A meta-analysis approach with filtering for identifying gene-level gene–environment interactions

Abstract

There is a growing recognition that gene–environment interaction (G × E) plays a pivotal role in the development and progression of complex diseases. Despite a wealth of genetic data on various complex diseases/traits generated from association and sequencing studies, detecting G × E via genome-wide analysis remains challenging due to power issues. In genome-wide G × E studies, a common strategy to improve power is to first conduct a filtering test and retain only the genetic variants that pass the filtering step for subsequent G × E analyses. Two-stage, multistage, and unified tests have been proposed to jointly consider the filtering statistics in G × E tests. However, such G × E tests based on data from a single study may still be underpowered. Meanwhile, large-scale consortia have been formed to borrow strength across studies and populations. In this work, motivated by existing single-study G × E tests with filtering and the needs for meta-analysis G × E approaches based on consortia data, we propose a meta-analysis framework for detecting gene-based G × E effects, and introduce meta-analysis-based filtering statistics in the gene-level G × E tests. Simulations demonstrate the advantages of the proposed method—the ofGEM test. We apply the proposed tests to existing data from two breast cancer consortia to identify the genes harboring genetic variants with age-dependent penetrance (i.e., gene–age interaction effects). We develop an R software package ofGEM for the proposed meta-analysis tests.

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Non-enhanced MRI in combination with color Doppler flow imaging for improving diagnostic accuracy of parotid gland lesions

Abstract

Purpose

To determine the value of non-enhanced MRI in combination with color Doppler flow imaging (CDFI) for differentiating malignant parotid tumors from benign ones.

Methods

This retrospective study analyzed 51 parotid gland lesions (39 benign and 12 malignant) in 51 patients who underwent preoperative CDFI as well as non-enhanced MRI including T₁-weighted, T₂-weighted, and diffusion-weighted imaging (DWI). Degrees of intratumor vascularity were categorized into four grades basing on CDFI findings. The relationships between the lesion and its adjacent external carotid artery and retromandibular vein were inspected on T₁-weighted and T₂-weighted images. Apparent diffusion coefficient (ADC) values were calculated from diffusion-weighted images, and were used to classify the parotid gland lesions with and without reference to the CDFI findings. The classification results were compared using the McNemar test. Sensitivity, specificity, and accuracy percentages were calculated when the non-enhanced MRI/CDFI findings were used to differentiate benign lesions from malignant ones.

Results

The diagnostic accuracy (96.1 vs 82.4%) was significantly improved when ADCs were used together with CDFI findings for classifying parotid gland lesions compared to when ADCs were used alone. Pleomorphic adenomas had the highest ADCs. The ADC thresholds were 1.425 × 10⁻³ mm²/s for differentiating pleomorphic adenomas from carcinomas, 0.999 × 10⁻³ mm²/s for differentiating pleomorphic adenomas from other benign lesions, and 0.590 × 10⁻³ mm²/s for differentiating benign lesions other than pleomorphic adenomas from lymphomas.

Conclusion

Combining CDFI with non-enhanced MRI can improve the diagnostic accuracy of MRI for classifying parotid gland lesions.

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PLCγ2 promotes apoptosis while inhibits proliferation in rat hepatocytes through PKCD/JNK MAPK and PKCD/p38 MAPK signalling

Abstract

Objectives

The PLCG2 (PLCγ2) gene is a member of PLC gene family encoding transmembrane signalling enzymes involved in various biological processes including cell proliferation and apoptosis. Our earlier study indicated that PLCγ2 may be involved in the termination of regeneration of the liver which is mainly composed of hepatocytes, but its exact biological function and molecular mechanism in liver regeneration termination remains unclear. This study aims to examine the role of PLCγ2 in the growth of hepatocytes.

Materials and methods

A recombinant adenovirus expressing PLCγ2 was used to infect primary rat hepatocytes. PLCγ2 mRNA and protein levels were detected by qRT-PCR and Western blot. The subcellular location of PLCγ2 protein was tested by an immunofluorescence assay. The proliferation of hepatocytes was measured by MTT assay. The cell cycle and apoptosis were analysed by flow cytometry. Caspase-3, -8 and -9 activities were measured by a spectrophotometry method. Phosphorylation levels of PKCD, JNK and p38 in the infected cells were detected by Western blot. The possible mechanism underlying the role of PLCγ2 in hepatocyte growth was also explored by adding a signalling pathway inhibitor.

Results

Hepatocyte proliferation was dramatically reduced, while cell apoptosis was remarkably increased. The results demonstrated that PLCγ2 increased the phosphorylation of PKCD, p38 and JNK in rat hepatocytes. After PKCD activity was inhibited by the inhibitor Go 6983, the levels of both p-p38 and p-JNK MAPKs significantly decreased, and PLCγ2-induced cell proliferation inhibition and cell apoptosis were obviously reversed.

Conclusions

This study showed that PLCγ2 regulates hepatocyte growth through PKCD-dependently activating p38 MAPK and JNK MAPK pathways; this result was experimentally based on the further exploration of the effect of PLCγ2 on hepatocyte growth in vivo.

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Ethosuximide-induced Stevens–Johnson syndrome: Beneficial effect of early intervention with high-dose corticosteroid therapy

Abstract

We report two rare cases of childhood epilepsy patients who developed ethosuximide-induced Stevens–Johnson syndrome (SJS). Unlike typical SJS, the initial eruption of both patients presented well-demarcated, infiltrating firm papules mainly on the cheeks and the extensor aspects of the arms (case 1), and multiple vesicles on the soles and oral aphthosis (case 2), which closely mimicked viral exanthema. We diagnosed both patients with ethosuximide-induced SJS, based on the dosing period and the positive results of drug-induced lymphocyte stimulation test. Systemic corticosteroids are usually selected as a standard therapy for SJS, despite controversial results regarding their effectiveness. In case 1, an i.v. pulse therapy of methylprednisolone (30 mg/kg, 3 days consecutively) was initiated on day 7 from the onset of illness, and an i.v. immunoglobulin (400 mg/kg, 5 days consecutively) was added the following day. In case 2, an i.v. prednisone treatment (1 mg/kg, for 1 week) was initiated on day 4 from the onset. Eventually, the early therapeutic interventions resulted in good outcomes in both patients.

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Case of deep vein thrombosis in a patient with advanced malignant melanoma treated with dabrafenib and trametinib

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Immunocryosurgery as monotherapy for lentigo maligna or combined with surgical excision for lentigo maligna melanoma

Abstract

The incidence of lentigo maligna (LM), in situ (LM) or invasive (lentigo maligna melanoma, LMM), has increased during the last decades. Due to functional or cosmetic outcomes, optimal treatment with surgical excision may not be appropriate in some cases. We tried less invasive therapy, immunocryosurgery, as a single treatment for LM or combined with surgery for LMM, with better aesthetic results. Three patients with LM or LMM not amenable to complete surgical excision were selected. LMM patients underwent limited surgical resection of the invasive area. Subsequently, a combined treatment with topical imiquimod and cryosurgery was performed. The LM patient received immunocryosurgery directly. All of them were free of local and systemic disease at 48, 42 and 41 months after discontinuation of therapy. We consider that immunocryosurgery is an alternative option for LM or even for LMM (after removal of the invasive tissue with narrow margins) in poor surgical candidates, with good therapeutic, functional and cosmetic results.

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Benign cephalic histiocytosis: A case with infiltration of CD1a-positive langerin-negative cells

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Goodbye iOS app

Almost 10 years ago I coded up the first Radiopaedia iOS app. Since then we have had a few different version and a small but useful amount of content. One of the reasons for its existence was that at the time the website was horrible to use on mobile devices. Since then, we have spent a significant amount of effort in improving the mobile version of the app and have created new ways for users to curate and share cases. 

It is, therefore, time to say goodbye to the Radiopaedia iOS app. 

For now, the app still works and we will be leaving it on the app store, however, we will not be updating the app and it is very likely that with future updates to iOS the app will no longer work. This will probably happen when iOS 12 is released later in 2018. 

I wanted to thank all of you for your patronage. The small proceeds from the sale of the case packs have helped pay for the continued development of the site.

Frank

 

Associate Professor Frank Gaillard is the Founder and Editor in Chief of Radiopaedia.org. He is also an academic neuroradiologist and Director of Research in the Radiology Department of the Royal Melbourne Hospital/University of Melbourne in Melbourne, Australia.

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Resuscitative Endovascular Balloon Occlusion of the Aorta Using a Low-Profile Device is Easy and Safe for Emergency Physicians in Cases of Life-Threatening Hemorrhage

Publication date: Available online 10 February 2018
Source:The Journal of Emergency Medicine
Author(s): Takahiro Shoji, Takehiko Tarui, Takashi Igarashi, Yuki Mochida, Hiroyuki Morinaga, Yasuhiko Miyakuni, Yoshitaka Inoue, Yasuhiko Kaita, Hiroshi Miyauchi, Yoshihiro Yamaguchi
BackgroundBleeding from hemorrhagic shock can be immediately controlled by blocking the proximal part of the hemorrhagic point using either resuscitative thoracotomy for aortic cross-clamping or insertion of a large-caliber (10–14Fr) resuscitative endovascular balloon occlusion of the aorta (REBOA) device via the femoral artery. However, such methods are very invasive and have various complications. With recent progress in endovascular treatment, a low-profile REBOA device (7Fr) has been developed.ObjectiveThe objective of this study was to report our experience of this low-profile REBOA device and to evaluate the usefulness of emergency physician−operated REBOA in life-threatening hemorrhagic shock.MethodsTen patients with refractory hemorrhagic shock underwent REBOA using this device via the femoral artery. All REBOA procedures were performed by emergency physicians. The success rate of the insertion, vital signs, and REBOA-related complications were evaluated.ResultsMedian age was 54 years (interquartile range 33–78 years). The causes of hemorrhagic shock were trauma (n = 4; 1 blunt and 3 penetrating), ruptured abdominal aortic aneurysm (n = 3), and obstetric hemorrhage (n = 3). Two patients had cardiopulmonary arrest upon arrival. REBOA procedure was successful in all patients, and all became hemodynamically stable to undergo definitive interventions after REBOA. There were no REBOA-related complications. The mortality rate within 24 h and 30 days was 40%.ConclusionsThis REBOA device was useful for emergency physicians in life-threatening hemorrhagic shock because of its ease in handling and low invasiveness.



