dorsal filopodia. Deletion of the MyTH4-FERM region, however, completely abolishes Myo10's filopodia-promoting activity, as does deletion of the motor domain. Additional experiments on the mechanism of Myo10 action indicate that it acts downstream of Cdc42 and can promote filopodia in the absence of VASP proteins. Together, these data demonstrate that Myo10 is a molecular motor that functions in filopodia formation.


Acute erythroid leukemia.
Acute erythroid leukemia (AEL) is an uncommon type of acute myeloid leukemia (AML), representing less than 5% of all cases. Acute erythroid leukemia is characterized by a predominant erythroid proliferation, and in the current World Health Organization (WHO) classification scheme there are 2 subtypes: erythroleukemia (erythroid/myeloid leukemia) and pure erythroid leukemia. Morphologic findings are most important for establishing the diagnosis. The erythroleukemia subtype, which is most common, is defined as the presence of 50% or more erythroid precursors and 20% or more blasts in the nonerythroid component. The pure erythroid leukemia subtype is composed of 80% or more immature erythroblasts. Although these morphologic criteria appear straightforward, AEL overlaps with other types of AML and myelodysplastic syndrome that are erythroid rich. To provide an update of AEL, including clinical presentation, morphologic features, immunophenotype, and cytogenetic and molecular data. As the erythroleukemia subtype is most common, the literature and this review are biased towards this subtype of AEL. Clinicopathologic, cytogenetic, and molecular information were extracted from our review of pertinent literature and a subset of AEL cases in the files of The University of Texas M. D. Anderson Cancer Center (Houston) and University of South Alabama (Mobile). The current WHO criteria for establishing the diagnosis of AEL reduce the frequency of this entity, as cases once classified as the erythroleukemia subtype are now reclassified as other types of AML, particularly AML with myelodysplasia-related changes and therapy-related AML. This reclassification also may have prognostic significance for patients with the erythroleukemia subtype of AEL. In contrast, the current WHO criteria appear to have little impact on the frequency and poor prognosis of patients with the pure erythroid leukemia subtype of AEL. Molecular studies, preferably using high-throughput methods, are needed for a better understanding of the pathogenesis of AEL, and for developing diagnostic and prognostic markers.


Visual short-term memory load suppresses temporo-parietal junction activity and induces inattentional blindness.
The right temporo-parietal junction (TPJ) is critical for stimulus-driven attention and visual awareness. Here we show that as the visual short-term memory (VSTM) load of a task increases, activity in this region is increasingly suppressed. Correspondingly, increasing VSTM load impairs the ability of subjects to consciously detect the presence of a novel, unexpected object in the visual field. These results not only demonstrate that VSTM load suppresses TPJ activity and induces inattentional blindness, but also offer a plausible neural mechanism for this perceptual deficit: suppression of the stimulus-driven attentional network.


A patient-centered approach to nurse orientation.
An orientation pathway was developed using a patient-centered approach. The pathway provides a guide or "road map" for the preceptor and new nurse to care for high-volume patient populations in medical and surgical units. Benefits include application of the nursing process, promotion of critical thinking skills, reduction of reality shock, and improvement in job satisfaction and retention. This article describes the rationale behind the approach and its application to nurse orientation. Steps in the process are described. Staff development educators can use the steps to develop orientation pathways for other practice settings.


Characterizations of the mirror attenuator mosaic: solar diffuser plate.
The mirror attenuator mosaic (MAM), a solar diffuser plate, was used for the flight calibration of the broadband shortwave (0.2-5-microm) and total (0.2 to >200-microm) Earth Radiation Budget Experiment scanning thermistor bolometer radiometers. The MAM solar-reflecting surface cosisted of a tightly packed array of vacuum-deposited aluminum, concave spherical mirrors, while its solar-absorbing surface consisted of black chrome. The effective reflectance of the MAM was constant to within +/-2% after almost 2 years in orbit, a marked improvement over earlier solar diffusers.


