Improved selectivity and cytotoxic effects of irinotecan via liposomal delivery: A comparative study on Hs68 and HeLa cells.
Irinotecan (CPT-11) is an effective chemotherapeutic agent widely used to treat different cancers. Otherwise, the liposomal delivery of anti-tumor agents has been shown to be a promising strategy. The aim of this study has been to analyze the effect of liposomal CPT-11 (CPT-11lip) on two human cell lines (Hs68 and HeLa) to establish the suitability of this CPT-11 nanocarrier. We have demonstrated the highest uptake of CPT-11lip in comparison with that of CPT-11sol, in lactate buffer, and that CPT-11lip was internalized in the cells through an endocytic process whereas CPT-11sol does so by passive diffusion. CPT-11lip was not cytotoxic to normal fibroblast Hs68 cells, but induced a massive apoptosis accompanied by cell senescence in HeLa cells. CPT-11lip treatment modified the morphology of HeLa cells, induced different cell cycle alterations and accumulated into lysosomes in both cell lines. In particular, CPT-11lip treatment showed that surviving HeLa cells remained in a state of senescence whereas only a temporal growth arrest was induced in Hs68 cells. Results of RT-PCR indicated that the different responses in Hs68 (survival) and HeLa cells (apoptotic death), seemed to be induced by a p53- and p53- independent mechanism, respectively. An analysis of DNA damage also determined that released CPT-11 from liposomes was able to reach the nucleus and exert a genotoxic effect in both cell lines, which was repaired in Hs68 but not in HeLa cells. All results indicate that phospholipid-cholesterol liposomes possess optimum properties for CPT-11 delivery, being biocompatible and selectively cytotoxic against HeLa tumorigenic cells.


Stable GaSe-Like Phosphorus Carbide Monolayer with Tunable Electronic and Optical Properties from Ab Initio Calculations.
On the basis of density functional theory (DFT) calculations, we propose a stable two-dimensional (2D) monolayer phosphorus carbide (PC) with a GaSe-like structure, which has intriguing electronic and optical properties. Our calculated results show that this 2D monolayer structure is more stable than the other allotropes predicted by Tománek et al. [Nano Lett., 2016, 16, 3247⁻3252]. More importantly, this structure exhibits superb optical absorption, which can be mainly attributed to its direct band gap of 2.65 eV. The band edge alignments indicate that the 2D PC monolayer structure can be a promising candidate for photocatalytic water splitting. Furthermore, we found that strain is an effective method used to tune the electronic structures varying from direct to indirect band-gap semiconductor or even to metal. In addition, the introduction of one carbon vacancy in such a 2D PC structure can induce a magnetic moment of 1.22 µB. Our findings add a new member to the 2D material family and provide a promising candidate for optoelectronic devices in the future.


Effect of Insulin on Proximal Tubules Handling of Glucose: A Systematic Review.
Renal proximal tubules reabsorb glucose from the glomerular filtrate and release it back into the circulation. Modulation of glomerular filtration and renal glucose disposal are some of the insulin actions, but little is known about a possible insulin effect on tubular glucose reabsorption. This review is aimed at synthesizing the current knowledge about insulin action on glucose handling by proximal tubules. Method. A systematic article selection from Medline (PubMed) and Embase between 2008 and 2019. 180 selected articles were clustered into topics (renal insulin handling, proximal tubule glucose transport, renal gluconeogenesis, and renal insulin resistance). Summary of Results. Insulin upregulates its renal uptake and degradation, and there is probably a renal site-specific insulin action and resistance; studies in diabetic animal models suggest that insulin increases renal SGLT2 protein content; in vivo human studies on glucose transport are few, and results of glucose transporter protein and mRNA contents are conflicting in human kidney biopsies; maximum renal glucose reabsorptive capacity is higher in diabetic patients than in healthy subjects; glucose stimulates SGLT1, SGLT2, and GLUT2 in renal cell cultures while insulin raises SGLT2 protein availability and activity and seems to directly inhibit the SGLT1 activity despite it activating this transporter indirectly. Besides, insulin regulates SGLT2 inhibitor bioavailability, inhibits renal gluconeogenesis, and interferes with Na+K+ATPase activity impacting on glucose transport. Conclusion. Available data points to an important insulin participation in renal glucose handling, including tubular glucose transport, but human studies with reproducible and comparable method are still needed.


Nutritional State, Immunological and Biochemical Parameters, and Mortality in the ICU: An Analytical Study.
Intensive care unit (ICU) hospitalization involves critically ill patients with multiple diseases and possible complications, including malnutrition, which increases hospital stay and mortality. Therefore, identifying the patient's prior nutritional state, following up during hospitalization, and implementing early intervention positively affect patient's vital situations at discharge. The objective of this study is to determine the nutritional state of patients admitted to an ICU in Cali (Colombia) in 2019 and its association with immunological and biochemical parameters and mortality observed during hospitalization. This was an observational, analytical, and retrospective study of patients admitted to an ICU in a clinic in Cali (Colombia) from 1 January to 31 March 2019. The association between their nutritional state and outcome variables such as hospital stay, immunological and biochemical function, and mortality was analyzed. Logistic regression was used to predict patients' vital status at hospital discharge. In terms of the nutritional level, low weight was observed in 17.5% patients, and overweight/obesity was observed in 53.5% of the population. Nutritional state was associated with leukocytosis. The patients with lymphocytosis had longer hospital stays than those with normal lymphocyte ranges. Age, blood leukocytes, and creatinine and potassium levels increased the risk of mortality. Lymphocyte values have been used as predictors of severity and hospitalization time. The scientific literature has also evidenced a higher leukocyte count in people with obesity, and such leukocytosis is associated with the risk of mortality. The results of blood and laboratory tests determining kidney function and blood electrolytes allow for the prediction of mortality risk in critically ill patients.


[Absorption spectra study for fullerene-doped in polystyrene film].
The absorption spectra of C60 and C70-doped in polystyrene film and in solution were studied. The experiment results showed that the positions of the absorption peaks for C60-doped in polystyrene film moved a little toward longer wavelength than in n-hexane, and regular solid material appeared while the ratio of C60-doped in the film increased; The absorption peaks for C70-doped in polystyrene film were almost in consistent with that in solution. We suggest that C60 molecules may be connected as "microcrystalline" in polystyrene film, while C70 may be exist as single molecule or particle less than C60 in it. The preliminary model for the growth of "microcrystslline" in polystyrene film has been proposed.


The social construction of target populations and the transformation of prison-based AIDS policy: a descriptive case study.
When interpreting policy changes, it is important to understand the social construction of those whom the policy affects. Policy Design Perspective by Schneider and Ingram (1993) concentrates on the construction of "agents" and "targets" in an attempt to comprehend policy formation and transformation. The following descriptive case study uses this design to assess the evolution of one prison's AIDS policy. This institution's HIV/AIDS policy originally was quite restrictive in nature, but the changing perceptions of the agents and targets allowed a more humanistic approach to emerge in the handling of HIV-positive inmates.


Genomic landscape of high-grade meningiomas.
High-grade meningiomas frequently recur and are associated with high rates of morbidity and mortality. To determine the factors that promote the development and evolution of these tumors, we analyzed the genomes of 134 high-grade meningiomas and compared this information with data from 587 previously published meningiomas. High-grade meningiomas had a higher mutation burden than low-grade meningiomas but did not harbor any statistically significant mutated genes aside from NF2. High-grade meningiomas also possessed significantly elevated rates of chromosomal gains and losses, especially among tumors with monosomy 22. Meningiomas previously treated with adjuvant radiation had significantly more copy number alterations than radiation-induced or radiation-naïve meningiomas. Across serial recurrences, genomic disruption preceded the emergence of nearly all mutations, remained largely uniform across time, and when present in low-grade meningiomas, correlated with subsequent progression to a higher grade. In contrast to the largely stable copy number alterations, mutations were strikingly heterogeneous across tumor recurrences, likely due to extensive geographic heterogeneity in the primary tumor. While high-grade meningiomas harbored significantly fewer overtly targetable alterations than low-grade meningiomas, they contained numerous mutations that are predicted to be neoantigens, suggesting that immunologic targeting may be of therapeutic value.


Can markers of collagen turnover or other biomarkers contribute to the diagnostics of heart failure with normal left ventricular ejection fraction?
Plasma levels of some biomarkers and markers of collagen turnover may reflect myocardial structural abnormalities associated with diastolic dysfunction. The aim of this study was to determine whether these markers could contribute to the diagnostics of heart failure with normal ejection fraction (HFNEF). 91 patients with exertional dyspnea and normal left ventricular ejection fraction and 20 healthy controls underwent plasma analysis of markers of collagen turnover and other biomarkers, spirometry, and resting and exercise echocardiography. 38 patients with dyspnea had evidence of HFNEF, diagnosed at the early stage. Compared to the remaining patients, those with HFNEF had a significantly higher plasma levels of carboxy-terminal telopeptide of collagen type I (median 4.5 µg/L vs. 3.5 µg/L, P<0.05) and big endothelin (median 1.1 pmol/L vs 0.9 pmol/L, P<0.05). Univariate logistic regression analysis revealed a significant association between HFNEF and the following biomarkers: big endothelin, amino-terminal propeptide of type III procollagen (PIIINP), and matrix metalloproteinase-2 (MMP-2). However, none of these biomarkers independently contributed to the HFNEF diagnostics in a multivariate logistic regression analysis. Plasma levels of big endothelin, PIIINP, and MMP-2 were found to be associated with the presence of early diagnosed HFNEF. However, none of these biomarkers contributed independently to current noninvasive HFNEF diagnostics recommended by the European Society of Cardiology guidelines.


New technique of endoscopic sphincterotomy with iso-tome® to incise the distal papillary roof in patients with choledocholiths and choledochoduodenal fistula.
It is sometimes difficult to incise the dis-tal papillary roof (PR) completely in patients with choledocho-liths and choledochoduodenal fistula (CDF). The Iso-Tome® (MTW-Endoskopie W. Haag KG), which is helpful in prevent-ing electrical leakage, has good orientation capabilities and can be easily placed at the orifice of the CDF or ampulla of Vater (AV). We aimed to evaluate the efficacy of endoscopic sphincterotomy (ES) with the Iso-Tome® for cutting the distal PR. Between May 2003 and July 2012, 35 pa-tients were analyzed retrospectively. The distal PR was cut downward and/or upward using the Iso-tome® until the pink intrapapillary mucosa was fully exposed. Downward incisions were performed from the opening of the CDF to the orifice of the AV; upward incisions were performed in reverse. Spontaneous or artificial CDF occurred in four and 31 pa-tients, respectively. The technical and therapeutic success rates were 94.3% (33/35) and 94.3% (33/35), respectively. There was no case of electrical damage to the pink intrapap-illary mucosa. Adverse events occurred in 2.9% (1/35; 1, mild bleeding) of patients. The new technique of ES with the Iso-tome® is feasible and useful for effectively incising the distal PR in patients with CDF and choledocho-liths. (Gut Liver, 2015;9231-238).


