MicroRNAs based regulation of cytokine regulating immune expressed genes and their transcription factors in COVID-19.
Coronavirus disease 2019 is characterized by the elevation of a broad spectrum of inflammatory mediators associated with poor disease outcomes. We aimed at an in-silico analysis of regulatory microRNA and their transcription factors (TF) for these inflammatory genes that may help to devise potential therapeutic strategies in the future. The cytokine regulating immune-expressed genes (CRIEG) were sorted from literature and the GEO microarray dataset. Their co-differentially expressed miRNA and transcription factors were predicted from publicly available databases. Enrichment analysis was done through mienturnet, MiEAA, Gene Ontology, and pathways predicted by KEGG and Reactome pathways. Finally, the functional and regulatory features were analyzed and visualized through Cytoscape. Sixteen CRIEG were observed to have a significant protein-protein interaction network. The ontological analysis revealed significantly enriched pathways for biological processes, molecular functions, and cellular components. The search performed in the miRNA database yielded ten miRNAs that are significantly involved in regulating these genes and their transcription factors. An in-silico representation of a network involving miRNAs, CRIEGs, and TF, which take part in the inflammatory response in COVID-19, has been elucidated. Thus, these regulatory factors may have potentially critical roles in the inflammatory response in COVID-19 and may be explored further to develop targeted therapeutic strategies and mechanistic validation.


Synthesis and evaluation of 9-anilinothiazolo[5,4-b]quinoline derivatives as potential antitumorals.
Five new 9-anilinothiazolo[5,4-b]quinoline derivatives (compounds 5, 7, 9, 10, 11) have been prepared. Some of the compounds were prepared by coupling properly substituted anilines to the novel compound 9-chloro-2-(methylthio)thiazolo[5,4-b]quinoline. Of these, compound 7 (9-anilino-2-[[2-(N,N-diethylamino)ethyl]amino]thiazolo[5,4-b]quinoline) showed the best cytotoxic activity in several cell lines. All compounds demonstrated DNA binding in nanomolar range. Compound 7 inhibited the (14)C-thymidine incorporation into DNA. Results indicate that these derivatives deserve more considerations as potential antitumoral drugs.


Efficacy of an Innovative Device in Reducing Discomfort during Local Anesthesia Administration in Children: A Clinical Study.
To assess the efficacy of an innovative vibrating device and compare it with the conventional method in reducing discomfort during the administration of local anesthesia. Forty children in the age-group of 4-8 years requiring local anesthesia for routine dental procedures were allocated to either a control or experimental group, with 20 children in each group. The preoperative assessment of behavior was carried out using the Frankl Behavior Rating Scale. Both groups received local anesthesia using the intraoral conventional approach. However, in the experimental group, a vibrating device was simultaneously placed over the cheek during local anesthesia administration. The SEM (sounds, eyes, motor) scale was used to assess the level of comfort or pain during the administration of local anesthesia. Data were subjected to statistical analysis and the level of significance was considered at 5%. The mean SEM score in the control group was 6.65 ± 21.95 which was significantly higher than 3.80 ± 1.15 in the experimental group (p < 0.001). The vibrating device was useful and effective in reducing pain and discomfort during intraoral local anesthesia administration. Subramaniam P, Ghai SK. Efficacy of an Innovative Device in Reducing Discomfort during Local Anesthesia Administration in Children: A Clinical Study. Int J Clin Pediatr Dent 2021;14(3):353-356.


Apolipoprotein E genotype and incident ischemic stroke: the Atherosclerosis Risk in Communities Study.
A relationship between the apolipoprotein E (apoE) genotype and ischemic stroke has been inconsistently reported. We explored this relation in the Atherosclerosis Risk in Communities Study (ARIC). The ARIC cohort involves 15 792 men and women, aged 45 to 64 years at baseline and sampled from 4 U.S. communities. Between 1987 and 2001, 498 incident ischemic strokes occurred. After stratifying by race and sex and adjusting for other nonlipid risk factors, there was no significant relation between the apoE genotype and incident stroke, except in black women (hazard ratio for epsilon2 genotype relative to epsilon3/epsilon3=0.53; 95% CI, 0.28 to 0.99). For the most part, in this middle-aged sample, apoE was not a risk factor for incident ischemic stroke.


Prognostic significance of preoperative MRI findings in young patients with breast cancer.
The objective is to evaluate the prognostic value of preoperative magnetic resonance imaging (MRI) findings in breast cancer patients aged less than 40 years. This retrospective, single-center study evaluated 92 women aged <40 years who received a diagnosis of invasive breast carcinoma between 2008 and 2012. These patients underwent a breast MRI before treatment and follow-up at the same institution. Kaplan-Meier survival curves were used to analyze overall survival, with the log-rank test used to compare different groups. Cox regression analysis was used to estimate hazard ratios (HRs) with 95% confidence interval (95% CI) values. The mean age of the patients was 34 years (range: 25-39 years) and the mean tumor size was 3.9 cm in maximal dimension (range: 0.7-10.5 cm). Recurrence was observed in 21 (22.8%) patients and 15 (16.3%) patients did not survive during a mean follow-up period of 5.4 ± 1.9 years. MRI findings associated with worse overall survival included tumor size >5 cm (HR:5.404; 95% CI:1.922-15.198; p = 0.017), presence of non-mass enhancement (HR:3.730; 95% CI:1.274-10.922; p = 0.016) and multifocal tumor (HR:3.618; 95% CI:1.151-11.369; p = 0.028). Inconclusion, MRI findings that are suggestive of more extensive disease were associated with worse overall survival in young breast cancer patients.


Comparison of echocardiographic findings with laboratory parameters in obese children.
Aim The purpose of our study was to evaluate the association between insulin resistance and left ventricular size and function in obese children. Material and methods A total of 79 cases aged 10-16 years and diagnosed with obesity and 79 healthy and non-obese cases as controls were included in the study. Patient and control groups were divided into three groups in terms of age as group 1 (10-12 years), group 2 (12-14 years), and group 3 (14-16 years). Fasting blood glucose, lipid profile, and fasting insulin levels of the cases were assessed. Mitral valve E and A waves, left ventricular ejection fraction, fractional shortening, end-diastolic and end-systolic diameters, left atrium diameter, and septal wall thickness were measured using echocardiography. Measurements of septal diastolic thicknesses, left atrium diameter, and left ventricular end-systolic diameter of all the three groups obtained by echocardiography were statistically higher compared with the controls. In all the patient groups, the mitral valve E/A ratio was >1. In groups 2 and 3, there was a positive correlation between fasting insulin levels and HOMA-IR and left ventricular end-systolic diameter, end-diastolic diameter, and septal systolic and diastolic wall thicknesses. In paediatric obesity, identification of early cardiac changes will be significant in allowing early diagnosis and treatment of cardiovascular diseases.


Delineation of serologically distinct monomorphic determinants of human MHC class II antigens: evidence of heterogeneity in their topographical distribution.
Three monoclonal antibodies (mAbs), FMC4, FMC14 and FMC15, which react with invariant sites of major histocompatibility complex (MHC) class II (Ia-like) molecules were studied in various serological assays. Sequential immunodepletion experiments show that all three epitopes are present on the same class II molecules. However, a minor subset may exist which does not express epitope 15. In competitive binding assays, using several different B-lymphoblastoid cell lines (B-LCLs), e.g. BRISTOL-8 8392, B-85, RAJI, 8866, CESS-B and LD-B, FMC4 did not block the binding of FMC14, or FMC15, and vice versa. In contrast, mutual inhibition was observed between FMC14 and FMC15. Furthermore, pairwise combinations of saturating amounts of FMC4 + FMC14 and FMC4 + FMC15 gave additive binding whilst FMC14 + FMC15 did not. These results demonstrate that epitopes 4 and 14/15 are spatially distinct; 14 and 15 on the other hand appear to be spatially related. However, contrary to this partial and reciprocal inhibition was consistently observed between FMC4 and FMC14 on two other LCLs, namely DAUDI and BALM-2. Furthermore, on certain cells, FMC14 and FMC15 show markedly disparate binding. Taken together, these observations indicate that the juxtaposition of certain epitopes on class II antigens can vary according to the cell type. This demonstrates a hitherto unreported heterogeneity of antigenic determinants and of their topographical distribution on the class II molecule.


The temporal dynamics of emotion comparison depends on low-level attentional factors.
Humans are predisposed to attend to emotions conveyed by facial expressions. However, compulsory attraction to emotions gets challenging when multiple emotional stimuli compete for attention, as in the emotion comparison task. In this task, participants are asked to choose which of two simultaneously presented faces displays the most positive (happiest) or negative (angriest) emotion. Participants usually respond faster to the face displaying the most intense emotion. This effect is stronger for face pairs that contain globally positive rather than negative emotional faces. Both effects are consistent with an attentional capture phenomenon driven by the perceptual salience of facial expressions. In the present experiment, we studied the temporal dynamics of attentional capture in the emotion comparison task by tracking participants' eye movements using gaze-contingent displays and responses. Our results show that, on the first fixation, participants were more accurate and dwelled longer on the left target face when it displayed the most intense emotion within the pair. On the second fixation, the pattern was reversed, with higher accuracy and longer gaze time on the right target face. Overall, our pattern of gazing behavior indicates that the typical results observed in the emotion comparison task arise from the optimal combination over time of two low-level attentional factors: the perceptual salience of emotional stimuli and the scanning habit of participants.


Correlation between HPV sperm infection and male infertility.
Human papillomavirus (HPV) is one of the most common sexually transmitted diseases which comprises a group of small DNA viruses that infect both cutaneous and mucous squamous epithelia. Liquid bead microarray technology (LBMA) were used to evaluate 24 HPV genotypes in confirmed fertile and infertile males of North China so that the effects of HPV infection on semen parameters and relationship with male infertility could be discussed. A total of 1138 subjects were recruited in this study; 142 were HPV-positive (12.48%). Among 523 confirmed fertile males, only 35 were HPV-positive (6.70%), and two of them had multiple infections. Among 615 infertile males, 107 were HPV-positive (17.4%), and 29 of them had multiple infections. Infertile males had a relatively high HPV infection rate compared with confirmed fertile males. Sperm progressive motility (PR) and the normal morphology rate were significantly decreased in HPV-positive subjects. HPV-45, HPV-52, HPV-18, HPV-59 and HPV-16 infections were more frequently in infertile males. Hence, HPV infection is closely related to male infertility which will decrease sperm PR and morphology. HPV-45, HPV-52, HPV-18, HPV-59 and HPV-16 infection seems to be major risk factors.


