Novel synthetic chalcone-coumarin hybrid for Aβ aggregation reduction, antioxidation, and neuroprotection.

Abstract:
BACKGROUND
Aggregation of misfolded amyloid β (Aβ) in senile plaques causes oxidative stress and neuronal death in Alzheimer's disease (AD). Compounds possessing antiaggregation and antioxidant properties are promising candidate compounds for AD treatment.

METHODS
We examined the potential of synthetic derivatives of licochalcone A and coumarin for inhibiting Aβ aggregation, scavenging reactive oxygen species (ROS), and providing neuroprotection by using biochemical assays and Tet-On Aβ-GFP 293/SH-SY5Y cell models for AD.

RESULTS
Among test compounds, LM-031, a novel chalcone-coumarin hybrid, inhibited Aβ aggregation and scavenged free oxygen radicals. LM-031 markedly reduced Aβ misfolding and ROS as well as promoted neurite outgrowth and inhibited acetylcholinesterase in Tet-On Aβ-GFP 293/SH-SY5Y cells. Mechanistic studies showed upregulation of the HSPB1 chaperone, NRF2/NQO1/GCLC pathway, and CREB/BDNF/BCL2 pathway. Decreased neurite outgrowth upon the induction of Aβ-GFP was rescued by LM-031, which was counteracted by knockdown of HSPB1, NRF2, or CREB.

CONCLUSION
Taken together, these findings demonstrate that LM-031 exhibited antiaggregation, antioxidant, and neuroprotective effects against Aβ toxicity by enhancing HSPB1 and the NRF2-related antioxidant pathway as well as by activating the CREB-dependent survival and antiapoptosis pathway. These results imply that LM-031 may be a new therapeutic compound for AD.

Aβ aggregation reduction
antioxidation
neuroprotection
therapeutics
Alzheimer’s disease
chalcone‐coumarin hybrid


Associations of organochlorine pesticides and polychlorinated biphenyls in visceral vs. subcutaneous adipose tissue with type 2 diabetes and insulin resistance.

Abstract: Background exposure to organochlorine (OC) pesticides and polychlorinated biphenyls (PCBs) has been linked to type 2 diabetes. As OC pesticides and PCBs mainly accumulate in adipose tissue and there are physiological and clinical differences between visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), we explored if there were associations of OC pesticides and PCBs in VAT or SAT with type 2 diabetes and insulin resistance. Participants were 50 patients with or without type 2 diabetes who underwent surgery for either cancer or benign liver or gallbladder lesions. We analyzed 14 OC pesticides and 22 PCB congeners in both VAT and SAT. Insulin resistance was estimated using homeostasis model assessment (HOMA). Although concentrations of OC pesticides and PCBs were strongly correlated between VAT and SAT, absolute concentrations differed substantially between them. In particular, concentrations of all PCBs were consistently about 5-10 times higher in VAT than SAT, but these patterns were independent of diabetes status. Some OC pesticides or PCBs, such as dichlorodiphenyltrichloroethanes (DDTs), chlordanes, and PCBs with 5 or less chlorides showed significant associations with diabetes or insulin resistance. For example, when tertiles of concentration-based summary measures were used, adjusted ORs were 1.0, 2.3, and 9.0 (P trend=0.02) for DDTs in VAT and 1.0, 2.1, and 5.7 (P trend=0.08) for PCBs with 5 or less chlorides. This study generally confirmed previous findings using serum concentrations. It would be useful to study pharmacodynamics of POPs in VAT and SAT further.

Kim|Ki-Su|KS|
Lee|Yu-Mi|YM|
Kim|Sang Geol|SG|
Lee|In-Kyu|IK|
Lee|Hyo-Jeong|HJ|
Kim|Ji-Hyun|JH|
Kim|Jeongkook|J|
Moon|Hyo-Bang|HB|
Jacobs|David R|DR|
Lee|Duk-Hee|DH|

homeostasis model assessment–insulin resistance

P P P P P P P P P P P P P P P P P P U U U U U U U M M U P U P


CHA2DS2-VASc and R2-CHA2DS2-VASc scores predict in-hospital and post-discharge outcome in patients with myocardial infarction.

Abstract:
Introduction
The CHA2DS2-VASc and R2-CHA2DS2-VASc scores were initially designed to evaluate the risk of cerebrovascular events in patients with atrial fibrillation. However, these scales consist of parameters which are well known as general risk factors for cardiovascular events.

Aim
To assess the role of the CHA2DS2-VASc and R2-CHA2DS2-VASc scores in predicting outcome of patients with myocardial infarction (MI).

Material and methods
We enrolled 212 consecutive patients with both ST-elevation and non-ST-elevation MI referred for primary percutaneous coronary intervention (PCI). Patients were divided into two groups depending on the CHA2DS2-VASc score: ≤ 3 (low score) and > 3 points (high score).

Results
The group with a CHA2DS2-VASc score > 3 points consisted of 93 (44%) patients. Follow-up was available in 200 (94.3%) patients with median duration of 10 (Q1: 6; Q3: 13) months. During the follow-up all-cause mortality was greater in patients from the high score group (21%) compared to patients with lower scores (8%) (p = 0.009). Recurrent MI was found in 4% of patients from the low score group and in 13% of patients from the high score group (p = 0.024). The combined endpoint of cardiovascular mortality, recurrent non-fatal MI and non-fatal stroke occurred in 13% of lower score patients and in 30% of patients with a score > 3 points (p = 0.002). In a Cox regression model both scores were predictors of all-cause mortality with a hazard ratio of 1.31 per 1 point increase for the CHA2DS2-VASc score (p = 0.004) and 1.36 for the R2-CHA2DS2-VASc score (p < 0.001).

Conclusions
The CHA2DS2-VASc and R2-CHA2DS2-VASc scores predict in-hospital and post-discharge outcome in patients with acute MI undergoing primary PCI.

Węgiel|Michał|M| Rakowski|Tomasz|T| Dziewierz|Artur|A| Wojtasik-Bakalarz|Joanna|J| Sorysz|Danuta|D| Bartuś|Stanisław|S| Surdacki|Andrzej|A| Dudek|Dariusz|D|


Role of Jagged1-mediated Notch Signaling Activation in the Differentiation and Stratification of the Human Limbal Epithelium.

Abstract: The Notch signaling pathway plays a key role in proliferation and differentiation. We investigated the effect of Jagged 1 (Jag1)-mediated Notch signaling activation in the human limbal stem/progenitor cell (LSC) population and the stratification of the limbal epithelium in vitro. After Notch signaling activation, there was a reduction in the amount of the stem/progenitor cell population, epithelial stratification, and expression of proliferation markers. There was also an increase of the corneal epithelial differentiation. In the presence of Jag1, asymmetric divisions were decreased, and the expression pattern of the polarity protein Par3, normally present at the apical-lateral membrane of basal cells, was dispersed in the cells. We propose a mechanism in which Notch activation by Jag1 decreases p63 expression at the basal layer, which in turn reduces stratification by decreasing the number of asymmetric divisions and increases differentiation.

González|Sheyla|S|
Halabi|Maximilian|M|
Ju|David|D|
Tsai|Matthew|M|
Deng|Sophie X|SX|

D002454:Cell Differentiation
D004848:Epithelium
D006801:Humans
D000072100:Jagged-1 Protein
D016850:Limbus Corneae
D051880:Receptors, Notch
D015398:Signal Transduction

Notch signaling
differentiation
stratification
limbal epithelium
limbal stem cells


Progress toward understanding chromosome silencing by Xist RNA.

Abstract: The X inactive-specific transcript (Xist) gene is the master regulator of X chromosome inactivation in mammals. Xist produces a long noncoding (lnc)RNA that accumulates over the entire length of the chromosome from which it is transcribed, recruiting factors to modify underlying chromatin and silence X-linked genes in cis Recent years have seen significant progress in identifying important functional elements in Xist RNA, their associated RNA-binding proteins (RBPs), and the downstream pathways for chromatin modification and gene silencing. In this review, we summarize progress in understanding both how these pathways function in Xist-mediated silencing and the complex interplay between them.

Brockdorff|Neil|N|
Bowness|Joseph S|JS|
Wei|Guifeng|G|

D018160:Receptors, Cytoplasmic and Nuclear

Xist
X chromosome inactivation
chromatin
LBR
NCoR–HDAC3
Polycomb
RBM15
SPEN
m6A RNA methylation


Significance of AZD1152 as a potential treatment against Aurora B overexpression in acute promyelocytic leukemia.

Abstract: Aurora B kinase as a chromosomal passenger protein plays multiple roles in regulating mitosis and cytokinesis. The function of Aurora B in leukemic cells has made it an important treatment target. In this study, we explored the expressions of Aurora (A, B, and C) kinases in newly diagnosed acute promyelocytic leukemia (APL) patients. In addition, we investigated the effects of AZD1152 as a specific inhibitor of Aurora B on cell survival, DNA synthesis, nuclear morphology, apoptosis induction, cell cycle distribution, and gene expression in an APL-derived NB4 cell line. Our results showed that Aurora B was overexpressed in 88 % of APL patients. AZD1152 treatment of NB4 cells led to viability reduction and G2/M arrest followed by an increase in cell size and polyploidy induction. These giant cells showed morphological evidence of mitotic catastrophe. AZD1152 treatment induced activation of G2/M checkpoint which in turn led to transient G2/M arrest in a p21-independent manner. Lack of functional p53 in NB4 cells might provide an opportunity to escape from G2/M block and to endure repeated rounds of replication and polyploidy. Treated cells were probably eliminated via p73-mediated overexpression of BAX, PUMA, and APAF1 and downregulation of survivin and MCL-1. In summary, AZD1152 treatment led to endomitosis and polyploidy in TP53-mutated NB4 cells. These giant polyploid cells might undergo mitotic catastrophe and p73-mediated apoptosis. It seems that induction of polyploidy via AZD1152 could be a novel form of anti-cancer therapy for APL that may be clinically accessible in the near future.

Ghanizadeh-Vesali|Samad|S|
Zekri|Ali|A|
Zaker|Farhad|F|
Zaghal|Azam|A|
Yousefi|Meysam|M|
Alimoghaddam|Kamran|K|
Ghavamzadeh|Ardeshir|A|
Ghaffari|Seyed H|SH|

D015972:Gene Expression Regulation, Neoplastic

AZD1152
Acute promyelocytic leukemia
Aurora B kinase
Apoptosis
Cell cycle arrest
p73


The Use Fibrin Sealant after Spinal Intradural Tumor Surgery: Is It Necessary?

Abstract:
OBJECTIVE
A fibrin sealant is commonly applied after closure of an incidental or intended durotomy to reduce the complications associated with the leakage of cerebrospinal fluid. Routine usage might not be essential after closure of an intended durotomy, which has clear cut-margins. We investigated the efficacy of fibrin sealants for primary intradural spinal cord tumor surgery.

METHODS
A retrospective review was performed for 231 consecutive surgically treated patients with primary intradural spinal cord tumors without extradural extension. Fibrin sealants were not used for 47 patients (group I: age, 51.57±16.75 years) and were applied to 184 patients (group II: age, 48.8±14.7 years). The surgical procedures were identical except for the use of a fibrin sealant after closure of the durotomy. The primary outcome was the occurrence of complications (wound problems, hematoma collection, infection, and neurological deterioration). The covariates were age, sex, body mass index, operation time, pre-/postoperative ambulation, number of laminectomies, and type of tumor.