[Contractility of the surviving myocardium following experimental infarct].
The contractile function of the non-infarcted myocardium was examined in adult cats following myocardial infarction produced by ligation of several branches of the LAD and circumflex coronary artery. Two and seven days following infarction, after determination of intracardiac pressures, papillary muscles were excised from the non-infarcted portion of the right ventricle and transferred into a myograph for analysis of contractile function. One week following infarction, force-velocity relations of the surviving myocardium showed a shift downward and to the left in comparison to sham-operated controls. At the same time, there was a decline in actively developed force at Lmax to be deserved, which appeared to be caused by a decrease in the rate of force development. Two days following infarction, similar changes were to be observed, although to a lesser extent. There appears to be a distinct loss of contractility in the remaining viable myocardium following experimental infarction.


Stereochemistry and rearrangement reactions of hydroxylignanolactones.
Various conflicting data on the rearrangement and absolute stereochemistry of hydroxylignano-9,7'-lactones are resolved using 18O labeled compounds, also confirmed by an X-ray analysis of a pure lignano-9,7'-lactone enantiomer, obtained for the first time. Under NaH/DMF rearrangement conditions a silyl protected hydroxylignano-9,9'-lactone underwent an unexpected silyl migration.


Inhibition of the activation of Hageman factor (factor XII) by platelet factor 4.
Platelet factor 4 is a polypeptide constituent of platelet alpha granules that is released during platelet aggregation and inhibits heparin-mediated reactions. Hageman factor (factor XII) is a plasma proenzyme that, when activated by certain negatively charged agents, initiates clotting via the intrinsic pathway of thrombin formation. In earlier studies using crude systems, platelet factor 4 inhibited activation of Hageman factor by dextran sulfate or cerebrosides, but not activation of Hageman factor by kaolin or ellagic acid. In the present study we examined the mechanisms of inhibition by platelet factor 4, using purified reagents. Platelet factor 4 inhibited activation of Hageman factor by ellagic acid, as measured by amidolysis of a synthetic substrate of activated Hageman factor, an effect inhibited by heparin or by an anti-platelet factor 4 antiserum. Coating glass tubes with platelet factor 4 before addition of normal plasma significantly lengthened the partial thromboplastin time of normal plasma. In addition, the clot-promoting properties of kaolin were inhibited by its prior exposure to platelet factor 4. Thus, the inhibitory properties of platelet factor 4 directed against the activation of Hageman factor were confirmed in a purified system. In this purified system, in contrast to earlier studies using crude systems, platelet factor 4 inhibited activation of Hageman factor by glass, ellagic acid, or kaolin.


Concomitant Injuries Associated With ACL Rupture in Elite Professional Alpine Ski Racers and Soccer Players: A Comparative Study With Propensity Score Matching Analysis.
For elite professional soccer players and alpine skiers, injuries associated with anterior cruciate ligament (ACL) rupture, such as meniscal, cartilage, or collateral ligament lesions, could result in a delayed return to sport compared with isolated ACL injury. The purpose of the study was to provide a detailed description of associated injuries at the time of primary ACL reconstruction in elite soccer players and alpine skiers. It was hypothesized that soccer players and skiers would present different typical injury patterns due to different injury mechanisms. Cohort study; Level of evidence, 3. Surgical reports and arthroscopic images of elite professional soccer players and alpine skiers who underwent primary ACL reconstruction at a single institution between January 2010 and June 2022 were analyzed retrospectively. The presence and location of multiligamentous injury, meniscal tears, and chondral lesions were compared between the athlete groups. A propensity score matching analysis with 1:1 ratio was performed between skiers and soccer players to limit the effect of selection bias. Included were ACL reconstruction data representative of 37 soccer players and 44 alpine skiers. Meniscal pathology was found in 32 (86%) soccer players and 30 (68%) skiers. Chondral injuries were reported in 11 (30%) soccer players and 15 (34%) skiers. Results of the propensity score matching analysis in 15 pairs of soccer players and skiers indicated that soccer players had a significantly higher rate of medial meniscal injuries (73% vs 27%; P = .03) and lateral posterior root tears (33% vs 0%; P = .04) compared with skiers. A higher prevalence of combined chondral and meniscal injuries versus isolated ACL injuries was observed in both groups of athletes. Professional soccer players were characterized by higher prevalence of medial meniscal tears and lateral posterior root lesions compared with professional alpine skiers.


Oncostatin M Induction of Monocyte Chemoattractant Protein 1 is Inhibited by Anti-oncostatin M Receptor Beta Monoclonal Antibody KPL-716.
To evaluate cellular response to oncostatin M (OSM) in comparison to interleukin (IL)-31, we analyzed monocyte chemoattractant protein 1 (MCP-1) as a readout for OSM responses with and without IL-4, IL-13, anti-OSM receptor β monoclonal antibody KPL-716, and anti-IL-31 receptor α antibody in human epidermal keratinocytes and human dermal fibroblasts in vitro. In human epidermal keratinocytes, OSM significantly induced STAT3 or STAT1 phosphorylation and synergized with IL-13 or IL-4 in elevating MCP-1. In human dermal fibroblasts, OSM results were similar, and leukemia inhibitory factor or IL-31 minimally activated STAT3 but not MCP-1. OSM significantly stimulated mRNA for type II IL-4 receptor and type II OSM receptor. KPL-716, not anti-IL-31Rα, significantly attenuated MCP-1 response to OSM and OSM + IL-4 in human epidermal keratinocytes and human dermal fibroblasts. OSM, not leukemia inhibitory factor or IL-31, synergized with IL-4 and IL-13 in human epidermal keratinocytes and human dermal fibroblasts, suggesting therapeutic potential of KPL-716 in inflammatory dermatologic diseases distinct from IL-31 inhibition.


The Association between Patient-Reported Pain and Doctors' Language Proficiency in Clinical Practice.
Patients' limited literacy and language fluency of different kinds cause them problems in navigating the medical interview. However, it is not known how physicians' native language skills affect the reported intensity of pain among Finnish emergency patients. Data were collected with two consecutive questionnaires in 16 healthcare centres and outpatient departments along the Finnish coast. Swedish and Finnish speaking 18-65-year-old emergency patients were eligible for this study. Our patients were predominantly Finnish speakers. Patient-rated poor language skills in Finnish among the physicians in ED setting increased statistically significantly pain reported by the Finnish speaking patients and their dissatisfaction with the health service. These patients were also less motivated to adhere to the instructions given by their physician. Patients speaking various languages reported less degree of pain. Foreign physicians' poor language proficiency in Finnish was expected to explain only some of the patients' pain experience. Physicians' good native language skills may help to reduce pain experience. Despite concordant language communication, other unknown barriers in the interaction might reduce the magnitude of pain reported.


Screening for posttraumatic stress disorder in a general psychiatric outpatient setting.
Posttraumatic stress disorder (PTSD) may affect survivors of a number of accidents and illnesses, in addition to violence victims and combat veterans. Prior research suggests that PTSD may be underdiagnosed when trauma is not the presenting problem. Thus, a PTSD screening scale might have utility in routine clinical settings. The authors evaluated the screening performance of the Posttraumatic Diagnostic Scale (PDS) in a general psychiatric setting. Results indicated that the PDS performed as well in this setting as it did in the original trauma-focused validation studies, independent of PTSD status as a primary, versus secondary, reason for presenting. A simple cutoff score was adequate for case identification. There were no gender effects, and the scale performed equally well among patients with, versus without, a depressive diagnosis.


Gardner's syndrome: a clinical and genetic study of a family.
Gardner syndrome (GS) is an autosomal dominant genetic disorder with almost complete penetrance (80%) and variable expression. GS is a variant of familial adenomatous polyposis and characterized by extracolonic manifestations including osteomas and soft tissue tumors (desmoid tumors, epidermoid cysts). We describe clinical and surgical approaches in a family in which the genetic disorder was diagnosed in 3 generations. The studied family underwent clinical history and instrumental and genomic studies. Two members of this family, affected with GS, underwent surgery for skeletal osteomas. The patients that we treated with clinical-instrumental monitoring for a period of 5 years had no major disturbances of the stomatognathic system and no clinical signs of pathology of the gastrointestinal tract, eyes, or endocrine systems. The orofacial complex disorders are exclusively functional and esthetic, concerning primarily the stomatognathic system. We had no cases of malignant transformation of osteomatosis lesions. Clinical sequelae are manly facial eumorphy and occlusion problems of the temporomandibular joint.


Bioboxes: standardised containers for interchangeable bioinformatics software.
Software is now both central and essential to modern biology, yet lack of availability, difficult installations, and complex user interfaces make software hard to obtain and use. Containerisation, as exemplified by the Docker platform, has the potential to solve the problems associated with sharing software. We propose bioboxes: containers with standardised interfaces to make bioinformatics software interchangeable.


ATPbind: Accurate Protein-ATP Binding Site Prediction by Combining Sequence-Profiling and Structure-Based Comparisons.
Protein-ATP interactions are ubiquitous in a wide variety of biological processes. Correctly locating ATP binding sites from protein information is an important but challenging task for protein function annotation and drug discovery. However, there is no method that can optimally identify ATP binding sites for different proteins. In this study, we report a new composite predictor, ATPbind, for ATP binding sites by integrating the outputs of two template-based predictors (i.e., S-SITE and TM-SITE) and three discriminative sequence-driven features of proteins: position specific scoring matrix, predicted secondary structure, and predicted solvent accessibility. In ATPbind, we assembled multiple support vector machines (SVMs) based on a random undersampling technique to cope with the serious imbalance phenomenon between the numbers of ATP binding sites and of non-ATP binding sites. We also constructed a new gold-standard benchmark data set consisting of 429 ATP binding proteins from the PDB database to evaluate and compare the proposed ATPbind with other existing predictors. Starting from a query sequence and predicted I-TASSER models, ATPbind can achieve an average accuracy of 72%, covering 62% of all ATP binding sites while achieving a Matthews correlation coefficient value that is significantly higher than that of other state-of-the-art predictors.