Socioeconomic disparities in lung cancer mortality in Belgian men and women (2001-2011): does it matter who you live with?
Ample studies have observed an adverse association between individual socioeconomic position (SEP) and lung cancer mortality. Moreover, the presence of a partner has shown to be a crucial determinant of health. Yet, few studies have assessed whether partner's SEP affects health in addition to individual SEP. This paper will study whether own SEP (education), partner's SEP (partner's education) and own and partner's SEP combined (housing conditions), are associated with lung cancer mortality in Belgium. Data consist of the Belgian 2001 census linked to register data on cause-specific mortality for 2001-2011. The study population includes all married or cohabiting Belgian inhabitants aged 40-84 years. Age-standardized lung cancer mortality rates (direct standardization) and mortality rate ratios (Poisson regression) were computed for the different SEP groups. In men, we observed a clear inverse association between all SEP indicators (own and partner's education, and housing conditions) and lung cancer mortality. Men benefit from having a higher educated partner in terms of lower lung cancer mortality rates. These observations hold for both middle-aged and older men. For women, the picture is less uniform. In middle-aged and older women, housing conditions is inversely associated with lung cancer mortality. As for partner's education, for middle-aged women, the association is rather weak whereas for older women, there is no such association. Whereas the educational level of middle-aged women is inversely associated with lung cancer mortality, in older women this association disappears in the fully adjusted model. Both men and women benefit from being in a relationship with a high-educated partner. It seems that for men, the educational level of their partner is of great importance while for women the housing conditions is more substantial. Both research and policy interventions should allow for the family level as well.


[Advances of hypoxia and lung cancer].
Lung cancer is one of the malignant tumors with fastest growing rates in incidence and mortality in our country, also with largest threat to human health and life. However, the exact mechanisms underlying lung cancer development remain unclear. The microenvironment of tumor hypoxia was discovered in 1955, but hypoxia in lung cancer tissues had not been successfully detected till 2006. Further studies show that hypoxia not only functions through the resistance to radiotherapy, but also regulates lung cancer development, invasion, metastasis, chemotherapy resistance and prognosis through an important oncogene HIF (hypoxia inducible factor), with its regulators PHD (prolyl hydroxylase domain) and pVHL (product of von Hippel-Lindau gene). Therefore, hypoxia, HIF, PHD and pVHL should be considered as potential therapeutic targets for lung cancer pathogenesis and progression.


Evidence that an excitatory connection between the periaqueductal gray and nucleus raphe magnus mediates stimulation produced analgesia.
Both electrical stimulation and injection of morphine into the midbrain periaqueductal gray (PAG) produce analgesia in the rat. There is evidence that this analgesic effect is mediated by a descending system that involves nucleus raphe magnus (NRM) and adjacent reticular formation. In the studies reported here, the activity of the cells in the PAG was increased by microinjection of glutamate in this area and its effect on both the activity of single cells in the NRM and on a flexion reflex elicited by noxious heat was measured. It is shown that an increase in the firing rate of the cells in the PAG is associated with a raised threshold for flexion and is also correlated with an increase in the firing rate of a majority of the cells in the NRM. This effect on the flexion reflex can be abolished by (a) lesion of the nucleus raphe magnus and a small area of the reticular formation surrounding this nucleus and (b) by nalazone 20 min after its i.v. injection. It is concluded that there is an excitatory connection between the periaqueductal gray and the nucleus raphe magnus and that activation of this system can cause analgesia.


Design of a lipid nano-delivery system containing recombinant Candida albicans chitinase 3 as a potential vaccine against fungal infections.
Opportunistic fungi cause lethal systemic infections and impose high medical costs to health systems. The World Health Organization has recognized the importance of fungal infections, including them in its global priority list guiding research, development, and discovery of new therapeutic approaches. Fungal vaccine development has been proposed as one of the treatment and prevention strategies in the last decade. In this study, we present the design of a lipid antigen delivery system based on Dioctadecyldimethylammonium bromide: Monoolein (DODAB: MO) containing recombinant Candida albicans Chitinase 3 (Cht3) for modulation the immune response against fungal infections. Several DODAB:MO liposomes containing Cht3 were prepared and those prepared by the incubation method and containing 5 µg/mL Cht3 were selected due to their favorable size, ζ-potential and stability, suited for antigen delivery applications. The encapsulation of Cht3 in these liposomes resulted in a significant increase in cellular uptake compared to empty liposomes, demonstrating their efficacy in delivering the antigen. Moreover, the liposomes proved to be safe for use in immunization procedures. Subcutaneous administration of Cht3 liposomes elicited a Th1/Th17 immune response profile, associated with the production of high levels of antibodies against Cht3. These antibodies recognized both the native and the recombinant forms of the protein, opsonizing mother-yeast at the cell scars, which has the potential to disrupt cell separation and hinder yeast growth. The findings suggest that the designed lipid antigen delivery system shows promise as a potential candidate for enhancing immune responses against fungal infections, offering a valuable strategy for future fungal vaccine development.


Drug therapy in Alzheimer disease: an update for the oral health care provider.
Alzheimer disease (AD) is a progressive neurologic disorder that manifests as memory loss, personality changes, global cognitive dysfunction, and functional impairment. As the United States population continues to age, the prevalence of AD will rise. Accordingly, oral health care providers will be more likely to treat patients affected by this disease; therefore, it is necessary to understand the pharmacologic agents used for the management of AD. This article provides an update of the available drug therapies for AD and discusses their implications on the oral and dental health of patients.


Real clinical management of patients with isolated superior mesenteric artery dissection in Japan.
Due to the rarity of this condition, clinical treatment and outcomes in isolated superior mesenteric artery dissection (ISMAD) patients remain unknown. The primary aim of this retrospective multicenter study was to elucidate the treatment strategies and in-hospital outcomes for ISMAD patients by using administrative data. We retrospectively analyzed patients that were primarily diagnosed with ISMAD using the Diagnosis Procedure Combination data collected at 141 hospitals in Japan in 2015. Patients with comorbidities that included "aneurysm" were excluded. A total of 221 ISMAD without aneurysm patients (male: 90.5%; mean age: 52.5±10.1 years) were enrolled, and 95 (67.4%) of these encountered just one ISMAD case per year. We found only one (0.5%) in-hospital death and length of stay for ISMAD patients was 13.2±9.1 days. One-third of patients received antiplatelet therapy (32.1%) and anticoagulation therapies, such as heparin (38.9%) and warfarin (10.0%). A total of 146 (66.1%) patients received antihypertensive treatment (either orally or via an intravenous route) during hospitalization. Twelve (5.4%) patients underwent surgical procedures during hospitalization as follows: 4 (33.3%) patients underwent bypass surgery, 3 (25.0%) patients underwent exploratory laparotomies, 2 (16.7%) patients underwent bowel resection, 1 (8.3%) patient underwent a thrombectomy, and 2 (16.7%) patients underwent surgical angioplasties. We found that conservative therapy for ISMAD patients without aneurysm is safe and is also associated with a low rate of surgical intervention in clinical practice.


Cancer incidence among Chernobyl cleanup workers from Estonia: A 34-year follow-up.
From 1986 to 1991, 4831 men from Estonia were sent to clean up radioactively contaminated areas near Chernobyl (Chornobyl). Their cancer incidence during 1986 to 2019 was compared to that of the male population of Estonia. The cohort of cleanup workers was linked to national population and cancer registers based on unique personal identification numbers. Nineteen (0.4%) workers could not be traced. A total of 4812 men contributing 120 770 person-years of follow-up were eligible for the analyses. Standardized incidence ratios (SIR) and adjusted relative risks (ARR, expressed as ratios of SIRs) with 95% confidence intervals (CI) were calculated. A total of 687 incident cancer cases were registered in the cohort (SIR 1.11, 95% CI 1.03-1.19). Presumptive radiation-related cancers combined were in excess, but not when smoking- and alcohol-related cancers were excluded (SIR 0.92, 95% CI 0.71-1.18). For smoking-related cancers, the SIR was 1.24 (95% CI 1.13-1.36) and for alcohol-related cancer the SIR was 1.53 (95% CI 1.31-1.75). Less educated workers had a higher risk of all cancers (ARR = 1.21, 95% CI 1.02-1.44) and smoking-related cancers (ARR = 1.42, 95% CI 1.14-1.76). An elevated risk of alcohol-related cancers was evident 15 to 24 years (vs <15 years) after return from the Chernobyl area. This updated register-based follow-up of Chernobyl cleanup workers from Estonia revealed an excess of radiation-related cancer sites combined, but the excess was not apparent after excluding cancers associated with smoking and alcohol.


Resveratrol inhibits Toxoplasma gondii-induced lung injury, inflammatory cascade and evidences of its mechanism of action.
Toxoplasma gondii is an opportunistic protozoan that can infect host to cause toxoplasmosis. We have previously reported that resveratrol (RSV) has protective effects against liver damage in T. gondii infected mice. However, the effect of RSV on lung injury caused by T. gondii infection and its mechanism of action remain unclear. In this work, we studied the protective effects of RSV on lung injury caused by T. gondii infection and explored the underlying mechanism. Molecular docking and localized surface plasmon resonance assay were used to detect the molecular interactions between RSV and target proteins. In vitro, the anti-T. gondii effects and potential anti-inflammatory mechanisms of RSV were investigated by quantitative competitive-PCR, RT-PCR, ELISA, Western blotting and immunofluorescence using RAW 264.7 cells infected with tachyzoites of T. gondii RH strain. In vivo, the effects of RSV on lung injury caused by T. gondii infection were assessed by observing pathological changes and the expression of inflammatory factors of lung. RSV inhibited T. gondii loads and T. gondii-derived heat shock protein 70 (T.g.HSP70) expression in RAW 264.7 cells and lung tissues. Moreover, RSV interacts with T.g.HSP70 and toll-like receptor 4 (TLR4), respectively, and interferes with the interaction between T.g.HSP70 and TLR4. It also inhibited the overproduction of inducible nitric oxide synthase, TNF-α and high mobility group protein 1 (HMGB1) by down-regulating TLR4/nuclear factor kappa B (NF-κB) signaling pathway, which is consistent with the effect of TLR4 inhibitor CLI-095. In vivo, RSV improved the pathological lung damage produced by T. gondii infection, as well as decreased the number of inflammatory cells in bronchoalveolar lavage fluid and the release of HMGB1 and TNF-α. These findings indicate that RSV can inhibit the proliferation of T. gondii and T.g.HSP70 expression both in vitro and in vivo. RSV can inhibit excessive inflammatory response by intervening T.g.HSP70 and HMGB1 mediated TLR4/NF-κB signaling pathway activation, thereby ameliorating lung injury caused by T. gondii infection. The present study provides new data that may be useful for the development of RSV as a new agent for the treatment of lung damage caused by T. gondii infection.


