Πέμπτη 7 Φεβρουαρίου 2019

Characterization of functional subgroups among genetically identified cholinergic neurons in the pedunculopontine nucleus

Abstract

The pedunculopontine nucleus (PPN) is a part of the reticular activating system which is composed of cholinergic, glutamatergic and GABAergic neurons. Early electrophysiological studies characterized and grouped PPN neurons based on certain functional properties (i.e., the presence or absence of the A-current, spike latency, and low threshold spikes). Although other electrophysiological characteristics of these neurons were also described (as high threshold membrane potential oscillations, great differences in spontaneous firing rate and the presence or absence of the M-current), systematic assessment of these properties and correlation of them with morphological markers are still missing. In this work, we conducted electrophysiological experiments on brain slices of genetically identified cholinergic neurons in the PPN. Electrophysiological properties were compared with rostrocaudal location of the neuronal soma and selected morphometric features obtained with post hoc reconstruction. We found that functional subgroups had different proportions in the rostral and caudal subregions of the nucleus. Neurons with A-current can be divided to early-firing and late-firing neurons, where the latter type was found exclusively in the caudal subregion. Similar to this, different parameters of high threshold membrane potential oscillations also showed characteristic rostrocaudal distribution. Furthermore, based on our data, we propose that high threshold oscillations rather emerge from neuronal somata and not from the proximal dendrites. In summary, we demonstrated the existence and spatial distribution of functional subgroups of genetically identified PPN cholinergic neurons, which are in accordance with differences found in projection and in vivo functional findings of the subregions. Being aware of functional differences of PPN subregions will help the design and analysis of experiments using genetically encoded opto- and chemogenetic markers for in vivo experiments.



http://bit.ly/2t8Y8Kk

TGF-β signaling pathway mediated by deubiquitinating enzymes

Abstract

Ubiquitination is a reversible cellular process mediated by ubiquitin-conjugating enzymes, whereas deubiquitinating enzymes (DUBs) detach the covalently conjugated ubiquitin from target substrates to counter ubiquitination. DUBs play a crucial role in regulating various signal transduction pathways and biological processes including apoptosis, cell proliferation, DNA damage repair, metastasis, differentiation, etc. Since the transforming growth factor-β (TGF-β) signaling pathway participates in various cellular functions such as inflammation, metastasis and embryogenesis, aberrant regulation of TGF-β signaling induces abnormal cellular functions resulting in numerous diseases. This review focuses on DUBs regulating the TGF-β signaling pathway. We discuss the molecular mechanisms of DUBs involved in TGF-β signaling pathway, and biological and therapeutic implications for various diseases.



http://bit.ly/2tbsbkD

Developmental and functional characteristics of the thoracic aorta perivascular adipocyte

Abstract

Thoracic aorta perivascular adipose tissue (T-PVAT) has critical roles in regulating vascular homeostasis. However, the developmental characteristics and cellular lineage of adipocyte in the T-PVAT remain unclear. We show that T-PVAT contains three long strip-shaped fat depots, anterior T-PVAT (A-T-PVAT), left lateral T-PVAT (LL-T-PVAT), and right lateral T-PVAT (RL-T-PVAT). A-T-PVAT displays a distinct transcriptional profile and developmental origin compared to the two lateral T-PVATs (L-T-PVAT). Lineage tracing studies indicate that A-T-PVAT adipocytes are primarily derived from SM22α+ progenitors, whereas L-T-PVAT contains both SM22α+ and Myf5+ cells. We also show that L-T-PVAT contains more UCP1+ brown adipocytes than A-T-PVAT, and L-T-PVAT exerts a greater relaxing effect on aorta than A-T-PVAT. Angiotensin II-infused hypertensive mice display greater macrophage infiltration into A-T-PVAT than L-T-PVAT. These combined results indicate that L-T-PVAT has a distinct development from A-T-PVAT with different cellular lineage, and suggest that L-T-PVAT and A-T-PVAT have different physiological and pathological functions.



http://bit.ly/2t9Ileh

Comprehensive review on how platinum- and taxane-based chemotherapy of ovarian cancer affects biology of normal cells

Abstract

One of the most neglected aspects of chemotherapy are changes, and possible consequences of these changes, that occur in normal somatic cells. In this review, we summarize effects of selected drugs used to treat ovarian cancer (platin derivatives—cisplatin and carboplatin; and taxanes—paclitaxel and docetaxel) on cellular metabolism, acquisition of reactive stroma features, cellular senescence, inflammatory reactions, apoptosis, autophagy, mitophagy, oxidative stress, DNA damage, and angiogenesis in various types of normal cells, including fibroblasts, epithelial cells, endothelial cells, and neurons. The activity of these drugs against the normal cells is presented from a broader perspective of their desirable anti-tumoral effects.



http://bit.ly/2ULGlEI

Identification of CD36 as a new interaction partner of membrane NEU1: potential implication in the pro-atherogenic effects of the elastin receptor complex

Abstract

In addition to its critical role in lysosomes for catabolism of sialoglycoconjugates, NEU1 is expressed at the plasma membrane and regulates a myriad of receptors by desialylation, playing a key role in many pathophysiological processes. Here, we developed a proteomic approach dedicated to the purification and identification by LC–MS/MS of plasma membrane NEU1 interaction partners in human macrophages. Already known interaction partners were identified as well as several new candidates such as the class B scavenger receptor CD36. Interaction between NEU1 and CD36 was confirmed by complementary approaches. We showed that elastin-derived peptides (EDP) desialylate CD36 and that this effect was blocked by the V14 peptide, which blocks the interaction between bioactive EDP and the elastin receptor complex (ERC). Importantly, EDP also increased the uptake of oxidized LDL by macrophages that is blocked by both the V14 peptide and the sialidase inhibitor 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA). These results demonstrate, for the first time, that binding of EDP to the ERC indirectly modulates CD36 sialylation level and regulates oxidized LDL uptake through this sialidase. These effects could contribute to the previously reported proatherogenic role of EDP and add a new dimension in the regulation of biological processes through NEU1.



http://bit.ly/2UNLQ5U

Revisiting Dscam diversity: lessons from clustered protocadherins

Abstract

The complexity of neuronal wiring relies on the extraordinary recognition diversity of cell surface molecules. Drosophila Dscam1 and vertebrate clustered protocadherins (Pcdhs) are two classic examples of the striking diversity from a complex genomic locus, wherein the former encodes more than 10,000 distinct isoforms via alternative splicing, while the latter employs alternative promoters to attain isoform diversity. These structurally unrelated families show remarkably striking molecular parallels and even similar functions. Recent studies revealed a novel Dscam gene family with tandemly arrayed 5′ cassettes in Chelicerata (e.g., the scorpion Mesobuthus martensii and the tick Ixodes scapularis), similar to vertebrate clustered Pcdhs. Likewise, octopus shows a more remarkable expansion of the Pcdh isoform repertoire than human. These discoveries of Dscam and Pcdh diversification reshape the evolutionary landscape of recognition molecule diversity and provide a greater understanding of convergent molecular strategies for isoform diversity. This article reviews new insights into the evolution, regulatory mechanisms, and functions of Dscam and Pcdh isoform diversity. In particular, the convergence of clustered Dscams and Pcdhs is highlighted.



http://bit.ly/2UPHco5

How toll-like receptors reveal monocyte plasticity: the cutting edge of antiinflammatory therapy

Abstract

Toll-like receptors (TLR)s are central in immune response by recognizing pathogen-associated molecular patterns (PAMP)s. If they are essential to eliminate pathogens in earlier stages of infection, they also might play a role in homeostasis and tissue repair. TLR versatility parallels the plasticity of monocytes, which represent an heterogeneous population of immune cells. They are rapidly recruited to sites of infection and involved in clearance of pathogens and in tissue healing. This review underlines how TLRs have proved to be an interesting tool to study the properties of monocytes and why different therapeutic strategies exploring monocyte plasticity may be relevant in the context of chronic inflammatory disorders.



http://bit.ly/2UPzg6m

Pathological effects of ionizing radiation: endothelial activation and dysfunction

Abstract

The endothelium, a tissue that forms a single layer of cells lining various organs and cavities of the body, especially the heart and blood as well as lymphatic vessels, plays a complex role in vascular biology. It contributes to key aspects of vascular homeostasis and is also involved in pathophysiological processes, such as thrombosis, inflammation, and hypertension. Epidemiological data show that high doses of ionizing radiation lead to cardiovascular disease over time. The aim of this review is to summarize the current knowledge on endothelial cell activation and dysfunction after ionizing radiation exposure as a central feature preceding the development of cardiovascular diseases.



http://bit.ly/2tbsdcf

Attenuation of Sepsis-Induced Cardiomyopathy by Regulation of MicroRNA-23b Is Mediated Through Targeting of MyD88-Mediated NF-κB Activation

Abstract

Myocardial cell injury or cardiomyopathy is associated with excessive inflammatory response and apoptosis of cardiac myocytes during sepsis. MicroRNA-23b (miR-23b) is a multifunctional miRNA that is considered to regulate immunosuppression in sepsis. The aim of this study was to examine the effect of miR-23b on cardiomyopathy induced by sepsis and to explore the potential mechanism involved. Sprague-Dawley rats were subjected to cecal ligation and puncture (CLP), and the level of miR-23b at different time points was measured by quantitative real-time polymerase chain reaction (qPCR). Then, we overexpressed miR-23b in vivo and in vitro. The rats were subjected to CLP 7 days after transfection. Cardiac function, inflammatory response, and heart tissues were examined 3 days thereafter. In an in vitro experiment, H9C2 cardiomyoblasts were stimulated with lipopolysaccharide (LPS) after transfection of miR-23b, following which apoptosis and the level of NF-κB were analyzed. The expression of miR-23b was upregulated during polymicrobial sepsis, and transfection of miR-23b lentivirus improved the outcome of sepsis-induced cardiomyopathy by attenuating inflammatory responses and protecting against histopathological damage. In in vitro experiments, elevated miR-23b inhibited excessive apoptosis of cardiomyocytes, which may be because activation of the NF-κB signaling pathway was inhibited by the decreased levels of TRAF6 and IKKβ. Therefore, miR-23b improved sepsis-induced cardiomyopathy by attenuating the inflammatory response, suppressing apoptosis, and preventing NF-κB activation via targeted inhibition of TRAF6 and IκκB. These results indicated that miR-23b may represent a novel therapeutic approach for clinical treatment of sepsis-induced cardiomyopathy.



http://bit.ly/2td5T20

Correction to: Schisandrin B Attenuates Inflammation in LPS-Induced Sepsis through miR-17-5p Downregulating TLR4



http://bit.ly/2UTEoX9

Evaluation and management of the child with hypothyroidism

Abstract

Background

Thyroid hormones are critical for early neurocognitive development as well as growth and development throughout childhood. Prompt recognition and treatment of hypothyroidism is, therefore, of utmost importance to optimize physical and neurodevelopmental outcomes.

Data sources

A PubMed search was completed in Clinical Queries using the key terms "hypothyroidism".

