Preincubation with a low-dose hydrogen peroxide enhances anti-oxidative stress ability of BMSCs.
To investigate the effects of low-concentration hydrogen peroxide pretreatment on the anti-oxidative stress of the bone marrow mesenchymal stem cells (BMSCs). Rabbit BMSCs were isolated and cultured by density gradient centrifugation combined with the adherence method. Then, the third generation of well-grown BMSCs was continuously treated with 50-μM hydrogen peroxide (H2O2) for 8 h as the optimal pretreatment concentration and the BMSCs were continuously applied for 24 h with 500 μM H2O2, and the optimal damage concentration was determined as the oxidative stress cell model. The experiment was divided into three groups: control group, high-concentration H2O2 injury group (500 μM), and low-concentration H2O2 pretreatment group (50 μM + 500 μM). In each group, the DCFH-DA fluorescence probe was used to detect the reactive oxygen species (ROS). ELISA was used to detect the activity of superoxide dismutase (SOD) and catalase (CAT), and the TBA method was used to detect malondialdehyde (MDA). The mitochondrial membrane potential was detected by JC-1. The cell viability was detected by CCK-8 method, while flow cytometry and TUNEL/DAPI double staining were performed to detect cell apoptosis. Hence, the effect of H2O2 pretreatment on the anti-oxidative stress of BMSCs was investigated. One-way analysis of variance was performed using SPSS 19.0 statistical software, and P < 0.05 was considered statistically significant. A large number of typical BMSCs were obtained by density gradient centrifugation and adherent culture. The oxidative stress cell model was successfully established by 500-μM H2O2. Compared with the high-concentration H2O2 injury group, the low-concentration H2O2 pretreatment reduced the production of ROS [(62.33 ± 5.05), P < 0.05], SOD and CAT activities significantly increased (P < 0.05), and MDA levels significantly decreased (P < 0.05). The mitochondrial membrane potential fluorescence changes, the ratio of red/green fluorescence intensity of the high-concentration H2O2 injury group was less, and the ratio of the low-concentration H2O2 pretreatment group was significantly higher than that. The ratio of red/green increased by about 1.8 times (P < 0.05). The cell viability and survival rate of BMSCs were significantly increased in low-concentration H2O2 pretreatment group (P < 0.05), and the cell apoptosis rate was significantly decreased (P < 0.05). Pretreatment with low-concentration H2O2 can enhance the anti-oxidative stress ability and reduce their apoptosis of BMSCs under oxidative stress.


Shaping Liquid Crystals with Gold Nanoparticles: Helical Assemblies with Tunable and Hierarchical Structures Via Thin-Film Cooperative Interactions.
The availability of helical assemblies of plasmonic nanoparticles with precisely controlled and tunable structures can play a key role in the future development of chiral plasmonics and metamaterials. Here, a strategy to efficiently yield helical structures based on the cooperative interactions of liquid crystals and gold nanoparticles in thin films is developed. These nanocomposites exhibit exceptional long-range hierarchical order across length scales, which results from the growth mechanism of nanoparticle-coated twisted nanoribbons and their ability to form organized bundles. The helical assembly formation is governed by the presence of rationally functionalized nanoparticles. Importantly, the thickness of the achieved nanocomposites can be reversibly reconfigured owing to the polymorphic nature of the liquid crystal. The versatility of the proposed approach is demonstrated by preparing helices assembled from nanoparticles of different geometries and dimensions (spherical and rod-like). The described strategy may become an enabling technology for structuring nanoparticle assemblies with high precision and fabricating optically active materials.


The use of polymyxin B and C3H/HeJ mouse spleen cells as criteria for endotoxin contamination.
We have performed experiments designed to evaluate the potential contribution of endotoxin contamination to lymphocyte reponses. Saline and EDTA extracts of 4 different strains of gram negative bacteria were examined for their capacity to initiate mitogenic responses in murine spleen cells. As compared to phenol extracts of these bacteria which contain primarily lipopolysaccharide-LPS, these saline and EDTA extracts were significantly less active in this assay. The mitogenic activity which was present was also manifest in spleen cells from the C3H/HeJ mouse, whereas phenol-extracted LPS preparations were inactive. In addition, mitogenic activity of saline and EDTA extracts was not blocked by polymyxin B, an agent known to abrogate LPS mediated responses. We conclude that LPS contamination may not normally be as significant a problem as had earlier been assumed. However, when endotoxin contamination is present, neither the use of C3H/HeJ spleen cells nor polymyxin B is an appropriate test to evaluate this possibility.


Prophylaxis against hypomagnesaemia induced by cis-platinum combination chemotherapy.
Hypomagnesaemia is recognised as a feature of the renal tubular defect produced by cis-platinum therapy for cancer. It may be sufficiently severe to cause tetany and grand mal fits. Attempts to correct established hypomagnesaemia whilst continuing cis-platinum therapy have not proved satisfactory. We have therefore investigated the prophylactic addition of 3 g magnesium sulphate to the high-dose platinum regimen with which metastatic malignant teratoma is treated in this unit. Serum magnesium levels have been measured in eight patients treated in this way and compared with those recorded for eight matched patients previously treated without routine magnesium supplements. Magnesium levels fell into the range frequently associated with clinical manifestation in five of the eight unsupplemented patients and only one of those given magnesium prophylactically. Mean serum magnesium levels were significantly higher in the supplemented group when compared using the paired t-test (P less than 0.01). Routine supplementation with intravenous magnesium sulphate is a simple and effective way of preventing symptomatic hypomagnesaemia associated with cis-platinum therapy.


Computational modeling studies reveal the origin of the binding preference of 3-(3,4-di hydroisoquinolin-2(1H)-ylsulfonyl)benzoic acids for AKR1C3 over its isoforms.
As a key regulator for hormone activity, human aldo-keto reductase family 1 member C3 (AKR1C3) plays crucial roles in the occurrence of various hormone-dependent or independent malignancies. It is a promising target for treating castration-resistant prostate cancer (CRPC). However, the development of AKR1C3 specific inhibitors remains challenging due to the high sequence similarity to its isoform AKR1C2. Here, we performed a combined in silico study to illuminate the inhibitory preference of 3-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic acids for AKR1C3 over AKR1C2, of which compound 38 can achieve up to 5000-fold anti-AKR1C3 selectivity. Our umbrella sampling (US) simulations together with end-point binding free energy calculation MM/GBSA uncover that the high inhibition selectivity originates from the different binding modes, namely "Inward" and "Outward," of this compound series in AKR1C3 and AKR1C2, respectively. In AKR1C3/38, the tetrahydroquinoline moiety of 38 is accommodated inside the SP1 pocket and interacts favorably with surrounding residues, while, in AKR1C2/38, the SP1 pocket is too small to hold the bulky tetrahydroquinoline group that instead moves out of the pocket with 38 transitioning from an "Inward" to an "Outward" state. Further 3D-QSAR and energy decomposition analyses suggest that SP1 in AKR1C3 prefers to bind with a rigid bicyclic moiety and the modification of the R3 group has important implication for the compound's activity. This work is the first attempt to elucidate the selectivity mechanism of inhibitors toward AKR1C3 at the atomic level, which is anticipated to propel the development of next-generation AKR1C3 inhibitors with enhanced efficacy and reduced "off-target" effect for CRPC therapy.


Surgical Resection for Hepatoblastoma-Updated Survival Outcomes.
Hepatoblastoma is the most common liver malignancy in the pediatric age group. The management of hepatoblastoma involves multidisciplinary approach. Patients with hepatoblastoma who underwent liver resection between 2000 and 2013 were analyzed and survival outcomes were studied. The crude incidence rate of hepatoblastoma at the Madras Metropolitan Tumor Registry (MMTR) is 0.4/1,00,000 population per year. Twelve patients underwent liver resection for hepatoblastoma during the study period; this included eight males and four females. The median age at presentation was 1.75 years (Range 5 months to 3 years). The median serum AFP in the study population was 20,000 ng/ml (Range 4.5 to 1,40,000 ng/ml). Three patients had stage I, one patient had stage II, and eight patients had stage III disease as per the PRETEXT staging system. Two patients were categorized as high risk and ten patients were categorized as standard risk. Seven of these patients received two to four cycles of neoadjuvant chemotherapy (PLADO regimen), and one patient received neoadjuvant radiation up to 84 Gy. Major liver resection was performed in nine patients. Nine patients received adjuvant chemotherapy. The most common histological subtype was embryonal type. Microscopic margin was positive in three cases. One patient recurred 7 months after surgery and the site of failure was the lung. The 5-year overall survival of the case series was 91%. The median survival was 120 months. Liver resections can be safely performed in pediatric populations after neoadjuvant treatment. Patients undergoing surgery had good disease control and long-term survival.


RBP2 induces stem-like cancer cells by promoting EMT and is a prognostic marker for renal cell carcinoma.
Renal cell carcinoma (RCC), one of the most common kidney cancers, has a poor prognosis. Epithelial to mesenchymal transition (EMT) is a hallmark of carcinoma invasion and metastasis. Several studies have examined the molecular regulation of EMT, but the relationship between histone demethylases and EMT is little understood. In this study, we investigated the role of retinoblastoma-binding protein-2 (RBP2), a histone demethylase that is highly expressed in RCC and is positively correlated with poor RCC prognosis in the regulation of EMT. We found that ectopic overexpression of RBP2 can induce cancer stem cell-like (CSC) phenotypes through EMT in RCC cells by converting them to a more mesenchymal phenotype. This results in increased resistance to apoptosis, which leads to enhanced tumor growth in xenograft models. Together, our data show that RBP2 is an epigenetic regulator that has an important role in the initiation of CSC phenotypes through EMT, leading to tumor progression. RBP2 is also a novel biomolecule for RCC diagnosis, and prognosis and may be a therapeutic target.


Prenatal diagnosis and genetic counseling of an inherited Xq24q25 deletion associated with normal phenotype.
Copy number variants (CNVs) are an important source of normal and pathogenic genome variations. CNVs identified in prenatal cases need careful considerations and correct interpretation if those are harmless or harmful variants from the norm. A 28-year-old, gravida 1, para 0, woman underwent amniocentesis at 17 weeks of gestation because the noninvasive prenatal testing (NIPT) results revealed a 9.8 Mb deletion from Xq24 to Xq25. GTG-banding karyotype analysis was performed on cultured amniocytes. Chromosomal microarray analysis (CMA) on uncultured amniocytes was performed. Chromosomal GTG-banding of the cultured amniocytes revealed a karyotype of 46,XX. CMA detected a 9.5-Mb chromosomal deletion in the region of Xq24q25 (arr[GRCh37] Xq24q25(118,975,436_128,444,692) × 1). The present report highlights that an integration of prenatal ultrasound, NIPT, karyotype analysis, CMA and genetic counseling is helpful for the prenatal diagnosis of chromosomal deletions/duplications.


