Comparison of Neural Network and Logistic Regression Analysis to Predict the Probability of Urinary Tract Infection Caused by Cystoscopy.
Urinary tract infections (UTIs) are the most common infections among hospitalized patients. Cystoscopy is a minimally invasive procedure to check bladder disease, among the patients receiving procedure, approximately 10% of patients may experience UTI. In this study, a neural network model with high accuracy, sensitivity, and specificity was developed to predict the probability of UTIs caused by cystoscopic procedures. To reduce antibiotic overuse during cystoscopic procedures, the model can provide clinicians with a rapid assessment of whether patients require prophylactic antibiotics. Patients who underwent cystoscopic procedures at China Medical University Beigang Hospital from 2016 to 2019 were retrospectively reviewed. A total of 1647 patients were enrolled, and 147 cases of urinary tract infection occurred. An artificial neural network (ANN) and logistic regression analysis were used to develop the prediction models, and the two models were compared. The logistic regression analysis model had an accuracy of 91%, sensitivity of 2%, and specificity of 99%, indicating that the logistic regression model predicted that most patients had a low risk of infection. The neural network model had a high accuracy of 85%, sensitivity of 80%, and specificity of 88%. Because the logistic regression model had low sensitivity and missed most cases of UTI, the logistic regression model is inappropriate for clinical application. The neural network model has superior predictive ability and can be considered a tool in clinical practice.


Using pseudogene database to identify lineage-specific genes and pseudogenes in humans and chimpanzees.
It has been revealed that gene content changes, or gene gains or losses, have played an important role in the evolution of modern humans. As one of the major players accounting for gene content changes, gene pseudogenization is abundant in mammalian genomes, and approximately 20000 pseudogenes have been identified in ape genomes. Therefore, it is an interesting question how to exploit rich information embedded in pseudogenes. Here, I present a bioinformatic pipeline that utilizes a pseudogene database to identify both lineage-specific genes and pseudogenes in humans and chimpanzees. I found 6 human-specific gene gains (HSGs), 1 chimpanzee-specific gene gain, and 4 chimpanzee-specific pseudogenes, most not discovered in previous studies. Further analysis showed that HSGs have been evolving under strong purifying selection and are broadly expressed, indicating strong functional constraint. This study demonstrates the usage of pseudogene information in comparative genomics and suggests that new genes during primate evolution may acquire essential functions in a short time. The pipeline developed here could also be applied to other species.


Benchmarks of improved complete basis set extrapolation schemes designed for standard CCSD(T) atomization energies.
Simple modifications of complete basis set extrapolation formulas chosen from the literature are examined with respect to their abilities to reproduce a diverse set of 183 reference atomization energies derived primarily from very large basis set standard, frozen core coupled-cluster singles, doubles plus perturbative triples (CCSD(T)) with the aug-cc-pVnZ basis sets. This reference set was augmented with a few larger chemical systems treated with explicitly correlated CCSD(T)-F12b using a quadruple zeta quality basis set followed by extrapolation to complete basis set limit. Tuning the extrapolation formula parameters for the present reference set resulted in substantial reductions in the error metrics. In the case of the best performing approach, the aVnZ extrapolated results are equivalent to or better than results obtained from raw aV(n + 3)Z basis set calculations. To the extent this behavior holds for molecules outside the reference set, it represents an improvement of at least one basis set level over the original formulations and a further significant reduction in the amount of computer time needed to accurately approximate the basis set limit.


Burden of injury from explosive remnants of conflict in Lao PDR and Cambodia.
In postconflict settings, a substantial number of injuries and related disabilities are caused by land mines and explosive remnants of war. This article reviews the literature on the prevalence of these injuries and subsequent disabilities in Cambodia and Lao PDR. Three major electronic databases were systematically for publications on the prevalence of these injuries. Six studies met the inclusion criteria. Five of these were in Cambodia and 1 in Lao PDR. None of these studies could estimate national prevalence rates of these injuries; only 2 considered the broader impact of related disabilities. The different methodological approaches and limitations of the studies prevented statistical synthesis. The studies reviewed suggested accurate estimates of the prevalence of war injuries and consequent disabilities are missing. There is a need for a comprehensive epidemiological research to quantify the burden that results from such injuries.


snRNAs are reduced in the syncytiotrophoblast: a possible mechanism for regulation of human placental protein production.
The multinucleate syncytiotrophoblast of the human placenta is formed by fusion of the underlying cytotrophoblast progenitor cells. The large surface area of the syncytiotrophoblast is necessary for transport functions while it also serves as the site of synthesis of hormones and steroids. Studies of syncytiotrophoblast transcription are puzzling, demonstrating that many of the nuclei in the multinucleated syncytium are transcriptionally inactive. To further elucidate RNA activity in the syncytiotrophoblast, we investigated expression of snRNAs involved in RNA splicing. Using RNA in situ hybridization, we observed that snRNAs were markedly reduced in the syncytium throughout the course of pregnancy. Recapitulating these results in primary trophoblasts and in trophoblast cell lines in vitro, we found, using qRT-PCR and RNA in situ hybridization, that snRNA expression is reduced in trophoblasts cultured under fusion conditions. Our finding that snRNA is markedly reduced in the syncytiotrophoblast suggests that the placenta has evolved a balance between the large surface area essential for its transport function and the need to regulate protein production in the multinucleated syncytium.


Pattern of Change in Renal Function Following Radical Nephrectomy for Renal Cell Carcinoma.
Radical nephrectomy (RN) is an independent risk factor for the development of chronic kidney disease (CKD) in those with renal cell carcinoma (RCC). We aimed to examine the pattern of change in post-operative renal function in patients who underwent RN for RCC over a 3 year period at our institution. We performed a retrospective review of histological and biochemical findings in patients undergoing RN for RCC over a 38 month period. Estimated glomerular filtration rate (eGFR) was recorded pre- and post-operatively and at follow-up. We analysed data on 131 patients (median follow-up 24 months). The proportion of patients with advanced CKD increased significantly at follow-up with 48 (85.7%) patients, classified as having stage 2 CKD pre-operatively, being re-classified as stage 3-5. Mean eGFR was significantly lower pre-operatively (76.6 mL/min/1.73 m2) compared to hospital discharge (61 mL/min/1.73 m2, p < 0.001) and follow-up (55.5 mL/min/1.73 m2, p < 0.001). Those with pT1 tumours sustained a significantly greater decline in eGFR compared to other stages. In conclusion, patients with pT1 a and pT1 b tumours sustain a disproportionate decline in renal function and may benefit the most from NSS.


[Primary culture and characterization of human ovarian surface epithelial cells].
Primary culture and characterization of the human ovarian surface epithelial cells were carried out to make a preliminary trial of the histogenetic consideration of common epithelial tumors of the ovary utilizing in vitro systems. Ovarian surface epithelial cells were harvested from strips of surgically excised ovary using an explant culture method and submitted to studies. The cells appeared flat epithelioid in shape and arranged in a cobblestone pattern. Immunocytochemical stainings by the PAP method revealed that these epithelioid cells were keratin and vimentin positive. The cells grew in the medium of RPMI 1640 with 10% fetal calf serum and the growth rate was accelerated significantly when supplemented with hEGF (10 ng/ml) and hydrocortisone (0.5 microgram/ml). When epithelioid cells were cultivated on Matrigel coated glass, some morphological changes were brought about by treating them with TPA (10 ng/ml) or sodium butyrate (1.5 mM). When the cells were cultivated on type I collagen gel, the arrangement of the cells appeared to be mostly monolayer. Grown in Matrigel overlaid on type I collagen gel, the cells grouped and arranged seemingly in spreading branches. Although no malignant transformation has been observed, some morphological changes reminiscent of metaplastic change were seen in some of the cultured cells when the media were treated repeatedly with 5-azacytidine (3 microM), the DNA hypomethylating agent. The results reported may help to some extent to clarify the biological nature of ovarian surface epithelial cells including ovarian tumorigenesis which still remains unknown.


Randomized controlled trial of telephone-delivered cognitive behavioral therapy for chronic insomnia.
To compare the efficacy of telephone-delivered cognitive-behavioral therapy for insomnia to an information pamphlet control on sleep and daytime functioning at pretreatment, posttreatment, and 12-wk follow-up. Randomized controlled parallel trial. N/A. Thirty individuals with chronic insomnia (27 women, age 39.1 ± 14.4 years, insomnia duration 8.7 ± 10.7 years). Cognitive behavioral therapy for insomnia (CBTI) delivered in up to eight weekly telephone sessions (CBTI-Phone, n = 15) versus an information pamphlet control (IPC, n = 15). Sleep/wake diary, sleep-related questionnaires (Insomnia Severity Index, Pittsburgh Sleep Quality Index, 16-item Dysfunctional Beliefs and Attitudes about Sleep), and daytime symptom assessments (fatigue, depression, anxiety, and quality of life) were completed at pretreatment, posttreatment, and 12-wk follow-up. Linear mixed models indicated that sleep/wake diary sleep efficiency and total sleep time improved significantly at posttreatment in both groups and remained stable at 12-wk follow-up. More CBTI-Phone than IPC patients showed posttreatment improvements in unhelpful sleep-related cognitions (P < 0.001) and were classified as "in remission" from insomnia at follow-up (P < 0.05). Posttreatment effect sizes on most daytime symptoms were large (Cohen d = 0.8-2.5) for CBTI-Phone patients and small to moderate (Cohen d = -0.1-0.6) for IPC patients. All CBTI-Phone patients completed posttreatment and 12-wk follow-up assessments, but three IPC patients discontinued the study. The findings provide preliminary support for telephone-delivered CBTI in the treatment of chronic insomnia. Future larger-scale studies with more diverse samples are warranted. Some individuals with insomnia may also benefit from pamphlet-delivered CBTI with brief telephone support. Arnedt JT; Cuddihy L; Swanson LM; Pickett S; Aikens J; Chervin RD. Randomized controlled trial of telephone-delivered cognitive behavioral therapy for chronic insomnia. SLEEP 2013;36(3):353-362.