Results

Hypothyroidism may be present at birth (congenital hypothyroidism) or develop later in life (acquired hypothyroidism). Thyroid dysgenesis and dyshormonogenesis account for approximately 85% and 15% of permanent cases of congenital primary hypothyroidism, respectively. More than 95% of infants with congenital hypothyroidism have few, if any, clinical manifestations of hypothyroidism. Newborn screening programs allow early detection of congenital hypothyroidism. In developed countries, Hashimoto thyroiditis is the most common cause of goiter and acquired hypothyroidism in children and adolescents. Globally, iodine deficiency associated with goiter is the most common cause of hypothyroidism. Central hypothyroidism is uncommon and may be associated with other congenital syndromes and deficiencies of other pituitary hormones. Familiarity of the clinical features would allow prompt diagnosis and institution of treatment.

Conclusions

To optimize neurocognitive outcome in infants with congenital hypothyroidism, treatment with levothyroxine should be started as soon as possible, preferably within the first 2 weeks of life. Children with acquired hypothyroidism should also be treated early to ensure normal growth and development as well as cognitive outcome. The target is to keep serum TSH < 5 mIU/L and to maintain serum free T4 or total T4 within the upper half of the age-specific reference range, with elimination of all symptoms and signs of hypothyroidism.



http://bit.ly/2RKSbgE

Screening for Obstructive Sleep Apnea: Should We Do It?

Abstract

Purpose of Review

Obstructive sleep apnea (OSA) is prevalent and underdiagnosed. It is associated with significant comorbidities and early detection and treatment might lead to improvement in important clinical outcomes. This paper will review current evidence on screening for OSA in the primary care setting and in certain high-risk groups.

Recent Findings

The 2017 United States Preventative Services Taskforce evidence review on OSA screening noted a lack of high-quality evidence linking OSA screening with important clinical outcomes and on the accuracy of proposed screening tools.

Summary

OSA symptoms are usually not discussed in the primary care setting. A screening tool such as a questionnaire is a simple approach that could be easily implemented in this setting. Further study into the long-term cardiovascular and mortality benefits of the treatment of OSA, randomized controlled trials linking the implementation of screening and improvement in important clinical outcomes, and the accuracy of available screening tools as well as their generalizability to the primary care population is needed to improve the strength of their recommendation and their adoption.



http://bit.ly/2SEbYTi

Improving Adherence to PAP Therapy: an Update

Abstract

Purpose of Review

Positive airway pressure (PAP) therapy is the "gold standard" of treatment for obstructive sleep apnea; however, rates of non-adherence to PAP therapy remain high despite device improvements and the inclusion of PAP education programs in most comprehensive sleep disorders clinics. We aimed to review recent evidence-based trends for improving PAP adherence.

Recent Findings

Remote monitoring and telemedicine interventions in conjunction with mobile patient engagement applications have shown promise in facilitating uptake and maintenance of PAP use. New focus on the bedpartner dyad and managing comorbid conditions are also notable, though more recent evidence for specific interventions is limited.

Summary

Recent trends suggest a shift towards developing more patient-centered programs to support PAP adherence. Advancements in telemedicine and interactive mobile health technologies represent the most promising area of growth for PAP adherence interventions. Continued efforts focused on treatments that address socio-relational factors and comorbid conditions seem warranted.



http://bit.ly/2RMYZua

Evidence for M2 macrophage activation in patients with enthesitis-related arthritis category of juvenile idiopathic arthritis

Abstract

Recently, an increase in CD163+ macrophages in ileal biopsies from ankylosing spondylitis patients and an increase in intermediate monocytes in enthesitis-related arthritis (ERA) have been reported. Thus, we studied sCD163 levels as M2 macrophage marker in serum and synovial fluid (SF) of ERA children and CD163 expression on monocyte subsets. Serum samples from ERA patients and healthy controls (HC) were assayed for sCD163 (ELISA). Serum and SF from ERA patients were analyzed when available from same patient (paired samples). In 10 patients, the CD163 expression level was analyzed on monocyte subsets by flow cytometry. Results are expressed as median (interquartile range (IQR)). Sera from 85 patients, SF from 32 ERA patients, and serum from 46 HC were analyzed. The average age at inclusion was 16 ± 3.24 years and age at onset was 11.2 ± 2.79 years. Seventy-nine of them were boys and HLA-B27 was positive in 64/80 patients. The median serum sCD163 levels were higher in patients [1080 (1305.2) ng/ml] than HC [780 (812.5) ng/ml; p < 0.001]. The SF levels [9000 (1250) ng/ml] were much higher than serum [3800 (3287.66) ng/ml; p < 0.001]. Disease activity data was available in 56 patients. Mean tender joint count was 2 (3), swollen joint count was 2 (2), ESR was 70 (65) mm and CRP was 7.1 (8.9) mg/dl. Serum sCD163 levels correlated with SF but not with disease activity. Intermediate monocytes (CD14+CD16+) from ERA patients had higher CD163 expression than HC. Elevated sCD163 levels in ERA patient's sera and even higher levels in paired SF suggest towards activation of alternatively activated macrophages in ERA. Lack of correlation with activity may suggest that they have an immune-regulatory role in ERA.



http://bit.ly/2WXQMqS

Distribution of Mycelia of Morchella esculenta in Wild Field

Abstract

It was well-known that Morchella esculenta has a life cycle including vegetative hyphae, sclerotia, primordia, and fruiting bodies, but there is no report yet about the influence of mycelial mass on fruiting process. Since 2014, we have developed an ELISA method to detect the content of Morchella esculenta. In this study, we utilized this method to measure the mycelia content, and find the correlation between mycelial content and fruiting in the wild. The study demonstrated the changes of mycelial concentration at different location around fruiting spot.



http://bit.ly/2RNpgIw

Community-Level Physiological Profiling for Microbial Community Function in Broiler Ceca

Abstract

Poultry production is a major agricultural output worldwide. It is known that the gut health of broilers is essential for their growth and for providing wholesome products for human consumption. Previously, the microbial diversity of broiler ceca was studied at the genetic level. However, the functional diversity and metabolic activity of broiler cecal bacterial communities are not fully investigated. Recently, the EcoPlates™ from Biolog, Inc. have been used for characterizing bacterial communities from various environments. In this study, we applied these plates to physiologically profile cecal bacterial communities in broilers. The ceca were aseptically excised from 6-week-old broilers, and their contents were suspended in phosphate buffered saline. The cultures in the EcoPlates™ were incubated at 42 °C for 5 days in an OmniLog® system. Responses of the bacterial communities to the various chemicals as carbon sources were measured on formazan production. The results show sigmoidal growth curves with three phases in all 12 cecal samples. Cecal bacterial communities could not use 11 carbon substrates for carbon sources; instead, they used pyruvic acid methyl ester, glycogen, glucose-1-phosphate and N-acetyl-d-glucosamine most frequently. Each bacterial community metabolized various numbers of the substrates at different rates among broilers. In the future, modification of the culture conditions to mimic the gut environment is needed. More investigations on the effects of nutrients, Salmonella or Campylobacter on physiological functions of cecal bacterial communities will provide insights into the improvement of animal well-being, saving production expenditures for producers and providing safer poultry products for human consumption.



http://bit.ly/2WMhyCh

High-Dose Paraquat Induces Human Bronchial 16HBE Cell Death and Aggravates Acute Lung Intoxication in Mice by Regulating Keap1/p65/Nrf2 Signal Pathway

Abstract

Paraquat (PQ) intoxication seriously endangers human beings' health, however, the underlying mechanisms are still unclear. Here we found that PQ inhibits human bronchial 16HBE cell proliferation and promotes cell apoptosis, necrosis as well as ROS generation in a dose dependent manner. Of note, low-dose PQ (50 μM) induces cell autophagy, increases Nrf2 as well as p65 levels and has little impacts on Keap1, while high-dose PQ (500 μM) inhibits autophagy, upregulates Keap1 as well as downregulates p65 and Nrf2. In addition, we verified that p65 overexpression increases Nrf2 and its downstream targets in 16HBE cells, which are reversed by synergistically knocking down Nrf2. Our further results showed that high-dose PQ's effects on cell proliferation, apoptosis, ROS levels and autophagy are reversed by p65 overexpression. Besides, the protective effects of overexpressed p65 on high-dose PQ (500 μM) treated 16HBE cells are abrogated by synergistically knocking down Nrf2. In vivo experiments also showed that high-dose PQ promotes inflammatory cytokines secretion, lung fibrosis and cell apoptosis, inhibits cell proliferation in mice models by regulating Keap1/p65/Nrf2 signal pathway. Therefore, we concluded that high-dose PQ (500 μM) inhibits 16HBE cell proliferation and autophagy, promotes cell death and mice lung fibrosis by regulating Keap1/p65/Nrf2 signal pathway.



http://bit.ly/2UKwFu9

Use of FDA’s Sentinel System to Quantify Seizure Risk Immediately Following New Ranolazine Exposure

Abstract

Introduction

Neurological complications including seizures have been reported with ranolazine. We sought to quantify the risk of seizure-related hospitalizations or emergency department events following ranolazine exposure in the Sentinel System (2006–2015).

Study Design and Setting

Eligibility criteria were new use of ranolazine after 183 days washout period and absence of seizure diagnoses, anti-epileptic drugs, or seizure-related disorders during the baseline period.

Results

Among 52,155 ranolazine users, we identified 28 seizures in the 1–32 days after new ranolazine dispensing: 12 occurring in days 1–10 (high-risk window), 11 in days 11–20 (moderate-risk window) and 5 in the control window (days 21–32). Assuming an equal likelihood of seizure events across the 32-day observation window, we estimate an attributable risk of 0.9 excess cases per 10,000 exposed users. Using a self-controlled risk interval design with exact logistic regression, seizures were elevated in the high-risk window (relative risk [RR] 2.88 (95% confidence interval [CI] 1.01–8.33) compared with the control window. No significant increased risk was observed in the moderate window. Half of the seizure cases had a diagnosis of renal disease, although seizure risk was not significant (RR 3.20 [CI 0.82–14.01]). A majority of patients in both risk windows were 75 years or older.

Conclusion

Our study suggests risk among younger ranolazine patients is rare. Given the imprecision of the risk estimates, we interpret the elevated seizure risk following ranolazine exposure with caution. Further analysis in a larger elderly population is warranted.



http://bit.ly/2tcpYW8

Chronic hepatitis B viral infection among RA patients—a cross-sectional control study

Abstract

Background and objectives

Rheumatoid arthritis (RA) is the most common inflammatory joint disorder presenting also with extra-articular manifestations. As many other autoimmune diseases, it has been suggested that infectious diseases might contribute to its emergence. Hepatitis viruses were suggested by several reports as a trigger of RA onset. We aimed to assess the association between RA and chronic hepatitis B viral infection (HBV).

Methods

Patients with RA were compared with age- and sex-matched controls regarding the proportion of chronic HBV infection in a case-control study. The chi-square and t tests were used for univariate analysis, whereas a logistic regression model was used for multivariate analysis. The study was performed utilizing the medical database of Clalit Health Services.

Results

There was a significantly higher proportion of chronic HBV infection in RA patients compared with controls (1.19% vs 0.63%, respectively; p < 0.001). In a multivariate logistic regression analysis, RA was significantly associated with chronic HBV infection (OR = 1.89, 95%CI 1.55–2.29, p < 0.001).