Y25130 hydrochloride, a selective 5HT3 receptor antagonist has potent antimitogenic and apoptotic effect on HT29 colorectal cancer cell line.
Serotonin (5-hydroxytryptamine, 5-HT) is known to be a mitogenic factor in several malignancies. It elicits its mitogenic effect through a wide range of 5-HT receptor subtypes and several internal cellular transcription pathways. According to wide distribution of 5-HT3 and 5-HT4 receptors in the gastrointestinal tract, the main aim of this study was to investigate the effect of these receptor agonists and antagonists in a colorectal cell line. In cell culture, we investigated the effects of 5-HT, 5-HT3 and 5-HT4 receptor agonists and antagonists on proliferation of HT29 cells. We also tested apoptosis for the receptor antagonists with TUNEL apoptosis test. In addition, we assayed effects of 5-HT receptor antagonists on cell cycle kinetics with flow cytometery. Proliferation assay revealed that phenylbiguanide (a 5-HT3 receptor selective agonist) increased proliferation of HT29 cells significantly and Y25130 hydrochloride (a 5-HT3 receptor antagonist) had the opposite effect; but for 5-HT4 receptor antagonist, these effects were not significant. In addition, potent apoptotic and cell cycle arresting effect was found for a selective 5-HT3 receptor antagonist but we have not seen any significant effect for the 5-HT4 receptor antagonist. The findings of this study provide strong evidence for the potential role of 5-HT3 receptors in colorectal cancer.


FORCED SWIMMING STRESS-INDUCED CHANGES IN THE PHYSIOLOGICAL AND BIOCHEMICAL PARAMETERS IN ALBINO RATS.
The effects of fresh water swimming and cold water swimming for one day, 7 days and 15 days were studied on the total body weight, weight of the heart, kidney, adrenals, blood sugar level, serum cholesterol level, total leucocyte count, absolute neutrophil count and absolute eosinophil count in albino rats. The stress session in each day lasted for 45 min. Though the body weight of the animals decreased significantly during the initial period, when the stress period was prolonged, there was recovery in the body weight. There was a significant increase in the weight of the heart, kidney and adrenal glands after both types of stress. A significant leucopenia, eosinopenia and neutropenia along with significant hypoglycemia and hypocholesterolemia was observed in all the subgroups. A maximum stress response was seen upto a period of 7 days and the stress response decreased when the stress period was prolonged to 15 days in the physiological parameters studied. This could be due to the adaptation or habituation for the continued stress. There was no sign of adaptation in the case of biochemical parameters studied. A statistically significant physiological and biochemical changes were observed even after one day of forced swimming stress.


Transforming growth factor-beta signaling in epithelial cells.
Transforming growth factor (TGF)-beta is a potent growth suppressor of epithelial cells. Resistance to TGF-beta, however, occurs frequently in solid tumors of epithelial origin and contributes to the uncontrolled growth of these tumors. Although mutant receptor proteins contribute to TGF-beta insensitivity, deregulation of TGF-beta signaling cascades represents an equally important mechanism underlying TGF-beta resistance. Identification of abnormal regulation of signaling components in tumor epithelial cells will lead to the development of selective therapeutic approaches to repair the relevant signaling cascade(s) and reverse the growth anomaly. Within the past few years, great strides have been made in defining signaling pathways for TGF-beta. For example, our laboratory has demonstrated a direct correlation between TGF-beta-mediated growth inhibition of epithelial cells and activation of Ras and three members of the mitogen-activated protein kinase (MAPK) superfamily. The TGF-beta signaling events were sustained, dose-dependent, and absent in TGF-beta-resistant cells. Further, up-regulation of both p27Kip1 and p21Cip1, nuclear events important for the growth inhibitory effect of TGF-beta, are completely dependent upon the activation of Ras. However, Ras-independent pathways are also activated simultaneously with the Ras/MAPK pathways to mediate the final TGF-beta growth inhibitory outcome. One such pathway includes the SMAD signaling components that control TGF-beta-mediated gene transcription, currently under active study by a number of laboratories, including our own. Future efforts in this field will focus on defining the significance of these signaling proteins and pathways in mediating specific TGF-beta responses. Moreover, additional novel signaling proteins are sure to be identified.


Personality profiles in patients with eating disorders.
The present review focused on the personality profiles of patients with eating disorders. Studies using the Structured Clinical Interview for DSM-III-R Personality Disorder showed high rates of diagnostic co-occurrence between eating disorders and personality disorders. The most commonly observed were histrionic, obsessive-compulsive, avoidant, dependent and borderline personality disorders. Studies using the Cloninger's personality theory suggested that high Harm Avoidance might be relevant to the pathology of anorexia nervosa and high Novelty Seeking and Harm Avoidance to bulimia nervosa. Moreover, high Self-Directedness was suggested to be associated with favorable outcome in bulimia nervosa. The assessment of personality in a cross-sectional study, however, might be influenced by the various states of the illness. Therefore, a sophisticated longitudinal study will be required to advance this area of research.