Prevalence and impact of cardiovascular risk factors in Bucaramanga, Colombia: results from the Countrywide Integrated Noncommunicable Disease Intervention Programme (CINDI/CARMEN) baseline survey.
Although cardiovascular diseases are the main cause of death in the region, there are few data on the prevalence of cardiovascular risk factors in Latin American. We studied the distribution and impact of cardiovascular risk factors in Bucaramanga, Colombia. We conducted a cross-sectional study in a random sample of 2989 subjects 15-64 years old. Population attributable risks were estimated from Framingham risk scores. Smoking prevalence was 16.2% (men 26.3%; women 10.5%). Hypertension prevalence was 9.9% in women and 8.8% in men, but reached 50% in those 60-64 years old. After adjustment for body mass index, men were more likely to be hypertensive, but only if under 40 years old. Obesity was more frequent in women (15.7%) than in men (8.7%), even after age-adjustment. About 46% of the participants were overweight or obese. Women also had higher prevalence of high total cholesterol (19.7 versus 15.7%) and high low-density lipoprotein-cholesterol (23.9 versus 19.5%), but lower prevalence of low high-density lipoprotein (HDL)-cholesterol (22.2 versus 37.6%). Only low-HDL prevalence was significantly different after body mass index and age-adjustment. The prevalence of diabetes was similar in men and women (4%), but age and body mass index-adjusted impaired fasting glucose prevalence was 60% higher in women. Population attributable risks were larger and similar for high total cholesterol, hypertension, and large waist-to-hip ratio (19%). Women had higher prevalence of all risk factors with the exception of smoking and low-HDL. Reduction in cholesterol levels, blood pressure and obesity is a priority to control the ongoing epidemic of cardiovascular diseases in this population.


Optimizing antifungal drug dosing and monitoring to avoid toxicity and improve outcomes in patients with haematological disorders.
Antifungal prophylaxis, empirical therapy and treatment of established fungal infections in the haematology population may be associated with significant toxicity or drug interactions leading to sub-therapeutic antifungal drug concentrations and poorer clinical outcomes. These risks may be minimised by clinical assessment, laboratory monitoring of biochemical or haematological indices, avoidance of particular drug combinations and dose modification in certain circumstances. Specific measures, such as the optimal timing of oral drug administration in relation to meals, use of pre-hydration and electrolyte supplementation may also be required. For certain agents, therapeutic drug monitoring (TDM) is warranted where non-compliance, non-linear pharmacokinetics, a narrow therapeutic window, suspected drug interaction or unexpected toxicity are encountered. Pharmacokinetics and pharmacodynamics of clinical relevance to the haematology population are discussed for the azole, polyene and echinocandin classes of antifungal agents. The evidence supporting an association between TDM and enhanced treatment outcomes is presented for individual antifungal drugs, and recommendations for clinical practice are provided. Further randomised study of newer antifungal agents, such as posaconazole, is required to explore the potential for improved clinical outcomes in association with TDM.


Influence of proquazone (Biarison) on the levels of complement components (C3 and C4) in synovial fluid and on IgM in serum in patients with active rheumatoid arthritis. A preliminary report.
Four patients with erosive rheumatoid arthritis and one with psoriasis arthropathy were treated with 600-900 mg/day proquazone for 4-7 weeks. All patients had acute knee effusions. The complement components C3 and C4, as well as IgG, IgA, IgM and total protein, were measured in both the synovial fluid and serum before and after treatment. In the 4 patients with rheumatoid arthritis, a marked increase in C3 and/or C4 levels in the synovial fluid was found, correlating in 3 cases with a good clinical response. However, no corresponding changes in complement levels were recorded in the serum. The patient with psoriasis arthropathy did not show any reaction. These preliminary results suggest that proquazone may influence the immunological processes in rheumatoid arthritis.


Overexpression of the cell adhesion molecules DDR1, Claudin 3, and Ep-CAM in metaplastic ovarian epithelium and ovarian cancer.
A better understanding of the molecular pathways underlying the development of epithelial ovarian cancer (EOC) is critical to identify ovarian tumor markers for use in diagnostic or therapeutic applications. The aims of this study were to integrate the results from 14 transcript profiling studies of EOC to identify novel biomarkers and to examine their expression in early and late stages of the disease. A database incorporating genes identified as being highly up-regulated in each study was constructed. Candidate tumor markers were selected from genes that overlapped between studies and by evidence of surface membrane or secreted expression. The expression patterns of three integral membrane proteins, discoidin domain receptor 1 (DDR1), claudin 3 (CLDN3), and epithelial cell adhesion molecule, all of which are involved in cell adhesion, were evaluated in a cohort of 158 primary EOC using immunohistochemistry. We confirmed that these genes are highly overexpressed in all histological subtypes of EOC compared with normal ovarian surface epithelium, identifying DDR1 and CLDN3 as new biomarkers of EOC. Furthermore, we determined that these genes are also expressed in ovarian epithelial inclusion cysts, a site of metaplastic changes within the normal ovary, in borderline tumors and in low-grade and stage cancer. A trend toward an association between low CLDN3 expression and poor patient outcome was also observed. These results suggest that up-regulation of DDR1, CLDN3, and epithelial cell adhesion molecule are early events in the development of EOC and have potential application in the early detection of disease.


[Acquisition of resistance associated with impairment of metabolic activation of anticancer drugs].
Some of anticancer drugs must undergo bioactivation in order to exert their anticancer activity. Those include most of antimetabolites, mitomycin C, cyclophosphamide and a camptothecin analog CPT-11. The latter two drugs are usually activated in liver or plasma, and the others are converted to active metabolites in the target cells. A number of biochemical mechanisms of resistance have been proposed and for the drugs to be activated in cancer cells impairment of activation enzymes were reported as one of the mechanisms; for example, deoxycytidine kinase for cytarabine and gemcitabine, orotate phosphoribosyl transferase for 5-fluorouracil, hypoxanthine-guanine phosphoribosyl transferase for 6-mercaptopurine, folylpolyglutamate synthetase for methotrexate and DT-diaphorase for mitomycin C were concerned.


[Surgical Treatment of Esophageal Cancer-New Technologies, Modern Concepts].
In Germany esophageal cancer is mostly treated in specialized centers according to national and international guidelines in a multimodal and interdisciplinary setting. In the next few years centralization of esophageal surgery will continue in Germany due to new national regulations on minimum case volumes. This article highlights new technologies for surgical treatment of esophageal cancer and also depicts the current oncological concepts from the perspective of a high-volume center.


Vitamin D Treatment in Patients with Hashimoto's Thyroiditis may Decrease the Development of Hypothyroidism.
The relationship between Hashimoto's thyroiditis and vitamin D has been demonstrated in several studies. The aim of the present study was to evaluate vitamin D concentrations in patients with Hashimoto's thyroiditis, the effect of vitamin D therapy on the course of disease, and to determine changes in thyroid autoantibody status and cardiovascular risk after vitamin D therapy. We included 75 patients with Hashimoto's thyroiditis and 43 healthy individuals. Vitamin D deficiency is defined as a 25-hydroxy vitamin D (25(OH)D3) concentration less than 20ng/mL. Vitamin D deficient patients were given 50.000 units of 25(OH)D3 weekly for eight weeks in accordance with the Endocrine Society guidelines. All evaluations were repeated after 2 months of treatment. Patients with Hashimoto's thyroiditis had significantly lower vitamin D concentrations compared with the controls (9.37±0.69 ng/mL vs 11.95±1.01 ng/mL, p < 0.05, respectively). Thyroid autoantibodies were significantly decreased by vitamin D replacement treatment in patients with euthyroid Hashimoto's thyroiditis. Also, HDL cholesterol concentrations improved in the euthyroid Hashimoto group after treatment. The mean free thyroxine (fT4) concentrations were 0.89±0.02 ng/dL in patients with Hashimoto's thyroiditis and 1.07±0.03 ng/dL in the healthy control group (p < 0.001). The mean thyroid volumes were 7.71±0.44 mL in patients with Hashimoto's thyroiditis and 5.46±0.63 mL in the healthy control group (p < 0.01). Vitamin D deficiency is frequent in Hashimoto's thyroiditis and treatment of patients with this condition with Vitamin D may slow down the course of development of hypothyroidism and also decrease cardiovascular risks in these patients. Vitamin D measurement and replacement may be critical in these patients.


Single Frequency Impedance Analysis on Reduced Graphene Oxide Screen-Printed Electrode for Biomolecular Detection.
A biofunctionalized reduced graphene oxide (rGO)-modified screen-printed carbon electrode (SPCE) was constructed as an immunosensor for C-reactive protein (CRP) detection, a biomarker released in early stage acute myocardial infarction. A different approach of single frequency analysis (SFA) study was utilized for the biomolecular sensing, by monitoring the response in phase angle changes obtained at an optimized frequency resulting from antigen-antibody interactions. A set of measurements were carried out to optimize a frequency where a maximum change in phase angle was observed, and in this case, we found it at around 10 Hz. The bioelectrode was characterized by contact angle measurements, scanning electron microscopy, and electrochemical techniques. A concentration-dependent response of immunosensor to CRP with the change in phase angle, at a fixed frequency of 10 Hz, was found to be in the range of 10 ng mL-1 to 10 μg mL-1 in PBS and was fit quantitative well with the Hill-Langmuir equation. Based on the concentration-response data, the dissociation constant (K d) was found to be 3.5 nM (with a Hill coefficient n = 0.57), which indicated a negative cooperativity with high anti-CRP (antibody)-CRP (antigen) binding at the electrode surface. A low-frequency analysis of sensing with an ease of measurement on a disposable electroactive rGO-modified electrode with high selectivity and sensitivity makes it a potential tool for biological sensors.


Circulating MicroRNAs as Diagnostic Biomarkers for Motor Neuron Disease.
Motor neuron disease (MND) is a kind of neurodegenerative disease that selectively invades spinal cord anterior horn cells, brainstem motor neurons, cortical pyramidal cells and the pyramidal tract. The main clinical features are the symptoms and signs of impaired upper and lower motor neurons, manifested as muscle weakness, atrophy and pyramidal tract signs. Histopathology has shown the disappearance of pyramidal cells in the motor cortex, loss of motor neurons in the anterior horn of the spinal cord and brainstem, and degeneration of the corticospinal tract. Due to the lack of effective treatment methods, the prognosis is generally poor, so it is of great significance to confirm the diagnosis early by various means. However, the current diagnosis of MND mainly relies on the combination of clinical manifestations and neurophysiological examinations, lacking effective means of early diagnosis. Circulating microRNA (CmiRNA) is a kind of stable miRNA molecule in serum, plasma and other body fluids, which has the characteristics of distinct differential expression, sensitive detection and convenient sample collection. As a possible new biomarker of MND, CmiRNA can not only reveal the pathophysiological process of MND, but also monitor disease progression and response to drug therapy. With the development of miRNA detection technology, more and more CmiRNAs as biomarkers with potential diagnostic value have been investigated. In this review, we explored the possibility of circulating samples as different sources of biomarkers for the diagnosis of MND, analyzing the progress of CmiRNA detection techniques, and presenting potential diagnostic MND biomarkers that have been reported.