Conclusions

Patients with RA have a greater proportion of chronic HBV infection than matched controls. Screening for HBV infection among RA patients may be warranted.



http://bit.ly/2tarqrQ

Delineation of proapoptotic signaling of anthracene-shelled M 2 L 4 metallacapsules and their synergistic activity with curcumin in cisplatin-sensitive and resistant tumor cell lines

Summary

Since the introduction of cisplatin into clinical practice a few decades ago, the topic of metal-based drugs has expanded significantly. Recent examples emphasize on metallosupramolecules as an emerging class of compounds with diverse properties. They can trigger unique cellular events in malignant cells or serve as molecular hosts for various biologically active compounds, including anticancer agents. The anthracene-shelled M2L4 coordination nanocapsules under research have already proved very high anticancer potency with remarkable selectivity and lack of cross-resistance. In this study, we provide an oncopharmacological evaluation of the Pt(II)- and Pd(II)-clipped M2L4 nanocapsules; we report a thorough analysis of their synergistic effects in combined treatments with the pleiotropic anticancer agent curcumin. We examined changes in cellular expression of several apoptosis-related proteins in a panel of tumor cell lines with different chemosensitivity towards cisplatin, i.e. HT-29, HL-60 and its resistant strains HL-60/CDDP and HL-60/Dox, in order to assess the molecular mechanisms of their antitumor activity The results of the immunoassay concluded activation of the mitochondrial apoptotic pathway in all the screened tumor lines. A prevalent modulation of the extrinsic apoptotic signaling cascade was observed in the chemoresistant variants. Curcumin interactions of the tested compounds were estimated against the cisplatin-refractory cell line HT-29 via the Chou-Talalay method (CTM), whereby the palladium species yielded superior synergistic activity as compared to their platinum analogues.



http://bit.ly/2TC0sVR

LEF1-AS1 contributes to proliferation and invasion through regulating miR-544a/ FOXP1 axis in lung cancer

Summary

Long non-coding RNAs (lncRNAs) are increasingly recognized as important regulators in tumor development. This study aims to investigate the potential role oflncRNALEF1-AS1, in the progression of lung cancer. Quantitative real-time PCR (qRT-PCR) and western blot assays showed that LEF1-AS1 was upregulated while miR-544a was downregulated in lung cancer specimens and cells. Overexpression of LEF1-AS1 led to the enhancement of cell proliferation and invasion, revealed by CCK-8 assay and transwell assay. A negative correlation was found between LEF1-AS1 and miR-544a. BLAST analysis and dual-luciferase assay confirmed that FOXP1 is a downstream effector of miR-544a. Therefore, the LEF1-AS1/miR-544a/FOXP1 axis is an important contributor to lung cancer progression. Collectively, our novel data uncovers a new mechanism that governs tumor progression in lung cancer and provides new targets that may be used for disease monitoring and therapeutic intervention of lung cancer.



http://bit.ly/2Bp7tlY

Delineation of proapoptotic signaling of anthracene-shelled M 2 L 4 metallacapsules and their synergistic activity with curcumin in cisplatin-sensitive and resistant tumor cell lines

Summary

Since the introduction of cisplatin into clinical practice a few decades ago, the topic of metal-based drugs has expanded significantly. Recent examples emphasize on metallosupramolecules as an emerging class of compounds with diverse properties. They can trigger unique cellular events in malignant cells or serve as molecular hosts for various biologically active compounds, including anticancer agents. The anthracene-shelled M2L4 coordination nanocapsules under research have already proved very high anticancer potency with remarkable selectivity and lack of cross-resistance. In this study, we provide an oncopharmacological evaluation of the Pt(II)- and Pd(II)-clipped M2L4 nanocapsules; we report a thorough analysis of their synergistic effects in combined treatments with the pleiotropic anticancer agent curcumin. We examined changes in cellular expression of several apoptosis-related proteins in a panel of tumor cell lines with different chemosensitivity towards cisplatin, i.e. HT-29, HL-60 and its resistant strains HL-60/CDDP and HL-60/Dox, in order to assess the molecular mechanisms of their antitumor activity The results of the immunoassay concluded activation of the mitochondrial apoptotic pathway in all the screened tumor lines. A prevalent modulation of the extrinsic apoptotic signaling cascade was observed in the chemoresistant variants. Curcumin interactions of the tested compounds were estimated against the cisplatin-refractory cell line HT-29 via the Chou-Talalay method (CTM), whereby the palladium species yielded superior synergistic activity as compared to their platinum analogues.



http://bit.ly/2TC0sVR

LEF1-AS1 contributes to proliferation and invasion through regulating miR-544a/ FOXP1 axis in lung cancer

Summary

Long non-coding RNAs (lncRNAs) are increasingly recognized as important regulators in tumor development. This study aims to investigate the potential role oflncRNALEF1-AS1, in the progression of lung cancer. Quantitative real-time PCR (qRT-PCR) and western blot assays showed that LEF1-AS1 was upregulated while miR-544a was downregulated in lung cancer specimens and cells. Overexpression of LEF1-AS1 led to the enhancement of cell proliferation and invasion, revealed by CCK-8 assay and transwell assay. A negative correlation was found between LEF1-AS1 and miR-544a. BLAST analysis and dual-luciferase assay confirmed that FOXP1 is a downstream effector of miR-544a. Therefore, the LEF1-AS1/miR-544a/FOXP1 axis is an important contributor to lung cancer progression. Collectively, our novel data uncovers a new mechanism that governs tumor progression in lung cancer and provides new targets that may be used for disease monitoring and therapeutic intervention of lung cancer.



http://bit.ly/2Bp7tlY

Idiopathic pulmonary fibrosis: prognostic impact of histologic honeycombing in transbronchial lung cryobiopsy

Abstract

Background

Prognostic evaluation in idiopathic pulmonary fibrosis (IPF) may be important as it can guide management decisions, but the potential role of honeycomb changes in providing information about outcome and survival of patients with IPF, particularly if diagnosed using cryobiopsy, has not been evaluated. Aim of this study was to determinate whether a relationship exists between honeycombing on cryobiopsy and clinical/radiological picture and outcome in patients with IPF and to assess whether the same pathologic criteria that have been used to define the UIP pattern (usual interstitial pneumonia) for surgical biopsy can also be applied to cryobiopsy.

Methods

Sixty-three subjects with a multidisciplinary diagnosis of IPF and a UIP pattern on cryobiopsy were evaluated. Patients were classified into two sub-groups depending on the presence of honeycombing on histology.

Results

The presence of honeycombing on cryobiopsy did not identify a specific phenotype of patients as it did not correlate with radiological and clinical picture and it was not associated neither with the risk of death (p = 0.1192) or with the event-free survival (p = 0.827); a higher number of samples and the presence of pleura on biopsy were instead associated with an increase in the finding of honeycombing.

Conclusions

The same pathologic criteria that have been used to define the UIP pattern in surgical biopsies (with honeycombing changes considered as non-mandatory for the definition of the pattern itself) can be applied to cryobiopsy samples, as the presence of these changes do not define different clinical or radiological phenotypes of patients with IPF.



http://bit.ly/2Giv2AE

Biocontrol of Brettanomyces/Dekkera bruxellensis in alcoholic fermentations using saccharomycin-overproducing Saccharomyces cerevisiae strains

Abstract

Microbial contamination of alcoholic fermentation processes (e.g. winemaking and fuel-ethanol production) is a serious problem for the industry since it may render the product unacceptable and/or reduce its productivity, leading to large economic losses. Brettanomyces/Dekkera bruxellensis is one of the most dangerous microbial contaminant of ethanol industrial fermentations. In the case of wine, this yeast species can produce phenolic compounds that confer off-flavours to the final product. In fuel-ethanol fermentations, D. bruxellensis is a persistent contaminant that affects ethanol yields and productivities. We recently found that Saccharomyces cerevisiae secretes a biocide, which we named saccharomycin, composed of antimicrobial peptides (AMPs) derived from the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Saccharomycin is active against several wine-related yeast species, namely D. bruxellensis. However, the levels of saccharomycin naturally secreted by S. cerevisiae during alcoholic fermentation are not sufficient to ensure the complete death of D. bruxellensis. Therefore, the aim of the present work was to construct genetically modified S. cerevisiae strains to overproduce these GAPDH-derived AMPs. The expression levels of the nucleotides sequences encoding the AMPs were evaluated in the modified S. cerevisiae strains by RT-qPCR, confirming the success of the recombinant approach. Furthermore, we confirmed by immunological tests that the modified S. cerevisiae strains secreted higher amounts of the AMPs by comparison with the non-modified strain, inducing total death of D. bruxellensis during alcoholic fermentations.



http://bit.ly/2ShjSmg

An approach based on mixed hierarchical clustering and optimization for graph analysis in social media network: toward globally hierarchical community structure

Abstract

As the massive size of contemporary social networks poses a serious challenge to the scalability of traditional graph clustering algorithms and the evaluation of discovered communities, we develop, in this manuscript, an approach used to discover hierarchical community structure in large networks. The introduced hybrid technique combines the strengths of bottom-up hierarchical clustering method with that of top-down hierarchical clustering. In fact, the first approach is efficient in identifying small clusters, while the second one is good at determining large ones. Our mixed hierarchical clustering technique, based on the assumption that there exists an initial solution composed of k classes and the combination of the two previously mentioned methods, does not the change of the number of partitions, modifies the repartition of the initial classes. At the end of the introduced clustering process, a fixed point, representing a local optimum of the cost function which measures the degree of importance between two partitions, is obtained. Consequently, the introduced combined model leads to the emergence of local community structure. To avoid this local optimum and detect community structure converged to the global optimum of the cost function, the detection of community structures, in this study, is not considered only as a clustering problem, but as an optimization issue. Besides, a novel mixed hierarchical clustering algorithm based on swarms intelligence is suggested for identifying community structures in social networks. In order to validate the proposed method, performances of the introduced approach are evaluated using both real and artificial networks as well as internal and external clustering evaluation criteria.



http://bit.ly/2Gg5KDk

Climate change adaptation, social capital, and the performance of polycentric governance institutions

Abstract

How do patterns of interactions among policy actors shape their ability to contribute to climate change adaptation decision-making processes in fragmented regional governance settings? We address this question through statistical models of adaptation policy actors' assessments of access to scientific/technical information as well as their perceptions of cooperation and procedural fairness across numerous adaptation decision-making processes operating in the Lake Victoria region, East Africa. We measured actors' collaborative interactions as well as their participation in task forces, steering committees, and other policy forums that have emerged in response to the challenges of building adaptive capacity to the effects of climate change in the region. Because information access, cooperation, and procedural fairness are shaped by social processes, we tested how the performance of policy forums varied according to different measures of social capital. Specifically, we distinguished between bridging social capital (the value of relationships that span or broker between distinct subgroups) and bonding social capital (which results from frequent interaction or from clustered relationships within subgroups). We found that measures of bridging social capital had a positive effect on actors' assessments of their access to information in policy forums, but a negative effect on their perceptions of cooperation and procedural fairness in forums. In contrast, measures of bonding social capital had a positive effect on cooperation and procedural fairness, but no effect on information access. Taken together, our results suggest that different forms of social capital have separate—and potentially opposing—effects on distinct measures of the performance of adaptation policy forums. The relative importance of each performance measure, which may vary from one policy forum to another, should guide efforts to encourage different forms of social capital across the numerous decision-making processes that comprise regional climate change adaptation governance systems.



