Preemptive analgesia with a single low dose of intrathecal morphine in multilevel posterior lumbar interbody fusion surgery: a double-blind, randomized, controlled trial.

Abstract:
BACKGROUND CONTEXT
Patients undergoing lumbar spinal surgery may experience considerable pain in the early postoperative period, and poor pain control after multilevel lumbar spinal fusion surgery is frequently associated with multiple complications and delayed discharge from hospital.

PURPOSE
The current study evaluated the efficacy and safety of preemptive analgesia with intrathecal morphine (ITM) in patients undergoing multilevel posterior lumbar spinal fusion surgery.

STUDY DESIGN
Double-blinded, randomized, controlled trial.

PATIENT SAMPLE
Ninety-two patients aged between 18 and 80 years who were scheduled to undergo elective lumbar laminectomy (L3-S1) and dual-level fusions.

OUTCOME MEASURES
The primary endpoint was the degree of postoperative pain at rest and during movement evaluated using a 10-point visual analogue scale. The secondary outcomes included the consumption of analgesics, the patient-assessed postoperative and satisfaction scores, adverse effects, time to first ambulation, and length of hospital stay.

METHODS
Patients were randomly allocated to either the ITM group that received 0.2 mg of ITM or the control (CON) group that received 2 ml of 0.9% saline as a skin infiltration 30 minutes prior to anesthesia induction.

RESULTS
The ITM group had a significantly lower visual analogue scale score than the CON group during the first 3 days postoperatively (at rest, P=0.000, during movement, P=0.000). The ITM group used significantly less sufentanil than the CON group in the first 3 days postoperatively (p=.000) in patient-controlled intravenous analgesia, as well as in supplemental analgesic demands. The ITM group reported a greater degree of satisfaction with the whole hospitalization experience than the CON group (2.4±0.6 vs. 1.9±0.6, p=.000). The two groups did not significantly differ regarding adverse effects, length of hospital stay, and time taken to regain the ability to walk without support.

CONCLUSIONS
Preemptive analgesia with ITM results in significantly improved early postoperative pain control and decreased postoperative patient-controlled intravenous analgesia consumption, with no increase in adverse effects.

Wang|Yujie|Y| Guo|Xiangyang|X| Guo|Zhaoqing|Z| Xu|Mao|M|

Multilevel posterior lumbar interbody fusion surgery


Early birth registration at a center in rural India.

Abstract:
BACKGROUND
Registration of birth is mandatory in India however due to various issues compliance for timely birth registration has been poor.

OBJECTIVE
The objective of this study was to determine time elapsed between birth and registration and describe the socio-demographic profile of registered births at a rural center.

MATERIALS AND METHODS
A cross-sectional descriptive study was undertaken and all births registered at a primary health center of a block during the period 2010 and 2011 were retrieved and data collection carried using structured proforma based on birth formats under civil registration system (CRS). House to house visit was undertaken to identify births without registration.

RESULTS
A total of 340 and 276 births were registered during 2010 and 2011 respectively. Time elapsed between birth and registration was computed to be lower, i.e., 9.38 days (±7.46) during 2011 in-comparison with 10.52 days (±8.73) in 2010. On a positive note, higher level of education and marriage of women beyond legal age of 18 years was noticed in 2011 in comparison with 2010. Overall, institutional birth stood at a very encouraging note (66.2%). All (100%) births during the study period were registered at this (rural) or higher center (urban) depending on the place of delivery. An omission/commission of birth format is highlighted that needs urgent attention of the authorities.

DISCUSSION
Majority (>92%) of birth registration occurred with-in the stipulated period of 21 days as prescribed under CRS and our study indicates early birth registration in a rural area of Haryana, India.

Sachdeva|Sandeep|S| Nagar|Mukesh|M| Tyagi|Ajay|A| Sachdeva|Ruchi|R| Kumar|Vijay|V|

Birth
time
civil registration
farmer
sex ratio
socio-demography rural
training


Vitexin inhibits Aβ25-35 induced toxicity in Neuro-2a cells by augmenting Nrf-2/HO-1 dependent antioxidant pathway and regulating lipid homeostasis by the activation of LXR-α.

Abstract: Amyloid beta (Aβ) formation is one of the neuropathological hallmarks of Alzheimer's disease (AD), which induces the generation of reactive oxygen species (ROS), further leading to the alteration of several signalling pathways. In the present study, vitexin has been evaluated for its neuroprotective activity against Aβ25-35 induced toxicity in Neuro-2a cells. Results of cell free studies indicated that vitexin significantly inhibited the aggregation of Aβ25-35. Studies in Neuro-2a cells revealed that Aβ25-35 significantly affected the cell viability by inducing ROS mediated toxicity and apoptosis. However, pre-treatment of Neuro-2a cells with vitexin (50 μM) significantly restored the cell viability up to 92.86 ± 5.57%. Vitexin has been found to inhibit the production of free radicals and suppress ROS mediated lipid peroxidation, protein oxidation and loss of membrane potential. Also, vitexin modulated the expression of genes involved in antioxidant response mechanisms (Nrf-2, HO-1), cholesterol metabolism (LXR-α, APOE, ABCA-1, Seladin-1), and endoplasmic reticulum stress (Grp78, Gadd153) to offer neuroprotection. Aβ25-35 induced caspase-3 activation, and Bax protein expression was also found to be significantly inhibited by vitexin. Taken together, our results indicate that vitexin offers neuroprotection to cells in part via augmenting the antioxidant mechanisms, maintaining lipid homeostasis and inhibiting apoptosis induced by Aβ.

Malar|Dicson Sheeja|DS|
Suryanarayanan|Venkatesan|V|
Prasanth|Mani Iyer|MI|
Singh|Sanjeev Kumar|SK|
Balamurugan|Krishnaswamy|K|
Devi|Kasi Pandima|KP|

D000091342:Endoplasmic Reticulum Chaperone BiP


Timing of vitamin K antagonist re-initiation following intracranial hemorrhage in mechanical heart valves: Systematic review and meta-analysis.

Abstract:
BACKGROUND
While evidence supports resumption of vitamin K antagonists (VKAs) among mechanical heart valve (MHV) patients presenting with anticoagulant-associated intracranial hemorrhage (ICH), ideal timing of resumption is uncertain.

OBJECTIVE
To determine the optimal timing of VKA re-initiation and its associated clinical outcomes.

METHODS
We performed a systematic review and a meta-analysis of studies published from January 1950 to August 2015. We extracted data on the location of initial ICH, use of cranial surgery, presence of atrial fibrillation, MHV type and position, number of MHVs, and timing of VKA resumption. Outcomes including valve thrombosis, thromboembolic events or ICH recurrence were recorded. Meta-regression analysis was conducting with controlling for covariates. We calculated absolute risks, and assessed the effect of anticoagulant resumption timing on ICH recurrence.

RESULTS
23 case-series and case-reports were identified. Overall ICH recurrence was 13% (95% confidence interval [CI], 7%-25%), while valve thrombosis and ischemic strokes occurred at 7% (95% CI, 3%-17%) and 12% (95% CI, 5%-23%) respectively. A trend towards lower ICH recurrence was observed with delayed VKA resumption (slope estimate -0.2154, p=0.10). Recurrence rate ranged from 50% with VKA resumption at 3days to 0% with resumption at 16days.

CONCLUSION
Among patients with MHV, there is inadequate data to suggest an optimal timing of VKA re-initiation following an ICH, though delayed restart appears to be protective against recurrence but is associated with higher risk of thrombosis. Our analysis suggests 4-7days might be an ideal time with least risk of thrombosis or ICH recurrence.

AlKherayf|Fahad|F|
Xu|Yan|Y|
Gandara|Esteban|E|
Westwick|Harrison|H|
Moldovan|Ioana Doina|ID|
Wells|Philip S|PS|

Intracranial hemorrhage
Anticoagulant
Mechanical valve
Warfarin


Seeing the Forest and the Trees: Default Local Processing in Individuals with High Autistic Traits Does Not Come at the Expense of Global Attention.

Abstract: Atypical sensory perception is one of the most ubiquitous symptoms of autism, including a tendency towards a local-processing bias. We investigated whether local-processing biases were associated with global-processing impairments on a global/local attentional-scope paradigm in conjunction with a composite-face task. Behavioural results were related to individuals' levels of autistic traits, specifically the Attention to Detail subscale of the Autism Quotient, and the Sensory Profile Questionnaire. Individuals showing high rates of Attention to Detail were more susceptible to global attentional-scope manipulations, suggesting that local-processing biases associated with Attention to Detail do not come at the cost of a global-processing deficit, but reflect a difference in default global versus local bias. This relationship operated at the attentional/perceptual level, but not response criterion.

Stevenson|Ryan A|RA|
Sun|Sol Z|SZ|
Hazlett|Naomi|N|
Cant|Jonathan S|JS|
Barense|Morgan D|MD|
Ferber|Susanne|S|

Local processing
Attention
Autism spectrum disorder
Composite-face effect
Face recognition
Global processing
Sensory processing
Vision


The effect of a situation model nursing education action program on gender-bias awareness and gender-friendliness barriers in novice nursing students.

Abstract:
AIM
This study presents a workshop on the Situation Model Nursing Education Action program, examines how to promote gender awareness and decrease barriers related to differences in gender friendliness through the implementation of this program and tracks the trends of the relevant variables.

DESIGN
Pre- and post-observations and a cohort study were conducted.

METHODS
A total of 58 nursing students (42 females and 16 males) were included. Nursing students were offered a gender-care intervention as two 90-minute workshops and surveys that measure gender awareness and gender friendliness were administered.

RESULTS
The results concerned gender-bias awareness and gender-friendliness barriers scores across the four weeks of the program intervention, with the generalized estimated difference score compared with the Week 1 baseline. Mean student scores showed that gender-bias awareness was significantly decreased at Week 2 (p < .001) and Week 4 (p < .001) and that mean gender-friendliness barrier scores significantly declined at Week 4 (p < .001).

CONCLUSIONS
The findings indicate that a faculty professional learning community workshop that facilitates intentional behavioral change can help faculty to become aware of gender bias, which can improve students' gender awareness through clinical case discussion and lead to a decline in barriers to students' gender friendliness.

Pai|Hsiang-Chu|HC| Wu|Pei-Ling|PL| Hsu|Wen-Yi|WY| Hung|Chao-An|CA| Liu|Nai-Yu|NY| Yen|Wen-Jiuan|WJ|

Program
Nursing student
Gender awareness
Evaluation
Gender mainstreaming
Professional socialization


exomeSuite: Whole exome sequence variant filtering tool for rapid identification of putative disease causing SNVs/indels.

Abstract: Exome and whole-genome analyses powered by next-generation sequencing (NGS) have become invaluable tools in identifying causal mutations responsible for Mendelian disorders. Given that individual exomes contain several thousand single nucleotide variants and insertions/deletions, it remains a challenge to analyze large numbers of variants from multiple exomes to identify causal alleles associated with inherited conditions. To this end, we have developed user-friendly software that analyzes variant calls from multiple individuals to facilitate identification of causal mutations. The software, termed exomeSuite, filters for putative causative variants of monogenic diseases inherited in one of three forms: dominant, recessive caused by a homozygous variant, or recessive caused by two compound heterozygous variants. In addition, exomeSuite can perform homozygosity mapping and analyze the variant data of multiple unrelated individuals. Here we demonstrate that filtering of variants with exomeSuite reduces datasets to a fraction of a percent of their original size. To the best of our knowledge this is the first freely available software developed to analyze variant data from multiple individuals that rapidly assimilates and filters large data sets based on pattern of inheritance.