Eradication of Acinetobacter baumannii/Enterobacter cloacae complex in an open proximal tibial fracture and closed drop foot correction with a multidisciplinary approach using the Taylor Spatial Frame®: a case report.
Multi-drug-resistant bacteria (e.g. Carbapenem-resistant Acinetobacter baumannii, extended-spectrum betalactamase or carbapenemase-producing enterobacteriaceae) are emerging in early-onset infections. So far, there is no report describing the eradication of these bacteria in a osseous infection of an open proximal tibial fracture in combination with the hexapod technology to address both osseous consolidation and closed drop foot correction. After sustaining a proximal tibial fracture (Gustilo 3B), a 41-year-old man was primarily treated with open reduction and internal fixation by a locking plate and split-thickness skin graft in the home country. At the time of admission to our hospital there was a significant anterolateral soft tissue defect covered with an already-necrotic split-thickness graft and suspicious secretion. CAT and MRI scans revealed no signs of osseous healing, intramedullary distinctive osteomyelitis, as well as a large abscess zone in the dorsal compartment. Multiple wound smears showed multi-drug-resistant bacteria: Acinetobacter baumannii (Carbapenem resistant) as well as Enterobacter cloacae complex (AmpC overexpression). After implant removal, excessive osseous and intramedullary debridements using the Reamer Irrigator Aspirator (RIA®) as well as initial negative pressure wound therapy were performed. Colistin hand-modelled chains and sticks were applied topically as well as an adjusted systemic antibiotic scheme was applied. After repetitive surgical interventions, the smears showed bacterial eradication and the patient underwent soft tissue reconstruction with a free vascularized latissimus dorsi muscle flap. External fixation was converted to a hexapod fixator (TSF®) to correct primary varus displacement, axial assignment and secure osseous healing. A second ring was mounted to address the fixed drop foot in a closed fashion without further intervention. At final follow-up, 12 months after trauma, the patient showed good functional recovery with osseous healing, intact soft tissue with satisfactory cosmetics and no signs of reinfection. A multidisciplinary approach with orthopaedic surgeons for debridement, planning and establishing osseous and joint correction and consolidation, plastic surgeons for microvascular muscle flaps for soft tissue defect coverage as well as clinical microbiologists for the optimized anti-infective treatment is essential in these challenging rare cases. Level IV.


Sequence learning in human ocular smooth pursuit.
It has been established that repeated presentation of a transient target motion stimulus such as a constant-velocity ramp leads to the build up of steady state (SS), anticipatory smooth pursuit eye movements after two or three presentations. Each SS response is then composed of the anticipatory component of nonvisual origin, a visual component associated with the stimulus presentation and another nonvisual component that represents the decay of the response after extinction of the stimulus. Here we investigated the interactions that occur when each motion stimulus was itself a sequence containing more than one ramp component. Ramp components had a velocity of 15 degrees /s or 30 degrees /s to left or right and were separated by gaps of 200 ms duration. In an initial experiment, responses to 2-ramp stimuli were examined and compared with responses to the single-ramp stimuli from which they were constituted. We present evidence that the anticipatory, nonvisual components of the double-ramp response result from the linear summation of the nonvisual components of the responses to the constituent single-ramp components. In a 2nd experiment, we examined responses to a wide variety of 4-ramp sequences and again found evidence that, in the SS, the responses were formed from the linear summation of the constituent single-ramp components. Regression analysis performed on the velocity at onset of each ramp component indicated that this nonvisual part of the response was predictive of the upcoming ramp component. To confirm this, unexpected changes were introduced into single ramp components of the 4-ramp sequence after at least five prior presentations of the sequence had allowed a SS response to be established. Subjects continued to initiate a response to the modified component that was appropriate in velocity and direction for the corresponding part of the previous sequence and inappropriate for the newly modified stimulus. This preprogrammed response persisted unmodified for more than 170 ms after onset of the modified ramp component. In contrast, in the second presentation of the new sequence, the anticipatory component of the response was highly correlated with the SS response of the new sequence, but not with that of the prior sequence, showing that the preprogrammed response had been modified very rapidly. Similar behaviour was observed whichever of the 4-ramp components was modified, indicating that the velocity and direction of the anticipatory response to each component had been preprogrammed. The results suggest that velocity information related to at least four elements of a sequence can be temporarily stored and subsequently released with appropriate temporal order to form an anticipatory response throughout the whole sequence.


Clinical characteristics and outcome of the capsular warning syndrome: a multicenter study.
The capsular warning syndrome is defined as recurrent transient lacunar syndromes that usually precede a capsular infarction. Several aspects regarding the clinical management are controversial. We report the clinical and radiological characteristics of a multicenter series of patients with capsular warning syndrome, as well as their functional outcome during the follow-up. We sought to describe the clinico-radiological spectrum of the capsular warning syndrome and to report the functional outcomes and recurrences of these patients during the follow-up. We conducted a multicenter study that collected clinical and radiological data from patients with capsular warning syndrome during 2003-2013. Capsular warning syndrome was defined as the succession of three or more motor or sensory-motor lacunar syndromes within a period of 72 h, with complete recovery between them. We recorded the functional outcome (favorable when Rankin scale score ≤2) and recurrences during follow-up. Our study included 42 patients whose mean age was 66.4 ± 10 years; 71.4% of them were men. The mean number of episodes before a permanent neurological impairment occurred or before a complete recovery of symptoms was 5.1 ± 2.3. Up to 30 patients (71.2%) had an acute infarct visible on the neuroimaging (computed tomography/magnetic resonance imaging). The internal capsule was the most frequent infarct location (50%), but other locations were noted. Twelve patients (28.6%) received thrombolysis in the acute phase. A favorable outcome was observed in 39 patients (92.9%). After a mean follow-up of 35 ± 29 months, only one patient suffered a recurrent ischemic stroke. Capsular warning syndrome preceded an ischemic infarction in 71.2% of patients. In addition to the internal capsule, other locations were noted. The most effective treatment remains unclear. The functional prognosis is favorable in most patients and recurrences are rare.


A rapid and simple approach to preparation of monoclonal antibody based on DNA immunization.
Inoculation with purified specific protein is usually the first step for preparation of monoclonal antibody (mAb). But it is quite difficult to obtain pure proteins especially with natural structures. Here we attempt to replace the protein inoculation with DNA immunization in the preparation of mAb. The eukaryotic expression vectors pcDNA3-PreS2/S and pVAX-PreS2/S encoding the HBV M protein were constructed and prepared for DNA immunization. Female BALB/c mice developed a well antibody response to the target antigen after muscle injection with corresponding plasmids. The mice with effective antibodies induced were used for preparation of mAb. We found the mice immunized with three administrations of pcDNA3-PreS2/S and boosted by intrasplenic injection with the same plasmid could be exploited for preparation of mAb. And positive hybridoma cell 2D3 that can secrete specific mAb was cloned and analyzed. Our studies demonstrate that gene immunization may provide a convenient and efficient way to prepare mAbs.


Effects of glucocorticoids on B-cell subpopulations in patients with IgG4-related disease.
Glucocorticoids induce prompt clinical improvement in patients with IgG4-related disease (IgG4-RD) but their mechanisms of action in this specific condition are not fully understood. B lymphocytes appear central to IgG4-RD pathogenesis because B-cell depletion with rituximab leads to swift clinical responses. In the present work we aim to assess the effects of glucocorticoids on B-cell subpopulations in patients with IgG4-RD. Fifty patients with active untreated IgG4-RD and 20 healthy controls were enrolled in the present study. Flow cytometry analysis for total circulating CD19+ and CD20+ cells, naïve B cells, memory B cells, plasmablasts, and plasma cells was performed at baseline in all patients, and after 6 months of glucocorticoid treatment in 30 patients. Correlation studies with biomarkers of disease activity were also performed. At baseline, patients with IgG4-RD showed reduced CD19+ and CD20+ B cells compared to healthy controls, but increased circulating plasmablasts and plasma cells. Circulating plasmablasts and plasma cells correlated with clinical and serological biomarkers of IgG4-RD activity. Glucocorticoid-induced disease remission was accompanied by a reduction of naïve B cell count, an increase of memory B cells, and by a depletion of circulating plasmablasts and plasma cells. CD19+ and CD20+ B cells, were not affected by glucocorticoids. The efficacy of glucocorticoids in IgG4-RD is associated with selective effects on different B-cell subpopulations. Further studies are warranted to fully understand possible perturbations of the naïve and memory B-cell compartments in patients with IgG4-RD.


Regulation of aldosterone production from zona glomerulosa cells by ANG II and cAMP: evidence for PKA-independent activation of CaMK by cAMP.
Aldosterone production in zona glomerulosa (ZG) cells of adrenal glands is regulated by various extracellular stimuli (K(+), ANG II, ACTH) that all converge on two major intracellular signaling pathways: an increase in cAMP production and calcium (Ca(2+)) mobilization. However, molecular events downstream of the increase in intracellular cAMP and Ca(2+) content are controversial and far from being completely resolved. Here, we found that Ca(2+)/calmodulin-dependent protein kinases (CaMKs) play a predominant role in the regulation of aldosterone production stimulated by ANG II, ACTH, and cAMP. The specific CaMK inhibitor KN93 strongly reduced ANG II-, ACTH-, and cAMP-stimulated aldosterone production. In in vitro kinase assays and intact cells, we could show that cAMP-induced activation of CaMK, using the adenylate cyclase activator forskolin or the cAMP-analog Sp-5,6-DCI-cBIMPS (cBIMPS), was not mediated by PKA. Activation of the recently identified cAMP target protein Epac (exchange protein directly activated by cAMP) by 8-pCPT-2'-O-Me-cAMP had no effect on CaMK activity and aldosterone production. Furthermore, we provide evidence that cAMP effects in ZG cells do not involve Ca(2+) or MAPK signaling. Our results suggest that ZG cells, in addition to PKA and Epac/Rap proteins, contain other as yet unidentified cAMP mediator(s) involved in regulating CaMK activity and aldosterone secretion.


Inequities in Health Outcomes in Children and Adults With Type 1 Diabetes: Data From the T1D Exchange Quality Improvement Collaborative.
Health care inequities among racial and ethnic groups remain prevalent. For people with type 1 diabetes who require increased medical access and care, disparities are seen in access to care and health outcomes. This article reports on a study by the T1D Exchange Quality Improvement Collaborative evaluating differences in A1C, diabetic ketoacidosis (DKA), severe hypoglycemia, and technology use among racial and ethnic groups. In a diverse cohort of nearly 20,000 children and adults with type 1 diabetes, A1C was found to differ significantly among racial and ethnic groups. Non-Hispanic Blacks had higher rates of DKA and severe hypoglycemia and the lowest rate of technology use. These results underscore the crucial need to study and overcome the barriers that lead to inequities in the care and outcomes of people with type 1 diabetes.