http://bit.ly/2tdHidn

Uncertainty as a determinant of attentional control settings

Abstract

Previous studies have demonstrated that attentional capture occurs based on attentional control settings. These settings specify what features are selected for processing as well as what features are filtered out. To examine how attentional control settings are flexibly constructed when target and/or distractor features are uncertain, the current paper presents four experiments in which the numbers of target and distractor features were manipulated. The results showed that attentional control settings were configured in terms of a fixed feature when either the target or the distractor feature was uncertain and the other was fixed over trials. In addition, attention was tuned towards the specific target feature based on attentional control settings when both target and distractor features were either fixed or uncertain. The selectivity of the target or distractor feature in the attentional control setting depended on which of the target and distractor features were defined with uncertainty. These results indicate that attentional control settings are flexibly determined by given task demands, especially including the predictability of target and distractor features.



http://bit.ly/2DZCmPo

Enhanced activity and substrate tolerance of 7α-hydroxysteroid dehydrogenase by directed evolution for 7-ketolithocholic acid production

Abstract

7-Ketolithocholic acid (7-KLCA) is an important intermediate for the synthesis of ursodeoxycholic acid (UDCA). UDCA is the main effective component of bear bile powder that is used in traditional Chinese medicine for the treatment of human cholesterol gallstones. 7α-Hydroxysteroid dehydrogenase (7α-HSDH) is the key enzyme used in the industrial production of 7-KLCA. Unfortunately, the natural 7α-HSDHs reported have difficulty meeting the requirements of industrial application, due to their poor activities and strong substrate inhibition. In this study, a directed evolution strategy combined with high-throughput screening was applied to improve the catalytic efficiency and tolerance of high substrate concentrations of NADP+-dependent 7α-HSDH from Clostridium absonum. Compared with the wild type, the best mutant (7α-3) showed 5.5-fold higher specific activity and exhibited 10-fold higher and 14-fold higher catalytic efficiency toward chenodeoxycholic acid (CDCA) and NADP+, respectively. Moreover, 7α-3 also displayed significantly enhanced tolerance in the presence of high concentrations of substrate compared to the wild type. Owing to its improved catalytic efficiency and enhanced substrate tolerance, 7α-3 could efficiently biosynthesize 7-KLCA with a substrate loading of 100 mM, resulting in 99% yield of 7-KLCA at 2 h, in contrast to only 85% yield of 7-KLCA achieved for the wild type at 16 h.



http://bit.ly/2tbuDHZ

Fusion of heart rate variability and salivary cortisol for stress response identification based on adverse childhood experience

Abstract

Adverse childhood experiences have been suggested to cause changes in physiological processes and can determine the magnitude of the stress response which might have a significant impact on health later in life. To detect the stress response, biomarkers that represent both the Autonomic Nervous System (ANS) and Hypothalamic-Pituitary-Adrenal (HPA) axis are proposed. Among the available biomarkers, Heart Rate Variability (HRV) has been proven as a powerful biomarker that represents ANS. Meanwhile, salivary cortisol has been suggested as a biomarker that reflects the HPA axis. Even though many studies used multiple biomarkers to measure the stress response, the results for each biomarker were analyzed separately. Therefore, the objective of this study is to propose a fusion of ANS and HPA axis biomarkers in order to classify the stress response based on adverse childhood experience. Electrocardiograph, blood pressure (BP), pulse rate (PR), and salivary cortisol (SCort) measures were collected from 23 healthy participants; 11 participants had adverse childhood experience while the remaining 12 acted as the no adversity control group. HRV was then computed from the ECG and the HRV features were extracted. Next, the selected HRV features were combined with the other biomarkers using Euclidean distance (ed) and serial fusion, and the performance of the fused features was compared using Support Vector Machine. From the result, HRV-SCort using Euclidean distance achieved the most satisfactory performance with 80.0% accuracy, 83.3% sensitivity, and 78.3% specificity. Furthermore, the performance of the stress response classification of the fused biomarker, HRV-SCort, outperformed that of the single biomarkers: HRV (61% Accuracy), Cort (59.4% Accuracy), BP (78.3% accuracy), and PR (53.3% accuracy). From this study, it was proven that the fused biomarkers that represent both ANS and HPA (HRV-SCort) able to demonstrate a better classification performance in discriminating the stress response. Furthermore, a new approach for classification of stress response using Euclidean distance and SVM named as ed-SVM was proven to be an effective method for the HRV-SCort in classifying the stress response from PASAT. The robustness of this method is crucial in contributing to the effectiveness of the stress response measures and could further be used as an indicator for future health.

Graphical abstract



http://bit.ly/2MYGan6

Understanding lipogenesis by dynamically profiling transcriptional activity of lipogenic promoters in Yarrowia lipolytica

Abstract

Lipogenesis is a complicated process involving global transcriptional reprogramming of lipogenic pathways. It is commonly believed that nitrogen starvation triggers a metabolic shift that reroutes carbon flux from Krebs cycles to lipogenesis. In this study, we systematically surveyed and dynamically profiled the transcriptional activity of 22 lipogenic promoters aiming to delineate a picture how nitrogen starvation regulates lipogenesis in Y. lipolytica. These lipogenic promoters drive the expression of critical pathways that are responsible for the generation of reducing equivalents (NADPH), carbon backbones (acetyl-CoA, malonyl-CoA, DHAP, etc.), synthesis and degradation of fatty acids. Specifically, our investigated promoters span across an array of metabolic pathways, including glycolysis, Krebs cycle, pentose phosphate pathway, mannitol cycle, glutamine–GABA cycle, fatty acid and lipid synthesis, glyoxylate, β-oxidation, and POM (pyruvate–oxaloacetate–malate) cycle. Our work provides evidences that mannitol cycle, glutamine–GABA cycle and amino acid degradation, pyruvate oxidation, and acetate assimilation pathways are lipogenesis-related steps involved in generating cytosolic NADPH and acetyl-CoA precursors. This systematic investigation and dynamic profiling of lipogenic promoters may help us better understand lipogenesis, facilitate the formulation of structure-based kinetic models, as well as develop efficient cell factories for fuels and chemical production in oleaginous species.



http://bit.ly/2HY9J9l

Peculiar EEG signatures, ictal drinking and long-term follow-up in anti-LGI1 encephalitis



http://bit.ly/2GvzsUa

Helicobacter pylori infection in children: an overview of diagnostic methods

Abstract

Children differ from adults regarding Helicobacter pylori (H. pylori) infection in many terms. H. pylori infection represents a key factor in the pathogenesis of duodenal ulcer and chronic gastritis in children. H. pylori infection causes some extraintestinal diseases as well as gastrointestinal diseases. Although, among these illnesses in children, symptoms like recurrent abdominal pain are not specific. Moreover, the role of the pathogen in the growth faltering, iron deficiency anemia, and asthma still remains controversial. A reliable method to detect H. pylori infection is a crucial issue, sand is still a matter of active debate. The tests applied for H. pylori diagnosis are grouped as either invasive or non-invasive methods. Invasive methods consist of endoscopic evaluation, the rapid urease test (RUT), histology, and bacterial culture. Non-invasive tests include the urea breath test (UBT), stool antigen test (SAT), serology, and molecular diagnostic approaches. Use of endoscopy is a pre-requisite for all invasive methods and poses difficulties in children as it is a difficult procedure and requires patient's cooperation. For this reason, the non-invasive tests have been commonly used in children, although their accuracy is not very reliable in some cases. Invasive tests may be opted to confirm the diagnosis as and when needed. This review presents the diagnostic tests used to detect H. pylori infection in children.



http://bit.ly/2HVkwkr

Probing the Depth of the Myocardium: Vasculature, Transit Time, and Perfusion Within the Left Ventricular Wall

Abstract

The branching architecture of arterial trees traversing the thickness of the left ventricular wall is studied to determine the way in which adequate blood supply is provided to myocardial tissue at different depths within the wall thickness from arterial trees originating at the epicardial surface. The study is based on micro-CT images of tissue biopsies, coupled with a dedicated vascular tree analysis program. The results show that this combination of methodologies allows a more detailed and much more accurate exploration of the vasculature within the sampled tissue than is possible by histological means. The spatial density of the smallest resolvable "end" arterioles is found to be higher in the sub-endocardial region than in the sub-epicardial region, with vascular branching architecture consistent with a fractal structure. The concept of "transit time" is introduced as an approximate measure of the time it takes bulk flow to reach different regions of the myocardium. Our data suggest that a transit time differential is a major contributor to the equalization of transmural perfusion gradient against unequal distribution of "end' arteriolar density.



http://bit.ly/2SyllDX

Academic Vocabulary Knowledge and Reading Comprehension Skills Among Seventh-Graders in Arabic as L1

Abstract

The current study attempted to investigate the contribution of an intervention program to fostering Arabic academic vocabulary knowledge and reading comprehension skills among seventh grade Arabic native speaking pupils. For this purpose, 247 pupils from four schools in northern Israel have participated in the study. Arabic literacy units that targeted academic vocabulary and reading comprehension skills were administrated for a period of 5 months. To assess the efficacy of the intervention program, academic vocabulary tests (receptive and productive) as well as reading comprehension test were administrated. As indicated by the results, the interventional group showed significantly higher performance in reading comprehension and productive academic vocabulary when compared to the control group. In contrast, no significant improvement was noted in receptive academic vocabulary knowledge. Taken together, the study results point to the contribution of comprehensive and direct academic vocabulary instructional approaches to promoting academic vocabulary knowledge and reading comprehension of academic texts. Moreover, it stresses the need for policy change and curricular adjustments in Arabic language instruction, acknowledging the importance of fostering academic language skills in the road to academic success.



http://bit.ly/2Blwv55

What are the best isometric exercises of muscle potentiation?

Abstract

Purpose

The aim of this study was to follow post-activation potentiation (PAP), low-frequency fatigue (LFF), metabolic-induced fatigue and post-contractile depression (PCD) in response to different isometric muscle contraction modalities.

Methods

Young healthy men (N = 120) were randomly assigned to one of ten exercise modality groups which differed in contraction duration (5–60 s), activation pattern (intermittent or continuous contractions), activation mode (voluntary or stimulated), and intensity [maximal or submaximal (50%)]. Isometric maximal voluntary contraction (MVC), and electrically induced knee extension torque were measured at baseline and at regular intervals for 60 min after exercise.

Results

Muscle contraction modalities involving 5 s MVC were the most effective for PAP, whereas the lowest PAP effectiveness was found after the 12 × 5-MVC modality. After all of the 5–15 s MVC and 6 × 5-MVC protocols, the potentiation of the twitch rate was significantly higher than that recorded after continuous 30–60 s protocols (P < 0.001). Tetanic maximal torque (100 Hz) potentiation occurred 5 min after 15–30 s repetitive MVC modalities and after modality involving 15 electrical stimuli (P < 0.05).