P-MSC-derived extracellular vesicles facilitate diabetic wound healing via miR-145-5p/ CDKN1A-mediated functional improvements of high glucose-induced senescent fibroblasts.
Persistent hyperglycaemia in diabetes causes functional abnormalities of human dermal fibroblasts (HDFs), partially leading to delayed skin wound healing. Extracellular vesicles (EVs) containing multiple pro-healing microRNAs (miRNAs) have been shown to exert therapeutic effects on diabetic wound healing. The present study aimed to observe the effects of EVs derived from placental mesenchymal stem cells (P-MSC-EVs) on diabetic wound healing and high glucose (HG)-induced senescent fibroblasts and to explore the underlying mechanisms. P-MSC-EVs were isolated by differential ultracentrifugation and locally injected into the full-thickness skin wounds of diabetic mice, to observe the beneficial effects on wound healing in vivo by measuring wound closure rates and histological analysis. Next, a series of assays were conducted to evaluate the effects of low (2.28 x 1010 particles/ml) and high (4.56 x 1010 particles/ml) concentrations of P-MSC-EVs on the senescence, proliferation, migration, and apoptosis of HG-induced senescent HDFs in vitro. Then, miRNA microarrays and real-time quantitative PCR (RT-qPCR) were carried out to detect the differentially expressed miRNAs in HDFs after EVs treatment. Specific RNA inhibitors, miRNA mimics, and small interfering RNA (siRNA) were used to evaluate the role of a candidate miRNA and its target genes in P-MSC-EV-induced improvements in the function of HG-induced senescent HDFs. Local injection of P-MSC-EVs into diabetic wounds accelerated wound closure and reduced scar widths, with better-organized collagen deposition and decreased p16INK4a expression. In vitro, P-MSC-EVs enhanced the antisenescence, proliferation, migration, and antiapoptotic abilities of HG-induced senescent fibroblasts in a dose-dependent manner. MiR-145-5p was found to be highly enriched in P-MSC-EVs. MiR-145-5p inhibitors effectively attenuated the P-MSC-EV-induced functional improvements of senescent fibroblasts. MiR-145-5p mimics simulated the effects of P-MSC-EVs on functional improvements of fibroblasts by suppressing the expression of cyclin-dependent kinase inhibitor 1A and activating the extracellular signal regulated kinase (Erk)/protein kinase B (Akt) signaling pathway. Furthermore, local application of miR-145-5p agomir mimicked the effects of P-MSC-EVs on wound healing. These results suggest that P-MSC-EVs accelerate diabetic wound healing by improving the function of senescent fibroblasts through the transfer of miR-145-5p, which targets cyclin-dependent kinase inhibitor 1A to activate the Erk/Akt signaling pathway. P-MSC-EVs are promising therapeutic candidates for diabetic wound treatment.


Compaction of quasi-one-dimensional elastoplastic materials.
Insight into crumpling or compaction of one-dimensional objects is important for understanding biopolymer packaging and designing innovative technological devices. By compacting various types of wires in rigid confinements and characterizing the morphology of the resulting crumpled structures, here, we report how friction, plasticity and torsion enhance disorder, leading to a transition from coiled to folded morphologies. In the latter case, where folding dominates the crumpling process, we find that reducing the relative wire thickness counter-intuitively causes the maximum packing density to decrease. The segment size distribution gradually becomes more asymmetric during compaction, reflecting an increase of spatial correlations. We introduce a self-avoiding random walk model and verify that the cumulative injected wire length follows a universal dependence on segment size, allowing for the prediction of the efficiency of compaction as a function of material properties, container size and injection force.


Minimizing human error in radiopharmaceutical preparation and administration via a bar code-enhanced nuclear pharmacy management system.
The objective of this project was to ensure correct radiopharmaceutical administration through the use of a bar code system that links patient and drug profiles with on-site information management systems. This new combined system would minimize the amount of manual human manipulation, which has proven to be a primary source of error. The most common reason for dosing errors is improper patient identification when a dose is obtained from the nuclear pharmacy or when a dose is administered. A standardized electronic transfer of information from radiopharmaceutical preparation to injection will further reduce the risk of misadministration. Value stream maps showing the flow of the patient dose information, as well as potential points of human error, were developed. Next, a future-state map was created that included proposed corrections for the most common critical sites of error. Transitioning the current process to the future state will require solutions that address these sites. To optimize the future-state process, a bar code system that links the on-site radiology management system with the nuclear pharmacy management system was proposed. A bar-coded wristband connects the patient directly to the electronic information systems. The bar code-enhanced process linking the patient dose with the electronic information reduces the number of crucial points for human error and provides a framework to ensure that the prepared dose reaches the correct patient. Although the proposed flowchart is designed for a site with an in-house central nuclear pharmacy, much of the framework could be applied by nuclear medicine facilities using unit doses. An electronic connection between information management systems to allow the tracking of a radiopharmaceutical from preparation to administration can be a useful tool in preventing the mistakes that are an unfortunate reality for any facility.


X-ray microanalysis of uterine secretion in the mouse.
In an attempt to characterize ion transport mechanisms in the uterine epithelium the effect of diuretics on the elemental composition of the uterine secretion was investigated by X-ray microanalysis. Mice were treated with a variety of diuretics and Sephadex beads were incubated in situ in the uterus where they absorbed the uterine secretion. In animals treated with furosemide, bumetanide, or amiloride, the concentration of Na, K, and Cl in the uterine secretion was significantly decreased. After treatment with acetazolamide, only the K concentration was significantly decreased. Treatment with diuretics also decreased the concentration of P and S in the uterine secretion, indicating that less mucus was absorbed to the Sephadex beads. Transmission electron microscopy confirmed that treatment with amiloride and furosemide decreased the amount of mucus covering the epithelium. A possible explanation is that because of lack of water, the uterine mucus cannot leave the lumen of the uterine glands and reach the surface of the epithelium where the beads are. The data strongly suggest that Na+, K+, and Cl- transport in the uterine epithelium is dependent on a basolaterally situated Na(+)-(K+)-Cl(-)-cotransport mechanism. Disturbance of normal ion and water transport apparently affects the composition and consistency of the mucus, which may help explain abnormalities in cervical mucus in patients with cystic fibrosis.


Zirconia-Reinforced Lithium Silicate Ceramic - A 2-Year Follow-up of a Clinical Experience with Anterior Crowns.
The aim of this manuscript is to describe 2-year follow-up of a clinical experience with a zirconia-reinforced lithium silicate ceramic for an anterior rehabilitation with single metal-free crowns. The maxillary-central incisor teeth crowns were made by zirconium-reinforced lithium silicate and covered with porcelain were obtained with a digital impression with the intra-oral scanner of the CEREC system as a basis for virtual design, as well as a laminate for the left lateral maxillary incisor, based on a "double scanning" technique. Lithium silicate material seems to be a safe and satisfactory alternative for anterior crowns' rehabilitation.


FOOD IMAGE ANALYSIS: SEGMENTATION, IDENTIFICATION AND WEIGHT ESTIMATION.
We are developing a dietary assessment system that records daily food intake through the use of food images taken at a meal. The food images are then analyzed to extract the nutrient content in the food. In this paper, we describe the image analysis tools to determine the regions where a particular food is located (image segmentation), identify the food type (feature classification) and estimate the weight of the food item (weight estimation). An image segmentation and classification system is proposed to improve the food segmentation and identification accuracy. We then estimate the weight of food to extract the nutrient content from a single image using a shape template for foods with regular shapes and area-based weight estimation for foods with irregular shapes.


Synthesis and characterization of tetrathiafulvalene-substituted di- and tetraethynylethenes with p-nitrophenyl acceptors.
Novel di- and tetraethynylethene (DEE and TEE) compounds functionalized with tetrathiafulvalene (TTF) donor groups and p-nitrophenyl acceptor groups were synthesized by palladium-catalyzed cross-coupling reactions under various conditions. The molecules are strong chromophores and were investigated for their optical properties. Placement of two TTFs and two p-nitrophenyls about a central TEE core provides a molecule with a high third-order optical nonlinearity. The molecules experience reversible oxidations of the TTF units, and the optical properties of the oxidized species were elucidated by spectroelectrochemistry. The degree of quinoid character of the p-nitrophenyl in the molecules was determined by X-ray crystallography.


Phenotypic variation among three broiler pure lines for Marek's disease, coccidiosis, and antibody response to sheep red blood cells.
To identify candidate genes, chicken lines with the most divergent phenotypes are usually crossed to generate resource mapping populations, for example, either backcrossed or F2 populations. Linkage between the genetic marker and the phenotypic trait locus is then tested in the mapping population. As an initial step in the development of a mapping population from commercial broilers, the goal of the current research was to evaluate the phenotypic variation among three pure lines for antibody response to SRBC and in resistance to two economically important poultry diseases, Marek's disease (MD) and coccidiosis (Eimeria acervulina). Chicks from each line were received and separated into three experimental studies to evaluate each of their responses. In summary, broiler Line 3 had significantly lower antibody responses to SRBC immunizations compared to the other two lines, and nonvaccinated birds from Line 3 were also more susceptible to MD. With coccidiosis, the response was complex, and ranking of the lines was dependent on the age of infection, and whether it was a first or second challenge. With the first challenge, Line 1 was most susceptible at the younger age (Day 30), whereas Line 3 was susceptible at the older age (Day 58). Upon the second challenge, broiler Line 1 remained susceptible at the younger age, but Line 2 was more susceptible at the older age. Line 3 was completely resistant to the second challenge at the older age. Thus, although the broiler lines have been intensively selected for productivity and general livability, this study also demonstrates that the lines differ for immune response and disease resistance. Based on the phenotypic differences between Lines 1 and 3, they were chosen to establish a mapping population for identifying candidate genes that affect MD and coccidiosis in commercial broiler chickens.


The current state of hormonal therapy for prostate cancer.
Androgen deprivation therapy remains a mainstay of treatment for men with prostate cancer. New uses for hormonal therapy, including use in the adjuvant and neoadjuvant setting, are being evaluated. Prevention of the side effects of therapy has led to the development of alternative schedules and therapeutics.