Maranhao|B|B|
Biswas|P|P|
Duncan|J L|JL|
Branham|K E|KE|
Silva|G A|GA|
Naeem|M A|MA|
Khan|S N|SN|
Riazuddin|S|S|
Hejtmancik|J F|JF|
Heckenlively|J R|JR|
Riazuddin|S A|SA|
Lee|P L|PL|
Ayyagari|R|R|

Exome
Filtering
Software
Homozygosity mapping
Mendelian disease


Impact of body mass index on the predictive capacity of the COPD-6 device in the detection of airflow obstruction.

Abstract:
BACKGROUND AND OBJECTIVE
The portable COPD-6 device has been validated as a screening tool for airflow obstruction through the quantification of the FEV1/FEV6 ratio. To date, however, the impact of body mass index (BMI) on its ability to predict airflow obstruction has not been evaluated. The aim of the study was to assess the predictive ability of COPD-6 to detect airflow obstruction based on the patient's BMI.

MATERIAL AND METHOD
A prospective and open cohort study in which 223 subjects who underwent conventional spirometry and COPD-6 were included. The area under the curve ROC (AUC) of FEV1/FEV6 was analysed in the detection of obstruction for all patients in addition to BMI (BMI<30kg/m2 and BMI≥30kg/m2). Sensitivity and specificity, negative and positive predictive value as well as likelihood ratio were calculated to determine the cut-off point of COPD-6 FEV1/FEV6 ratio with greater predictive capacity.

RESULTS
The COPD-6 allows ruling out airflow obstruction with AUC of the estimated ROC curve of 88% (95% CI 83-93). The cut-off point FEV1/FEV6 of 0.74-0.76 shows the best predictive capacity. However, this capacity is altered according to BMI with an increase in false positives in subjects with BMI≥30kg/ m2 when using the same cut-off point for the whole sample.

CONCLUSION
The choice of cut-off point FEV1/FEV6 for the detection of obstruction should be adjusted to the patient's BMI.

Figueira Gonçalves|Juan Marco|JM|
Pérez Méndez|Lina Inmaculada|LI|
Guzmán Sáenz|Cristina|C|
Díaz Pérez|David|D|
Viña Manrique|Pedro|P|
Pedrero García|Arturo José|AJ|

D029424:Pulmonary Disease, Chronic Obstructive

Body mass index
Spirometry
Chronic obstructive pulmonary disease
Enfermedad pulmonar obstructiva crónica
Espirometría
FEV(6)
Índice de masa corporal


Chemically Reduced Graphene Oxide for the Assessment of Food Quality: How the Electrochemical Platform Should Be Tailored to the Application.

Abstract: Graphene platforms have been drawing considerable attention in electrochemistry for the detection of various electroactive probes. Depending on the chemical composition and properties of the probe, graphene materials with diverse structural features may be required to achieve an optimal electrochemical performance. This work comprises a comparative study on three chemically modified graphenes, obtained from the same starting material and with different oxygen functionalities and structural defects (graphene oxide (GO), chemically reduced graphene oxide (CRGO), and thermally reduced graphene oxide (TRGO)) towards the electrochemical detection of quinine, an important flavoring agent present in tonic-based beverages. In general, the reduced graphenes, namely CRGO and TRGO, showed enhanced performance in terms of calibration sensitivity and selectivity, due to the improved heterogeneous electron-transfer rates on their surfaces. In particular, CRGO provided the best overall electrochemical performance, which can be attributed to its higher density of structural defects and reduced amount of oxygen functionalities. For this reason, CRGO was employed for the electrochemical detection of quinine in commercial tonic drink samples, showing high sensitivity and selectivity, and therefore representing a valid low-cost alternative to more complicated and time consuming traditional analytical methods.

Chng|Chu'Er|C|
Ambrosi|Adriano|A|
Chua|Chun Kiang|CK|
Pumera|Martin|M|
Bonanni|Alessandra|A|

graphene
electrochemistry
quinine
food analysis


Healthcare utilization and costs among patients with non-functioning pituitary adenomas.

Abstract:
PURPOSE
Non-functioning pituitary adenomas (NFPA) have a substantial impact on patients' health status, yet research on the extent of healthcare utilization and costs among these patients is scarce. The objective was to determine healthcare usage, associated costs, and their determinants among patients treated for an NFPA.

METHODS
In a cross-sectional study, 167 patients treated for an NFPA completed four validated questionnaires. Annual healthcare utilization and associated costs were assessed through the medical consumption questionnaire (MTA iMCQ). In addition, the Leiden Bother and Needs Questionnaire for pituitary patients (LBNQ-Pituitary), Short Form-36 (SF-36), and EuroQol (EQ-5D) were administered. Furthermore, age, sex, endocrine status, treatment, and duration of follow-up were extracted from the medical records. Associations were analyzed using logistic/linear regression.

RESULTS
Annual healthcare utilization included: consultation of an endocrinologist (95% of patients), neurosurgeon (14%), and/or ophthalmologist (58%). Fourteen percent of patients had ≥1 hospitalization(s) and 11% ≥1 emergency room visit(s). Mean overall annual healthcare costs were € 3040 (SD 6498), highest expenditures included medication (31%), inpatient care (28%), and specialist care (17%). Factors associated with higher healthcare utilization and costs were greater self-perceived disease bother and need for support, worse mental and physical health status, younger age, and living alone.

CONCLUSION
Healthcare usage and costs among patients treated for an NFPA are substantial and were associated with self-perceived health status, disease bother, and healthcare needs rather than endocrine status, treatment, or duration of follow-up. These findings suggest that targeted interventions addressing disease bother and unmet needs in the chronic phase are needed.

Lobatto|Daniel J|DJ|0000-0002-2523-8707
van den Hout|Wilbert B|WB|
Zamanipoor Najafabadi|Amir H|AH|
Steffens|Anath N V|ANV|
Andela|Cornelie D|CD|
Pereira|Alberto M|AM|
Peul|Wilco C|WC|
van Furth|Wouter R|WR|
Biermasz|Nienke R|NR|
Vliet Vlieland|Thea P M|TPM|

D010342:Patient Acceptance of Health Care

Healthcare utilization
Costs
Pituitary adenoma
NFPA
Multidisciplinary
Value based healthcare


Need for Cognition Is Positively Related to Promotion Focus and Negatively Related to Prevention Focus.

Abstract: Need for cognition (NFC) and regulatory focus (RF) are important variables with individual differences relevant to motivation and goal pursuit. These constructs are widely used in the literature, often separately; no work has simultaneously examined the need for cognition scale (NCS) and Lockwood's general regulatory focus measure (GRFM). Here, we explore shared theoretical underpinnings of the two constructs and assess whether they may be driven by common underlying factors. Considering purported overlaps between these scales and other constructs (e.g., personality and cognitive processes), we take a strong inference approach to test hypothesized bridges between the two measures. In a large (N = 853) sample, we found NCS to be related positively to GRFM promotion and negatively to GRFM prevention scores, suggesting mutual ties with behavioral inhibition system/behavioral activation system, intrinsic motivation, openness, and creativity. A generalized approach motivation, as well as intrinsic motivation, may thus drive both NFC and RF.

Oiknine|Ashley H|AH|
Pollard|Kimberly A|KA|
Khooshabeh|Peter|P|
Files|Benjamin T|BT|

behavioral inhibition/behavioral activation systems


Process evaluation of team-based care in people aged >65 years with type 2 diabetes mellitus.

Abstract:
OBJECTIVE
The prevalence of type 2 diabetes mellitus (T2DM) is increasing globally and there is critical need develop interventions to improve health outcomes among older people. The Group Appointments in Primary Care (GAP) study was a randomised controlled trial designed to test the efficacy of a group and team-based medical visit programme to lower haemoglobin A1c among patients with T2DM. We aimed to understand the barriers and facilitators to implement the GAP intervention within a primary care setting, with an emphasis on patient experience.

RESEARCH DESIGN AND METHODS
This was a qualitative exploratory study. Data were gathered from semistructured interviews conducted with the first cohort of GAP study participants (n=15) at baseline and intervention completion. GAP participants were aged >65, diagnosed with T2DM and from one primary care clinic. The interview questions identified the patient perspectives and factors relating to their attendance at seven group medical visits that were part of the intervention programme. Data were analysed using framework analysis.

RESULTS
We identified four themes that captured participants' experiences: (1) Education: learning with professionals, learning with one another; (2) Social Support: common interests, common problems; (3) Setting: ease of location, ease of conversation and (4) Impact: expectations met, empowerment gained. The GAP intervention increased participants' self-reported diabetes literacy and self-management skills.

CONCLUSIONS
We learnt that: accessible community centres, not primary care offices, were the ideal location for GAP; the consistent leadership of the primary care physician was valued by participants; and, the content related to exercise and healthy diet were viewed as impactful. Also, learning was achieved through content delivered by clinical experts, and by T2DM experts with lived experience-the GAP peers. Our findings highlight the important role of group learning.

TRIAL REGISTRATION NUMBER
NCT02002143.

Sims Gould|Joanie|J|0000-0003-1260-5405
Tong|Catherine|C|
Ly|Jessica|J|
Vazirian|Sara|S|
Windt|Adriaan|A|
Khan|Karim|K|

D000368:Aged
D000369:Aged, 80 and over
D001955:British Columbia
D003151:Community Health Centers
D003924:Diabetes Mellitus, Type 2
D000072001:Diet, Healthy
D015444:Exercise
D006442:Glycated Hemoglobin A
D006297:Health Services Accessibility
D006801:Humans
D007857:Leadership
D007858:Learning
D010348:Patient Care Team
D010353:Patient Education as Topic
D011320:Primary Health Care
D017064:Process Assessment, Health Care
D000075082:Proof of Concept Study
D016037:Single-Blind Method
D012944:Social Support

team-based care
general diabetes
geriatric medicine
qualitative research


Quantitative evaluation of human bone mesenchymal stem cells rescuing fulminant hepatic failure in pigs.

Abstract:
OBJECTIVE
Stem cell transplantation provides a promising alternative for the treatment of fulminant hepatic failure (FHF). However, it lacks fundamental understanding of stem cells' activities. Our objective was to clarify stem cell-recipient interactions for overcoming barriers to clinical application.

DESIGN
We used an in-house large-animal (pig) model of FHF rescue by human bone marrow mesenchymal stem cells (hBMSCs) and profiled the cells' activities. The control and transplantation groups of pigs (n=15 per group) both received a D-galactosamine (D-Gal) injection (1.5 g/kg). The transplantation group received hBMSCs via intraportal vein infusion (3×106 cells/kg) immediately after D-Gal administration. The stem cell-recipient interactions were quantitatively evaluated by biochemical function, cytokine array, metabolite profiling, transcriptome sequencing and immunohistochemistry.