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Hematuria in an Adult with Congenital Heart Disease

Publication date: Available online 10 February 2018
Source:The Journal of Emergency Medicine
Author(s): Jennifer Noble, Shahnawaz M. Amdani, Richard U. Garcia, Rajan Arora
BackgroundAdults with congenital heart disease (CHD) in the United States now outnumber children with CHD, due in part to the improvement in surgical and medical management. This growing population may present postoperatively to the emergency department (ED) with nonspecific complaints from unforseen complications secondary to cardiac intervention.Case ReportWe describe a 39-year-old male who presented to the ED with hematuria and dysuria after he underwent percutaneous device ventricular septal defect (VSD) closure 10 days before. Upon initial evaluation, laboratory results confirmed a urinary tract infection and hematuria. Given persistent red discoloration of urine and easy fatigability, further investigation and re-evaluation found him to be anemic secondary to intravascular hemolysis. Cardiac catheterization showed residual shunting through the VSD device margins causing the hemolysis. Although this is a rare complication of VSD device closure, the patient's initial presentation of hematuria and dysuria presented a unique diagnostic challenge.Why Should an Emergency Physician Be Aware of This?Patients with underlying CHD require emergency physicians to consider a multidisciplinary approach to properly diagnose and facilitate treatment.



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Brugada-Type Pattern on Electrocardiogram Associated with High-Dose Loperamide Abuse

Publication date: Available online 10 February 2018
Source:The Journal of Emergency Medicine
Author(s): Christie Sun, Jessica A. Brice, Richard F. Clark
BackgroundLoperamide has been increasing in popularity recently for its effects separate from treatment of diarrhea. In large doses or in combination with other agents, it can lead to desirable effects in the central nervous system. However, cardiotoxicity has been reported with its abuse.Case ReportA 49-year-old male who had been chronically abusing loperamide was found to have Brugada-like changes on his electrocardiogram (ECG). He had no other clinical symptoms associated with Brugada syndrome and did not have similar findings on previous ECGs. After abstaining from further loperamide use during hospitalization, this pattern slowly resolved without clinically significant dysrthymias.Why Should an Emergency Physician Be Aware of This?A patient with a history of loperamide abuse is at risk for cardiotoxicity. While other dysrhythmias are reported more commonly with loperamide abuse, Brugada-like ECG changes can occur and warrant appropriate consultation and prompt follow-up.



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A Human Bite on the Scrotum: Case Report and Review of Management in the Emergency Department

Publication date: Available online 10 February 2018
Source:The Journal of Emergency Medicine
Author(s): Dorothy Ng, Thomas Chan, Sohil Pothiawala
BackgroundHuman bites involving the genitalia rarely present to the emergency department (ED). They have the potential to cause life-threatening secondary infections as well as serious physical and functional damage.Case ReportWe report a case of an adult male who sustained a human bite to the scrotum, resulting in a ragged laceration on the anterior scrotum, with a devascularized flap and necrotic edges overlying the wound.Why Should an Emergency Physician Be Aware of This?Human bites to the scrotum are rare and, hence, the experience of emergency physicians treating patients presenting with these injuries may be minimal. This puts patients at risk of underevaluation or suboptimal treatment. The rapid initiation of antibiotics in the ED and thorough wound debridement will prevent infections, aid healing, and lead to improved outcomes by preserving organ function and integrity. We therefore present a systematic approach to the management of patients with human bite to the scrotum in the ED.



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Selenite and methylseleninic acid epigenetically affects distinct gene sets in myeloid leukemia: A genome wide epigenetic analysis

Publication date: Available online 10 February 2018
Source:Free Radical Biology and Medicine
Author(s): Prajakta Khalkar, Hani Abdulkadir Ali, Paula Codó, Nuria Díaz Argelich, Anni Martikainen, Mohsen Karimi Arzenani, Sören Lehmann, Julian Walfridsson, Johanna Ungerstedt, Aristi P. Fernandes
Selenium compounds have emerged as promising chemotherapeutic agents with proposed epigenetic effects, however the mechanisms and downstream effects are yet to be studied. Here we assessed the effects of the inorganic selenium compound selenite and the organic form methylseleninic acid (MSA) in a leukemic cell line K562, on active (histone H3 lysine 9 acetylation, H3K9ac and histone H3 lysine 4 tri-methylation, H3K4me3) and repressive (histone H3 lysine 9 tri-methylation, H3K9me3) histone marks by Chromatin immunoprecipitation followed by DNA sequencing (ChIP-Seq). Both selenite and MSA had major effects on histone marks but the effects of MSA were more pronounced. Gene ontology analysis revealed that selenite affected genes involved in response to oxygen and hypoxia, whereas MSA affected distinct gene sets associated with cell adhesion and glucocorticoid receptors, also apparent by global gene expression analysis using RNA sequencing. The correlation to adhesion was functionally confirmed by a significantly weakened ability of MSA treated cells to attach to fibronectin and linked to decreased expression of integrin beta 1. A striking loss of cellular adhesion was also confirmed in primary patient AML cells. Recent strategies to enhance the cytotoxicity of chemotherapeutic drugs by disrupting the interaction between leukemic and stromal cells in the bone marrow are of increasing interest; and organic selenium compounds like MSA might be promising candidates. In conclusion, these results provide new insight on the mechanism of action of selenium compounds, and will be of value for the understanding, usage, and development of new selenium compounds as anticancer agents.

Graphical abstract

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Marker-Assisted Introgression of Saltol QTL Enhances Seedling Stage Salt Tolerance in the Rice Variety “Pusa Basmati 1”

Marker-assisted selection is an unequivocal translational research tool for crop improvement in the genomics era. Pusa Basmati 1 (PB1) is an elite Indian Basmati rice cultivar sensitive to salinity. Here, we report enhanced seedling stage salt tolerance in improved PB1 genotypes developed through marker-assisted transfer of a major QTL, Saltol. A highly salt tolerant line, FL478, was used as the Saltol donor. Parental polymorphism survey using 456 microsatellite (SSR)/QTL-linked markers revealed 14.3% polymorphism between PB1 and FL478. Foreground selection was carried out using three Saltol-linked polymorphic SSR markers RM8094, RM493, and RM10793 and background selection by 62 genome-wide polymorphic SSR markers. In every backcross generation, foreground selection was restricted to the triple heterozygotes of foreground markers, which was followed by phenotypic and background selections. Twenty-four near isogenic lines (NILs), with recurrent parent genome recovery of 96.0–98.4%, were selected after two backcrosses followed by three selfing generations. NILs exhibited agronomic traits similar to those of PB1 and additional improvement in the seedling stage salt tolerance. They are being tested for per se performance under salt-affected locations for release as commercial varieties. These NILs appear promising for enhancing rice production in salinity-affected pockets of Basmati Geographical Indication (GI) areas of India.

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Vitrification of one-cell mouse embryos in cryotubes

Publication date: Available online 8 February 2018
Source:Cryobiology
Author(s): Shinsuke Seki, Keita Basaki, Yukie Komatsu, Yasuyoshi Fukuda, Megumi Yano, Yuhei Matsuo, Takahiro Obata, Yukihisa Matsuda, Kazutoshi Nishijima
Preventing intracellular ice formation is essential to cryopreserve cells. Prevention can be achieved by converting cell water into a non-crystalline glass, that is, to vitrify. The prevailing belief is that to achieve vitrification, cells must be suspended in a solution containing a high concentration of glass-inducing solutes and cooled rapidly. In this study, we vitrified 1-cell mouse embryos and examined the effect of the cooling rate, the warming rate, and the concentration of cryoprotectant on cell survival. Embryos were vitrified in cryotubes. The vitrification solutions used were EFS20, EFS30, and EFS40, which contained ethylene glycol (20, 30 and 40% v/v, respectively), Ficoll (24%, 21%, and 18% w/v, respectively) and sucrose (0.4 0.35, and 0.3 M, respectively). A 5-μl EFS solution suspended with 1-cell embryos was placed in a cryotube. After 2 min in an EFS solution at 23 °C, embryos were vitrified by direct immersion into liquid nitrogen. The sample was warmed at 34 °C/min, 4,600 °C/min and 6,600 °C/min. With EFS40, the survival was low regardless of the warming rate. With EFS30 and EFS20, survival was also low when the warming rate was low, but increased with higher warming rates, likely due to prevention of intracellular ice formation. When 1-cell embryos were vitrified with EFS20 and warmed rapidly, almost all of the embryos developed to blastocysts in vitro. Moreover, when vitrified 1-cell embryos were transferred to recipients at the 2-cell stage, 43% of them developed to term. In conclusion, we developed a vitrification method for 1-cell mouse embryos by rapid warming using cryotubes.



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What is our place in the natural world?

A new exhibition, Mark Dion: Theatre of the natural world, sets out to explore the impact of our scientific endeavours. Plus, our rundown of the top upcoming events.

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We support the raising of standards in #patient care. Choose from our array of free e-learning modules + courses to… https://t.co/27cCpIzzRg

We support the raising of standards in #patient care. Choose from our array of free e-learning modules + courses to… https://t.co/27cCpIzzRg

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Serum and dietary zinc and copper in Iranian girls

Publication date: Available online 10 February 2018
Source:Clinical Biochemistry
Author(s): Kayhan Gonoodi, Alireza Moslem, Susan Darroudi, Mahsa Ahmadnezhad, Zahra Mazloum, Maryam Tayefi, Seyed Amir Tabatabaei Zadeh, Saeid Eslami, Mojtaba Shafiee, Zahra Khashayarmanesh, Hamideh Moalemzadeh Haghighi, Gordon A. Ferns, Majid Ghayour-Mobarhan
ObjectiveGirls with micronutrient deficiencies may have impaired growth and development, and furthermore this may also impact on their childbearing. We have investigated the relationship between serum zinc and copper concentrations, dietary zinc and copper intake and anthropometric and demographic parameters, and cardiovascular risk factors, in 408 girls living in northeastern Iran.MethodsA total of 408 healthy girls, aged 12–18 years old, were included in our study. Serum zinc and copper concentrations were measured by flame atomic absorption (Varian AA240FS) and zinc and copper intake were assessed using a 3-day dietary record.ResultsThere was a weak correlation between serum and dietary zinc intake (r = 0.117, p = 0.018). The correlation between serum and dietary copper approached significance (r = −0.094, p = 0.056). The mean serum zinc and copper concentrations were 14.61 ± 2.71 μmol/l and 19.48 ± 8.01 μmol/l respectively. Height, total cholesterol (TC) and low-density lipoprotein (LDL) were positively correlated with serum copper concentration. Subjects with high serum copper concentrations (>24 μmol/L) were found to have a significantly higher fasting blood glucose (FBG) compared to subjects with normal, or low serum copper concentrations (p = 0.033). Girls who were in the 5th percentile or greater for height were found to have higher serum copper concentrations than girls in other height categories.ConclusionThere was a weak relationship between dietary and serum concentrations of zinc. Copper status was associated with anthropometric and biochemical parameters, including FBG and lipid profile. Further studies are required to define the role of copper in metabolic health.