Serological characterization of the enterobacterial common antigen substitution of the lipopolysaccharide of Yersinia enterocolitica O : 3.
Enterobacterial common antigen (ECA) is a polysaccharide present in all members of Enterobacteriaceae anchored either via phosphatidylglycerol (PG) or LPS to the outer leaflet of the outer membrane (ECAPG and ECALPS, respectively). Only the latter form is ECA-immunogenic. We previously demonstrated that Yersinia enterocolitica O : 3 and its rough (O-specific polysaccharide-negative) mutants were ECA-immunogenic, suggesting that they contained ECALPS; however, it was not known which part of the LPS core region was involved in ECA binding. To address this, we used a set of three deep-rough LPS mutants for rabbit immunization. The polyvalent antisera obtained were: (i) analysed for the presence of anti-LPS and anti-ECA antibodies; (ii) treated with caprylic acid (CA) to precipitate IgM antibodies and protein aggregates; and (iii) adsorbed with live ECA-negative bacteria to obtain specific anti-ECA antisera. We demonstrated the presence of antibodies specific for both ECAPG and ECALPS in all antisera obtained. Both CA treatment and adsorption with ECA-negative bacteria efficiently removed anti-LPS antibodies, resulting in specific anti-ECA sera. The LPS of the ECALPS-positive deepest-rough mutant contained only lipid A and 3-deoxy-d-manno-oct-2-ulosonic acid (Kdo) residues of the inner core, suggesting that ECALPS was linked to the Kdo region of LPS in Y. enterocolitica O : 3.


Effects of diet source and vaccination for porcine circovirustype 2 and Mycoplasma hyopneumoniae on nursery pig performance.
Two experiments were conducted to evaluate the effect of nursery diet sources, porcine circovirustype 2 (PCV2) and Mycoplasma hyopneumoniae (M. hyo) vaccines, and vaccination timing on pig (Sus scrofa) performance. In Exp. 1, a total of 400 pigs (5.6 BW, 1.03 kg SD) were used in a 20-d study. Treatments were arranged in a 4 × 2 factorial in a blocked design (5 pigs/pen and10 pens/treatment), with main effects of diet manufacturing source (A, B, C, or D) and vaccination timing (d 0 or 8). On either d 0 (weaning) or 8, pigs received 2 vaccines (Circumvent PCV, Intervet/Schering-Plough Animal Health, Millsboro, DE; and RespiSure One, Pfizer Animal Health, New York, NY). A pre-determined amount of segregated early weaning (SEW) diet (0.45 kg/pig) was fed followed by a transition diet until d 8, and a common diet from d 8 to 20. Diet source affected (P < 0.001) ADG during the first 4 d and affected (P ≤ 0.02) ADG and ADFI from d 4 to 8. There were no differences (P ≥ 0.18) among diet sources once pigs were fed a common diet (d 8 to 20). Overall, diet source did not affect ADG; but ADFI tended (P = 0.06) to be decreased for pigs fed Diet C compared with those fed Diets A, B, and D. Pigs vaccinated on d 0 had decreased (P ≤ 0.01) ADG and ADFI (d 4 to 8 and d 0 to 8), resulting in lighter (P = 0.003) BW on d 8 than those of pigs not yet vaccinated (d 8). However, overall ADG was not affected by vaccination timing. In Exp. 2, 360 pigs (5.9 SD, 0.91 kg BW) were used in a 35-d trial to evaluate the effects of different vaccines. Treatments were arranged in a 3 by 2 factorial in a blocked design (5 pigs/pen and 12 pens/treatment). Main effects included PCV2 vaccine (none; CircoFLEX, Boehringer Ingelheim Vetmedica Inc., St. Joseph, MO; or Circumvent PCV); with or without M. hyo vaccine (RespiSure, Pfizer Animal Health, New York, NY). Overall, pigs vaccinated with Circumvent PCV had decreased (P < 0.02) ADG and ADFI compared with CircoFLEX-vaccinated or control pigs. On d 35, pigs vaccinated with Circumvent PCV weighed less (P < 0.01) than CircoFLEX-vaccinated or control pigs. RespiSure-vaccinated pigs had decreased (P ≤ 0.05) ADG compared with control pigs from d 14 to 21 and d 21 to 29. On d 35, RespiSure-vaccinated pigs tended (P = 0.06) to weigh and consume less than control pigs. These data indicate diet source and vaccination timing affects pig performance after weaning. Vaccination for PCV2 and M. hyo independently reduced ADG and ADFI, but the effect was product-dependent.


The tissue-specific metabolic effects of the PPARα agonist ciprofibrate in insulin-resistant male individuals: a double-blind, randomized, placebo-controlled crossover study.
Insulin resistance is characterized by ectopic fat accumulation leading to cardiac diastolic dysfunction and nonalcoholic fatty liver disease. The objective of this study was to determine whether treatment with the peroxisome proliferator-activated receptor-α (PPARα) agonist ciprofibrate has direct effects on cardiac and hepatic metabolism and can improve insulin sensitivity and cardiac function in insulin-resistant volunteers. Ten insulin-resistant male volunteers received 100 mg/d of ciprofibrate and placebo for 5 weeks in a randomized double-blind crossover study. Insulin-stimulated metabolic rate of glucose (MRgluc) was measured using dynamic 18 F-fluorodeoxyglucose-positron emission tomography (18 F-FDG-PET). Additionally, cardiac function, whole-body insulin sensitivity, intrahepatic lipid content, skeletal muscle gene expression, 24-hour blood pressure, and substrate metabolism were measured. Whole-body insulin sensitivity, energy metabolism, and body composition were unchanged after ciprofibrate treatment. Ciprofibrate treatment decreased insulin-stimulated hepatic MRgluc and increased hepatic lipid content. Myocardial net MRgluc tended to decrease after ciprofibrate treatment, but ciprofibrate treatment had no effect on cardiac function and cardiac energy status. In addition, no changes in PPAR-related gene expression in muscle were found. Ciprofibrate treatment increased hepatic lipid accumulation and lowered MRgluc, without affecting whole-body insulin sensitivity. Furthermore, parameters of cardiac function or cardiac energy status were not altered upon ciprofibrate treatment.


Maternal influences on growth and development of full-sibling foals.
Six pairs of full-sibling Quarter Horse foals were produced by non-surgical embryo transfer and immediate rebreeding of donor mares. Each pair of donor/recipient mares consisted of one multiparous (donor) and one nulliparous (recipient) mare of similar body type and size. Milk yield was determined within 2 d of 8, 15, 22, 29 d (early lactation); 45, 60 d (midlactation); and 90, 120 d (late lactation) postpartum by the weigh-suckle-weigh method. On the following day, milk samples were collected, and foals were weighed and measured for wither height, heart girth, metacarpal length, metatarsal length, carpus height, tarsus height, and hip height. Mean gestation length was longer (P < .05) in nulliparous mares than multiparous mares (343 vs 333 d). Daily milk production was greater (P < .05) during early lactation (12.1 vs 10.8 kg) and tended to be greater (P = .08) during midlactation (11.7 vs 10.4) in multiparous mares but was similar between groups in late lactation. Milk composition was similar between groups throughout lactation. Foals produced by multiparous mares weighed more (P < .03) throughout early lactation (70.4 vs 63.1 kg), but no differences in weights occurred between foals from multiparous and nulliparous mares through mid- and late lactation. Average daily weight gain (ADG) was similar between foal groups through early and midlactation. During late lactation, ADG tended to be greater (P = .07) in foals from nulliparous mares (1.05 vs .92 kg/d). These data suggest that nulliparous and multiparous mares of the same breed and similar body type and size produce foals with no differences in size and weight by 4 mo of age.


Many-body van der Waals interactions beyond the dipole approximation.
Long-ranged van der Waals (vdW) interactions are most often treated via Lennard-Jones approaches based on the combination of two-body and dipolar approximations. While beyond-dipole interactions and many-body contributions were separately addressed, little is known about their combined effect, especially in large molecules and relevant nanoscale systems. Here, we provide a full many-body description of vdW interactions beyond the dipole approximation, efficiently applicable to large-scale systems. Dipole-quadrupole interactions consistently exhibit large magnitude up to nm-scale separations, while many-body effects lead to system-dependent screening effects, which can reduce vdW interactions by a large fraction. Combined many-body and multipolar terms emerge as an essential ingredient for the reliable description of vdW interactions in molecular and nanoscale systems.


Role of Mas Receptor Antagonist A799 in Renal Blood Flow Response to Ang 1-7 after Bradykinin Administration in Ovariectomized Estradiol-Treated Rats.
Background. The accompanied role of Mas receptor (MasR), bradykinin (BK), and female sex hormone on renal blood flow (RBF) response to angiotensin 1-7 is not well defined. We investigated the role of MasR antagonist (A779) and BK on RBF response to Ang 1-7 infusion in ovariectomized estradiol-treated rats. Methods. Ovariectomized Wistar rats received estradiol (OVE) or vehicle (OV) for two weeks. Catheterized animals were subjected to BK and A799 infusion and mean arterial pressure (MAP), RBF, and renal vascular resistance (RVR) responses to Ang 1-7 (0, 100, and 300 ng kg(-1) min(-1)) were determined. Results. Percentage change of RBF (%RBF) in response to Ang1-7 infusion increased in a dose-dependent manner. In the presence of BK, when MasR was not blocked, %RBF response to Ang 1-7 in OVE group was greater than OV group significantly (P < 0.05). Infusion of 300 ng kg(-1) min(-1) Ang 1-7 increased RBF by 6.9 ± 1.9% in OVE group versus 0.9 ± 1.8% in OV group. However when MasR was blocked, %RBF response to Ang 1-7 in OV group was greater than OVE group insignificantly. Conclusion. Coadministration of BK and A779 compared to BK alone increased RBF response to Ang 1-7 in vehicle treated rats. Such observation was not seen in estradiol treated rats.


Ginkgolide B Suppresses Methamphetamine-Induced Microglial Activation Through TLR4-NF-κB Signaling Pathway in BV2 Cells.
Accumulating evidence suggests that microglial cells have altered morphology and proliferation in different brain regions of methamphetamine (Meth) abusers and Meth-abusing animal models. However, the possible mechanisms underlying Meth-induced microglial activation remain poorly understood. Meanwhile, Toll-like receptor4 (TLR4) is closely associated with inflammation. Therefore the aim of the present study was to assess whether Meth treatment affects TLR4 expression; in addition, we evaluated the effects of ginkgolide B (GB), a diterpene lactone extracted from Ginkgo biloba, on Meth-mediated inflammation. BV2 cells were treated with Meth. Interestingly, Meth treatment significantly increased TLR4 expression, activated the NF-κB signaling pathway, and promoted TNF-α, IL-6 and IL-1β excretion. These effects, however, were partially attenuated by GB pre-treatment. To further confirm the role of TLR4 in Meth-mediated inflammation, the siRNA technology was applied to knock down TLR4, which resulted in hampered Meth-mediated inflammatory responses, confirming the important role of TLR4 in this process. Taken together, our findings suggested that Meth exposure results in BV2 cell activation, in association with TLR4 upregulation. GB could attenuate Meth-induced inflammation, at least partially through TLR4-NF-κB signaling pathway, therefore, targeting TLR4 may constitute a potential intervention strategy for Meth mediated neuroinflammation.