Multicentre patch test study of air-oxidized ethoxylated surfactants.
Frequent exposure to water and surfactants is considered to be the main cause of hand eczema from wet work. Ethoxylated surfactants are susceptible to oxidation and some of the oxidation products formed have proved to be contact sensitizers in guinea pigs. The question of human sensitization to oxidized surfactants was addressed in a multicentre study in the Stockholm region. 528 consecutive dermatitis patients were patch tested with widely used ethoxylated surfactants in oxidized and non-oxidized form as well as certain identified oxidation compounds. 61 patients presented with mild, clearly irritant reactions to some of the surfactants tested. 18 patients showed not only erythema but also oedema and/or papules and vesicles, using a morphologic descriptive system for reading the patch test reactions. These reactions occurred mostly to oxidized surfactants and oxidation products. When retesting 9 of these 18 patients only an allergic reaction to acetaldehyde was confirmed. We conclude that oxidized ethoxylated surfactants have increased irritant potential compared to non-oxidized material. Our working hypothesis is that oxidized surfactants of technical quality exert a lower risk of sensitization than do oxidized homologous pure surfactants. Among the potential allergens formed during autoxidation, formaldehyde and acetaldehyde must be considered as a source of unexpected exposure.


Synergistic roles of vapor- and liquid-phase epitaxy in the seed-mediated synthesis of substrate-based noble metal nanostructures.
Colloidal growth modes reliant on the replication of the crystalline character of a preexisting seed through homoepitaxial or heteroepitaxial depositions have enriched both the architectural diversity and functionality of noble metal nanostructures. Equivalent syntheses, when practiced on seeds formed on a crystalline substrate, must reconcile with the fact that the substrate enters the syntheses as a chemically distinct bulk-scale component that has the potential to impose its own epitaxial influences. Herein, we provide an understanding of the formation of epitaxial interfaces within the context of a hybrid growth mode that sees substrate-based seeds fabricated at high temperatures in the vapor phase on single-crystal oxide substrates and then exposed to a low-temperature liquid-phase synthesis yielding highly faceted nanostructures with a single-crystal character. Using two representative syntheses in which gold nanoplates and silver-platinum core-shell structures are formed, it is shown that the hybrid system behaves unconventionally in terms of epitaxy in that the substrate imposes an epitaxial relationship on the seed but remains relatively inactive as the metal seed imposes an epitaxial relationship on the growing nanostructure. With epitaxy transduced from substrate to seed to nanostructure through what is, in essence, a relay system, all of the nanostructures formed in a given synthesis end up with the same crystallographic orientation relative to the underlying substrate. This work advances the use of substrate-induced epitaxy as a synthetic control in the fabrication of on-chip devices reliant on the collective response of identically aligned nanostructures.


Brewed Robusta Coffee Increases Nickel Ion Release from Dental Alloys: An In Vitro Study.
Alloys in oral cavity always interact with dynamic oral environment, such as pH, temperature, salivary conditions, and dietary habits. Coffee can further decrease pH in the oral cavity. Thus, coffee may increase the release of metal ions that may lead to various health diseases. This study aimed to quantitively investigate the effect of brewed Robusta coffee on the nickel ion release and their morphological structures; Methods: 20 alloy specimens were divided into 4 groups and placed in solutions for 48 and 168 h: (1) distilled water, (2) artificial saliva, (3) Robusta coffee, and (4) mixture of artificial saliva and Robusta coffee. AAS, XRF, and SEM were used for examinations; Results: The release of Ni2+ was found in all groups and robust release were found in the coffee only and mixture of coffee + artificial saliva solution after 168 h. Likewise, SEM showed that internal oxidation was high after 168 h of immersion; Conclusions: The concentration of nickel increased in saliva of low pH due to brewed coffee. Though the release of these ions is still within the tolerable amount in human body, it should be realized that it usually lasts for months or years. Dentists should be cautious when using instructions for patients with a history of allergies especially for dietary with low acidity.


Religious versus Conventional Internet-based Cognitive Behavioral Therapy for Depression.
The accessibility and efficacy of two Internet-supported interventions for depression: conventional cognitive behavioral therapy (C-CBT) and religious CBT (R-CBT) were investigated. Depressed participants (N = 79) were randomly assigned to either active treatment or wait-listed control group. Self-report measures of depression, anxiety, and life quality were collected before, immediately after, and 6 months after the intervention. Significant differences among the three conditions emerged at post-intervention with medium to large effect sizes (Cohen's d between 0.45 and 1.89), but no differences between the R-CBT and C-CBT were found. However, the addition of religious components to CBT contributed to the initial treatment appeal for religious participants, thus increasing the treatment accessibility.