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IJMS, Vol. 19, Pages 547: The Roles of Mitochondrion in Intergenomic Gene Transfer in Plants: A Source and a Pool

IJMS, Vol. 19, Pages 547: The Roles of Mitochondrion in Intergenomic Gene Transfer in Plants: A Source and a Pool

International Journal of Molecular Sciences doi: 10.3390/ijms19020547

Authors: Nan Zhao Yumei Wang Jinping Hua

Intergenomic gene transfer (IGT) is continuous in the evolutionary history of plants. In this field, most studies concentrate on a few related species. Here, we look at IGT from a broader evolutionary perspective, using 24 plants. We discover many IGT events by assessing the data from nuclear, mitochondrial and chloroplast genomes. Thus, we summarize the two roles of the mitochondrion: a source and a pool. That is, the mitochondrion gives massive sequences and integrates nuclear transposons and chloroplast tRNA genes. Though the directions are opposite, lots of likenesses emerge. First, mitochondrial gene transfer is pervasive in all 24 plants. Second, gene transfer is a single event of certain shared ancestors during evolutionary divergence. Third, sequence features of homologies vary for different purposes in the donor and recipient genomes. Finally, small repeats (or micro-homologies) contribute to gene transfer by mediating recombination in the recipient genome.

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What is our place in the natural world?

A new exhibition, Mark Dion: Theatre of the natural world, sets out to explore the impact of our scientific endeavours. Plus, our rundown of the top upcoming events.

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IJERPH, Vol. 15, Pages 315: A Physical Health Profile of Youths Living with a “Hikikomori” Lifestyle

IJERPH, Vol. 15, Pages 315: A Physical Health Profile of Youths Living with a “Hikikomori” Lifestyle

International Journal of Environmental Research and Public Health doi: 10.3390/ijerph15020315

Authors: John Yuen Yoyo Yan Victor Wong Wilson Tam Ka-Wing So Wai-Tong Chien

A cross-sectional study was designed to understand the impacts of “hikikomori” lifestyle on physical health. A total of 104 eligible hikikomori cases were recruited from the social services network of Hong Kong with a mean age of 19.02 ± 3.62 (ranged 13–31) year-old, and had completed the set of questionnaires and a series of anthropometric and physical health measurements. Despite SF36 score of 84.0 indicated good physical functioning in general, participants were lived sedentarily with high incidence of hypertension at 15.4% and prehypertension at 31.7%. Occurrence of hypertension and prehypertension in cases living as hikikomori >6 months were 3 times and 1.5 times higher than those newly onset cases, respectively. The blood pressure levels were correlated with age and all obesity index parameters measured including waist circumference and body mass index. Results also observed a shift of body weight from underweight to overweight and obesity along the hikikomori duration. Half of the hypertensive cases involved the elevation of systolic blood pressure, which suggested higher odds of cardiovascular complications. In conclusion, the hikikomori lifestyle could be a risk behavior that may harm the younger generation physically by promoting obesity and hypertension and probably other chronic illnesses.

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IJMS, Vol. 19, Pages 546: The Low-Renin Hypertension Phenotype: Genetics and the Role of the Mineralocorticoid Receptor

IJMS, Vol. 19, Pages 546: The Low-Renin Hypertension Phenotype: Genetics and the Role of the Mineralocorticoid Receptor

International Journal of Molecular Sciences doi: 10.3390/ijms19020546

Authors: Rene Baudrand Anand Vaidya

A substantial proportion of patients with hypertension have a low or suppressed renin. This phenotype of low-renin hypertension (LRH) may be the manifestation of inherited genetic syndromes, acquired somatic mutations, or environmental exposures. Activation of the mineralocorticoid receptor is a common final mechanism for the development of LRH. Classically, the individual causes of LRH have been considered to be rare diseases; however, recent advances suggest that there are milder and “non-classical” variants of many LRH-inducing conditions. In this regard, our understanding of the underlying genetics and mechanisms accounting for LRH, and therefore, potentially the pathogenesis of a large subset of essential hypertension, is evolving. This review will discuss the potential causes of LRH, with a focus on implicated genetic mechanisms, the expanding recognition of non-classical variants of conditions that induce LRH, and the role of the mineralocorticoid receptor in determining this phenotype.

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Martin Vahlensieck, Maximilian Reiser: MRI of the musculoskeletal system : Thieme, Stuttgart, New York, Delhi, Rio de Janeiro, 2018, 677 p., format 23.5 × 31.5 cm, 2062 illustrations, ISBN 978-3-13-1165725, eISBN 978-3-13-1607928.

Martin Vahlensieck, Maximilian Reiser: MRI of the musculoskeletal system : Thieme, Stuttgart, New York, Delhi, Rio de Janeiro, 2018, 677 p., format 23.5 × 31.5 cm, 2062 illustrations, ISBN 978-3-13-1165725, eISBN 978-3-13-1607928.

Surg Radiol Anat. 2018 Feb 09;:

Authors: Grignon B

PMID: 29427175 [PubMed - as supplied by publisher]

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Cancers, Vol. 10, Pages 49: Beyond Brooding on Oncometabolic Havoc in IDH-Mutant Gliomas and AML: Current and Future Therapeutic Strategies

Cancers, Vol. 10, Pages 49: Beyond Brooding on Oncometabolic Havoc in IDH-Mutant Gliomas and AML: Current and Future Therapeutic Strategies

Cancers doi: 10.3390/cancers10020049

Authors: Hanumantha Madala Surendra Punganuru Viswanath Arutla Subhasis Misra T. Thomas Kalkunte Srivenugopal

Isocitrate dehydrogenases 1 and 2 (IDH1,2), the key Krebs cycle enzymes that generate NADPH reducing equivalents, undergo heterozygous mutations in >70% of low- to mid-grade gliomas and ~20% of acute myeloid leukemias (AMLs) and gain an unusual new activity of reducing the α-ketoglutarate (α-KG) to D-2 hydroxyglutarate (D-2HG) in a NADPH-consuming reaction. The oncometabolite D-2HG, which accumulates >35 mM, is widely accepted to drive a progressive oncogenesis besides exacerbating the already increased oxidative stress in these cancers. More importantly, D-2HG competes with α-KG and inhibits a large number of α-KG-dependent dioxygenases such as TET (Ten-eleven translocation), JmjC domain-containing KDMs (histone lysine demethylases), and the ALKBH DNA repair proteins that ultimately lead to hypermethylation of the CpG islands in the genome. The resulting CpG Island Methylator Phenotype (CIMP) accounts for major gene expression changes including the silencing of the MGMT (O6-methylguanine DNA methyltransferase) repair protein in gliomas. Glioma patients with IDH1 mutations also show better therapeutic responses and longer survival, the reasons for which are yet unclear. There has been a great surge in drug discovery for curtailing the mutant IDH activities, and arresting tumor proliferation; however, given the unique and chronic metabolic effects of D-2HG, the promise of these compounds for glioma treatment is uncertain. This comprehensive review discusses the biology, current drug design and opportunities for improved therapies through exploitable synthetic lethality pathways, and an intriguing oncometabolite-inspired strategy for primary glioblastoma.

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Serum bilirubin level predicts post-operative overall survival in oral squamous cell carcinoma

Abstract

Background

Aberrant level of serum bilirubin, marker of hepatobiliary and hematological disorders, was associated with patient prognosis in several human malignances. In the present study, we aim to evaluate the predictive value of serum bilirubin for clinicopathologic characteristics and survival of patients with oral squamous cell carcinoma (OSCC).

Methods

This study retrospectively reviewed 129 patients with OSCC and 129 normal controls matched for age and sex. The association between levels of preoperative direct bilirubin (DBIL), indirect bilirubin (IBIL), total bilirubin (TBIL) and clinical variables was analyzed. A proportional hazards regression model was used to find out the independent predictors of survival.

Results

Significantly lower TBIL (p = 0.009) and IBIL (p < 0.001) were found in OSCC patients compared with normal controls. DBIL (p = 0.011) and lymph-node metastasis (p = 0.031) were found to be independent prognostic factors. Patients with higher DBIL (≥4.0 μM) had longer overall survival than those with lower DBIL (p = 0.002). Patients with both lymph-node metastasis and lower DBIL showed the shortest overall survival (p = 0.001).

Conclusions

Lower DBIL was associated with a poorer prognosis and may be regarded as an independent prognostic marker for patients with OSCC.

This article is protected by copyright. All rights reserved.

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Bioreducible amino acid-derived polymeric nanoparticles for delivery of functional proteins.

Bioreducible amino acid-derived polymeric nanoparticles for delivery of functional proteins.

Colloids Surf B Biointerfaces. 2018 Feb 05;164:396-405

Authors: Kallar AR, Muthu J, Selvam S

Abstract
We report the preparation of protein encapsulated amino acid derived redox-responsive nanoparticles (NPs) as effective nanocarriers for intracellular delivery of proteins. More specifically, acryloyl derivatives of lysine, ornithine, cystine and cystamine, were employed as monomers and disulfide crosslinkers for non-covalent encapsulation of model protein bovine serum albumin (BSA) and were interfacially crosslinked via free radical polymerization to form redox-responsive protein NPs. Notably, prepared NPs exhibited high protein loading content between 37 and 45%, averaged ∼400 nm in hydrodynamic size and possessed a mean surface charge of -15 mV. Furthermore, blank polymeric NPs displayed exceptional cytocompatibility with cell viability exceeding 92% at concentrations as high as 4 mg/mL, while redox-responsive protein NPs displayed glutathione (GSH)-dependent BSA release behavior in vitro. Additionally, cellular uptake studies confirmed that protein NPs entered MDA-MA-231 cells predominantly via the endocytic pathway. Upon cellular internalization, redox-responsive NPs delivered protein into cytosol of cells within 60 min demonstrating intrinsic endosomolytic characteristics and efficient protein release under cytoplasmic high GSH conditions. Most importantly, insulin analog-loaded NPs significantly increased glucose consumption in HepG2 cultures confirming protein stability and retention of protein function. Cumulatively, our approach presents a simple yet effective strategy for intracellular delivery of biologically active proteins for various biomedical applications.

PMID: 29427946 [PubMed - as supplied by publisher]

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Decreased resistance of sublethally injured Escherichia coli O157:H7 to salt, mild heat, nisin and acids induced by high pressure carbon dioxide.

Decreased resistance of sublethally injured Escherichia coli O157:H7 to salt, mild heat, nisin and acids induced by high pressure carbon dioxide.