Electrically conducting diamond films grown on platinum foil for neural stimulation.
With the strong drive towards miniaturization of active implantable medical devices and the need to improve the resolution of neural stimulation arrays, there is keen interest in the manufacture of small electrodes capable of safe, continuous stimulation. Traditional materials such as platinum do not possess the necessary electrochemical properties to stimulate neurons safely when electrodes are very small (i.e. typically less than about 300 µm (78 400 µm2)). While there are several commercially viable alternative electrode materials such as titanium nitride and iridium oxide, an attractive approach is modification of existing Pt arrays via a high electrochemical capacitance material coating. Such a composite electrode could still take advantage of the wide range of fabrication techniques used to make platinum-based devices. The coating, however, must be biocompatible, exhibit good adhesion and ideally be long lasting when implanted in the body. Platinum foils were roughened to various degrees with regular arrays of laser milled pits. Conducting diamond films were grown on the foils by microwave plasma chemical vapor deposition. The adhesion strength of the films to the platinum was assessed by prolonged sonication and accelerated aging. Electrochemical properties were evaluated and compared to previous work. In line with previous results, diamond coatings increased the charge injection capacity of the platinum foil by more than 300% after functionalization within an oxygen plasma. Roughening of the underlying platinum substrate by laser milling was required to generate strong adhesion between the diamond and the Pt foil. Electrical stress testing, near the limits of safe operation, showed that the diamond films were more electrochemically stable than platinum controls. The article describes a new method to protect platinum electrodes from degradation in vivo. A 300% increase in charge injection means that device designers can safely employ diamond coated platinum stimulation electrodes at much smaller sizes and greater density than is possible for platinum.


Direct hydrogen selenide (H2Se) release from activatable selenocarbamates.
Hydrogen selenide (H2Se) is a possible bioregulator, potential gasotransmitter, and important precursor in biological organoselenium compound synthesis. Early tools for H2Se research have benefitted from available mechanistic understanding of analogous small molecules developed for detecting or delivering H2S. A now common approach for H2S delivery is the use of small molecule thiocarbamates that can be engineered to release COS, which is quickly converted to H2S by carbonic anhydrase. To expand our understanding of the chemical underpinnings that enable H2Se delivery, we investigated whether selenocarbamates undergo similar chemistry to release carbonyl selenide (COSe). Using both light- and hydrolysis-activated systems, we demonstrate that unlike their lighter thiocarbamate congeners, selenocarbamates release H2Se directly with concomitant isocyanate formation rather than by the intermediate release of COSe. This reaction mechanism for direct H2Se release is further supported by computational investigations that identify a ΔΔG‡ ∼ 25 kcal mol-1 between the H2Se and COSe release pathways in the absence of protic solvent. This work highlights fundamentally new approaches for H2Se release from small molecules and advances the understanding of reactivity differences between reactive sulfur and selenium species.


Chemiluminescence and oxygen radical generation by Walker carcinosarcoma cells following chemotactic stimulation.
The peptide N-formyl-Met-Leu-Phe stimulates chemotaxis and metastasis in rat Walker carcinosarcoma cells by a receptor-mediated pathway. Since oxygen radical generation follows chemotactic stimulation in leukocytes, we looked for similar responses in the Walker tumor. Upon incubation with 10(-6) M N-formyl-Met-Leu-Phe, Walker cells elicited chemiluminescence in the presence of 5 X 10(-5) M luminol. The response peaked within 2 min and was maintained for greater than 20 min; it was dose dependent with a 50% maximal effective dose (ED50) value of 4.5 X 10(-8) comparable to the 50% maximal effective dose value for chemotaxis. The responses were significantly reduced but not abolished in the absence of calcium in the external medium and were elicited by the ionophore A23187. The lipoxygenase inhibitor nordihydroguaiaretic acid had almost no effect in decreasing the response, while flurbiprofen, a cyclooxygenase inhibitor was very effective at 10(-6) M. Evidence for the generation of oxygen radicals included: (a) marked inhibition of light emission in the absence of oxygen; (b) inhibition in the presence of superoxide dismutase, catalase, and mannitol; and (c) dose-dependent reduction of acetylated cytochrome c. We postulate that activation of circulating tumor cells may facilitate metastasis by the release of toxic oxygen species.


PIF3 is a negative regulator of the CBF pathway and freezing tolerance in Arabidopsis.
Light and temperature are major environmental factors that coordinately control plant growth and survival. However, how plants integrate light and temperature signals to better adapt to environmental stresses is poorly understood. PHYTOCHROME-INTERACTING FACTOR 3 (PIF3), a key transcription factor repressing photomorphogenesis, has been shown to play a pivotal role in mediating plants' responses to various environmental signals. In this study, we found that PIF3 functions as a negative regulator of Arabidopsis freezing tolerance by directly binding to the promoters of C-REPEAT BINDING FACTOR (CBF) genes to down-regulate their expression. In addition, two F-box proteins, EIN3-BINDING F-BOX 1 (EBF1) and EBF2, directly target PIF3 for 26S proteasome-mediated degradation. Consistently, ebf1 and ebf2 mutants were more sensitive to freezing than were the wild type, and the pif3 mutation suppressed the freezing-sensitive phenotype of ebf1 Furthermore, cold treatment promoted the degradation of EBF1 and EBF2, leading to increased stability of the PIF3 protein and reduced expression of the CBF genes. Together, our study uncovers an important role of PIF3 in Arabidopsis freezing tolerance by negatively regulating the expression of genes in the CBF pathway.


Analysis by immunoblotting of human cytomegalovirus antibody in sera of renal transplant recipient.
Human cytomegalovirus-infected cell polypeptides were immunoreacted by sera of renal transplant recipients and compared with those reactive with sera of healthy adult donors by means of the Western immunoblotting technique. At least 15 polypeptides with molecular weights of 155K, 123K, 102K, 89K, 79K, 71K, 65K, 60K, 55K, 50K, 46K, 42K, 38K, 33K, and 28K were immunoreacted. Sera obtained serially from renal transplant recipients reacted with most of these polypeptides and reacted more frequently and intensely with the smaller polypeptide species such as 38K, 33K, and 28K, compared with sera of healthy seropositive adults. The implications of these findings are discussed.


[Therapeutic possibilities in idiopathic headaches. Analysis of about 1000 cases].
This work is an attempt to find an answer to the question: once arrived at the diagnostic identification of a certain type of idiopathic headache, which treatment should be followed? On the basis of recent researches and experience acquired during ten years' activity of our Headache Unit, a diagnostic identification can be made for migraine (in all its types and evolution stages), cluster headache, tension headache and pure psycogenic headache. Among the most widely used drugs, positive pharmacological results were obtained with: cyproheptadine, pizotifen, cinnarizine, lysergic acid derivatives, histamine, reserpine, clonidine and a barbituric acid derivative. The therapeutic cycles were standardized, for each drug, in the way of administration, dosage and total duration of the treatment. A comparison between the data obtained and the pre-therapeutic situation was made. When repeated, the most efficacious therapeutic cycle was evaluated. According to Pearson's dispersion index, each group of patients improved respresents 16.68% of the expected total results (frequency of attacks reduced to 50%, 25% and 0%): for cyproheptadine, pizotifen, methysergide, histamine, clonidine and allil-propyl-malonylurea, the "p" is less than 0.001; for cinnarizine, less than 0.02. This "a posteriori" analysis does not take into account the placebo control, the "anticipation effect", and the "carry over effect". It cannot therefore be a comparison of efficacy among the various drugs. An evaluation based on "among patients" and "inside patient" method by means of the cross over system, can instead give some useful suggestion about which treatment is to be recommended to patients suffering from recurrent headaches. With regard to migraine sufferers: cinnarizine, cyproheptadine, clonidine, histamine, pizotifen und reserpine. For cluster headaches: cinnarizine, cyproheptadine, clonidine, histamine and reserpine. For tension headaches: cyproheptadine. For pure psychogenic headache: allyl-propyl-malonylurea. For migraine attacks or parossystic crises in the course of ondulating or continuous headaches, positive therapeutic results, statistically significant, were obtained with an association of indomethacin, caffeine and prochlorperazine.


GATA Transcription Factors: Basic Principles and Related Human Disorders.
The development of mature blood cell from hematopoietic stem cells is regulated by transcription factors that coordinate the expression of lineage-specific genes. GATA transcription factors are zinc finger DNA-binding proteins that play crucial roles in various biological processes, including hematopoiesis. Among GATA family proteins, GATA-1, GATA-2, and GATA-3 are essential for hematopoiesis. GATA-1 functions to promote development of erythrocytes, megakaryocytes, eosinophils, and mast cells. Mutations in GATA-1 are associated with acute megakaryoblastic leukemia (AMKL), congenital erythroid hypoplasia (Diamond-Blackfan anemia; DBA), and X-linked anemia and/or thrombocytopenia. Conversely, GATA-2 functions early in hematopoiesis and is required for maintenance and expansion of hematopoietic stem cells (HSCs) and/or multipotent progenitors. GATA-2 mutations are associated with immunodeficiency, lymphedema, myelodysplastic syndrome (MDS), and leukemia. Furthermore, decreased GATA-2 expression may contribute to the pathophysiology of aplastic anemia. GATA-3 has an important role in T cell development, and has been suggested to be involved in the pathophysiology of acute lymphoblastic leukemias. This review summarizes current knowledge on hematological disorders associated with GATA-1 and GATA-2 mutations.


Association between Reflux Esophagitis Incidence and Palmar Hyperhidrosis.
The autonomic dysfunction in palmar hyperhidrosis (PH) includes not only sympathetic overactivity but also parasympathetic impairment. A decrease of parasympathetic tone has been noted in gastroesophageal reflux disease of neonates and adults. Patients with reflux esophagitis have a defective anti-reflux barrier. The association between reflux esophagitis and PH is deliberated in this article. The National Health Insurance Database in Taiwan was used. At first-time visits, PH patients were identified by the International Classification of Disease, 9th Revision, Clinical Modification disease code of 780.8 without endoscopic thoracic sympathectomy. Patients were matched by age and gender as control groups. The reflux esophagitis incidence was assessed using disease codes 530.11, 530.81, and 530.85. The factors related to reflux esophagitis were established by the Cox proportional regression model. The risk of reflux esophagitis in PH patients had a hazard ratio of 3.457 (95% confidence interval: 3.043-3.928) after adjustment of the other factors. We confirmed the association between reflux esophagitis and PH. Health care providers must be alerted to this relationship and other risk factors of reflux esophagitis to support suitable treatments to improve the quality of life of patients.