RESULTS
All pigs in the control group died within an average of 3.22 days, whereas 13/15 pigs in the transplantation group lived >14 days. The cytokine array and metabolite profiling analyses revealed that hBMSC transplantation suppressed D-Gal-induced life-threatening cytokine storms and stabilised FHF within 7 days, while human-derived hepatocytes constituted only ∼4.5% of the pig hepatocytes. The functional synergy analysis of the observed profile changes indicated that the implanted hBMSCs altered the pigs' cytokine responses to damage through paracrine effects. Delta-like ligand 4 was validated to assist liver restoration in both pig and rat FHF models.

CONCLUSIONS
Our results delineated an integrated model of the multifaceted interactions between stem cells and recipients, which may open a new avenue to the discovery of single molecule-based therapeutics that simulate stem cell actions.

Shi|Dongyan|D| Zhang|Jianing|J| Zhou|Qian|Q| Xin|Jiaojiao|J| Jiang|Jing|J| Jiang|Longyan|L| Wu|Tianzhou|T| Li|Jiang|J| Ding|Wenchao|W| Li|Jun|J| Sun|Suwan|S| Li|Jianzhou|J| Zhou|Ning|N| Zhang|Liyuan|L| Jin|Linfeng|L| Hao|Shaorui|S| Chen|Pengcheng|P| Cao|Hongcui|H| Li|Mingding|M| Li|Lanjuan|L| Chen|Xin|X| Li|Jun|J|

D047908:Intracellular Signaling Peptides and Proteins

D045164:Mesenchymal Stem Cell Transplantation

STEM CELLS
FULMINANT HEPATIC FAILURE
CYTOKINES


Acute effects of fatty acids on autophagy in NPY neurones.

Abstract: High-fat diet (HFD) feeding is deleterious to hypothalamic tissue, leading to inflammation and lipotoxicity, as well as contributing to central insulin resistance. Autophagy is a process that restores cellular homeostasis by degrading malfunctioning organelles and proteins. Chronic HFD-feeding down-regulates hypothalamic autophagy. However, the effects of short-term HFD-feeding and the saturated fatty acid palmitate (PA) on hypothalamic autophagy and in neurones that express neuropeptide Y (NPY) and agouti-related peptide remains unknown. Therefore, we assessed hypothalamic autophagy after 1 and 3 days of HFD-feeding. We also injected PA i.c.v and analysed the modulation of autophagy in hypothalamic tissue. Both interventions resulted in changes in autophagy-related gene profiles without significant differences in protein content of p62 and LC3B-II, markers of the autophagy pathway. When we assessed native NPY neurones in brain slices from PA-treated animals, we observed increased levels of Atg7 and LC3B protein in response to PA treatment, indicating the induction of autophagy. We then tested the direct effects of fatty acids using the immortalised hypothalamic NPY-expressing neuronal cell model mHypoE-46. We found that PA, but not palmitoleate (PO) (a monounsaturated fatty acid), was able to induce autophagy. Co-treatment with PA and PO was able to block the PA-mediated induction of autophagy, as assessed by flow cytometry. When the de novo ceramide synthesis pathway was blocked with myriocin pre-treatment, we observed a decrease in PA-mediated induction of autophagy, although there was no change with the toll-like receptor 4 inhibitor, TAK-242. Taken together, these findings provide evidence that saturated and unsaturated fatty acids can differentially regulate hypothalamic autophagy and that ceramide synthesis may be an important mediator of those effects. Understanding the mechanisms by which dietary fats affect autophagy in neurones involved in the control of energy homeostasis will provide potential new pathways for targeting and containing the obesity epidemic.

Reginato|Andressa|A|
Siqueira|Beatriz Piatezzi|BP|
Miyamoto|Josiane Érica|JÉ|
Portovedo|Mariana|M|
Costa|Suleyma de Oliveira|SO|
de Fante|Thaís|T|
Rodrigues|Hosana Gomes|HG|
Ignácio-Souza|Letícia Martins|LM|
Torsoni|Márcio Alberto|MA|
Torsoni|Adriana Souza|AS|
Le Stunff|Hervé|H|
Belsham|Denise D|DD|0000-0002-7065-8591
Milanski|Marciane|M|0000-0002-6322-5368

autophagy palmitate palmitoleate obesity hypothalamus lipids


Does infection with Chlamydia trachomatis induce long-lasting partial immunity? Insights from mathematical modelling.

Abstract:
OBJECTIVES
To explore whether existence of long-lasting partial immunity against reinfection with Chlamydia trachomatis is necessary to explain C. trachomatis prevalence patterns by age and sexual risk, and to provide a plausible estimate for the effect size, defined here as a reduction in susceptibility to reinfection.

METHODS
A population-based mathematical model was constructed to describe C. trachomatis natural history and transmission dynamics by age and sexual risk. The model was parameterised using natural history, and epidemiological and sexual behaviour data, and applied for UK and US data. Sensitivity analyses were conducted to assess the robustness of predictions to variations in model structure and to examine the impact of alternative assumptions for the mechanism underlying partial immunity.

RESULTS
Partial immunity against reinfection was found necessary to explain observed C. trachomatis prevalence patterns by age and sexual risk. The reduction in susceptibility to reinfection was estimated at 93% using UK data (95% uncertainty interval (UI)=88%-97%) and at 67% using US data (95% UI=24%-88%). The model-structure sensitivity analyses affirmed model predictions. The immunity-mechanism sensitivity analyses suggested a mechanism of susceptibility reduction against reinfection or a mechanism of infectious-period duration reduction upon reinfection.

CONCLUSIONS
A strong long-lasting partial immunity against C. trachomatis reinfection should be present to explain observed prevalence patterns. The mechanism of immunity could be either a reduction in susceptibility to reinfection or a reduction in duration of infection on reinfection. C. trachomatis infection appears to naturally elicit a strong long-lasting immune response, supporting the concept of vaccine development.

Omori|Ryosuke|R|
Chemaitelly|Hiam|H|
Althaus|Christian L|CL|
Abu-Raddad|Laith J|LJ|

immunity
reinfection
prevalence
epidemiology
mathematical model.
sexually transmitted infection


The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) : Exploring the changes in anticoagulant practice in patients with non-valvular atrial fibrillation in the Netherlands.

Abstract: There are over 385,000 cases of atrial fibrillation (AF) in the Netherlands, with over 45,000 new cases each year. Among other things, AF patients are at high risk of stroke. Patients are often prescribed oral anticoagulation, such as vitamin K antagonists (VKA), to mitigate these risks. A recently introduced class of oral anticoagulants, non-vitamin K antagonists (NOAC), is quickly gaining currency in global clinical practice. This study provides insight into the changes these new drugs will bring about in Dutch clinical practice.GARFIELD-AF is a large-scale observational AF patient registry initiated in 2009 to track the evolution of global anticoagulation practice, and to study the impact of NOAC therapy in AF in particular. The registry includes a wide array of baseline characteristics and has a particular focus on: (1) bleeding and thromboembolic events; (2) international normalised ratio fluctuations; and (3) therapy compliance and persistence patterns. The results in this paper provide the baseline characteristics of the first cohorts of Dutch participants in this registry and discuss some of the consequences of the changes in anticoagulation practice.Although VKA therapy remains overwhelmingly favoured by Dutch practitioners, NOACs are clearly gaining in popularity. Between 2011 and 2014, NOACs constituted an increasingly large proportion of prescriptions for oral anticoagulants.The insights provided by the GARFIELD-AF registry can be used by healthcare systems to inform better budgetary strategies, by practitioners to better tailor treatment pathways to patients, and finally to promote awareness of the various available treatment options and their associated risks and benefits for patients.

Ten Cate|V|V|
Ten Cate|H|H|
Verheugt|F W A|FW|

Anticoagulants
Registries
Atrial fibrillation
Netherlands
Stroke


Pathogen elimination and prevention within a regulated, Designated Pathogen Free, closed pig herd for long-term breeding and production of xenotransplantation materials.

Abstract:
BACKGROUND
We established a Source Animal (barrier) Facility (SAF) for generating designated pathogen-free (DPF) pigs to serve as donors of viable organs, tissues, or cells for xenotransplantation into clinical patients. This facility was populated with caesarian derived, colostrum deprived (CDCD) piglets, from sows of conventional-specific (or specified) pathogen-free (SPF) health status in six cohorts over a 10-month period. In all cases, CDCD piglets fulfilled DPF status including negativity for porcine circovirus (PCV), a particularly environmentally robust and difficult to inactivate virus which at the time of SAF population was epidemic in the US commercial swine production industry. Two outbreaks of PCV infection were subsequently detected during sentinel testing. The first occurred several weeks after PCV-negative animals were moved under quarantine from the nursery into an animal holding room. The apparent origin of PCV was newly installed stainless steel penning, which was not sufficiently degreased thereby protecting viral particles from disinfection. The second outbreak was apparently transmitted via employee activities in the Caesarian-section suite adjacent to the barrier facility. In both cases, PCV was contained in the animal holding room where it was diagnosed making a complete facility depopulation-repopulation unnecessary.

METHOD
Infectious PCV was eliminated during both outbreaks by the following: euthanizing infected animals, disposing of all removable items from the affected animal holding room, extensive cleaning with detergents and degreasing agents, sterilization of equipment and rooms with chlorine dioxide, vaporized hydrogen peroxide, and potassium peroxymonosulfate, and for the second outbreak also glutaraldehyde/quaternary ammonium. Impact on other barrier animals throughout the process was monitored by frequent PCV diagnostic testing.

RESULT
After close monitoring for 6 months indicating PCV absence from all rooms and animals, herd animals were removed from quarantine status.

CONCLUSION
Ten years after PCV clearance following the second outbreak, due to strict adherence to biosecurity protocols and based on ongoing sentinel diagnostic monitoring (currently monthly), the herd remains DPF including PCV negative.

Noordergraaf|Jeske|J| Schucker|Adrienne|A| Martin|Mike|M| Schuurman|Henk-Jan|HJ| Ordway|Brianne|B| Cooley|Kevin|K| Sheffler|Marie|M| Theis|Kara|K| Armstrong|Chasa|C| Klein|Laura|L| Hansen|Doug|D| Olson|Megan|M| Schlechter|Lisa|L| Spizzo|Tom|T|0000-0001-8278-2461

xenotransplantation
DPF
porcine circovirus
swine
designated pathogen free herd
source animal facility


The Privatization of Public Hospitals: Its Impact on Financial Performance.

Abstract: This study examined the effects of public hospitals' privatization on financial performance. We used a sample of nonfederal acute care public hospitals from 1997 to 2013, averaging 434 hospitals per year. Privatization was defined as conversion from public status to either private not-for-profit (NFP) or private for-profit (FP) status. Financial performance was measured by operating margin (OM) and total margin (TM). We used hospital level and year fixed effects linear panel regressions with nonlagged independent and control variables (Model 1), lagged by 1 year (Model 2), and lagged by 2 years (Model 3). Privatization to FP was associated with 17% higher OM (Model 2) and 9% higher OM (Model 3), compared with 3%, 4%, and 6% higher OM for privatization to NFP for all three Models, respectively. Privatization to FP was associated with 7% higher TM (Model 2) and privatization to NFP was associated with 2% higher TM (Model 3).

privatization
public hospitals
financial performance


Bisoprolol/amlodipine combination therapy improves blood pressure control in patients with essential hypertension following monotherapy failure.

Abstract:
OBJECTIVE
The efficacy of a bisoprolol/amlodipine fixed-dose combination (FDC) in patients with essential hypertension who had not responded to bisoprolol or amlodipine monotherapy was investigated.