Conclusions

The findings demonstrate that post-activation potentiation was most effective after brief duration continuous and repetitive MVC protocols. To understand the resultant warm-up of motor performance, it is necessary to recognize the coexistence of muscle PAP, tetanic maximal force potentiation, rapid recovery of metabolic muscle, and central muscle activation processes, as well as prolonged LFF and prolonged PCD.



http://bit.ly/2TCUgNk

Modified Lower Blepharoplasty with Fat Repositioning via Transconjunctival Approach to Correct Tear Trough Deformity

Abstract

Background

Over the years, many techniques have been described to correct tear trough deformity (TTD). Fat-repositioning lower blepharoplasty via a transconjunctival approach is increasingly applied due to its satisfactory rejuvenating effect. However, those methods have disadvantages such as a complicated surgical approach, residual scar, and long recovery time.

Objectives

We modified the surgical technique of fat-repositioning transconjunctival lower blepharoplasty with an effective but easy internal fixation method via a supraperiosteal approach.

Methods

From January 2014 to December 2017, 110 patients underwent bilateral modified lower blepharoplasty with fat-repositioning. Preoperatively, the grade of TTD was evaluated according to Barton's grading system. Postoperative results and complications were assessed during the follow-up period.

Results

TTD was ameliorated in 97.73% of the cases; the remaining 2.27% cases with no improvement underwent revision and achieved Grade 0 on Barton's grading system thereafter. All patients were satisfied with the final outcome. Few postoperative complications were observed, none of which led to a permanent condition. Three cases of local depression and one case of local bulge were treated with surgical refinements. One case of postoperative hemorrhage was healed by electrocautery.

Conclusions

Our modified method of transconjunctival lower blepharoplasty with fat repositioning is safe and effective to improve TTD without severe orbital skin laxity.

Level of Evidence IV

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.



http://bit.ly/2TDgONM

Arterielle Fehlanlage eines Portkatheters



http://bit.ly/2DjLcG1

Grenzsituationen in der Chirurgie



http://bit.ly/2Se0nel

Dank an die Gutachter 2018



http://bit.ly/2DiMLEe

Der multimorbide Gefäßpatient – erweitern endovaskuläre Techniken den Grenzbereich?

Zusammenfassung

Die Beantwortung der Frage, inwieweit endovaskuläre Techniken bei einem multimorbiden Gefäßpatienten den Grenzbereich erweitern, hängt von der Lokalisation der Gefäßerkrankung und ihrem Stadium ab. Bei multimorbiden Gefäßpatienten mit begrenzter Lebenserwartung und asymptomatischer Karotisstenose ist weder ein endovaskuläres noch ein offenes Vorgehen angezeigt, vielmehr ist die konservative Behandlung („beste medikamentöse Therapie") zu bevorzugen. Bei symptomatischer Karotisstenose hat bei speziellen anatomischen Gegebenheiten wie kontralateraler Karotisverschluss, kontralaterale Rekurrensparese, Rezidivstenose nach Endarteriektomie, radikale „neck dissection" oder Strahlentherapie im Halsbereich das endovaskuläre Vorgehen seine Indikationen. Bei der Versorgung des intakten abdominalen Aortenaneurysmas (AAA) reduzieren endovaskuläre Prozeduren speziell bei älteren Patienten das perioperative Risiko, womit sie in dieser Gruppe die Indikation zum Eingriff erweitern können, unter der Voraussetzung, dass die Lebenserwartung so behandelter Patienten noch einige Jahre beträgt. Beim rupturierten AAA ist die Datenlage offen, es gibt aber Hinweise dafür, dass mit der Etablierung von EVAR („endovascular aortic repair") der Anteil an therapierten Patienten zunimmt, bei denen bisher nach Eintreffen im Krankenhaus auf einen Eingriff gänzlich verzichtet wurde. Bei der kritischen Extremitätenischämie schließlich ist mit Propagierung der endovaskulären Techniken weniger die Indikation zum invasiven Eingriff ausgeweitet worden, vielmehr hat das endovaskuläre Vorgehen die offene Bypasschirurgie verdrängt, was sich in einer geringeren perioperativen Morbidität, speziell bei älteren gebrechlichen Patienten, positiv bemerkbar macht.



http://bit.ly/2SeMVHh

Peri-operative, intravenous clindamycin may improve the resolution rate of hypertension after Roux-en-Y gastric bypass in morbidly obese patients

Abstract

Background

Recent studies have suggested that potential aberrant alterations in the gastrointestinal microbiome contribute to the development of cardiovascular disease, specifically hypertension. Bariatric surgery produces significant sustained weight loss and hypertension resolution likely through multiple mechanisms which includes beneficial changes in the gut microbiome. We hypothesized that the type of prophylactic antibiotic given for bariatric surgery could impact the resolution rate of hypertension by altering the post-operative gastrointestinal microflora.

Methods

A retrospective analysis of adult bariatric patients who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) between 2012 and 2016 was conducted. The standard antibiotic prophylaxis was cefazolin, or clindamycin in patients with a penicillin allergy. Univariate analyses were performed comparing the differing peri-operative antibiotic treatments with resolution of hypertension at 2-week (± 1 week), 6-week (± 2 weeks), 3-month (± 2 weeks), 6-month (± 6 weeks), and 1-year (± 2 months) follow-up appointments. The criterion for resolution of hypertension was no longer requiring medication at time of follow-up.

Results

In total, 123 RYGB and 88 SG patients were included. No significant differences were found between cefazolin and clindamycin regarding hypertension resolution rates after SG. However, patients who underwent RYGB and received clindamycin had a significantly higher rate of hypertension resolution compared to cefazolin. This effect started at 2 weeks post-operatively (52.4% vs. 23.5% respectively, p = 0.008) and persisted up to the 1-year (57.9% vs. 44.0% respectively, p = 0.05).

Conclusion

Prophylactic peri-operative, intravenous clindamycin was associated with significantly increased resolution of post-operative hypertension compared to cefazolin. This finding was not observed in SG patients. Future studies are needed to confirm the mechanism of action for this novel finding is due to the differing modifications of the gastrointestinal microflora after RYGB resulting from the specific peri-operative antibiotic administered.



http://bit.ly/2Di9lgj

Reliability of four tests to assess body posture and the range of selected movements in individuals with spinal muscular atrophy

Abstract

Background

The majority of individuals with spinal muscular atrophy (SMA) experience progressive skeletal deformities which may affect the quality of life and mobility. To date, no studies have evaluated the reliability of tests assessing body posture and joint mobility in SMA patients. The purpose of this study was to assess the reliability of Cervical Rotation test (CR), Supine Angle of Trunk Rotation test (SATR), Hip Extension test (HE) and Pelvic Obliquity test (PO) developed to evaluate the musculoskeletal system in SMA individuals.

Methods

Thirty individuals (12 girls and 18 boys) aged 4–15 with SMA type II (n = 24) and III (n = 6) confirmed by genetic examinations were qualified for the study. The participants were examined twice by three physiotherapists on the same day. The examination included four tests, i.e. CR, SATR, HE and PO tests aimed at assessing ranges of rotation in the cervical spine, chest deformities, ranges of hip extension and pelvis position while sitting. Statistical calculations were made with the use of statistical software IBM SPSS Statistics version 20. Reliability was assessed using the Intraclass Correlation Coefficient (ICC).

Results

Intraobserver reliability was excellent for CR (ICC range 0.839–0.911), SATR (ICC range 0.918–0.939 - the upper part of the sternum; ICC range 0.951–0.975 - the lower part of the sternum), HE (ICC range 0.988–0,991) and PO (ICC range 0.896–0.935) tests.

The interobserver ICC reached the excellent values in CR (ICC range 0.912–0.920), SATR (ICC = 0.888 - the upper part of the sternum, ICC = 0.951 - the lower part of the sternum), HE (ICC range 0.922–0.923) and PO (ICC = 0.928) tests.

Conclusions

CR, SATR, HE and PO tests are reliable and may be used for examining individuals with SMA. The application of these tests provides a possibility to detect early changes in the musculoskeletal system in children and adolescents and to assess the effectiveness of the implemented pharmacotherapy and rehabilitation.



http://bit.ly/2SjIECn

Comparation and evaluation of the accuracy of the sulcus localization method to establish the medial patellofemoral ligament femoral tunnel: a cadaveric and clinical study

Abstract

Background

In anatomic medial patellofemoral ligament (MPFL) reconstruction, malpositioning of the MPFL femoral tunnel is common. A palpable sulcus reportedly exists at the anatomic femoral attachment of the MPFL. The present study aimed to investigate the accuracy of the sulcus localization method to establish the MPFL femoral tunnel.

Methods

A cadaveric study was first done on 12 knees to evaluate the accuracy of the sulcus localization method to establish the entry points of the MPFL femoral tunnel in comparison with the midpoint and fluoroscopic localization methods. The center of the native MPFL femoral attachment was served as the reference in the cadaveric study. A clinical study was then performed to further evaluate the accuracy of the sulcus localization method in 53 patients (60 knees). Schöttle's point was served as the reference in the clinical study. Femoral tunnel placement was defined as accurate when it was less than 5 mm from Schöttle's point. In both the cadaveric and clinical studies, MPFL femoral tunnel placement was assessed on postoperative reconstructed three-dimensional computed tomography images. In the cadaveric study, the accuracy of different localization methods was compared using analysis of variance.

Results

In the cadaveric study, the mean distances from the native MPFL attachment to the femoral tunnel entry point were 4.2 ± 1.0 mm (range 2.4–5.6 mm), 4.4 ± 1.4 mm (range 1.8–6.6 mm) and 2.9 ± 0.8 mm (range 1.9–4.4 mm) using the midpoint, fluoroscopic, and sulcus localization methods, respectively; this distance significantly differed between the midpoint and sulcus localization methods, and between the fluoroscopic and sulcus localization methods (p ≤ .05). While there were no significant differences between the midpoint and fluoroscopic localization methods (n.s.). In the clinical study, the mean distance between the femoral tunnel and Schöttle's point was 3.5 ± 1.5 mm (range 0.4–6.1 mm), with accurate tunnel placement achieved in 49 of 60 cases (82%).

Conclusion

The sulcus localization method can accurately guide MPFL femoral tunnel placement. This method might be useful for orthopedic surgeons.

Level of evidence

IV



http://bit.ly/2Dh2aF1

Responsiveness and Adaptation to Salt Stress of the REDOX-RESPONSIVE TRANSCRIPTION FACTOR 1 (RRTF1) Gene are Controlled by its Promoter

Abstract

The REDOX-RESPONSIVE TRANSCRIPTION FACTOR 1 (RRTF1) gene encodes a member of the ERF/AP2 transcription factor family involved in redox homeostasis. The RRTF1 gene shows tissue-specific responsiveness to various abiotic stress treatments including a response to salt stress in roots. An interesting feature of this response is an adaptation phase that follows its activation, when promoter levels revert to a base line level, even if salt stress is maintained. It is unclear if adaption is controlled by a switch in promoter activity or by changes in transcript levels. Here we show that the RRTF1 promoter is sufficient for the control of both activation and adaptation to salt stress. As constitutive expression of RRTF1 turned out to be detrimental to the plant, we propose that promoter-regulated adaptation evolved as a protection mechanism to balance the beneficial effects of short-term gene activation and the detrimental effects of long-term gene expression.



http://bit.ly/2TALPlx

Fundamental Motor Skill Interventions for Children and Adolescents on the Autism Spectrum: a Literature Review

Abstract

In addition to the core characteristics of ASD, recent research has demonstrated that children on the autism spectrum develop motor skills differently, often delayed, compared with peers. Motor skill interventions can help improve motor skills, which in turn can increase the likelihood of participating in physical activity (PA) and potential to build social skills. However, research in this area is limited. A search of several prominent databases revealed a total of five empirical studies focused on building gross motor skills for children on the autism spectrum. Although the reviewed studies varied in the delivery and focus of intervention, overall, the reviewed studies suggest a positive effect from any intervention for children on the autism spectrum. Further research in this area is necessary to better understand the most effective means of delivering a motor skill intervention.



http://bit.ly/2MSo6uA

Pharmacogenomic–pharmacokinetic study of selective estrogen-receptor modulators with intra-patient dose escalation in breast cancer

Abstract

Background

An association between CYP2D6 polymorphisms and tamoxifen (TAM) efficacy has not been confirmed, partly due to unreliable prediction of active metabolite exposure solely by CYP2D6 activity. The efficacy of TAM dose escalation appears limited in poor TAM metabolizers. Since the chlorine atom on the side chain of toremifene (TOR) prevents 4-hydroxylation by CYP2D6, its contribution to active conversion of TOR is minor. We examined the role of TOR and its dose escalation among poor TAM metabolizers.