Lichen photosynthesis in relation to CO2 concentration.
Photosynthetic CO2 dependencies were measured for six lichen species, representing a variety of morphologies and collected from widely different habitats. All curves exhibited a linear increase in photosynthesis with increasing CO2 concentrations at the lower range of CO2 values, but little photosynthetic variation with increasing CO2 concentrations at the upper range of CO2 values. Half maximal CO2 concentration estimates varied from 147-440 μl CO2·l1, but had broadly overlapping confidence intervals. We conclude that lichen CO2 dependencies are basically similar to those reported for higher plants and discuss the reasons why widely varying results have previously been published.


Characteristics of bioavailable organic phosphorus in sediment and its contribution to lake eutrophication in China.
This study aims to establish the relative importance of sediment organic phosphorus (Po) to the total P and the major classes of organic molecules that contribute to sediment Po, determined by measuring their susceptibility to enzymatic hydrolysis, across a suite of lakes ranging from oligotrophic to eutrophic status. The results showed that Po accounted for 21-60% of total P, and bioavailable Po accounted for 9-34% of Po in the sediments. The bioavailable Po includes mainly labile (H2O-Po) and moderately labile (NaOH-Po) P forms. For H2O-Po (accounting for only1.4% of Po), 53% (average) was labile monoester P, 28% was diester P and 17% was phytate-like P. For NaOH-Po (accounting for 9-33% of Po), 32% was labile monoester P, 33% was phytate-like P and 18% was diester P. The composition of bioavailable Po, determined by enzyme assays, was related to the lake nutrient levels, which implies that sediment bioavailable Po could act as an effective indicator for lake eutrophic status. With the increase of lake nutrient levels, bioavailable Po content and alkaline phosphatase activity in the sediment all increased, indicating that Po represents an important and bioavailable source of P that increases with eutrophication, and could contribute to internal loading and resistance of eutrophic lakes to remediation. This implies that eutrophic lakes would maintain long-term eutrophic status and algal bloom phenomena even after the external input of P was controlled and the total P concentration of water has declined. Thus, in order to reduce the release risk of sediment P more efficiently and effectively, sediment P control technique should focus not only on reducing the total P and inorganic P, but should also pay close attention to the removal of bioavailable Po.


Full opening of helix bundle crossing does not lead to NaK channel activation.
A critical part of ion channel function is the ability to open and close in response to stimuli and thus conduct ions in a regulated fashion. While x-ray diffraction studies of ion channels suggested a general steric gating mechanism located at the helix bundle crossing (HBC), recent functional studies on several channels indicate that the helix bundle crossing is wide-open even in functionally nonconductive channels. Two NaK channel variants were crystallized in very different open and closed conformations, which served as important models of the HBC gating hypothesis. However, neither of these NaK variants is conductive in liposomes unless phenylalanine 92 is mutated to alanine (F92A). Here, we use NMR to probe distances at near-atomic resolution of the two NaK variants in lipid bicelles. We demonstrate that in contrast to the crystal structures, both NaK variants are in a fully open conformation, akin to Ca2+-bound MthK channel structure where the HBC is widely open. While we were not able to determine what a conductive NaK structure is like, our further inquiry into the gating mechanism suggests that the selectivity filter and pore helix are coupled to the M2 helix below and undergo changes in the structure when F92 is mutated. Overall, our data show that NaK exhibits coupling between the selectivity filter and HBC, similar to K+ channels, and has a more complex gating mechanism than previously thought, where the full opening of HBC does not lead to channel activation.


Dataset of macrobenthic species, organic matter content and grain-size distribution in surficial seafloor sediments in outer continental shelf, pockmark fields and Capbreton Canyon tributaries in the southeastern Bay of Biscay.
This dataset presents the macrobenthic species abundance and biomass in soft bottom areas located at southeastern Bay of Biscay. Data on organic matter content and grain-size distribution in surficial seafloor sediments is also provided. Samples were obtained with Shipek and Smith-McIntyre type grabs in several surveys carried out between 2010 and 2020, covering a range of depths of 32-2241 m. Abundance and biomass of macrobenthic species are given. This database is useful for (i) research on spatial variability of macrobenthic communities, and (ii) baseline knowledge of species in the area. The research article on these data [1] was published in the journal Regional Studies in Marine Science. Title: Macrofaunal variability in the continental shelf and canyons in the southeastern Bay of Biscay.


The protective effect of Schisandra chinensis (Turcz.) Baill. polysaccharide on DSS-induced ulcerative colitis in mice via the modulation of gut microbiota and inhibition of NF-κB activation.
Schisandra chinensis (Turcz.) Baill, a fruit utilized in traditional Chinese medicine (TCM), has a long history of medical application. It has been used to treat diseases of the gastrointestinal tract. Schisandra chinensis (Turcz.) Baill polysaccharide (SACP) is an important biologically active ingredient that has been shown to have a variety of beneficial effects including immune regulation and anti-oxidative properties. Ulcerative colitis (UC) is a complicated gastrointestinal inflammatory disease. We explore the protective effect of SACP against UC. Schisandra chinensis (Turcz.) Baill polysaccharide significantly reduced the disease activity index (DAI) and levels of myeloperoxidase(MPO) and malondialdehyde (MDA) in colonic tissue. It also alleviated weight loss and histopathological damage of mice. The expression of MUC2 and occludin proteins was increased and the barrier function of the colonic mucosa was enhanced by SACP treatment. NF-κB pathway activation was also inhibited and the production of pro-inflammatory cytokines was decreased whereas anti-inflammatory cytokines were increased. 16SrDNA sequencing of fecal flora showed that SACP increased the abundance of Muribaculaceaeunclassified, LachnospiraceaeNK4A136group and reduced the abundance of Bacteroides and Erysipelatoclostridium. Schisandra chinensis (Turcz.) Baill polysaccharide can protect against Dextran Sulfate Sodium Salt (DSS)-induced ulcerative colitis in mice. © 2023 Society of Chemical Industry.


Zirconium(Ⅳ)-based metal-organic framework for determination of imidacloprid and thiamethoxam pesticides from fruits by UPLC-MS/MS.
Zirconium(Ⅳ)-based metal-organic framework (MOF)-UiO-66-NH2 was fabricated to adsorb the imidacloprid and thiamethoxam in fruit samples before analysis using UPLC-MS/MS. The UiO-66-NH2 was confirmed by SEM, FTIR, and XRD. Key experimental parameters were investigated by response surface methodology (RSM). The desirability recovery of imidacloprid was 94.52% under optimum conditions (mount of adsorbent = 52.48 mg, volume of eluent = 5.18 mL, pH = 9, extraction time = 15 min). The desirability recovery of thiamethoxam was 93.57% under optimum conditions (mount of adsorbent = 50.58 mg, volume of eluent = 2.6 mL, pH = 5.65, extraction time = 11.94 min). Under the optimal conditions, the actual recovery of imidacloprid and thiamethoxam was 92.39% and 94.37%, respectively. Besides, the method was applied successfully to detect imidacloprid and thiamethoxam in different fruit samples. The results demonstrated that the UiO-66-NH2 is an excellent adsorbent for the extraction imidacloprid and thiamethoxam from fruit samples.


Comparison of six biological markers for the diagnosis of tuberculous pleuritis.
We sought a marker to differentiate tuberculous pleural effusions from nontuberculous pleural effusions, which otherwise can be difficult. We studied 55 patients with pleural effusions, 20 (36%) with tuberculous pleuritis and 35 (64%) with a nontuberculous etiology. Pleural fluid levels of adenosine deaminase, interferon (INF)-gamma, interleukin (IL)-12p40, IL-18, immunosuppressive acidic protein, and soluble IL-2 receptors were measured and were subjected to receiver operating characteristic analysis. INF-gamma had the greatest sensitivity and specificity for tuberculous pleuritis among the six biological markers studied. The determination of INF-gamma levels in pleural fluid is the most informative in the diagnosis of tuberculous effusion.


Interprofessional Care in Obstetrics and Gynecology.
Interprofessional care relates to providing care to an individual in an integrated system of professionals who share and shift the care given, depending on the individual and population need. By broadening the scope of care given by health-care workers (HCWs) or shifting tasks through interprofessional care in Obstetrics and Gynecology, more women and their newborns can benefit from safe deliveries, decreased perinatal morbidity and mortality and through screening and early treatment prevent morbidity and mortality secondary to gynecologic diseases.


Misdiagnosis of HIV infection by HIV-1 plasma viral load testing: a case series.
The availability of sensitive assays for plasma HIV viral load and the trend toward earlier and more aggressive treatment of HIV infection has led to the inappropriate use of these assays as primary tools for the diagnosis of acute HIV infection. To describe limitations in the use of plasma viral load testing for the diagnosis of HIV infection. Case series. Academic medical centers in Providence, Rhode Island, and Worcester, Massachusetts. Three persons in whom HIV infection was falsely diagnosed by plasma viral load testing. Laboratory measures and clinical outcomes. Two cases of false-positive results obtained by using branched-chain DNA plasma viral load assays and one case of a false-positive result obtained by using reverse transcriptase-polymerase chain reaction plasma viral load assay are reported. All three plasma viral load tests yielded positive results with low values (1254 copies/mL, 1574 copies/mL, and 1300 copies/mL). Infection with HIV was initially diagnosed in all three patients, but each patient subsequently tested negative by HIV-1 enzyme-linked immunosorbent assay and repeated plasma viral load testing. Physicians should exercise caution when using plasma viral load assays to detect primary HIV infection, particularly when the pretest probability of infection is low.


Uptake and elimination of arsenobetaine by the mussel Mytilus edulis is related to salinity.
The high concentrations of the naturally occurring arsenic compound arsenobetaine in marine animals, in comparison with freshwater animals, has led to the suggestion that salinity is a factor in its accumulation. In separate experiments, we investigated the uptake and elimination of arsenobetaine by the mussel Mytilus edulis when maintained under three salinity regimes (32, 24, and 16 practical salinity units). Both uptake and elimination of arsenobetaine depended on the salinity of the water in a manner leading to higher concentrations at the higher salinity. The data are consistent with a proposed role of arsenobetaine as an adventitiously acquired osmolyte, and readily explain field data for freshwater and marine animals.