Inhibition of secondary caries lesion progression using fluoride varnish.
The purpose of this study was to determine the efficacy of fluoride varnish (FV) in inhibiting progression of secondary caries (SC). In a first experiment, human teeth, restored either with amalgam or resin composite, were exposed for 4 days to a microbial caries model. Half of each specimen was then painted with an acid-resistant nail varnish to maintain the baseline SC lesion. Specimens were then either treated with a FV (removed after 24 h) or not treated (control groups) prior to being exposed for 4 more days to the caries model. A second experiment was conducted to compare the effect that the varnish (with and without fluoride) had on SC development around amalgam. Confocal laser scanning microscopy data from these experiments suggested that the application of a FV to early, active SC lesions significantly slowed down their progression. Furthermore, the application of a placebo varnish showed a trend towards slowing down lesion progression, suggesting that the effect of FV on SC is not only due to its fluoride release.


Radioimmunotherapy-augmented BEAM chemotherapy vs BEAM alone as the high-dose regimen for autologous stem cell transplantation (ASCT) in relapsed follicular lymphoma (FL): a retrospective study of the EBMT Lymphoma Working Party.
Relapse remains the most common cause of treatment failure in patients receiving autologous stem cell transplantation (ASCT) for follicular lymphoma (FL). The aim of this study was to evaluate the effect of adding radioimmunotherapy or rituximab (R) to BEAM (carmustine, etoposide, ara-c, melphalan) high-dose therapy for ASCT in patients with relapsed FL. Using the European Society for Blood and Marrow Transplantation registry, we conducted a cohort comparison of BEAM (n=1973), Zevalin-BEAM (Z-BEAM) (n=207) and R-BEAM (n=179) and also a matched-cohort analysis of BEAM vs Z-BEAM including 282 and 154 patients, respectively. BEAM, Z-BEAM and R-BEAM groups were well balanced for age, time from diagnosis to ASCT and disease status at ASCT. The cumulative incidences of relapse (IR) at 2 years were 34, 34 and 32% for Z-BEAM, R-BEAM and BEAM, respectively. By multivariate analysis, there were no significant differences with Z-BEAM or R-BEAM compared with BEAM for IR, non-relapse mortality, event-free survival or overall survival. With the caveat that the limitations of registry analyses have to be taken into account, this study does not support adding radioimmunotherapy or R to BEAM in ASCT for relapsed FL. However, we cannot rule out the existence a particular subset of patients who could benefit from Z-BEAM conditioning that cannot be identified in our series, and this should be tested in a randomized trial.


Automatic preoperative planning of DBS electrode placement using anatomo-clinical atlases and volume of tissue activated.
Deep brain stimulation (DBS) is a procedure requiring accurate targeting and electrode placement. The two key elements for successful planning are preserving patient safety by ensuring a safe trajectory and creating treatment efficacy through optimal selection of the stimulation point. In this work, we present the first approach of computer-assisted preoperative DBS planning to automatically optimize both the safety of the electrode's trajectory and location of the stimulation point so as to provide the best clinical outcome. Building upon the findings of previous works focused on electrode trajectory, we added a set of constraints guiding the choice of stimulation point. These took into account retrospective data represented by anatomo-clinical atlases and intersections between the stimulation region and sensitive anatomical structures causing side effects. We implemented our method into automatic preoperative planning software to assess if the algorithm was able to simultaneously optimize electrode trajectory and the stimulation point. Leave-one-out cross-validation on a dataset of 18 cases demonstrated an improvement in the expected outcome when using the new constraints. The distance to critical structures was not reduced. The intersection between the stimulation region and structures sensitive to stimulation was minimized. Introducing these new constraints guided the planning to select locations showing a trend toward symptom improvement, while minimizing the risks of side effects, and there was no cost in terms of trajectory safety.


Preliminary study of the pharmacokinetics of desmethyldiazepam administered as drops or tablets.
Desmethyldiazepam (Vegesan) was administered in the form of 5-mg and 10-mg tablets and of 10-mg drops to 4 male and 4 female young healthy volunteers. The plasma levels of desmethyldiazepam were measured over 168 h. The time courses could be fitted to the one- or to the two-compartment model. The mean half-lives of elimination came to 75.3 +/- 32.0 (SD) h (5-mg tablets), 66.5 +/- 21.0 (SD) h (10-mg tablets) and 78.4 +/- 33.2 (SD) h (10-mg drops). The bioavailability of desmethyldiazepam from tablets and from drops was practically the same. The bioavailability appeared to be independent of dose in this range. A significantly higher total plasma clearance was calculated for the male than for the female volunteers after all three dosage forms (p less than 0.05). The total plasma clearance lay between 4.8 and 13.0 ml/min for the female and 12.4 and 24.3 ml/min for the male volunteers. Ingestion of the contraceptive pill is suggested as a possible cause of the sex differences.


ASEXUAL REPRODUCTION IN CESTODES (CYCLOPHYLLIDEA: TAENIIDAE): ECOLOGICAL AND PHYLOGENETIC INFLUENCES.
Asexual reproduction, a rare trait among cestodes in general, occurs in the "larval" (metacestode) stage of species of the family Taeniidae. The distribution of this trait among taeniid species is not consistent with an ecological hypothesis of current environmental predictability. We therefore chose a subset of the family and studied their phylogenetic relationships by Wagner parsimony analysis as a test of historical influences on asexual reproduction. We produced a consensus tree based on four 50-step trees with consistency indices of 0.38. Given these hypothetical relationships, we found that asexual reproduction either arose or was lost multiple times. Moreover, this consensus tree is incongruent with both definitive and intermediate host phylogenies, and asexual reproduction does not correlate with host transfers inferred from these phylogenies. Developmental and phylogenetic constraints on asexual reproduction therefore appear to have been minimal. Given current information, neither historical constraint nor explanations invoking adaptation based on environmental predictability can account for life-history variation in these cestodes.


Activation of PERK-ATF4-CHOP pathway as a novel therapeutic approach for efficient elimination of HTLV-1-infected cells.
Patients with adult T-cell leukemia (ATL) exhibit a poor prognosis and overall survival rate when treated with standard chemotherapy, highlighting the continued requirement for the development of novel safe and effective therapies for human T-cell leukemia virus type 1 (HTLV-1)-related diseases. In this study, we demonstrated that MK-2048, a second-generation HIV-1 integrase (IN) inhibitor, potently and selectively kills HTLV-1-infected cells. Differential transcriptome profiling revealed significantly elevated levels of gene expression of the unfolded protein response (UPR) PKR-like ER kinase (PERK) signaling pathway in ATL cell lines following MK-2048 treatment. We also identified a significant downregulation in glucose regulated protein 78 (GRP78), a master regulator of the UPR in the CD4+CADM1+ HTLV-1-infected cell population of primary HTLV-1 carrier peripheral blood mononuclear cells (PBMCs) (n = 9), suggesting that HTLV-1-infected cells are hypersensitive to endoplasmic reticulum (ER) stress-mediated apoptosis. MK-2048 efficiently reduced proviral loads in primary HTLV-1 carrier PBMCs (n = 4), but had no effect on the total numbers of these cells, indicating that MK-2048 does not affect the proliferation of HTLV-1-uninfected PBMCs. MK-2048 specifically activated the ER stress-related proapoptotic gene, DNA damage-inducible transcript 3 protein (DDIT3), also known as C/EBP homologous protein (CHOP), in HTLV-1-infected but not uninfected cells of HTLV-1-carrier PBMCs. Our findings demonstrated that MK-2048 selectively induces HTLV-1-infected cell apoptosis via the activation of the UPR. This novel regulatory mechanism of the HIV IN inhibitor MK-2048 in HTLV-1-infected cells provides a promising prophylactic and therapeutic target for HTLV-1-related diseases including ATL.


The impact of carbapenemases on antimicrobial development and therapy.
Carbapenems have been the most successful beta-lactam antibiotics in evading bacterial resistance. Nevertheless, acquired carbapenemases are increasingly reported, mostly in Pseudomonas and Acinetobacter isolates but occasionally also in Enterobacteriaceae. They include beta-lactamases of classes B (IMP and VIM), D (OXA-23 to -27) and A (IMI, KPC, NMC and SME). Major outbreaks of producers have occurred in a few centers and, in the US, there has been progressive erosion of carbapenem activity against Acinetobacter species, maybe due to carbapenemases. Acquired carbapenemases are still sufficiently rare not to have placed widespread constraints on chemotherapy, but there is reasonable concern that they will become a greater problem in the future. This is a good argument for continued caution with carbapenem use, and for extending this prudence to the oral and long half-life carbapenems shortly to become available. Most carbapenemase producers are broadly resistant to beta-lactams, and many are also resistant to fluoroquinolones and aminoglycosides. Clinicians facing infections caused by carbapenemase producers consequently are forced to use 'unusual' antibiotics such as polymyxins, isepamicin, minocycline and sulbactam (Pfizer Inc), which has inherent activity against A baumannii. Carbapenemase inhibitors might be developed in the future, despite difficulties in choosing the range of enzymes to target and obtaining broad-spectrum inhibition. For now, the best pharmaceutical strategy seems to lie in the development of novel antimicrobial classes with anti-Gram-negative activity, rather than in overcoming carbapenemases directly.


Factor inhibiting HIF1-A novel target of SUMOylation in the human placenta.
Adaptations to changes in oxygen are critical to ensure proper placental development, and impairments in oxygen sensing mechanisms characterize placental pathologies such as preeclampsia. In this study, we examined the involvement of SUMOylation, a reversible posttranslational modification, in the regulation of the asparaginyl hydroxylase Factor Inhibiting Hypoxia Inducible Factor 1 (FIH1) in the human placenta in development and in disease status. FIH1 protein abundance and spatial distribution in the developing placenta directly correlated with oxygen tension in vivo. Immunofluorescence analysis showed that early on FIH1 primarily localized to nuclei of cytotrophoblast cells, while after 10 weeks of gestation it was present in nuclei and cytoplasm of both cytotrophoblast and syncytiotrophoblast cells. Exposure of choriocarcinoma JEG-3 cells to hypoxia induced FIH1 SUMOylation by promoting its association to SUMO2/3. Transfection of JEG-3 cells with FIH1 constructs containing SUMO-mutated sites revealed that SUMOylation of FIH1 by SUMO2/3 targeted it for proteasomal degradation, particularly in hypoxia. SUMOylation of FIH1 directly impacted on HIF1A activity as determined by HIF-responsive luciferase assay. Co-immunoprecipitation analyses revealed enhanced FIH1-SUMO2/3 associations early in development, when FIH1 levels are low, while deSUMOylation of FIH1 by SENP3 increased later in gestation, when FIH1 levels are rising. In preeclampsia, decreased FIH1 protein expression associated with impaired deSUMOylation by SENP3 and increased association with the ubiquitin ligase RNF4. We propose a novel mode of regulation of FIH1 stability by dynamic SUMOylation and deSUMOylation in the human placenta in response to changing oxygen tension, thereby mediating HIF1A transcriptional activity in physiological and pathological conditions.