Cotesia vestalis teratocytes express a diversity of genes and exhibit novel immune functions in parasitism.
Some endoparasitoid wasps lay eggs that produce cells called teratocytes. In this study, we sequenced and analyzed the transcriptome of teratocytes from the solitary endoparasitoid Cotesia vestalis (Braconidae), which parasitizes larval stage Plutella xylostella (Plutellidae). Results identified many teratocyte transcripts with potential functions in affecting host immune defenses, growth or metabolism. Characterization of teratocyte-secreted venom-like protein 8 (TSVP-8) indicated it inhibits melanization of host hemolymph in vitro, while two predicted anti-microbial peptides (CvT-def 1 and 3) inhibited the growth of bacteria. Results also showed the parasitized hosts lacking teratocytes experienced higher mortality after immune challenge by pathogens than hosts with teratocytes. Taken together, these findings indicate that C. vestalis teratocytes secrete products that alter host immune functions while also producing anti-microbial peptides with functions that help protect the host from infection by other organisms.


L-methionine reduces oxidant stress in endothelial cells: role of heme oxygenase-1, ferritin, and nitric oxide.
The amino acid L-methionine is known to exert antioxidant effects by as yet unidentified mechanisms. In the present study, L-methionine led to a concentration-dependent induction of the antioxidant proteins heme oxygenase-1 (HO-1) and ferritin in cultured endothelial cells (ECV 304). HO-1 protein expression was accompanied by an increased catalytic activity of the enzyme. Long-term pre-incubation of endothelial cells with L-methionine reduced NADPH-mediated radical formation by up to 60%. The antioxidant effect of L-methionine was mimicked by the HO-1 product bilirubin, which suppressed free radical formation almost completely. Reduction of superoxide generation by L-methionine was inhibited in the presence of the nitric oxide (NO) synthase inhibitor L-NMMA, suggesting the involvement of endogenous NO in L-methionine-dependent cytoprotection. These findings demonstrate that L-methionine reduces free radical formation in endothelial cells, possibly through induction of heme oxygenase-1 and ferritin. This novel, indirect antioxidant action might be relevant for the preventive potential of methionine and methionine rich diets under conditions of inflammation and oxidative stress.


The expression levels of the sirtuins in patients with BCC.
Basal cell carcinoma (BCC) is the most common tumor in humans. Reduced expression of sirtuins interferes with DNA repair, which may cause mutations and genomic instability, and eventually leads to tumor development. In the present study, we investigate the expression levels of SIRT genes in non-tumoral and tumor tissues of patients with BCC. A total of 27 patients (16 males, 11 females) with BCC were included in the study; the mean age was 65.40 ± 10.74 years and mean follow-up was 2.5 ± 0.5 years. There were multiple synchronous lesions in six patients, and the remaining 21 patients had a single lesion. Tumor and non-tumoral tissue samples were collected from all patients, and mRNA expression levels of SIRT1-7 (Sirt1.1, Sirt1.2, Sirt2, Sirt3, Sirt4, Sirt5, Sirt6, and Sirt7) were examined by real-time PCR. The results showed that expressions of SIRT1.1, SIRT1.2, SIRT4, SIRT5, SIRT6, and SIRT7 mRNAs were unchanged in tumor tissues of BCC patients compared with non-tumoral tissue samples. Importantly, the expressions of SIRT2 and SIRT3 mRNAs were significantly reduced in tumor tissue samples from BCC patients compared with non-tumoral tissues (P = 0.02 and P = 0.03, respectively). In light of the previous reports that have demonstrated a link between SIRT proteins and cancer, our findings suggest that SIRT2 and SIRT3 may plan important roles in BCC pathogenesis and could be candidate prognostic biomarkers for BCC.


Reliability of lymphography as a diagnostic aid in the planning of treatment for bladder carcinoma.
To assess the accuracy of lymphography, 90 lymphograms were compared with surgical and histological findings. Histological correlation with the initial report was found in 65 to 90 cases (72%). Comparison of the original radiologist's report with a recent re-examination showed agreement between the two radiological evaluations in only 74%. Although improvement in diagnostic accuracy can perhaps be obtained, we cannot yet recommend lymphography as an aid in the planning of treatment for bladder carcinoma.


A novel COL7A1 gene mutation causing pretibial epidermolysis bullosa: report of a Chinese family with intra-familial phenotypical diversity.
Pretibial epidermolysis bullosa (PEB) is an extremely rare subtype of dominant dystrophic epidermolysis bullosa (DDEB) caused by mutation of the COL7A1 gene. More than 730 mutations have been identified in patients with DDEB, but only five mutations have been found to be related to PEB. In this study, a novel heterozygous nucleotide G>T transition at position 6101 in exon 73 of COL7A1 was detected, which resulted in a glycine to valine substitution (G2034V) in the triple-helical domain of type-VII collagen. This is the first report to show that one mutation caused a broad range of severity of disease in one family with PEB. These data suggest that c.6101G>T may influence the phenotype of PEB. They also contribute to the expanding database on COL7A1 mutations.


Spatial and temporal stability in the genetic structure of a marine crab despite a biogeographic break.
Elucidating the processes responsible for maintaining the population connectivity of marine benthic species mediated by larval dispersal remains a fundamental question in marine ecology and fishery management. Understanding these processes becomes particularly important in areas with a biogeographic break and unidirectional water movement along the sides of the break. Based on variability at 4209 single-nucleotide polymorphisms in 234 individuals, we determine the genetic structure, temporal genetic stability, and gene flow among populations of the commercially important mola rock crab Metacarcinus edwardsii in a system in southern Chile with a biogeographic break at latitude 42°S. Specimens were collected at eight sites within its geographic distribution, with collection at four of these sites was performed twice. Using population genetic approaches, we found no evidence of geographic or temporal population differentiation. Similarly, we found no evidence of an effect on gene flow of the biogeographic break caused by the the West Wind Drift Current. Moreover, migration analyses supported gene flow among all sites but at different rates for different pairs of sites. Overall, our findings indicate that M. edwardsii comprises a single large population with high levels of gene flow among sites separated by over 1700 km and demonstrate temporal stability in its genetic structure.


FDI-6 and olaparib synergistically inhibit the growth of pancreatic cancer by repressing BUB1, BRCA1 and CDC25A signaling pathways.
Inducing homologous recombination (HR) deficiency is a promising strategy to broaden the indication of PARP1/2 inhibitors in pancreatic cancer treatment. In addition to inhibition kinases, repression of the transcriptional function of FOXM1 has been reported to inhibit HR-mediated DNA repair. We found that FOXM1 inhibitor FDI-6 and PARP1/2 inhibitor Olaparib synergistically inhibited the malignant growth of pancreatic cancer cells in vitro and in vivo. The results of bioinformatic analysis and mechanistic study showed that FOXM1 directly interacted with PARP1. Olaparib induced the feedback overexpression of PARP1/2, FOXM1, CDC25A, CCND1, CDK1, CCNA2, CCNB1, CDC25B, BRCA1/2 and Rad51 to promote the acceleration of cell mitosis and recovery of DNA repair, which caused the generation of adaptive resistance. FDI-6 reversed Olaparib-induced adaptive resistance and inhibited cell cycle progression and DNA damage repair by repressing the expression of FOXM1, PARP1/2, BUB1, CDC25A, BRCA1 and other genes-involved in cell cycle control and DNA damage repair. We believe that targeting FOXM1 and PARP1/2 is a promising combination therapy for pancreatic cancer without HR deficiency.


Upgrading Pectin Production from Apple Pomace by Acetic Acid Extraction.
Pectin, as one of the most widely used functional polysaccharide, can be abundantly extracted from apple pomace which is the main by-product of apple juice industry. In the case of 110 min, 10% (w/w) acetic acid (AA), and 100 °C, extraction yield of pectin reached 19.6%. Compared with mineral acid-extracted pectin, the yield, molecular weight, galacturonic acid content, and DE of the AA-extracted pectin were higher while neutral sugars were lower. Furthermore, the AA-extracted pectin solution demonstrated a higher viscosity during the shear rate increased, and a higher G″ modulus than pectin extracted with mineral acid and commercial pectin possibly because of stronger polymer chain interaction, which was reflected in gel textural properties. The green approach for the pectin production, in terms of pectin components was developed from apple pomace using AA that was highly competitive and environmentally friendly process.


The formation of the avian scapula blade takes place in the hypaxial domain of the somites and requires somatopleure-derived BMP signals.
The avian scapula is a long bone located dorsally on the thorax. The cranial part that articulates with the upper limb is derived from the somatopleure of the forelimb field, while the caudal part, the scapula blade, originates from the dermomyotomes of brachial and thoracic somites. In previous studies, we have shown that scapula blade formation is intrinsically controlled by segment-specific information as well as extrinsically by ectoderm-derived signals. Here, we addressed the role of signals derived from the lateral plate mesoderm on scapula development. Chick-quail chimera experiments revealed that scapula precursor cells are located within the hypaxial domain of the dermomyotome adjacent to somatopleural cells. Barrier implantation between these two cell populations inhibited scapula blade formation. Furthermore, we identified BMPs as scapula-inducing signals from the somatopleure using injection of Noggin-producing cells into the hypaxial domain of scapula-forming dermomyotomes. We found that inhibition of BMP activity interfered with scapula-specific Pax1 expression and scapula blade formation. Taken together, we demonstrate that the scapula-forming cells located within the hypaxial somitic domain require BMP signals derived from the somatopleure for their specification and differentiation.


Radioimmunoassay of an invertebrate peptide hormone - the crustacean neurosecretory hyperglycemic hormone.
Antibodies against hyperglycemic hormone (CHH) of Carcinus were raised in rabbits by injection of extract from sinus glands which contain high concentrations of CHH. The antiserum neutralizes the biological activity of CHH and binds 125-J-CHH. A RIA for CHH was established and was used to measure the hormone content of sinus glands.


A neglected cervicovesical fistula diagnosed and repaired by combined hysteroscopy and laparoscopy: A case report and review of literature.
To analyze a case of neglected cervicovesical fistula with intrauterine adhesions caused by cesarean section. A 36-year-old female patient with a history of two previous cesarean sections complained of the absence of menstruation for the last 18 months. The diagnosis of the cervicovesical fistula was made through hysteroscopy and cystoscopy. The reconstruction of the uterus and bladder was achieved by a laparoscopic repair technique. The patient resumed normal menstruation postoperatively without complaining of any complications. Uterine continuity and cavity had been restored to normal at the second look of hysteroscopy. Cervicovesical fistula with intrauterine adhesions is very rare in our clinical work. Hysteroscopy might play an essential role in diagnosing cervicovesical fistula and IUA. In our literature review, a surgical approach was the mainstay and definitive management of the cervicovesical fistula following a cesarean section.