Int J Food Microbiol. 2018 Feb 01;269:137-143

Authors: Bi X, Wang Y, Hu X, Liao X

Abstract
Resistance of sublethally injured cells (SICs) of Escherichia coli O157:H7 induced by high pressure carbon dioxide (HPCD) to salt, low temperature, mild heat, nisin, acids and low pHs was investigated in this study. The SICs of E. coli were obtained following HPCD at 5 MPa and 25 °C for 40-60 min or 5 MPa and 45 °C for 20 min. The untreated cells could survive normally while the HPCD-treated cells showed 2.87 log10 cycles' reduction on tryptic soy agar (TSA) with 3% NaCl. The counts of the untreated cells were not significantly changed during 5 h incubation at 4 °C or 40 min incubation at 45 °C, and the HPCD-treated cells were also not affected by 5 h incubation at 4 °C but showed 1.75 log10 cycles' reduction at 45 °C for 40 min. The antimicrobial nisin caused an extra 0.25-1.0 log10 cycles' reduction of the HPCD-treated cells while the untreated cells was not inactivated by nisin. Except for oxalic acid (OA), citric acid (CA), malic acid (MA), tartaric acid (TA), lactic acid (LA), acetic acid (AA) and hydrochloric acid (HCl) did not inactivate the untreated cells, but all these seven acids caused a 0.74-1.53 log10 cycles' reduction of HPCD-treated cells. These results indicated that HPCD-induced SICs had a decreased resistance to salt, mild heat, nisin and acids. Moreover, the recovery test was used to investigate the sensitivity of the SICs to different pHs. Results showed that the SICs could not recover below or equal to pH 4.0. These promising results would open up the possibility of exploring the combination of other technologies (eg. mild heat, nisin and acids) with HPCD as hurdle approaches to inactivate target pathogens in foods.

PMID: 29427854 [PubMed - as supplied by publisher]

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Generation of patient-specific induced pluripotent stem cells from Leber's hereditary optic neuropathy.

Generation of patient-specific induced pluripotent stem cells from Leber's hereditary optic neuropathy.

Stem Cell Res. 2018 Jan 31;28:56-60

Authors: Lu HE, Yang YP, Chen YT, Wu YR, Wang CL, Tsai FT, Hwang DK, Lin TC, Chen SJ, Wang AG, Hsieh PCH, Chiou SH

Abstract
Leber's hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disease caused by homoplasmic point mutations in complex I subunit genes of mitochondrial DNA. In this report, we generated an induced pluripotent stem cell (iPSCs) line, TVGH-iPSC-010-09, from the peripheral blood mononuclear cells of a female patient with Leber's hereditary optic neuropathy (LHON) by using the Sendai-virus delivery system. The resulting iPSCs retained the disease-causing mitochondrial DNA mutation, expressed pluripotent markers and could differentiate into the three germ layers. We believe LHON patient-specific iPSCs provide a powerful in vitro model for evaluating the pathological phenotypes of the disease.

PMID: 29427840 [PubMed - as supplied by publisher]

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Australian nursing students' knowledge and attitudes towards pressure injury prevention: A cross-sectional study.

Australian nursing students' knowledge and attitudes towards pressure injury prevention: A cross-sectional study.

Int J Nurs Stud. 2018 Feb 02;81:14-20

Authors: Usher K, Woods C, Brown J, Power T, Lea J, Hutchinson M, Mather C, Miller A, Saunders A, Mills J, Zhao L, Yates K, Bodak M, Southern J, Jackson D

Abstract
AIM: The aim of this study was to assess student nurses' knowledge of and attitudes towards pressure injury prevention evidence-based guidelines.
BACKGROUND: Pressure injuries are a substantial problem in many healthcare settings causing major harm to patients, and generating major economic costs for health service providers. Nurses have a crucial role in the prevention of pressure injuries across all health care settings.
DESIGN: A multi-centered, cross-sectional study was conducted using a paper-based questionnaire with undergraduate nursing students enrolled in seven universities with campuses across five Australian states (Queensland, New South Wales, Western Australia, Victoria and Tasmania).
METHODS: Data were collected from nursing students using two validated instruments (Pressure Ulcer Knowledge Assessment Instrument and Attitude Toward Pressure Ulcer Prevention Instrument), to measure students' pressure injury prevention knowledge and attitudes.
RESULTS: Students reported relatively low pressure injury prevention knowledge scores (51%), and high attitude scores (78%). Critical issues in this study were nursing students' lack of knowledge about preventative strategies to reduce the amount and duration of pressure/shear, and lower confidence in their capability to prevent pressure injury. Level of education and exposure to working in a greater number of different clinical units were significantly related to pressure injury prevention knowledge and attitude scores.
CONCLUSION: The study findings highlight the need to implement a comprehensive approach to increasing Australian nursing students' pressure injury prevention and management knowledge, as well as ensuring that these students have adequate experiences in clinical units, with a high focus on pressure injury prevention to raise their personal capability.

PMID: 29427831 [PubMed - as supplied by publisher]

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Gout drugs use and risk of cancer: A case-control study.

Gout drugs use and risk of cancer: A case-control study.

Joint Bone Spine. 2018 Feb 07;:

Authors: Yang HC, Nguyen PAA, Islam MM, Huang CW, Poly TN, Iqbal U, Jack Li YC

Abstract
OBJECTIVE: Firm conclusion about whether short and long-term gout medications use has an impact on cancer risk remain inconclusive. The aim of this study was to investigate the association between gout drugs use and risk of cancer.
METHODS: We conducted a retrospective longitudinal population-based case-control study in Taiwan. Cases were identified all patients who were aged 20 years or above, and had a first time diagnosis of cancers for the period between 2001 and 2011. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were calculated by using conditional logistic regression.
RESULTS: We examined 601,733 cases and 2,406,932 matched controls. The adjusted odd ratio for any gout drugs use and overall cancer risk was 1.007 (95% CI, 0.994 -1.020). There was a significant risk of leukemia (AOR: 1.34, 95%CI 1.20-1.50), endometrial cancer (AOR: 1.33, 95%CI 1.12-1.57), non-Hodgkin's (AOR: 1.24, 95%CI 1.13-1.35), female breast cancer (AOR: 1.21, 95%CI 1.13-1.29), cervical cancer (AOR: 1.21, 95%CI 1.07-1.37). However, no association was observed in male group (AOR: 0.97, 95%CI 0.95-0.98) but female showed a significantly increased risk of cancer at any site (AOR: 1.107, 95%CI 1.08-1.13).
CONCLUSION: In summary, our results suggest that gout drugs increase risk of the most common cancers, particularly in leukemia, non-Hodgkin's, endometrial, breast and cervical cancer.

PMID: 29427783 [PubMed - as supplied by publisher]

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Enhanced tendon-to-bone repair through adhesive films.

Enhanced tendon-to-bone repair through adhesive films.

Acta Biomater. 2018 Feb 07;:

Authors: Linderman SW, Golman M, Gardner TR, Birman V, Levine WN, Genin GM, Thomopoulos S

Abstract
Tendon-to-bone surgical repairs have unacceptably high failure rates, possibly due to their inability to recreate the load transfer mechanisms of the native enthesis. Instead of distributing load across a wide attachment footprint area, surgical repairs concentrate shear stress on a small number of suture anchor points. This motivates development of technologies that distribute shear stresses away from suture anchors and across the enthesis footprint. Here, we present predictions and proof-of-concept experiments showing that mechanically-optimized adhesive films can mimic the natural load transfer mechanisms of the healthy attachment and increase the load tolerance of a repair. Mechanical optimization, based upon a shear lag model corroborated by a finite element analysis, revealed that adhesives with relatively high strength and low stiffness can, theoretically, strengthen tendon-to-bone repairs by over 10-fold. Lap shear testing using tendon and bone planks validated the mechanical models for a range of adhesive stiffnesses and strengths. Ex vivo human supraspinatus repairs of cadaveric tissues using multipartite adhesives showed substantial increase in strength. Results suggest that adhesive-enhanced repair can improve repair strength, and motivate a search for optimal adhesives.
STATEMENT OF SIGNIFICANCE: Current surgical techniques for tendon-to-bone repair have unacceptably high failure rates, indicating that the initial repair strength is insufficient to prevent gapping or rupture. In the rotator cuff, repair techniques apply compression over the repair interface to achieve contact healing between tendon and bone, but transfer almost all force in shear across only a few points where sutures puncture the tendon. Therefore, we evaluated the ability of an adhesive film, implanted between tendon and bone, to enhance repair strength and minimize the likelihood of rupture. Mechanical models demonstrated that optimally designed adhesives would improve repair strength by over 10-fold. Experiments using idealized and clinically-relevant repairs validated these models. This work demonstrates an opportunity to dramatically improve tendon-to-bone repair strength using adhesive films with appropriate material properties.

PMID: 29427745 [PubMed - as supplied by publisher]

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Interaction of proteins with lemon-juice/glutathione-derived carbon nanodot: Interplay of induced-aggregation and co-solubilization.

Interaction of proteins with lemon-juice/glutathione-derived carbon nanodot: Interplay of induced-aggregation and co-solubilization.

Int J Biol Macromol. 2018 Feb 07;:

Authors: Bihani O, Rai T, Panda D

Abstract
Carbon nanodots have generated huge interest in biomedical applications owing to unique emission property and good biocompatibility. In this study, a carbon nanodot is synthesized from a natural resource- lemon juice which is consumed in daily life and glutathione, a biologically active molecule. The synthesized nanodot possesses excitation-independent emission and nano-sheet like like with high graphitic content. Interaction of protein with CND is monitored by intrinsic fluorescence (trp residues), FT-IR and circular dichroism spectroscopy. Interestingly, at a lower concentration, nanodot promotes the protein aggregation. Whereas it solubilizes the protein aggregates at its higher concentration. Both induced-aggregation and co-solubilization are sequence-independent and dictated by nanodot. The study may shed light on the role of glutathione in glutathione-dependent glyoxalase system toward defense against glycation product.

PMID: 29427683 [PubMed - as supplied by publisher]

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Intracellular formyl peptide receptor regulates naïve CD4 T cell migration.

Intracellular formyl peptide receptor regulates naïve CD4 T cell migration.