RESULTS
Schwannoma was the most common pathology (n=134), followed by meningioma (n=35) and ependymoma (n=31). Complications occurred in 13 patients (3 in group I and 10 in group II, p=0.73). The postoperative ambulation status (p<0.01; odds ratio, 28.8; 95% confidence interval, 6.9-120.0) and operation time (p=0.04; cutoff, 229 minutes; sensitivity, 62%; specificity, 72%) were significant factors, whereas the use of a fibrin glue was not (p=0.47).

CONCLUSION
The use of a fibrin sealant might not be essential to reduce complications after surgery for primary spinal intradural tumor.

Won|Young Il|YI|
Kim|Chi Heon|CH|
Chung|Chun Kee|CK|
Jahng|Tae-Ahn|TA|
Park|Sung Bae|SB|

Cerebrospinal fluid
Fibrin tissue adhesive
Spinal cord neoplasms
Spine
Surgical wound infection


Associations of types of primary care facilities with adult vaccination and cancer screening in Japan.

Abstract:
OBJECTIVE
To examine the association between primary care facility types and the quality of preventive care, especially adult vaccination and cancer screening, with a focus on the differences between community clinics and hospitals.

DESIGN
Multicenter cross-sectional study.

SETTING
A primary care practice-based research network in Japan (25 primary care facilities).

PARTICIPANTS
Adult outpatients for whom the participating facility serves as their usual source of care.

INTERVENTION
None.

MAIN OUTCOME MEASURES
Influenza and pneumococcal vaccination delivery and performance of colorectal, breast and cervical cancer screening.

RESULTS
Data collected from 1725 primary care outpatients were analyzed. After adjustment of possible confounders and clustering within facilities, hospital-based practices were significantly associated with poorer uptake of influenza [adjusted odds ratio (aOR) = 0.64, 95% confidence interval (CI) 0.42-0.96] and pneumococcal vaccines (aOR = 0.55, 95% CI 0.40-0.75) and colorectal cancer screening (aOR = 0.59, 95% CI 0.39-0.88) compared with clinic-based practices. In contrast, the associations of types of primary care facilities with uptake of breast and cervical cancer screening were not statistically significant.

CONCLUSIONS
Differences in the performance of adult vaccination and cancer screening raised concerns about the provision of preventive care at hospital-based compared with clinic-based primary care practices. Efforts to improve preventive care at hospital-based primary care practices should help to promote equalization of the quality of primary care. Further study is needed on the comparisons of other quality indicators among different structures of primary care facilities.

D000328:Adult
D000368:Aged
D000369:Aged, 80 and over
D000554:Ambulatory Care Facilities
D001943:Breast Neoplasms
D015179:Colorectal Neoplasms
D003430:Cross-Sectional Studies
D055088:Early Detection of Cancer
D005260:Female
D006801:Humans
D007252:Influenza Vaccines
D007564:Japan
D008875:Middle Aged
D010044:Outpatient Clinics, Hospital
D022242:Pneumococcal Vaccines
D011320:Primary Health Care
D011795:Surveys and Questionnaires
D002583:Uterine Cervical Neoplasms
D014611:Vaccination

vaccination
ambulatory care
early detection of cancer
preventive medicine
primary health care
quality of health care


How do external factors contribute to the hypocoagulative state in trauma-induced coagulopathy? - In vitro analysis of the lethal triad in trauma.

Abstract:
BACKGROUND
External factors following trauma and iatrogenic intervention influence blood coagulation and particularly clot formation. In particular, three external factors (in detail dilution via uncritical volume replacement, acidosis and hypothermia), in combination, referred to as the "lethal triad", substantially aggravate the hypocoagulative state after trauma. Contribution of these external factors to the resulting hypocoagulative state in trauma and especially their influence on primary haemostasis has still not been investigated systematically. This study aims to assess this contribution to the aggravating hypocoagulative state in trauma-induced coagulopathy (TIC) using an in vitro simulation assay. Emphasis is given to platelet contribution to clot formation and to the investigation of how platelet activation alters under the respective conditions.

METHODS
To simulate the conditions of lethal triad in vitro, whole blood samples taken from five healthy volunteers were introduced to the respective conditions. Besides standard coagulation testing, thrombelastometric analysis and differentiated platelet mapping were performed.

RESULTS
All three simulated conditions induced significant impairments of clot formation (clot formation time, CFT; α -angle) and propagation (maximum clot firmness, MCF; Diameter A5-A25), with the highest impact under hypothermia and dilution. Consistently, lethal triad resulted in an additive effect of all conditions. None of the simulated conditions induced a statistically relevant change in coagulation initiation assessed by EXTEM and FIBTEM thrombelastometry. Platelet contribution to clot formation decreased gradually under the respective conditions, reaching statistical significance for simulated dilution, and attaining its greatest extent under the conditions of lethal triad (Δtrias/baseline 0.59; p = 0.01). Consistent, reduced CD62 expression levels were observed under experimental acidosis (Δacidosis/baseline 0.32; p = 0.006), dilution (Δdilution/baseline 0.34; p = 0.01) and lethal triad (Δlethal triad/baseline 0.24; p = 0.01).

CONCLUSION
The respective external factors of lethal triad play a pivotal role in the development of coagulopathy, essentially influencing the kinetics of clot formation, and to a varying extent clot diameter, as measured by thrombelastometry. Moreover, impairment of platelet function under the conditions of lethal triad plays a key role in the pathophysiology of TIC, resulting in reduced responsiveness to stimulation with ADP that might also be present after trauma. Our data indicate that impairment of primary haemostasis contribute to the hypocoagulative state in TIC after trauma aggravated by external factors of lethal triad.

Lethal triad
Acidosis in trauma
Dilution in trauma
Hypothermia in trauma
PlateletMapping®
ROTEM®


The 2021 WHO Classification of Tumors of the Thymus and Mediastinum: What Is New in Thymic Epithelial, Germ Cell, and Mesenchymal Tumors?

Abstract: This overview of the fifth edition of the WHO classification of thymic epithelial tumors (including thymomas, thymic carcinomas, and thymic neuroendocrine tumors [NETs]), mediastinal germ cell tumors, and mesenchymal neoplasms aims to (1) list established and new tumor entities and subtypes and (2) focus on diagnostic, molecular, and conceptual advances since publication of the fourth edition in 2015. Diagnostic advances are best exemplified by the immunohistochemical characterization of adenocarcinomas and the recognition of genetic translocations in metaplastic thymomas, rare B2 and B3 thymomas, and hyalinizing clear cell carcinomas. Advancements at the molecular and tumor biological levels of utmost oncological relevance are the findings that thymomas and most thymic carcinomas lack currently targetable mutations, have an extraordinarily low tumor mutational burden, but typically have a programmed death-ligand 1high phenotype. Finally, data underpinning a conceptual advance are illustrated for the future classification of thymic NETs that may fit into the classification scheme of extrathoracic NETs. Endowed with updated clinical information and state-of-the-art positron emission tomography and computed tomography images, the fifth edition of the WHO classification of thymic epithelial tumors, germ cell tumors, and mesenchymal neoplasms with its wealth of new diagnostic and molecular insights will be a valuable source for pathologists, radiologists, surgeons, and oncologists alike. Therapeutic perspectives and research challenges will be addressed as well.

Marx|Alexander|A|
Chan|John K C|JKC|
Chalabreysse|Lara|L|
Dacic|Sanja|S|
Detterbeck|Frank|F|
French|Christopher A|CA|
Hornick|Jason L|JL|
Inagaki|Hiroshi|H|
Jain|Deepali|D|
Lazar|Alexander J|AJ|
Marino|Mirella|M|
Marom|Edith M|EM|
Moreira|Andre L|AL|
Nicholson|Andrew G|AG|
Noguchi|Masayuki|M|
Nonaka|Daisuke|D|
Papotti|Mauro G|MG|
Porubsky|Stefan|S|
Sholl|Lynette M|LM|
Tateyama|Hisashi|H|
Thomas de Montpréville|Vincent|V|
Travis|William D|WD|
Rajan|Arun|A|
Roden|Anja C|AC|
Ströbel|Philipp|P|

WHO classification
Thymoma
Thymic carcinoma
Thymic neuroendocrine tumor
Germ cell tumor
NET G3


Guidelines Adaptation to the COVID-19 Outbreak for the Management of Hepatocellular Carcinoma.

Abstract: COVID-19 pandemic rendered the surgical approach as well as the surgical indication very complex due to the outstanding consumption of public health system' resources, especially in the intensive care subdivision. A multidisciplinary team-based strategy is necessary to adapt guidelines and medical practices to the actual situation. The aim of this study is to evaluate the changes in the therapeutic algorithm in a small group of patients with hepatocellular carcinoma (HCC) enlisted for surgery during the COVID-19 outbreak.  A multidisciplinary strategy has been adopted to allocate HCC patients to a treatment that permitted to reduce the risk of complications and the hospital stay, thus preventing contamination by the virus. Nasopharyngeal swab and a chest radiograph were performed in all patients within 48 hours before the surgical procedure: in the suspected cases with negative COVID tests, we prudently postponed surgery and repeated the diagnostic tests after 15 days.  During the emergency state, 11 HCC patients were treated (8 laparoscopic ablations and 3 hepatic resections). We reported only 1 postoperative complication (hemothorax) and 1 death during the follow-up for COVID pneumonia. Comparing our performances with those in the same time frame in the past 4 years, we treated a similar number of HCC patients, obtaining a decrease in operative timing (P = .0409) and hospital stay (P = .0412) (Fig. 2b) with similar rates of immediate postoperative complications, without ICU admissions.  An adapted algorithm for the treatment of HCC to COVID outbreak permitted to manage safely these patients by identifying those most at risk of evolution of the neoplastic disease.

Santambrogio|Roberto|R|
Farina|Gabriella|G|
D'Alessandro|Valentina|V|
Iacob|Giulio|G|
Gemma|Marco|M|
Zappa|Marco Antonio|MA|

hepatocellular carcinoma
COVID-19 pandemic
hepatic resection
ablation therapies
liver cirrhosis


Application of validity theory and methodology to patient-reported outcome measures (PROMs): building an argument for validity.

Abstract:
BACKGROUND
Data from subjective patient-reported outcome measures (PROMs) are now being used in the health sector to make or support decisions about individuals, groups and populations. Contemporary validity theorists define validity not as a statistical property of the test but as the extent to which empirical evidence supports the interpretation of test scores for an intended use. However, validity testing theory and methodology are rarely evident in the PROM validation literature. Application of this theory and methodology would provide structure for comprehensive validation planning to support improved PROM development and sound arguments for the validity of PROM score interpretation and use in each new context.

OBJECTIVE
This paper proposes the application of contemporary validity theory and methodology to PROM validity testing.

ILLUSTRATIVE EXAMPLE
The validity testing principles will be applied to a hypothetical case study with a focus on the interpretation and use of scores from a translated PROM that measures health literacy (the Health Literacy Questionnaire or HLQ).

DISCUSSION
Although robust psychometric properties of a PROM are a pre-condition to its use, a PROM's validity lies in the sound argument that a network of empirical evidence supports the intended interpretation and use of PROM scores for decision making in a particular context. The health sector is yet to apply contemporary theory and methodology to PROM development and validation. The theoretical and methodological processes in this paper are offered as an advancement of the theory and practice of PROM validity testing in the health sector.

Hawkins|Melanie|M|0000-0001-5704-0490
Elsworth|Gerald R|GR|
Osborne|Richard H|RH|

D000071066:Patient Reported Outcome Measures

Validation
Validation
Patient-reported outcome measure
PROM
Health literacy
Health Literacy Questionnaire (HLQ)
IUA
Interpretation/use argument
Interpretive argument
Qualitative methods
Validity
Validity argument


Physical co-morbidity among treatment resistant vs. treatment responsive patients with major depressive disorder.