Impaired trafficking of choline transporter-like protein-1 at plasma membrane and inhibition of choline transport in THP-1 monocyte-derived macrophages.
The present study investigates choline transport processes and regulation of choline transporter-like protein-1 (CTL1) in human THP-1 monocytic cells and phorbol myristate 13-acetate (PMA)-differentiated macrophages. Choline uptake is saturable and therefore protein-mediated in both cell types, but its transport characteristics change soon after treatments with PMA. The maximal rate of choline uptake intrinsic to monocytic cells is greatly diminished in differentiated macrophages as demonstrated by alterations in V(max) values from 1,973 +/- 118 to 380 +/- 18 nmol x mg(-1) x min(-1), when the binding affinity did not change significantly (K(m) values 56 +/- 8 and 53 +/- 6 microM, respectively). Treatments with hemicholinim-3 effectively inhibit most of the choline uptake, establishing that a choline-specific transport protein rather than a general transporter is responsible for the observed kinetic parameters. mRNA screening for the expression of various transporters reveals that CTL1 is the most plausible candidate that possesses the described kinetic and inhibitory properties. Fluorescence-activated cell sorting analyses at various times after PMA treatments further demonstrate that the disappearance of CTL1 protein from the cell surface follows the same trend as the reduction in choline uptake. Importantly, the loss of functional CTL1 from the cell surface occurs without significant changes in total CTL1 protein or its mRNA level indicating that an impaired CTL1 trafficking is the key contributing factor to the reduced choline uptake, subsequent to the PMA-induced THP-1 differentiation to macrophages.


Research grants on alcohol and immunology including acquired immunodeficiency syndrome (AIDS)--NIAAA.
The National Institute on Alcohol Abuse and Alcoholism (NIAAA) announces the availability of a special program announcement for Research Grants on Alcohol and Immunology including Acquired Immunodeficiency Syndrome (AIDS). These awards will be to support research grants to study the role of heavy alcohol consumption in lowering resistance to infectious diseases. Areas of research interest include epidemiology, immunology, bacteriology, nutrition, virology, and pathology as well as other relevant clinical and biomedical disciplines. In addition, studies of the relation of alcohol consumption as a potential cofactor in the development of AIDS are encouraged. Support may be requested for up to 5 years. It is anticipated that up to $1 million per year will be available to support research grants under this announcement.


Breast Cancer; Discovery of Novel Diagnostic Biomarkers, Drug Resistance, and Therapeutic Implications.
Breast cancer is the second most reported cancer in women with high mortality causing millions of cancer-related deaths annually. Early detection of breast cancer intensifies the struggle towards discovering, developing, and optimizing diagnostic biomarkers that can improve its prognosis and therapeutic outcomes. Breast cancer-associated biomarkers comprise macromolecules, such as nucleic acid (DNA/RNA), proteins, and intact cells. Advancements in molecular technologies have identified all types of biomarkers that are exclusively studied for diagnostic, prognostic, drug resistance, and therapeutic implications. Identifying biomarkers may solve the problem of drug resistance which is a challenging obstacle in breast cancer treatment. Dysregulation of non-coding RNAs including circular RNAs (circRNAs) and microRNAs (miRNAs) initiates and progresses breast cancer. The circulating multiple miRNA profiles promise better diagnostic and prognostic performance and sensitivity than individual miRNAs. The high stability and existence of circRNAs in body fluids make them a promising new diagnostic biomarker. Many therapeutic-based novels targeting agents have been identified, including ESR1 mutation (DNA mutations), Oligonucleotide analogs and antagonists (miRNA), poly (ADP-ribose) polymerase (PARP) in BRCA mutations, CDK4/6 (cell cycle regulating factor initiates tumor progression), Androgen receptor (a steroid hormone receptor), that have entered clinical validation procedure. In this review, we summarize the role of novel breast cancer diagnostic biomarkers, drug resistance, and therapeutic implications for breast cancer.


An Assessment of the Nutritional Value of the Preschool Food Rations for Children from the Wroclaw District, Poland-The Case of a Big City.
The evaluation of nutrition is an essential element of preventing chronic diseases and can be used to determine nutritional recommendations. A child spends about 7-8 h a day in a kindergarten; therefore, meals served there should be balanced appropriately to ensure the full psychophysical development of the young organism. At preschool age, children develop eating habits that can have life-long effects. Based on 10-day menus, the study aimed to estimate the energy and nutritional value of children's diets at four randomly selected kindergartens in the Wroclaw district, Poland. In total, 80 menus were analyzed (40 for summer and 40 for autumn). The data from kindergartens were analyzed based on the Diet 6D computer program. Regardless of the kindergarten, the analyzed food rations showed irregularities related to excessive supplies (in reference to the dietary recommendations) of sucrose, fiber, salt, magnesium, and vitamin A. The preschool food rations did not cover demands with respect to PUFA n-3, PUFA-n-6, calcium, and vitamin D. The observed irregularities confirm the need to monitor the content of energy and nutrients in preschool menus to be able to correct any dietary errors.