Molecular Characterization and Antibacterial Activity Analysis of Two Novel Penaeidin Isoforms from Pacific White Shrimp, Litopenaeus vannamei.
Penaeidins were important immunity effector molecules, which played a crucial role in innate immunity system of penaeid shrimp. Here, we reported two penaeidin isoforms from Litopenaeus vannamei, which were named as Lva-PEN 2 and Lva-PEN 3 according to the respective structure features. The results of amino acid sequence multiple alignments showed that high similarities existed among these penaeidins. A signal peptide sequence and a cysteine-rich domain which contained six cysteine amino acid residues existed in each penaeidin at the same time. Besides, there was a proline-rich motif which was composed of eight proline residues existed in each penaeidin. After the expression profile analysis was studied, we found that both Lva-pen 2 and Lva-pen 3 transcripts were up-regulated at 48 h after bacteria challenge. Except for the antibacterial activity against Gram-positive bacteria like other penaeidins, these two penaeidins could strongly bind to bacteria and possessed antiproteinase activity. It was speculated that these two penaeidins could prevent bacteria pervasion through bacteria-binding activity and antiproteinase activity. Meantime, the proline-rich motif played a crucial role in these biological processes.


[Comparison of the psychosocial benefits of augmentation and reduction mammaplasty in women. Retrospective study of 122 women].
Plastic surgery procedures are being increasingly used on the female mammae. Our study involved procedures for reduction or augmentation of breast size in 83 and 39 noncancer patients, respectively. In order to answer the question of whether more psychosocial benefits are to be expected in reduction or augmentation operations, the following aspects were explored in patient interviews: social, personality/psychological, sexual satisfaction, professional and leisure time, and honest evaluation of the results. These data should have bearing on focussing the preoperative explanation of the operation to the patient.


Disordered eating behavior and body weight and shape relatives' criticism in overweight and obese 15- to 19-year-old females.
This study evaluated the link between relatives' criticism of overweight or obese teenage girls' figure and body weight and their relationship with their mothers, fathers and siblings, affection, self-esteem, the internalization of the aesthetic body thin ideal, depressive symptoms and disordered eating behaviors (DEB). The sample comprised 2174 senior high school students aged 15 to 19. Teenagers criticized by their relatives showed higher DEB, without interaction between Body Mass Index (BMI) and DEB. The structural equations model showed DEB was primarily explained by the internalization of the body aesthetic thin ideal, family's criticism, BMI and depressive symptoms.


New atherogenic index for the prediction of carotid atherosclerosis based on the non-ultrasensitive c-reactive protein/HDL ratio.
Current guidelines recommend cardiovascular risk assessment as a preventive measure for cardiovascular diseases, whose fundamental etiology is arteriosclerosis. One of the tools used to estimate risk in clinical practice are atherogenic indices (AI), ratios between lipid fractions with well-established reference ranges. Despite its widespread use, there is still limited information on its clinical utility. In recent years, some research has reinforced the role of inflammation in the etiology and chronicity of the atherosclerotic process. The inclusion of inflammatory parameters in the AI calculation could improve its diagnostic performance in the detection of arteriosclerosis. We sought to evaluate a new AI as a ratio between C-reactive protein (CRP) values and high-density lipoprotein cholesterol (HDL) values. A total of 282 asymptomatic patients with no history of cardiovascular disease were included in the study. Laboratory tests with lipid profile and CRP, and carotid ultrasound to assess the presence of atheromatosis were performed in all of them. The new AI is established as the ratio between non-ultrasensitive CRP value in mg/dL (multiplied by 100) and HDL value in mg/dL. It was compared with the Castelli I and II indices, and the plasma atherogenic index. The optimal cut-off point of the new AI was value=1 as determined by ROC curve, with an area under the curve of 0.678 (95% CI 0.60-0.75; p<0.001). Mean age of patients was 60.4±14.5 years. A total of 118 patients (41.8% of total) had carotid arteriosclerosis. When evaluating the diagnostic performance of different AIs, we found that CRP·100/HDL ratio showed the highest values of sensitivity and positive predictive value (0.73 and 0.68, respectively) compared to the Castelli I and II indices, and the plasma atherogenic index. It was also the only predictor of carotid atheromatosis both when considering its values quantitatively (with OR 1.4 [95% CI 1.1-1.7]; p=0.005), and qualitatively (with OR 2.9 [95% CI 1.5-5.5]; p<0.001) in patients with a CRP·100/HDL ratio>1. The new PCR·100/HDL index showed the best diagnostic performance in the detection of carotid atheromatosis compared to other classic AIs in this Spanish population of asymptomatic patients.


Aquatic insect assemblages of man-made permanent ponds, Buenos Aires city, Argentina.
Freshwater habitats are important elements within urban green space and they are endangered by various types of human activity. With the aim to increase the knowledge about species biodiversity in urban ecosystems, we characterised the assemblages of aquatic insects in four permanent man-made ponds in Buenos Aires city (Argentina) during a 1-year period. We recorded 32 species with Sigara spp. (Hemiptera) as the most abundant. The removal of aquatic vegetation from the studied ponds may have affected both the establishment and permanence of the insect community. Swimmers were the dominant group in the studied sites, followed by burrowers and sprawlers, and only a few strictly climbers were collected. Therefore, all sampled ponds were dominated by collectors (principally gatherers), secondarily by predators and only few shredders were detected, which was much affected by the removal of macrophytes. Non-parametric abundance indexes estimated a number of species very close to the observed number in each site. Conversely, the incidence indexes estimated more species because there were many more taxa present only in one sample than those represented by few individual in a sample. Our data provides some insights on the community of man-made ponds that can improve the management of these aquatic urban habitats. Considering that macrophytes affect animal assemblages due to their role as physical structures that increase the complexity or heterogeneity of habitats, they should not be removed by authorities in order to promote biodiversity.


[Impact of vortioxetine on sexual function compared to other antidepressants].
To analyze the impact of the antidepressant vortioxetine on sexual function, compared to selective serotonin reuptake inhibitors (SSRIs) and mixed selective serotonin and norepinephrine reuptake inhibitors (IRSN or Dual) in patients with depression. Analytical, observational, longitudinal and prospective study, which included men and women over 18years of age, with depressive disorder and sexual activity with a partner, separating them into two groups: (i)study, starting treatment with vortioxetine; (2)control, maintaining treatment with SSRIs or Duals. Three visits were made: inclusion, follow-up at 4weeks and final 3months from inclusion. The total follow-up period was 3months. A total of 87 patients were included (mean age 46.85years). At the end of the study, significant differences (SD) were found in the mean value of the sum of the scores of the evaluative domains of the sexual response of the Women's Sexual Function Questionnaire (FSM-2) between the study group and the control (22.42±4.39 and 16.13±7.76, respectively), with a lower risk of sexual dysfunction in women treated with vortioxetine. Also, lower risk of sexual dysfunction in these same women in the domains of desire, lubrication, orgasm, sexual frequency and sexual satisfaction. These differences were not found when assessing male sexual function. Women treated with vortioxetine presented better sexual function than those treated with SSRIs or Duals and a lower risk of sexual dysfunction.


Opioid treatment for agitation in patients with advanced dementia.
Some patients with advanced dementia cannot convey the experience of pain verbally and may react to pain with aggressive and agitated behaviors. We hypothesized that unrecognized pain could contribute to agitation and that low dose opioid therapy might reduce agitation by reducing pain. We therefore attempted to determine the effect of opioids on agitation in demented patients. We administered placebo for 4 weeks and a long-acting opioid for another 4 weeks to nursing home patients with advanced dementia and severe agitation despite treatment with psychotropic drugs. Patients and study nurses did not know if the medication administered was placebo or opioid. We measured the Cohen-Mansfield Agitation Inventory (CMAI) score at baseline and every two weeks. Among 47 patients who entered the study, 25 completed the two phases. The median age for the 25 patients was 85.5 years. Analyses of the data of these 25 patients and of the patients <85 years-old showed no significant differences in agitation level between the placebo and opioid phases. However, among the 13 patients who completed the study and were > or =85 years old, the agitation level at the end of the opioid phase was significantly lower than at the end of the placebo phase (mean change in CMAI score: -6.4; 95% confidence interval (CI): -10.96, -1.8). The decrease in agitation in the patients > or =85 years old persisted after adjusting for sedation. The results remained unchanged when we expanded the analyses to include four > or =85 patients who dropped out of the study after the second week of the opioid phase. Low dose, long-acting opioids can lessen agitation that is difficult to control in very old (> or =85) patients with advanced dementia.


Investigating Inter- and Intrasample Diversity of Single-Cell RNA Sequencing Datasets.
Tumor heterogeneity can arise from a variety of extrinsic and intrinsic sources and drives unfavorable outcomes. With recent technological advances, single-cell RNA sequencing has become a way for researchers to easily assay tumor heterogeneity at the transcriptomic level with high resolution. However, ongoing research focuses on different ways to analyze this big data and how to compare across multiple different samples. In this chapter, we provide a practical guide to calculate inter- and intrasample diversity metrics from single-cell RNA sequencing datasets. These measures of diversity are adapted from commonly used metrics in statistics and ecology to quantify and compare sample heterogeneity at single-cell resolution.


Canonical Wnt signaling is involved in switching from cell proliferation to myogenic differentiation of mouse myoblast cells.
Wnt/β-catenin signaling is involved in various aspects of skeletal muscle development and regeneration. In addition, Wnt3a and β-catenin are required for muscle-specific gene transcription in embryonic carcinoma cells and satellite-cell proliferation during adult skeletal muscle regeneration. Downstream targets of canonical Wnt signaling are cyclin D1 and c-myc. However both target genes are suppressed during differentiation of mouse myoblast cells, C2C12. Underlying molecular mechanisms of β-catenin signaling during myogenic differentiation remain unknown. Using C2C12 cells, we examined intracellular signaling and gene transcription during myoblast proliferation and differentiation. We confirmed that several Wnt signaling components, including Wnt9a, Sfrp2 and porcupine, were consistently upregulated in differentiating C2C12 cells. Troponin T-positive myotubes were decreased by Wnt3a overexpression, but not Wnt4. TOP/FOP reporter assays revealed that co-expression with Wnt4 reduced Wnt3a-induced luciferase activity, suggesting that Wnt4 signaling counteracted Wnt3a signaling in myoblasts. FH535, a small-molecule inhibitor of β-catenin/Tcf complex formation, reduced basal β-catenin in the cytoplasm and decreased myoblast proliferation. K252a, a protein kinase inhibitor, increased both cytosolic and membrane-bound β-catenin and enhanced myoblast fusion. Treatments with K252a or Wnt4 resulted in increased cytoplasmic vesicles containing phosphorylated β-catenin (Tyr654) during myogenic differentiation. These results suggest that various Wnt ligands control subcellular β-catenin localization, which regulate myoblast proliferation and myotube formation. Wnt signaling via β-catenin likely acts as a molecular switch that regulates the transition from cell proliferation to myogenic differentiation.