Esophagitis as a complication of the combination of lenvatinib and pembrolizumab for advanced endometrial cancer: A case report.
Pembrolizumab is a monoclonal antibody targeting the programmed cell death protein 1 (PD-1). It is used in the management and treatment of various oncologic conditions. To name a few: refractory and advanced melanoma, non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), renal cell carcinoma and gastric cancer. It is also approved for metastatic mismatch repair deficient (dMMR) endometrial carcinoma after failure of front-line chemotherapy. Lenvatinib is an oral multikinase inhibitor that targets vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor-a, RET, and KIT. The combination of lenvatinib and pembrolizumab has proven to be more effective together than as monotherapy. Here, we present the case of a patient who probably developed lenvatinib-related esophagitis, a complication not previously described in the literature to our knowledge.Case presentation.We describe a 65 years old female with metastatic endometrial cancer who presented dysphagia after a few months of lenvatinib plus pembrolizumab treatment. Upper endoscopy results revealed a very fragile upper esophageal mucosa with mucosal lacerations, consistent with grade 2 esophagitis. The biopsy showed esophagitis with mixed lymphocytic and eosinophilic inflammation and apoptotic component. Pembrolizumab was then stopped pending the results of the biopsy, following the recommendations of the gastroenterologist. Dysphagia, however, remained unchanged. In the meantime, the lenvatinib had to be stopped due to a dental procedure, and the patient noted a marked improvement in her symptoms. After discussion with the gastroenterologist, pembrolizumab was resumed and lenvatinib was suspended. The patient was also started on a PPI twice daily since the first digestive exploration. 1 month later, upper endoscopy showed complete recovery, the patient's symptoms improved, and lenvatinib was resumed. However, symptoms of dysphagia resumed a few days later. Lenvatinib was finally resumed at a reduced dose without reappearance in her symptoms. We present a case of oesophagitis as a likely complication of lenvatinib for advanced endometrial cancer. The initiation of PPI and dose reduction of the lenvatinib allowed the patient to successfully go back on treatment.


Chromatin targeting drugs in cancer and immunity.
Recent advances in the enzymology of transcription and chromatin regulation have led to the discovery of proteins that play a prominent role in cell differentiation and the maintenance of specialized cell functions. Knowledge about post-synthetic DNA and histone modifications as well as information about the rules that guide the formation of multimolecular chromatin-bound complexes have helped to delineate gene-regulating pathways and describe how these pathways are altered in various pathological conditions. The present review focuses on the emerging area of therapeutic interference with chromatin function for the purpose of cancer treatment and immunomodulation.


[First clinical and materials experience with full porcelain crowns and In-Ceram bridge system].
The all-ceramic crown- and bridge-system In-Ceram uses a glass-infiltrated, sintered alumina-ceramic core material. The construction of bridges seems to be possible due to the high bending strength of the core material. The results concerning marginal fit and aesthetics are very pleasing. However, long-term results with this material are not available.


Nurses' attitude on pressure injury prevention: A systematic review and meta-analysis based on the pressure ulcer prevention instrument (APuP).
Prevention of pressure ulcers (PU) is one of the most important indicators of the quality of patient care that may be influenced by the attitude of nurses. Nurses are responsible for maintaining the integrity of the skin and preventing its complications. The aim of this study was to assess the overall attitude of nurses on PU prevention based on their scores on the Attitude towards Pressure ulcer Prevention instrument (APuP). In this systematic review and meta-analysis, databases including Web of Science, Science Direct, PubMed, and Scopus were searched, using the following keywords: Pressure Ulcer, Pressure injury, Bedsore, Pressure Sore, Decubitus Ulcer, Attitude, and their possible combinations. Heterogeneity of studies was assessed with I2 index and Cochrane-Q test. Based on heterogeneity between the studies, the data were analyzed using a random effects model. All the analyses were performed using STATA v.16 software. Twelve studies with a sample size of 7824 people were analyzed. The overall score of attitude towards pressure ulcer prevention was 70.84% (95% CI: 66.34-75.35) and the highest and lowest scores were related to the dimensions of individual priority (78.83%, 95% CI: 74.69-82.97) and competence (70.11%, 95% CI: 67.24-72.94), respectively. The percentage of the total score of attitude towards pressure ulcer prevention in nurses was higher than nursing students (72.15%, 95% CI: 67.10-77.20 vs. 67%, 95% CI: 53.80-80.20). Sensitivity analysis confirmed the stability of the results. Publication bias was significant (p = 0.036). The attitude of nurses and nursing students towards the prevention of pressure ulcers was moderate, and providing the necessary training to these groups was essential.


Effect of fructose consumption on insulin sensitivity in nondiabetic subjects: a systematic review and meta-analysis of diet-intervention trials.
High fructose consumption has been suggested to contribute to several features of metabolic syndrome including insulin resistance, but to our knowledge, no previous meta-analyses have investigated the effect of fructose on insulin sensitivity in nondiabetic subjects. We performed a systematic review and meta-analysis of controlled diet-intervention studies in nondiabetic subjects to determine the effect of fructose on insulin sensitivity. We searched MEDLINE, EMBASE, and the Cochrane Library for relevant trials on the basis of predetermined eligibility criteria. Two investigators independently performed the study selection, quality assessment, and data extraction. Results were pooled with the use of the generic inverse-variance method with random effects weighting and were expressed as mean differences (MDs) or standardized mean differences (SMDs) with 95% CIs. Twenty-nine articles that described 46 comparisons in 1005 normal-weight and overweight or obese participants met the eligibility criteria. An energy-matched (isocaloric) exchange of dietary carbohydrates by fructose promoted hepatic insulin resistance (SMD: 0.47; 95% CI: 0.03, 0.91; P = 0.04) but had no effect on fasting plasma insulin concentrations (MD: -0.79 pmol/L; 95% CI: -6.41, 4.84 pmol/L; P = 0.78), the homeostasis model assessment of insulin resistance (HOMA-IR) (MD: 0.13; 95% CI: -0.07, 0.34; P = 0.21), or glucose disposal rates under euglycemic hyperinsulinemic clamp conditions (SMD: 0.00; 95% CI: 20.41, 0.41; P = 1.00). Hypercaloric fructose (∼25% excess of energy compared with that of the weight-maintenance control diet) raised fasting plasma insulin concentrations (MD: 3.38 pmol/L; 95% CI: 0.03, 6.73 pmol/L; P < 0.05) and induced hepatic insulin resistance (SMD: 0.77; 95% CI: 0.28, 1.26; P < 0.01) without affecting the HOMA-IR (MD: 0.18; 95% CI: -0.02, 0.39; P = 0.08) or glucose disposal rates (SMD: 0.10; 95% CI: -0.21, 0.40; P = 0.54). Results may have been limited by the low quality, small sample size, and short duration (mostly <60 d) of included trials. Short-term fructose consumption, in isocaloric exchange or in hypercaloric supplementation, promotes the development of hepatic insulin resistance in nondiabetic adults without affecting peripheral or muscle insulin sensitivity. Larger and longer-term studies are needed to assess whether real-world fructose consumption has adverse effects on insulin sensitivity and long-term outcomes.


Younger age at initiation of the human papillomavirus (HPV) vaccination series is associated with higher rates of on-time completion.
Vaccination rates for human papillomavirus (HPV) have remained disappointingly low. It is critical to identify methods to increase on-time vaccine series completion rates (before 13 or 15years). To determine whether younger age (9 to 10years of age) at HPV vaccine series initiation was associated with improved on-time completion rates compared to initiation at 11 to 12years, we examined the prevalence of on-time HPV vaccine series completion rates from August 2006 through December 2012 in a large, population-based cohort of children and adolescents (aged 9.5 to 27years) residing in Olmsted County, MN on December 31, 2012 (n=36,223). We compared age at vaccine initiation between individuals who successfully completed both 2 and 3 doses of the vaccination series on-time (before age 13.5 or 15.0years) using multivariate logistic regression. On-time completion of both 2 and 3 doses of the vaccine series by age 13.5 or 15.0years was significantly associated with initiation at 9 to 10years as compared to 11 to 12years after adjusting for sex, race, insurance status, frequent health care visits, and year of first vaccination (all p<.01). Interventions focused on beginning the vaccination series at 9 to 10years of age may result in higher rates of timely series completion.


Higher-harmonic adaptation and the detection of squarewave gratings.
Adaptation to a high contrast sinewave grating of 1 c/deg spatial frequency causes a large increase in the contrast threshold for a 1 c/deg test grating, but fails to raise the threshold for a squarewave grating of 0.33 c/deg, although the sensitivity of the "channel" tuned to both the third and fifth harmonic components of the squarewave test grating should be thoroughly suppressed. Following sequential adaptation to sinewave gratings of 1 and 3 c/deg spatial frequency, detection of squarewave gratings at 0.33 c/deg likewise remains unaffected. In contrast, after adaptation to a 0.33 c/deg squarewave grating with missing fundamental the contrast threshold for a squarewave test grating of the same frequency is increased by 0.25 log unit, although the higher harmonic component frequencies are less affected than by sequential sinewave adaptation. The results suggest that independent spatial frequency channels detecting harmonic components are not alone sufficient to account for the visibility of low frequency squarewaves.


Germ cell specification and ovary structure in the rotifer Brachionus plicatilis.
The segregation of the germline from somatic tissues is an essential process in the development of all animals. Specification of the primordial germ cells (PGCs) takes place via different strategies across animal phyla; either specified early in embryogenesis by the inheritance of maternal determinants in the cytoplasm of the oocyte ('preformation') or selected later in embryonic development from undifferentiated precursors by a localized inductive signal ('epigenesis'). Here we investigate the specification and development of the germ cells in the rotifer Brachionus plicatilis, a member of the poorly-characterized superphyla Lophotrochozoa, by isolating the Brachionus homologues of the conserved germ cell markers vasa and nanos, and examining their expression using in situ hybridization. Bpvasa and Bpnos RNA expression have very similar distributions in the Brachionus ovary, showing ubiquitous expression in the vitellarium, with higher levels in the putative germ cell cluster. Bpvas RNA expression is present in freshly laid eggs, remaining ubiquitous in embryos until at least the 96 cell stage after which expression narrows to a small cluster of cells at the putative posterior of the embryo, consistent with the developing ovary. Bpnos RNA expression is also present in just-laid eggs but expression is much reduced by the four-cell stage and absent by the 16-cell stage. Shortly before hatching of the juvenile rotifer from the egg, Bpnos RNA expression is re-activated, located in a subset of posterior cells similar to those expressing Bpvas at the same stage. The observed expression of vasa and nanos in the developing B. plicatilis embryo implies an epigenetic origin of primordial germ cells in Rotifer.