Controls on the cell cycle.
The control of cell proliferation, in physiological terms, depends not so much on our understanding of the sequence of biochemical events unfolding as a cell progresses through its proliferation cycle, as upon the recognition by a tissue of the demands for functional cells of a particular type. After considering the modes of control possible, i.e. by recruitment of resting G0-state cells into cycle or by modifying the proliferative behaviour of already proliferating cells, haemopoietic tissue is used as a model to illustrate how the principles of proliferation control in specific cell lineages can be effected. Although the mode of stem cell control is different from that in the maturing populations, all depend on a co-ordination of negative feedback loops for inhibitor and stimulator which are specific to that cell population. The concept of a 'quantal' cell cycle is considered but its application to control in an adult steady-state tissue must be modified to take account of microenvironmental influences which are shown, by their cellular organization, to be an important feature in haemopoietic and probably all other tissues.


HIV delays IFN-α production from human plasmacytoid dendritic cells and is associated with SYK phosphorylation.
Plasmacytoid dendritic cells (pDC) are the major producers of type I interferons (IFNs) in humans and rapidly produce IFN-α in response to virus exposure. Although HIV infection is associated with pDC activation, it is unclear why the innate immune response is unable to effectively control viral replication. We systematically compared the effect of HIV, Influenza, Sendai, and HSV-2 at similar target cell multiplicity of infection (M.O.I.) on human pDC function. We found that Influenza, Sendai, HSV-2 and imiquimod are able to rapidly induce IFN-α production within 4 hours to maximal levels, whereas HIV had a delayed induction that was maximal only after 24 hours. In addition, maximal IFN-α induction by HIV was at least 10 fold less than that of the other viruses in the panel. HIV also induced less TNF-α and MIP-1β but similar levels of IP-10 compared to other viruses, which was also mirrored by delayed upregulation of pDC activation markers CD83 and CD86. BDCA-2 has been identified as an inhibitory receptor on pDC, signaling through a pathway that involves SYK phosphorylation. We find that compared to Influenza, HIV induces the activation of the SYK pathway. Thus, HIV delays pDC IFN-α production and pDC activation via SYK phosphorylation, allowing establishment of viral populations.


[Anti-arrhythmic effectiveness of ethmozine, cordaron and rhythmodan in treating ischemic heart disease].
The authors observed 127 patients with different disorders of the cardiac rhythm treated with ethmozine, cordarone and rhythmodan. To assess the efficacy of the therapy circadian ECG was recorded on a magnetic tape with a portable cardiomonitor, exercise tests (bicycle ergometry, treadmill and walking under ECG control) were conducted. Good effect was seen after a course of treatment in patients with ventricular and atrial extrasystolae, paroxysms of supraventricular, ventricular tachycardia and auricular fibrillation. Cordarone was found effective in the Wolff-Parkinson - White syndrome and paroxysms of supraventricular tachycardia.


Normalized Power Variance: A new Field Orthogonal to Power in EEG Analysis.
To date, electroencephalogram (EEG) has been used in the diagnosis of epilepsy, dementia, and disturbance of consciousness via the inspection of EEG waves and identification of abnormal electrical discharges and slowing of basic waves. In addition, EEG power analysis combined with a source estimation method like exact-low-resolution-brain-electromagnetic-tomography (eLORETA), which calculates the power of cortical electrical activity from EEG data, has been widely used to investigate cortical electrical activity in neuropsychiatric diseases. However, the recently developed field of mathematics "information geometry" indicates that EEG has another dimension orthogonal to power dimension - that of normalized power variance (NPV). In addition, by introducing the idea of information geometry, a significantly faster convergent estimator of NPV was obtained. Research into this NPV coordinate has been limited thus far. In this study, we applied this NPV analysis of eLORETA to idiopathic normal pressure hydrocephalus (iNPH) patients prior to a cerebrospinal fluid (CSF) shunt operation, where traditional power analysis could not detect any difference associated with CSF shunt operation outcome. Our NPV analysis of eLORETA detected significantly higher NPV values at the high convexity area in the beta frequency band between 17 shunt responders and 19 non-responders. Considering our present and past research findings about NPV, we also discuss the advantage of this application of NPV representing a sensitive early warning signal of cortical impairment. Overall, our findings demonstrated that EEG has another dimension - that of NPV, which contains a lot of information about cortical electrical activity that can be useful in clinical practice.


Measurement Properties of Visual Analogue Scale, Numeric Rating Scale, and Pain Severity Subscale of the Brief Pain Inventory in Patients With Low Back Pain: A Systematic Review.
The Visual Analogue Scale (VAS), Numeric Rating Scale (NRS), and Pain Severity subscale of the Brief Pain Inventory (BPI-PS) are the most frequently used instruments to measure pain intensity in low back pain. However, their measurement properties in this population have not been reviewed systematically. The goal of this study was to provide such systematic evidence synthesis. Six electronic sources (MEDLINE, EMBASE, CINAHL, PsycINFO, SportDiscus, Google Scholar) were searched (July 2017). Studies assessing any measurement property in patients with nonspecific low back pain were included. Two reviewers independently screened articles and assessed risk of bias using the COSMIN checklist. For each measurement property, evidence quality was rated as high, moderate, low, or very low (GRADE approach) and results were classified as sufficient, insufficient, or inconsistent. Ten studies assessed the VAS, 13 the NRS, 4 the BPI-PS. The 3 instruments displayed low or very low quality evidence for content validity. High-quality evidence was only available for NRS insufficient measurement error. Moderate evidence was available for NRS inconsistent responsiveness, BPI-PS sufficient structural validity and internal consistency, and BPI-PS inconsistent construct validity. All VAS measurement properties were underpinned by no, low, or very low quality evidence; likewise, the other measurement properties of NRS and BPI-PS. PERSPECTIVES: Despite their broad use, there is no evidence clearly suggesting that one among VAS, NRS, and BPI-PS has superior measurement properties in low back pain. Future adequate quality head-to-head comparisons are needed and priority should be given to assessing content validity, test-retest reliability, measurement error, and responsiveness.


An Evidence-Based Multidisciplinary Approach Focused at Creating Algorithms for Targeted Therapy of BSIs, cUTIs, and cIAIs Caused by Enterobacterales in Critically Ill Adult Patients.
Prompt implementation of appropriate targeted antibiotic therapy represents a valuable approach in improving clinical and ecological outcome in critically septic patients. This multidisciplinary opinion article focused at developing evidence-based algorithms for targeted antibiotic therapy of bloodstream (BSIs), complicated urinary tract (cUTIs), and complicated intrabdominal infections (cIAIs) caused by Enterobacterales. The aim was to provide a guidance for intensive care physicians either in appropriately placing novel antibiotics or in considering strategies for sparing the broadest-spectrum antibiotics. A multidisciplinary team of experts (one intensive care physician, one infectious disease consultant, one clinical microbiologist and one MD clinical pharmacologist), performed several rounds of assessment to reach agreement in developing six different algorithms according to the susceptibility pattern (one each for multi-susceptible, extended-spectrum beta-lactamase-producing, AmpC beta-lactamase-producing, Klebsiella pneumoniae carbapenemase (KPC)-producing, OXA-48-producing, and Metallo-beta-lactamase (MBL)-producing Enterobacterales). Whenever multiple therapeutic options were feasible, a hierarchical scale was established. Recommendations on antibiotic dosing optimization were also provided. In order to retrieve evidence-based support for the therapeutic choices proposed in the algorithms, a comprehensive literature search was performed by a researcher on PubMed-MEDLINE from inception until March 2021. Quality and strength of evidence was established according to a hierarchical scale of the study design. Only articles published in English were included. It is expected that these algorithms, by allowing prompt revision of antibiotic regimens whenever feasible, appropriate place in therapy of novel beta-lactams, implementation of strategies for sparing the broadest-spectrum antibiotics, and pharmacokinetic/pharmacodynamic optimization of antibiotic dosing regimens, may be helpful either in improving clinical outcome or in containing the spread of antimicrobial resistance.


Report on the clinical workstation and clinical data repository utilization at UNC Hospitals.
On December 1, 1993, we implemented version 2.1 of the Clinical Workstation-Clinical Data Repository application in the Ambulatory Care Center. This version of the workstation allowed access of laboratory data from the clinical data repository that had been populated by a real-time HL7 interface between the Clinical Data Repository and the Laboratory Information System. This implementation completed a major part of the Clinical Workstation project. Also in December, we implemented a security system that records the date and time, user logon code, clinical workstation functions used, and the patient medical record number on whom data were displayed. In addition to the security function, this system has proven to be a valuable tool in evaluating the utilization of the clinical workstation and is the source of the data presented in this paper.


Association of angiotensin-converting enzyme gene polymorphism with pulse pressure and its interaction with obesity status in Heilongjiang province.
Angiotensin I converting enzyme (ACE) gene is one of the most-studied candidate genes related to essential hypertension (EH). Pulse pressure (PP) may reflect vascular stiffness, especially in patients with EH, and has been used to predict EH. Previous evidence has indicated that obesity is a traditional risk factor of hypertension. The aim of the present study was to investigate the interaction between the obesity status and ACE gene polymorphisms on the development of high level of PP. A total of 1980 adults (1024 hypertensive and 956 normotensive) were included in this study and genotyped for ACE gene polymorphisms. The results showed that rs4343 and rs4351 in ACE gene were risk factors of high level of pulse pressure (p < 0.05). We also detected positive interactions between the two SNPs and obesity status in the pathway of high level PP.


Self-knowledge reduces conflict by biasing one of plural possible answers.
The authors investigated whether self-knowledge has a function to reduce conflict by biasing one of two choices during occupational choice (e.g., Which occupation do you think you could do better?-dancer or chemist). In the three experiments, event-related brain potentials were recorded. Experiment 1 revealed that the amplitude of the conflict-related negativity (CRN) reflects strength of conflict during occupational choice. Results of Experiment 2 demonstrated that the CRN amplitude during occupational choice was smaller when self-knowledge was activated than when other-knowledge was activated. Experiment 3 showed that the CRN amplitude during occupational choice was decreased more when self-knowledge that biases one choice of occupation was activated than when self-knowledge that does not bias was activated. These results suggest that self-knowledge reduces conflict by biasing one of multiple choices in situations where two or more possible correct answers can be given.