Abstract: Co-morbid physical illness has been suggested to play an important role among the factors contributing to treatment resistance in patients with major depressive disorder. In the current study we compared the rate of physical co-morbidity, defined by ICD-10, among a large multicenter sample of 702 patients with major depressive disorder. A total of 356 of the participants were defined as treatment resistant depression (TRD) patients-having failed two or more adequate antidepressant trials. No significant difference was found between TRD and non-TRD participants in the prevalence of any ICD-10 category. This finding suggests that although physical conditions such as diabetes, thyroid dysfunction, hypertension, ischemic heart disease, and peptic diseases are often accompanied by co-morbid MDD, they do not necessarily have an impact on the course of MDD or the likelihood to respond to treatment. Marginally higher rates of co-morbid breast cancer, migraine and glaucoma were found among TRD participants. Possible explanations for these findings and their possible relation to TRD are discussed.

Amital|D|D| Fostick|L|L| Silberman|A|A| Calati|R|R| Spindelegger|C|C| Serretti|A|A| Juven-Wetzler|A|A| Souery|D|D| Mendlewicz|J|J| Montgomery|S|S| Kasper|S|S| Zohar|J|J|

D039721:Diagnostic and Statistical Manual of Mental Disorders

D011569:Psychiatric Status Rating Scales

Physical co-morbidity
Treatment resistance
Treatment response
Depression


Nivolumab for Metastatic Cutaneous Squamous Cell Carcinoma.

Abstract: Nivolumab is a programmed death receptor 1 (PD-1) inhibitor. It is part of a group of drugs known as immune checkpoint blockers, which enable potent and durable T-cell responses against several tumors. We report the case of a patient with a metastatic squamous cell carcinoma, who is being treated with nivolumab. This patient achieved a complete response and continues treatment without progression signs, supporting the notion that PD-1 inhibition can induce long-term remission and is well tolerated in this type of patient.

Oro-Ayude|Marcos|M|
Suh-Oh|Hae Jin|HJ|
Sacristán-Santos|Victor|V|
Vázquez-Bartolomé|Patricia|P|
Flórez|Ángeles|Á|

Nivolumab
Squamous cell carcinoma
Immunotherapy
PD-1 checkpoint inhibitor


Biochemical study on occupational inhalation of benzene vapours in petrol station.

Abstract: inhalation of benzene vapours promote various and dangerous health problems. Fuel station workers are most susceptible to benzene inhalation toxicity. Samples were collected twice, at beginning of the study and 6 months later from 40 fuel station workers from different egyptian governorates and 10 control healthy volunteers. Fuel station workers were sub divided into four groups according to years working in the station. All of them are exposed to benzene vapours and exhausts during their duties, their work shifts were 8 hrs./day. Results indicated that; benzene vapours exposure induced significant increasing in serum Lead and Cadmium and Myeloperoxidase (MPO) enzyme activity levels. This goes with marked immunologic changes presented by decreases in immunoglobulins; IgA and IgG, along with increases in levels of IgM and IgE. Also, Malondialdehyde (MDA) levels were significantly increased. Meanwhile, reduction in some other biochemical parameters including; Copper, Zinc and Iron micronutrients, as well as; Superoxide Dismutase (SOD), Catalase (CAT) enzyme levels and Glutathione (GSH) content. Hence, the study inferred that prolonged benzene inhalation can lead to biochemical and immune disorders, probably through potentiating oxidative stress and inflammation pathways.

Abdel Maksoud|H A|HA|
Elharrif|Mohamed G|MG|
Mahfouz|M K|MK|
Omnia|M A|MA|
Abdullah|M H|MH|
Eltabey|M E|ME|

Benzene vapours
Oxidative stress
Petrol stations workers


Electroacupuncture inhibits the corneal ROS/TXNIP/NLRP3 signaling pathway in a rat model of dry eye syndrome.

Abstract:
BACKGROUND
Electroacupuncture (EA) treatment has been found to ameliorate clinical symptoms in patients with dry eye, but its mechanisms are still not entirely clear.

OBJECTIVE
To study the regulation of EA on ocular surface function and the corneal reactive oxygen species (ROS)/thioredoxin-interacting protein (TXNIP)/Nod-like receptor protein 3 (NLRP3) inflammatory signaling pathway in dry eye syndrome (DES) model rats.

METHODS
Male Sprague-Dawley (SD) rats were randomly divided into five groups: Normal, Model, Model + EA, Model + NAC (N-actetylcysteine) and Model + NS (normal saline). The DES model was developed by subcutaneous injection of scopolamine hydrobromide with exposure to an air draft in the latter four groups. After intervention, the Schirmer I test (SIT), tear film break-up time (BUT) and ROS content were measured, the histopathological changes of corneal tissues were observed, and the mRNA and protein expression levels of TXNIP, NLRP3, apoptosis-associated Speck-like protein containing CARD (ASC), caspase-1, interleukin (IL)-1β and IL-18 were detected.

RESULTS
Compared with the Model group, the SIT and BUT increased significantly in the Model + EA group after intervention (p < 0.05), and the corneal injury was improved. Corneal ROS content declined in both Model + EA and Model + NAC groups (p < 0.05), and mRNA expression of TXNIP, NLRP3, ASC and caspase-1 also decreased (p < 0.01). Corneal protein expression of TXNIP, NLRP3, IL-1β and IL-18 decreased significantly in the Model + EA group (p < 0.01).

CONCLUSION
Inhibiting the ROS/TXNIP/NLRP3 signaling pathway may be the mechanism underlying the role of EA in improving corneal injury in DES model rats.

electroacupuncture
dry eye syndrome
Nod-like receptor protein 3
cornea


Most of the genetic covariation between major depressive and alcohol use disorders is explained by trait measures of negative emotionality and behavioral control.

Abstract:
BACKGROUND
Mental health disorders commonly co-occur, even between conceptually distinct syndromes, such as internalizing and externalizing disorders. The current study investigated whether phenotypic, genetic, and environmental variance in negative emotionality and behavioral control account for the covariation between major depressive disorder (MDD) and alcohol use disorder (AUD).

METHOD
A total of 3623 members of a national twin registry were administered structured diagnostic telephone interviews that included assessments of lifetime histories of MDD and AUD, and were mailed self-report personality questionnaires that assessed stress reactivity (SR) and behavioral control (CON). A series of biometric models were fitted to partition the proportion of covariance between MDD and AUD into SR and CON.

RESULTS
A statistically significant proportion of the correlation between MDD and AUD was due to variance specific to SR (men = 0.31, women = 0.27) and CON (men = 0.20, women = 0.19). Further, genetic factors explained a large proportion of this correlation (0.63), with unique environmental factors explaining the rest. SR explained a significant proportion of the genetic (0.33) and environmental (0.23) overlap between MDD and AUD. In contrast, variance specific to CON accounted for genetic overlap (0.32), but not environmental overlap (0.004). In total, SR and CON accounted for approximately 70% of the genetic and 20% of the environmental covariation between MDD and AUD.

CONCLUSIONS
This is the first study to demonstrate that negative emotionality and behavioral control confer risk for the co-occurrence of MDD and AUD via genetic factors. These findings are consistent with the aims of NIMH's RDoC proposal to elucidate how transdiagnostic risk factors drive psychopathology.

Ellingson|J M|JM|
Richmond-Rakerd|L S|LS|
Statham|D J|DJ|
Martin|N G|NG|
Slutske|W S|WS|

Alcohol use disorder
negative emotionality
behavioral control
internalizing
externalizing
major depressive disorder
behavior genetics
co-morbidity
dual diagnosis
research domain criteria


Penipyrols C-G and methyl-penipyrol A, α-pyrone polyketides from the mangrove derived fungus Penicillium sp. HDN-11-131.

Abstract: Six new α-pyrone polyketides, penipyrols C-G (1-5) and methyl-penipyrol A (6), together with one biogenetically related known compound, penipyrol A (7), were isolated from the extract of fungus Penicillium sp. HDN-11-131. Their structures including the absolute configurations were established by extensive spectroscopic analysis, Mosher's method, and ECD calculations as well as biogenic considerations. Compounds 1-4 possess a rare skeleton featuring γ-butyrolactone linked to α-pyrone ring through double bond. Compound 1 can induce pancreatic β-cell regeneration in zebrafish at 10 μM, which demonstrated promising anti-diabetes potential.

Wang|Lu|L| Shi|Yeqin|Y| Che|Qian|Q| Zhu|Tianjiao|T| Zhang|Guojian|G| Zhang|Xiaokun|X| Li|Mingyu|M| Li|Dehai|D|

α-Pyrone
Polyketides
γ-Butyrolactone
β-cell regeneration
Zebrafish
Diabetes


Betel Quid Health Risks of Insulin Resistance Diseases in Poor Young South Asian Native and Immigrant Populations.

Abstract: Betel quid, traditionally prepared with areca nut, betel leaf, and slaked lime, has been consumed for thousands of years, mainly in the form of chewing. Originally used for cultural, medicinal, and ceremonial purposes mainly in South Asian countries, its use has recently spread across the globe due to its psychoactive, euphoric, and aphrodisiac properties. Now it is widely used as a social lubricant and source of financial profit. Unfortunately, the profit motive has led to high rates of habitual consumption with eventual conversion to addiction among young girls and boys. Moreover, the worrisome practice of including tobacco in quid preparations has grown, particularly among pregnant women. Major health concerns include increased rates of malignancy, oral pathology, and cardiovascular, hepatic, fertility, metabolic, and neuropsychiatric disorders. Metabolic disorders and insulin resistance disease states such as type 2 diabetes, obesity, and metabolic syndrome contribute to cognitive decline and neurodegeneration. Mechanistically, the constituents of areca nut/betel quid are metabolized to N-nitroso compounds, i.e., nitrosamines, which are carcinogenic at high doses and cause insulin resistance following chronic low-level exposures. From an epidemiological perspective, the rising tide of insulin resistance diseases including obesity, diabetes, and dementias that now disproportionately burden poor countries has been propagated by rapid commercialization and enhanced access to betel quid. Public health measures are needed to impose socially and ethically responsible barriers to yet another cause of global health disparity.

de la Monte|Suzanne M|SM|
Moriel|Natalia|N|
Lin|Amy|A|
Abdullah Tanoukhy|Nada|N|
Homans|Camille|C|
Gallucci|Gina|G|
Tong|Ming|M|
Saito|Ayumi|A|

betel quid
tobacco
diabetes
nitrosamine
dementia
arecoline


Increased Aortic Valve Calcification in Familial Hypercholesterolemia: Prevalence, Extent, and Associated Risk Factors.

Abstract:
BACKGROUND
Familial hypercholesterolemia is typically caused by LDL receptor (LDLR) mutations that result in elevated levels of LDL cholesterol (LDL-C). In homozygous FH, the prevalence of aortic valve calcification (AoVC) reaches 100% and is often symptomatic.

OBJECTIVES
The objective of this study was to investigate the prevalence, extent, and risk-modifiers of AoVC in heterozygous FH (he-FH) that are presently unknown.

METHODS
Asymptomatic patients with he-FH and 131 non-familial hypercholesterolemia controls underwent CT computed tomography calcium scoring. AoVC was defined as the presence of calcium at the aortic valve leaflets. The extent of AoVC was expressed in Agatston units, as the AoVC-score. We compared the prevalence and extent of AoVC between cases and controls. In addition, we investigated risk modifiers of AoVC, including the presence of LDLR mutations without residual function (LDLR-negative mutations), maximum untreated LDL-cholesterol (maxLDL), LDL-C, blood pressure, and coronary artery calcification (CAC).