Methods

The pharmacokinetics (PK) and pharmacogenomics (PGx) of TAM and TOR were studied. Correlation between PK and CYP2D6 inhibitor use, smoking status, and PGx were examined by regression analysis. For patients showing low endoxifen levels, an intra-patient dose escalation of TOR was conducted, and TOR was increased from 40 to 120 mg for ≥ 24 weeks with PK sampling. Total activity was calculated as the sum of the concentration of each active metabolite adjusted by their respective in vitro activities.

Results

Fifty and 11 of the 273 participating patients had endoxifen levels < 15 and < 7.5 ng/mL, respectively. The CYP2D6 genotype was the major determinant for TAM activity (p < 0.01). Smoking status (p = 0.07) and the CYP2C19 phenotype (p = 0.07), but not the CYP2D6 genotype (p = 0.61), showed marginally significant effects on TOR activity. TOR activity increased significantly with dose escalation, even among poor TAM metabolizers, and was maintained for ≥ 24 weeks.

Conclusion

TOR might be a valid alternative to TAM in patients predicted to be poor TAM metabolizers.



http://bit.ly/2DYqNIo

Tight junction proteins at the blood–brain barrier: far more than claudin-5

Abstract

At the blood–brain barrier (BBB), claudin (Cldn)-5 is thought to be the dominant tight junction (TJ) protein, with minor contributions from Cldn3 and -12, and occludin. However, the BBB appears ultrastructurally normal in Cldn5 knock-out mice, suggesting that further Cldns and/or TJ-associated marvel proteins (TAMPs) are involved. Microdissected human and murine brain capillaries, quickly frozen to recapitulate the in vivo situation, showed high transcript expression of Cldn5, -11, -12, and -25, and occludin, but also abundant levels of Cldn1 and -27 in man. Protein levels were quantified by a novel epitope dilution assay and confirmed the respective mRNA data. In contrast to the in vivo situation, Cldn5 dominates BBB expression in vitro, since all other TJ proteins are at comparably low levels or are not expressed. Cldn11 was highly abundant in vivo and contributed to paracellular tightness by homophilic oligomerization, but almost disappeared in vitro. Cldn25, also found at high levels, neither tightened the paracellular barrier nor interconnected opposing cells, but contributed to proper TJ strand morphology. Pathological conditions (in vivo ischemia and in vitro hypoxia) down-regulated Cldn1, -3, and -12, and occludin in cerebral capillaries, which was paralleled by up-regulation of Cldn5 after middle cerebral artery occlusion in rats. Cldn1 expression increased after Cldn5 knock-down. In conclusion, this complete Cldn/TAMP profile demonstrates the presence of up to a dozen TJ proteins in brain capillaries. Mouse and human share a similar and complex TJ profile in vivo, but this complexity is widely lost under in vitro conditions.



http://bit.ly/2MYcJl6

Francesca Biagioli: Space, Number, and Geometry from Helmholtz to Cassirer



http://bit.ly/2HTabWi

Blockage of the P2X7 Receptor Attenuates Harmful Changes Produced by Ischemia and Reperfusion in the Myenteric Plexus

Abstract

Introduction

Our work analyzed the effects of a P2X7 receptor antagonist, Brilliant Blue G (BBG), on rat ileum myenteric plexus following ischemia and reperfusion (ISR) induced by 45 min of ileal artery occlusion with an atraumatic vascular clamp with 24 h (ISR 24-h group) or 14 d of reperfusion (ISR 14-d group).

Material and methods

Either BBG (50 mg/kg or 100 mg/kg, BBG50 or BBG100 groups) or saline (vehicle) was administered subcutaneously 1 h after ischemia in the ISR 24-h group or once daily for the 5 d after ischemia in the ISR 14-d group (n = 5 per group). We evaluated the neuronal density and profile area by examining the number of neutrophils in the intestinal layers, protein expression levels of the P2X7 receptor, intestinal motility and immunoreactivity for the P2X7 receptor, nitric oxide synthase, neurofilament-200, and choline acetyl transferase in myenteric neurons.

Results

The neuronal density and profile area were restored by BBG following ISR. The ischemic groups showed alterations in P2X7 receptor protein expression and the number of neutrophils in the intestine and decreased intestinal motility, all of which were recovered by BBG treatment.

Conclusion

We concluded that ISR morphologically and functionally affected the intestine and that its effects were reversed by BBG treatment, suggesting the P2X7 receptor as a therapeutic target.



http://bit.ly/2DWVYUv

Predictive Value of Procalcitonin in Acute Severe Ulcerative Colitis: Not Quite PerfeCT?



http://bit.ly/2GyQfWF

Real-World Experience with Tofacitinib in IBD at a Tertiary Center

Abstract

Background and Aims

Many inflammatory bowel disease (IBD) patients do not respond to medical therapy. Tofacitinib is a first-in-class, partially selective inhibitor of Janus kinase, recently approved for treating patients with ulcerative colitis (UC). We describe our experience with the use of tofacitinib for treatment of patients with moderate-to-severe IBD.

Methods

This is a retrospective, observational study of the use of tofacitinib in IBD. Patients with medically resistant IBD were treated orally with 5 mg or 10 mg twice daily. Clinical response and adverse events were assessed at 8, 26, and 52 weeks. Objective response was assessed endoscopically, radiologically, and biochemically.

Results

58 patients (53 UC, 4 Crohn's, 1 pouchitis) completed at least 8 weeks of treatment with tofacitinib. 93% of the patients previously failed treatment with anti-TNF. At 8 weeks of treatment, 21 patients (36%) achieved a clinical response, and 19 (33%) achieved clinical remission. Steroid-free remission at 8 weeks was achieved in 15 patients (26%). Of the 48 patients followed for 26 weeks, 21% had clinical, steroid-free remission. Of the 26 patients followed for 12 months, 27% were in clinical, steroid-free remission. Twelve episodes of systemic infections were noted, mostly while on concomitant steroids. One episode of herpes zoster infection was noted during follow-up.

Conclusions

In this cohort of patients with moderate-to-severe, anti-TNF resistant IBD, tofacitinib induced clinical response in 69% of the patients. 27% were in clinical, steroid-free remission by 1 year of treatment. Tofacitinib is an effective therapeutic option for this challenging patient population.



http://bit.ly/2DWVIVx

Gastrointestinal Hemorrhage in Patients with Acute Ischemic Stroke: Should Endoscopy Be Within the Scope of Practice?



http://bit.ly/2Gvq1UH

Early Response to Corticosteroid and Baseline C-Reactive Protein Predicts Outcomes in Children with Moderate to Severe Ulcerative Colitis

Abstract

Background

Initial response to corticosteroids (CS) is recognized as a strong predictor of outcomes in ulcerative colitis (UC).

Aim

To compare outcomes of early poor responders (PR) versus good responders (GR) to initial CS at 1, 2, and 3 years from diagnosis.

Methods

In this retrospective study, we report longitudinal outcomes of children with moderate–severe UC, initiating oral/IV CS < 1 month of diagnosis and a minimum follow-up (FU) of 1 year. CS resistance (CSR) and CS dependency (CSD) were combined as PR, and those with CS-free remission (CSFR) at 6 months were GR.

Results

Of 116 children with UC, 76 (33 males) fulfilled study criteria. Median age at diagnosis was 12 years (IQR 12–14), and a median FU was 48 months (IQR 27–65). Thirty-five (46%, CSR = 10, CSD = 25) were PR, and 41 (54%) were GR. Mean relapse (2.39 vs. 1.1, p = 0.0009), acute severe UC flare-up (40% vs. 9.7%, p = 0.002), and colectomy rates (34.2% vs. 2.4%) were greater in PR versus GR, despite frequent early (< 6 months) use of azathioprine (74% vs. 27%, p = 0.004) and anti-TNFs (43% vs. 2.4%, p = 0.0001). Cumulative colectomy at 3 years was lowest in those with GR versus CSD and CSR (2.4% vs. 28% and 50% p = 0.001). On univariate analysis, CRP > 20 mg/L at diagnosis, Mayo Clinical Score > 1 at 3 months, and PR predicted colectomy. On multivariate regression, only baseline CRP > 20 mg/L predicted colectomy (HR 4.9, p = 0.03).

Conclusions

Baseline CRP and poor response to initial CS are associated with unfavorable outcomes in children with UC.



http://bit.ly/2DWVw8L

ERCP Success Rate and Periampullary Diverticula: The Pocket Makes No Difference



http://bit.ly/2GwI9gT

Competitive Endogenous RNA (ceRNA) Regulation Network of lncRNA–miRNA–mRNA in Colorectal Carcinogenesis

Abstract

Background

Competitive endogenous RNA (ceRNA) regulation suggested complex network of all transcript RNAs including long noncoding RNAs (lncRNAs), which can act as natural miRNA sponges to inhibit miRNA functions and modulate mRNA expression. Until now, the specific ceRNA regulatory mechanism of lncRNA–miRNA–mRNA in colorectal cancer (CRC) still remains unclear.

Materials and Methods

RNA sequencing data of 478 colon adenocarcinoma cases and 41 controls as well as 166 rectum adenocarcinoma cases and 10 controls were obtained from The Cancer Genome Atlas (TCGA) to investigate the significant changes of lncRNAs, miRNAs and mRNAs in colorectal carcinogenesis. The target lncRNAs and mRNAs of miRNAs were predicted by miRWalk. Functional and enrichment analyses were conducted by DAVID database. The lncRNA–miRNA–mRNA interaction network was constructed using Cytoscape.

Results

We constructed ceRNA regulatory networks including 22 up-regulated lncRNAs, 12 down-regulated miRNAs and 122 up-regulated mRNAs, as well as 8 down-regulated lncRNAs, 43 up-regulated miRNAs and 139 down-regulated mRNAs. The GO enrichment showed that up-regulated genes mainly enriched in biological process including organic anion transport, collagen catabolic process, wound healing, Wnt receptor signalling and in pathways of tyrosine metabolism, taurine and hypotaurine metabolism, melanogenesis and phenylalanine metabolism. For down-regulated genes, significant enrichment was found in biological process of metal ion homeostasis, transmission of nerve impulse, cell–cell signalling, transmembrane transport and in pathways of ABC transporters, neuroactive ligand–receptor interaction, retinol metabolism, nitrogen metabolism and steroid hormone biosynthesis.