4C-ing the Igh Landscape.
The assembly of antigen receptors in developing B lymphocytes is determined by the spatio-temporal organization of the immunoglobulin heavy chain locus (Igh). In this issue of Immunity, Medvedovic et al. (2013) provide a comprehensive dynamic view of the Igh locus architecture.


Machine learning for enumeration of cell colony forming units.
As one of the most widely used assays in biological research, an enumeration of the bacterial cell colonies is an important but time-consuming and labor-intensive process. To speed up the colony counting, a machine learning method is presented for counting the colony forming units (CFUs), which is referred to as CFUCounter. This cell-counting program processes digital images and segments bacterial colonies. The algorithm combines unsupervised machine learning, iterative adaptive thresholding, and local-minima-based watershed segmentation to enable an accurate and robust cell counting. Compared to a manual counting method, CFUCounter supports color-based CFU classification, allows plates containing heterologous colonies to be counted individually, and demonstrates overall performance (slope 0.996, SD 0.013, 95%CI: 0.97-1.02, p value < 1e-11, r = 0.999) indistinguishable from the gold standard of point-and-click counting. This CFUCounter application is open-source and easy to use as a unique addition to the arsenal of colony-counting tools.


The clinical significance of autoantibodies to the proliferating cell nuclear antigen (PCNA).
Autoantibodies targeting the proliferating cell nuclear antigen (PCNA) were first described over 30 years ago and are historically most commonly associated with systemic lupus erythematosus (SLE). The primary antigenic target is a 34 kDa protein that is part of the DNA polymerase delta multi-protein complex. A number of diagnostic platforms have incorporated PCNA into their diagnostic assays and algorithms. However, little is known about the clinical utility of autoantibodies to PCNA, especially with novel detection systems. This review will focus on the history of the discovery of the PCNA autoantigen and the current status of the diagnostic significance of anti-PCNA and suggest future studies that are required to strengthen our understanding of their clinical utility.


Near crash characteristics among risky drivers using the SHRP2 naturalistic driving study.
Previous research have focused extensively on crashes, however near crashes provide additional data on driver errors leading to critical events as well as evasive maneuvers employed to avoid crashes. The Strategic Highway Research Program 2 (SHRP2) Naturalistic Driving Study contains extensive data on real world driving and offers a reliable methodology to study near crashes. The current study utilized the SHRP2 database to compare the rate and characteristics associated with near crashes among risky drivers. A subset from the SHRP2 database consisting of 4,818 near crashes for teen (16-19 yrs), young adult (20-24 yrs), adult (35-54 yrs), and older (70+ yrs) drivers was used. Near crashes were classified into seven incident types: rear-end, road departure, intersection, head-on, side-swipe, pedestrian/cyclist, and animal. Near crash rates, incident type, secondary tasks, and evasive maneuvers were compared across age groups. For rear-end near crashes, near crash severity, max deceleration, and time-to-collision at braking were compared across age. Near crash rates significantly decreased with increasing age (p < 0.05). Young drivers exhibited greater rear-end (p < 0.05) and road departure (p < 0.05) near crashes compared to adult and older drivers. Intersection near crashes were the most common incident type among older drivers. Evasive maneuver type did not significantly vary across age groups. Near crashes exhibited a longer time-to-collision at braking (p < 0.01) compared to crashes. These data demonstrate increased total near crash rates among young drivers relative to adult and older drivers. Prevalence of specific near crash types also differed across age groups. Timely execution of evasive maneuvers was a distinguishing factor between crashes or near crashes. Practical Applications: These data can be used to develop more targeted driver training programs and help OEMs optimize ADAS to address the most common errors exhibited by risky drivers.


Hospital burden of long-term genitourinary and gastrointestinal toxicity after radical radiotherapy for prostate cancer.
Treatment options for prostate cancer (PCa) include radical radiotherapy (RT) and radical prostatectomy, both of which have comparable oncological outcomes. The aim of this study was to investigate the hospital burden of long-term genitourinary and gastrointestinal toxicity among patients with PCa who were treated with radiotherapy at our institution. The radiotherapy department database was used retrospectively to identify all patients who underwent radiotherapy for PCa from January 2006 to January 2008. The patient administration system from each public hospital in the region was interrogated and all patient points of contact were recorded. Minimum follow up was 5 years. Individual patient charts were reviewed and factors that might influence outcomes were documented. We identified 112 patients. The mean age at diagnosis was 66 (44-76) and the median PSA was 12.1 (3.2-38). The mean duration of follow-up was 7.8 yrs. Twenty-three patients (20%) presented to the Emergency Department (ED) with late onset toxicity. Nine patients had more than 2 ED attendances. Twenty-five patients (22%) were investigated for genitourinary toxicity. Forty-seven patients (42%) underwent investigation for gastrointestinal side-effects and 45% of these required argon therapy (21/47). We found a significant hospital burden related to the management of gastrointestinal and genitourinary toxicity post radical radiotherapy for prostate cancer. As health care reforms gain momentum, policy makers must take into account the considerable longitudinal health care cost related to radiotherapy. It is also important that patients are counselled carefully in relation to potential long-term side-effects.


Effects of tracheal instillation of natural surfactant in premature lambs. I. Clinical and autopsy findings.
Ten pairs of twin lambs 118--122 days of gestation were given either natural surfactant or diluent endotracheally before the first breath. By using the premature twin lamb model, we have been able to show that instillation of natural surfactant produced 100% survival for the duration of the study period (2 hr); stable blood gases on room air; lungs that became increasingly compliant while on the respirator; generally well aerated lungs at autopsy; good lung pressure-volume relationships; normal lung surface tension measurements; and histologic evidence of good alveolar expansion with large amounts of free intraluminal phospholipid, no epithelial damage, and no hyaline membranes. It is concluded that tracheal instillation of natural surfactant into the premature lamb protects the lungs from developing many features characteristic of the respiratory distress syndrome.


Biomechanics of passive knee joint in drawer: load transmission in intact and ACL-deficient joints.
A non-linear 3D finite element model of the passive human tibiofemoral knee joint consisting of two bony structures and their articular cartilage layers, menisci, and four principal ligaments was used to investigate the detailed response of the unconstrained joint under up to 100 N posterior femoral force at different flexion angles from 0 to 90 degrees. The analysis was repeated after the transection of the anterior cruciate ligament (ACL). The boundary conditions were selected to assure a stable and unconstrained response of the joint throughout the range of motion. The results indicated the ACL as the primary structure to resist the drawer load throughout the range of flexion considered and that the joint primary and coupled laxities substantially increased in its absence. At full extension under drawer, forces in collateral ligaments increased significantly resulting in larger overall contact forces as the ACL was transected. In the ACL-deficient joint, such large forces in collateral ligaments, however, diminished as flexion angle varied from 0 to 90 degrees. At full extension or flexion angles up to approximately 30 degrees, the medial meniscus and adjacent medial tibial and femoral cartilage layers were subjected to substantially larger loads and stresses following the transection of the ACL. Adequate consideration of such couplings is important in avoiding further damage to joint structures subsequent to an injury and restoring adequate function following injuries to primary components.


Reconsidering the Dispositional Essentialist Canon.
Dispositional Essentialism is a unified anti-Humean account of the metaphysics of low-level physical properties and laws of nature. In this paper, I articulate the view that I label Canonical Dispositional Essentialism (CDE), which comprises a structuralist metaphysics of properties and an account of laws as relations in the property structure. I then present an alternative anti-Humean account of properties and laws (still somewhat in the dispositional essentialist spirit). This account rejects CDE's structuralist metaphysics of properties in favour of a view of properties as qualitative grounds of dispositions and it rejects CDE's view of laws as relations in favour of a view of laws as features of an efficient description of possible property distributions. I then defend this view over CDE on the grounds that it can overcome an explanatory shortcoming of CDE and that it achieves a level of continuity with science that CDE fails to achieve. The upshot of this paper is a significant narrowing of the range of possibilities in which the absolutely best unified account of laws and properties resides.


Solid stress and elastic energy as measures of tumour mechanopathology.
Solid stress and tissue stiffness affect tumour growth, invasion, metastasis and treatment. Unlike stiffness, which can be precisely mapped in tumours, the measurement of solid stresses is challenging. Here, we show that two-dimensional spatial mappings of solid stress and the resulting elastic energy in excised or in situ tumours with arbitrary shapes and wide size ranges can be obtained via three distinct and quantitative techniques that rely on the measurement of tissue displacement after disruption of the confining structures. Application of these methods in models of primary tumours and metastasis revealed that: (i) solid stress depends on both cancer cells and their microenvironment; (ii) solid stress increases with tumour size; and (iii) mechanical confinement by the surrounding tissue significantly contributes to intratumoural solid stress. Further study of the genesis and consequences of solid stress, facilitated by the engineering principles presented here, may lead to significant discoveries and new therapies.


A highly specific and sensitive nanoimmunosensor for the diagnosis of neuromyelitis optica spectrum disorders.
A precise diagnosis for neuromyelitis optica spectrum disorders (NMOSD) is crucial to improve patients' prognostic, which requires highly specific and sensitive tests. The cell-based assay with a sensitivity of 76% and specificity of 100% is the most recommended test to detect anti-aquaporin-4 antibodies (AQP4-Ab). Here, we tested four AQP4 external loop peptides (AQP461-70, AQP4131-140, AQP4141-150, and AQP4201-210) with an atomic force microscopy nanoimmunosensor to develop a diagnostic assay. We obtained the highest reactivity with AQP461-70-nanoimunosensor. This assay was effective in detecting AQP4-Ab in sera of NMOSD patients with 100% specificity (95% CI 63.06-100), determined by the cut-off adhesion force value of 241.3 pN. NMOSD patients were successfully discriminated from a set of healthy volunteers, patients with multiple sclerosis, and AQP4-Ab-negative patients. AQP461-70 sensitivity was 81.25% (95% CI 56.50-99.43), slightly higher than with the CBA method. The results with the AQP461-70-nanoimmunosensor indicate that the differences between NMOSD seropositive and seronegative phenotypes are related to disease-specific epitopes. The absence of AQP4-Ab in sera of NMOSD AQP4-Ab-negative patients may be interpreted by assuming the existence of another potential AQP4 peptide sequence or non-AQP4 antigens as the antibody target.