RESEARCH DESIGN AND METHODS
In an 18 week, multicenter, randomized, comparative phase III study (ClinicalTrials.gov identifier: NCT01977794), patients with blood pressure uncontrolled by bisoprolol or amlodipine monotherapy (5 mg OD) began treatment with bisoprolol/amlodipine FDC 5/5 mg OD. Patients with controlled blood pressure (BP) at week 6/12 continued at current FDC strength, and patients with uncontrolled BP received FDC dose uptitration (maximum dose: 10/10 mg). The primary efficacy endpoint was change in systolic blood pressure (SBP) at week 18 versus baseline (corresponding to SBP under monotherapy), and secondary endpoints included change from baseline in SBP after week 6/12 and percentage of BP-controlled patients at week 6, 12 and 18. Safety was assessed by number/types of adverse events (AEs).

RESULTS
Two hundred patients were randomized to treatment (100 with uncontrolled BP under bisoprolol and 100 under amlodipine monotherapy). Overall, 196 patients were eligible for analysis. The patient groups displayed similar mean SBP reductions from baseline by study end (bisoprolol monotherapy failure: 25.9 ± 12.82 mmHg reduction; amlodipine monotherapy failure: 24.7 ± 11.67 mmHg reduction; p < 0.001 for both). Overall mean SBP decreased by 25.3 ± 12.25 mmHg (p < 0.001). Mean heart rate reductions were also observed (bisoprolol monotherapy failure: 6.6 ± 9.67 bpm reduction; amlodipine monotherapy failure: 11.5 ± 8.65 bpm reduction; p < 0.001 for both). Most patients (83.2%) displayed BP control with bisoprolol/amlodipine 5/5 mg at 6 weeks. Treatment was well tolerated at all dose levels; treatment-related AEs (mostly of mild/moderate intensity) were reported by 52.5% of patients, with no severe or serious treatment-related AEs reported. As the study focused on hypertension, total cardiovascular risk was not assessed.

CONCLUSIONS
Bisoprolol/amlodipine FDC therapy is associated with significant BP improvements in patients with essential hypertension following monotherapy failure.

Amlodipinebisoprololblood pressure controlcardiovascularfixed-dose combinationhypertensionsecond-line therapy


The Pain Divide: a cross-sectional analysis of chronic pain prevalence, pain intensity and opioid utilisation in England.

Abstract:
OBJECTIVES
Our central research question was, in England, are geographical inequalities in opioid use driven by health need (pain)? To answer this question, our study examined: (1) if there are regional inequalities in rates of chronic pain prevalence, pain intensity and opioid utilisation in England; (2) if opioid use and chronic pain are associated after adjusting for individual-level and area-level confounders.

DESIGN
Cross-sectional study design using data from the Health Survey for England 2011.

SETTING
England.

PRIMARY AND SECONDARY OUTCOME MEASURES
Chronic pain prevalence, pain intensity and opioid utilisation.

PARTICIPANTS
Participant data relating to chronic pain prevalence, pain intensity and opioid usage data were obtained at local authority level from the Health Survey for England 2011; in total, 5711 respondents were included in our analysis.

METHODS
Regional and local authority data were mapped, and a generalised linear model was then used to explore the relationships between the data. The model was adjusted to account for area-level and individual-level variables.

RESULTS
There were geographical variations in chronic pain prevalence, pain intensity and opioid utilisation across the English regions-with evidence of a 'pain divide' between the North and the South, whereby people in the North of England more likely to have 'severely limiting' or 'moderately limiting' chronic pain. The intensity of chronic pain was significantly and positively associated with the use of opioid analgesics.

CONCLUSIONS
There are geographical differences in chronic pain prevalence, pain intensity and opioid utilisation across England-with evidence of a 'pain divide'. Given the public health concerns associated with the long-term use of opioid analgesics-and their questionable activity in the management of chronic pain-more guidance is needed to support prescribers in the management of chronic pain, so the initiation of opioids can be avoided.

Todd|Adam|A|0000-0003-1496-9341 Akhter|Nasima|N| Cairns|Joanne-Marie|JM| Kasim|Adetayo|A| Walton|Nick|N| Ellison|Amanda|A| Chazot|Paul|P| Eldabe|Sam|S| Bambra|Clare|C|

public health
health policy
pain management


Mechanisms of Atherosclerosis Induced by Postprandial Lipemia.

Abstract: Postprandial lipemia plays an important role in the formation, occurrence, and development of atherosclerosis, and it is closely related to coronary heart disease and other diseases involving endothelial dysfunction, oxidative stress, inflammation, and other mechanisms. Therefore, it has become a focus area for further research. The studies on postprandial lipemia mainly include TG, TRL, VLDL, CM, and remnant cholesterol. Diurnal triglyceride patterns and postprandial hyperlipidemia are very relevant and are now insufficiently covered. The possible mechanisms between postprandial lipemia and cardiovascular disease have been reviewed in this article by referring to relevant literature in recent years. The research progress on the effects of postprandial lipemia on endothelial function, oxidative stress, and inflammation is highlighted. The intervention of postprandial lipemia is discussed. Non-medicinal intervention such as diet and exercise improves postprandial lipemia. As medicinal intervention, statin, fibrate, ezetimibe, omega-3 fatty acids, and niacin have been found to improve postprandial lipid levels. Novel medications such as pemafibrate, PCSK9, and apoCIII inhibitors have been the focus of research in recent years. Gut microbiota is closely related to lipid metabolism, and some studies have indicated that intestinal microorganisms may affect lipid metabolism as environmental factors. Whether intervention of gut microbiota can reduce postprandial lipemia, and therefore against AS, may be worthy of further study.

Zhao|Yixi|Y| Liu|Longtao|L| Yang|Shengjie|S| Liu|Guijian|G| Pan|Limin|L| Gu|Chun|C| Wang|Yang|Y| Li|Dan|D| Zhao|Ran|R| Wu|Min|M|

atherosclerosis
postprandial lipemia
endothelial dysfunction
oxidative stress
inflammation
triglyceride


Migrating into the Tumor: a Roadmap for T Cells.

Abstract: Tumors can be divided into 'hot' (T cell inflamed) or 'cold' (T cell noninflamed) according to the presence of immune cells. In this review, we discuss variables that influence T cell migration into the tumor microenvironment. Chemokines can attract T cells to the tumor site and tumor intrinsic pathways can influence the composition of local chemokines. Tumor-induced vasculature can hamper T cell migration. Other immune cells and tumor-derived molecules can block T cell proliferation and survival. It is important to better understand these mechanisms in order to target them therapeutically. Enhancing T cell infiltration may increase response rates to immunotherapy and increase survival.

van der Woude|Lieke L|LL|
Gorris|Mark A J|MAJ|
Halilovic|Altuna|A|
Figdor|Carl G|CG|
de Vries|I Jolanda M|IJM|

migration
T cells
immune cells
tumor microenvironment.
immunotherapy
biomarkers


Gene drive systems: do they have a place in agricultural weed management?

Abstract: There is a pressing need for novel control techniques in agricultural weed management. Direct genetic control of agricultural pests encompasses a range of techniques to introduce and spread novel, fitness-reducing genetic modifications through pest populations. Recently, the development of CRISPR-Cas9 gene editing has brought these approaches into sharper focus. Proof of concept for CRISPR-Cas9-based gene drives has been demonstrated for the control of disease-vectoring insects. This article considers whether and how gene drives may be applied in agricultural weed management, focusing on CRISPR-Cas9-based systems. Population-suppression drives might be employed to introduce and proliferate deleterious mutations that directly impact fitness and weediness, whereas population-sensitizing drives would seek to edit weed genomes so that populations are rendered more sensitive to subsequent management interventions. Technical challenges relating to plant transformation and gene editing in planta are considered, and the implementation of gene drives for timely and sustainable weed management is reviewed in the light of weed population biology. The technical, biological, practical and regulatory challenges remain significant. Modelling-based studies can inform how and if gene drives could be employed in weed populations. These studies are an essential first step towards determining the utility of gene drives for weed management. © 2018 The Author. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

D000383:Agriculture
D064113:CRISPR-Cas Systems
D000075423:Gene Drive Technology
D058728:Weed Control

gene drive
weed management
direct genetic control
CRISPR-Cas9
herbicide resistance


Pediatric Craniovertebral Junction Surgery.

Abstract: The craniovertebral junction (CVJ) has attracted more attention in pediatric medicine in recent years due to the progress in surgical technologies allowing a direct approach to the CVJ in children. The CVJ is the site of numerous pathologies, most originating in bone anomalies resulting from abnormal CVJ development. Before discussing the surgical approaches to CVJ, three points should be borne in mind: first, that developmental anatomy demonstrates age-dependent mechanisms and the pathophysiology of pediatric CVJ anomalies; second, that CT-based dynamic simulations have improved our knowledge of functional anatomy, enabling us to locate CVJ lesions with greater certainty; and third, understanding the complex structure of the pediatric CVJ also clarifies the surgical anatomy. This review begins with a description of the embryonic developmental process of the CVJ, comprising ossification and resegmentation of the somite. From the clinical perspective, pediatric CVJ lesions can be divided into three categories: developmental bony anomalies with or without instability, stenotic CVJ lesions, and others. After discussing surgery and management based on this classification, the author describes surgical outcomes on his hands, and finally proceeds to address controversial issues specific for pediatric CVJ surgery. The lessons, which the author has gleaned from his experience in pediatric CVJ surgery, are also presented briefly in this review. Recent technological progress has facilitated pediatric surgery of the CVJ. However, it is important to recognize that we are still far from reliably and consistently obtaining satisfactory results. Further progress in this area awaits contributions of the coming generations of pediatric surgeons.

pediatrics
craniovertebral junction
surgery
congenital anomaly
embryology


Abiraterone and Ionizing Radiation Alter the Sphingolipid Homeostasis in Prostate Cancer Cells.

Abstract: Prostate cancer (PC) is one of the most common leading causes of cancer-related death in men. Currently, the main therapeutic approaches available for PC are based on the androgen deprivation and on radiotherapy. However, despite these treatments being initially effective in cancer remission, several patients undergo recurrence, developing a most aggressive and resistant PC.Emerging evidence showed that abiraterone acetate drug will reduce PC recurrence by a mechanism independent of the inhibition of Cytochrome P450 17α-hydroxylase/17,20-lyase. Here we describe the involvement in the abiraterone-mediated PC cell death of a particular class of bioactive lipids called sphingolipids (SL). Sphingolipids are components of plasma membrane (PM) that organize macromolecular complexes involved in the control of several signaling pathways including the tumor cell death induced by radiotherapy. Here, we show for the first time that both in androgen-sensitive and insensitive PC cells abiraterone and ionizing radiation induce a reorganization of the plasma membrane SL composition. This event is triggered by activation of the PM-associated glycohydrolases that induce the production of cytotoxic ceramide by the in situ hydrolyses of glycosphingolipids. Taken together our data open a new scenario on the SL involvement in the therapy of PC.

Murdica|Valentina|V|
Mancini|Giulia|G|
Loberto|Nicoletta|N|
Bassi|Rosaria|R|
Giussani|Paola|P|
Di Muzio|Nadia|N|
Deantoni|Chiara|C|
Prinetti|Alessandro|A|
Aureli|Massimo|M|
Sonnino|Sandro|S|

Abiraterone
Ionizing radiation
Sphingolipids
Prostate cancer
Plasma membrane
Glycohydrolases
Sialidase Neu3


Gudder's Theorem and the Born Rule.