Application of computer-aided drug repurposing in the search of new cruzipain inhibitors: discovery of amiodarone and bromocriptine inhibitory effects.
Cruzipain (Cz) is the major cystein protease of the protozoan Trypanosoma cruzi , etiological agent of Chagas disease. From a 163 compound data set, a 2D-classifier capable of identifying Cz inhibitors was obtained and applied in a virtual screening campaign on the DrugBank database, which compiles FDA-approved and investigational drugs. Fifty-four approved drugs were selected as candidates, four of which were acquired and tested on Cz and T. cruzi epimastigotes. Among them, the antiparkinsonian and antidiabetic drug bromocriptine and the antiarrhythmic amiodarone showed dose-dependent inhibition of Cz and antiproliferative activity on the parasite.


Unilateral Condylar Hyperplasia With Active Bony Overgrowth: A Case Report.
Condylar hyperplasia (CH) is an overgrowth disorder of the temporomandibular joint bones caused by growth center overactivity of the mandibular condyle. Although the disorder is mostly idiopathic, several etiologies have been proposed. CH presents as progressive facial asymmetry with functional abnormalities. A combination of clinical, histopathological, and radiological findings is crucial to determine the diagnosis. Several diagnostic algorithms have been described in the literature. Management of CH is variable and depends on the growth of the bone. Here, we present the case of a 36-year-old female who presented with progressive facial asymmetry which was diagnosed as unilateral CH with active bony overgrowth.


Associations between Childhood Abuse and Chronic Pain in Adults with Substance Use Disorders.
Both childhood abuse and chronic pain are common in people with substance use disorders (SUDs). Studies have found that exposure to childhood abuse is associated with chronic pain in adulthood; however, few studies have examined this association in people with SUDs. Objectives: This study aimed to characterize the association between childhood abuse and chronic pain presence and severity in adults with SUDs. Methods: Data were obtained from 672 treatment-seeking participants with SUDs on an inpatient detoxification unit. Regression models evaluated whether childhood physical or sexual abuse was associated with the likelihood of chronic pain and severity of several pain-related characteristics: pain catastrophizing, pain severity, and pain interference. Results: Childhood physical and sexual abuse were significantly associated with a greater likelihood of chronic pain in adulthood. In the adjusted analyses, childhood physical abuse was associated with worse pain severity, whereas childhood sexual abuse was associated with greater pain catastrophizing and worse pain interference. Conclusions: Childhood physical and sexual abuse were associated with a greater likelihood of chronic pain in adults with SUDs. Among those with chronic pain, exposure to childhood abuse was associated with a more severe symptom profile, characterized by greater pain severity, more catastrophic interpretations of pain, and more pain-related interference with daily life. People with SUDs and a history of childhood abuse may benefit from screening for pain and interventions to reduce pain catastrophizing. These findings highlight the importance of longitudinal research to understand mechanisms linking childhood abuse exposure to later pain and substance misuse.


Liver MR Imaging in Children: Current Concepts and Technique.
Magnetic resonance (MR) imaging is increasingly being used for comprehensive evaluation of liver diseases in children because of the lack of radiation and better lesion detection and characterization. Liver examination involves routine sequences such as T2-weighted, balanced steady-state free precession, and in-phase and out-of-phase sequences. Dynamic imaging is an essential component of liver examination to characterize focal lesions and involves capturing snapshots of the passage of contrast material in the arterial, portal venous, equilibrium, and sometimes hepatobiliary phases, generally by using T1-weighted three-dimensional gradient-echo sequences. Optimal arterial phase imaging is important for detection and characterization of hypervascular lesions. In the equilibrium phase, the concentration of contrast material is similar in the microvasculature and the extracellular interstitial space. Some superficial, spreading, inflammatory lesions are better seen on equilibrium phase images. Meticulous attention to intravenous access and use of an appropriate timing method are critical for successful dynamic imaging. Commonly used contrast media for liver imaging include gadolinium-based extracellular contrast agents and hepatobiliary contrast agents. A portion of hepatobiliary contrast agents such as gadoxetate and gadobenate is taken up by hepatocytes and excreted through bile. Hepatobiliary phase images acquired after hepatobiliary contrast agent administration are increasingly used to characterize liver lesions in children, such as focal nodular hyperplasia. Interpretation of liver MR images involves synthesis of information acquired from evaluation of background hepatic parenchyma, detection of lesions, and evaluation of signal intensity characteristics on images obtained with various sequences to arrive at a diagnosis or reasonable differential diagnoses. Understanding the appropriate technique, sequences, and contrast media when performing pediatric liver MR imaging is important for high diagnostic yield. (©)RSNA, 2016.