Earthquake rupture below the brittle-ductile transition in continental lithospheric mantle.
Earthquakes deep in the continental lithosphere are rare and hard to interpret in our current understanding of temperature control on brittle failure. The recent lithospheric mantle earthquake with a moment magnitude of 4.8 at a depth of ~75 km in the Wyoming Craton was exceptionally well recorded and thus enabled us to probe the cause of these unusual earthquakes. On the basis of complete earthquake energy balance estimates using broadband waveforms and temperature estimates using surface heat flow and shear wave velocities, we argue that this earthquake occurred in response to ductile deformation at temperatures above 750°C. The high stress drop, low rupture velocity, and low radiation efficiency are all consistent with a dissipative mechanism. Our results imply that earthquake nucleation in the lithospheric mantle is not exclusively limited to the brittle regime; weakening mechanisms in the ductile regime can allow earthquakes to initiate and propagate. This finding has significant implications for understanding deep earthquake rupture mechanics and rheology of the continental lithosphere.


Maternal cardiopulmonary resuscitation.
The perinatal resuscitation history in Japan is short, with the earliest efforts in the field of neonatology. In contrast, the standardization and dissemination of maternal resuscitation is lagging. With the establishment of the Maternal Death Reporting Project and the Maternal Death Case Review and Evaluation Committee in 2010, with the aim of reducing maternal deaths, the true situation of maternal deaths came to light. Subsequently, in 2015, the Japan Council for the Dissemination of Maternal Emergency Life Support Systems (J-CIMELS) was established to educate and disseminate simulations in maternal emergency care; training sessions on maternal resuscitation are now conducted in all prefectures. Since the launch of the project and council, the maternal mortality rate in Japan (especially due to obstetric critical hemorrhage) has gradually decreased. This has been probably achieved due to the tireless efforts of medical personnel involved in perinatal care, as well as the various activities conducted so far. However, there are no standardized guidelines for maternal resuscitation yet. Therefore, a committee was set up within the Japan Resuscitation Council to develop a maternal resuscitation protocol, and the Guidelines for Maternal Resuscitation 2020 was created in 2021. These guidelines are expected to make the use of high-quality resuscitation methods more widespread than ever before. This presentation will provide an overview of the Guidelines for Maternal Resuscitation 2020.


Predictive values of anti-cyclic citrullinated peptide antibodies and rheumatoid factor in relation to serological aspects of the ACR/EULAR 2010 classification criteria for rheumatoid arthritis.
Objective: In this retrospective population-based register study, we wanted to determine the positive predictive values (PPVs) of immunoglobulin M rheumatoid factor (IgM RF) and anti-citrullinated protein antibodies (ACPAs) at 3 × upper normal limit (UNL), since they are weighted equally in the American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) 2010 criteria for rheumatoid arthritis (RA).Methods: Test results, ordering unit, test date, and patient social security number were collected from the Department of Clinical Immunology at Odense University Hospital from 2007 to 2016 and merged with patient diagnosis from the Danish National Patient Registry.Results: The PPV of IgM RF at 3 × UNL was 14%, compared to a PPV of 43% for ACPAs at 3 × UNL.Conclusion: The PPV of ACPAs is higher than the PPV of IgM RF at 3 × UNL. These findings are not reflected in the ACR/EULAR 2010 classification criteria for RA.


PREY ADAPTATION AS A CAUSE OF PREDATOR-PREY CYCLES.
We analyze simple models of predator-prey systems in which there is adaptive change in a trait of the prey that determines the rate at which it is captured by searching predators. Two models of adaptive change are explored: (1) change within a single reproducing prey population that has genetic variation for vulnerability to capture by the predator; and (2) direct competition between two independently reproducing prey populations that differ in their vulnerability. When an individual predator's consumption increases at a decreasing rate with prey availability, prey adaptation via either of these mechanisms may produce sustained cycles in both species' population densities and in the prey's mean trait value. Sufficiently rapid adaptive change (e.g., behavioral adaptation or evolution of traits with a large additive genetic variance), or sufficiently low predator birth and death rates will produce sustained cycles or chaos, even when the predator-prey dynamics with fixed prey capture rates would have been stable. Adaptive dynamics can also stabilize a system that would exhibit limit cycles if traits were fixed at their equilibrium values. When evolution fails to stabilize inherently unstable population interactions, selection decreases the prey's escape ability, which further destabilizes population dynamics. When the predator has a linear functional response, evolution of prey vulnerability always promotes stability. The relevance of these results to observed predator-prey cycles is discussed.


Pediatric dermatology emergencies.
Many pediatric skin conditions can be safely monitored with minimal intervention, but certain skin conditions are emergent and require immediate attention and proper assessment of the neonate, infant, or child. We review the following pediatric dermatology emergencies so that clinicians can detect and accurately diagnose these conditions to avoid delayed treatment and considerable morbidity and mortality if missed: staphylococcal scalded skin syndrome (SSSS), impetigo, eczema herpeticum (EH), Langerhans cell histiocytosis (LCH), infantile hemangioma (IH), and IgA vasculitis.


Medical ethics in Latin America: a new interest and commitment.
Recent visits to five Latin American nations indicate that some medical professionals are eager to increase the role of bioethics in their countries. Conversations with key figures there point up similarities and differences among Latin nations, and between Latin countries and the United States, in their approaches to ethics. Opportunities exist for U.S. bioethicists to help get bioethics teaching and research off the ground in Latin America.


Angiotensin converting enzyme immunohistochemistry in rat brain and pituitary gland: correlation of isozyme type with cellular localization.
We have localized angiotensin converting enzyme in rat brain and pituitary gland immunohistochemically with an anti-rat lung angiotensin converting enzyme monoclonal antibody. The distribution of immunoreactive angiotensin converting enzyme is identical with that of binding sites for the angiotensin converting enzyme inhibitor, [3H]captopril. Most intense staining is in the choroid plexus and subfornical organ, with intermediate values in the caudate-putamen, globus pallidus, entopeduncular nucleus, pars reticulata of the substantia nigra, posterior pituitary and anterior pituitary. Lower levels are observed in the supraoptic and paraventricular nuclei of the hypothalamus. Within the basal ganglia angiotensin converting enzyme immunoreactivity is distributed throughout the neuropil; no cell bodies are stained, even after colchicine treatment. The punctate pattern of immunoreactivity in the anterior pituitary corresponds to the distribution of endothelial cells. The posterior pituitary is stained diffusely. Angiotensin converting enzyme is increased by 45% in the posterior lobe after pituitary stalk section, demonstrating that this diffuse staining is associated with pituicytes. Antibody specificity was demonstrated by the immunoaffinity purification of angiotensin converting enzyme to homogeneity from crude tissue extracts using anti-angiotensin converting enzyme antibody and protein A-sepharose. The apparent molecular weight by sodium dodecyl sulfate polyacrylamide gel electrophoresis of lung, choroid plexus and anterior pituitary angiotensin converting enzyme is 175,000. In the substantia nigra and caudate putamen, where angiotensin converting enzyme is localized to neuronal as opposed to epithelial cells, the molecular weight is 165,000. The pituicyte angiotensin converting enzyme of the posterior pituitary is 170,000 daltons.


Calcite as a bone substitute. Comparison with hydroxyapatite and tricalcium phosphate with regard to the osteoblastic activity.
Close to the bone mineral phase, the calcic bioceramics, such as hydroxyapatite (HA) and β-tricalcium phosphate (β-TCP), are commonly used as substitutes or filling materials in bone surgery. Besides, calcium carbonate (CaCO3) is also used for their excellent biocompatibility and bioactivity. However, the problem with the animal-origin aragonite demands the new technique to synthesize pure calcite capable of forming 3D bone implant. This study aims to manufacture and evaluate a highly-pure synthetic crystalline calcite with good cytocompatibility regarding to the osteoblasts, comparing to that of HA and β-TCP. After the manufacture of macroporous bioceramic scaffolds with the identical internal architecture, their cytocompatibility is studied through MC3T3-E1 osteoblasts with the tests of cell viability, proliferation, vitality, etc. The results confirmed that the studied process is able to form a macroporous material with a controlled internal architecture, and this synthesized calcite is non-cytotoxic and facilitate the cell proliferation. Indeed requiring further improvement, the studied calcite is definitely an interesting alternative not only to coralline aragonite but also to calcium phosphate ceramics, particularly in bone sites with the large bone remodelling.


Vibrational lifetimes of hydrogen on lead films: an ab initio molecular dynamics with electronic friction (AIMDEF) study.
Using density functional theory and Ab Initio Molecular Dynamics with Electronic Friction (AIMDEF), we study the adsorption and dissipative vibrational dynamics of hydrogen atoms chemisorbed on free-standing lead films of increasing thickness. Lead films are known for their oscillatory behaviour of certain properties with increasing thickness, e.g., energy and electron spillout change in discontinuous manner, due to quantum size effects [G. Materzanini, P. Saalfrank, and P. J. D. Lindan, Phys. Rev. B 63, 235405 (2001)]. Here, we demonstrate that oscillatory features arise also for hydrogen when chemisorbed on lead films. Besides stationary properties of the adsorbate, we concentrate on finite vibrational lifetimes of H-surface vibrations. As shown by AIMDEF, the damping via vibration-electron hole pair coupling dominates clearly over the vibration-phonon channel, in particular for high-frequency modes. Vibrational relaxation times are a characteristic function of layer thickness due to the oscillating behaviour of the embedding surface electronic density. Implications derived from AIMDEF for frictional many-atom dynamics, and physisorbed species will also be given.


Effect of odors in asthma.
Many patients complain that some odors worsen their asthma. Perfume and cologne are two of the most frequently mentioned offenders. Four patients with a history of worsening of asthma on exposure to cologne underwent challenge with a cologne, and their pulmonary function was tested before, during, and after the exposure. Forced expiratory volume in one second declined 18 to 58 percent below the baseline period during the 10-minute exposure and gradually increased in the next 20 minutes. Saline placebo pretreatment did not affect the response to subsequent challenge. Single-blind pretreatment with metaproterenol and atropine prevented decline in one-second forced expiratory volume in three of four patients and blunted the response in the other. Cromolyn sodium prevented decline in one of four, and occlusion of nostrils prevented decline in one of three. A survey of 60 asthmatic patients revealed a history of respiratory symptoms in 57 on exposure to one or more common odors. Odors are an important cause of worsening of asthma.