RESULTS
We included 145 asymptomatic patients with he-FH (93 men; mean age 52 ± 8 years) and 131 non-familial hypercholesterolemia controls. The prevalence (%) and AoVC-score (median, IQR) were higher in he-FH patients than in controls: 41%, 51 (9-117); and 21%, 21 (3-49) (p < 0.001 and p = 0.007). Age, untreated maxLDL, CAC, and diastolic blood pressure were independently associated with AoVC. LDLR-negative mutational he-FH was the strongest predictor of the AoVC-score (OR: 4.81; 95% CI: 2.22 to 10.40; p = <0.001).

CONCLUSIONS
Compared to controls, he-FH is associated with a high prevalence and a large extent of subclinical AoVC, especially in patients with LDLR-negative mutations, highlighting the critical role of LDL-C metabolism in AoVC etiology.

Ten Kate|Gert-Jan R|GR|
Bos|Sven|S|
Dedic|Admir|A|
Neefjes|Lisan A|LA|
Kurata|Akira|A|
Langendonk|Janneke G|JG|
Liem|Anho|A|
Moelker|Adriaan|A|
Krestin|Gabriel P|GP|
de Feyter|Pim J|PJ|
Roeters van Lennep|Jeanine E|JE|
Nieman|Koen|K|
Sijbrands|Eric J|EJ|

aortic valve calcification
familial hypercholesterolemia
LDLR-negative mutation
coronary artery calcification
calcific aortic stenosis
low-density lipoprotein receptor


Rapid evaluation of leaching potential of heavy metals from municipal solid waste incineration fly ash.

Abstract: Municipal solid waste incineration fly ash is directly landfilled after solidification in the industry. The rapid evaluation of contaminant leaching is required before the landfill of fly ash. In order to reduce the time to evaluate the effect of solidification, a set of rapid evaluation method was developed through the determination of characteristic index, heavy metal leaching analysis, principal component analysis, and mathematical model construction. It was found that f-CaO, acid neutralizing capacity, pH and soluble calcium were negatively correlated with heavy metal leaching. The soluble chlorine was positively correlated with heavy metal leaching. The effect of each feature indicators on heavy metal leaching was evaluated using principal component analysis and mathematical analysis software R.3.4.4. Furthermore, R.3.4.4 was used to detect the optimal model and the excess probability formula by stepwise linear regression and logistic regression analysis method. By introducing the measured value of feature indicator into the excess probability formula, the rate of excess-standard of heavy metals leaching can be preliminarily determined. Based on the above ideas, a rapid detection and evaluation system could be developed according to the local leaching standards and the components of fly ash selected locally.

Yue|Yang|Y| Liu|Zeyuan|Z| Liu|Zhongzhe|Z| Zhang|Jia|J| Lu|Min|M| Zhou|Jizhi|J| Qian|Guangren|G|

Heavy metals
Rapid detection
Leaching characteristics
MSWI fly ash


Primary nocturnal enuresis: Assessment and treatment at a single referral center.

Abstract:
BACKGROUND
The aim of this study was to investigate the prevalence of primary monosymptomatic and non-monosymptomatic nocturnal enuresis (PMNE and PNMNE) and associated factors in a major referral center for NE in Abu Dhabi.

METHODS
Children referred to the Paediatric Continence Clinic, between 2014 and 2016, for PNE were included in the study. Exclusion criteria were neuropathic bladder, abnormality of the bladder and bowel, urethral stenosis, neurological and psychiatric problems, non-completion of the diagnostic protocol, and follow up <6 months.

RESULTS
A total of 128 patients were included in the study: 82 boys (64.1%) and 46 girls (35.9%). A total of 42.7% of boys and 8.7% of girls had PMNE, and 57.3% of boys and 91.3% of girls had PNMNE. Constipation was present in 46% of patients. In the male PNMNE group, 74.5% had overactive bladder (OAB), 10.6%, dysfunctional voiding (DV); and 14.9%, OAB + DV. In the female PNMNE group, 35.7% had OAB; 21.4%, DV; 40.5%, OAB + DV; and 2.4%, underactive bladder. A total of 97% and 86 of children with PMNE and PNMNE, respectively, had resolution of NE. Boys had a significantly higher incidence of PMNE, and girls, of DV.

CONCLUSION
In Abu Dhabi, NE is often associated with bladder dysfunction or DV, mostly in girls, and with constipation. High intake of dry, low fiber foods, along with hot weather and the stress of city living negatively affect the incidence of fecal retention and of NE. A multimodal approach, including the treatment of constipation, led to a satisfactory resolution of PNE in almost 90% of cases.

nocturnal enuresis
constipation
overactive bladder
dysfunctional voiding


Experiences of children with trisomy 18 referred to pediatric palliative care services on two continents.

Abstract: Children with trisomy 18 that survive beyond the neonatal period have multiple congenital anomalies, neurodevelopmental disability, and high mortality rates. The experience of children with trisomy 18 who receive pediatric palliative care services is largely unknown. We conducted a retrospective review of children with trisomy 18 receiving pediatric palliative care services at both Boston Children's Hospital, USA and Great Ormond Street Hospital, UK from January 1, 2004 to January 1, 2015. Fifty-eight children with trisomy 18 were referred to pediatric palliative care, 38 in the United Kingdom, 20 in the United States. Median age at referral was 19 days (2-89) in the United Kingdom, and 25 days (1-463) in the United States. Median length of time being followed by pediatric palliative care was 32 days (1-1,637) in the United Kingdom and 67 days (3-2,442) in the United States. The only significant difference in the two cohorts (p = .001) was in likelihood of receiving cardiac surgical intervention-37% in the United States, 0% the United Kingdom. Children with trisomy 18 receive pediatric palliative care services, with variable age at referral and for a variable length of time. Further research is needed to understand the experience of children with trisomy 18 and their families receiving pediatric palliative care services.

Mullin|Jonathan|J|0000-0001-6175-6520 Wolfe|Joanne|J| Bluebond-Langner|Myra|M| Craig|Finella|F|

D019468:Disease Management
D019538:Health Care Surveys
D006801:Humans
D007223:Infant
D007231:Infant, Newborn
D010166:Palliative Care
D011379:Prognosis
D012017:Referral and Consultation
D016019:Survival Analysis
D000073842:Trisomy 18 Syndrome
D006113:United Kingdom
D014481:United States


Reliability, Laterality and the Effect of Respiration on the Measured Corrected Flow Time of the Carotid Arteries.

Abstract:
BACKGROUND
Corrected flow time (FTc) measured via sonography of the carotid artery is a novel method that has shown promising results for predicting fluid responsiveness in shock states. It is a rapid and noninvasive examination that can be taught to emergency physicians with ease. However, its reliability has not been assessed, and the effects of several variables, including respiration and side of evaluation, are unclear.

OBJECTIVES
The objectives were to compare carotid FTc during different phases of the respiratory cycle, (at end-inspiration and end-expiration), to compare FTc reproducibility among providers, and to compare FTc on the right and left sides in a given individual.

METHODS
The FTc of both the right and left carotid arteries was measured in 16 healthy volunteers during an inspiratory hold and an expiratory hold. Examinations were completed by three sonographers blinded to previous results and were analyzed for reliability and reproducibility.

RESULTS
Reliability and reproducibility were poor when comparing sonographers under all circumstances. No significant differences were found when comparing left vs. right sides of measurement regardless of respiratory phase.

CONCLUSION
Although this method for predicting fluid responsiveness has many promising aspects, reproducibility between sonographers was found to be poor. No significant difference was found between the two sides of the body or respiratory phase.

Doctor|Michael|M|
Siadecki|Sebastian D|SD|
Cooper|Denrick|D|
Rose|Gabriel|G|
Drake|Aaran B|AB|
Ku|Melvin|M|
Suprun|Maria|M|
Saul|Turandot|T|

corrected flow time
carotid artery
critical care
ultrasound
volume responsiveness


Nutrition Delivery During Pediatric Extracorporeal Membrane Oxygenation Therapy.

Abstract:
BACKGROUND
Macronutrient delivery during pediatric ECMO therapy can be challenging. We examined predictors of nutrient delivery in the first 2 weeks of extracorporeal membrane oxygenation (ECMO) therapy in the pediatric intensive care unit (ICU).

METHODS
Details of macronutrient delivery were recorded in children (newborn-18 years of age) who survived 24 hours after cannulation to ECMO over a 3-year period (2012-2015).

RESULTS
We analyzed data from 54 consecutive eligible patients, 43% female, with median (interquartile range) ECMO duration of 8.5 (6-24) days, age 0.1 (0, 16) months, ICU length of stay 32 (21, 60) days, and 28-day mortality 13%. Median weight for age z score declined from -0.1 at admission to -1.2 at 30 days (P = 0.013). At least 80% goal energy and protein was delivered in 35 (65%) and 33 (61%) patients, respectively, by day 7; 10% of energy and 11% protein goal was delivered enterally. Parenteral nutrition (PN) was utilized in 47 (87%) patients, initiated by day 1 (1, 3). Enteral nutrition (EN) was successfully delivered in 49 (94%) patients (35% postpyloric), initiated by day 6 (2, 16). Younger age (P = 0.01) and venoarterial mode of ECMO (P = 0.0014) were associated with lower EN delivery. Use of umbilical artery catheters or vasoactive infusions did not impede EN delivery. Late PN delivery was associated with cumulative protein deficits (P = 0.019) and failure to achieve nutrient delivery goals by day 7.

CONCLUSIONS
Optimal nutrient delivery was achieved in most patients by day 7, predominantly via PN. Early EN is feasible in low volumes, but PN may be essential to prevent cumulative energy and protein deficits during the first week of ECMO.

Armstrong|Lindsey B|LB|
Ariagno|Katelyn|K|
Smallwood|Craig D|CD|
Hong|Charles|C|
Arbuthnot|Mary|M|
Mehta|Nilesh M|NM|

extracorporeal membrane oxygenation
pediatric intensive care
parenteral nutrition
enteral nutrition
congenital diaphragmatic hernia
critically ill


An economic evaluation of adaptation pathways in coastal mega cities: An illustration for Los Angeles.

Abstract: Sea level rise and uncertainty in its projections pose a major challenge to flood risk management and adaptation investments in coastal mega cities. This study presents a comparative economic evaluation method for flood adaptation measures, which couples a cost-benefit analysis with the concept of adaptation pathways. Our approach accounts for uncertainty in sea level rise projections by allowing for flexibility of adaptation strategies over time. Our method is illustrated for Los Angeles County which is vulnerable to flooding and sea level rise. Results for different sea level rise scenarios show that applying adaptation pathways can result in higher economic efficiency (up to 10%) than individual adaptation strategies, despite the loss of efficiency at the initial strategy. However, we identified 'investment tipping points', after which a transition could decrease the economic efficiencies of a pathway significantly. Overall, we recommend that studies evaluating adaptation strategies should integrate cost-benefit analysis frameworks with adaptation pathways since this allows for better informing decision makers about the robustness and economic desirability of their investment choices.

de Ruig|Lars T|LT|
Barnard|Patrick L|PL|
Botzen|W J Wouter|WJW|
Grifman|Phyllis|P|
Hart|Juliette Finzi|JF|
de Moel|Hans|H|
Sadrpour|Nick|N|
Aerts|Jeroen C J H|JCJH|

Adaptation pathways
Sea level rise
Uncertainty
Cost-benefit analysis
Climate change
Flood risk analysis


"Decoding versus comprehension": Brain responses underlying reading comprehension in children with autism.