Kinetic modeling of β-chloroprene metabolism: Probabilistic in vitro-in vivo extrapolation of metabolism in the lung, liver and kidneys of mice, rats and humans.
β-Chloroprene (chloroprene) is carcinogenic in inhalation bioassays with B6C3F1 mice and Fischer rats, but the potential effects in humans have not been adequately characterized. In order to provide a better basis for evaluating chloroprene exposures and potential effects in humans, we have explored species and tissue differences in chloroprene metabolism. This study implemented an in vitro-in vivo extrapolation (IVIVE) approach to parameterize a physiologically based pharmacokinetic (PBPK) model for chloroprene and evaluate the influence of species and gender differences in metabolism on target tissue dosimetry. Chloroprene metabolism was determined in vitro using liver, lung and kidney microsomes from male or female mice, rats, and humans. A two compartment PK model was used to estimate metabolism parameters for chloroprene in an in vitro closed vial system, which were then extrapolated to the whole body PBPK model. Two different strategies were used to estimate parameters for the oxidative metabolism of chloroprene: a deterministic point-estimation using the Nelder-Mead nonlinear optimization algorithm and probabilistic Bayesian analysis using the Markov Chain Monte Carlo technique. Target tissue dosimetry (average amount of chloroprene metabolized in lung per day) was simulated with the PBPK model using the in vitro-based metabolism parameters. The model-predicted target tissue dosimetry, as a surrogate for a risk estimate, was similar between the two approaches; however, the latter approach provided a measure of uncertainty in the metabolism parameters and the opportunity to evaluate the impact of that uncertainty on predicted risk estimates.


Dorsal root ganglion neurons with central processes in both dorsal and ventral roots in rats.
Axonal transport of fluorescent dyes, Diamidino yellow dihydrochloride (DY) and Fast blue (FB), applied to the cut distal ends of dorsal and ventral roots, respectively, was studied in order to determine whether any dorsal root ganglion (DRG) neurons have processes in both dorsal and ventral roots. A total of 359 DRG neurons are double labeled in 14 ganglia (L6 and S1) from 6 different animals, thus suggesting a possibility of many DRG neurons having multiple central processes. The somata of the double-labeled DRG neurons are small to medium in size with a mean diameter of 29 microns. These data are consistent with findings that the majority of ventral root afferent fibers are unmyelinated or small myelinated axons.


Imaging Artifacts of Liquid Embolic Agents on Conventional CT in an Experimental in Vitro Model.
Endovascular embolization using liquid embolic agents is a safe and effective treatment option for AVMs and dural arteriovenous fistulas. The aim of this study was to assess the degree of artifact inducement by the most frequently used liquid embolic agents in conventional CT in an experimental in vitro model. Dimethyl-sulfoxide-compatible tubes were filled with the following liquid embolic agents (n = 10, respectively): Onyx 18, all variants of Squid, PHIL 25%, PHIL LV, and n-BCA mixed with iodized oil. After inserting the tubes into a CT imaging phantom, we acquired images. Artifacts were graded quantitatively by the use of Hounsfield units in a donut-shaped ROI using a customized software application that was specifically designed for this study and were graded qualitatively using a 5-point scale. Quantitative and qualitative analyses revealed the most artifacts for Onyx 18 and the least artifacts for n-BCA, PHIL 25%, and PHIL LV. Squid caused more artifacts compared with PHIL, both for the low-viscosity and for the extra-low-viscosity versions (eg, quantitative analysis, Squid 18: mean ± SD, 30.3 ± 9.7 HU versus PHIL 25%: mean ± SD, 10.6 ± 0.8 HU; P < .001). Differences between the standard and low-density variants of Squid were observed only quantitatively for Squid 12. There were no statistical differences between the different concentrations of Squid and PHIL. In this systematic in vitro analysis investigating the most commonly used liquid embolic agents, relevant differences in CT imaging artifacts could be demonstrated. Ethylene-vinyl alcohol-based liquid embolic agents induced more artifacts compared with liquid embolic agents that use iodine as a radiopaque component.


Growth and differentiation of the gubernaculum testis during testicular descent in the pig: changes in the extracellular matrix, DNA content, and hyaluronidase, beta-glucuronidase, and beta-N-acetylglucosaminidase activities.
The gubernaculum testis is a loose connective tissue organ that plays an essential mechanical role in testicular descent. In the pig, the first phase of descent (transabdominal migration) is brought about by growth of the gubernaculum through the inguinal canal into the scrotum and simultaneous somatic growth of the fetus. During the second phase the gubernaculum condenses, thus allowing the testis to descend into the scrotum. The nature of gubernaculum development (growth and differentiation) was investigated with respect to cell proliferation, extracellular matrix (ECM) composition, and acid hydrolases. Deoxyribonucleic acid (DNA) was used as a measure of cell number and hydroxyproline (HYP) was an estimate of interstitial collagen. The first phase of gubernaculum development was characterized by rapid cell proliferation and concomitant synthesis of sulphated glycosaminoglycans (S-GAG), hyaluronic acid (HA) and collagen. During the second phase cell proliferation ceased and DNA concentration increased. The amount of S-GAG remained closely related to the amount of DNA while HYP increased further. However, HA decreased during the second phase and thus HA metabolism seems to play a crucial role in biphasic development of the gubernaculum. The activities of the enzymes that are needed for biodegradation of HA (hyaluronidase, beta-glucuronidase and beta-N-acetylglucosaminidase) were measured in gubernaculum homogenate from animals during the first and second phase of testicular descent. These enzymes were detectable in gubernaculum and rose during the second phase of testicular descent. It was concluded that a very distinct dichotomy in the nature of gubernaculum development during the first and second phase could be discerned with respect to cell proliferation rate and ECM synthesis and degradation. These observations provide useful tools for future in vivo and in vitro investigations into the process and regulation of testicular descent.


The impact of multiple non-pharmaceutical interventions on controlling COVID-19 outbreak without lockdown in Hong Kong: A modelling study.
The 'third wave' of COVID-19 in Hong Kong, China was suppressed by non-pharmaceutical interventions (NPIs). Although social distancing regulations were quickly strengthened, the outbreak continued to grow, causing increasing delays in tracing and testing. Further regulations were introduced, plus 'targeted testing' services for at-risk groups. Estimating the impact of individual NPIs could provide lessons about how outbreaks can be controlled without radical lockdown. However, the changing delays in confirmation time challenge current modelling methods. We used a novel approach aimed at disentangling and quantifying the effects of individual interventions. We incorporated the causes of delays in tracing and testing (i.e. load-efficiency relationship) and the consequences from such delays (i.e. the proportion of un-traced cases and the proportion of traced-cases with confirmation delay) into a deterministic transmission model, which was fitted to the daily number of cases with and without an epi‑link (an indication of being contact-traced). The effect of each NPI was then calculated. The model estimated that after earlier relaxation of regulations, Re rose from 0.7 to 3.2. Restoration of social distancing to the previous state only reduced Re to 1.3, because of increased delay in confirmation caused by load on the contact-tracing system. However, Re decreased by 20.3% after the introduction of targeted testing and by 17.5% after extension of face-mask rules, reducing Re to 0.9 and suppressing the outbreak. The output of the model without incorporation of delay failed to capture important features of transmission and Re. Changing delay in confirmation has a significant impact on disease transmission and estimation of transmissibility. This leads to a clear recommendation that delay should be monitored and mitigated during outbreaks, and that delay dynamics should be incorporated into models to assess the effects of NPIs. City University of Hong Kong and Health and Medical Research Fund.


Incidence of malnutrition in children aged 0-6 years in Sivas, an eastern province of Turkey.
Malnutrition grades of 1000 children were established by various anthropometric measures in Sivas area. The general malnutrition rate was 30.5% according to weight for age, 27.7% for weight for height and 33.7% for mid upper arm circumference (MUAC) to head circumference (HC) ratio. The rates of severe malnutrition were noted to be low (1.8-2.2%) when using these criteria. Malnutrition in the 0-3 month babies was misleading, when measurement were solely based on the MUAC/HC ratio.


The impact of increasing antimicrobial resistance in the treatment of urosepsis.
Urosepsis accounts for up to 20-30% of all sepsis cases; however, increasing antimicrobial resistance is posing a significant threat to patient's outcomes. The aim of this study was to look at the prevalence of multi-drug resistant (MDR) organisms in patients admitted with urosepsis and their effect on the treatment and outcome of patients in our hospital. A total of 2679 urine cultures and 654 blood cultures performed in Connolly Hospital Emergency Department were reviewed between 2016 and 2018. Patients were included if they had a matching urine culture and blood culture performed within 24 h of admission. We compared patient demographics and underlying co-morbidities between patients admitted with urosepsis secondary to MDR organisms and non-MDR organisms. Our study included 85 patients admitted with urosepsis. The most common causative pathogen was Escherichia coli, and 34.1% (n = 29) of pathogens were classified as an MDR organism. Patients admitted with urosepsis from long-term care facilities were 2.3 times more likely to have urosepsis due to a MDR organism compared with patients admitted from the community. Patients admitted with urosepsis secondary to a MDR organism were also more likely to have co-morbidities such as diabetes and dementia. The high rate of antimicrobial resistance in patients admitted with urosepsis poses a challenge in prescribing the most appropriate antibiotics. It is crucial that prescribers follow local antibiotic guidelines for the treatment of urosepsis and are cognisant of the risk of specific patient groups presenting with urosepsis due to MDR organisms.


Caffeine causes glycerophosphorylcholine accumulation through ryanodine-inhibitable increase of cellular calcium and activation of phospholipase A2 in cultured MDCK cells.
Glycerophosphrylocholine (GPC) is a renal medullary compatible organic osmolyte that is derived from choline via phosphatidylcholine, which is catalyzed in part by phospholipase A2 (PLA2) and its degradation by GPC: choline phosphodiesterase (GPC: choline PDE). We found that caffeine elevated intracellular free calcium ([Ca2+]i) and GPC level in cultured MDCK cells, canine kidney epithelial cells, and propose a possible biochemical mechanism. When MDCK cells were incubated for 3 h with 1 to 10 mM caffeine, cellular GPC was elevated in a dose-dependent manner, and this occurred independently of the extracellular osmolality. Caffeine stimulated the rate of [14C]choline incorporation into [14C]GPC and PLA2 activity. Whereas, GPC: choline PDE activity was accompanied by less of increase. These enzyme changes demonstrate the increased net synthesis of MDCK GPC. In order to identify what triggers the PLA2 activation, [Ca2+]i was measured by using a fluorescence dye, Fura-2. Caffeine (10 mM) resulted in a typical transient increase in MDCK [Ca2+]i concentration, and this increase was greatly inhibited by pretreatment of MDCK cells with 10 mM ryanodine for 5 min. Ryanodine (10 mM) also inhibited the caffeine-induced stimulation of PLA2 activity. These findings provide the first evidence that caffeine in MDCK cells causes a ryanodine-inhibitable increase of [Ca2+]i and PLA2 activity, resulting in cellular GPC accumulation.