Abstract: We derive the Born probability rule from Gudder's theorem-a theorem that addresses orthogonally-additive functions. These functions are shown to be tightly connected to the functions that enter the definition of a signed measure. By imposing some additional requirements besides orthogonal additivity, the addressed functions are proved to be linear, so they can be given in terms of an inner product. By further restricting them to act on projectors, Gudder's functions are proved to act as probability measures obeying Born's rule. The procedure does not invoke any property that fully lies within the quantum framework, so Born's rule is shown to apply within both the classical and the quantum domains.

spinors in quantum and classical physics


Dynamically Tuning Particle Interactions and Assemblies at Soft Interfaces: Reversible Order-Disorder Transitions in 2D Particle Monolayers.

Abstract: Particles trapped at fluid interfaces experience long-range interactions that determine their assembly behavior. Because particle interactions at fluid interfaces tend to be unusually strong, once particles organize themselves into a 2D assembly, it is challenging to induce changes in their microstructure. In this report, a new approach is presented to induce reversible order-disorder transitions (ODTs) in the 2D monolayer of colloidal particles trapped at a soft gel-fluid interface. Particles at the soft interface, consisting of a nonpolar superphase and a weakly gelled subphase, initially form a monolayer with a highly ordered structure. The structure of this monolayer can be dynamically varied by the addition or removal of the oil phase. Upon removing the oil via evaporation, the initially ordered particle monolayer undergoes ODT, driven by capillary attractions. The ordered monolayer can be recovered through disorder-to-order transition by simply adding oil atop the particle-laden soft interface. The possibility to dynamically tune the interparticle interactions using soft interfaces can potentially enable control of the transport and mechanical properties of particle-laden interfaces and provide model systems to study particle-laden soft interfaces that are relevant to biological tissues or organs.

assemblies
soft interfaces
order-disorder transitions
colloids
interparticle interactions
morphological reversibility


Vascular smooth muscle cell phenotype is defined by Ca2+-dependent transcription factors.

Abstract: Ca(2+) is an important second messenger in vascular smooth muscle cells (VSMCs). Therefore, VSMCs exercise tight control of the intracellular Ca(2+) concentration ([Ca(2+)]i) by expressing a wide repertoire of Ca(2+) channels and transporters. The presence of several pathways for Ca(2+) influx and efflux provides many possibilities for controlling [Ca(2+)]i in a spatial and temporal manner. Intracellular Ca(2+) has a dual role in VSMCs; first, it is necessary for VSMC contraction; and, second, it can activate multiple transcription factors. These factors are cAMP response element-binding protein, nuclear factor of activated T lymphocytes, and serum response factor. Furthermore, it was recently reported that the C-terminus of voltage-dependent L-type Ca(2+) calcium channels can regulate transcription in VSMCs. Transcription regulation in VSMCs modulates the expression patterns of genes, including genes coding for contractile and cytoskeleton proteins, and those promoting proliferation and cell growth. Depending on their gene expression, VSMCs can exist in different functional states or phenotypes. The majority of healthy VSMCs show a contractile phenotype, characterized by high contractile ability and a low proliferative rate. However, VSMCs can undergo phenotypic modulation with different physiological and pathological stimuli, whereby they start to proliferate, migrate, and synthesize excessive extracellular matrix. These events are associated with injury repair and angiogenesis, but also with the development of cardiovascular pathologies, such as atherosclerosis and hypertension. This review discusses the currently known Ca(2+)-dependent transcription factors in VSMCs, their regulation by Ca(2+) signalling, and their role in the VSMC phenotype.

Kudryavtseva|Olga|O|
Aalkjaer|Christian|C|
Matchkov|Vladimir V|VV|

nuclear factor of activated T lymphocytes (NFAT)


Exploring the role of gender and women in the political economy of health in armed conflict: a narrative review.

Abstract:
BACKGROUND
The ripple effects of protracted armed conflicts include: significant gender-specific barriers to accessing essential services such as health, education, water and sanitation and broader macroeconomic challenges such as increased poverty rates, higher debt burdens, and deteriorating employment prospects. These factors influence the wider social and political determinants of health for women and a gendered analysis of the political economy of health in conflict may support strengthening health systems during conflict. This will in turn lead to equality and equity across not only health, but broader sectors and systems, that contribute to sustainable peace building.

METHODS
The methodology employed is a multidisciplinary narrative review of the published and grey literature on women and gender in the political economy of health in conflict.

RESULTS
The existing literature that contributes to the emerging area on the political economy of health in conflict has overlooked gender and specifically the role of women as a critical component. Gender analysis is incorporated into existing post-conflict health systems research, but this does not extend to countries actively affected by armed conflict and humanitarian crises. The analysis also tends to ignore the socially constructed patriarchal systems, power relations and gender norms that often lead to vastly different health system needs, experiences and health outcomes.

CONCLUSIONS
Detailed case studies on the gendered political economy of health in countries impacted by complex protracted conflict will support efforts to improve health equity and understanding of gender relations that support health systems strengthening.

Gender
Women
Political economy
Health
Conflict
Health systems
Peace


Searching for the one(s): Using Probiotics as Anthelmintic Treatments.

Abstract: Helminths are a major health concern as over one billion people are infected worldwide and, despite the multiple efforts made, there is still no effective human vaccine against them. The most important drugs used nowadays to control helminth infections belong to the benzimidazoles, imidazothiazoles (levamisole) and macrocyclic lactones (avermectins and milbemycins) families. However, in the last 20 years, many publications have revealed increasing anthelmintic resistance in livestock which is both an economical and a potential health problem, even though very few have reported similar findings in human populations. To deal with this worrying limitation of anthelmintic drugs, alternative treatments based on plant extracts or probiotics have been developed. Probiotics are defined by the Food and Agriculture Organization as live microorganisms, which, when consumed in adequate amounts, confer a health benefit to the host. It has been proven that probiotic microbes have the ability to exert an immunomodulatory effect both at the mucosa and the systemic level. The immune response against gastrointestinal helminths is characterized as a type 2 response, with high IgE levels, increased numbers and/or activity of Th2 cells, type 2 innate lymphoid cells, eosinophils, basophils, mast cells, and alternatively activated macrophages. The oral administration of probiotics may contribute to controlling gastrointestinal helminth infections since it has been demonstrated that these microorganisms stimulate dendritic cells to elicit a type 2 or regulatory immune response, among other effects on the host immune system. Here we review the current knowledge about the use of probiotic bacteria as anthelmintic therapy or as a complement to traditional anthelmintic treatments. Considering all research papers reviewed, we may conclude that the effect generated by probiotics on helminth infection depends not only on the parasite species, their stage and localization but also on the administration scheme.

Saracino|Maria Priscila|MP|
Vila|Cecilia Celeste|CC|
Baldi|Pablo César|PC|
González Maglio|Daniel Horacio|DH|

probiotics
helminths
regulatory immune response
inflammation
type 2 immune response


Genes associated with Type 2 Diabetes and vascular complications.

Abstract: Type 2 Diabetes (T2D) is a chronic disease associated with a number of micro- and macrovascular complications that increase the morbidity and mortality of patients. The risk of diabetic complications has a strong genetic component. To this end, we sought to evaluate the association of 40 single nucleotide polymorphisms (SNPs) in 21 candidate genes with T2D and its vascular complications in 503 T2D patients and 580 healthy controls. The genes were chosen because previously reported to be associated with T2D complications and/or with the aging process. We replicated the association of T2D risk with IGF2BP rs4402960 and detected novel associations with TERT rs2735940 and rs2736098. The addition of these SNPs to a model including traditional risk factors slightly improved risk prediction. After stratification of patients according to the presence/absence of vascular complications, we found significant associations of variants in the CAT, FTO, and UCP1 genes with diabetic retinopathy and nephropathy. Additionally, a variant in the ADIPOQ gene was found associated with macrovascular complications. Notably, these genes are involved in some way in mitochondrial biology and reactive oxygen species regulation. Hence, our findings strongly suggest a potential link between mitochondrial oxidative homeostasis and individual predisposition to diabetic vascular complications.

Montesanto|Alberto|A|
Bonfigli|Anna Rita|AR|
Crocco|Paolina|P|
Garagnani|Paolo|P|
De Luca|Maria|M|
Boemi|Massimo|M|
Marasco|Elena|E|
Pirazzini|Chiara|C|
Giuliani|Cristina|C|
Franceschi|Claudio|C|
Passarino|Giuseppe|G|
Testa|Roberto|R|
Olivieri|Fabiola|F|
Rose|Giuseppina|G|

D020022:Genetic Predisposition to Disease

Type 2 Diabetes
diabetes complications
SNP
aging
genetic profile


Romosozumab Followed by Antiresorptive Treatment Increases the Probability of Achieving Bone Mineral Density Treatment Goals.

Abstract: Increases in bone mineral density (BMD) with osteoporosis treatment are associated with reduced fracture risk. Increasing BMD is therefore a goal of osteoporosis therapy. Here, we compare the probability of achieving a T-score of > -2.5 over 3 years at the total hip (TH) or lumbar spine (LS) in women with osteoporosis, ≥55 years of age, after the following treatment sequences: 1 year romosozumab followed by 2 years denosumab (FRAME and FRAME extension trials), 1 year romosozumab followed by 2 years alendronate, or alendronate-only for 3 years (ARCH trial). Probabilities of attaining the BMD target within 1 year of treatment were also determined. At both skeletal sites, in women with a baseline Tscore ≥ -2.7, there was >50% probability of achieving the BMD target with any 3-year regimen. The probability of achieving the target BMD in those with a baseline TH Tscore equal to -3.0 was 61% with romosozumab/denosumab, 38% with romosozumab/alendronate, and 9% with alendronate. In those with a baseline LS Tscore equal to -3.0, the probability of achieving a T-score > -2.5 was 93% with romosozumab/denosumab, 81% with romosozumab/alendronate, and 55% with alendronate. With 1 year of treatment, in patients with a baseline TH T-score equal to -2.7, the probability of reaching the target Tscore with romosozumab was 71% to 78% and 38% with alendronate. For patients with an initial LS T-score equal to -3.0, the probability of achieving the target T-score over 1 year was 85% to 86% with romosozumab and 25% for alendronate. Our findings suggest baseline BMD and the probability of achieving BMD T-score goals are factors to consider when selecting initial treatment for patients with osteoporosis. As baseline T-score falls below -2.7 (TH) and -3.0 (LS), alendronate has <50% likelihood of achieving a BMD goal above osteoporosis range, whereas these probabilities remain relatively high for regimens beginning with romosozumab. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

ANTIRESORPTIVES
OSTEOPOROSIS
ANABOLICS
CLINICAL TRIALS
DXA


Bacillus Calmette-Guérin immunotherapy for bladder cancer: a review of immunological aspects, clinical effects and BCG infections.