Biochem Biophys Res Commun. 2018 Feb 07;:

Authors: Lee HY, Jeong YS, Lee M, Kweon HS, Huh YH, Park JS, Hwang JE, Kim K, Bae YS

Abstract
We found that formyl peptide receptor (FPR) 1 and FPR3 were expressed intracellularly and/or the nucleus of naïve CD4 T cell. Activation of naïve CD4 T cells with synthetic intracellular agonists dTAT-WKYMVm and CTP-WKYMVm for FPR members stimulated CD4 T cell migration via pertussis toxin-sensitive manner. Knockdown of FPR1, but not knockdown of FPR3, blocked dTAT-WKYMVm-induced naïve CD4 T cell migration. Stimulation of naïve CD4 T cells with dTAT-WKYMVm elicited the activation of ERK, p38 MAPK, and Akt. Activation of CD4 T cells with anti-CD3 and anti-CD28 antibodies caused surface expression of FPR1 and FPR3, but not FPR2. CD4 T cells isolated from sepsis patients expressed the three members of FPR family on their cell surface. Taken together, our results suggest that intracellular FPR in naïve CD4 T cells and surface FPRs in activated CD4 T cells might regulate immune responses by regulating CD4 T cell activity.

PMID: 29427663 [PubMed - as supplied by publisher]

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Germline Gain-of-Function MYD88 Mutation in a Child with Severe Arthritis.

Germline Gain-of-Function MYD88 Mutation in a Child with Severe Arthritis.

J Allergy Clin Immunol. 2018 Feb 07;:

Authors: Sikora KA, Bennett JR, Vyncke L, Deng Z, Tsai WL, Pauwels E, Layh-Schmitt G, Brundidge A, Navid F, Zaal KJM, Hanson E, Gadina M, Staudt LM, Griffin TA, Tavernier J, Peelman F, Colbert RA

PMID: 29427642 [PubMed - as supplied by publisher]

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Brg1 promotes liver fibrosis via activation of hepatic stellate cells.

Brg1 promotes liver fibrosis via activation of hepatic stellate cells.

Exp Cell Res. 2018 Feb 07;:

Authors: Li H, Lan J, Han C, Guo K, Wang G, Hu J, Gong J, Luo X, Cao Z

Abstract
Liver fibrosis, an important health concern associated to chronic liver injury that provides a permissive environment for cancer development, is characterized by the persistent deposition of extracellular matrix components mainly derived from activated hepatic stellate cells (HSCs). Brg1, the core subunit of the SWI/SNF chromatin remodeling complex, has been proved to associated with nonalcoholic steatohepatitis which may progress to cirrhosis. Herein, we determined whether Brg1 regulates liver fibrosis and examined its mechanism by focusing on HSCs activation. In this study, we demonstrate that Brg1 is elevated in human and mouse fibrotic liver tissues and Brg1 mediate the profibrotic response in activated HSCs. Our data indicate that Brg1 regulates the activation of HSCs through TGFβ/Smad signal pathway. Moreover, Brg1 deficiency mice displayed decreased HSCs activation in vitro and liver fibrogenesis after chronic damage by CCl4 administration. In addition, Brg1 expression is positively correlated with liver fibrosis in cirrhotic patients and may be a prognostic factor in HCC. Collectively, we demonstrate that Brg1 promotes liver fibrosis by activating HSCs and may represent a potential target for anti-fibrotic therapies.

PMID: 29427621 [PubMed - as supplied by publisher]

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Quality and future of clinical laboratories: the Vico's whole cyclical theory of the recurring cycles.

Quality and future of clinical laboratories: the Vico's whole cyclical theory of the recurring cycles.

Clin Chem Lab Med. 2018 Feb 10;:

Authors: Plebani M

Abstract
In the last few decades, laboratory medicine has undergone monumental changes, and laboratory technology, which has made enormous advances, now has new clinical applications thanks to the identification of a growing number of biomarkers and risk factors conducive to the promotion of predictive and preventive interventions that have enhanced the role of laboratory medicine in health care delivering. However, the paradigm shift in the past 50 years has led to a gap between laboratory and clinic, with an increased risk of inappropriateness in test request and interpretation, as well as the consolidation of analytical work in focused factories and megastructurers oriented only toward achieving greater volumes, decreasing cost per test and generating a vision of laboratory services as simple commodities. A careful historical revision of the changing models for delivering laboratory services in the United States leads to the prediction that there are several reasons for counteracting the vision of clinical laboratory as a commodity, and restoring the true nature of laboratory services as an integral part of the diagnosis and therapy process. The present study, which reports on internal and external drivers for change, proposes an integrated vision of quality in laboratory medicine.

PMID: 29427552 [PubMed - as supplied by publisher]

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Endogenous Biological Factors Modulated by Substrate Stiffness Regulate Endothelial Differentiation of Mesenchymal Stem Cells.

Endogenous Biological Factors Modulated by Substrate Stiffness Regulate Endothelial Differentiation of Mesenchymal Stem Cells.

J Biomed Mater Res A. 2018 Feb 10;:

Authors: Jiang YC, Jiao HL, Lee MS, Wang T, Turng LS, Li Q, Li WJ

Abstract
During the process of tissue regeneration facilitated by stem cells, physical properties of a scaffold affect behavior and activities of the cell. To enhance differentiation of human mesenchymal stem cells (MSCs) into endothelial-like cells (ELCs), we used electrospun fibrous substrates with different stiffness to enhance the differentiation. A simple method of annealing with different lengths of treatment time was employed to modulate stiffness of electrospun fibrous substrates without changing their chemistry. We seeded MSCs on substrates with different stiffness to study how stiffness of a culture substrate affects differentiation of MSCs into ELCs. Results of RT-PCR and western blotting revealed that stiffer substrates with the average surface modulus of 7.82 MPa induced differentiated MSCs to express more VEGF, CD31, and vWF mRNA transcripts and proteins than softer ones with that of 3.8 or 1.44 MPa. We also found that the production of macrophage migration inhibitory factor (MIF) in ELCs was increased with substrate stiffness. After silencing MIF mRNA, MSCs during differentiation showed lower expression levels of VEGF, CD31, and vWF than control cells whereas VEGF-silenced and control cells expressed comparable levels of MIF, indicating that MIF is an upstream molecule regulating VEGF in the mechanism. Our findings provide new insight into how stiffness of a culture substrate regulates differentiation of MSCs into ELCs. This article is protected by copyright. All rights reserved.

PMID: 29427535 [PubMed - as supplied by publisher]

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Multi-omics approach to elucidate the gut microbiota activity. Metaproteomics and metagenomics connection.

Multi-omics approach to elucidate the gut microbiota activity. Metaproteomics and metagenomics connection.

Electrophoresis. 2018 Feb 10;:

Authors: Guirro M, Costa A, Gual-Grau A, Mayneris-Perxachs J, Torrell H, Herrero P, Canela N, Arola L

Abstract
Over the last few years, the application of high-throughput meta-omics methods has provided great progress in improving the knowledge of the gut ecosystem and linking its biodiversity to host health conditions, offering complementary support to classical microbiology. Gut microbiota plays a crucial role in relevant diseases such as obesity or cardiovascular disease, and its regulation be closely influenced by several factors, such as dietary composition. In fact, polyphenol-rich diets are the most palatable treatment to prevent hypertension associated with cardiovascular disease, although the polyphenol-microbiota interactions have not been completely elucidated. For this reason, the aim of this study was to evaluate microbiota effect in obese rats supplemented by, after being fed with cafeteria or standard diet, using a multi meta-omics approaches combining strategy of metagenomics and metaproteomics analysis. We reported that cafeteria diet induces obesity, resulting in changes in the microbiota composition, which are related to functional alterations at proteome level. In addition, hesperidin supplementation alters microbiota diversity and also proteins involved in important metabolic pathways. Overall, going deeper into strategies to integrate omics sciences is necessary to understand the complex relationships between the host, gut microbiota and diet. This article is protected by copyright. All rights reserved.

PMID: 29427518 [PubMed - as supplied by publisher]

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Managing High-Cost Healthcare Users: The International Search for Effective Evidence-Supported Strategies.

Managing High-Cost Healthcare Users: The International Search for Effective Evidence-Supported Strategies.

J Am Geriatr Soc. 2018 Feb 10;:

Authors: Lee JY, Muratov S, Tarride JE, Holbrook AM

Abstract
High-cost healthcare users (HCUs) are a small proportion of the population who use a disproportionate amount of healthcare resources. Although the phenomenon occurs across the entire age spectrum, older adults represent the majority of HCUs. HCUs have drawn increasing attention internationally from clinicians, health policy-makers, and government administrators. Many experts have suggested that the short- and long-term sustainability of the healthcare system is threatened unless current approaches to the care and healthcare costs of this population are modified. Complex case management and care coordination models are being implemented internationally to address HCUs despite a lack of strong evidence to support their effectiveness in improving clinical outcomes or savings in costs of care. We review what is known about HCUs and the available evidence for the effectiveness of interventions designed to manage their high and costly healthcare use.

PMID: 29427509 [PubMed - as supplied by publisher]

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Chemical reactivation of fluorescein isothiocyanate immunofluorescence-labeled resin-embedded samples.

Chemical reactivation of fluorescein isothiocyanate immunofluorescence-labeled resin-embedded samples.

J Biomed Opt. 2018 Feb;23(2):1-4

Authors: Li L, Rao G, Lv X, Chen R, Cheng X, Wang X, Zeng S, Liu X

Abstract
Resin embedding is widely used and facilitates microscopic imaging of biological tissues. In contrast, quenching of fluorescence during embedding process hinders the application of resin embedding for imaging of fluorescence-labeled samples. For samples expressing fluorescent proteins, it has been demonstrated that the weakened fluorescence could be recovered by reactivating the fluorophore with alkaline buffer. We extended this idea to immunofluorescence-labeling technology. We showed that the fluorescence of pH-sensitive fluorescein isothiocyanate (FITC) was quenched after resin embedding but reactivated after treating by alkaline buffer. We observed 138.5% fluorescence preservation ratio of reactivated state, sixfold compared with the quenched state in embedding resin, which indicated its application for fluorescence imaging of high signal-to-background ratio. Furthermore, we analyzed the chemical reactivation mechanism of FITC fluorophore. This work would show a way for high-resolution imaging of immunofluorescence-labeled samples embedded in resin.

PMID: 29427410 [PubMed - in process]

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Dynamic 2D self-phase-map Nyquist ghost correction for simultaneous multi-slice echo planar imaging.

Dynamic 2D self-phase-map Nyquist ghost correction for simultaneous multi-slice echo planar imaging.