Abstract: Despite intact decoding ability, deficits in reading comprehension are relatively common in children with autism spectrum disorders (ASD). However, few neuroimaging studies have tested the neural bases of this specific profile of reading deficit in ASD. This fMRI study examined activation and synchronization of the brain's reading network in children with ASD with specific reading comprehension deficits during a word similarities task. Thirteen typically developing children and 18 children with ASD performed the task in the MRI scanner. No statistically significant group differences in functional activation were observed; however, children with ASD showed decreased functional connectivity between the left inferior frontal gyrus (LIFG) and the left inferior occipital gyrus (LIOG). In addition, reading comprehension ability significantly positively predicted functional connectivity between the LIFG and left thalamus (LTHAL) among all subjects. The results of this study provide evidence for altered recruitment of reading-related neural resources in ASD children and suggest specific weaknesses in top-down modulation of semantic processing.

Bednarz|Haley M|HM|
Maximo|Jose O|JO|
Murdaugh|Donna L|DL|
O'Kelley|Sarah|S|
Kana|Rajesh K|RK|

Reading comprehension
Autism
Word similarities
Functional connectivity
Semantic processing
Functional MRI


Acute kidney injury and inflammatory response of sepsis following cecal ligation and puncture in d-galactose-induced aging rats.

Abstract:
BACKGROUND
Recently, the d-galactose (d-gal)-induced mimetic aging rat model has been widely used in studies of age-associated diseases, which have shown that chronic d-gal exposure induces premature aging similar to natural aging in rats. With the increasing rate of sepsis in the geriatric population, an easy-access animal model for preclinical studies of elderly sepsis is urgently needed. This study investigates whether a sepsis model that is established in d-gal-induced aging rats can serve as a suitable model for preclinical studies of elderly patients with sepsis.

OBJECTIVE
To investigate the acute kidney injury (AKI) and inflammatory response of sepsis following cecal ligation and puncture (CLP) in d-gal-induced aging rats.

METHODS
Twelve-week-old male Sprague Dawley rats were divided into low-dose d-gal (L d-gal, 125 mg/kg/d), high-dose d-gal (H d-gal, 500 mg/kg/d), and control groups. After daily subcutaneous injection of d-gal for 6 weeks, the CLP method was used to establish a sepsis model.

RESULTS
The mortality was 73.3%, 40%, and 33.3% in the H d-gal, L d-gal, and control groups, respectively. Blood urea nitrogen, creatinine, plasma neutrophil gelatinase-associated lipocalin, interleukin-6, interleukin-10, and tumor necrosis factor-α were markedly increased in the H d-gal group after establishment of the sepsis model (H d-gal vs control, P<0.05 at 12 h and 24 h post-CLP). The rate of severe AKI (RIFLE-F) at 24 h post-CLP was 43% for both the control and L d-gal groups and 80% for the H d-gal group.

CONCLUSION
High-dose- d-gal-induced aging rats are more likely to die from sepsis than are young rats, and probably this is associated with increased severity of septic AKI and an increased inflammatory response. Therefore, use of the high-dose- d-gal-induced aging rat model of sepsis for preclinical studies can provide more useful information for the treatment of sepsis in elderly patients.

Liu|Chao|C| Hu|Jie|J| Mao|Zhi|Z| Kang|Hongjun|H| Liu|Hui|H| Fu|Wanlei|W| Lv|Yangfan|Y| Zhou|Feihu|F|

acute kidney injury
inflammatory response
cecal ligation and puncture
aging rat
d-galactose


Matrix Vaginal Rings for Female Dogs-Effect of Altering Dimensions on Mechanical Properties and Dissolution Characteristics, and In vivo Safety Study.

Abstract: The vaginal rings research is almost exclusively focused on rings for human medicine, although the dosage form offers improvement of therapeutic effect in other mammals as well. This contribution studied an effect of varying dimension parameters (diameter 20, 30 or 40 mm; height 3, 4 or 5 mm; width of annulus 5, 7.5 or 10 mm) on mechanical properties and dissolution behaviour of silicone vaginal rings with constant drug amount, intended for use in dogs. Results showed that altering dimensions influenced mechanical properties (compressive force, tensile strength and resistance of removal thread), in vitro drug release and water uptake. The removal thread resistance was increasing with increasing height and width. Compression force was higher for the rings with smaller diameter. The total drug release was increasing with decreasing height and rising diameter, surface area and water uptake during dissolution test. The initial dissolution rate was slower for the rings with higher width. As the best candidate for use in model dog subjects, the ring with 30 mm diameter, 3 mm height and 7.5 mm width was found. These drug-free vaginal rings were further tested in in vivo safety study. The results did not show any major deviation from the physiological conditions. Graphical abstract.

Nováková Tkadlečková|Veronika|V|
Pitronová|Veronika|V|
Kubová|Kateřina|K|
Pavloková|Sylvie|S|
Elbl|Jan|J|
Novotný|Robert|R|
Vetchý|David|D|
Vysloužil|Jakub|J|

vaginal ring
dimension parameters
drug release
DOE, design of experiment
silicone elastomer


Novel Hybrid Scheduling Technique for Sensor Nodes with Mixed Criticality Tasks.

Abstract: Sensor networks become increasingly a key technology for complex control applications. Their potential use in safety- and time-critical domains has raised the need for task scheduling mechanisms specially adapted to sensor node specific requirements, often materialized in predictable jitter-less execution of tasks characterized by different criticality levels. This paper offers an efficient scheduling solution, named Hybrid Hard Real-Time Scheduling (H²RTS), which combines a static, clock driven method with a dynamic, event driven scheduling technique, in order to provide high execution predictability, while keeping a high node Central Processing Unit (CPU) utilization factor. From the detailed, integrated schedulability analysis of the H²RTS, a set of sufficiency tests are introduced and demonstrated based on the processor demand and linear upper bound metrics. The performance and correct behavior of the proposed hybrid scheduling technique have been extensively evaluated and validated both on a simulator and on a sensor mote equipped with ARM7 microcontroller.

Micea|Mihai-Victor|MV| Stangaciu|Cristina-Sorina|CS| Stangaciu|Valentin|V| Curiac|Daniel-Ioan|DI|

hybrid scheduling
real-time scheduling
schedulability analysis
control system
hard real-time system
mixed-criticality system


Involvement of Hippocampal D1-Like Dopamine Receptors in the Inhibitory Effect of Cannabidiol on Acquisition and Expression of Methamphetamine-Induced Conditioned Place Preference.

Abstract: Cannabidiol (CBD) is a non-psychotomimetic compound with strong potential to decrease the psychostimulant's rewarding effect with unclear receptors. Furthermore, as a part of the reward circuit, the hippocampus plays a crucial role in regulating the reward properties of drugs as determined by conditioned place preference (CPP). In the current research, CPP was used to evaluate the role of intra-CA1 microinjection of D1-like dopamine receptor antagonists in CBD's inhibitory effect on the acquisition and expression phases of methamphetamine (METH). Animals were treated by METH (1 mg/kg; sc) in a five-day schedule to induce CPP. To find out the impact of D1-like dopamine receptor antagonist, SCH23390, in the CA1 on the inhibitory influence of CBD on the acquisition of METH, the rats received intra-CA1 administration of SCH23390 (0.25, 1, and 4 µg/0.5 µl) following ICV treatment of CBD (10 µg/5 µl) over conditioning phase of METH. Furthermore, animals were given SCH23390 in the CA1 ensuing ICV microinjection of CBD (50 µg/5 µl) in the expression phase of METH to rule out the influence of SCH23390 on the suppressive effect of CBD on the expression of METH CPP. Intra-CA1 microinjection of SCH23390 abolished CBD's suppressive impact on both METH-induced CPP phases without any side effect on the locomotion. The current research disclosed that CBD inhibited the rewarding characteristic of METH via D1-like dopamine receptors in the CA1 region of the hippocampus.

D1-like dopamine receptor
Cannabidiol
Conditioned place preference
Reward
Methamphetamine
Rat
Dopamine system
Hippocampal CA1 region


The Function of Inositol Phosphatases in Plant Tolerance to Abiotic Stress.

Abstract: Inositol signaling is believed to play a crucial role in various aspects of plant growth and adaptation. As an important component in biosynthesis and degradation of myo-inositol and its derivatives, inositol phosphatases could hydrolyze the phosphate of the inositol ring, thus affecting inositol signaling. Until now, more than 30 members of inositol phosphatases have been identified in plants, which are classified intofive families, including inositol polyphosphate 5-phosphatases (5PTases), suppressor of actin (SAC) phosphatases, SAL1 phosphatases, inositol monophosphatase (IMP), and phosphatase and tensin homologue deleted on chromosome 10 (PTEN)-related phosphatases. The current knowledge was revised here in relation to their substrates and function in response to abiotic stress. The potential mechanisms were also concluded with the focus on their activities of inositol phosphatases. The general working model might be that inositol phosphatases would degrade the Ins(1,4,5)P3 or phosphoinositides, subsequently resulting in altering Ca2+ release, abscisic acid (ABA) signaling, vesicle trafficking or other cellular processes.

Jia|Qi|Q|0000-0002-5327-5417 Kong|Defeng|D| Li|Qinghua|Q| Sun|Song|S| Song|Junliang|J| Zhu|Yebao|Y| Liang|Kangjing|K| Ke|Qingming|Q| Lin|Wenxiong|W| Huang|Jinwen|J|

inositol
phosphatase
stress
phosphatidylinositol
signaling pathway


Synthesis, density functional theory (DFT) studies and urease inhibition activity of chiral benzimidazoles.

Abstract: A variety of benzimidazole by the heterocyclization of orthophenylenediamine were synthesized in 69-86% yields. The synthesized compounds 3a-f and 6a-f were characterized and further investigated as jack bean urease inhibitors. Density functional theory (DFT) studies were performed utilizing the basis set B3LYP/6-31G (d, p) to acquire perception into their structural properties. Frontier molecular orbital (FMO) analysis of all compounds 3a-f and 6a-f was computed at the same level of theory to get a notion about their chemical reactivity and stability. The mapping of the molecular electrostatic potential (MEP) over the entire stabilized molecular geometry indicated the reactive centers. They exhibited urease inhibition activity with IC50 between 22 and 99 μM. Compounds containing withdrawing groups on the benzene ring (3d, 6d) were not showing significant urease inhibition. The value obtained for 3a, 3b, 3f had shown their significant urease inhibition for both theoretical and experimental. Notably, the compound having S-configuration (3a) (22.26 ± 6.2 μM) was good as compared to its R enantiomer 3f (31.42 ± 23.3 μM). Despite this, we elaborated the computational studies of the corresponding compounds, to highlight electronic effect which include HOMO, LUMO, Molecular electrostatic potential (MEP) and molecular docking.

Aman|Hasil|H| Rashid|Naghmana|N| Ashraf|Zaman|Z| Bibi|Aamna|A| Chen|Hsin-Tsung|HT| Sathishkumar|Nadaraj|N|

Density functional theory
Urease inhibition
Benzimidazole
HOMO
LUMO
Molecular docking
Organic chemistry
Pharmaceutical chemistry
Theoretical chemistry


Conventional Chiralpak ID vs. capillary Chiralpak ID-3 amylose tris-(3-chlorophenylcarbamate)-based chiral stationary phase columns for the enantioselective HPLC separation of pharmaceutical racemates.