Geographic variation in tobacco use in India: a population-based multilevel cross-sectional study.
This study aims to quantify the extent to which people's use of tobacco products varies by local areas (city ward and village) across India and the variation in this clustering by tobacco products. Cross-sectional study. Data on 73 954 adults across 2547 city wards and villages were available for analysis from 30 states and 2 union territories in India. We included as primary outcomes self-reported any tobacco use, current cigarette smoking, current bidi smoking, current smokeless tobacco use and a derived variable for dual use describing respondents who engaged in both smoking and smokeless tobacco use. The median risk of an individual using tobacco was 1.64 times greater if a person hypothetically moved from an area of low to high risk of tobacco use (95% CI: 1.60 to 1.69). Area-level partitioning of variation differed by tobacco product used. Median ORs ranged from 1.77 for smokeless tobacco use to 2.53 for dual use. Tobacco use is highly clustered geographically in India. To be effective in India, policy interventions should be directed to influence specific local contextual factors on adult tobacco use. Where people live in India influences their use of tobacco, and this association may be greater than has been observed in other settings. Tailoring tobacco control policies for local areas in India may, therefore, provide substantial public health benefits.


Adhesion molecules, activin and inhibin--candidates for the biochemical prediction of hypertensive diseases in pregnancy?
The aim of the prospective study was to compare standard parameters as Doppler ultrasound and 24-h blood pressure measurement with possible maternal serological markers regarding their prognostic value in predicting hypertensive diseases in pregnancy. Twenty-four-hour blood pressure measurement was performed before and after 32+0 gestational week in 57 pregnant women with either chronic hypertension ( n=13), preeclampsia ( n=21), pregnancy-induced hypertension (PIH; n=12) or normotension ( n=11). Blood samples were taken and the concentrations of soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), activin A and inhibin A were determined as well as serum uric acid, creatinine, total serum protein and serum albumin. Doppler ultrasound of the uterine arteries was examined before 32+0 gestational week in the same patients. For the statistical evaluation Kruskal-Wallis-Test and Mann-Whitney-U-Test were performed. Differences in the predictive value were evaluated by receiver-operating characteristics. VCAM-1 was significantly elevated in women developing hypertensive diseases as compared to normotensive women (preeclampsia: p<0.001; PIH: p<0.05; chronic hypertension: p<0.001). In early pregnancy activin A and inhibin A were significantly higher in preeclamptic patients than in the other groups (activin A: normotension: p<0.005; PIH: p<0.001; chronic hypertension: p<0.005) (inhibin A: normotension: p<0.005; PIH: p<0.001; chronic hypertension: p<0.01), thus suggesting them to be specific markers for the development of preeclampsia. Mean arterial pressure was significantly elevated in preeclampsia ( p<0.001) and chronic hypertension ( p<0.005) as compared to normotensives. Twenty-four-hour blood pressure monitoring with determination of mean arterial pressure and measurement of VCAM-1, activin A and inhibin A as serum parameters can be suggested as useful tests in the specific prediction of different types of hypertensive diseases in pregnancy.


The in vivo association of BiP with newly synthesized proteins is dependent on the rate and stability of folding and not simply on the presence of sequences that can bind to BiP.
Immunoglobulin heavy chain-binding protein (BiP) is a member of the hsp70 family of chaperones and one of the most abundant proteins in the ER lumen. It is known to interact transiently with many nascent proteins as they enter the ER and more stably with protein subunits produced in stoichiometric excess or with mutant proteins. However, there also exists a large number of secretory pathway proteins that do not apparently interact with BiP. To begin to understand what controls the likelihood that a nascent protein entering the ER will associate with BiP, we have examined the in vivo folding of a murine lambdaI immunoglobulin (Ig) light chain (LC). This LC is composed of two Ig domains that can fold independent of the other and that each possess multiple potential BiP-binding sequences. To detect BiP binding to the LC during folding, we used BiP ATPase mutants, which bind irreversibly to proteins, as "kinetic traps." Although both the wild-type and mutant BiP clearly associated with the unoxidized variable region domain, we were unable to detect binding of either BiP protein to the constant region domain. A combination of in vivo and in vitro folding studies revealed that the constant domain folds rapidly and stably even in the absence of an intradomain disulfide bond. Thus, the simple presence of a BiP-binding site on a nascent chain does not ensure that BiP will bind and play a role in its folding. Instead, it appears that the rate and stability of protein folding determines whether or not a particular site is recognized, with BiP preferentially binding to proteins that fold slowly or somewhat unstably.


Development and assessment of disinfectant efficacy test methods for regulatory purposes.
The United States Environmental Protection Agency regulates pesticidal products, including products with antimicrobial activity. Test guidelines have been established to inform manufacturers of which methodology is appropriate to support a specific efficacy claim. This paper highlights efforts designed to improve current methods and the development and assessment of new test methods.


Early motor disturbances in Rett syndrome and its pathophysiological importance.
Assessment of the development of motor function of Rett syndrome (RTT) revealed hypotonia with failure of crawling and disturbance in skillful hand manipulation are shown as early motor signs. Clinical evaluation has revealed the former as postural hypotonia with failure in locomotion and neurophysiological examinations have showed this to be due to hypofunction of the aminergic neurons of the brainstem. The latter signs are considered to indicate dysfunction of the corticospinal tract at higher levels. As the signs appear along with deceleration of head growth, dysfunction of the noradrenergic neuron, which is involved in synaptogenesis in the cerebral cortex, is postulated as the cause. The characteristic stereotyped hand movements appear in early childhood after loss of purposeful hand use and are underlain by rigid hypertonus. Neurophysiological examinations have indicated that these are due to hypofunction of the nigrostriatal (NS) dopamine (DA) neuron. By comparison with animal experimental work the neurohistochemical changes in the substantia nigra of the autopsied brain of RTT suggest a lesion caused by the dysfunction of the pedunculopontine nucleus, induced by dysfunction of the brainstem aminergic neurons which modulate postural tone and locomotion. Hypofunction of the aminergic neurons also cause 'leakage' of atonia into non-REM stages which lead to disturbances in the autonomic nervous system through inhibition of the reflex system. The grade of disturbance of locomotion closely matches the grade in abnormalities of higher cortical function as indicated by the development of meaningful words. The loci of missense mutation of methyl CPG binding domain of MECP 2gene which affect locomotion severely also markedly impaired their effects on the formation of the heterochromatin. Thus, dysfunction of the aminergic neurons of the brainstem which regulate postural tone and locomotion is proposed as the primary lesion.


A pilot randomized controlled trial of a commercial diet and exercise weight loss program in minority breast cancer survivors.
Obesity is associated with poorer breast cancer outcomes and losing weight postdiagnosis may improve survival. As Hispanic and black women have poorer breast cancer prognosis than non-Hispanic whites diagnosed at similar age and stage, and have higher rates of obesity, effective weight loss strategies are needed. We piloted a randomized, waitlist-controlled, crossover study to examine the effects and feasibility of the commercial Curves weight loss program among Hispanic, African American and Afro-Caribbean breast cancer survivors. Women with stage 0-IIIa breast cancer ≥ 6 months posttreatment, sedentary, and BMI ≥ 25 kg/m(2) were randomized to the immediate arm (IA): 6 months of the Curves program followed by 6 months of observation; or the waitlist control arm (WCA): 6 months of observation followed by 6 months of the Curves program. The Curves program uses a 30-min exercise circuit and a high-vegetable/low-fat/calorie-restricted diet. A total of 42 women enrolled (79% Hispanic, 21% black), mean age 51 (range 32-69) and mean BMI 33.2(± 5.9) kg/m(2); 91% were retained at month 12. At month 6, women in the IA lost an average 3.3% (± 3.5%) of body weight (range: 1.7% gain to 10.6% loss), as compared with 1.8% (± 2.9%) weight loss in the WCA (P = 0.04). At month 12, on average women in the IA regained some but not all of the weight lost during the first 6 months (P = 0.02). Minority breast cancer survivors were recruited and retained in a weight loss study. Six months of the Curves program resulted in moderate weight loss, but weight loss was not maintained postintervention. Future interventions should identify methods to increase uptake and maintenance of weight loss behaviors.


Reversal of experimental renal fibrosis by BMP7 provides insights into novel therapeutic strategies for chronic kidney disease.
Bone morphogenic protein-7 (BMP7) is a morphogen that is important for kidney development and which is also an integral part of the kidney's physiological response to repair of acute kidney injury. Several studies demonstrate that preexisting renal BMP7 pathways can be utilized by administering recombinant BMP7 to protect the kidney in experimental models of chronic kidney disease (CKD). Effectiveness of recombinant BMP7 in animal studies raises the possibility that the BMP7 pathway could be equally utilized to treat patients with CKD and interstitial fibrosis. However, regulation of BMP7 activity in the kidney is complex. BMP7 activity in the kidney is not only determined by availability of BMP7 itself, but also by a balance of agonists, such as Kielin/chordin-like protein (KCP) or BMP receptors, and antagonists including gremlin, noggin, or uterine sensitization-associated gene-1 (USAG-1). Presence of BMP7 agonists and antagonists has to be considered when recombinant BMP7 is supplemented to treat injured kidneys. Here we summarize recent insights into the role of BMP7 in acute and chronic kidney injury and discuss the implications for future directions of antifibrotic therapies.