[Skin and stress].
The concept of stress was developed based on data from experimental pathology and psychology studies. Selye defined stress and described the physiologic changes induced by stress, under the designation "general adaptation syndrome". The interactive aspect of stress has since then been emphasized. Stress results from a unique interaction between a thinking individual and a physical or social environment. The presence in humans of a mental apparatus capable of thinking, reminiscing, and fantasizing accounts for the specific features of stress as a clinical condition. It follows that psychosomatic dermatology cannot be satisfied with defining and documenting stress, with establishing a link between stress and a disorder of the skin (an organ that plays a unique role in communication), and with evaluating the biological mechanism underlying the skin lesions. Another essential goal is to understand why an individual patient, with his or her unique history, develops a skin disorder as a manifestation of an inability to cope with adversity. Two psychologic factors should be taken into account in dermatology, namely stress and the personality of the person subjected to the stress. What makes a life event stressful is often the personality of the subject experiencing the event.


The absolute configuration of isochamigrene: new insights into the cyclisation mechanism of trichodiene synthase.
Isochamigrene, a side product of the trichodiene synthase, which is a key enzyme from the biosynthesis of the trichothecene mycotoxins from Fusarium spp., was enantioselectively synthesised and compared to the natural product from Fusarium sporotrichioides. As a result, its absolute configuration was assigned to (S)-isochamigrene. Implications for the recently extensively discussed cyclisation mechanism towards trichodiene and its side products are discussed.


Summary Report of Journal Operations, 2016.
Presents a summary report of journal operations compiled from the 2016 annual reports of the Council of Editors and from Central Office records. Also includes a summary report of division journal operations compiled from the 2016 annual reports of the division journal editors. (PsycINFO Database Record


The case for Pain Insomnia Depression Syndrome (PIDS): a symptom cluster in chronic nonmalignant pain.
This commentary suggests that pain, insomnia, and depression might be considered as a symptom cluster in chronic nonmalignant pain and that it might be called Pain Insomnia Depression Syndrome, or PIDS. Evidence is provided in support of the designation. The author suggests acceptance of PIDS would increase awareness of the pain comorbidities insomnia and depression, and this might lead to improved symptom management and better clinical outcomes.


Does exercise pulmonary hypertension exist?
The exercise definition of pulmonary hypertension using a mean pulmonary artery pressure threshold of greater than 30 mmHg was abandoned following the 4th World Pulmonary Hypertension Symposium in 2008, as this definition was not supported by evidence and healthy individuals frequently exceed this threshold. Meanwhile, the clinical value of exercise pulmonary hemodynamic testing has also been questioned. Recent data support the notion that an abnormal pulmonary hemodynamic response during exercise (or exercise pulmonary hypertension) is associated with symptoms and exercise limitation. Pathophysiologic mechanisms accounting for the development of exercise pulmonary hypertension include increased vascular resistance, excessive elevation in left atrial pressure and/or increased volume of trapped air during exercise, resulting in a steep rise in pulmonary artery pressure relative to cardiac output. Recent evidence suggests that exercise pulmonary hypertension may be defined by a mean pulmonary artery pressure surpassing 30 mmHg together with a simultaneous total pulmonary resistance exceeding 3 WU. Exercise pulmonary hypertension is a clinically relevant entity and an improved definition has been suggested based on new evidence. Exercise pulmonary hemodynamics may help unmask early or latent disease, particularly in populations that are at high risk for the development of pulmonary hypertension.


[The intestinal parasites in the food handlers of Tunis area: study of 8502 stool samples (1998-2008)].
The food handlers control is one of the major measures of the National program against intestinal parasitoses in Tunisia. The collected data allow regular updates of the prevalence and profile of the involved parasitic species and note possible evolutions in time. From 1998 to 2008, 8502 stool samples of food handlers working in Tunis area were examined in the laboratory of Parasitology, Pasteur Institute of Tunis. The mean prevalence of intestinal parasites was 13.5% (1152 positive samples). The protozoa were the most detected parasites (93% of the species observed). Among the pathogenic or potentially pathogenic parasites, Dientamoeba fragilis (15.5%) and Giardia intestinalis (7.6%) were the most frequently encountered. Entamoeba (E.) histolytica/dispar was diagnosed in 41 subjects (a prevalence of 05%). Hymenolepis nana was the most frequent helminth (45% of the whole parasites). Therapeutic failures were noticed in 43.8% of infection by this cestode because of the lack of the appropriate antihelminthic. The identification using PCR of cysts and/or vegetative forms of E. histolytica/dispar revealed the exclusive presence of E. dispar.


[Celiac disease presenting as an intestinal intussusception. Report of one case].
The usual form of presentation of celiac disease is chronic diarrhoea and deficiencies of vitamin D, vitamin K, iron and vitamin B12, due to malabsorption. Intestinal obstruction secondary to an intussusception is rare in adults and usually is a complication of carcinoma of the colon or post-operative adhesions. We report a 45 year-old female consulting for diarrhoea and vomiting lasting one week and progressive abdominal bloating. A plain abdominal X ray showed air fluid levels in the small bowel and a CT scan showed an intussusception. She was operated and discharged but continued with diarrhoea. She was admitted again and a new CT scan showed three intussusceptions that were resolved with the administration of oral contrast media. Antiendomisial antibodies were positive and a celiac disease was diagnosed. After one year with a gluten free diet, the patient remains asymptomatic.


Two-species asymmetric competition: effects of age structure on intra- and interspecific interactions.
1. The patterns of density-dependent resource competition and the mechanisms leading to competitive exclusion in an experimental two-species insect age-structured interaction were investigated. 2. The modes of competition (scramble or contest) and strength of competition (under- to overcompensatory) operating within and between the stages of the two species was found to be influenced by total competitor density, the age structure of the competitor community and whether competition is between stages of single or two species. 3. The effect of imposed resource limitation on survival was found to be asymmetric between stages and species. Environments supporting both dominant and subordinate competitors were found to increase survival of subordinate competitors at lower total competitor densities. Competitive environments during development within individual stage cohorts (i.e. small or large larvae), differed from the competitive environment in lumped age classes (i.e. development from egg-->pupae). 4. Competition within mixed-age, stage or species cohorts, when compared with uniform-aged or species cohorts, altered the position of a competitive environment on the scramble-contest spectrum. In some cases the competitive environment switched from undercompensatory contest to overcompensatory scramble competition. 5. Such switching modes of competition suggest that the relative importance of the mechanisms regulating single-species population dynamics (i.e. resource competition) may change when organisms are embedded within a wider community.


Fluorescent polymeric assemblies as stimuli-responsive vehicles for drug controlled release and cell/tissue imaging.
Polymer assemblies with good biocompatibility, stimuli-responsive properties and clinical imaging capability are desirable carriers for future biomedical applications. Herein, we report on the synthesis of a novel anthracenecarboxaldehyde-decorated poly(N-(4-aminophenyl) methacryl amide-oligoethyleneglycolmonomethylether methacrylate) (P(MAAPAC-MAAP-MAPEG)) copolymer, comprising fluorescent chromophore and acid-labile moiety. This copolymer can assemble into micelles in aqueous solution and shows a spherical shape with well-defined particle size and narrow particle size distribution. The pH-responsive property of the micelles has been evaluated by the change of particle size and the controlled release of guest molecules. The intrinsic fluorescence property endows the micelles with excellent cell/tissue imaging capability. Cell viability evaluation with human hepatocellular carcinoma BEL-7402 cells demonstrates that the micelles are nontoxic. The cellular uptake of the micelles indicates a time-dependent behavior. The H22-tumor bearing mice treated with the micelles clearly exhibits the tumor accumulation. These multi-functional nanocarriers may be of great interest in the application of drug delivery.


Processing of mutated proinsulin with tetrabasic cleavage sites to mature insulin reflects the expression of furin in nonendocrine cell lines.
Furin is a mammalian propeptide-processing endoprotease in nonendocrine cells and has been demonstrated to be present in virtually all nonendocrine cells, including fibroblasts, epithelial cells, and hepatocytes. Furin cleaves the concensus processing site -Arg-4-X-3-Lys/Arg-2-Arg-1 decreases X+1-. Some subunit-containing precursor proteins, including an insulin receptor precursor, possess an additional basic residue at position -3, thus forming a tetrabasic processing site. This implies that a tetrabasic processing site must be easily cleavable in nonendocrine cells. We created a mutant proinsulin DNA with a peptide structure comprised of B- and A-chains linked to the C-peptide by a pair of tetrabasic residues, in the following order: B-chain-Arg-Arg-Lys-Arg-C peptide-Arg-Arg-Lys-Arg-A-chain. The native proinsulin structure was B-chain-Arg-Arg-C-peptide-Lys-Arg-A-chain. Both the native and mutant proinsulins were expressed in the following four cell lines: a monkey kidney-derived cell line (COS-7), a Chinese hamster ovary-derived cell line (CHO), a human liver cancer-derived cell line (HepG2), and a mouse fibroblast-like cell line (NIH3T3). We used these cell lines because they contain different quantities of furin mRNA, ranking as follows: NIH3T3 > HepG2 > COS > CHO. When mutant insulin was expressed in these cells, the conversion of proinsulin to mature insulin was approximately 85% in NIH3T3, 70% in HepG2, 60% in COS, and 50% in CHO. The conversion correlated well with the furin expression in each cell line as measured by the density of its Northern blot band. Moreover, in CHO, the cell line with the lowest furin expression, coexpression of mutant proinsulin with furin resulted in complete conversion of proinsulin to mature insulin.


Amplification of DNA sequences during chicken cartilage and neural retina differentiation.
[3H]BrdUrd-substituted DNA probes were prepared from organ cultures of differentiating chicken neural retina and cell cultures of stage 24 chicken limb buds. Reassociation reactions using the neural retina probe demonstrated amplification of DNA sequences during differentiation of neural retina. This probe also contained sequences present in greater numbers in heart DNA than in DNA from undifferentiated neural retina. Reassociation reactions of both differentiated cartilage and differentiated neural retina DNA with both the neural retina probe and the cartilage probe demonstrated that at least part of the amplified sequences are tissue specific.


Digits and narratives of the experience of Italian families facing premature births.
The objective of the research was to understand the experience of families living a premature birth and to outline the current care plan in Italy. The survey was addressed to 150 parents of children born under the 34th week of pregnancy. Topics of the investigation were the implications on their family, social and working contexts, determined through a questionnaire enriched by a collection of narratives. Written testimonies were clustered through a Narrative Medicine method and matched with quantitative information. The main respondents were mothers of severe and moderate preterm children. Except for the Kangaroo Care, services were not uniformed amongst the centers and few home care supports resulted available for families. Sixty-seven percent of the mothers could not obtain a prolonged maternity leave and described the impacts on their working activities. Narratives revealed a low level of prevention, information and awareness on the risks of prematurity amongst families, few local networks among Neonatal Intensive Care Unit (NICU) teams, gynecologists and pediatricians, and the shortage of support for parents at work; these actions were collected in a Position Paper. Findings showed the integration between families' coping strategies and the offered care services for preterm births. Narrative tools could represent the bridge between families and health care teams.