Magn Reson Med. 2018 Feb 09;:

Authors: Yarach U, Tung YH, Setsompop K, In MH, Chatnuntawech I, Yakupov R, Godenschweger F, Speck O

Abstract
PURPOSE: To develop a reconstruction pipeline that intrinsically accounts for both simultaneous multislice echo planar imaging (SMS-EPI) reconstruction and dynamic slice-specific Nyquist ghosting correction in time-series data.
METHODS: After 1D slice-group average phase correction, the separate polarity (i.e., even and odd echoes) SMS-EPI data were unaliased by slice GeneRalized Autocalibrating Partial Parallel Acquisition. Both the slice-unaliased even and odd echoes were jointly reconstructed using a model-based framework, extended for SMS-EPI reconstruction that estimates a 2D self-phase map, corrects dynamic slice-specific phase errors, and combines data from all coils and echoes to obtain the final images.
RESULTS: The percentage ghost-to-signal ratios (%GSRs) and its temporal variations for MB3Ry 2 with a field of view/4 shift in a human brain obtained by the proposed dynamic 2D and standard 1D phase corrections were 1.37 ± 0.11 and 2.66 ± 0.16, respectively. Even with a large regularization parameter λ applied in the proposed reconstruction, the smoothing effect in fMRI activation maps was comparable to a very small Gaussian kernel size 1 × 1 × 1 mm3 .
CONCLUSION: The proposed reconstruction pipeline reduced slice-specific phase errors in SMS-EPI, resulting in reduction of GSR. It is applicable for functional MRI studies because the smoothing effect caused by the regularization parameter selection can be minimal in a blood-oxygen-level-dependent activation map.

PMID: 29427393 [PubMed - as supplied by publisher]

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STARCH DIGESTIBILITY: PAST, PRESENT, AND FUTURE.

STARCH DIGESTIBILITY: PAST, PRESENT, AND FUTURE.

J Sci Food Agric. 2018 Feb 10;:

Authors: Bello-Perez LA, Flores-Silva PC, Agama-Acevedo E, Tovar J

Abstract
In the last century, starch present in foods was considered to be completely digested. However, during the eighties, studies on starch digestion started to show that besides digestible starch, which could be rapidly or slowly hydrolysed, there was a variable fraction that resisted hydrolysis by digestive enzymes. That fraction was named resistant starch (RS) and it encompasses those forms of starch that are not accessible to human digestive enzymes but can be fermented by the colonic microbiota, producing short chain fatty acids. RS has been classified into five types, depending on the mechanism governing its resistance to enzymatic hydrolysis. Early research on RS was focused on the methods to determine its content in foods and its physiological effects, including fermentability in the large intestine. Later on, due to the interest of the food industry, methods to increase the RS content of isolated starches were developed. Nowadays, the influence of RS on the gut microbiota is a relevant research topic due to its potential health-related benefits. This review summarizes over 30 years of investigation on starch digestibility, its relationship with human health, the methods to produce RS and its impact on the microbiome.

PMID: 29427318 [PubMed - as supplied by publisher]

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Naringenin Decreases α-Synuclein Expression and Neuroinflammation in MPTP-Induced Parkinson's Disease Model in Mice.

Naringenin Decreases α-Synuclein Expression and Neuroinflammation in MPTP-Induced Parkinson's Disease Model in Mice.

Neurotox Res. 2018 Feb 09;:

Authors: Mani S, Sekar S, Barathidasan R, Manivasagam T, Thenmozhi AJ, Sevanan M, Chidambaram SB, Essa MM, Guillemin GJ, Sakharkar MK

Abstract
The present study was designed to ascertain the role of naringenin (NGN), a citrus fruit flavanone, against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced α-synuclein (SYN) pathology and neuroinflammation in a mouse model. NGN was administered to C57BL/6J mice once a day for 5 consecutive days prior to the MPTP intoxication. On day 5, 40-50 min after the NGN or vehicle administration, MPTP was injected in two divided doses (2× 40 mg/kg, i.p. at 16 h apart). The animals were observed for motor functions 48 h after the first MPTP injection. The animals were then euthanized, the brains collected to analyze SYN pathology, cytokines, and oxidative stress levels in the substantia nigra region. The NGN significantly downregulated SYN and upregulated dopamine transporter (DAT) and tyrosine hydroxylase (TH) protein expressions. It also downregulated tumor necrosis factor-α (TNFα) and interleukin 1β (IL1β) mRNA expressions and improved superoxide dismutase levels. It also reduced glutathione levels when compared to vehicle-treated PD animals. The upregulation of TH corroborates to an increase in dopamine, DOPAC, and homovanillic acid turnover and motor functions with NGN treatment. To summarize, NGN, a dietary flavone, has the potential to counteract MPTP-induced dopaminergic degeneration by regulating SYN pathology, neuroinflammation, and oxidative stress. This warrants the investigation of NGN's potential effects in a genetic model of PD.

PMID: 29427283 [PubMed - as supplied by publisher]

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Urban Renewal Mega Projects and Residents' Quality of Life: Evidence from Historical Religious Center of Mashhad Metropolis.

Urban Renewal Mega Projects and Residents' Quality of Life: Evidence from Historical Religious Center of Mashhad Metropolis.

J Urban Health. 2018 Feb 09;:

Authors: Forouhar A, Hasankhani M

Abstract
Urban decay is the process by which a historical city center, or an old part of a city, falls into decrepitude and faces serious problems. Urban management, therefore, implements renewal mega projects with the goal of physical and functional revitalization, retrieval of socioeconomic capacities, and improving of quality of life of residents. Ignoring the complexities of these large-scale interventions in the old and historical urban fabrics may lead to undesirable consequences, including an additional decline of quality of life. Thus, the present paper aims to assess the impact of renewal mega projects on residents' subjective quality of life, in the historical religious district of the holy city of Mashhad (Samen District). A combination of quantitative and qualitative methods of impact assessment, including questionnaires, semi-structured personal interviews, and direct observation, is used in this paper. The results yield that the Samen Renewal Project has significantly reduced the resident's subjective quality of life, due to its undesirable impacts on physical, socio-cultural, and economic environments.

PMID: 29427264 [PubMed - as supplied by publisher]

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Prefoldin, a jellyfish-like molecular chaperone: functional cooperation with a group II chaperonin and beyond.

Prefoldin, a jellyfish-like molecular chaperone: functional cooperation with a group II chaperonin and beyond.

Biophys Rev. 2018 Feb 09;:

Authors: Sahlan M, Zako T, Yohda M

Abstract
Prefoldin is a hexameric molecular chaperone found in the cytosol of archaea and eukaryotes. Its hexameric complex is built from two related classes of subunits and has the appearance of a jellyfish: its body consists of a double beta-barrel assembly with six long tentacle-like coiled coils protruding from it. Using the tentacles, prefoldin captures an unfolded protein substrate and transfers it to a group II chaperonin. The prefoldin-group II chaperonin system is thought to be important for the folding of newly synthesized proteins and for their maintenance, or proteostasis, in the cytosol. Based on structural information of archaeal prefoldins, the mechanisms of substrate recognition and prefoldin-chaperonin cooperation have been investigated. In contrast, the role and mechanism of eukaryotic PFDs remain unknown. Recent studies have shown that prefoldin plays an important role in proteostasis and is involved in various diseases. In this paper, we review a series of studies on the molecular mechanisms of archaeal prefoldins and introduce recent findings about eukaryotic prefoldin.

PMID: 29427249 [PubMed - as supplied by publisher]

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Sporadic pediatric papillary thyroid carcinoma harboring the ETV6/NTRK3 fusion oncogene in a 7-year-old Japanese girl: a case report and review of literature.

Sporadic pediatric papillary thyroid carcinoma harboring the ETV6/NTRK3 fusion oncogene in a 7-year-old Japanese girl: a case report and review of literature.

J Pediatr Endocrinol Metab. 2018 Feb 10;:

Authors: Otsubo R, Mussazhanova Z, Akazawa Y, Sato A, Matsuda K, Matsumoto M, Yano H, Matsuse M, Mitsutake N, Ando T, Niino D, Nagayasu T, Nakashima M

Abstract
BACKGROUND: There have been great concerns about pediatric thyroid cancers after the accident at the Fukushima Daiichi Nuclear Power Plant in 2011.
CASE PRESENTATION: We report a case of a 7-year-old Japanese girl with sporadic papillary thyroid carcinoma (PTC) harboring an ETV6/NTRK3 rearrangement. The patient presented with tumors in both lobes and underwent thyroidectomy followed by radioactive iodine (RAI) ablation. Histopathology showed a classic type of PTC with cervical lymph node metastasis.
CONCLUSIONS: Genetic evaluation showed ETV6/NTRK3 fusion but no BRAF mutations or RET/PTC rearrangements. RET/PTC rearrangement and BRAF mutations often contribute to the pathogenesis of PTC; however, rearrangements of NTRK genes are relatively rare in pediatric PTC. Although NTRK rearrangement has been shown to often present unique pathological types and infiltrative architectures in the western population, such findings were not observed in this patient. Thus, the present case of classic PTC with ETV6/NTRK3 rearrangement highlights the disparate collection of clinic-pathological features compared to the trend in the western population. We therefore emphasize the need to further accumulate clinical as well as genetic data in pediatric PTCs.

PMID: 29427554 [PubMed - as supplied by publisher]

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Apple, condom, and cocaine – body stuffing in prison: a case report

Drug dealers and drug users resort to body stuffing to hastily conceal illicit drugs by ingesting their drug packets. This practice represents a medical challenge because rupture of the often insecure packagin...

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IJMS, Vol. 19, Pages 543: Determination of Proteinaceous Selenocysteine in Selenized Yeast

IJMS, Vol. 19, Pages 543: Determination of Proteinaceous Selenocysteine in Selenized Yeast

International Journal of Molecular Sciences doi: 10.3390/ijms19020543

Authors: Katarzyna Bierla Ryszard Lobinski Joanna Szpunar

A method for the quantitation of proteinaceous selenocysteine (SeCys) in Se-rich yeast was developed. The method is based on the reduction of the Se-Se and S-Se bridges with dithiotretiol, derivatization with iodoacetamide (carbamidomethylation), followed by HPLC-ICP MS. The chromatographic conditions were optimized for the total recovery of the proteinaceous selenocysteine, the minimum number of peaks in the chromatogram (reduction of derivatization products of other Se-species present) and the baseline separation. A typical chromatogram of a proteolytic digest of selenized yeast protein consisted of up to five peaks (including SeMet, carbamidomethylated (CAM)-SeCys, and Se(CAM)2) identified by retention time matching with available standards and electrospray MS. Inorganic selenium non-specifically attached to proteins and selenomethionine could be quantified (in the form of Se(CAM)2) along with SeCys. Selenocysteine, selenomethionine, inorganic selenium, and the water soluble-metabolite fraction accounted for the totality of selenium species in Se-rich yeast.