Abstract: Bacillus Calmette-Guérin (BCG) immunotherapy for bladder cancer has been used since 1976 when the first evidence of its ability to lower recurrence and progression rates was published. Today, BCG immunotherapy is the choice of care for high-grade non-muscle invasive bladder cancer (NMIBC) after transurethral resection. This article presents indications and procedure of BCG instillations, and outlines the effects on recurrence and progression of NMIBC. The BCG-induced immunity in NMIBC is not yet fully understood. Animal studies point towards BCG inducing specific tumour immunity. We describe the current knowledge of how this immunity is induced, from internalization of BCG bacilli in urothelial cells, to cytokine- and chemokine-mediated recruitment of neutrophils, monocytes, macrophages, T cells, B cells and natural killer cells. In addition, we describe the process of trained immunity, the non-specific protective effects of BCG. Recent studies also indicate that dysbiosis of the urinary microbiome may cause lower urinary tract dysfunction. Side effects of BCG bladder instillations range from common, mild and transient symptoms, such as dysuria and flu-like symptoms, to more severe and rarely occurring life-threatening complications. We review the literature and give an overview of reported incidences and management of BCG infections after intravesical instillation.

Larsen|Emilie Stavnsbjerg|ES|
Joensen|Ulla Nordström|UN|
Poulsen|Alicia Martin|AM|
Goletti|Delia|D|
Johansen|Isik Somuncu|IS|

D000283:Administration, Intravesical
D000818:Animals
D001500:BCG Vaccine
D006801:Humans
D007167:Immunotherapy
D009163:Mycobacterium bovis
D009364:Neoplasm Recurrence, Local
D001743:Urinary Bladder
D001749:Urinary Bladder Neoplasms

immunotherapy
bladder cancer
BCG
BCG infection
intravesical instillation


Loss of the BBSome perturbs endocytic trafficking and disrupts virulence of Trypanosoma brucei.

Abstract: Cilia (eukaryotic flagella) are present in diverse eukaryotic lineages and have essential motility and sensory functions. The cilium's capacity to sense and transduce extracellular signals depends on dynamic trafficking of ciliary membrane proteins. This trafficking is often mediated by the Bardet-Biedl Syndrome complex (BBSome), a protein complex for which the precise subcellular distribution and mechanisms of action are unclear. In humans, BBSome defects perturb ciliary membrane protein distribution and manifest clinically as Bardet-Biedl Syndrome. Cilia are also important in several parasites that cause tremendous human suffering worldwide, yet biology of the parasite BBSome remains largely unexplored. We examined BBSome functions in Trypanosoma brucei, a flagellated protozoan parasite that causes African sleeping sickness in humans. We report that T. brucei BBS proteins assemble into a BBSome that interacts with clathrin and is localized to membranes of the flagellar pocket and adjacent cytoplasmic vesicles. Using BBS gene knockouts and a mouse infection model, we show the T. brucei BBSome is dispensable for flagellar assembly, motility, bulk endocytosis, and cell viability but required for parasite virulence. Quantitative proteomics reveal alterations in the parasite surface proteome of BBSome mutants, suggesting that virulence defects are caused by failure to maintain fidelity of the host-parasite interface. Interestingly, among proteins altered are those with ubiquitination-dependent localization, and we find that the BBSome interacts with ubiquitin. Collectively, our data indicate that the BBSome facilitates endocytic sorting of select membrane proteins at the base of the cilium, illuminating BBSome roles at a critical host-pathogen interface and offering insights into BBSome molecular mechanisms.

Langousis|Gerasimos|G|
Shimogawa|Michelle M|MM|
Saada|Edwin A|EA|
Vashisht|Ajay A|AA|
Spreafico|Roberto|R|
Nager|Andrew R|AR|
Barshop|William D|WD|
Nachury|Maxence V|MV|
Wohlschlegel|James A|JA|
Hill|Kent L|KL|

BBSome virulence cilium clathrin ubiquitin


Using Twitter to Surveil the Opioid Epidemic in North Carolina: An Exploratory Study.

Abstract:
BACKGROUND
Over the last two decades, deaths associated with opioids have escalated in number and geographic spread, impacting more and more individuals, families, and communities. Reflecting on the shifting nature of the opioid overdose crisis, Dasgupta, Beletsky, and Ciccarone offer a triphasic framework to explain that opioid overdose deaths (OODs) shifted from prescription opioids for pain (beginning in 2000), to heroin (2010 to 2015), and then to synthetic opioids (beginning in 2013). Given the rapidly shifting nature of OODs, timelier surveillance data are critical to inform strategies that combat the opioid crisis. Using easily accessible and near real-time social media data to improve public health surveillance efforts related to the opioid crisis is a promising area of research.

OBJECTIVE
This study explored the potential of using Twitter data to monitor the opioid epidemic. Specifically, this study investigated the extent to which the content of opioid-related tweets corresponds with the triphasic nature of the opioid crisis and correlates with OODs in North Carolina between 2009 and 2017.

METHODS
Opioid-related Twitter posts were obtained using Crimson Hexagon, and were classified as relating to prescription opioids, heroin, and synthetic opioids using natural language processing. This process resulted in a corpus of 100,777 posts consisting of tweets, retweets, mentions, and replies. Using a random sample of 10,000 posts from the corpus, we identified opioid-related terms by analyzing word frequency for each year. OODs were obtained from the Multiple Cause of Death database from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER). Least squares regression and Granger tests compared patterns of opioid-related posts with OODs.

RESULTS
The pattern of tweets related to prescription opioids, heroin, and synthetic opioids resembled the triphasic nature of OODs. For prescription opioids, tweet counts and OODs were statistically unrelated. Tweets mentioning heroin and synthetic opioids were significantly associated with heroin OODs and synthetic OODs in the same year (P=.01 and P<.001, respectively), as well as in the following year (P=.03 and P=.01, respectively). Moreover, heroin tweets in a given year predicted heroin deaths better than lagged heroin OODs alone (P=.03).

CONCLUSIONS
Findings support using Twitter data as a timely indicator of opioid overdose mortality, especially for heroin.

D000079803:Data Management
D006801:Humans
D009657:North Carolina
D000080052:Opioid Epidemic
D009293:Opioid-Related Disorders
D011159:Population Surveillance
D012189:Retrospective Studies
D061108:Social Media


Efficient Polymer-Mediated Delivery of Gene-Editing Ribonucleoprotein Payloads through Combinatorial Design, Parallelized Experimentation, and Machine Learning.

Abstract: Chemically defined vectors such as cationic polymers are versatile alternatives to engineered viruses for the delivery of genome-editing payloads. However, their clinical translation hinges on rapidly exploring vast chemical design spaces and deriving structure-function relationships governing delivery performance. Here, we discovered a polymer for efficient intracellular ribonucleoprotein (RNP) delivery through combinatorial polymer design and parallelized experimental workflows. A chemically diverse library of 43 statistical copolymers was synthesized via combinatorial RAFT polymerization, realizing systematic variations in physicochemical properties. We selected cationic monomers that varied in their pKa values (8.1-9.2), steric bulk, and lipophilicity of their alkyl substituents. Co-monomers of varying hydrophilicity were also incorporated, enabling elucidation of the roles of protonation equilibria and hydrophobic-hydrophilic balance in vehicular properties and performance. We screened our multiparametric vector library through image cytometry and rapidly uncovered a hit polymer (P38), which outperforms state-of-the-art commercial transfection reagents, achieving nearly 60% editing efficiency via nonhomologous end-joining. Structure-function correlations underlying editing efficiency, cellular toxicity, and RNP uptake were probed through machine learning approaches to uncover the physicochemical basis of P38's performance. Although cellular toxicity and RNP uptake were solely determined by polyplex size distribution and protonation degree, respectively, these two polyplex design parameters were found to be inconsequential for enhancing editing efficiency. Instead, polymer hydrophobicity and the Hill coefficient, a parameter describing cooperativity-enhanced polymer deprotonation, were identified as the critical determinants of editing efficiency. Combinatorial synthesis and high-throughput characterization methodologies coupled with data science approaches enabled the rapid discovery of a polymeric vehicle that would have otherwise remained inaccessible to chemical intuition. The statistically derived design rules elucidated herein will guide the synthesis and optimization of future polymer libraries tailored for therapeutic applications of RNP-based genome editing.

ribonucleoproteins
machine learning
CRISPR
high-throughput experimentation
polymeric gene delivery


Self-Medication and Associated Factors Among Pregnant Women Attending Antenatal Care at Kemisie General Hospital, North East Ethiopia.

Abstract:
Introduction
Self-medication is an important part of daily self-care, without the supervision of health professionals. It is commonly practiced by pregnant women all over the world and may result in maternal and fetal risks. Hence, this study assessed self-medication practices and associated factors among pregnant women attending Kemisie General Hospital.

Methods
A facility-based cross-sectional study was conducted using a structured questionnaire on pregnant women who were attending antenatal care at Kemisie General Hospital. A simple random sampling technique was employed to select the study participants. Descriptive and inferential statistics were computed using the Statistical Package for Social Sciences version 20.

Results
Among 223 pregnant women, 60 (26.9%; 95% CI: 20.9%, 32.9%) and 111 (48.9%; 95% CI: 43%, 58%) practiced self-medication on conventional and herbal medicine, respectively. The predictors of self-medication of conventional medicine among pregnant women were prior experience to the drug (P-value: 0.00, AOR=126.04, 95% CI: 32.55-488.04) and no pervious history of abortion (P-value: 0.00, AOR=0.01,95% CI:0.002-0.04), while college educational level (P-value: 0.00, AOR=13.45,95%, CI: 3.58-50.5), history prior herbal medicine use (P-value: 0.00, AOR=9, 95% CI: 3.32-24.39), Ruta chalepensis (P-value:0.001,AOR=193.7,95% CI:8.64-4342.1) and Ocimum lamiifolium type of herb use (P-value: 0.004, AOR=12.72, 95% CI: 2.27-71.38), and 5-10km health facility distance (P-value:0.022, AOR=0.1, 95% CI: 0.01-0.73) were predictors for self-medication practice of herbal medicines among pregnant women.

Conclusion
Nearly one-third and two-third of pregnant women practiced self-medication on conventional and herbal medicine, respectively. Prior experience to the drug and no previous history of abortion associated with self-medication of conventional medicine, while college educational level, history prior herbal medicine use, Ruta chalepensis and, Ocimum lamiifolium type of herb use, and 5-10km distance were predictors for self-medication practice of herbal medicines. Improving health service coverage and awareness creation on rational medication use is recommended to prevent fetal and maternal risks.

self-medication
pregnant women
herbal medicine
conventional medicine


Dynamic prediction of risk of death using history of cancer recurrences in joint frailty models.

Abstract: Evaluating the prognosis of patients according to their demographic, biological, or disease characteristics is a major issue, as it may be used for guiding treatment decisions. In cancer studies, typically, more than one endpoint can be observed before death. Patients may undergo several types of events, such as local recurrences and distant metastases, with death as the terminal event. Accuracy of clinical decisions may be improved when the history of these different events is considered. Thus, it may be useful to dynamically predict patients' risk of death using recurrence history. As previously applied within the framework of joint models for longitudinal and time to event data, we propose a dynamic prediction tool based on joint frailty models. Joint modeling accounts for the dependence between recurrent events and death, by the introduction of a random effect shared by the two processes. We estimate the probability of death between the prediction time t and a horizon t + w, conditional on information available at time t. Prediction can be updated with the occurrence of a new event. We proposed and compared three prediction settings, taking into account three different information levels. The proposed tools are applied to patients diagnosed with a primary invasive breast cancer and treated with breast-conserving surgery, followed for more than 10 years in a French comprehensive cancer center.