Correction: An evaluation of the chemical content and microbiological contamination of Anatolian bee venom.
[This corrects the article DOI: 10.1371/journal.pone.0255161.].


Defective gene expression of MnSOD in cancer cells.
Reactive oxygen species (ROS) have been frequently implicated in the initiation and promotion phases of carcinogenesis. Antioxidant enzymes, which can antagonize this process, are lowered in a number of malignancies. The enzyme most commonly decreased is the mitochondrial Mn-containing superoxide dismutase (MnSOD) encoded by a nuclear gene mapped on the band 6q21, a region frequently deleted in several human tumours. The close association of del(6q) with diminution of MnSOD has led to suggest that MnSOD might be a new type of tumour-suppressor gene. This hypothesis is also sustained by the finding that transfection of MnSOD cDNA into human melanoma cell lines suppress the malignant phenotype. There are, however, conflicting observations that tend to ascribe the deficiency of the MnSOD activity more to a defect in the expression of the gene than to its deletion. In many transformed cell lines, including some with marked del(6q), there is no change in the dosage of the MnSOD gene and the enzyme is highly inducible by various pro-oxidant agents. Transition metals (Mn, Fe) have been found to be highly deficient in human and rodent tumours. Owing to the second messenger function of ROS in activating transcription factors (NF-kB, AP-1) and to the ability of Mn to facilitate the dismutation of O2- to H2O2 and of Fe to participate in the Fenton reaction, we propose that in the early stage of carcinogenesis an impairment of the signal transduction machinery, related to the metal deficiency, might limit the binding to DNA of transcription factors and cause the defect in the MnSOD gene expression.


Photothermia at the nanoscale induces ferroptosis via nanoparticle degradation.
The Fe(II)-induced ferroptotic cell death pathway is an asset in cancer therapy, yet it calls into question the biocompatibility of magnetic nanoparticles. In the latter, Fe(II) is sequestered within the crystal structure and is released only upon nanoparticle degradation, a transition that is not well understood. Here, we dissect the chemical environment necessary for nanoparticle degradation and subsequent Fe(II) release. Importantly, temperature acts as an accelerator of the process and can be triggered remotely by laser-mediated photothermal conversion, as evidenced by the loss of the nanoparticles' magnetic fingerprint. Remarkably, the local hot-spot temperature generated at the nanoscale can be measured in operando, in the vicinity of each nanoparticle, by comparing the photothermal-induced nanoparticle degradation patterns with those of global heating. Further, remote photothermal irradiation accelerates degradation inside cancer cells in a tumor spheroid model, with efficiency correlating with the endocytosis progression state of the nanoparticles. High-throughput imaging quantification of Fe2+ release, ROS generation, lipid peroxidation and cell death at the spheroid level confirm the synergistic thermo-ferroptotic therapy due to the photothermal degradation at the nanoparticle level.


Cyaphide-Azide 1,3-Dipolar Cycloaddition Reactions: Scope and Applicability.
Several examples of the cyaphide-azide 1,3-dipolar cycloaddition reaction to afford metallo-triazaphospholes are reported. The gold(I) triazaphospholes Au(IDipp)(CPN3 R) (IDipp=1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene; R=t Bu, Ad, Dipp), magnesium(II) triazaphospholes, {Mg(Dipp NacNac)(CPN3 R)}2 (Dipp NacNac=CH{C(CH3 )N(Dipp)}2 , Dipp=2,6-diisopropylphenyl; R=t Bu, Bn), and germanium(II) triazaphosphole Ge(Dipp NacNac)-(CPN3 t Bu) can be prepared straightforwardly, under mild conditions and in good yields, in a manner reminiscent of the classic alkyne-azide click reaction (albeit without a catalyst). This reactivity can be extended to compounds with two azide functional groups such as 1,3-diazidobenzene. It is shown that the resulting metallo-triazaphospholes can be used as precursors to carbon-functionalized species, including protio- and iodo-triazaphospholes.


Hyoscine butylbromide in pain reduction associated with ultrasound-guided manual vacuum aspiration: a randomized placebo-controlled trial.
What is the effect of adding an anti-spasmodic drug to an existing ultrasound-guided manual vacuum aspiration (USG-MVA) protocol to alleviate immediate post-procedure abdominal cramping pain in women treated for early pregnancy loss? Double-blind, placebo-controlled, randomized controlled trial conducted between February 2018 and January 2020. Participants were assigned to receive a 1-ml intravenous injection containing 20-mg hyoscine butylbromide (HBB) (n=55) or saline (n =56) as a control immediately before USG-MVA. Primary outcome was reduced abdominal pain after adding a 20-mg dose of HBB to the current pain control regimen. Secondary outcomes were vaginal pain, complications and side-effects, women's pre- and post-procedure psychological state, physiological stress (saliva alpha-amylase) and procedure pain control satisfaction. Two-way mixed ANOVA was used to evaluate the main effects and interactions. VAS abdominal pain scores in the HBB group were 16% lower immediately after and 21% lower 2 h after surgery (not statistically significant). Two-way ANOVA indicated that time (F[1108] = 83.41, P < 0.001) was the only significant main effect for reduced abdominal pain after the procedure and vaginal pain score (F[1108] = 180.1, P < 0.0001) but not drug received. No adverse events were reported. No significant difference was found for psychological state, physiological stress and procedure pain control satisfaction between the two groups. Anti-spasmodic drugs can help to reduce abdominal cramping pain associated with USG-MVA; HBB produced an insignificant decrease in abdominal pain score. Further studies with longer acting or larger doses of anti-spasmodic drugs are warranted.


Diffuse noxious inhibitory controls (DNIC). II. Lack of effect on non-convergent neurones, supraspinal involvement and theoretical implications.
(1) Diffuse noxious inhibitory controls (DNIC) were tested for their effect on noxious only, non-noxious and proprioceptive cells in the dorsal horn of the intact anaesthetized rat. Unlike convergent neurones, as described in the previous paper, there was no effect of DNIC on these neurones. It is concluded that convergent neurones are specifically inhibited by DNIC. (2) The effect of DNIC could not be demonstrated for convergent neurones in the spinal animal. Thus the neuronal substrate for DNIC must involve supraspinal structures. (3) Because of the level of firing in convergent neurones induced by hair and touch receptors, presumably constantly and randomly activated in the freely moving animal, a noxious message arriving at higher centres may be partly masked by this background noise. On the basis of the known role of convergent neurones in nociception, we propose the following mechanism which may interpret this paradoxical convergence: two pools of convergent neurones are influenced by a painful peripheral stimulation, one segmental pool being activated whilst the remaining population of cells is inhibited; the "contrast" between the messages from these two pools may well produce a significant pain signalling output from the convergent dorsal horn cells. (4) These results and their theoretical implications are discussed with regard to the concept of the "analgesic system", certain clinical observations and the paradoxical pain relieving effects of counterirritation and some forms of acupuncture.


Effects of intra-articular inoculation with Mycoplasma bovis on immunological responses in calf joints.
Mycoplasma arthritis that caused by Mycoplasma bovis exhibit severe lameness. This disease is difficult to cure with antibiotics, but the detailed pathological mechanisms have not been fully clarified. In this study, we examined the effects of intra-articular inoculation with M. bovis on immunological responses in calf joints. We inoculated three calves each with M. bovis or phosphate buffer saline (control) into the right stifle joint and dissected them at 15 days postinoculation. Mycoplasma bovis-inoculated calves exhibited swelling of the stifle joint, increases in synovial fluid, fibrin deposition, and cartilage thinning. Intracellular M. bovis was detected in synovial tissues analyzed by immunohistochemistry and transmission electron microscopy. Messenger RNA expressions of interleukin (IL)-1β, IL-6, IL-8, IL-12p40, and IL-17A in synovial fluid cells and synovial tissues from M. bovis-inoculated calves were significantly higher than those from control calves. Protein levels of these cytokines in synovial fluid from M. bovis-inoculated calves were markedly higher than those from control calves. Our study clarified that inoculation with M. bovis into the stifle joint induced the production of inflammatory cytokines by synovial fluid cells and synovial tissues, causing a severe inflammatory response in joints. Additionally, M. bovis could invade cells in synovial tissues, which may have aided it in evading antibiotics and host immune surveillance.


The influence of acute venous congestion on the guinea pig cochlea.
The effects of sudden occlusion of the vein of the cochlear aqueduct (VCAQ) on the cochlear blood flow, endocochlear potential (EP), endolymphatic and perilymphatic fluid pressures (PE and PP) were studied in the guinea pig. Cochlear blood flow showed a sudden decrease, and EP began to drop within 90 s, ranging from 50 to 70 mV in 5 of 11 animals studied, recovering to normal levels when the animals were placed on a continuous inhalation of carbogen. The PE and PP increased simultaneously (max. PE = 3.4 +/- 1.4 mm Hg; max. PP = 2.5 +/- 1.0 mm Hg) and returned to their initial values after 5 min. The EP was sustained within the normal range, even when there was an apparent decrease in cochlear blood flow (61.4 +/- 8.4%). We believe that variations in EP following VCAQ occlusion were due to anatomical differences in collateral venous communications among the animals studied. Carbogen inhalation produced uniform recovery patterns, indicating that individual collateral vessel responses were eliminated.


Caldesmon: anomalous electrophoretic behaviour in polyacrylamide gel.
In SDS gels caldesmon (Mr = 140 kDa) and myosin light chain kinase (Mr = 130 kDa) migrate as a closely separated doublet. When glycerol is added to the gel caldesmon is characterized by an anomalous migration. In fact under this latter condition, the distance between caldesmon and myosin light chain kinase is enhanced by two-three times. The nature of putative caldesmon and myosin light chain kinase was confirmed by physicochemical, enzymatic and immunological methods.


The UK National Flap Registry (UKNFR): A National Database for all pedicled and free flaps in the UK.
The UK National Flap Registry (UKNFR) is a cross-speciality National Clinical Audit with participation by the British Association of Plastic Reconstructive and Aesthetic Surgeons (BAPRAS), British Association of Head and Neck Oncologists (BAHNO), British Association of Oral and Maxillofacial Surgeons (BAOMS) and Association of Breast Surgery (ABS). The aim of UKNFR is to collect information about all major pedicled and free flap operations carried out in the UK and through that, assess the quality of care we provide for patients. This audit will allow appropriate comparison of clinical performance with national standards and provide useful data on changing trends. Participation in audit is integral to appraisal and revalidation in the UK.