Abstract: A comparative enantioselective analysis using immobilized amylose tris-(3-chlorophenylcarbamate) as chiral stationary phase in conventional high-performance liquid chromatography (HPLC) with Chiralpak ID (4.6 mm ID × 250 mm, 5 µm silica gel) and micro-HPLC with Chiralpak ID-3 (0.30 mm ID × 150 mm, 3 µm silica gel) was conducted. Pharmaceutical racemates of 12 pharmacological classes, namely, α- and β-blockers, anti-inflammatory drugs, antifungal drugs, dopamine antagonists, norepinephrine-dopamine reuptake inhibitors, catecholamines, sedative hypnotics, diuretics, antihistaminics, anticancer drugs, and antiarrhythmic drugs were screened under normal phase conditions. The effect of an organic modifier on the analyte retentions and enantiomer recognition was investigated. Baseline separation was achieved for 1-acenaphthenol, carprofen, celiprolol, cizolirtine carbinol, miconazole, tebuconazole, 4-hydroxy-3-methoxymandelic acid, 1-indanol, 1-(2-chlorophenyl)ethanol, 1-phenyl-2-propanol, flavanone, 6-hydroxyflavanone, 4-bromogluthethimide, and pentobarbital on the 4.6 mm ID packed with a 5 µm silica column using conventional HPLC. Nonetheless, baseline separation was achieved for aminoglutethimide, naftopidil, and thalidomide on the 0.3 mm ID packed with a 3 µm silica capillary column.

D002851:Chromatography, High Pressure Liquid

Chiralpak ID-3
amylose tris-(3-chlorophenylcarbamate)
micro-HPLC
chiral separations
normal phase chromatography


Synthesis and anti-cancer cell activity of pseudo-ginsenoside Rh2.

Abstract: β-d-Glucopyranoside,(3β,12β,20E)-12,25-dihydroxydammar-20(22)-en-3-yl (pseudo-ginsenoside Rh2) and its 20Z-isomer were synthesized from ginsenoside Rh2 under a mild condition, via a simple three-step called acetylation, elimination-addition and saponification. In addition, their activities were evaluated by eight different human tumor cells, compared with ginsenoside Rh2 group. Results indicated that the reaction in the side chain might greatly enhance the anti-proliferative activity of ginsenosides.

Qian|Guangtao|G| Wang|Zhicai|Z| Zhao|Jinyu|J| Li|Dandan|D| Gao|Wei|W| Wang|Baohui|B| Sui|Dayuan|D| Qu|Xiangru|X| Chen|Yanping|Y|

D000970:Antineoplastic Agents
D045744:Cell Line, Tumor
D049109:Cell Proliferation
D036145:Ginsenosides
D006801:Humans
D015394:Molecular Structure

Synthesis
Ginsenoside
Human tumor cells
Steroid derivatives


No clinically significant pharmacokinetic interactions between dolutegravir and daclatasvir in healthy adult subjects.

Abstract:
BACKGROUND
Daclatasvir (DCV) is an NS5A replication complex inhibitor recently approved for chronic hepatitis C virus treatment.

METHODS
To assess drug interactions between the HIV integrase strand transfer inhibitor dolutegravir (DTG) and DCV, subjects were randomized into 1 of 2 sequences in an open-label, 3-period, crossover study. Subjects received either DTG 50 mg once daily or DCV 60 mg once daily for 5 days in periods 1 and 2 and DTG 50 mg plus DCV 60 mg once daily for 5 days in period 3, with no washout between periods 2 and 3. Between periods 1 and 2, there was a washout period of at least 7 days.

RESULTS
The geometric least-squares mean ratios (90 % confidence intervals) of DCV area under the concentration-time curve over a dosing interval (AUC0-τ), maximum observed concentration (Cmax), and concentration at the end of the dosing interval (Cτ) were 0.978 (0.831-1.15), 1.03 (0.843-1.25), and 1.06 (0.876-1.29), respectively, when DCV was administered with DTG compared with DCV alone. Compared with DTG alone, coadministration of DTG with DCV increased DTG AUC0-τ, Cmax, and Cτ by approximately 33, 29, and 45 %, respectively.

CONCLUSIONS
DCV plasma exposure was not meaningfully affected by DTG. Coadministration of DTG with DCV resulted in slight increases in DTG AUC0-τ, Cmax, and Cτ. Accumulated safety and tolerability data in humans receiving DTG to date suggests this effect is not considered clinically significant. DTG and DCV can be coadministered without dose adjustment.

TRIAL REGISTRATION
Registered on March 6, 2014 with ClinicalTrials.gov; registration number: NCT02082808 and as Study ID: 201102 on the ViiV Clinical Study Registry.

Ross|Lisa L|LL|
Song|Ivy H|IH|
Arya|Niki|N|
Choukour|Mike|M|
Zong|Jian|J|
Huang|Shu-Pang|SP|
Eley|Timothy|T|
Wynne|Brian|B|
Buchanan|Ann M|AM|

Pharmacokinetics
Interactions
Drug interactions
Adult medicine
Infectious disease


Immunizations.

Abstract: Vaccination is one of the most effective preventative health measures in modern times. It has positively affected the incidence and prevalence of a myriad of diseases, as well as improved both their morbidity and mortality. It is essential that health care providers understand the value of this intervention, promote comprehensive immunization coverage within their community, and recognize the underlying principles that guide decisions regarding vaccination. Factors important to consider before immunization administration include the type of vaccination, its recommended timing and intervals, and the presence of contraindications, precautions, or other special considerations.

Immunization
Vaccine
Prevention
Health maintenance
Public health
Shots


Arsenic Hyperaccumulation Strategies: An Overview.

Abstract: Arsenic (As) pollution, which is on the increase around the world, poses a growing threat to the environment. Phytoremediation, an important green technology, uses different strategies, including As uptake, transport, translocation, and detoxification, to remediate this metalloid. Arsenic hyperaccumulator plants have developed various strategies to accumulate and tolerate high concentrations of As. In these plants, the formation of AsIII complexes with GSH and phytochelatins and their transport into root and shoot vacuoles constitute important mechanisms for coping with As stress. The oxidative stress induced by reactive oxygen species (ROS) production is one of the principal toxic effects of As; moreover, the strong antioxidative defenses in hyperaccumulator plants could constitute an important As detoxification strategy. On the other hand, nitric oxide activates antioxidant enzyme and phytochelatins biosynthesis which enhances As stress tolerance in plants. Although several studies have focused on transcription, metabolomics, and proteomic changes in plants induced by As, the mechanisms involved in As transport, translocation, and detoxification in hyperaccumulator plants need to be studied in greater depth. This review updates recent progress made in the study of As uptake, translocation, chelation, and detoxification in As hyperaccumulator plants.

Souri|Zahra|Z|
Karimi|Naser|N|
Sandalio|Luisa M|LM|

arsenic
hyperaccumulators
phytoremediation
phytochelatins
reactive oxygen species
nitric oxide
glutathione


Bacterial Cellulose: Production, Modification and Perspectives in Biomedical Applications.

Abstract: Bacterial cellulose (BC) is ultrafine, nanofibrillar material with an exclusive combination of properties such as high crystallinity (84%-89%) and polymerization degree, high surface area (high aspect ratio of fibers with diameter 20-100 nm), high flexibility and tensile strength (Young modulus of 15-18 GPa), high water-holding capacity (over 100 times of its own weight), etc. Due to high purity, i.e., absence of lignin and hemicellulose, BC is considered as a non-cytotoxic, non-genotoxic and highly biocompatible material, attracting interest in diverse areas with hallmarks in medicine. The presented review summarizes the microbial aspects of BC production (bacterial strains, carbon sources and media) and versatile in situ and ex situ methods applied in BC modification, especially towards bionic design for applications in regenerative medicine, from wound healing and artificial skin, blood vessels, coverings in nerve surgery, dura mater prosthesis, arterial stent coating, cartilage and bone repair implants, etc. The paper concludes with challenges and perspectives in light of further translation in highly valuable medical products.

bacterial cellulose
biomedical applications
carbon source
ex situ modification
in situ modification


Treatment outcomes of patients with MDR-TB in Nepal on a current programmatic standardised regimen: retrospective single-centre study.

Abstract:
OBJECTIVES
The objectives of this study were to evaluate treatment in patients on current programmatic multidrug-resistant tuberculosis (MDR-TB) regimen and verify eligibility for the 9-month regimen and therapeutic drug monitoring (TDM).

METHODS
We performed a retrospective chart review of patients with MDR-TB receiving standardised regimen at the German Nepal TB Project Clinic, Nepal, between 2014 and 2016. Eligibility for the 9-month regimen and indications for TDM were evaluated.

RESULTS
Out of 107 available patients' medical records, 98 were included. In this centre, the MDR-TB treatment success rates were 69.0% in 2015, 86.6% in 2016 and 86.5% in 2017. The median time to sputum smear conversion was 60 days (60-90 IQR) and culture conversion was 60 days (60-90 IQR). Observed side effects did not impact treatment outcomes. No difference in treatment success rates was observed between patients with predisposing risk factors and those without. Only 49% (36/74) of patients were eligible for the 9-month regimen and 23 patients for TDM according to American Thoracic Society guideline criteria.

CONCLUSIONS
Nepalese patients with MDR-TB on ambulatory care had good treatment outcome after programmatic treatment. Implementation of the new WHO oral MDR-TB treatment regimen may further improve treatment results. The 9-month regimen and TDM should be considered as part of programmatic care.

Ghimire|Samiksha|S|
Karki|Samriddhi|S|
Maharjan|Bhagwan|B|
Kosterink|Jos G W|JGW|
Touw|Daan J|DJ|
van der Werf|Tjip S|TS|
Shrestha|Bhabana|B|
Alffenaar|Jan-Willem|JW|


A multifunctional microfluidic platform for generation, trapping and release of droplets in a double laminar flow.

Abstract: Droplet microfluidics, involving micrometer-sized emulsion of droplets is a growing subfield of microfluidics which attracts broad interest due to its application on biological assays. Droplet-based systems have been used as microreactors as well as to encapsulate many biological entities for biomedical and biotechnological applications. Here, a novel microfluidic device is presented for the generation, trapping and release of aqueous including hydrogel droplets in a double laminar oil flow. This platform enables the storage and release of picoliter-sized droplets in two different carrier oils by using hydrodynamic forces without the need of electrical forces or optical actuators. Furthermore, this design allows droplets to be selectively and simultaneously exposed to two different conditions and collected on demand. Successful encapsulation of hepatoma H35 cells was performed on-chip. Viability of cell-laden droplets was performed off-chip to assess the potential applications in 3D encapsulation cell culture and drug discovery assays.

Microfluidics
Hydrogel droplet
Hydrodynamic force
Cell-laden droplets


Proceedings of the 2018 Santa Fe Bone Symposium: Advances in the Management of Osteoporosis.

Abstract: The Santa Fe Bone Symposium is an annual meeting devoted to clinical applications of recent advances in skeletal research. The 19th Santa Fe Bone Symposium convened August 3-4, 2018, in Santa Fe, New Mexico, USA. Attendees included physicians of many specialties, fellows in training, advanced practice providers, clinical researchers, and bone density technologists. The format consisted of lectures, case presentations by endocrinology fellows, and panel discussions, with all involving extensive interactive discussions. Topics were diverse, including an evolutionary history of calcium homeostasis, osteoporosis treatment in the very old, optimizing outcomes with orthopedic surgery, microbiome and bone, new strategies for combination and sequential therapy of osteoporosis, exercise as medicine, manifestations of parathyroid hormone excess and deficiency, parathyroid hormone as a therapeutic agent, cell senescence and bone health, and managing patients outside clinical practice guidelines. The National Bone Health Alliance conducted a premeeting on development of fracture liaison services. A workshop was devoted to Bone Health TeleECHO (Bone Health Extension for Community Healthcare Outcomes), a strategy of ongoing medical education for healthcare professions to expand capacity to deliver best practice skeletal healthcare in underserved communities and reduce the osteoporosis treatment gap.