RNA-protein complexes that form in the spinach chloroplast atpI 5' untranslated region can be divided into two subcomplexes, each comprised of unique cis-elements and trans-factors.
Control of gene expression in chloroplasts is critically dependent upon post-transcriptional mechanisms, most of which require formation of RNA-protein complexes. The 5' untranslated regions (5'UTRs) of chloroplast mRNAs have been shown to affect stability and/or translation of the message. These effects are mediated by the binding of specific protein(s) to the 5'UTR. We can detect such 5'UTR-protein complexes in vitro and have previously shown that the same polypeptide(s) bind many spinach chloroplast 5'UTRs (Robida et al. 2002). Here we report investigations on the RNA elements and protein factors involved in formation of these complexes. Comparison of the atpI 5'UTR, which serves as the representative 5'UTR for these experiments, among 12 angiosperms revealed two phylogenetically conserved regions upstream of a putative ribosome binding site. To determine whether the two conserved regions interact to form a single polypeptide-binding site, binding assays were performed with RNAs containing only one of the two. Those experiments revealed that the entire 5'UTR could be separated into two binding sites for chloroplast polypeptides, each containing one of the two conserved regions. Competition binding assays using the individual binding sites established that each was bound by different polypeptide(s). These data support the hypothesis that there are at least two unique polypeptides involved in these 5'UTR-protein complexes, each binding specifically to a different site within the 5'UTR.


PIP5 Kinases Regulate Membrane Phosphoinositide and Actin Composition for Targeted Granule Secretion by Cytotoxic Lymphocytes.
How cytotoxic T lymphocytes (CTLs) sense T cell receptor (TCR) signaling in order to specialize an area of plasma membrane for granule secretion is not understood. Here, we demonstrate that immune synapse formation led to rapid localized changes in the phosphoinositide composition of the plasma membrane, both reducing phosphoinositide-4-phosphate (PI(4)P), PI(4,5)P2, and PI(3,4,5)P3 and increasing diacylglycerol (DAG) and PI(3,4)P2 within the first 2 min of synapse formation. These changes reduced negative charge across the synapse, triggering the release of electrostatically bound PIP5 kinases that are required to replenish PI(4,5)P2. As PI(4,5)P2 decreased, actin was depleted from the membrane, allowing secretion. Forced localization of PIP5Kβ across the synapse prevented actin depletion, blocking both centrosome docking and secretion. Thus, PIP5Ks act as molecular sensors of TCR activation, controlling actin recruitment across the synapse, ensuring exquisite co-ordination between TCR signaling and CTL secretion.


Mercury in dated sediment cores from coastal ponds of St Thomas, USVI.
We collected seven cores from five coastal ponds in St Thomas, USVI, dated them via 210Pb, and measured their Hg profiles. Levels ranged from 20 to 100ngg-1 and always increased upward to the surface or a shallow mixed zone. Taking into account differences in sediment accumulation rates and the presence or absence of a mixed zone, all sites revealed similar deposition histories. Mercury levels were at low, possibly pristine, values until the early to mid-20th century. Then they then doubled or quadrupled steadily until about 1990, after which Hg became relatively constant. We conclude that Hg in the sediments of these ponds came from long range deposition directly to the ponds and to their watersheds. Constant levels in recent years may be caused by transfer from watersheds, a pathway that is delayed compared to direct deposition from the atmosphere.


The DOT1L inhibitor Pinometostat decreases the host-response against infections: Considerations about its use in human therapy.
Patients with acute myeloid leukemia frequently present translocations of MLL gene. Rearrangements of MLL protein (MLL-r) in complexes that contain the histone methyltransferase DOT1L are common, which elicit abnormal methylation of lysine 79 of histone H3 at MLL target genes. Phase 1 clinical studies with pinometostat (EPZ-5676), an inhibitor of DOT1L activity, demonstrated the therapeutic potential for targeting DOT1L in MLL-r leukemia patients. We previously reported that down-regulation of DOT1L increases influenza and vesicular stomatitis virus replication and decreases the antiviral response. Here we show that DOT1L inhibition also reduces Sendai virus-induced innate response and its overexpression decreases influenza virus multiplication, reinforcing the notion of DOT1L controlling viral replication. Accordingly, genes involved in the host innate response against pathogens (RUBICON, TRIM25, BCL3) are deregulated in human lung epithelial cells treated with pinometostat. Concomitantly, deregulation of some of these genes together with that of the MicroRNA let-7B, may account for the beneficial effects of pinometostat treatment in patients with MLL-r involving DOT1L. These results support a possible increased vulnerability to infection in MLL-r leukemia patients undergoing pinometostat treatment. Close follow up of infection should be considered in pinometostat therapy to reduce some severe side effects during the treatment.


Armored modified vaccinia Ankara in cancer immunotherapy.
Cancer immunotherapy relies on unleashing the patient´s immune system against tumor cells. Cancer vaccines aim to stimulate both the innate and adaptive arms of immunity to achieve durable clinical responses. Some roadblocks for a successful cancer vaccine in the clinic include the tumor antigen of choice, the adjuvants employed to strengthen antitumor-specific immune responses, and the risks associated with enhancing immune-related adverse effects in patients. Modified vaccinia Ankara (MVA) belongs to the family of poxviruses and is a versatile vaccine platform that combines several attributes crucial for cancer therapy. First, MVA is an excellent inducer of innate immune responses leading to type I interferon secretion and induction of T helper cell type 1 (Th1) immune responses. Second, it elicits robust and durable humoral and cellular immunity against vector-encoded heterologous antigens. Third, MVA has enormous genomic flexibility, which allows for the expression of multiple antigenic and costimulatory entities. And fourth, its replication deficit in human cells ensures a excellent safety profile. In this review, we summarize the current understanding of how MVA induces innate and adaptive immune responses. Furthermore, we will give an overview of the tumor-associated antigens and immunomodulatory molecules that have been used to armor MVA and describe their clinical use. Finally, the route of MVA immunization and its impact on therapeutic efficacy depending on the immunomodulatory molecules expressed will be discussed.


Effect of long-term nursing intervention on quality of life and social support of patients with coronary heart disease after percutaneous coronary intervention.
To assess the effect of long-term nursing intervention on the quality of life and social support of patients after percutaneous coronary intervention (PCI). A randomised controlled trial was designed. A total of 60 patients with coronary heart disease treated with PCI were randomly divided into the control group and the intervention group. The patients in the control group received routine nursing care, while the patients in the intervention group received long-term nursing intervention. The Simplified Quality of Life Scale-Quality of Life Scale, the Coronary Heart Disease Self-Management Scale, and the Social Support Rating Scale were used to collect and analyse the data. After the intervention, the scores for quality of life, social support and self-management in the intervention group were higher than those in the control group, and the differences were statistically significant (p < 0.05). Long-term nursing intervention can improve the quality of life and sense of social support of patients with coronary heart disease after PCI.


Automatic measurement of drinking in rats: effects of hypophysectomy.
A new apparatus for the continuous measurement of drinking in the rats was assembled. The principle of the device is as follows: a cartridge which makes water drops (0.05 ml) is inserted between a water tank and a drinking spout. When a rat drinks, water falls into the cartridge drop by drop and the number of drops is electrically counted. The total count of drops per day, as well as counts at definite intervals, can be atuomatically printed out. To test apparatus reliability and applicability, drinking behavior in hypophysectomized rats was investigated in the light and dark phases, alternating every 12 hr. Activity and feeding in these phases were also observed. In the sham-operated rats, the total daily water intake was 30-40 ml, which corresponded to 10-15% of the body weight, and 85-95% of the total daily drinking counts were recorded in the dark phase. In the hypophysectomized rats, a large amount of water was drunk immediately after the operation. However, the high rate of drinking rapidly returned to near the normal level within a few days. Drinking in the dark phase decreased to about 75% of the total daily, but synchronization with the light-dark cycle was still maintained. The daily patterns of activity and eating ran nearly parallel with the drinking behavior. These results indicate that our drinkometer could have extensive applications within many fields of research.


CKB inhibits epithelial-mesenchymal transition and prostate cancer progression by sequestering and inhibiting AKT activation.
Epithelial-mesenchymal transition (EMT) contributes to tumor invasion, metastasis and drug resistance. AKT activation is key in a number of cellular processes. While many positive regulators for either EMT or AKT activation have been reported, few negative regulators are established. Through kinase cDNA screen, we identified brain-type creatine kinase (CKB or BCK) as a potent suppressor for both. As a ubiquitously expressed kinase in normal tissues, CKB is significantly downregulated in several solid cancer types. Lower CKB expression is significantly associated with worse prognosis. Phenotypically, CKB overexpression suppresses, while its silencing promotes, EMT and cell migration, xenograft tumor growth and metastasis of prostate cancer cells. AKT activation is one of the most prominent signaling events upon CKB silencing in prostate cancer cells, which is in line with prostate cancer TCGA data. EMT enhanced by CKB silencing is abolished by AKT inhibition. Mechanistically, CKB interacts with AKT and sequestrates it from activation by mTOR. We further elucidated that an 84aa fragment at C-terminus of CKB protein interacts with AKT's PH domain. Ectopic expression of the 84aa CKB fragment inhibits AKT activation, EMT and cell proliferation. Interestingly, molecular dynamics simulation on crystal structures of AKT and CKB independently demonstrates that AKT's PH domain and CKB's 84aa fragment establish their major interaction interface. In summary, we have discovered CKB as a negative regulator of EMT and AKT activation, revealing a new mode of their regulation . We have also demonstrated that CKB downregulation is a poor prognosticator, which is sufficient to promote prostate cancer progression.


Automatic detection of selective arterial devices for advanced visualization during abdominal aortic aneurysm endovascular repair.
Here we address the automatic segmentation of endovascular devices used in the endovascular repair (EVAR) of abdominal aortic aneurysms (AAA) that deform vascular tissues. Using this approach, the vascular structure is automatically reshaped solving the issue of misregistration observed on 2D/3D image fusion for EVAR guidance. The endovascular devices we considered are the graduated pigtail catheter (PC) used for contrast injection and the stent-graft delivery device (DD). The segmentation of the DD was enhanced using an asymmetric Frangi filter. The segmented geometries were then analysed using their specific features to remove artefacts. The radiopaque markers of the PC were enhanced using a fusion of Hessian and newly introduced gradient norm shift filters. Extensive experiments were performed using a database of images taken during 28 AAA-EVAR interventions. This dataset was divided into two parts: the first half was used to optimize parameters and the second to compile performances using optimal values obtained. The radiopaque markers of the PC were detected with a sensitivity of 88.3% and a positive predictive value (PPV) of 96%. The PC can therefore be positioned with a majority of its markers localized while the artefacts were all located inside the vessel lumen. The major parts of the DD, the dilatator tip and the pusher surfaces, were detected accurately with a sensitivity of 85.9% and a PPV of 88.7%. The less visible part of the DD, the stent enclosed within the sheath, was segmented with a sensitivity of 63.4% because the radiopacity of this region is low and uneven. The centreline of the DD in this stent region was alternatively traced within a 0.74 mm mean error. The automatic segmentation of endovascular devices during EVAR is feasible and accurate; it could be useful to perform elastic registration of the vascular lumen during endovascular repair.