The effect of stress hormones on the interorgan flux of amino acids and on the concentration of free amino acids in skeletal muscle.
Plasma concentrations of free amino acids have previously been found to decrease posttraumatically and this decrease can be reproduced by infusion of stress hormones. The mechanisms underlying this effect has not been investigated and therefore 14 healthy subjects were studied by infusing adrenaline alone or a combination of adrenaline, glucagon, and cortisol, in dosages giving pathophysiological plasma concentrations of the hormones. The influence on the interorgan fluxes of free amino acids and on the concentrations of free amino acids in skeletal muscle were determined. During hormone infusion splanchnic oxygen consumption doubled, indicating an increase in metabolic activity. There was a significant decrease in the arterial plasma level of all amino acids except alanine. Significant increases in alanine flux was noted, the release from one leg doubled and the splanchnic uptake increased by 60%. After only 1 h all essential amino acids showed a significantly decreased concentration in muscle while the level of alanine was increased. There were no differences between the two hormone groups. The results indicate that stress hormones can initiate an increased formation of alanine in skeletal muscle and an increase in alanine transport from the periphery to the splanchnic area.


Parthenolide inhibits proliferation and invasion, promotes apoptosis, and reverts the cell-cell adhesion loss through downregulation of NF-κB pathway TNF-α-activated in colorectal cancer cells.
The activation of the nuclear factor-κB (NF-κB) pathway has been associated with the development and progression of colorectal cancer (CRC). Parthenolide (PTL), a well-known inhibitor of the NF-κB pathway, has emerged as an alternative treatment. However, whether PTL activity is tumor cell-specific and dependent on the mutational background has not been defined. This study investigated the antitumor role of PTL after tumor necrosis factor-α (TNF-α) stimulation in various CRC cell lines with different mutational statuses of TP53. We observed that CRC cells displayed different patterns of basal p-IκBα levels; PTL reduced cell viability according to p-IκBα levels and p-IκBα levels varied among the cell lines according to the time of TNF-α stimulation. High concentrations of PTL reduced more effectively p-IκBα levels than low doses of PTL. However, PTL increased total IκBα levels in Caco-2 and HT-29 cells. In addition, PTL treatment downregulated p-p65 levels in HT-29 and HCT-116 cells stimulated by TNF-α in a dose-dependent manner. Moreover, PTL induced cell death via apoptosis and reduced the proliferation rate of TNF-α-treated HT-29 cells. Finally, PTL downregulated the messenger RNA levels of interleukin-1β, a downstream cytokine of NF-κB, reverted the E-cadherin-mediated disorganization of cell-cell contacts, and decreased the invasion of HT-29 cells. Together, these results suggest a differential antitumoral activity of PTL on CRC cells with different mutational statuses of TP53, modulating cell death, survival, and proliferation underlying the NF-κB pathway TNF-α-induced. Therefore, PTL has emerged as a potential treatment for CRC in an inflammatory NF-κB-dependent manner.


Inhibiting aberrant signal transducer and activator of transcription protein activation with tetrapodal, small molecule Src homology 2 domain binders: promising agents against multiple myeloma.
The signal transducer and activator of transcription (STAT) proteins represent a family of cytoplasmic transcription factors that regulate a pleiotropic range of biological processes. In particular, Stat3 protein has attracted attention as it regulates the expression of genes involved in a variety of malignant processes, including proliferation, survival, migration, and drug resistance. Multiple myeloma (MM) is an incurable hematologic malignancy that often exhibits abnormally high levels of Stat3 activity. Although current treatment strategies can improve the clinical management of MM, it remains uniformly incurable with a dismal median survival time post-treatment of 3-4 years. Thus, novel targeted therapeutics are critically needed to improve MM patient outcomes. We herein report the development of a series of small molecule Stat3 inhibitors with potent anti-MM activity in vitro. These compounds showed high-affinity binding to Stat3's SH2 domain, inhibited intracellular Stat3 phosphorylation, and induced apoptosis in MM cell lines at low micromolar concentrations.


Nature of airway inflammation and remodeling in chronic cough.
Chronic cough may be a result of asthma and non-asthma causes, but it is unclear whether there are specific inflammatory or remodeling changes. We determined airway mucosal changes in patients presenting with asthmatic cough and cough associated with non-asthmatic causes. Patients with chronic cough of non-asthmatic (n=33; postnasal drip/rhinitis in 6, gastroesophageal reflux in 5, bronchiectasis in 3, and idiopathic in 19) and asthmatic (n=14) causes and 15 healthy controls underwent fiberoptic bronchoscopy. Morphometry of bronchial biopsies and capsaicin cough sensitivity were assessed. Compared with controls, submucosal eosinophils and neutrophils were increased in patients with asthmatic cough (P<.005) and submucosal mast cells in patients with non-asthmatic cough (P=.01). Sub-basement membrane thickness, goblet cell area, vascularity, and vessel size were also increased in both groups. Smooth muscle area was higher only in patients with non-asthmatic cough (P=.0007 vs control and P=.019 vs asthmatic cough). None of the pathologic changes were related to the duration of coughing. Cough sensitivity was heightened in patients with non-asthmatic cough compared with controls and patients with asthmatic cough. The degree of goblet cell hyperplasia and epithelial shedding positively correlated with cough sensitivity in patients with non-asthmatic cough (r=0.43; P=.01; and r=0.40; P=.02, respectively). Features of airway wall remodeling are prominent in the airways with non-asthmatic as well as asthmatic cough. These are linked to chronic cough rather than to asthma. Mast cell hyperplasia rather than eosinophilia is distinctive for non-asthmatic cough.


Sensitivity of immunocompetent cells of DBA/2 and C57Bl/6 mice to cyclophosphamide.
T cells were most sensitive to cyclophosphamide in DBA/2 mice, while in C57Bl/6 mice both T and B cells were sensitive. The formation of antibody-producing cells and the production of specific antibodies were delayed in DBA/2 mice immunized after pretreatment with antitumor drug. Accumulation of antibody-producing cells in the spleen was more active in immunized C57Bl/6 mice treated with cyclophosphamide compared to animals not treated with cyclophosphamide.


PGRN promotes migration and invasion of epithelial ovarian cancer cells through an epithelial mesenchymal transition program and the activation of cancer associated fibroblasts.
In this paper, we aimed to explore whether progranulin (PGRN) could induce epithelial ovarian cancer cells to undergo an epithelial mesenchymal transition (EMT) program directly and through its activation of cancer associated fibroblasts (CAFs) indirectly. Immunohistochemistry(IHC) staining of tissue samples of 78 cases of epithelial ovarian cancer (EOC) patients found that PGRN expression levels were negatively correlated with E-cadherin levels (r=-0.289, P=0.013) and positively correlated with Slug levels (r=0.332, P=0.003); Cell experiments showed that PGRN overexpression could increase the migratory and invasive abilities of A2780 cells significantly. Moreover, high doses (62ng/ml) of recombinant PGRN could induce 14.7 fold high expression of smooth muscle actin α (α-SMA) in human normal fibroblasts. In addition, patients with both high levels of PGRN and α-SMA in their tissue samples had the worst disease free survival (DFS) and overall survival (OS) than those with low levels of PGRN or α-SMA. All the results suggest that PGRN could promote invasiveness of EOC cells through an EMT program directly and through activation of CAFs indirectly. This may provide a new effective therapy target for EOC.


EPSPatNet86: eight-pointed star pattern learning network for detection ADHD disorder using EEG signals.
Objective.The main objective of this work is to present a hand-modelled one-dimensional signal classification system to detect Attention-Deficit Hyperactivity Disorder (ADHD) disorder using electroencephalography (EEG) signals.Approach.A novel handcrafted feature extraction method is presented in this research. Our proposed method uses a directed graph and an eight-pointed star pattern (EPSPat). Also, tunable q wavelet transforms (TQWT), wavelet packet decomposition (WPD), statistical extractor, iterative Chi2 (IChi2) selector, and the k-nearest neighbors (kNN) classifier have been utilized to develop the EPSPat based learning model. This network uses two wavelet decomposition methods (TQWT and WPD), and 85 wavelet coefficient bands are extracted. The proposed EPSPat and statistical feature creator generate features from the 85 wavelet coefficient bands and the original EEG signal. The learning network is termed EPSPatNet86. The main purpose of the presented EPSPatNet86 is to detect abnormalities of the EEG signals. Therefore, 85 wavelet subbands have been generated to extract features. The created 86 feature vectors have been evaluated using the Chi2 selector and the kNN classifier in the loss value calculation phase. The final features vector is created by employing a minimum loss-valued eight feature vectors. The IChi2 selector selects the best feature vector, which is fed to the kNN classifier. An EEG signal dataset has been used to demonstrate the presented model's EEG signal classification ability. We have used an ADHD EEG dataset since ADHD is a commonly seen brain-related ailment.Main results.Our developed EPSPatNet86 model can detect the ADHD EEG signals with 97.19% and 87.60% accuracy using 10-fold cross and subject-wise validations, respectively.Significance.The calculated results demonstrate that the presented EPSPatNet86 attained satisfactory EEG classification ability. Results show that we can apply our developed EPSPatNet86 model to other EEG signal datasets to detect abnormalities.


Quantitative computed tomography imaging-based classification of cement dust-exposed subjects with an artificial neural network technique.
Cement dust exposure is likely to affect the structural and functional alterations in segmental airways and parenchymal lungs. This study develops an artificial neural network (ANN) model for identifying cement dust-exposed (CDE) subjects using quantitative computed tomography-based airway structural and functional features. We obtained the airway features in five central and five sub-grouped segmental regions and the lung features in five lobar regions and one total lung region from 311 CDE and 298 non-CDE (NCDE) subjects. The five-fold cross-validation method was adopted to train the following classification models:ANN, support vector machine (SVM), logistic regression (LR), and decision tree (DT). For all the classification models, linear discriminant analysis (LDA) and genetic algorithm (GA) were applied for dimensional reduction and hyperparameterization, respectively. The ANN model without LDA was also optimized by the GA method to observe the effect of the dimensional reduction. The genetically optimized ANN model without the LDA method was the best in terms of the classification accuracy. The accuracy, sensitivity, and specificity of the GA-ANN model with four layers were greater than those of the other classification models (i.e., ANN, SVM, LR, and DT using LDA and GA methods) in the five-fold cross-validation. The average values of accuracy, sensitivity, and specificity for the five-fold cross-validation were 97.0%, 98.7%, and 98.6%, respectively. We demonstrated herein that a quantitative computed tomography-based ANN model could more effectively detect CDE subjects when compared to their counterpart models. By employing the model, the CDE subjects may be identified early for therapeutic intervention.