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IJMS, Vol. 19, Pages 544: Bacterial Heterologous Expression System for Reconstitution of Chloroplast Inner Division Ring and Evaluation of Its Contributors

IJMS, Vol. 19, Pages 544: Bacterial Heterologous Expression System for Reconstitution of Chloroplast Inner Division Ring and Evaluation of Its Contributors

International Journal of Molecular Sciences doi: 10.3390/ijms19020544

Authors: Hiroki Irieda Daisuke Shiomi

Plant chloroplasts originate from the symbiotic relationship between ancient free-living cyanobacteria and ancestral eukaryotic cells. Since the discovery of the bacterial derivative FtsZ gene—which encodes a tubulin homolog responsible for the formation of the chloroplast inner division ring (Z ring)—in the Arabidopsis genome in 1995, many components of the chloroplast division machinery were successively identified. The knowledge of these components continues to expand; however, the mode of action of the chloroplast dividing system remains unknown (compared to bacterial cell division), owing to the complexities faced in in planta analyses. To date, yeast and bacterial heterologous expression systems have been developed for the reconstitution of Z ring-like structures formed by chloroplast FtsZ. In this review, we especially focus on recent progress of our bacterial system using the model bacterium Escherichia coli to dissect and understand the chloroplast division machinery—an evolutionary hybrid structure composed of both bacterial (inner) and host-derived (outer) components.

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IJERPH, Vol. 15, Pages 313: A Descriptive Longitudinal Study of Changes in Vape Shop Characteristics and Store Policies in Anticipation of the 2016 FDA Regulations of Tobacco Products, Including E-Cigarettes

IJERPH, Vol. 15, Pages 313: A Descriptive Longitudinal Study of Changes in Vape Shop Characteristics and Store Policies in Anticipation of the 2016 FDA Regulations of Tobacco Products, Including E-Cigarettes

International Journal of Environmental Research and Public Health doi: 10.3390/ijerph15020313

Authors: Sheila Yu Patricia Escobedo Robert Garcia Tess Cruz Jennifer Unger Lourdes Baezconde-Garbanati Leah Meza Steve Sussman

After proposing the “Deeming Rule” in 2014, the U.S. Food and Drug Administration (FDA) began regulating the manufacturing, marketing, and sales of electronic cigarette (e-cigarette) products as tobacco products in 2016. The current study conducted vape shop store observations and surveyed Los Angeles–area shop employees (assessing their beliefs, awareness, and perceptions of e-cigarettes and related FDA regulations) at two time points one year apart to better understand what vape shop retailers would do given FDA’s soon-to-be-enacted Deeming Rule. The study also compared retailer beliefs/awareness/actions and store characteristics immediately after the Deeming Rule proposal versus a year after the Rule had been proposed, right before its enactment. Two data collection waves occurred before the Deeming Rule enactment, with Year 1 surveying 77 shops (2014) and Year 2 surveying 61 shops (2015–2016). Between the data collection points, 16 shops had closed. Among the shops that were open at both time points, the majority (95% in Year 1; 74% in Year 2) were aware of some FDA regulations or other policies applying to vape shops. However, overall awareness of FDA regulations and state/local policies governing e-cigarettes significantly decreased from Year 1 to Year 2. At both time points, all shops offered customers free puffs of nicotine-containing e-liquids (prohibited by the then upcoming Deeming Rule). Perceptions of e-cigarette safety also significantly decreased between the years. Exploring vape shop retailer perceptions and store policies (i.e., free puffs/samples displays, perceptions of e-cigarette safety, etc.) over time will help the FDA assess the needs of the vape shop community and develop more effective retailer education campaigns and materials targeted to increase compliance with the newly enacted regulations.

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Vaccines, Vol. 6, Pages 10: Virus-Like-Vaccines against HIV

Vaccines, Vol. 6, Pages 10: Virus-Like-Vaccines against HIV

Vaccines doi: 10.3390/vaccines6010010

Authors: Anne-Marie Andersson Melanie Schwerdtfeger Peter Holst

Protection against chronic infections has necessitated the development of ever-more potent vaccination tools. HIV seems to be the most challenging foe, with a remarkable, poorly immunogenic and fragile surface glycoprotein and the ability to overpower the cell immune system. Virus-like-particle (VLP) vaccines have emerged as potent inducers of antibody and helper T cell responses, while replication-deficient viral vectors have yielded potent cytotoxic T cell responses. Here, we review the emerging concept of merging these two technologies into virus-like-vaccines (VLVs) for the targeting of HIV. Such vaccines are immunologically perceived as viruses, as they infect cells and produce VLPs in situ, but they only resemble viruses, as the replication defective vectors and VLPs cannot propagate an infection. The inherent safety of such a platform, despite robust particle production, is a distinct advantage over live-attenuated vaccines that must balance safety and immunogenicity. Previous studies have delivered VLVs encoded in modified Vaccinia Ankara vectors and we have developed the concept into a single-reading adenovirus-based technology capable of eliciting robust CD8+ and CD4+ T cells responses and trimer binding antibody responses. Such vaccines offer the potential to display the naturally produced immunogen directly and induce an integrated humoral and cellular immune response.

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IJMS, Vol. 19, Pages 541: Impact of Arginine to Cysteine Mutations in Collagen II on Protein Secretion and Cell Survival

IJMS, Vol. 19, Pages 541: Impact of Arginine to Cysteine Mutations in Collagen II on Protein Secretion and Cell Survival

International Journal of Molecular Sciences doi: 10.3390/ijms19020541

Authors: Salin Chakkalakal Juliane Heilig Ulrich Baumann Mats Paulsson Frank Zaucke

Inherited point mutations in collagen II in humans affecting mainly cartilage are broadly classified as chondrodysplasias. Most mutations occur in the glycine (Gly) of the Gly-X-Y repeats leading to destabilization of the triple helix. Arginine to cysteine substitutions that occur at either the X or Y position within the Gly-X-Y cause different phenotypes like Stickler syndrome and congenital spondyloepiphyseal dysplasia (SEDC). We investigated the consequences of arginine to cysteine substitutions (X or Y position within the Gly-X-Y) towards the N and C terminus of the triple helix. Protein expression and its secretion trafficking were analyzed. Substitutions R75C, R134C and R704C did not alter the thermal stability with respect to wild type; R740C and R789C proteins displayed significantly reduced melting temperatures (Tm) affecting thermal stability. Additionally, R740C and R789C were susceptible to proteases; in cell culture, R789C protein was further cleaved by matrix metalloproteinases (MMPs) resulting in expression of only a truncated fragment affecting its secretion and intracellular retention. Retention of misfolded R740C and R789C proteins triggered an ER stress response leading to apoptosis of the expressing cells. Arginine to cysteine mutations towards the C-terminus of the triple helix had a deleterious effect, whereas mutations towards the N-terminus of the triple helix (R75C and R134C) and R704C had less impact.

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IJMS, Vol. 19, Pages 542: Analysis of Peptide Ligand Specificity of Different Insect Adipokinetic Hormone Receptors

IJMS, Vol. 19, Pages 542: Analysis of Peptide Ligand Specificity of Different Insect Adipokinetic Hormone Receptors

International Journal of Molecular Sciences doi: 10.3390/ijms19020542

Authors: Elisabeth Marchal Sam Schellens Emilie Monjon Evert Bruyninckx Heather Marco Gerd Gäde Jozef Vanden Broeck Heleen Verlinden

Adipokinetic hormone (AKH) is a highly researched insect neuropeptide that induces the mobilization of carbohydrates and lipids from the fat body at times of high physical activity, such as flight and locomotion. As a naturally occurring ligand, AKH has undergone quite a number of amino acid changes throughout evolution, and in some insect species multiple AKHs are present. AKH acts by binding to a rhodopsin-like G protein-coupled receptor, which is related to the vertebrate gonadotropin-releasing hormone receptors. In the current study, we have cloned AKH receptors (AKHRs) from seven different species, covering a wide phylogenetic range of insect orders: the fruit fly, Drosophila melanogaster, and the yellow fever mosquito, Aedes aegypti (Diptera); the red flour beetle, Tribolium castaneum, and the large pine weevil, Hylobius abietis (Coleoptera); the honeybee, Apis mellifera (Hymenoptera); the pea aphid, Acyrthosiphon pisum (Hemiptera); and the desert locust, Schistocerca gregaria (Orthoptera). The agonistic activity of different insect AKHs, including the respective endogenous AKHs, at these receptors was tested with a bioluminescence-based assay in Chinese hamster ovary cells. All receptors were activated by their endogenous ligand in the nanomolar range. Based on our data, we can refute the previously formulated hypothesis that a functional AKH signaling system is absent in the beneficial species, Apis mellifera. Furthermore, our data also suggest that some of the investigated AKH receptors, such as the mosquito AKHR, are more selective for the endogenous (conspecific) ligand, while others, such as the locust AKHR, are more promiscuous and can be activated by AKHs from many other insects. This information will be of high importance when further analyzing the potential use of AKHRs as targets for developing novel pest control agents.

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Viruses, Vol. 10, Pages 77: Blood Mitochondrial DNA Content in HIV-Exposed Uninfected Children with Autism Spectrum Disorder

Viruses, Vol. 10, Pages 77: Blood Mitochondrial DNA Content in HIV-Exposed Uninfected Children with Autism Spectrum Disorder

Viruses doi: 10.3390/v10020077

Authors: Matthew Budd Kristina Calli Lindy Samson Jennifer Bowes Anthony Hsieh John Forbes Ari Bitnun Joel Singer Fatima Kakkar Ariane Alimenti Evelyn Maan M. Lewis Carole Gentile Hélène Côté Jason Brophy

Long-term outcomes of perinatal exposure to maternal antiretroviral therapy in HIV-exposed uninfected (HEU) children are unknown. However, both HIV antiretroviral therapy and autism spectrum disorder (ASD) have been associated with mitochondrial alterations. Leukocyte mitochondrial DNA (mtDNA) content can serve as a marker for mitochondrial dysfunction. In this cross-sectional, nested case-control study, HEU children with ASD were matched approximately 1:3 on age, sex, and ethnicity to HEU children without ASD, HIV-unexposed uninfected (HUU) controls, and HUU children with ASD. Leukocyte mtDNA content was measured using quantitative PCR. Among 299 HEU in this study, 14 (4.7%) were diagnosed with ASD, which is higher than the general population prevalence estimates. HEU children without ASD and HUU children with ASD had higher mtDNA content than HUU controls. HEU children with ASD had significantly higher mtDNA content than all other study groups. Our results suggest a clear association between elevated leukocyte mtDNA content and both HEU and ASD status. This may implicate mitochondrial dysfunction as a contributor to the high ASD prevalence observed in our cohort.