Colonic adenomatous polyposis syndromes: clinical management.
Colorectal cancer is one of the major causes of cancer deaths in both men and women. It is estimated that 5 to 10% of patients with colorectal cancer have an inherited germline mutation that predisposes them to cancer. Hereditary colorectal cancer syndromes can be divided into those associated with colonic polyposis - familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (aFAP), and MYH associated polyposis (MAP), and those not associated with colonic polyposis - hereditary nonpolyposis colon cancer (HNPCC). The hereditary polyposes are usually easier to diagnose than HNPCC, but their higher penetrance and variable phenotype pose some difficult problems in management and surveillance. The timing and type of surgical intervention, the management of desmoid risk, the treatment of rectal or pouch neoplasia, and the management of duodenal neoplasia are all questions that must be addressed in patients with FAP or MAP.


Lack of correlation between obturation limits and apical leakage.
The aim of this paper was to evaluate a possible correlation between obturation limits and leakage. Thirty-six extracted human mandibular incisors were used, characterized by straight and single canals, non-anatomical complexities, absence of previous endodontic treatment, complete root formation and patent foramen. For standardization of the specimens for the leakage analysis, foraminal instrumentation was performed up to a Flexofile #25 (Dentsply-Maillefer, Ballaigues, Switzerland). All specimens were instrumented and filled following the same protocol, and the obturation limits were measured using Axiovision 4.5 Software (Carl Zeiss Vision, Hallbergmoos, Germany). The specimens were then separated into three groups (n=12) according to the following variables: Group I--obturation limits ranging from 0 mm to 0.76 mm of the main apical foramen. Group II--obturation limits ranging from 0.77 mm to 0.98 mm of the main apical foramen. Group III--obturation limits ranging from 0.99 mm to 1.68 mm of the main apical foramen. Apical leakage was quantified by fluid filtration. The analyses were confronted using Pearson's test (p>0.05). Groups I, II and III showed Pearson correlation values (r2) of -0.152, -0.186 and 0.058, respectively. No correlation was found between the obturation limits and apical leakage.


Refinement and analysis of the structure of the first two domains of human CD4.
The structure of a fragment of human CD4 containing two immunoglobulin (Ig)-like domains has been determined by X-ray crystallography and refined at 2.2 A resolution. The structure determination involved iterative building and simulated-annealing refinement, beginning with a partial model. Comparison of domain 1 with an Ig variable domain shows that CD4 has a long and prominent CDR2-like loop (the C"C" corner) and shortened CC' and FG loops (which mediate dimerization in IgV modules). Comparison of domain 2 with Ig modules and domain 1 shows that it can be described as a truncated Ig V domain, in which strands C" and D are deleted. The intersheet disulfide in domain 2 is absent, and there is an altered packing of the two beta-sheets together with a remodeling of the hydrophobic core. The interface between domains 1 and 2 is a lap joint with an extensive hydrophobic surface. The key features of domain 1 that contribute to the interface are found at corresponding positions in domain 2, leading us to propose that the contact between domains 2 and 3 will resemble the one between domains 1 and 2.


Paraneoplastic cerebellar degeneration diagnosed by anti-Yo determination in a young woman with early breast cancer.
A 44-year-old woman diagnosed with a HER2 positive early breast cancer, receiving neoadjuvant treatment with paclitaxel and targeted agents, trastuzumab together with pertuzumab, presented to the emergency room with gait instability and upper right limb weakness. The neurological examination was compatible with cerebellar alteration showing right dissymmetry of the finger-nose and heel-knee manoeuvre. A head CT and a brain MRI were performed and negative. The electromyography showed alterations of the pyramidal pathway and somatosensory pathway. In order to determine the cause of the cerebellar affection, a lumbar puncture was performed. The cerebrospinal fluid analysis was non-specific, but the antineuronal anti-Yo antibody was positive, being diagnosed of a paraneoplastic cerebellar degeneration (PCD). A positron emission tomography CT ruled out metastatic disease. The patient completed four cycles of antiHER2 blockade and weekly paclitaxel, achieving a complete pathological response. One year later, she maintains a complete remission but the PCD still prevails.