Time is spine: What's over the horizon.
The overarching theme in the early treatment of acute spinal cord injury (SCI) is to reduce the extent of secondary damage to facilitate early neurological and functional recovery. Although multiple studies have brought us innovative and potential new therapies to treat SCI, ameliorating neural damage remains a formidable challenge. Knowledge translation of clinical and basic research studies has shown that surgical intervention is a valuable treatment modality; however, the role, timing and optimal technique in surgery remains a topic of great controversy. While evidence to support the concept of ultra-early surgery for acute SCI continues to emerge, current protocols and international guidelines that encourage reducing time from trauma to surgery support the concept of "Time is Spine". The present article provides a critical narrative review of the current best practice, with a particular focus on the timing of surgical intervention, which shapes our understanding of how time is of the essence in the management of acute SCI.


Effect of prednisone on plasma testosterone levels and on duration of phases of the menstrual cycle in hyperandrogenic women.
A group of 106 women of reproductive age with laboratory and clinical evidence of hyperandrogenism was treated with prednisone. The daily dosage varied between 7.5 and 10 mg. Ovulatory activity was assessed prior to and during therapy by basal body temperature and observation of changes in the cervical os and cervical mucus. Plasma testosterone levels were significantly suppressed by prednisone therapy. This was associated with initiation of ovulatory activity in 5 of 14 (35.7%) amenorrheic patients and 10 of 11 (90.9%) anovulatory patients. In 81 ovulatory patients, prednisone therapy resulted in statistically significant shortening of the follicular phase and lengthening of the luteal phase of the menstrual cycle. The mean length of the menstrual cycle was unchanged. Significant correlations between percentage suppression of plasma testosterone and shortening of the follicular phase or lengthening of the luteal phase were observed. Suppression of plasma testosterone by prednisone was maximal after 2 months of treatment, while the effect on the phases of the menstrual cycle was progressive with duration of treatment. The effects of prednisone at daily dosages of 7.5 or 10 mg were not significantly different. These results suggest that prednisone therapy in hyperandrogenic women exerts an effect on both phases of the menstrual cycle, possibly related to suppression of plasma testosterone levels.


Breast-conserving therapy in the management of early stage breast cancer: Our experience in 103 cases.
The aim of this study is to determine whether our results in breastconserving therapy of 103 patients with earlystage breast cancer are comparable to those of other facilities or not. From January 1990 to October 1999, 103 patients with earlystage breast cancer were treated by breastconserving surgery and whole breast irradiation. All patients were of Stages I or II, and the greatest dimensions of primary tumor were less than 3 cm. The median followup time was 47 months from the completion of postoperative radiotherapy. Local, regional and distant failure rates, and survival rate were presumed using the KaplanMeyer method. One patient suffered from local recurrence 30 months later. She was followed by simple mastectomy and kept from further recurrence. No regional relapse occurred. Distant metastases were seen in three patients:two patients in bones, and one patient in a bone and the liver after 19, 35, and 32 months, respectively. One patient died from disseminated cancer in 41 months. Only one patient died due to intercurrent disease. Both 5year and 10year diseasefree survival rates were 94.2%, and both 5year and 10year causespecific survival rates were 98.3%. Our results were comparable to previously reported data. In this stage although the followup time was too short to define the longterm outcome, it suggested that breast conserving therapy was acceptable and effective in the management of earlystage breast cancer.


YBYRÁ facilitates comparison of large phylogenetic trees.
The number and size of tree topologies that are being compared by phylogenetic systematists is increasing due to technological advancements in high-throughput DNA sequencing. However, we still lack tools to facilitate comparison among phylogenetic trees with a large number of terminals. The "YBYRÁ" project integrates software solutions for data analysis in phylogenetics. It comprises tools for (1) topological distance calculation based on the number of shared splits or clades, (2) sensitivity analysis and automatic generation of sensitivity plots and (3) clade diagnoses based on different categories of synapomorphies. YBYRÁ also provides (4) an original framework to facilitate the search for potential rogue taxa based on how much they affect average matching split distances (using MSdist). YBYRÁ facilitates comparison of large phylogenetic trees and outperforms competing software in terms of usability and time efficiency, specially for large data sets. The programs that comprises this toolkit are written in Python, hence they do not require installation and have minimum dependencies. The entire project is available under an open-source licence at http://www.ib.usp.br/grant/anfibios/researchSoftware.html .


MiR-15a/16 Regulates Apoptosis of Lung Epithelial Cells after Oxidative Stress.
Lung epithelial cell apoptosis is an important feature of hyperoxia-induced lung injury. Death receptor-associated extrinsic pathway and mitochondria-associated intrinsic pathway both mediate the development of lung epithelial cell apoptosis. Despite decades of research, molecular mechanisms of hyperoxia-induced epithelial cell apoptosis remain incompletely understood. Here we report a novel regulatory paradigm in response to hyperoxia-associated oxidative stress. Hyperoxia markedly up-regulated miR-15a/16 levels in lung epithelial cells, broncho-alveolar lavage fluid (BALF) and lung tissue. This effect was mediated by hyperoxia-induced reactive oxygen species (ROS). Functionally, miR-15a/16 inhibitors induced caspase 3-mediated lung epithelial cell apoptosis, in the presence of hyperoxia. MiR-15a/16 inhibitors robustly enhanced FADD level and down-regulated Bcl-2 expression. Consistently, cleaved caspase 8 and 9 were highly induced in the miR-15a/16 deficient cells, after hyperoxia. Using airway epithelial cell specific, miR-15a/16-/- mice, we found that Bcl-2 significantly reduced in lung epithelial cells in vivo after hyperoxia. In contrast, caspase 3, 8 and Bcl-2 associated death promoter (BAD) were highly elevated in the miR-15a/16-/- epithelial cells in vivo. Interestingly, in lung epithelial malignant cells, rather than benign cells, deletion of miR-15a/16 prevented apoptosis. Furthermore, deletion of miR-15a/16 in macrophages also prohibited apoptosis, opposite to what we have found in normal lung epithelial cells. Taken together, our data suggested that miR-15a/16 may exert differential roles in different cell types. MiR-15a/16 deficiency result in lung epithelial cell apoptosis in response to hyperoxia, via modulating both intrinsic and extrinsic apoptosis pathways.


Generation of a non-integrated induced pluripotent stem cell line (SMBCi009-A) from urine-derived cells of a Chinese Familial hypercholesterolemia patient.
Familial hypercholesterolemia (FH; OMIM: # 143890) is a common inherited autosomal dominant disease, characterized by high-level low-density lipoprotein cholesterol (LDL-C) in plasma. Elevated LDL-C levels is closely related with atherosclerotic plaques and premature cardiovascular disease if not treated in time. Here we generated an induced pluripotent stem cell (iPSC) line using urine cells (UCs) derived from an 8-year-old male FH patient who carrying two coding and pathogenic mutations of low-density lipoprotein receptor (LDLR) gene (exon12:c.C1747T and exon13: c. 1948 del G). This induced pluripotent stem cell line named SMBCi009-A can be used to understand more cellular details about FH.


Influence of cerclages on primary stability of tumor megaprostheses subjected to distal femur defects.
Purpose of this experimental study was to investigate the influence of cerclages on the primary stability of the MUTARS system using distally fractured synthetic femora. 4 MUTARS prostheses were implanted in synthetic femora respectively. Groups consisted of 4 intact bones, 4 fractured with cerclages and 4 fractured bones without cerclages. Spatial micromovements were measured with a high-precision rotational setup. The order from the weakest to the strongest torque transmission of the intact bones was rm1-rm4-rm2-rm3 (p=0.011) and of the fractured bones with cerclages rm4-rm1-rm3-rm2 (p=0.013). The MUTARS stems broke out of the fractured femoral shaft by removing cerclages (p<0.001) and by the influence of bone defect A (p<0.001). Overall micromovements of the intact bones were lower than those of the fractured bones without cerclages (p<0.001) and overall micromovements of the fractured bones with cerclages were lower than those of bones without cerclages (p<0.001). Due to high press-fit at the proximal and distal isthmus region fissural fractures of the femur may occur. This should always be taken into account. It is advisable to secure them and provide a prophylaxis for these fissural fractures by means of cerclages.


Correlation between volumetric CT imaging and autopsy measurements of glioblastoma size.
A three-dimensional reconstruction and display technique (THREAD SYSTEM) for serial computed tomography (CT) was employed in monitoring tumor volumes in two children under chemotherapy for glioblastoma multiforme of the cerebral hemispheres. Progressive diminution of tumor bulk was documented in the first patient and an increase in volume in the second. The first patient expired of the complications of his therapy and the second of transtentorial herniation. Independent measurements of the tumors as determined by a CT scan near the times of death and tumor dimensions measured at autopsy revealed good correlations between the radiographic and the anatomical data. The final CT measurement of tumor volume of 20 cm3 compared with an autopsy calculation of 13.3 cm3 in the first case. In the second case, CT volume was 417 cm3 and the actual volume of the primary tumor mass at autopsy was 437 cm3. The results suggest that the THREAD system is a practical method for monitoring the results of radiotherapy and chemotherapy in certain types of cerebral neoplasms.


Influence of peripheral arterial occlusive disease on muscular metabolism. Part 2: Changes in pyruvate, alanine, and urea concentration in femoral blood.
The metabolites pyruvate, alanine and urea were determined under resting conditions in blood from the femoral artery, femoral vein and cubital vein of 23 patients with stage II, 10 patients and 20 diabetics with stage IV PAOD as well as 19 healthy volunteers. Measurements were also carried out immediately and 20 min after ergometric calf exercise in the patients with stage II PAOD and the controls. In both patient groups with stage IV PAOD, there were lower arterial and venous alanine levels and higher urea concentrations at rest than in patients with adequate resting circulation, which is evidence for increased hepatic alanine extraction. After exercise, a significantly higher increase in the arteriovenous difference of pyruvate concentration was to be found in the patient group with stage II PAOD than in the control group. Moreover, there was a significant increase in femoral venous concentration and a rise in the arteriovenous difference of alanine, indicating muscular release, only in the PAOD patients and not in the volunteers in spite of a three times higher exercise load. The exercise-induced rise in femoral venous alanine correlated closely with those of pyruvate and ammonia. Alanine formation fulfills the function of a non-toxic carrier of muscularly produced amino groups and represents in PAOD a compensating mechanism that delays the limitation of muscular contractility. Alanine determination, especially in association with an exercise test, appears to be suitable for assessing the extent of anaerobic energy production in muscles of limbs affected by PAOD.


Speculative strategies for new antibacterials: all roads should not lead to Rome.
In concert with improvements in personal hygiene and public sanitation, the discovery and development of antibiotics during the latter half of the last century has reduced substantially the morbidity and mortality associated with bacterial diseases. However, the past decade has witnessed a sharp reduction in interest in antibacterial drug development by 'big pharma', compounded by a decline in the breadth of chemical space for new antibacterial molecules and a failure to exploit the plethora of cellular processes potentially targetable by novel classes of antibacterial molecules. This review focuses on some strategies relating to antibacterial chemotherapy, paths less trodden, which the author considers worthy of further exploration.