Lewiecki|E Michael|EM|
Bilezikian|John P|JP|
Giangregorio|Lora|L|
Greenspan|Susan L|SL|
Khosla|Sundeep|S|
Kostenuik|Paul|P|
Krohn|Kelly|K|
McClung|Michael R|MR|
Miller|Paul D|PD|
Pacifici|Roberto|R|

D000367:Age Factors
D000818:Animals
D016723:Bone Remodeling
D001842:Bone and Bones
D016922:Cellular Senescence
D005081:Exercise Therapy
D017102:Fracture Healing
D005598:Fractures, Spontaneous
D006801:Humans
D064307:Microbiota
D056687:Off-Label Use
D010024:Osteoporosis
D010281:Parathyroid Hormone
D017410:Practice Guidelines as Topic
D019936:Probiotics
D012307:Risk Factors
D016103:Spinal Fractures
D013123:Spinal Fusion

Osteoporosis Microbiome Parathyroid ECHO Microbiota


In situ stabilization of NAPL contaminant source-zones as a remediation technique to reduce mass discharge and flux to groundwater.

Abstract: Widely used flushing and in-situ destruction based remediation techniques (i.e. pump-and treat, enhanced-solubilization, and chemical oxidation/reduction) for sites contaminated by nonaqueous phase liquid (NAPL) contaminant sources have been shown to be ineffective at complete mass removal and reducing aqueous-phase contaminant of concern (COC) concentrations to levels suitable for site closure. A remediation method was developed to reduce the aqueous solubility and mass-flux of COCs within NAPL through the in-situ creation of a NAPL mixture source-zone. In contrast to remediation techniques that rely on the rapid removal of contaminant mass, this technique relies on the stabilization of difficult-to-access NAPL sources to reduce COC mass flux to groundwater. A specific amount (volume) of relatively insoluble n-hexadecane (HEXDEC) or vegetable oil (VO) was injected into a trichloroethene (TCE) contaminant source-zone through a bench-scale flow cell port (i.e. well) to form a NAPL mixture of targeted mole fraction (TCE:HEXDEC or TCE:VO). NAPL-aqueous phase batch tests were conducted prior to the flow-cell experiments to evaluate the effects of various NAPL mixture ratios on equilibrium aqueous-phase concentrations of TCE to design optimal NAPL (HEXDEC or VO) injection volumes for the flow-cell experiments. The NAPL-stabilization flow-cell experiments initiated and sustained significant reductions in COC concentration and mass flux due to a combination of both reduced relative permeability (increased NAPL-saturation) and via modification of NAPL composition (decreased TCE mole fraction). Variations in remediation performance (i.e. impacts on TCE concentration and mass flux reduction) between the different HEXDEC injection volumes were relatively minor, and therefore inconsistent with Raoult's Law predictions. This phenomenon likely resulted from non-uniform mixing of the injected HEXDEC with TCE in the source-zone. VO injection caused TCE concentrations and mass-flux to decrease more rapidly than with HEXDEC injections. This phenomenon occurred because the injected VO was observed to mix more uniformly with TCE in the source-zone due to a lower mobilization potential. The relative lower density differences (buoyancy effects) between VO and the flushing solution (water) was the primary factor contributing to the lower mobilization potential for VO. Overall, this study indicated that the delivery of HEXDEC or VO into the toxic TCE source-zone was effective in significantly reducing contaminant aqueous-phase concentration and mass-flux. However, the effectiveness of this in-situ NAPL stabilization technique depends on source delivery, uniform mixing of amendment, and that the amendment remains immobilized within and around the NAPL contaminant source.

Mateas|Douglas J|DJ|
Tick|Geoffrey R|GR|
Carroll|Kenneth C|KC|

D052918:Environmental Restoration and Remediation

Remediation
NAPL mixture
Flow-cell
Raoult's Law
Mass-flux reduction


The effect of N-acetyl cysteine on the volume of uterine leiomyoma: A randomized clinical trial.

Abstract:
OBJECTIVE
To conduct a clinical trial to investigate the effect of N-acetyl cysteine (NAC), a non-hormonal drug, on the volume of leiomyoma, the most common benign tumor in women.

METHODS
This study is a randomized clinical trial, which was performed in Semnan, Iran. Eligible women who were diagnosed with uterine leiomyoma using vaginal ultrasound were randomly assigned to receive NAC or placebo for 12 weeks. The change in the volume of Leiomyoma was considered to be the main variable in the efficacy evaluation. Reduction in the leiomyoma volume was calculated after intervention and data were entered in SPSS version 23.

RESULTS
Fifty individuals were enrolled in our study. 25 women received NAC, while 25 women took placebo. The mean volume of leiomyoma in group A was 5.71 cm3 and in group B was 6.56 cm3 . The mean rate of volume reduction in the A and B groups was 25.25 % and 1.08 %, respectively, which demonstrated a significant difference between the two groups (P < 0.004).

CONCLUSION
Although this trial recommends the use of NAC as a non-hormonal drug in the treatment of leiomyoma of the uterus, the possibility of treatment failure in controlling abnormal uterine bleeding cannot be ignored. Nevertheless, we can say it is feasible and effective in the reduction of leiomyoma volume.

N-acetyl cysteine
leiomyoma
benign tumor
free radical oxidation


Verbascoside production in long-term Buddleja cordata Kunth cell suspension cultures.

Abstract: Previously, our group reported the establishment of a white callus cell line of Buddleja cordata Kunth that is a high producer of the secondary metabolite, verbascoside (VB, also named acteoside), under suspension culture conditions. Here, we present experimental evidence of the sustained ability of that cellular line to grow and produce high amounts of VB for 5 years of continuous culture. Cellular line profiles were determined at the early (at the beginning) and late stages (at the end of 5 years of continuous subculturing) by analyzing relevant parameters of culture growth, i.e., specific growth rate [µ], doubling time [dt], and growth index [GI], as well as VB production. Late-stage cultures exhibited a 61% faster growth rate than early-stage subcultures, and 25 and 3% lower doubling time and growth index. The extents of growth phases were found to be different. Similar amounts of biomass were found (9.5 g and 9.4 g L-1). Verbascoside production increased parallel to cell growth; maximal yield level occurred in the mid-exponential phase and lasted until the end of the stationary phase (i.e., from the 15th to the 25th day and from the 9th to the 21st day for the early and late stages, correspondingly). The content of VB was higher in the late-stage culture (1.43 ± 0945 g L-1) than in the early-stage culture (1.21 ± 0.0286 g L-1). Productivity values point out the potential use of B. cordata cell line in the biotechnological production of VB and for research focused on the biochemistry of secondary metabolism.

Verbascoside
Buddleja cordata
Growth parameters
Long-term culture
Phenylpropanoid
Plant cell suspension cultures


Synchronized activation of striatal direct and indirect pathways underlies the behavior in unilateral dopamine-depleted mice.

Abstract: For more than three decades it has been known, that striatal neurons become hyperactive after the loss of dopamine input, but the involvement of dopamine (DA) D1- or D2-receptor-expressing neurons has only been demonstrated indirectly. By recording neuronal activity using fluorescent calcium indicators in D1 or D2 eGFP-expressing mice, we showed that following dopamine depletion, both types of striatal output neurons are involved in the large increase in neuronal activity generating a characteristic cell assembly of particular neurons that dominate the pattern. When we expressed channelrhodopsin in all the output neurons, light activation in freely moving animals, caused turning like that following dopamine loss. However, if the light stimulation was patterned in pulses the animals circled in the other direction. To explore the neuronal participation during this stimulation we infected normal mice with channelrhodopsin and calcium indicator in striatal output neurons. In slices made from these animals, continuous light stimulation for 15 s induced many cells to be active together and a particular dominant group of neurons, whereas light in patterned pulses activated fewer cells in more variable groups. These results suggest that the simultaneous activity of a large dominant group of striatal output neurons is intimately associated with parkinsonian symptoms.

assemblies
Parkinson's disease
basal ganglia
calcium imaging
optogenetics


Phlebotomus papatasi exposure cross-protects mice against Leishmania major co-inoculated with Phlebotomus duboscqi salivary gland homogenate.

Abstract: Leishmania parasites are inoculated into host skin together with sand fly saliva and multiple exposures to uninfected sand fly bites protect mice against Leishmania infection. However, sand fly vectors differ in composition of the saliva and therefore the protection elicited by their salivary proteins was shown to be species-specific. On the other hand, the optimal vaccine based on sand fly salivary proteins should be based on conserved salivary proteins conferring cross-reactivity. In the present study we therefore focused on cross-protective properties of saliva from Phlebotomus papatasi and Phlebotomus duboscqi, the two natural vectors of Leishmania major. Two groups of mice exposed to bites of P. papatasi and two control, non-immunized groups were infected with L. major promastigotes along with either P. papatasi or P. duboscqi salivary gland homogenate. All mice were followed for the development of Leishmania lesions, parasite burdens, specific antibodies, and for production of NO, urea, or cytokines by peritoneal macrophages. Protection against Leishmania infection was observed not only in exposed mice challenged with homologous saliva but also in the group challenged with P. duboscqi saliva. Comparing both exposed groups, no significant differences were observed in parasite load, macrophage activity, or in the levels of anti-L. major and anti-P. papatasi/P. duboscqi antibodies. This is the first study showing cross-protection caused by salivary antigens of two Phlebotomus species. The cross-protective effect suggests that the anti-Leishmania vaccine based on P. papatasi salivary proteins might be applicable also in areas where L. major is transmitted by P. duboscqi.

Lestinova|Tereza|T| Vlkova|Michaela|M| Votypka|Jan|J| Volf|Petr|P| Rohousova|Iva|I|

Phlebotomus papatasi
Cross-protection
Phlebotomus duboscqi
Sand fly saliva
Macrophage


Observation of 2D Conduction in Ultrathin Germanium Arsenide Field-Effect Transistors.

Abstract: We report the fabrication and electrical characterization of germanium arsenide (GeAs) field-effect transistors with ultrathin channels. The electrical transport is investigated in the 20-280 K temperature range, revealing that the p-type electrical conductivity and the field-effect mobility are growing functions of temperature. An unexpected peak is observed in the temperature dependence of the carrier density per area at ∼75 K. Such a feature is explained considering that the increased carrier concentration at higher temperatures and the vertical band bending combined with the gate field lead to the formation of a two-dimensional (2D) conducting channel, limited to few interfacial GeAs layers, which dominates the channel conductance. The conductivity follows the variable-range hopping model at low temperatures and becomes the band-type at higher temperatures when the 2D channel is formed. The formation of the 2D channel is validated through a numerical simulation that shows excellent agreement with the experimental data.

2D conduction
germanium arsenide
field-effect transistors
mobility
carrier density
variable-range hopping
temperature-dependent conduction


Outcomes in patients with short bowel syndrome after autologous intestinal reconstruction: Does etiology matter?

Abstract:
BACKGROUND
Short bowel syndrome (SBS) is the most common cause of intestinal failure in children. Many factors have been investigated in an attempt to define which parameters influence most survival and ability to wean off parenteral nutrition (PN). The aim of this study was to investigate if aetiology of SBS affects the outcomes in paediatric patients treated with autologous gastrointestinal reconstructive surgery.

METHODS
All children with SBS who underwent autologous gastrointestinal reconstructive surgery between 2002 and 2012 were retrospectively reviewed and outcome measures were recorded.