Protective effect of L-carnitine on testicular ischaemia-reperfusion injury in rats.
Testicular torsion is a urological emergency referred to as 'acute scrotum', because inappropriate treatment can lead to male subfertility and infertility. A possible cause of testicular damage is the ischaemia-reperfusion (I/R) injury attributed to oxygen free radicals. L-carnitine, a vitamin-like antioxidant, plays a pivotal role in the maturation of spermatozoa within the reproductive tract. The aim of the present paper was to determine the protective effect of L-carnitine on testicular I/R-induced injury. Thirty-two male rats were divided into 4 groups (n = 8). Testicular torsion was created by rotating the right testis 720 degrees in a clockwise direction. Group 1: sham-operated control; group 2: ischaemia; group 3: I/R; group 4: ischaemia-L-carnitine treatment-reperfusion group. L-carnitine (500 mg kg(-1), intraperitoneally) was administered before 30 min of detorsion in Group 4. After torsion (5 h) and detorsion (5 h), bilateral orchidectomy was performed. The malondialdehyde (MDA) level was evaluated in testes. Histopathologically, Johnsen's spermatogenesis criteria and mean seminiferous tubule diameter (MSTD) measurements were used. Testicular MDA levels were higher in the torsion group compared to the sham-control group (p < 0.05). Detorsion (reperfusion) caused a further increase in MDA levels (p < 0.05). Pretreatment with L-carnitine prevented a further increase in MDA levels (p < 0.05). Histologically, torsion caused some separation among germinal cells in the seminiferous tubules, which became much more prominent in the I/R group but was attenuated with L-carnitine pretreatment. In conclusion, L-carnitine pretreatment may have a protective effect in experimental testicular torsion-detorsion model in rats by its well-known antioxidant potential.


Unfulfilled inflammatory resolution leads to chronic inflammatory diseases.
Extract: Inflammatory conditions, particularly those that involve chronic inflammation, represent an area of great interest to the pharmaceutical industry. Regulated as they are by a diverse array of ligand-receptor interactions, inflammatory responses are amenable to small molecule pharmaceutical intervention and a wide variety of anti-histamines and anti-inflammatory treatments. Both steroidal and non-steroidal treatments have been developed to treat pro-inflammatory conditions. In their review, Gilroy et al. (2004) present the case for developing novel anti-inflammatory drugs not by finding more effective inhibitors of the inflammatory response, but by developing small molecule drugs that positively regulate the processes and mechanisms by which inflammatory responses are attenuated (i.e., the little known process of inflammatory resolution).


Impact of Electronic Health Record Systems on Prescribing Errors in Pediatric Clinics.
Medication errors are commonly reported in the pediatric population. While evidence supports the use of e-prescribing to prevent certain errors, prescribing with an electronic health record (EHR) system is not devoid of errors. Furthermore, the majority of EHRs are not equipped with functionalities addressing pediatric needs. This study analyzes three unique EHRs in three pediatric clinics. It describes the functionality of each system and identifies errors found in e-prescribed prescriptions. Finally, the study estimates the proportion of e-prescribing errors that could have been avoided if those EHRs had met requirements set by the American Academy of Pediatrics (AAP). The number of prescriptions reviewed for Clinics 1, 2, and 3, respectively, were: 477, 408, and 633 with total error rates of 13.2%, 8.8%, and 6.6%. The clinic EHRs included 21%, 26%, and 47% of the AAP pediatric requirements for safe and effective e-prescribing for children. If all AAP elements had been included in the EHRs, over 83% of errors in the examined e-prescriptions could have been prevented. This study demonstrates that EHR systems used by many pediatric clinic practices do not meet the standard set forth by the AAP. To ensure our most vulnerable population is better protected, it is imperative that medical technology tools adequately consider pediatric needs during development and that this is reflected in selected EHR systems.


The epidemiological profile of infections with multidrug-resistant Pseudomonas aeruginosa and Acinetobacter species.
Isolates of Pseudomonas aeruginosa or Acinetobacter species that are resistant to all, or almost all, commercially available antibiotics are now prevalent worldwide. Typically, these strains are recovered from patients in intensive care units who have ventilator-associated pneumonia. "Panresistant" strains can be defined as strains that are resistant to all beta -lactam and quinolone antibiotics recommended as empirical therapy for ventilator-associated pneumonia. These strains are well adapted to the hospital environment--molecular epidemiological studies have frequently revealed that only 1 or 2 clones caused outbreaks in intensive care units. However, panresistant strains may also be selected by antibiotic use. Given the lack of antibiotic options to treat infection with panresistant strains, enhanced surveillance for these organisms is necessary at unit-specific, institutional, and national levels.