Conclusion

We identified significantly altered lncRNAs, miRNAs and mRNAs in colorectal carcinogenesis, which might serve as potential biomarkers for tumorigenesis of CRC. In addition, the ceRNA regulatory network of lncRNA–miRNA–mRNA was constructed, which would elucidate novel molecular mechanisms involved in initiation and progression of CRC, thus providing promising clues for clinical diagnosis and therapy.



http://bit.ly/2DYfccg

Anterograde Endoscopic Ultrasound-Guided Pancreatic Duct Drainage: A Technical Review

Abstract

The advancement of pancreatic endotherapy has increased the availability of minimally invasive endoscopic pancreatic ductal drainage techniques. In this regard, familiarity with endoscopic ultrasound-guided pancreatic duct drainage (EUS-PDD) is critical for treatment of obstructed pancreatic ductal systems, especially in nonsurgical candidates and in patients desiring a minimally invasive approach. Two distinct forms of EUS-PDD exist, viz. rendezvous-assisted endoscopic retrograde pancreatography (rendezvous-assisted ERP) and anterograde EUS-PDD. Anterograde EUS-PDD refers to transmural anterograde passage of a pancreatic drainage catheter or stent directly into the main pancreatic duct, through either the gastric or enteral wall. Rendezvous-assisted ERP should be attempted after failed conventional ERP, and anterograde EUS-PDD should be considered if rendezvous-assisted ERP fails or is not technically feasible. Common clinical scenarios that fulfil these conditions are chronic pancreatitis with high-grade main pancreatic duct obstruction, surgically altered anatomy with ductal/anastomotic obstruction, pancreas divisum, and disconnected pancreatic duct syndrome. The focus of this review article is anterograde EUS-PDD and its indications, technique, and outcomes. It also provides a summary of our own experience with this procedure, and a video demonstration of the technique.



http://bit.ly/2GvprpZ

How the “Opt-In” Option Optimizes Organ Donation Rates



http://bit.ly/2DX2GcN

The Proceedings of the 16th Italian Convention of Investigators in Cystic Fibrosis



http://bit.ly/2SgrRAa

Age-dependent decline in neurogenesis of the hippocampus and extracellular nucleotides

Abstract

New neurons are continuously generated in the adult brain. This generation primarily occurs in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus. In the SGZ, neural stem cells (NSCs) give rise to glutamatergic granule cells that integrate into the hippocampal circuitry. Reduction of neurogenesis in the hippocampus impairs learning and memory, which suggests that this process is important for adult hippocampal function. Indeed, the neurogenesis is reduced in the progression of aging, which is thought to contribute to age-related cognitive impairment. Although the mechanism of age-dependent decline in neurogenesis remains largely obscure, astrocytes are thought to play a vital role in regulating NSC proliferation and differentiation. Both astrocytes and NSCs secrete nucleotides to the extracellular space and extracellular nucleotides bind to their receptors on the surface of target cells. In this review, the recent knowledge on adult neurogenesis in the hippocampus is summarized briefly, and possible role of extracellular nucleotides in the age-dependent changes of the adult neurogenesis is discussed.



http://bit.ly/2WNKpGA

Magnesium


Prostate Cancer Detection and Diagnosis: Role of Ultrasound with MRI Correlates

Abstract

Purpose of Review

Prostate cancer (PCA) detection and diagnosis has rapidly changed in recent years, with medical imaging playing an instrumental component. Multiparametric magnetic resonance imaging (MRI) has led to an alternative diagnostic pathway for patient triage and diagnosis. Ultrasound (US) is already essential to this pathway, and development of new US technologies ensures it will assume an even more important role.

Recent Findings

Conventional US is widely used for anatomic guidance during prostate biopsy, but has low PCA detection rates. Ultrasound elastography and contrast-enhanced US are promising for improving PCA detection, have been utilized in addition to traditional systemic biopsy, and provide complementary information to MRI.

Summary

Here we summarize the current clinical use and newest developments in prostate US. We also present their MRI correlates with the vision that the two modalities will be used closely together in the future to improve PCA care.



http://bit.ly/2DheEwv

Color clustering segmentation framework for image analysis of malignant lymphoid cells in peripheral blood

Abstract

Current computerized image systems are able to recognize normal blood cells in peripheral blood, but fail with abnormal cells like the classes of lymphocytes associated to lymphomas. The main challenge lies in the subtle differences in morphologic characteristics among these classes, which requires a refined segmentation. A new efficient segmentation framework has been developed, which uses the image color information through fuzzy clustering of different color components and the application of the watershed transformation with markers. The final result is the separation of three regions of interest: nucleus, entire cell, and peripheral zone around the cell. Segmentation of this zone is crucial to extract a new feature to identify cells with hair-like projections. The segmentation is validated, using a database of 4758 cell images with normal, reactive lymphocytes and five types of malignant lymphoid cells from blood smears of 105 patients, in two ways: (1) the efficiency in the accurate separation of the regions of interest, which is 92.24%, and (2) the accuracy of a classification system implemented over the segmented cells, which is 91.54%. In conclusion, the proposed segmentation framework is suitable to distinguish among abnormal blood cells with subtile color and spatial similarities.

Graphical Abstract

The segmentation framework uses the image color information through fuzzy clustering of different color components and the application of the watershed transformation with markers (Top). The final result is the separation of three regions of interest: nucleus, entire cell, and peripheral zone around the cell. The procedure is also validated by the implementation of a system to automatically classify different types of abnormal blood cells (Bottom)


http://bit.ly/2GjGNXV

Off-Label Teduglutide Therapy in Non-intestinal Failure Patients with Chronic Malabsorption

Abstract

Background

Teduglutide, a glucagon-like peptide 2 analog, has demonstrated efficacy in treating adult patients with short bowel syndrome (SBS) and dependence on parenteral nutrition (PN), but its role in chronic malabsorptive states that do not necessitate PN remains uncertain.

Aims

To evaluate teduglutide use beyond its approved indications and to discuss the results of this adjunctive treatment in patients resistant to established therapy.

Results

This series reports four patients treated with teduglutide off-label. The first case had Crohn's disease (CD) with persistent colocutaneous fistulae that demonstrated complete closure after 8 months of teduglutide therapy. The second case involved a PN-dependent CD patient with persistent fistulae and intra-abdominal abscesses who weaned off PN and had a significant improvement in her nutritional status after 3 months of teduglutide therapy. The third case had CD complicated by severe malnutrition and previous PN-associated line infections, but by 9 months of teduglutide therapy, she gained 5 kg and no longer required re-initiation of PN. The fourth case had a high-output diverting ileostomy with resultant impaired healing of a stage IV decubitus ulcer, and after 2 months of therapy, the patient's pre-albumin increased by 250% and the ulcer had decreased by 40% in size.

Conclusion

The use of teduglutide might be broadened to include patients with functional SBS not meeting strict criteria for intestinal failure. Further studies should evaluate the efficacy of teduglutide in patients who may require short-term small intestine rehabilitation or who have chronically impaired absorptive capacity not yet requiring PN.



http://bit.ly/2UFIkdI

Glypican-1 Promotes Tumorigenesis by Regulating the PTEN/Akt/β-Catenin Signaling Pathway in Esophageal Squamous Cell Carcinoma

Abstract

Background and Aims

Glypican-1 (GPC1), a cell-surface heparan sulfate proteoglycan, promotes the pathogenesis of many human cancers. This study focuses on the role of GPC1 in the promotion of cell proliferation and motility in esophageal squamous cell carcinoma (ESCC).

Methods

The expression and distribution of GPC1 were measured in tumor tissues from 248 ESCC patients using immunohistochemical (IHC) assays. Cell counting (kit-8), flow cytometry, Transwell, wound healing, IHC, and Western blotting assays were performed to examine the molecular mechanisms that underlie how GPC1 enhances cell proliferation and motility.

Results

The level of GPC1 was higher in ESCC tumor samples than in para-tumor tissues (IHC score: 5.42 ± 2.15 vs. 0.86 ± 0.96). Ectopic overexpression of GPC1 in EC9706 cells promoted cell growth and the G1/S phase transition; conversely, GPC1 knockdown in Eca109 cells attenuated cell proliferation and induced G2/M phase arrest. In addition, GPC1 upregulation enhanced ESCC cell motility and induced epithelial mesenchymal transition (EMT), as demonstrated by the aberrant expression of EMT markers. Mechanistically, we demonstrated that GPC1 increased levels of p-Akt and β-catenin and reduced PTEN expression in ESCC.

Conclusions

Our study indicated that GPC1 promotes the aggressive proliferation of ESCC cells by regulating the PTEN/Akt/β-catenin pathway. GPC1 may be a promising target for ESCC treatment.



http://bit.ly/2ta1VqP

Loss of target information in full pixel and subpixel target detection in hyperspectral data with and without dimensionality reduction

Abstract

In most hyperspectral target detection applications, targets are usually small and require both spatial as well as spectral detection. Hyperspectral imaging facilitates target detection (TD) applications greatly, however, due to large spectral content, hyperspectral data requires dimensionality reduction (DR) which also leads to loss of target information both at full pixel and subpixel level. Literature reports many DR and TD algorithms in practice. Several studies have focussed on assessing the loss of target information in DR, however, not much work seems to have been done to assess loss of target information in full pixel and subpixel TD in hyperspectral data with and without DR. This paper seeks to study various combinations of DR techniques combined with full pixel and subpixel TD algorithms. The results indicate that in the case of full pixel targets, both DR and TD contribute to the loss of target information, however, there is more loss of target information in the case when DR precedes TD in comparison to a case where TD is applied without DR. In the case of subpixel TD, however, there appears to be loss of subpixel target information in the case where TD alone is performed in comparison to a case where DR precedes TD.



http://bit.ly/2DgxpA8

Correction to: Phenotypic, Genetic, and Cytogenetic Evidence of Hybridization between Species of Trans-Andean Tamarins (Genus Saguinus )

This article is intended for inclusion in the Special Issue on Primate Hybridization and Hybrid Zones. It was however published in a separate issue, Volume 39 Issue 6 and is available at http://bit.ly/2MV3IZI.



http://bit.ly/2SvZnSa

Thoracoscopic thymectomy for juvenile myasthenia gravis

Abstract

Purpose

A randomized controlled trial of thymectomy in myasthenia gravis demonstrated improved clinical outcomes in adults, but data surrounding juvenile cases, especially those treated with minimally invasive approaches, are limited. Here, we review our experience with thoracoscopic thymectomy for juvenile myasthenia gravis (JMG) in the largest cohort to date.

Methods

All cases of thymectomy for JMG in a single tertiary referral center between 2007 and 2018 were reviewed (N = 50). Patients underwent left thoracoscopic approach with extended dissection and without use of monopolar energy. Demographics, diagnostic criteria, and clinical classification, as well as surgical data were collected. Clinical status and medications were reviewed in follow-up.

Results

The mean age at surgery was 10.5 ± 0.8 years. Ocular disease and generalized disease each comprised half of the cohort. No patients suffered complications or increased risk of morbidity or mortality with thymectomy. At any interval of follow-up through 3.5 years, 49.8% of patients were improved compared to their pre-operative presentation, and there was a significant trend towards decreased steroid use.