Effects of prostaglandins on the action of luteinizing hormone in dispersed rat intestitial cells.
Prostaglandins E1, E2, A1 and A2 at 10(-5) and 10(-4)M stimulated basal testosterone production in dispersed rat interstitial cells in vitro. They effectively inhibited steroidogenesis induced by ovine pituitary luteinizing hormone (LH) (0.2 nM), dibutyryl cyclic AMP-(DBC 0-5 mM), and cholera toxin (100 ng). PGF2 alpha (10(-3) to 10(-12)M) had no effect on either basal or hormonal or non-hormonal stimulated steroidogenesis in the cells. PGA1 and PGA2 were more effective inhibitors than PGE1 and E2. None of the PG's had any influence on 125I LH-receptor interaction. In view of this and the inhibition of DBC stimulated testosterone production, it may be suggested that the PG inhibition lies beyond the receptor-cyclic AMP formation step.


A case of Mycobacterium avium complex infection in an immunocompetent man presenting with pericarditis and an HRCT pattern of lymphangitis.
Non-tuberculous mycobacterial infections are rare in immunocompetent subjects. We describe the case of a 47-year-old previously healthy man with a Mycobacterium avium complex infection presenting with acute pericarditis and an atypical radiological pattern of lymphangitis.


Modified Bethesda system informing cytopathologic adequacy improves malignancy risk stratification in nodules considered benign or atypia(follicular lesion) of undetermined significance.
We modified the nondiagnostic/unsatisfactory category of the Bethesda system for reporting thyroid cytopathology to inform cytopathologic adequacy to better stratify the malignancy risk. Malignancy rates from 1,450 cytopathologic specimens not satisfying adequacy criteria from April 2011 to March 2016 were calculated based on sub-classification of the nondiagnostic/unsatisfactory category and sonographic patterns using matched surgical pathology. Rates were compared with those of 1,446 corresponding adequate specimens from July to December 2013. Upon resection, 63.2% of nondiagnostic, 36.7% of unsatisfactory + benign, 72.5% of unsatisfactory + atypia (follicular lesion) of undetermined significance, 98.1% of unsatisfactory + suspicious for malignancy, and 100.0% of unsatisfactory + malignant cases were confirmed to be malignant on surgical pathology. In nodules with inadequate specimens, those with high suspicion sonographic patterns had a malignancy rate (93.2%) higher than the others (45.5%) (p < 0.001). Nodules with unsatisfactory + benign specimens had a higher malignancy rate (36.7%) than satisfactory benign specimens (14.3%) (p = 0.020). For atypia (follicular lesion) of undetermined significance, the malignancy rate of inadequate specimens (72.5%) was higher than that of adequate specimens (51.3%) (p = 0.027). Sparse cellular samples with a few groups of benign follicular cells should not represent a benign lesion. There might be value in qualifying atypia (follicular lesion) of undetermined significance cases less than optimal.


Working with young adults with Type 1 diabetes: views of a multidisciplinary care team and implications for service delivery.
Young adults with Type 1 diabetes experience difficulties achieving glucose targets. Clinic attendance can be poor, although health and self-care tend to be better among those who attend regularly. Our aims were to describe staff views about challenges working with this age-group (16-21 years). Semistructured interviews were conducted with 14 staff from Sheffield Teaching Hospitals diabetes care team. Interviews were audio-recorded, transcribed and analysed using thematic analysis. Three main themes emerged. Unique challenges working with young adults included staff emotional burden, the low priority given to self-care by young adults and the complexity of the diabetes regimen. Working in a multidisciplinary team was complicated by differences in consultation styles, poor team cohesion and communication. An ideal service should include psychological support for the professional team, identification of key workers, and development of individualized care plans. Staff differed in their views about how to achieve optimal management for young adults, but emphasized the need for greater patient-centred care and a range of interventions appropriate for individual levels of need. They also wanted to increase their own skills and confidence working with this age-group. While these results reflect the views of staff working in only one diabetes centre, they are likely to reflect the views of professionals delivering care to individuals of this age; replication is needed to determine their generalizability.


NMR structure of a heterodimeric SAM:SAM complex: characterization and manipulation of EphA2 binding reveal new cellular functions of SHIP2.
The sterile alpha motif (SAM) for protein-protein interactions is encountered in over 200 proteins, but the structural basis for its interactions is just becoming clear. Here we solved the structure of the EphA2-SHIP2 SAM:SAM heterodimeric complex by use of NMR restraints from chemical shift perturbations, NOE and RDC experiments. Specific contacts between the protein surfaces differ significantly from a previous model and other SAM:SAM complexes. Molecular dynamics and docking simulations indicate fluctuations in the complex toward alternate, higher energy conformations. The interface suggests that EphA family members bind to SHIP2 SAM, whereas EphB members may not; correspondingly, we demonstrate binding of EphA1, but not of EphB2, to SHIP2. A variant of EphB2 SAM was designed that binds SHIP2. Functional characterization of a mutant EphA2 compromised in SHIP2 binding reveals two previously unrecognized functions of SHIP2 in suppressing ligand-induced activation of EphA2 and in promoting receptor coordinated chemotactic cell migration.


Standards of scoring, monitoring, and parameter targeting in German neurocritical care units: a national survey.
Optimal management of physiological parameters in neurological/neurosurgical intensive care units (NICUs) is largely unclear as high-quality evidence is lacking. The aim of this survey was to investigate if standards exist in the use of clinical scores, systemic and cerebral monitoring and the targeting of physiology values and in what way this affects clinical management in German NICUs. National survey, on-line anonymized questionnaire. German departments stating to run a neurological, neurosurgical or interdisciplinary neurological/neurosurgical intensive care unit were identified by a web-based search of all German hospitals and contacted via email. Responses from 78 German NICUs were obtained. Of 19 proposed clinical/laboratory/radiological scores only 5 were used regularly by >60 %. Bedside neuromonitoring (NM) predominantly consisted of transcranial Doppler sonography (94 %), electroencephalography (92 %) and measurement of intracranial pressure (ICP) (90 %), and was installed if patients had or were threatened by elevated ICP (86 %), had specific diseases like subarachnoid hemorrhage (51 %) or were comatose (35 %). Although mean trigger values for interventions complied with guidelines or wide-spread customs, individual trigger values varied widely, e.g., for hyperglycemia (maximum blood glucose between 120 and 250 mg/dl) or for anemia (minimum hemoglobin values between 5 and 10 g/dl). Although apparently aiming for standardization in neurocritical care, German NICUs show substantial differences in NM and monitoring-associated interventions. In terms of scoring and monitoring methods, German NICUs seem to be quite conservative. These survey results suggest a need of prospective and randomized interventional trials in neurocritical care to help define standards and target values.


Excitation energy dependence for the Li 1s X-ray photoelectron spectra of LiMn2O4.
The Li 1s XPS (X-ray Photoelectron Spectroscopy) spectra of LiMn2O4, which is one of the major positive-electrode materials in lithium-ion rechargeable batteries, and MnO2 as a reference material, were measured by a laboratory-type XPS spectrometer. The Li 1s peak was not observed in the spectra excited by the Mg Kalpha line (1253.6 eV), because the Li 1s peak overlapped the background of the Mn 3p peak of LiMn2O4. The photoionization cross section of Mn 3p was larger than that of Li 1s for Mg Kalpha excitation. Therefore, the XPS measurement of LiMn2O4 by soft X-ray synchrotron excitation was carried out at beamline BL-7B on NewSUBARU synchrotron facility. Excitation energies of 110, 120, 130, 140, 150 and 151.4 eV were selected. The Li 1s peak was clearly observed in these XPS spectra. In order to investigate the excitation energy dependence, the area ratio of the Li 1s and Mn 3p peaks in the XPS spectra was plotted against the excitation energy. As a result, when the excitation energy was 110 eV, the area ratio had the maximum value.


Low resolution structural characterization of the Hsp70-interacting protein - Hip - from Leishmania braziliensis emphasizes its high asymmetry.
The Hsp70 is an essential molecular chaperone in protein metabolism since it acts as a pivot with other molecular chaperone families. Several co-chaperones act as regulators of the Hsp70 action cycle, as for instance Hip (Hsp70-interacting protein). Hip is a tetratricopeptide repeat protein (TPR) that interacts with the ATPase domain in the Hsp70-ADP state, stabilizing it and preventing substrate dissociation. Molecular chaperones from protozoans, which can cause some neglected diseases, are poorly studied in terms of structure and function. Here, we investigated the structural features of Hip from the protozoa Leishmania braziliensis (LbHip), one of the causative agents of the leishmaniasis disease. LbHip was heterologously expressed and purified in the folded state, as attested by circular dichroism and intrinsic fluorescence emission techniques. LbHip forms an elongated dimer, as observed by analytical gel filtration chromatography, analytical ultracentrifugation and small angle X-ray scattering (SAXS). With the SAXS data a low resolution model was reconstructed, which shed light on the structure of this protein, emphasizing its elongated shape and suggesting its domain organization. We also investigated the chemical-induced unfolding behavior of LbHip and two transitions were observed. The first transition was related to the unfolding of the TPR domain of each protomer and the second transition of the dimer dissociation. Altogether, LbHip presents a similar structure to mammalian Hip, despite their low level of conservation, suggesting that this class of eukaryotic protein may use a similar mechanism of action.


Beta-propeller crystal structure of Psathyrella velutina lectin: an integrin-like fungal protein interacting with monosaccharides and calcium.
The lectin from the mushroom Psathyrella velutina recognises specifically N-acetylglucosamine and N-acetylneuraminic acid containing glycans. The crystal structure of the 401 amino acid residue lectin shows that it adopts a very regular seven-bladed beta-propeller fold with the N-terminal region tucked into the central cavity around the pseudo 7-fold axis. In the complex with N-acetylglucosamine, six monosaccharides are bound in pockets located between two consecutive propeller blades. Due to the repeats shown by the sequence the binding sites are very similar. Five hydrogen bonds between the protein and the sugar hydroxyl and N-acetyl groups stabilize the complex, together with the hydrophobic interactions with a conserved tyrosine and histidine. The complex with N-acetylneuraminic acid shows molecular mimicry with the same hydrogen bond network, but with different orientations of the carbohydrate ring in the binding site. The beta-hairpin loops connecting the two inner beta-strands of each blade are metal binding sites and two to three calcium ions were located in the structure. The multispecificity and high multivalency of this mushroom lectin, combined with its similarity to the extracellular domain of an important class of cell adhesion molecules, integrins, are another example of the outstanding success of beta-propeller structures as molecular binding machines in nature.