Immunosuppressive effects of mesenchymal stem cell transplantation in rat burn models.
This study is to investigate the effects of mesenchymal stem cell (MSC) transplantation in burn treatment. Wharton's Jelly was stripped from neonatal umbilical cord, and human umbilical cord MSCs were then cultured. Burn models were constructed in male SD rats weighted at 200±5 g, and the rats were randomly divided into control and MSCs transplantation groups. The rats in transplantation group were injected subcutaneously with MSCs (2×10(6)) at 24 h after burning. Blood samples were collected at 0 d, 1 d, 2 d, 3 d, 5 d and 7 d after burning and the contents of white blood cells (WBC), C-reactive protein (CRP), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-10 (IL-10 ) were detected. The wound healing rate at 7 d, 14 d, 21 d and 28 d together with the wound healing time were compared and analyzed statistically by analysis of variance (ANOVA). WBC and CRP in control group increased significantly at 1 d and 2 d, 2 d and 3 d, respectively. IFN-γ, IL-6 and IL-10 levels in serum showed increasing till 5th day and TNF-α arrived its peak value at 7th day. By contrast, WBC, CRP, TNF-α, IL-6 and IL-10 in the MSCs transplantation group showed slight increase after burning and the differences were verified by statistically analysis. IFN-γ showed no significant difference between the two groups. MSCs transplantation group showed significantly higher wound healing rate at 14 d, 21 d, 28 d and showed shorter wound healing time than control. MSCs transplantation could suppress secondary inflammatory reaction by lowering inflammatory cytokines after burning, thus promoting wound healing and scald repair in burn animal model.


Effects of Calcium Polystyrene Sulfonate Formulation Change from Dry Syrup to Oral Solution in Patients with Chronic Kidney Disease.
Calcium polystyrene sulfonate, a cation exchange resin preparation, is used to treat hyperkalaemia. The effects of switching from dry syrup to oral solution forms have been rarely evaluated. We investigated changes in serum potassium levels, incidence of adverse events, and patients' perception and satisfaction associated with the change in calcium polystyrene sulfonate dosage forms from dry syrup to oral solution in chronic kidney disease patients. The study population was comprised of 24 patients. The chronic kidney disease cause, glomerular filtration rate category, and albuminuria category was G4 in 10 cases (41.7%) and G5 in 8 cases (33.3%). No significant difference was observed between groups before and after the change in dosage form. Contrastingly, the ease of intake (P=0.0047), taste (P=0.0056), and satisfaction (P<0.001) indicated positive significant improvements. Changing the calcium polystyrene sulfonate dosage form from dry syrup to oral solution in patients with chronic kidney disease improved patient satisfaction while maintaining efficacy and safety. For patients in whom weight gain is not a problem, we recommend changing the dosage form from dry syrup to oral solution for calcium polystyrene sulfonate.


Correlations of LTα and NQO1 gene polymorphisms with childhood asthma.
To explore the correlation of the lymphotoxin alpha (LTα) and nicotinamide adenine dinucleotide phosphate quinone oxidoreductase 1 (NQO1) gene polymorphisms with childhood asthma. A total of 102 asthma children (observation group) and 80 healthy children (control group) were enrolled. The information was collected via questionnaires and the polymorphisms of LTα rs2844484 and NQO1 rs2917666 were examined with the TaqMan-MGB probe. Observation group had higher constituent ratios of contact with animal furs, personal history of infection, personal history of allergy, familial infection history and familial allergic history than those of control group (p<0.05). However, there were no differences in age, sex, passive smoking, purchase of new furniture and mask wearing between the two groups (p>0.05). The frequency of LTα rs2844484 genotype AA was significantly higher than that of genotype AG and GG (p<0.01), and NQO1 rs2917666 genotype CC showed notably higher frequency than that of genotype CG and GG (p<0.05). The frequency of LTα rs2844484 A allele was significantly higher than that of G allele (p<0.01), while NQO1 rs2917666 C allele had remarkably higher frequency than G allele (p<0.05). The comparisons of the recessive and additive modes revealed differences between the two groups (p<0.05). However, we did not observe significant difference in dominant mode between the two groups (p>0.05). The risk factors for childhood asthma include the contact with animal furs, personal history of infection, personal history of allergy, familial infection history and familial allergic history. Polymorphisms of LTα and NQO1 genes are correlated with childhood asthma.