Mauguen|Audrey|A| Rachet|Bernard|B| Mathoulin-Pélissier|Simone|S| MacGrogan|Gaetan|G| Laurent|Alexandre|A| Rondeau|Virginie|V|

prediction
cancer
frailty
recurrence history
joint model


Fusarium graminearum and Its Interactions with Cereal Heads: Studies in the Proteomics Era.

Abstract: The ascomycete fungal pathogen Fusarium graminearum (teleomorph stage: Gibberella zeae) is the causal agent of Fusarium head blight in wheat and barley. This disease leads to significant losses of crop yield, and especially quality through the contamination by diverse fungal mycotoxins, which constitute a significant threat to the health of humans and animals. In recent years, high-throughput proteomics, aiming at identifying a broad spectrum of proteins with a potential role in the pathogenicity and host resistance, has become a very useful tool in plant-fungus interaction research. In this review, we describe the progress in proteomics applications toward a better understanding of F. graminearum pathogenesis, virulence, and host defense mechanisms. The contribution of proteomics to the development of crop protection strategies against this pathogen is also discussed briefly.

Yang|Fen|F|
Jacobsen|Susanne|S|
Jørgensen|Hans J L|HJ|
Collinge|David B|DB|
Svensson|Birte|B|
Finnie|Christine|C|

Fusarium graminearum
proteomics
pathogenicity
Fusarium head blight
plant defense response


Breast imaging screening in a BRCA1-mutated lactating patient: A potential pitfall mimicking malignancy.

Abstract: Breast imaging screening during lactation poses a real clinical challenge, especially in high-risk patients. We presented the case of a 34-year-old BRCA1-mutated woman showing marked, asymmetric background parenchymal enhancement on the right breast suspicious for malignancy in the context of annual screening magnetic resonance imaging. The patient revealed that she was still occasionally breastfeeding her two-year-old child only from right side. Ultrasound evaluation reported typical benign lactational findings on the right enhancing breast. An in-depth understanding of expected/ physiologic breast changes during lactation and an accurate clinical-radiological correlation are required to appropriately guide patient management and avoid misdiagnosis.

Casinelli|Alice|A| Malavolta|Giulia|G| Caruso|Giuseppe|G| Capri|Oriana|O| Ballesio|Laura|L|

Background parenchymal enhancement
Magnetic resonance imaging
Breastfeeding
Ultrasound
Breast cancer


Grafting of polymers via ring-opening polymerization for electrochemical assay of alkaline phosphatase activity.

Abstract: As an important hydrolytic enzyme, abnormal activity of alkaline phosphatase (ALP) is closely associated with a variety of diseases. It has been identified as an important diagnostic indicator for clinical hepatobiliary and bone diseases. Herein, a novel electrochemical sensor based on signal amplification strategy through ring-opening polymerization (ROP) has been developed to assay of ALP activity. First of all, 3-mercaptopropanoic acid (MPA) was employed as a cross-linking agent to attach O-phosphoethanolamine to the electrode surface via amide bond. Then, ALP catalyzed the hydrolysis of phosphate monoester structures to hydroxyl groups, which could initiate ROP reaction. The polymer grafted on the electrode surface contains a large number of ferrocene electroactive molecules, which effectively increased the signal output of the electrochemical sensor and improved the sensitivity of ALP activity detection. Under optimum conditions, this electrochemical sensor rendered a satisfactory linear dependence over the range from 20 to 120 mU mL-1, with a low detection limit of 0.66 mU mL-1. Furthermore, this strategy presented satisfactory selectivity and interference resistance in human serum sample, and compared with clinical data, the relative error of the results obtained by this method was less than 5%. Thus, this method showed considerable potential for the detection of ALP activity in clinical application.

Zhu|Xin|X| Wang|Wenbin|W| Lu|Jing|J| Hao|Lulu|L| Yang|Huaixia|H| Liu|Yanju|Y| Si|Fuchun|F| Kong|Jinming|J|

Alkaline phosphatase
Electrochemical sensor
ROP
Biomarker
Polymerization signal amplification


Improving genomically recoded Escherichia coli to produce proteins containing non-canonical amino acids.

Abstract: A genomically recoded Escherichia coli strain that lacks all amber codons and release factor 1 (C321.∆A) enables efficient genetic encoding of chemically diverse, non-canonical amino acids (ncAAs) into proteins. While C321.∆A has opened new opportunities in chemical and synthetic biology, this strain has not been optimized for protein production, limiting its utility in widespread industrial and academic applications. To address this limitation, we describe the construction of a series of genomically recoded organisms that are optimized for cellular protein production. We demonstrate that the functional deactivation of nucleases (e.g., rne, endA) and proteases (e.g., lon) increases production of wild-type superfolder green fluorescent protein (sfGFP) and sfGFP containing two ncAAs up to ∼5-fold. Additionally, we introduce a genomic IPTG-inducible T7 RNA polymerase (T7RNAP) cassette into these strains. Using an optimized platform, we demonstrated the ability to introduce 2 identical N6 -(propargyloxycarbonyl)-L -Lysine residues site specifically into sfGFP with a 17-fold improvement in production relative to the parent strain. We envision that our library of organisms will provide the community with multiple options for increased expression of proteins with new and diverse chemistries. This article is protected by copyright. All rights reserved.

non-canonical amino acids
protein production
genomically recoded organism
orthogonal translational system


Endothelialization of cardiovascular devices.

Abstract: Blood-contacting surfaces of cardiovascular devices are not biocompatible for creating an endothelial layer on them. Numerous research studies have mainly sought to modify these surfaces through physical, chemical and biological means to ease early endothelial cell (EC) adhesion, migration and proliferation, and eventually to build an endothelial layer on the surfaces. The first priority for surface modification is inhibition of protein adsorption that leads to inhibition of platelet adhesion to the device surfaces, which may favor EC adhesion. Surface modification through surface texturing, if applicable, can bring some hopeful outcomes in this regard. Surface modifications through chemical and/or biological means may play a significant role in easy endothelialization of cardiovascular devices and inhibit smooth muscle cell proliferation. Cellular engineering of cells relevant to endothelialization can boost the positive outcomes obtained through surface engineering. This review briefly summarizes recent developments and research in early endothelialization of cardiovascular devices. STATEMENT OF SIGNIFICANCE: Endothelialization of cardiovascular implants, including heart valves, vascular stents and vascular grafts is crucial to solve many problems in our health care system. Numerous research efforts have been made to improve endothelialization on the surfaces of cardiovascular implants, mainly through surface modifications in three ways - physically, chemically and biologically. This review is intended to highlight comprehensive research studies to date on surface modifications aiming for early endothelialization on the blood-contacting surfaces of cardiovascular implants. It also discusses future perspectives to help guide endothelialization strategies and inspire further innovations.

D000327:Adsorption
D000818:Animals
D001672:Biocompatible Materials
D001705:Bioprosthesis
D001807:Blood Vessel Prosthesis
D002448:Cell Adhesion
D002465:Cell Movement
D049109:Cell Proliferation
D042783:Endothelial Cells
D004730:Endothelium, Vascular
D015316:Genetic Therapy
D006350:Heart Valve Prosthesis
D006801:Humans
D015607:Stents
D013499:Surface Properties
D023822:Tissue Engineering
D058017:Vascular Grafting

Endothelialization
Cardiovascular
Heart valve
Vascular stent
Vascular graft


Nitrosomonas europaea MazF Specifically Recognises the UGG Motif and Promotes Selective RNA Degradation.

Abstract: Toxin-antitoxin (TA) systems are implicated in prokaryotic stress adaptation. Previously, bioinformatics analysis predicted that such systems are abundant in some slowly growing chemolithotrophs; e.g., Nitrosomonas europaea. Nevertheless, the molecular functions of these stress-response modules remain largely unclear, limiting insight regarding their physiological roles. Herein, we show that one of the putative MazF family members, encoded at the ALW85_RS04820 locus, constitutes a functional toxin that engenders a TA pair with its cognate MazE antitoxin. The coordinate application of a specialised RNA-Seq and a fluorescence quenching technique clarified that a unique triplet, UGG, serves as the determinant for MazF cleavage. Notably, statistical analysis predicted that two transcripts, which are unique in the autotroph, comprise the prime targets of the MazF endoribonuclease: hydroxylamine dehydrogenase (hao), which is essential for ammonia oxidation, and a large subunit of ribulose 1,5-bisphosphate carboxylase/oxygenase (rbcL), which plays an important role in carbon assimilation. Given that N. europaea obtains energy and reductants via ammonia oxidation and the carbon for its growth from carbon dioxide, the chemolithotroph might use the MazF endoribonuclease to modulate its translation profile and subsequent biochemical reactions.

Miyamoto|Tatsuki|T| Yokota|Akiko|A| Ota|Yuri|Y| Tsuruga|Masako|M| Aoi|Rie|R| Tsuneda|Satoshi|S| Noda|Naohiro|N|

Nitrosomonas europaea
ammonia oxidation
MazEF
RNase
carbon fixation
sequence-specificity
toxin-antitoxin system


Serum malondialdehyde level: Surrogate stress marker in the Sikkimese diabetics.

Abstract:
BACKGROUND
The pbreakdown of phospholipids lead to accumulation of malondialdehyde (MDA) that is preferred as a surrogate marker of oxidative stress in diabetics.

OBJECTIVE
To compare serum MDA levels along with other biochemical parameters between type 2 diabetic patients with and without complications.

MATERIALS AND METHODS
This cross-sectional study was carried out in the Department of Biochemistry of a tertiary care teaching hospital in Sikkim on 60 type 2 diabetics and compared with 100 non-diabetic participants. The un-hemolyzed blood samples were used for estimation of biochemical parameters; MDA was estimated in serum by using trichloroacetic acid (TCA) and 1% thiobarbituric acid (TBA). Whole blood was used for estimation of glycated hemoglobin. The comparison of different parameters between cases and control was calculated by using Student's t test.

RESULTS
In the study and control groups, no significant difference was noted with regard to independent variables. The fasting and postprandial serum glucose along with glycated hemoglobin from whole blood and the lipid profile differed significantly between the study and control groups. Overall, tmean serum MDA level in the study group was significantly higher thanin the controls. Male sex, addiction to tobacco (smoking and smokeless inclusive), longer duration of diabetes (≥5 years), and presence of complications (both microvascular and macrovascular) significantly increased the MDA level.

CONCLUSION
To sum up, the serum MDA level was observed to be significantly high in diabetics with and without complication along with other parameters.

Bhutia|Yazum|Y|
Ghosh|Amrita|A|
Sherpa|Mingma L|ML|
Pal|Ranabir|R|
Mohanta|Pradip Kumar|PK|

malondialdehyde
Glycated hemoglobin
lipid peroxidation
type 2 diabetes mellitus


Squalene: More than a Step toward Sterols.