Molecular analysis of a developmentally regulated gene which is expressed in the larval salivary gland of Drosophila.
The polytene genome of the larval salivary gland of Drosophila undergoes dramatic alterations in localized transcriptional activity late in third-instar development. One of these changes involves the 20-OH ecdysone-mediated and coordinate repression of a dispersed set of intermolt puff sites. The DNA from one of these loci (that located within the 90BC interval) has been isolated by molecular cloning techniques. This DNA was shown to be present one time per haploid Drosophila genome and to contain a gene (designated the Group V gene) which is developmentally regulated. The Group V transcript was shown to accumulate only during third-instar larval development and to be located exclusively in the salivary gland. These results are consistent with the hypothesis that the Group V gene codes for a salivary gland glue protein.


Investigation of microRNA alterations in leukemias and lymphomas.
Alterations in miRNA genes play a critical role in the pathophysiology of many, perhaps all, human cancers: cancer initiation and progression can involve alterations of microRNA genes (miRNAs) encoding small noncoding RNAs that can regulate gene expression. The main mechanism of microRNoma (defined as the full complement of microRNAs present in a genome) alteration in cancer cell seems to result in aberrant gene expression characterized by abnormal levels of expression for mature and/or precursor miRNA sequences in comparison with the corresponding normal tissues. Loss or amplification of miRNA genes has been reported in a variety of cancers, and altered patterns of miRNA expression may affect cell cycle and survival programs. The causes of the widespread differential expression of miRNA genes between malignant and normal cells can be explained by the genomic location of these genes in cancer-associated genomic regions, by epigenetic mechanisms as well as by alterations of members of the processing machinery. Germline and somatic mutations in miRNAs or polymorphisms in the mRNAs targeted by miRNAs may also contribute to cancer predisposition and progression. miRNAs expression profiling has been exploited to identify miRNAs potentially involved in the pathogenesis of human cancers and has allowed the identification of signatures associated with diagnosis, staging, progression, prognosis, and response to treatment of human tumors. Here we present a flowchart of principal steps to produce, analyze, and understand the biological significance of miRNA microarray data.


RNA-binding proteins in diabetic microangiopathy.
As the most common complication of diabetes, the diabetic microangiopathy characterizes diabetic retinopathy (DR) and nephropathy (DN). Diabetic microangiopathy has always been a serious clinical problem. A wide variety of nucleic acid interacting factors called the RNA binding proteins (RBPS) take part in several crucial cellular processes. Over the past decade, studies have shown that RBPs have crucial part in both malignant tumors and diabetes, especially in diabetic microangiopathy. This review examined the research history of RBPS in DR and DN. We reviewed the literature and found that RBPS is potentially useful as therapeutic targets, diagnostic markers, or predict disease progression. HuR acts as a vital therapeutic targeting protein in diabetic microangiopathy. IGF2BP2, P311, TTP, YBX1, and MBNL1 have a potential role in the treatment of DN.


Metathesis reactions of pyrazolotriazinones generate dynamic combinatorial libraries.
[reaction: see text] Reversible metathesis reactions of pyrazolotriazinones and aliphatic aldehydes or ketones proceed in aqueous, phosphate-buffered media at pH 4 and 40-60 degrees C to generate thermodynamically controlled mixtures of heterocycles.


Downregulation of B3GNT6 is a predictor of poor outcomes in patients with colorectal cancer.
The B3GNT6 protein is a member of the O-GlcNAc transferase (OGT) family and is responsible for the production of the core 3 structure of O-glycans. It is generally expressed in the gastrointestinal (GI) tract; however, its clinical significance in colorectal cancer remains largely unexplored. We obtained mRNA transcriptomic sequencing data from 3 gene expression omnibus (GEO) datasets (GSE37182, GSE39582, GSE103512) and The Cancer Genome Atlas (TCGA) to compare the B3GNT6 mRNA levels between colorectal cancer and normal tissues and further evaluate its value as a prognostic marker in colorectal cancer. We further validated this at the protein level in our cohort using immunohistochemical staining of B3GNT6 as well as the Human Protein Atlas online database. B3GNT6 expression was downregulated in colorectal cancer tissues as compared to that in the normal tissues at both mRNA and protein levels. Downregulation of B3GNT6 expression was found to be associated with poor overall survival in patients with colorectal cancer as per the data in GSE39582 and TCGA databases. Low B3GNT6 mRNA levels were significantly associated with chromosome instability (CIN) and KRAS mutations in patients with colorectal cancer. Gene set enrichment analysis (GSEA) revealed that low B3GNT6 expression levels in colorectal cancer were associated with increased proteasome activity. The results of this study demonstrate that low expression of B3GNT6 is a potential biomarker for poor outcomes in patients with CRC. Moreover, the low expression of B3GNT6 may indicate more frequent activation of the KRAS/ERK signaling pathway, high CIN, and increased proteasomal activity. These novel findings may prove helpful for molecular diagnosis and provide a new therapeutic target for colorectal cancer.


Tumor type detection in brain MR images of the deep model developed using hypercolumn technique, attention modules, and residual blocks.
Brain cancer is a disease caused by the growth of abnormal aggressive cells in the brain outside of normal cells. Symptoms and diagnosis of brain cancer cases are producing more accurate results day by day in parallel with the development of technological opportunities. In this study, a deep learning model called BrainMRNet which is developed for mass detection in open-source brain magnetic resonance images was used. The BrainMRNet model includes three processing steps: attention modules, the hypercolumn technique, and residual blocks. To demonstrate the accuracy of the proposed model, three types of tumor data leading to brain cancer were examined in this study: glioma, meningioma, and pituitary. In addition, a segmentation method was proposed, which additionally determines in which lobe area of the brain the two classes of tumors that cause brain cancer are more concentrated. The classification accuracy rates were performed in the study; it was 98.18% in glioma tumor, 96.73% in meningioma tumor, and 98.18% in pituitary tumor. At the end of the experiment, using the subset of glioma and meningioma tumor images, it was determined which at brain lobe the tumor region was seen, and 100% success was achieved in the analysis of this determination. In this study, a hybrid deep learning model is presented to determine the detection of the brain tumor. In addition, open-source software was proposed, which statistically found in which lobe region of the human brain the brain tumor occurred. The methods applied and tested in the experiments have shown promising results with a high level of accuracy, precision, and specificity. These results demonstrate the availability of the proposed approach in clinical settings to support the medical decision regarding brain tumor detection.


Freeze-drying of emulsions--influence of congealing on granulometry research of a cryoprotective agent.
Emulsions of three different size distributions and five oil/water ratios of the finest of these distributions were congealed according to three different congealing processes before the freeze-drying operation. The influence of the various cryoprotective agents added was studied and the size change of the dispersed phase after congealing was examined.


What Do Former Residents Say About Their Nondesignated Preliminary Year? A Survey of Prelims' Experiences in a General Surgery Residency Program.
The nondesignated preliminary (NDP) position in general surgery (GS) offers a 1-year surgical training opportunity for medical school graduates prior to obtaining categorical residency positions. Given that there is little long-term follow-up on the experiences of NDP residents, we sought to determine how NDPs felt about their intern year in GS. A cross-sectional survey of all NDP GS interns from 1993 to 2018. Academic, tertiary care center with a large GS residency program (Mayo Clinic, Rochester, MN). NDP GS interns (n = 151). Two-hundred and four surveys were emailed and 151 (62%) former NDP residents responded. Exposure to diverse pathology (85%), opportunity to work with experts (85%) and operative experience (72%) were the top 3 positive experiences from the NDP year. The uncertainty of being an NDP resident (78%) and experience compared to categorical counterparts (32%) were cited as the top 2 negative experiences. While 73% (n = 110) considered their NDP year to have laid a "strong" foundation for their future career, most respondents felt that the year was stressful and suggested improving mentoring and support for preliminary residents. Eighty-two percent (n = 124) of respondents stated that, they would be willing to redo their preliminary year. Fifty-four percent (n = 82) of respondents stated that they might have preferred a categorical position at a smaller institution versus a preliminary year. Forty percent of respondents (n = 60) reported fewer interviews and 24% (n = 36) reported a similar number of interviews offered when applying to the Match as a PGY1 prelim resident. Pursuing the NDP year is difficult, given the uncertainty that looms and the immense pressure to perform well. While the vast majority of our NDPs obtained categorical residency spots following their 1 year of training, feedback from this survey using 25 years of experience suggests that we can and should do more to mentor, support, and assist these residents.


[Evidence-based medicine in professional training and education in practice? The integrated evidence-based medicine curriculum at the Medical School at the University of Witten/Herdecke]].
Applying the principles of evidence-based medicine in clinical practice is becoming more and more important for healthcare professionals in Germany. In this context Witten/Herdecke University has implemented an EbM Curriculum for medical students that is closely related to problem-based learning and clinical rotations within the scope of the six-year medical reform curriculum. Starting with the first semester, students will be able to acquire the necessary skills to search medical databases, to critically review the information retrieved according to EbM standards, to gather evidence for answering diagnostic or therapeutic questions during their clinical education and to ultimately participate in the development of clinical guidelines during their last year.


Magnetic resonance imaging scans are not a reliable tool for predicting symptomatic acromioclavicular arthritis.
We investigated whether magnetic resonance imaging (MRI) scans can accurately diagnose arthritis of the acromioclavicular joint (ACJ) because it has recently been suggested that bone marrow oedema on MRI scans is a predictive sign of symptomatic ACJ arthritis. The MRI scans of 43 patients (50 shoulders) who underwent ACJ excision for clinically symptomatic ACJ arthritis were compared to a control group of 43 age- and sex-matched patients (48 shoulders) who underwent an MRI scan for investigation of shoulder pain but did not have clinical symptoms or signs of ACJ arthritis. The scans were evaluated by an experienced musculoskeletal radiologist, who was blinded to the examination findings. Bone marrow oedema was present in only 15 (30%) shoulders in the ACJ excision group, although this was higher than the six shoulders in the asymptomatic group (p = 0.03). Forty-one (82%) shoulders in the symptomatic group had grade III/IV ACJ arthritis compared to 31 (65%) in the asymptomatic group (p = 0.05). However, 44 out of 48 (92%) shoulders in the asymptomatic group had signs of osteoarthritis on MRI scans. In contrast to recent reports, the present study shows that MRI is not helpful in making the diagnosis of ACJ arthritis. A focused history and clinical examination should remain the mainstay for surgical decision making. Level 3.