Short and Medium Latency Responses in Participants With Chronic Ankle Instability.
The determinant role of medium latency responses (MLRs) during compensatory postural adjustments in postural stability and the lack of clarity about the mechanisms behind chronic ankle instability (CAI) sustain the hypothesis that these postural responses are impaired in this condition. However, to the best of our knowledge, no authors have assessed MLRs in patients with CAI; most of the research regarding compensatory postural adjustments has been directed at the timing of short latency responses (SLRs). To evaluate bilateral compensatory postural responses, including SLRs and MLRs, in response to a unilateral simulated ankle-sprain mechanism in participants with CAI. Case-control study. Laboratory. Twenty-four participants with CAI and 20 controls. Bilateral electromyography of the peroneus longus (PL), peroneus brevis, tibialis anterior (TA), and soleus (SOL) muscles was collected during a unilateral sudden-inversion perturbation (30°). Muscle-onset activations and magnitudes of SLRs and MLRs in the support and perturbed positions. Participants with CAI showed (1) later-onset activation of the TA and SOL in the uninjured limb and bilateral decreases in the magnitude of the TA MLR in the support position, (2) increased magnitude of the PL MLR in the uninjured limb in the support and perturbed positions, and (3) increased magnitude of the PL SLR and MLR in the injured limb in the perturbed position. Chronic ankle instability was associated with later TA and SOL activation in the uninjured limb and bilaterally decreased magnitude of the TA MLR in the support position.


Hematologic Malignancies Are Associated with Adverse Perioperative Outcomes following Total Knee Arthroplasty.
The treatment of hematologic malignancies has advanced over the years, resulting in an improved survival of patients. As a result, these patients may be a part of the increasing population requiring total knee arthroplasty (TKA); however, they might be at a higher risk of adverse perioperative outcomes. The purpose of this study was to determine the perioperative outcomes (complications, length of stay [LOS], and costs) of patients with hematologic malignancies following TKA. This study used the Nationwide Inpatient Sample (NIS) to identify patients who underwent TKA in the United States from 2000 to 2011. Patients diagnosed with any hematologic malignancy (N = 24,714) were then stratified by Hodgkin's disease (N = 791), Non-Hodgkin's lymphoma (N = 7,096), plasma cell dyscrasias (N = 1,621), leukemia (N = 8,005), myeloproliferative disease (N = 5,746), and/or myelodysplastic syndromes (N = 1,608) for determining the complications that occurred during admission. Propensity matching was performed for demographics, hospital characteristics, and comorbidities, which yielded 24,491 patients with any hematologic malignancy and 24,458 control patients. Additionally, propensity matching was performed for the hematologic malignancy subtypes. Multivariable regression models were used to analyze the surgical and medical complications, LOS, and costs. The annual frequency of THA in patients with any hematologic malignancy increased from 2000 to 2011 (p < 0.0001). Hematologic malignancies were associated with an increased risk of any surgery-related complication (odds ratio [OR] = 1.31, p < 0.0001) and any general medical complication (OR = 1.38, p < 0.0001). Patients with any hematologic malignancy had increased odds of complications, including acute postoperative anemia (OR = 1.29, p < 0.0001), hematoma/seroma (OR = 1.65, p < 0.02), peripheral vascular disease (OR = 2.23, p = 0.046), deep venous thrombosis (DVT) (OR = 1.95, p = 0.02), and blood transfusion (OR = 1.61, p < 0.0001). Hematologic malignancies were associated with an increased incremental LOS (0.13 d, p < 0.0001) and an increased incremental cost ($788, p < 0.0001). Thus, we conclude that following TKA, patients with hematologic malignancies are at an increased risk of perioperative complications, longer LOS, and higher costs. The risk quantification for adverse perioperative outcomes in association with an increased cost may help design different risk stratification and reimbursement methods in such patients when undergoing TKA.


Specific inhibition of a human papillomavirus E2 trans-activator by intracellular delivery of its repressor.
Papillomaviruses are the causative agents of benign and malignant epithelial tumors of the skin and mucosa. They encode a DNA-binding protein, E2, that regulates viral transcription and replication, making it an important therapeutic target. By deleting the amino-terminal trans-activation domain of human papillomavirus type 16 (HPV-16) E2 while retaining its carboxy-terminal DNA binding and dimerization domain, an E2 repressor (E2R) that efficiently inhibits transcriptional activation by full-length HPV E2 was generated. To deliver this repressor protein into animal cells, we have utilized the human immunodeficiency virus type 1 (HIV-1) Tat protein which itself is taken up efficiently into intact cells. Chimeras of E2R and the cellular uptake domain of Tat specifically inhibited E2-dependent reporter gene expression in COS-7 cells. Treatment of cervical intraepithelial neoplasia cells having episomally replicating HPV-31 DNA with this Tat-E2R protein led to a dose-dependent loss of HPV DNA copies and inhibition of cell growth. Tat-mediated delivery can be a valuable tool for assessing protein function and may allow the development of novel therapeutic proteins having intracellular targets.


Cell cycle regulation by the Wee1 inhibitor PD0166285, pyrido [2,3-d] pyimidine, in the B16 mouse melanoma cell line.
Wee1 kinase plays a critical role in maintaining G2 arrest through its inhibitory phosphorylation of cdc2. In previous reports, a pyridopyrimidine molecule PD0166285 was identified to inhibit Wee1 activity at nanomolar concentrations. This G2 checkpoint abrogation by PD0166285 was demonstrated to kill cancer cells, there at a toxic highest dose of 0.5 muM in some cell lines for exposure periods of no longer than 6 hours. The deregulated cell cycle progression may have ultimately damaged the cancer cells. We herein report one of the mechanism by which PD0166285 leads to cell death in the B16 mouse melanoma cell line. Tumor cell proliferation was determined by counting cell numbers. Cell cycle distribution was determined by flow cytometry. Morphogenesis analysis such as microtubule stabilization, Wee1 distribution, and cyclin B location were observed by immunofluorescence confocal microscopy. An immunoblot analysis of cdc2-Tyr15, cyclin D, E, p16, 21, 27, and Rb. A real-time PCR of the mRNA of cyclin D were completed. In our experiment, B16 cells also dramatically abrogated the G2 checkpoint and were found to arrest in the early G1 phase by treatment with 0.5 muM for 4 hours observed by flow cytometry. Cyclin D mRNA decreased within 4 hours observed by Real-time PCR. Rb was dephosphrylated for 24 hours. However, B16 cells did not undergo cell death after 0.5 muM treatment for 24 hours. Immnofluoscence microscopy showed that the cells become round and small in the morphogenesis. More interesting phenomena were that microtubule stabilization was blocked, and Wee1 distribution was restricted after treatment for 4 hours. We analyzed the effect of Wee1 inhibitor PD0166285 described first by Wang in the G2 transition in the B16 melanoma cell line. The inhibitor PD0166285 abrogated G2/M checkpoint inducing early cell division. Moreover, we found that the treatment of cells with the inhibitor is related to microtubule stabilization and decrease in cyclin D transcription. These effects together suggest that Wee1 inhibitor may thus be a potentially useful anti-cancer therapy.


Gold Nanorod-Assisted Photothermal Therapy Decreases Bleeding during Breast Cancer Surgery in Dogs and Cats.
For localized tumors, gold nanorod (AuNR)-assisted plasmonic photothermal therapy (PPTT) is a potentially effective alternative to traditional surgery, in which AuNRs absorb near-infrared light and convert it to heat in order to kill cancer cells. However, for large tumors (volume ≥ 20 cm3), an uneven distribution of AuNRs might cause inhomogeneity of the heat distribution inside the tumor. Surgery is frequently recommended for removing large tumors, but it is associated with a high risk of cancer recurrence and metastasis. Here, we applied PPTT before surgery, which showed improved treatment for large tumors. We divided the animals (eight cats/dogs) into two groups: Group I (control), where three cases were solely treated with surgery, laser, or AuNRs alone, resulting in recurrence and metastasis; and Group II, where animals were treated with PPTT before surgery. In Group II, four out of the five cases had tumor regression without any recurrence or metastasis. Interestingly, we observed that applying PPTT before surgery displayed reduced bleeding during tumor removal, supported by histopathology that showed altered blood vessels. In conclusion, our study showed that applying AuNR-assisted PPTT (AuNRs-PPTT) before surgery could significantly affect blood vessels inside the tumor, leading to a decreased amount of bleeding during surgery, which can potentially decrease the risk of metastasis and blood loss during surgery.


[Serum annexin A2 level is significantly elevated in patients with coronary heart disease].
To analyze the correlation of annexin A2 with coronary atherosclerotic heart disease (CAD) and the severity of CAD. We collected data from a total of 200 inpatients admitted in our department between August, 2017 and August, 2019. According to the. of coronary angiography, the patients were divided into CAD group (n=150) and non-CAD (n=50), and the CAD patients was further divided, according to their clinical stability, into stable angina (SAP) group and acute coronary syndrome (ACS) group. Serum levels of annexin A2, MPO and PON1 were detected in all these patients, and their correlations with CAD, disease severity, and degree of coronary artery stenosis were analyzed.ResultsThe levels of annexin A2 and MPO were significantly higher in CAD patients than in non-CAD patients (P < 0.05). Among the CAD patients, those with ACS had significantly higher levels of annexin A2 (P < 0.05) and lower levels of PON-1 (P < 0.05) than those with SAP, but annexin A2 level was not significantly correlated with coronary lesion count, Gensini score, or the co-morbidity of diabetes. Annexin A2 is significantly elevated in patients with CAD, especially in those with ACS, and can be used as a predictor of clinical instability.