Conclusion

Thoracoscopic thymectomy is a safe treatment for juvenile myasthenia gravis in pediatric patients over a wide range of ages, body masses, and symptoms. Our experience adds evidence that pediatric patients likely benefit from thymectomy with improved clinical status and reduced medications.



http://bit.ly/2RGLWdH

Quality of life and functional outcome in Swedish children with low anorectal malformations: a follow-up study

Abstract

Purpose

The aim was to investigate the quality of life and bowel function in children with low anorectal malformations (ARM).

Additional aim

To evaluate the Swedish version the Hirschsprung's Disease/Anorectal Malformation Quality of life Questionnaire (HAQL).

Methods

Forty-four children and their parents were invited to complete the HAQL and the Bowel Function Score (BFS). Healthy children participated as controls and completed the HAQL.

Results

Seventeen children and 18 mothers completed the HAQL. The children reported impaired function in the physical symptom (PH) fecal continence (FC) and laxative diet (LD) domains compared to controls. Compared with their mothers, they reported impaired physical function and more symptoms in the emotional functioning (EMF) and PH domains. 27 families completed the BFS; 63% reported normal bowel function, 33% moderate outcome and one patient, comprising 4%, poor outcome. Evaluation of the HAQL, FC, EMF and PH domains showed no obvious conflicts.

Conclusions

The children did not differ much regarding their QoL, even though they appeared to have impaired bowel function and worse emotional functioning compared to controls. The mothers underestimated their children's physical symptoms and overestimated their emotional functioning. Evaluated domains in the HAQL appear to work as intended, but the questionnaire needs further development.



http://bit.ly/2WKWtYV

Physiologic serum 1,25 dihydroxyvitamin D is inversely associated with prostatic Ki67 staining in a diverse sample of radical prostatectomy patients

Abstract

Purpose

To investigate the correlation between serum 25 hydroxyvitamin D, prostatic 25 hydroxyvitamin D, and serum 1,25 dihydroxyvitamin D, and their respective associations with prostatic tumor proliferation at the time of radical prostatectomy.

Methods

In this cross-sectional analysis of 119 men undergoing radical prostatectomy, serum from whole blood and expressed prostatic fluid was collected on the day of surgery. Tumor proliferation was measured in the dominant tumor on formalin-fixed prostatectomy tissues by immunohistochemical staining for Ki67 and quantified by Aperio imaging analysis.

Results

The sample included 88 African Americans (74%) and 31 (26%) European Americans. Serum and prostatic levels of 25 hydroxyvitamin D were correlated with each other (Spearman's rho (ρ) = 0.27, p = 0.004), and there was also a correlation between serum 25 hydroxyvitamin D and 1,25 dihydroxyvitamin D (ρ = 0.34, p < 0.001).

Serum and prostatic 25 hydroxyvitamin D levels were not correlated with Ki67 staining in tumor cells. Serum 1,25 dihydroxyvitamin D was inversely correlated with Ki67 staining in tumor cells (ρ = − 0.30, p = 0.002). On linear regression, serum 1,25 dihydroxyvitamin D was negatively associated with Ki67 staining in tumor cells (β − 0.46, 95% CI − 0.75, − 0.04, p = 0.04).

Conclusion

The correlation between physiologic serum levels of 25 hydroxyvitamin D with both prostatic 25 hydroxyvitamin D and serum 1,25 dihydroxyvitamin D suggests that serum levels are reasonable biomarkers of vitamin D status. Furthermore, serum 1,25 dihydroxyvitamin D has an inverse association with Ki67 staining in tumor cells at physiologic levels and may protect against tumor progression.



http://bit.ly/2Dlz5sm

Comparison of short-term heart rate variability indexes evaluated through electrocardiographic and continuous blood pressure monitoring

Abstract

Heart rate variability (HRV) analysis represents an important tool for the characterization of complex cardiovascular control. HRV indexes are usually calculated from electrocardiographic (ECG) recordings after measuring the time duration between consecutive R peaks, and this is considered the gold standard. An alternative method consists of assessing the pulse rate variability (PRV) from signals acquired through photoplethysmography, a technique also employed for the continuous noninvasive monitoring of blood pressure. In this work, we carry out a thorough analysis and comparison of short-term variability indexes computed from HRV time series obtained from the ECG and from PRV time series obtained from continuous blood pressure (CBP) signals, in order to evaluate the reliability of using CBP-based recordings in place of standard ECG tracks. The analysis has been carried out on short time series (300 beats) of HRV and PRV in 76 subjects studied in different conditions: resting in the supine position, postural stress during 45° head-up tilt, and mental stress during computation of arithmetic test. Nine different indexes have been taken into account, computed in the time domain (mean, variance, root mean square of the successive differences), frequency domain (low-to-high frequency power ratio LF/HF, HF spectral power, and central frequency), and information domain (entropy, conditional entropy, self entropy). Thorough validation has been performed using comparison of the HRV and PRV distributions, robust linear regression, and Bland–Altman plots. Results demonstrate the feasibility of extracting HRV indexes from CBP-based data, showing an overall relatively good agreement of time-, frequency-, and information-domain measures. The agreement decreased during postural and mental arithmetic stress, especially with regard to band-power ratio, conditional, and self-entropy. This finding suggests to use caution in adopting PRV as a surrogate of HRV during stress conditions.

Graphical abstract



http://bit.ly/2DWQuJ8

Analysis of In Vivo Activity of the Bovine Cholesterol Hydroxylase/Lyase System Proteins Expressed in Escherichia coli

Abstract

The cholesterol hydroxylase/lyase (CHL) system, located in the mitochondria of the mammalian adrenal cortex cells, consists of cytochrome P450scc (CYP11A1), adrenodoxin (Adx), and adrenodoxin reductase (AdR) and performs the first stage of the steroidogenesis: AdR and Adx enable the electron transfer between NADPH and cytochrome P450scc, and P450scc catalyzes the conversion of cholesterol into pregnenolone. CHL system was reconstructed in Escherichia coli using the polycistronic plasmid pTrc99A/CHL. In E. coli cells, the recombinant proteins form the catalytically active system. CHL activity towards 22R-hydroxycholesterol was 4.0 ± 1.3 nmol pregnenolone/h per 1 mg homogenate protein. The alteration of the order of heterologous cDNAs in the expression cassette from AdR–Adx–P450scc to P450scc–Adx–AdR results in alteration of stoichiometric ratio P450scc/Adx/AdR from 1:1.45:4.2 to 1:1.67:0.98; the former ratio is more optimal for the functioning of the cytochrome P450scc. The application of modified cDNA of Adx (AdxS112W) does not increase the CHL activity; however, the introduction of the second copy of AdxS112W gene into the expression cassette increases both the expression level of АdxS112W and the CHL activity in comparison with P450scc/АdxS112W/AdR system. In vivo activity of the CHL system in bacteria is limited by the substrate uptake by bacterial cells: it varied in the range of 0.05–0.62 mg pregnenolone/l resting cell suspension per 1-day cultivation, depending on the type and concentration of permeabilizing agents in the medium. The obtained results contribute to the knowledge of CHL system functioning in living bacteria.



http://bit.ly/2RM63Ht

Phage Display Libraries: From Binders to Targeted Drug Delivery and Human Therapeutics

Abstract

The application of repertoire selection technologies for the study and characterization of tumor heterogeneity is an area of great interest in the field of tumor biology and immunotherapy. Among the most promising approaches, phage display has been successfully used to select peptides and antibody fragments to a variety of different targets, including cancer cells, immune cells and cytokines. Peptides selected from phage display have been used to guide the delivery of lytic peptides, cytotoxic drugs, and nanoparticles to cancer cells with the aim to obtain more efficient and less toxic therapeutics. Additionally, antibodies developed through phage display are being used in the treatment of autoimmune diseases and in some cases metastatic cancers. This review provides a short description of how phage libraries are designed, and highlights the conversion of the isolated binders into human therapeutics and use in targeted therapies.



http://bit.ly/2WKRc3z

Effect of acceleration on the rate of power development and neural activity of the leg extensors across the adult life span

Abstract

Purpose

The rate of power development (RPD) represents the capacity to rapidly generate power during a dynamic muscle contraction. As RPD is highly susceptible to aging, its decline can have important functional consequences. However, the effect of age on RPD in response to rapid changes in movement velocity (cfr. fall incidence) is not yet clear. Therefore, the present study aimed to examine the effect of age on RPD and neural drive in response to different accelerations.

Methods

Three maximal isokinetic leg extensor tests at 540°/s with different initial acceleration phases at 3200, 5700 and 7200°/s2 were performed. RPD, which is the slope of the power-time curve during the acceleration phase, was calculated for 83 subjects aged between 20 and 69 years. Mean electromyography signal amplitude was determined for rectus femoris (RF), vastus lateralis (VL) and biceps femoris muscles.

Results

The average annual age-related decline rate of RPD at highest acceleration was − 2.93% and was − 1.52% and − 1.82% higher compared to lower acceleration rates (p < 0.001). This deficit can probably be explained by an age-related impairment in neural drive during the first 75 ms of the acceleration phase, as evidenced by a reduced RF and VL neuromuscular activity of − 0.30% and − 0.36% at highest versus lowest acceleration (p < 0.05).

Conclusion

These findings highlight the inability of aged individuals to quickly respond to abrupt changes in movement velocity, which requires more focus in training and prevention programs.



http://bit.ly/2MTAWJb

The influence of local skin temperature on the sweat glands maximum ion reabsorption rate

Abstract

Purpose

Changes in mean skin temperature (Tsk) have been shown to modify the maximum rate of sweat ion reabsorption. This study aims to extend this knowledge by investigating if modifications could also be caused by local Tsk.

Methods

The influence of local Tsk on the sweat gland maximum ion reabsorption rates was investigated in ten healthy volunteers (three female and seven male; 20.8 ± 1.2 years, 60.4 ± 7.7 kg, 169.4 ± 10.4 cm) during passive heating (water-perfused suit and lower leg water immersion). In two separate trials, in a randomized order, one forearm was always manipulated to 33 °C (Neutral), whilst the other was manipulated to either 30 °C (Cool) or 36 °C (Warm) using water-perfused patches. Oesophageal temperature (Tes), forearm Tsk, sweat rate (SR), galvanic skin conductance (GSC) and salivary aldosterone concentrations were measured. The sweat gland maximum ion reabsorption rates were identified using the ∆SR threshold for an increasing ∆GSC.

Results

Thermal [Tes and body temperature (Tb)] and non-thermal responses (aldosterone) were similar across all conditions (p > 0.05). A temperature-dependent response for the sweat gland maximum ion reabsorption rates was evident between 30 °C (0.18 ± 0.10 mg/cm2/min) and 36 °C (0.28 ± 0.14 mg/cm2/min, d = 0.88, p < 0.05), but not for 33 °C (0.22 ± 0.12 mg/cm2/min), d = 0.44 and d = 0.36, p > 0.05.

Conclusion

The data indicate that small variations in local Tsk may not affect the sweat gland maximum ion reabsorption rates but when the local Tsk increases by > 6 °C, ion reabsorption rates also increase.



http://bit.ly/2SCB6d2