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Cancers, Vol. 10, Pages 48: Early Diagnosis to Improve the Poor Prognosis of Pancreatic Cancer

Cancers, Vol. 10, Pages 48: Early Diagnosis to Improve the Poor Prognosis of Pancreatic Cancer

Cancers doi: 10.3390/cancers10020048

Authors: Masataka Kikuyama Terumi Kamisawa Sawako Kuruma Kazuro Chiba Shinya Kawaguchi Shuzo Terada Tatsunori Satoh

Pancreatic cancer (PC) has a poor prognosis due to delayed diagnosis. Early diagnosis is the most important factor for improving prognosis. For early diagnosis of PC, patients with clinical manifestations suggestive of PC and high risk for developing PC need to be selected for examinations for PC. Signs suggestive of PC (e.g., symptoms, diabetes mellitus, acute pancreatitis, or abnormal results of blood examinations) should not be missed, and the details of risks for PC (e.g., familial history of PC, intraductal mucin producing neoplasm, chronic pancreatitis, hereditary pancreatitis, or life habit) should be understood. Multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI) can be performed for diagnosing PC, but the diagnostic ability of these examinations for PC is limited. Endoscopic diagnostic procedures, such as endoscopic ultrasonography, including fine-needle aspiration, and endoscopic retrograde pancreatocholangiography, including Serial Pancreatic-juice Aspiration Cytologic Examination (SPACE), could be recommended for a detailed examination to diagnose pancreatic carcinoma earlier.

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Biosensors, Vol. 8, Pages 15: Probing Contaminant-Induced Alterations in Chlorophyll Fluorescence by AC-Dielectrophoresis-Based 2D-Algal Array

Biosensors, Vol. 8, Pages 15: Probing Contaminant-Induced Alterations in Chlorophyll Fluorescence by AC-Dielectrophoresis-Based 2D-Algal Array

Biosensors doi: 10.3390/bios8010015

Authors: Coralie Siebman Orlin Velev Vera Slaveykova

The investigation of contaminant impact on algae requires rapid and reliable cell collection and optical detection. The capability of alternative current (AC) dielectrophoresis (DEP) collection of whole cell arrays with combined fluorescence microscopy detection to follow the alterations of chlorophyll fluorescence during environmental contaminant exposure was explored. The application of an AC-field of 100 V cm−1, 100 Hz for 30 min to capture and immobilize the cells of green alga Chlamydomonas reinhardtii in two-dimensional (2D) arrays does not induce changes in chlorophyll fluorescence. The results demonstrate that DEP-based 2D-arrays allow non-invasive detection of chlorophyll fluorescence change upon exposure to high concentrations of copper oxide nanoparticles and ionic copper. These results were in agreement with data obtained by flow cytometry used as a comparative method. The tool was also applied to follow the effect of a number of ubiquitous contaminants such as inorganic mercury, methylmercury, and diuron. However, a statistically significant short-term effect was observed only for mercury. Overall, DEP-based 2D-arrays of algal cells with fluorescence detection appear to be suitable for stain-free probing the effects on the photosynthetic microorganisms in highly polluted environment.

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IJERPH, Vol. 15, Pages 312: Rapid Screening of Cadmium in Rice and Identification of Geographical Origins by Spectral Method

IJERPH, Vol. 15, Pages 312: Rapid Screening of Cadmium in Rice and Identification of Geographical Origins by Spectral Method

International Journal of Environmental Research and Public Health doi: 10.3390/ijerph15020312

Authors: Fang Li Jihua Wang Li Xu Songxue Wang Minghui Zhou Jingwei Yin Anxiang Lu

The accuracy, repeatability and detection limits of the energy-dispersive X-ray fluorescence (XRF) spectrometer used in this study were tested to verify its suitability for rapid screening of cadmium in samples. Concentrations of cadmium in rice grain samples were tested by the XRF spectrometer. The results showed that the apparatus had good precision around the national limit value (0.2 mg/kg). Raman spectroscopy has been analyzed in the discrimination of rice grain samples from different geographical origins within China. Scanning time has been discussed in order to obtain better Raman features of rice samples. A total of 31 rice samples were analyzed. After spectral data pre-treatment, principal component analysis (PCA), K-means clustering (KMC), hierarchical clustering (HC) and support vector machine (SVM) were performed to discriminate origins of rice samples. The results showed that the geographical origins of rice could be classified using Raman spectroscopy combined with multivariate analysis.

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IJMS, Vol. 19, Pages 539: Metabolic Effects of FecB Gene on Follicular Fluid and Ovarian Vein Serum in Sheep (Ovis aries)

IJMS, Vol. 19, Pages 539: Metabolic Effects of FecB Gene on Follicular Fluid and Ovarian Vein Serum in Sheep (Ovis aries)

International Journal of Molecular Sciences doi: 10.3390/ijms19020539

Authors: Xiaofei Guo Xiangyu Wang Ran Di Qiuyue Liu Wenping Hu Xiaoyun He Jiarui Yu Xiaosheng Zhang Jinlong Zhang Katarzyna Broniowska Wei Chen Changxin Wu Mingxing Chu

The FecB gene has been discovered as an important gene in sheep for its high relationship with the ovulation rate, but its regulatory mechanism remains unknown. In the present study, liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) techniques were adopted to detect the metabolic effects of FecB gene in follicular fluid (FF) and ovarian vein serum (OVS) in Small Tail Han (STH) sheep. ANOVA and random forest statistical methods were employed for the identification of important metabolic pathways and biomarkers. Changes in amino acid metabolism, redox environment, and energy metabolism were observed in FF from the three FecB genotype STH ewes. Principal component analysis (PCA) and hierarchical clustering analysis (HCA) showed that metabolic effects of FecB gene are more pronounced in FF than in OVS. Therefore, the difference of the metabolic profile in FF is also affected by the FecB genotypes. In Spearman correlation analysis, key metabolites (e.g., glucose 6-phosphate, glucose 1-phosphate, aspartate, asparagine, glutathione oxidized (GSSG), cysteine-glutathione disulfide, γ-glutamylglutamine, and 2-hydrosybutyrate) in ovine FF samples showed a significant correlation with the ovulation rate. Our findings will help to explain the metabolic mechanism of high prolificacy ewes and benefit fertility identification.

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IJMS, Vol. 19, Pages 540: The T2238C Human Atrial Natriuretic Peptide Molecular Variant and the Risk of Cardiovascular Diseases

IJMS, Vol. 19, Pages 540: The T2238C Human Atrial Natriuretic Peptide Molecular Variant and the Risk of Cardiovascular Diseases

International Journal of Molecular Sciences doi: 10.3390/ijms19020540

Authors: Speranza Rubattu Sebastiano Sciarretta Simona Marchitti Franca Bianchi Maurizio Forte Massimo Volpe

Atrial natriuretic peptide (ANP) is a cardiac hormone which plays important functions to maintain cardio-renal homeostasis. The peptide structure is highly conserved among species. However, a few gene variants are known to fall within the human ANP gene. The variant rs5065 (T2238C) exerts the most substantial effects. The T to C transition at the 2238 position of the gene (13–23% allele frequency in the general population) leads to the production of a 30-, instead of 28-, amino-acid-long α-carboxy-terminal peptide. In vitro, CC2238/αANP increases the levels of reactive oxygen species and causes endothelial damage, vascular smooth muscle cells contraction, and increased platelet aggregation. These effects are achieved through the deregulated activation of type C natriuretic peptide receptor, the consequent inhibition of adenylate cyclase activity, and the activation of Giα proteins. In vivo, endothelial dysfunction and increased platelet aggregation are present in human subjects carrying the C2238/αANP allele variant. Several studies documented an increased risk of stroke and of myocardial infarction in C2238/αANP carriers. Recently, an incomplete response to antiplatelet therapy in ischemic heart disease patients carrying the C2238/αANP variant and undergoing percutaneous coronary revascularization has been reported. In summary, the overall evidence supports the concept that T2238C/ANP is a cardiovascular genetic risk factor that needs to be taken into account in daily clinical practice.

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Mechanism-based pharmacokinetic (MBPK) models describe the complex plasma kinetics of three antiretrovirals delivered by a long-acting anti-HIV drug combination nanoparticle formulation

Publication date: Available online 10 February 2018
Source:Journal of Controlled Release
Author(s): John C. Kraft, Lisa A. McConnachie, Josefin Koehn, Loren Kinman, Jianguo Sun, Ann C. Collier, Carol Collins, Danny D. Shen, Rodney J.Y. Ho
Existing oral antiretroviral (ARV) agents have been shown in human studies to exhibit limited lymph node penetration and lymphatic drug insufficiency. As lymph nodes are a reservoir of HIV, it is critical to deliver and sustain effective levels of ARV combinations in these tissues. To overcome lymph node drug insufficiency of oral combination ARV therapy (cART), we developed and reported a long-acting and lymphocyte-targeting injectable that contains three ARVs—hydrophobic lopinavir (LPV) and ritonavir (RTV), and hydrophilic tenofovir (TFV)—stabilized by lipid excipients in a nanosuspension. A single subcutaneous (SC) injection of this first-generation formulation of drug combination nanoparticles (DcNPs), named TLC-ART101, provided persistent ARV levels in macaque lymph node mononuclear cells (LNMCs) for at least 1 week, and in peripheral blood mononuclear cells (PBMCs) and plasma for at least 2 weeks, demonstrating long-acting pharmacokinetics for all three drugs. In addition, the lymphocyte-targeting properties of this formulation were demonstrated by the consistently higher intracellular drug concentrations in LNMCs and PBMCs versus those in plasma. To provide insights into the complex mechanisms of absorption and disposition of TLC-ART101, we constructed novel mechanism-based pharmacokinetic (MBPK) models. Based upon plasma PK data obtained after single administration of TLC-ART101 (DcNPs) and a solution formulation of free triple-ARVs, the models feature uptake from the SC injection site that respectively routes free and nanoparticle-associated ARVs via the blood vasculature and lymphatics, and their eventual distribution into and clearance from the systemic circulation. The models provided simultaneous description of the complex long-acting plasma and lymphatic PK profiles for all three ARVs in TLC-ART101. The long-acting PK characteristics of the three drugs in TLC-ART101 were likely due to a combination of mechanisms including: (1) DcNPs undergoing preferential lymphatic uptake from the subcutaneous space, (2) retention in nodes during lymphatic first-pass, (3) subsequent slow release of ARVs into blood circulation, and (4) limited extravasation of DcNP-associated ARVs that resulted in longer persistence in the circulation.

Graphical abstract

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