Gender Differences in Work-Life Integration, Career Satisfaction, and Burnout in Pediatric Emergency Medicine Physicians: A Cross-Sectional Analysis.
Women physicians report worse work-life integration, career satisfaction, and burnout than men. No studies have evaluated work-life integration and career satisfaction in pediatric emergency medicine (PEM) or explored gender differences for these outcomes. This study aims to (1) compare work-life integration, career satisfaction, and burnout in women and men PEM physicians and (2) compare associated individual and occupational factors to distinguish modifiable factors. We distributed an electronic survey to assess well-being parameters in PEM physicians. We assessed career satisfaction and work-life integration with single-item measures. We used a 2-item screen to measure burnout. We performed descriptive analyses, univariate analysis to compare gender differences, and multivariate logistic regression analysis for each outcome. Two hundred thirty-nine PEM physicians participated, yielding a response rate of 50% (57% women; age range, 30-80 years). Overall satisfaction with work-life integration was 42.9%, with 34.3% of women reporting appropriate work-life integration, compared with 55.4% of men (P = 0.001). Career satisfaction rate was 77.8%, with 71.6% of women reporting career satisfaction, compared with 86.1% of men (P = 0.008). Burnout rate was 44.5%, with 53.7% of women reporting burnout compared with 33.7% of men (P = 0.002). Modifiable factors identified include perception of unfair compensation, inadequate physical and mental health support provided by organization, feeling unappreciated, inadequate provider staffing, inadequate resources for patient care, lack of advance notice or control of work schedule, and inadequate sleep. Of PEM physicians, women have worse work-life integration, less career satisfaction, and more burnout than men. The PEM community should devote resources to modifiable occupational factors to improve gender disparities in well-being parameters.


Short-Term Central Adaptation in Benign Paroxysmal Positional Vertigo.
Objective: To elucidate the frequency, underlying mechanisms, and clinical implications of spontaneous reversal of positional nystagmus (SRPN) in benign paroxysmal positional vertigo (BPPV). Methods: We prospectively recruited 182 patients with posterior canal (PC, n = 119) and horizontal canal (HC) BPPV (n = 63) canalolithiasis. We analyzed the maximal slow phase velocity (maxSPV), duration, and time constant (Tc) of positional nystagmus, and compared the measures between groups with and without SRPN. We also compared the treatment outcome between two groups. Results: The frequency of SRPN in PC- and HC-BPPV was 47 and 68%, respectively. The maxSPVs were greater in BPPV with SRPN than without, larger in HC-BPPV than PC-BPPV (114.3 ± 56.8 vs. 57.1 ± 38.1°/s, p < 0.001). The reversed nystagmus last longer in HC-BPPV than PC-BPPV. The Tc of positional nystagmus got shorter in PC-BPPV with SRPN (3.7 ± 1.8 s) than without SRPN (4.5 ± 2.0 s, p = 0.034), while it was longer during contralesional head turning in HC-BPPV with SRPN (14.8 ± 7.5 s) than that of ipsilesional side (7.3 ±2.8 s, p < 0.001). The treatment response did not significantly differ between groups with and without SRPN in both PC- and HC-BPPV (p = 0.378 and p = 0.737, respectively). Conclusion: The SRPN is common in both PC- and HC-BPPV canalolithiasis. The intensity of rotational stimuli may be a major determinant for the development of short-term central adaptation which utilizes the velocity-storage system below a certain velocity limit. The presence of SRPN is not related to treatment outcome in BPPV.


Influence of GO-Antisense miRNA-21 on the Expression of Selected Cytokines at Glioblastoma Cell Lines.
Graphene oxide (GO) is a single layer of carbon atoms with unique properties, which are beneficial due to its surface functionalisation by miRNA. miRNAs are a non-coding small form of RNA that suppress the expression of protein-coding genes by translational repression or degradation of messenger RNA. Antisense miRNA-21 is very promising for future investigation in cancer therapy. This study aimed to detect cytokine expression levels after the administration of GO-antisense miRNA-21 into U87, U118, U251 and T98 glioma cell lines. U87, U118, U251 and T98 glioma cell line were investigated in term of viability, human cytokine expression level at protein and genes after treatment with GO, GO-antisense miRNA-21 and antisense miRNA-21. The delivery of antisense miRNA-21 into the glioma cell at in vitro investigation were conducted by GO based transfection and electroporation. The results of the protein microarray and gene expression profile showed that complexes of GO-antisense miRNA-21 modified the metallopeptidase inhibitor 2 (TIMP-2), interleukin-6 (IL-6), interleukin 8 (IL-8), intercellular adhesion molecule 1 (ICAM-1), and monocyte chemoattractant protein-1 (MCP-1) expression level compared to transfection by electroporation of antisense miRNA-21 at investigated glioblastoma cell lines. The TIMP-2 protein and gene expression level was upregulated after antisense miRNA-21 delivery by GO complex into U87, U251 and T98 glioblastoma cell lines comparing to the non-treated control group. The downregulation at protein expression level of ICAM - 1 was observed at U87, U118, U251 and T98 glioma cell lines. Moreover, the IL-8 expression level at mRNA for genes and protein was decreased significantly after delivery the antisense-miRNA-21 by GO compared to electroporation as a transfection method. This work demonstrated that the graphene oxide complexes with antisense miRNA-21 can effectively modulate the cytokine mRNA and protein expression level at U87, U118, U251 and T98 glioma cell lines.


Socioeconomic determinants of childhood obesity among primary school children in Guangzhou, China.
Socioeconomic inequalities in childhood obesity prevalence differ according to a country's stage of nutrition transition. The aim of this study was to determine which socioeconomic factors influence inequalities in obesity prevalence in Chinese primary school children living in an urban setting. We assessed obesity prevalence among 9917 children aged 5-12 years from a stratified random sample of 29 state-funded (residents) and private (migrants) schools in Guangzhou, China. Height and weight were objectively measured using standardised methods and overweight (+1 SD < BMI-for-age z-score ≤ +2 SD) and obesity (BMI-for-age z-score > +2 SD) were defined using the World Health Organisation reference 2007. Socioeconomic characteristics were ascertained through parental questionnaires. Generalised Linear Mixed Models with schools as a random effect were used to compare likelihood of overweight/obesity among children in private, with public schools, adjusting for child age and sex, maternal and paternal BMI and education level, and household per-capita income. The prevalence of overweight/obesity was 20.0 % (95 % CI 19.1 %-20.9 %) in resident compared with 14.3 % (95 % CI 13.0 %-15.4 %) in migrant children. In the adjusted model, the odds of overweight/obesity remained higher among resident children (OR 1.36; 1.16-1.59), was higher in boys compared with girls (OR 2.56; 2.24-2.93), and increased with increasing age (OR 2.78; 1.95-3.97 in 11-12 vs 5-6 year olds), per-capita household income (OR 1.27; 1.01-1.59 in highest vs lowest quartile) and maternal education (OR 1.51; 1.16-1.97 in highest vs lowest). Socioeconomic differences were most marked in older boys, and were only statistically significant in resident children. The socioeconomic gradient for childhood obesity in China is the reverse of the patterns seen in countries at more advanced stages of the obesity epidemic. This presents an opportunity to intervene and prevent the onset of social inequalities that are likely to ensue with further economic development. The marked gender inequality in obesity needs further exploration.


[Statistical methods for relative risk estimation and applications in case-cohort study].
Objective: To systematically introduce the design of case-cohort study and the statistical methods of relative risk estimation and their application in the design. Methods: First, we introduced the basic principles of case-cohort study design. Secondly, Prentice's method, Self-Prentice method and Barlow method were described in the weighted Cox proportional hazard regression models in detail, finally, the data from the Shanghai Women's Health Study were used as an example to analyze the association between obesity and liver cancer incidence in the full cohort and case-cohort sample, and the results of parameters from each method were compared. Results: Significant association was observed between obesity and risk for liver cancer incidence in women in both the full cohort and the case-cohort sample. In the Cox proportional hazard regression model, the partial regression coefficients of the full cohort and the case-cohort sample fluctuated with the adjustment of confounding factors, but the hazard ratio estimates of them were close. There was a difference in the standard error of the partial regression coefficient between the full cohort and the case-cohort sample. The standard error of the partial regression coefficient of the case-cohort sample was larger than that of the full cohort, resulting in a wider 95% confidence interval of the relative risk. In the weighted Cox proportional hazard regression model, the standard error of the partial regression coefficient of Prentice's method was closer to the parameter estimates from full cohort than Self-Prentice method and Barlow method, and the 95% confidence interval of hazard ratio was closer to that of the full cohort. Conclusions: Case-cohort design could yield parameter results closer to the full cohort by collecting and analyzing data from sub-cohort members and patients with the disease, and reduce sample size and improve research efficiency. The results suggested that Prentice's method would be preferred in case-cohort design.


Synthesis and characterization of dextran-peptide-methotrexate conjugates for tumor targeting via mediation by matrix metalloproteinase II and matrix metalloproteinase IX.
We designed and synthesized new dextran-peptide-methotrexate conjugates for tumor-targeted delivery of chemotherapeutics via the mediation of matrix metalloproteinase II (MMP-2) and matrix metalloproteinase IX (MMP-9), both being widely known tumor-associated enzymes. A robust and flexible synthesis procedure and process monitoring chromatography assays were developed. The linker chemistry and the backbone charge were optimized to allow high sensitivity of the conjugates toward the targeted enzymes. The optimal conjugate carries Pro-Val-Gly-Leu-Ile-Gly as the peptide linker, and the charge on the dextran backbone is fully neutralized. In the presence of the targeted enzymes, the peptide was cleaved and peptidyl methotrexate was released, with a kcat/Km value of 1.21 x 10(5) M(-1) s(-1) for MMP-2 and 3.60 x 10(3) M(-1) s(-1) for MMP-9, respectively. Satisfactory stability of the new conjugates was demonstrated in serum containing conditions, suggesting the conjugates can remain intact in systemic circulation. These findings supported the tumor targeting capability of the new conjugates and warranted further investigation with in vivo study.


How name descriptiveness impacts proper name learning in young and older adults.
To elucidate the impact of name descriptiveness and aging on learning new names, 26 young and 26 healthy older participants learned visibly-descriptive (e.g., Lengthy for a giraffe), psychologically-descriptive (e.g., Classy), and non-descriptive (e.g., Sam) proper names for previously-unknown cartoon characters. More visibly-descriptive names were learned than psychologically- or non-descriptive names, which did not differ from each other. There was also a differential benefit for older adults when the name was visibly-descriptive of the referent, such that older adults learned visibly-descriptive names as well as young adults but there were substantial age-related deficits in learning psychologically- and non-descriptive names.


Sympathetic nerve activity during sleep, exercise, and mental stress.
This brief review describes recent findings on the differential regulation of sympathetic nerve activity and its role in regulating systemic arterial pressure during rapid eye-movement sleep, non-rapid-eye movement sleep, exercise and freezing behavior (mental stress). We describe the mechanisms underlying the differential regulation of sympathetic outflows and how they act in concert to orchestrate adjustments of cardiovascular function for the whole body, which are optimized to match changes in organ activity in daily activity.