Abstract: Squalene (SQ) is a natural triterpene widely distributed in nature. It is a metabolic intermediate of the sterol biosynthetic pathway and represents a possible target in different metabolic and oxidative stress-related disorders. Growing interest has been focused on SQ's antioxidant properties, derived from its chemical structure. Strong evidence provided by ex vivo models underline its scavenging activity towards free radicals, whereas only a few studies have highlighted its effect in cellular models of oxidative stress. Given the role of unbalanced free radicals in both the onset and progression of several cardiovascular diseases, an in depth evaluation of SQ's contribution to antioxidant defense mechanisms could represent a strategic approach in dealing with these pathological conditions. At present experimental results overall show a double-edged sword role of squalene in cardiovascular diseases and its function has to be better elucidated in order to establish intervention lines focused on its features. This review aims to summarize current knowledge about endogenous and exogenous sources of SQ and to point out the controversial role of SQ in cardiovascular physiology.

squalene
antioxidants
oxidative stress
cardiovascular diseases
RNS
ROS


A high density SLAF-SNP genetic map and QTL detection for fibre quality traits in Gossypium hirsutum.

Abstract:
BACKGROUND
Upland Cotton (Gossypium hirsutum) is a very important cash crop known for its high quality natural fiber. Recent advances in sequencing technologies provide powerful tools with which to explore the cotton genome for single nucleotide polymorphism marker identification and high density genetic map construction toward more reliable quantitative trait locus mapping.

RESULTS
In the present study, a RIL population was developed by crossing a Chinese high fiber quality cultivar (Yumian 1) and an American high fiber quality line (CA3084), with distinct genetic backgrounds. Specific locus amplified fragment sequencing (SLAF-seq) technology was used to discover SNPs, and a genetic map containing 6254 SNPs was constructed, covering 3141.72 cM with an average distance of 0.5 cM between markers. A total of 95 QTL were detected for fiber quality traits in three environments, explaining 5.5-24.6% of the phenotypic variance. Fifty-five QTL found in multiple environments were considered stable QTL. Nine of the stable QTL were found in all three environments. We identified 14 QTL clusters on 13 chromosomes, each containing one or more stable QTL.

CONCLUSION
A high-density genetic map of Gossypium hirsutum developed by using specific locus amplified fragment sequencing technology provides detailed mapping of fiber quality QTL, and identification of 'stable QTL' found in multiple environments. A marker-rich genetic map provides a foundation for fine mapping, candidate gene identification and marker-assisted selection of favorable alleles at stable QTL in breeding programs.

Ali|Iftikhar|I|
Teng|Zhonghua|Z|
Bai|Yuting|Y|
Yang|Qing|Q|
Hao|Yongshui|Y|
Hou|Juan|J|
Jia|Yongbin|Y|
Tian|Lixia|L|
Liu|Xueying|X|
Tan|Zhaoyun|Z|
Wang|Wenwen|W|
Kenneth|Kiirya|K|
Sharkh|Abdalla Yousef Ahmed|AYA|
Liu|Dexin|D|
Guo|Kai|K|
Zhang|Jian|J|
Liu|Dajun|D|
Zhang|Zhengsheng|Z|

D021141:Nucleic Acid Amplification Techniques


Narrow-band pass filter array for integrated opto-electronic spectroscopy detectors to assess esophageal tissue.

Abstract: A strategy for spectroscopy tissue diagnosis using a small number of wavelengths is reported. The feasibility to accurately quantify tissue information using only 16 wavelengths is demonstrated with several wavelength reduction simulations of the existing esophageal data set. These results are an important step for the development of a miniaturized, robust and low-cost spectroscopy system. This system is based on a sub-millimeter high-selective filter array that offers prospects for a simplified miniature spectrographic detector for a future diagnostic tool to improve the diagnosis of dysplasia. Several thin-film optical filters are optimized and fabricated and its spectral performance is shown to be sufficient for the selection of specific wavelength bands.

Ferreira|Débora S|DS|
Mirkovic|Jelena|J|
Wolffenbuttel|Reinoud F|RF|
Correia|José H|JH|
Feld|Michael S|MS|
Minas|Graça|G|

(170.3890) Medical optics instrumentation

(170.6510) Spectroscopy, tissue diagnostics


Can brain impermeable BACE1 inhibitors serve as anti-CAA medicine?

Abstract:
BACKGROUND
Cerebral amyloid angiopathy (CAA) is characterized by the deposition of ß-amyloid peptides (Aß) in and surrounding the wall of microvasculature in the central nervous system, together with parenchymal amyloid plaques collectively referred to as cerebral amyloidosis, which occurs in the brain commonly among the elderly and more frequently in patients with Alzheimer's disease (AD). CAA is associated with vascular injury and may cause devastating neurological outcomes. No therapeutic approach is available for this lesion to date.

MAIN BODY
ß-Secretase 1 (BACE1) is the enzyme initiating Aß production. Brain permeable BACE1 inhibitors targeting primarily at the parenchymal plaque pathology are currently evaluated in clinical trials. This article presents findings in support of a role of BACE1 elevation in the development of CAA, in addition to plaque pathogenesis. The rationale, feasibility, benefit and strategic issues for developing BACE1 inhibitors against CAA are discussed. Brain impermeable compounds are considered preferable as they might exhibit sufficient anti-CAA efficacy without causing significant neuronal/synaptic side effects.

CONCLUSION
Early pharmacological intervention to the pathogenesis of CAA is expected to provide significant protection for cerebral vascular health and hence brain health. Brain impermeable BACE1 inhibitors should be optimized and tested as potential anti-CAA therapeutics.

Li|Jian-Ming|JM| Huang|Li-Ling|LL| Liu|Fei|F| Tang|Bei-Sha|BS| Yan|Xiao-Xin|XX|

D053829:Amyloid Precursor Protein Secretases

Cerebral amyloidosis
Alzheimer’s disease
Neurodegeneration
Vascular dementia
ß –Amyloid


Structure-based drug design, synthesis and screening of MmaA1 inhibitors as novel anti-TB agents.

Abstract: Tuberculosis is one of the leading causes of death across the world. The treatment regimens for tuberculosis are well established, but still the control of the disease faces many challenges such as lengthy treatment protocols, drug resistance and toxicity. In the present work, mycolic acid methyl transferase (MmaA1), a protein involved in the maturation of mycolic acids in the biochemical pathway of the Mycobacterium, was studied for novel drug discovery. The homology model of the MmaA1 protein was built and validated by using computational techniques. The MmaA1 protein has 286 amino acid residues consisting of 10 α-helices and 7 β-sheets. The active site of the MmaA1 protein was identified using CASTp, SiteMap and PatchDock. Virtual screening studies were performed with two small molecule ligand databases: Asinex synergy and Diverse_Elite_Gold_Platinum databases having a total of 43,446 molecules and generated 1,30,814 conformers against the predicted and validated active site of the MmaA1 protein. Binding analysis showed that the residues ASP 19, PHE 22, TRP 30, TYR 32, TRP 74 and ALA 77 of MmaA1 protein have consistent interactions with the ligands. The hit ligands were further filtered by in silico ADME properties to eliminate potentially toxic molecules. Of the top 10 molecules, 3-(2-morpholinoacetamido)-N-(1,4-dihydro-4-oxoquinazolin-6-yl) benzamide was synthesised and screened for in vitro anti-TB activity against Mtb H37Rv using MABA assay. The compound and its intermediates exhibited good in vitro anti-TB activity which can be taken up for future lead optimisation studies. Structure based virtual screening study was performed using a validated homology model against small molecules from two virtual compound libraries. Synthesised the lead compound 3-(2-morpholinoacetamido)-N-(1,4-dihydro-4-oxoquinazolin-6-yl)benzamide obtained from virtual screening. In vitro activity against Mtb H37Rv has given a promising result.

Veeravarapu|Hymavathi|H|
Malkhed|Vasavi|V|
Mustyala|Kiran Kumar|KK|
Vadija|Rajender|R|
Malikanti|Ramesh|R|
Vuruputuri|Uma|U|
Muthyala|Murali Krishna Kumar|MKK|

D000595:Amino Acid Sequence
D000995:Antitubercular Agents
D020134:Catalytic Domain
D015195:Drug Design
D004353:Drug Evaluation, Preclinical
D004791:Enzyme Inhibitors
D008024:Ligands
D008780:Methyltransferases
D062105:Molecular Docking Simulation
D009169:Mycobacterium tuberculosis
D009171:Mycolic Acids
D017433:Protein Structure, Secondary
D015203:Reproducibility of Results
D013329:Structure-Activity Relationship

MmaA1
Tuberculosis
Mycolic acid methyl transferase
Homology modelling
Virtual screening
MABA assay


Measuring brain synaptic vesicle protein 2A with positron emission tomography and [18F]UCB-H.

Abstract:
Introduction
Brain distribution of synaptic vesicle protein 2A was measured with fluorine-18 UCB-H ([18F]UCB-H) and positron emission tomography (PET).

Methods
Images of synaptic density were acquired in healthy volunteers (two young participants and two seniors). Input function was measured by arterial blood sampling (arterial input function) and derived from PET images using carotid activity (image-derived input function). Logan graphical analysis was used to estimate regional synaptic vesicle protein 2A distribution volume.

Results
[18F]UCB-H uptake was ubiquitous in cortical and subcortical gray matter. Arterial input function and image-derived input function provided regional distribution volume with a high linear relationship.

Discussion
The cerebral distribution of [18F]UCB-H is similar to that recently observed with carbon-11 UCB-J ([11C]UCB-J). An accurate [18F]UCB-H quantification can be performed without invasive arterial blood sampling when no suitable reference region is available, using dynamic PET carotid activity. Brain synaptic density can be studied in vivo in normal and pathological aging.

Bahri|Mohamed Ali|MA|
Plenevaux|Alain|A|
Aerts|Joël|J|
Bastin|Christine|C|
Becker|Guillaume|G|
Mercier|Joël|J|
Valade|Anne|A|
Buchanan|Tim|T|
Mestdagh|Nathalie|N|
Ledoux|Didier|D|
Seret|Alain|A|
Luxen|André|A|
Salmon|Eric|E|

Fluorine-18
PET
Alzheimer's disease
Neuroimaging
SV2A
Synapse density


The potential role of the adipokine HMGB1 in obesity and insulin resistance. Novel effects on adipose tissue biology.

Abstract: Discovery of the adipose tissue as a major source of signaling molecules almost three decades ago set a novel physiological paradigm that paved the way for the identification of metabolic organs as endocrine organs. Adipocytes, the main adipose tissue cell type, do not only represent the principal site of energy storage in form of triglycerides, but also produce a variety of molecules for short and long distance intercellular communication, named adipokines, which coordinate systemic responses. Although the best known adipokines identified and characterized hitherto are leptin and adiponectin, novel adipokines are continuously being described, what have significantly helped to elucidate the role of adipocyte biology in obesity and associated comorbidities. One of these novel adipokines is high-mobility group box 1 (HMGB1), a ubiquitous nuclear protein that has been recently reported to be dysregulated in obese dysfunctional adipocytes. Although the classical function of HMGB1 is related to inflammation and immunity, acting as an alarmin, novel advances evidence an active implication of HMGB1 in tissue remodeling and fibrosis. This review summarizes the current evidence on the mechanisms controlling HMGB1 release, as well as its role as a regulator of adipocyte function and extracellular matrix remodeling, with special emphasis on the potential of this novel adipokine as a target in the obesity treatment.

Guzmán-Ruiz|R|R|
Tercero-Alcázar|C|C|
López-Alcalá|J|J|
Sánchez-Ceinos|J|J|
Malagón|M M|MM|
Gordon|A|A|

HMGB1
Obesity
Insulin resistance
Adipocyte
Fibrosis