The Ages & Stages Questionnaire: Social-Emotional: A validation study of a mother-report questionnaire on a clinical mother-infant sample.
Mother-report questionnaires of infant socioemotional functioning are increasingly used to screen for clinical referral to infant mental health services. The validity of the Ages & Stages Questionnaire: Social Emotional (ASQ:SE; J. Squires, D. Bricker, K. Heo, & E. Twombly, 2002) was investigated in a sample of help-seeking mothers with young infants. It was compared with independent observer-rated dyadic interactions, and the quality of dyadic relationships was rated by expert clinicians. The ASQ:SE ratings also were compared with questionnaires on maternal psychological stress and distress. The ASQ:SE did not correlate significantly with either external ratings of dyadic interaction or clinically assessed relationship qualities, though the latter two were strongly associated with each other. In contrast, ASQ:SE scores were associated with questionnaires relating to maternal psychological distress. This was especially true for mothers classified as depressed. Furthermore, reports on the ASQ:SE were strongly predicted by maternal stress. The study points to some problems with the concurrent validity of the ASQ:SE in clinical samples. It also demonstrates a close link between mothers' psychological distress and their ratings of infant social and emotional functioning. Further research should investigate the extent to which the ASQ:SE specifically measures infant functioning or maternal distress, and how it functions in clinical versus nonclinical samples.


Plasmid-linked resistance to inorganic salts in Staphylococcus aureus.
The penicillinase plasmids, a series of extrachromosomal resistance factors in Staphylococcus aureus, were found to carry determinants of resistance to a series of inorganic ions as well as resistance to penicillin and, in some cases, erythromycin. Most of the ions involved were inhibitory but not lethal to the bacteria; the resistance markers conferred an increase in resistance by comparison with susceptible organisms of between 3- and 100-fold, depending on the ion involved. Separate genetic loci for resistance to arsenate, arsenite, lead, cadmium, mercuric, and bismuth ions were demonstrated. Resistance to antimony and resistance to zinc were also found but were not separated genetically from resistance to arsenite and cadmium, respectively. The ion resistance markers appeared to form a cluster on the plasmid, with no other known marker within it. Naturally occurring plasmids were observed that lacked one or more of these ion resistance markers, as well as penicillinase-negative strains that were resistant to one or more of the ions. The patterns of markers carried by these various strains may provide some understanding of the evolution of a plasmid linkage group.


The biological age linked to oxidative stress modifies breast cancer aggressiveness.
The incidence of breast cancer increases with age until menopause, and breast cancer is more aggressive in younger women. The existence of epidemiological links between breast cancer and aging indicates that both processes share some common mechanisms of development. Oxidative stress is associated with both cancer susceptibility and aging. Here we observed that ERBB2-positive breast cancer, which developed in genetically heterogeneous ERBB2-positive transgenic mice generated by a backcross, is more aggressive in chronologically younger than in older mice (differentiated by the median survival of the cohort that was 79 weeks), similar to what occurs in humans. In this cohort, we estimated the oxidative biological age using a mathematical model that integrated several subphenotypes directly or indirectly related to oxidative stress. The model selected the serum levels of HDL-cholesterol and magnesium and total AKT1 and glutathione concentrations in the liver. The grade of aging was calculated as the difference between the predicted biological age and the chronological age. This comparison permitted the identification of biologically younger and older mice compared with their chronological age. Interestingly, biologically older mice developed more aggressive breast cancer than the biologically younger mice. Genomic regions on chromosomes 2 and 15 linked to the grade of oxidative aging were identified. The levels of expression of Zbp1 located on chromosome 2, a gene related to necroptosis and inflammation, positively correlated with the grade of aging and tumour aggressiveness. Moreover, the pattern of gene expression of genes linked to the inflammation and the response to infection pathways was enriched in the livers of biologically old mice. This study shows part of the complex interactions between breast cancer and aging.


Focal adhesion kinase-related non-kinase ameliorates liver fibrosis by inhibiting aerobic glycolysis via the FAK/Ras/c-myc/ENO1 pathway.
Hepatic stellate cell (HSC) hyperactivation is a central link in liver fibrosis development. HSCs perform aerobic glycolysis to provide energy for their activation. Focal adhesion kinase (FAK) promotes aerobic glycolysis in cancer cells or fibroblasts, while FAK-related non-kinase (FRNK) inhibits FAK phosphorylation and biological functions. To elucidate the effect of FRNK on liver fibrosis at the level of aerobic glycolytic metabolism in HSCs. Mouse liver fibrosis models were established by administering CCl4, and the effect of FRNK on the degree of liver fibrosis in the model was evaluated. Transforming growth factor-β1 was used to activate LX-2 cells. Tyrosine phosphorylation at position 397 (pY397-FAK) was detected to identify activated FAK, and the expression of the glycolysis-related proteins monocarboxylate transporter 1 (MCT-1) and enolase1 (ENO1) was assessed. Bioinformatics analysis was performed to predict putative binding sites for c-myc in the ENO1 promoter region, which were validated with chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. The pY397-FAK level was increased in human fibrotic liver tissue. FRNK knockout promoted liver fibrosis in mouse models. It also increased the activation, migration, proliferation and aerobic glycolysis of primary hepatic stellate cells (pHSCs) but inhibited pHSC apoptosis. Nevertheless, opposite trends for these phenomena were observed after exogenous FRNK treatment in LX-2 cells. Mechanistically, the FAK/Ras/c-myc/ENO1 pathway promoted aerobic glycolysis, which was inhibited by exogenous FRNK. FRNK inhibits aerobic glycolysis in HSCs by inhibiting the FAK/Ras/c-myc/ENO1 pathway, thereby improving liver fibrosis. FRNK might be a potential target for liver fibrosis treatment.


A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress.
Cisplatin and its platinum analogs, carboplatin and oxaliplatin, are some of the most widely used cancer chemotherapeutics. Although cisplatin and carboplatin are used primarily in germ cell, breast and lung malignancies, oxaliplatin is instead used almost exclusively to treat colorectal and other gastrointestinal cancers. Here we utilize a unique, multi-platform genetic approach to study the mechanism of action of these clinically established platinum anti-cancer agents, as well as more recently developed cisplatin analogs. We show that oxaliplatin, unlike cisplatin and carboplatin, does not kill cells through the DNA-damage response. Rather, oxaliplatin kills cells by inducing ribosome biogenesis stress. This difference in drug mechanism explains the distinct clinical implementation of oxaliplatin relative to cisplatin, and it might enable mechanistically informed selection of distinct platinum drugs for distinct malignancies. These data highlight the functional diversity of core components of front-line cancer therapy and the potential benefits of applying a mechanism-based rationale to the use of our current arsenal of anti-cancer drugs.


The Prevalence of Intimate Partner Violence, Associated Risk Factors, and Other Moderating Effects: Findings From the Kenya National Health Demographic Survey.
Intimate partner violence (IPV) is not only a fundamental violation of human rights but also a major public health problem. IPV is the most predominant form of violence committed by men against women. Therefore, our study sought to determine the prevalence of IPV and other moderating factors associated with IPV among these women. This study utilized data from the 2014 Kenya Demographic and Health Survey (KDHS), a nationally representative household-based survey that utilizes a two-stage sampling design. Data was weighted and analyzed using Stata 12 for Windows. A total of 3,028 women were interviewed for the analysis. A majority of the women were aged between 20 and 29 years (1,305; 43.1%), with a greater proportion married (2,329; 76.9%) and identified as Protestant (2,181; 72.1%). On adjusted analysis, factors associated with experiencing IPV included women who: were aged between 40 and 49 years belonging to religions other than Catholic, Protestant, or practiced no religion, resided in urban areas, were currently working, had a poor Wealth Index, were not sexually assertive, had one sexual partner other than their husband/spouse, received money, gifts, or favors in return for sex, had no knowledge on HIV, had husbands/partners aged above 50 years, experienced an early sexual debut of less than 18 years and felt that their partners were justified in beating them. Gender-based violence is complex and multifaceted affecting individuals, families, and society at large and should be addressed from different spectrums of intervention. There is a need for interventions that reduce and prevent IPV through empowering women, creating jobs to accumulate wealth, creating a conducive environment within workplaces for those employed, educating women, and empowering school-aged children to avert IPV.


Facial symmetry in protein self-assembly.
Amyloids are self-assembled protein architectures implicated in dozens of misfolding diseases. These assemblies appear to emerge through a "selection" of specific conformational "strains" which nucleate and propagate within cells to cause disease. The short Abeta(16-22) peptide, which includes the central core of the Alzheimer's disease Abeta peptide, generates an amyloid fiber which is morphologically indistinguishable from the full-length peptide fiber, but it can also form other morphologies under distinct conditions. Here we combine spectroscopic and microscopy analyses that reveal the subtle atomic-level differences that dictate assembly of two conformationally pure Abeta(16-22) assemblies, amyloid fibers and nanotubes, and define the minimal repeating unit for each assembly.


Protein-tyrosine phosphatases: biological function, structural characteristics, and mechanism of catalysis.
The protein-tyrosine phosphatases (PTPases) superfamily consists of tyrosine-specific phosphatases, dual specificity phosphatases, and the low-molecular-weight phosphatases. They are modulators of signal transduction pathways that regulate numerous cell functions. Malfunction of PTPases have been linked to a number of oncogenic and metabolic disease states, and PTPases are also employed by microbes and viruses for pathogenicity. There is little sequence similarity among the three subfamilies of phosphatases. Yet, three-dimensional structural data show that they share similar conserved structural elements, namely, the phosphate-binding loop encompassing the PTPase signature motif (H/V)C(X)5R(S/T) and an essential general acid/base Asp residue on a surface loop. Biochemical experiments demonstrate that phosphatases in the PTPase superfamily utilize a common mechanism for catalysis going through a covalent thiophosphate intermediate that involves the nucleophilic Cys residue in the PTPase signature motif. The transition states for phosphoenzyme intermediate formation and hydrolysis are dissociative in nature and are similar to those of the solution phosphate monoester reactions. One strategy used by these phosphatases for transition state stabilization is to neutralize the developing negative charge in the leaving group. A conformational change that is restricted to the movement of a flexible loop occurs during the catalytic cycle of the PTPases. However, the relationship between loop dynamics and enzyme catalysis remains to be established. The nature and identity of the rate-limiting step in the PTPase catalyzed reaction requires further investigation and may be dependent on the specific experimental conditions such as temperature, pH, buffer, and substrate used. In-depth kinetic and structural analysis of a representative number of phosphatases from each group of the PTPase superfamily will most likely continue to yield insightful mechanistic information that may be applicable to the rest of the family members.