Photoswitch inhibitors of alpha-chymotrypsin--increased substitution and peptidic character in peptidomimetic boronate esters.
A series of peptidomimetic boronate esters containing the photoisomerisable azobenzene group has been synthesised and assayed against the serine protease alpha-chymotrypsin. Compounds with borophenylalanine inhibition groups were found to be inhibitors with micromolar activity, while those with aryl boronate inhibition groups were inactive. Selected compounds were isomerised by UV or visible light to obtain enriched states of the (Z) or (E) isomers, respectively, and assayed. A change in activity on photoisomerisation was observed, however some decomposition of the boronate group on irradiation was also observed, limiting reversibility.


Genome wide mapping of UBF binding-sites in mouse and human cell lines.
The upstream binding transcription factor (UBTF, also called UBF) is thought to function exclusively in RNA polymerase I (Pol I)-specific transcription of the ribosomal genes. We recently reported in Sanij et al. (2014) [1] that the two isoforms of UBF (UBF1/2) are enriched at Pol II-transcribed genes throughout the mouse and human genomes. By using chromatin immunoprecipitation coupled with deep sequencing (ChIP-seq) of UBF1/2, Pol I, Pol II, H3K9me3, H3K4me4, H3K9ac and H4 hyperacetylation, we reported a correlation of UBF1/2 binding with enrichments in Pol II and markers of active chromatin. In addition, we examined a functional role for UBF1/2 in mediating Pol II transcription by performing expression array analysis in control and UBF1/2 depleted NIH3T3 cells. Our data demonstrate that UBF1/2 bind highly active Pol II-transcribed genes and mediate their expression without recruiting Pol I. Furthermore, we reported ChIP-sequencing analysis of UBF1/2 in immortalized human epithelial cells and their isogenically matched transformed counterparts. Here we report the experimental design and the description of the ChIP-sequencing and microarray expression datasets uploaded to NCBI Sequence Research Archive (SRA) and Gene Expression Omnibus (GEO).


[Expression and prognostic significance of microenvironment related prognostic factors in patients with classical Hodgkin's lymphoma].
Objective: To observe the expression of three microenvironment related prognostic factors, i. e. programmed death 1 (PD-1), forkhead box protein 3(FOXP3) and colony-stimulating factor 1 receptor(CSF-1R) protein in classical Hodgkin's lymphoma (CHL) patients, and to explore the correlation between the protein expression and the prognosis of the patients. Methods: A total of 45 cases of CHL patients, who had been admitted to the Tianjin Medical University Cancer Institute and Hospital and Chinese PLA General Hospital from February 2005 to August 2010 were analyzed, including clinical features, prognostic factors, and treatment regimens. CHL patients' specimens were collected and the expression of PD-1, FOXP3, and CSF-1R proteins analyzed by immunohistochemical staining. Epstein-Barr virus encoded mRNA (EBER) was detected by in situ hybridization analysis. The relationship between the protein expression of PD-1, FOXP3 and CSF-1R and the patients' outcome was analyzed with clinical and follow-up data. Survival analysis was performed by Kaplan-Meier method, the Cox proportional hazard model was used to perform multivariate analysis. Results: In this cohort of 45 CHL patients, PD-1 positive was found in 7 cases (15.6%), FOXP3 high expression in 23 cases (51.1%), CSF-1R positive in 18 cases (40.0%). In the univariate analysis, the expression of FOXP3 and CSF-1R, International Prognostic Index (IPI) score, Ann Arbor stage and EBER were related with the patients' 5-year overall survival (OS); IPI score, the expression of FOXP3 and EBER were related with the patients' 5-year progress-free survival (PFS). Multivariate analysis indicated that CSF-1R protein expression was the independent prognostic factor affecting the patients' 5-year OS(HR: 8.918, P=0.020), and FOXP3 protein expression was the independent prognostic factor affecting the patients' 5-year PFS (HR: 0.122, P<0.001). And EBV was an independent prognostic factor of PFS and OS in the CHL patients. Conclusion: Microenvironment related prognostic factors FOXP3, CSF-1R and EBV may be independent prognostic factors of CHL and this study may provide novel strategies for targeted therapy of CHL.


Synthesis and cellular uptake of fluorescently labeled multivalent hyaluronan disaccharide conjugates of oligonucleotide phosphorothioates.
Clustered hyaluronan disaccharides were studied as mediators of cellular delivery of antisense oligonucleotides through receptor-mediated endocytosis. For this purpose, a synthetic route for preparation of an appropriately protected hyaluronic acid dimer bearing an aldehyde tether (1) was devised. Up to three non-nucleosidic phosphoramidite building blocks (2), each bearing two phthaloyl protected aminooxy groups, were then inserted into the 3'-terminus of the desired phosphorothioate oligodeoxyribonucleotide, and 6-FAM phosphoramidite was introduced into the 5'-terminus. After completion of the chain assembly, the aldehyde-tethered sugar ligands were attached to the deprotected aminooxy functions by on-support oximation. Three fluorescein-labeled phosphorothioate oligonucleotide glycoconjugates (28-30) containing two, four, or six hyaluronan disaccharides were prepared. The influence of the hyaluronan moieties on the cellular uptake of the thioated oligonucleotides was tested in a cell line expressing the hyaluronan receptor CD44. Specific uptake was not detected with this combination of multiple hyaluronan disaccharides.


Efficacy and safety of adjuvant EGFR-TKIs for resected non-small cell lung cancer: a systematic review and meta-analysis based on randomized control trials.
Postoperative adjuvant cisplatin-based chemotherapy had been the standard care in patients with completely resected high-risk stage IB to IIIA non-small cell lung cancer (NSCLC) for decades. However, the survival benefits were far from satisfactory in clinical practice. Thus, this meta-analysis was performed to compare the efficacy and safety of adjuvant epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with resected NSCLC based on updated literature and research. A systematic literature search based on random control trials (RCTs) was conducted with keywords on PubMed, Embase and the Cochrane library databases. All articles compared EGFR-TKIs to placebo or chemotherapy as adjuvant therapies for early-stage resected NSCLC. A meta-analysis was performed to generate combined hazard ratio (HR) with 95% confidence intervals (CI) for disease-free survival (DFS), overall survival (OS), and risk ratio (RR) with 95% CI for disease recurrence and adverse events (AEs). The Stata statistical software (version 14.0) was used to synthesis the data. A total of 9 RCTs comprising 3098 patients were included. Adjuvant EGFR-TKIs could significantly prolong DFS in patient with resected NSCLC harboring epidermal growth factor receptor (EGFR) mutations (HR 0.46, 95% CI 0.29-0.72), but had no impact on OS (HR 0.87, 95% CI 0.69-1.11). The subgroup analyses indicated that adjuvant EGFR-TKIs were superior in regard to DFS in most subgroups, including varied smoking status, EGFR mutations type, gender, age, Eastern Cooperative Oncology Group performance status and adenocarcinoma. Osimertinib resulted in decreased brain recurrence than first generation of EGFR-TKIs (RR 0.12, 95% CI 0.04-0.34 vs. RR 1.07, 95% CI 0.64-1.78, respectively). The AEs were generally manageable and tolerable. The incidence of high-grade (≥ 3) AEs including diarrhea (RR 5.68, 95% CI 2.94-10.98) and rash (RR 27.74, 95% CI 11.43-67.30) increased after adjuvant EGFR-TKIs treatment. Adjuvant EGFR-TKIs therapy could significantly prolong DFS in patients with completely resected early-stage EGFR mutation-positive NSCLC, but had no impact on OS. Adjuvant EGFR-TKIs could be an important treatment option in patients with resected early-stage EGFR-mutant NSCLC.


Avelumab: combining immune checkpoint inhibition and antibody-dependent cytotoxicity.
Immune checkpoint inhibition holds great promise for selected tumors. The human monoclonal antibody (mAB) avelumab is directed to programmed death ligand-1 (PD-L1) and is supposed to inhibit the immunosuppressive PD-L1/PD-1 interaction and, furthermore, effect antibody-dependent cytotoxicity (ADCC) lysis of tumor cells. Areas covered: This article presents an overview of the current means to activate the antitumor immune defense by targeting PD-1 or PD-L1 with mABs and their possible role in ADCC-mediated tumor cell elimination. Expert opinion: Avelumab contains a Fc region which can bind cognate receptors on immune effector cells and induce ADCC-mediated tumor cell lysis, in contrast to other mABs directed to PD-1/PD-L1 which lack the ability to trigger ADCC due to belonging to the IgG4 subclass or possessing a mutated Fc region. Preclinical and clinical data indicate that avelumab can be safely administered to cancer patients with a toxicity profile comparable to other mABs and without lysis of PD-L1-positive activated immune cells. This antibody yielded durable responses in a phase II trial in advanced Merkel cell carcinoma patients. Tumor cell lysis by avelumab prevents cells from resorting to alternative checkpoints as shown by targeting PD-1 and the upregulation of TIM-3.


Antimicrobial food equipment coatings: applications and challenges.
Emerging technologies in antimicrobial coatings can help improve the quality and safety of our food supply. The goal of this review is to survey the major classes of antimicrobial agents explored for use in coatings and to describe the principles behind coating processes. Technologies from a range of fields, including biomedical and textiles research, as well as current applications in food contact materials, are addressed, and the technical hurdles that must be overcome to enable commercial adaptation to food processing equipment are critically evaluated.


The Family System of Sexuality Communication: Extended Family Perceptions of Adolescent-Family Talk about Sex, with Sibling and Non-Sibling Comparison.
Talk with parents and extended family about sex and relationships can support adolescents' sexual health. However, few studies explore how parent and extended family communication with adolescents intersect. This study used thematic analysis to assess family roles in talk with teens about sex and relationships among a sample of 39 adult extended family members (such as aunts and uncles, and older siblings and cousins) in the United States. Analyses identified four themes in sexuality communication that address: why adolescents talk to extended family about sex and relationships, family engagement in these conversations, consistency of family messages, and family communication about adolescents. Findings identify variation in how family members interact with adolescents and one another regarding talk about sex and relationships. For example, some participants described family coordination of sexual messages to the teen, while others reported no family communication about this topic. Results also showed similarities and differences in how sibling and non-sibling extended family describe these processes. These findings identify the need to examine family talk about sex and relationships in the context of a larger family system, rather than only within dyadic relationships, and suggests possibilities for family-based interventions to support adolescents' sexual health.