RESULTS
Forty-three patients were divided into 4 groups according to aetiology (gastroschisis, volvulus, necrotizing enterocolitis (NEC), intestinal atresia). No significant differences were found among groups regarding survival and median age at surgery. The volvulus group had a lower pre-operative bowel length in comparison with gastroschisis and intestinal atresia and the lowest percentage of patients off PN (30%). Gastroschisis had the lowest rate of preserved ileocaecal valve (10%), while intestinal atresia had the highest (66%). For children who weaned off PN, intestinal atresia had also the longest time to achieve enteral autonomy (14.5months), while NEC had the shortest (3.5months), followed by gastroschisis (8.5months). None of the patients needed transplant.

CONCLUSIONS
In our experience it does not appear that diagnosis is significantly related to outcome and this is consistent with the conclusions of other reviews. However, it should be noted that in our series patients with volvulus had the worse outcome in terms of weaning off PN when compared with intestinal atresia.

TYPE OF STUDY
Retrospective Study.

LEVEL OF EVIDENCE
II.

Pederiva|Federica|F| Sgrò|Alberto|A| Coletta|Riccardo|R| Khalil|Basem|B| Morabito|Antonino|A|

Short bowel syndrome
Etiology
AGIR
Bowel lengthening


A novel CNS-homing peptide for targeting neuroinflammatory lesions in experimental autoimmune encephalomyelitis.

Abstract: Using phage peptide library screening, we identified peptide-encoding phages that selectively home to the inflamed central nervous system (CNS) of mice with experimental autoimmune encephalomyelitis (EAE), a model of human multiple sclerosis (MS). A phage peptide display library encoding cyclic 9-amino-acid random peptides was first screened ex-vivo for binding to the CNS tissue of EAE mice, followed by in vivo screening in the diseased mice. Phage insert sequences that were present at a higher frequency in the CNS of EAE mice than in the normal (control) mice were identified by DNA sequencing. One of the phages selected in this manner, denoted as MS-1, was shown to selectively recognize CNS tissue in EAE mice. Individually cloned phages with this insert preferentially homed to EAE CNS after an intravenous injection. Similarly, systemically-administered fluorescence-labeled synthetic MS-1 peptide showed selective accumulation in the spinal cord of EAE mice. We suggest that peptide MS-1 might be useful for targeted drug delivery to CNS in EAE/MS.

Acharya|Bodhraj|B|
Meka|Rakeshchandra R|RR|
Venkatesha|Shivaprasad H|SH|
Lees|Jason R|JR|
Teesalu|Tambet|T|
Moudgil|Kamal D|KD|

CNS
EAE
Multiple sclerosis
Homing peptide
Phage library
Probes
Targeted delivery


Hotspots of H1N1 influenza in India: analysis of reported cases and deaths (2010-2017).

Abstract: Influenza A (H1N1) caused significant mortality and morbidity globally. We identified the hotspots for H1N1 influenza in India using cases and deaths reported in the Integrated Disease Surveillance Program between 2010 and 2017. A total of 114,667 cases and 8543 deaths were reported from across India, at an overall case fatality rate of 7.5%. While Maharashtra accounted for 21% of cases and 31% of deaths, Delhi and Gujarat were ranked the highest based on the population-adjusted ranks for morbidity and mortality, respectively. The current analysis identified states and union territories in western India (Delhi, Punjab, Rajasthan, Gujarat and Maharashtra) to be especially vulnerable.


RNAi drives nonreciprocal translocations at eroding chromosome ends to establish telomere-free linear chromosomes.

Abstract: The identification of telomerase-negative HAATI (heterochromatin amplification-mediated and telomerase-independent) cells, in which telomeres are superseded by nontelomeric heterochromatin tracts, challenged the idea that canonical telomeres are essential for chromosome linearity and raised crucial questions as to how such tracts translocate to eroding chromosome ends and confer end protection. Here we show that HAATI arises when telomere loss triggers a newly recognized illegitimate translocation pathway that requires RNAi factors. While RNAi is necessary for the translocation events that mobilize ribosomal DNA (rDNA) tracts to all chromosome ends (forming "HAATIrDNA" chromosomes), it is dispensable for HAATIrDNA maintenance. Surprisingly, Dicer (Dcr1) plays a separate, RNAi-independent role in preventing formation of the rare HAATI subtype in which a different repetitive element (the subtelomeric element) replaces telomeres. Using genetics and fusions between shelterin components and rDNA-binding proteins, we mapped the mechanism by which rDNA loci engage crucial end protection factors-despite the absence of telomere repeats-and secure end protection. Sequence analysis of HAATIrDNA genomes allowed us to propose RNA and DNA polymerase template-switching models for the mechanism of RNAi-triggered rDNA translocations. Collectively, our results reveal unforeseen roles for noncoding RNAs (ncRNAs) in assembling a telomere-free chromosome end protection device.

Begnis|Martina|M|
Apte|Manasi S|MS|
Masuda|Hirohisa|H|
Jain|Devanshi|D|
Wheeler|David Lee|DL|
Cooper|Julia Promisel|JP|

RNAi
telomere
ALT
DNA repair
cancer
genome stability


Decisive differences in the bone repair processes of the metaphysis and diaphysis in young mice.

Abstract: Fractures are common traumatic injuries that mainly occur in the metaphyses of long bones such as the proximal humerus, distal radius, and proximal femur. However, most studies of fracture repair processes have focused on the diaphyseal region. In this study, we compared the bone repair processes of the metaphysis and the diaphysis of the mouse tibia. Bone apertures were formed in the tibial metaphysis and diaphysis. At indicated times after surgery, samples were collected, and the healing process was investigated using micro-computed tomography, as well as histological, immunohistochemical, and mRNA expression analyses. In the metaphysis, cartilage formation was not detected on the periosteal side. The bone aperture was filled with newly formed bone produced from bone marrow at day 7. In the case of the diaphysis, cartilage was formed around the aperture at day 4 and sequentially replaced by bone on the periosteal side. The bone aperture was filled with newly formed bone at day 14. In the bone marrow, expression of the osteogenic markers such as alkaline phosphatase, osteocalcin, and type I collagen, appeared earlier with metaphyseal injury than with diaphyseal injury. The mRNA expression of chondrogenesis markers was markedly upregulated in the diaphysis compared with that in the metaphysis on the periosteal side. These results indicate differences in the bone repair processes of the two regions, suggesting functional heterogeneity of the periosteum and bone marrow mesenchymal cells in response to bone fractures.

Inoue|Satoshi|S| Otsuka|Hirotada|H| Takito|Jiro|J| Nakamura|Masanori|M|

Metaphysis
Diaphysis
Bone marrow
Periosteum
Bone healing


Towards a greater understanding of anxiety sensitivity across groups: The construct validity of the Anxiety Sensitivity Index-3.

Abstract: The present study examined the factor structure, invariance properties, reliability, and validity of the Anxiety Sensitivity Index-3 (ASI-3, Taylor et al., 2007). Participants were recruited from a large, ethnically diverse southwestern university (n = 3651; 77.8% female; Mage = 22.06 years; 28% non-Hispanic White). Findings supported a bifactor structure for the ASI-3, which demonstrated measurement invariance across sex, race/ethnicity, age, and sexual minority status. Furthermore, the ASI-3 demonstrated strong reliability and validity, with the anxiety sensitivity general and specific factors (physical, cognitive, and social concerns) evidencing unique patterns of relations with symptoms of depression, suicidality, anxious arousal, and social anxiety. Clinically, these findings generally support the validity of the ASI-3 in measuring anxiety sensitivity across sex, age, race/ethnicity, and sexual minority status. Future work is needed to better understand the role anxiety sensitivity plays within specific demographic subgroups, particularly African-Americans, Asian Americans, and sexual minorities.

Jardin|Charles|C|
Paulus|Daniel J|DJ|
Garey|Lorra|L|
Kauffman|Brooke|B|
Bakhshaie|Jafar|J|
Manning|Kara|K|
Mayorga|Nubia A|NA|
Zvolensky|Michael J|MJ|

Anxiety sensitivity
Measurement invariance
Race/ethnicity
Gender
Sexual orientation


An exploration of the latent constructs of the STATIC-99.

Abstract: Although actuarial instruments are ubiquitously used in the field of sex offender recidivism risk assessment, there is limited empirical information about the underlying constructs from which they are derived. The following study utilized a nonparametric item response theory procedure, a Mokken analysis, and nonlinear factor analysis (Normal Ogive Harmonic Analysis Robust Method) to explore the underlying constructs of the STATIC-99 scores obtained for male sexual offenders (N = 451) referred for an evaluation to determine if they met criteria for civil commitment under a state's Sexually Violent Persons Law. The results from the analyses indicated that the STATIC-99 comprises the two previously identified constructs associated with sexual deviancy and antisocial behaviors as well as a third, additional construct, associated with the items pertaining to age and past marital-type relationships. These findings support Hanson and Thornton's assertion that sexual offender recidivism risk is multifactorial and not the result of a single underlying trait. Implications for future research are discussed.

Allen|Bradley P|BP|
Pflugradt|Dawn M|DM|

STATIC-99
latent traits
sexual offender assessment


Percolating hierarchical defect structures drive phase transformation in Ce1-x Gd x O2-x/2: a total scattering study.

Abstract: A new hierarchical approach is presented for elucidating the structural disorder in Ce1-x Gd x O2-x/2 solid solutions on different scale lengths. The primary goal of this investigation is to shed light on the relations between the short-range and the average structure of these materials via an analysis of disorder on the mesocopic scale. Real-space (pair distribution function) and reciprocal-space (Rietveld refinement and microstructure probing) analysis of X-ray powder diffraction data and electron spin resonance (ESR) investigations were carried out following this approach. On the local scale, Gd- and Ce-rich droplets (i.e. small regions a few ångströms wide) form, exhibiting either a distorted fluorite (CeO2) or a C-type (Gd2O3) structure in the whole compositional range. These droplets can then form C-type nanodomains which, for Gd concentrations x Gd ≤ 0.25, are embedded in the fluorite matrix. At the site percolation threshold p C for a cubic lattice (x Gd = p C ≃ 0.311), C-type nanodomains percolate inside each crystallite and a structural phase transformation is observed. When this occurs, the peak-to-peak ESR line width ΔH pp shows a step-like behaviour, which can be associated with the increase in Gd-Gd dipolar interactions. A general crystallographic rationale is presented to explain the fluorite-to-C-type phase transformation. The approach shown here could be adopted more generally in the analysis of disorder in other highly doped materials.

Scavini|Marco|M| Coduri|Mauro|M| Allieta|Mattia|M| Masala|Paolo|P| Cappelli|Serena|S| Oliva|Cesare|C| Brunelli|Michela|M| Orsini|Francesco|F| Ferrero|Claudio|C|

high-resolution X-ray powder diffraction


Triple jeopardy: adolescent experiences of sex work and migration in Zimbabwe.

Abstract: Adolescence, migration and sex work are independent risk factors for HIV and other poor health outcomes. They are usually targeted separately with little consideration on how their intersection can enhance vulnerability. We interviewed ten women in Zimbabwe who experienced sex work and migration during adolescence, exploring implications for their health and for services to meet their needs. For most, mobility was routine throughout childhood due to family instability and political upheaval. The determinants of mobility, e.g. inability to pay school fees or desire for independence from difficult circumstances, also catalysed entry into sex work, which then led to further migration to maximise income. Respondents described their adolescence as a time of both vulnerability and opportunity, during which they developed survival skills. While these women did not fit neatly into separate risk profiles of "sex worker" "migrant" or "adolescent", the overlap of these experiences shaped their health and access to services. To address the needs of marginalised populations we must understand the intersection of multiple risks, avoiding simplified assumptions about each category.

Busza|Joanna|J| Mtetwa|Sibongile|S| Chirawu|Petronella|P| Cowan|Frances|F|

Adolescents
Sex work
Migration
Zimbabwe
Sexual health