The importance of data structure in statistical analysis of dendritic spine morphology

Publication date: 15 February 2018
Source:Journal of Neuroscience Methods, Volume 296
Author(s): Veerle Paternoster, Anto P. Rajkumar, Jens Randel Nyengaard, Anders Dupont Børglum, Jakob Grove, Jane Hvarregaard Christensen
BackgroundDendritic spine morphology is heterogeneous and highly dynamic. To study the changing or aberrant morphology in test setups, often spines from several neurons from a few experimental units e.g. mice or primary neuronal cultures are measured. This strategy results in a multilevel data structure, which, when not properly addressed, has a high risk of producing false positive and false negative findings.MethodsWe used mixed-effects models to deal with data with a multilevel data structure and compared this method to analyses at each level. We apply these statistical tests to a dataset of dendritic spine morphology parameters to illustrate advantages of multilevel mixed-effects model, and disadvantages of other models.ResultsWe present an application of mixed-effects models for analyzing dendritic spine morphology datasets while correcting for the data structure.Comparison with existing methodsWe further show that analyses at spine level and aggregated levels do not adequately account for the data structure, and that they may lead to erroneous results.ConclusionWe highlight the importance of data structure in dendritic spine morphology analyses and highly recommend the use of mixed-effects models or other appropriate statistical methods to deal with multilevel datasets. Mixed-effects models are easy to use and superior to commonly used methods by including the data structure and the addition of other explanatory variables, for example sex, and age, etc., as well as interactions between variables or between variables and level identifiers.



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Simultaneous quantification of caffeine and chlorogenic acid in coffee green beans and varietal classification of the samples by HPLC-DAD coupled with chemometrics

Abstract

A chromatographic procedure (HPLC-DAD) using a relatively rapid gradient has been combined with a chemometric curve deconvolution method, multivariate curve resolution-alternating least squares (MCR-ALS), in order to quantify caffeine and chlorogenic acid in green coffee beans. Despite that the HPLC analysis (at these specific operating conditions) presents some coeluting peaks, MCR-ALS allowed their resolution and, consequently, the creation of a calibration curve to be used for the quantification of the analytes of interest; this procedure led to a high accuracy in the quantification of caffeine and chlorogenic acid present in the samples. In a second part of this study, the possibility of classifying the green coffee beans on the basis of their cultivar (Arabica or Robusta), by partial least squares discriminant analysis (PLS-DA) and soft independent modeling of class analogies (SIMCA), has been explored. SIMCA resulted in 100% of sensitivity and specificity for the Arabica class, while for the Robusta, it reached 66.7% of sensitivity and 100% of specificity, or 100% of sensitivity and 100% of specificity, depending on the extraction procedure followed prior to the chromatographic analysis; PLS-DA achieved 100% of correct classification independently of the procedure used for the extraction.

http://ift.tt/2nUUbG6

Wet deposition of atmospheric nitrogen contributes to nitrogen loading in the surface waters of Lake Tanganyika, East Africa: a case study of the Kigoma region

Abstract

Lake Tanganyika, an African Great Lake, is a complex tropical ecosystem that has been subjected to extreme climate-related changes in the last century, including seasonal changes in temperature and rainfall, decreased overall annual rainfall, and greater frequency of rainstorms. Atmospheric nitrogen (N) is an important component of the lake's N loading, but how long-term and seasonal changes in precipitation affect this loading still needs clarification. This study aimed to improve our understanding of the seasonal features of N deposition in the lake, by monitoring atmospheric N deposition concentrations and fluxes from March 2013 to February 2014. There was a significant temporal variation in wet N depositions in the study area. The distribution of the annual rainfall into major (March–May 299.8 mm) and minor (October–December 343.2 mm) rainy seasons translated into 20 and 30% of N deposition. In September and January–February, there was 10 and 12% precipitation, representing 43 and 7% of N deposition in the lake. Nitrogen deposition was highest in September due to farmlands' burning during the dry season (June–August), leading to N accumulation in the atmosphere. In conclusion, the pattern of N deposition appears to be driven by the unique climatic characteristics of the lake basin and to be closely associated with local anthropogenic activities.

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Chemotherapy is administered to a minority of hospitalized patients with diffuse large B-cell lymphoma and is associated with less likelihood of death during hospitalization

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Anita J. Kumar, Tobi Henzer, Angie Mae Rodday, Susan K. Parsons
BackgroundWhile treatment of DLBCL is largely outpatient, some patients require planned or unplanned admissions for chemotherapy, new diagnosis, relapse, or toxicity. We examined risk factors for receipt of inpatient chemotherapy and death during hospitalization.MethodsWe analyzed data from the 2012–2013 HCUP-NIS. We identified patient and hospital characteristics that were associated with chemotherapy administration and death.ResultsChemotherapy was given in 3260/11,150 (29.2%) of hospitalizations. Younger age, urban teaching hospitals, fewer chronic conditions, male sex, non-Medicare insurance, and "less likelihood of dying" were associated with chemotherapy. Chemotherapy portended lower odds of death; older age and longer hospitalizations were associated with increased odds of death.ConclusionWe identified socio-demographics and clinical characteristics associated with inpatient chemotherapy in DLBCL patients. Chemotherapy is associated with lower odds of death during hospitalization, suggesting that most chemotherapy is given appropriately to non-critically ill patients. Clinical acuity is a stronger predictor of death than socio-demographics.



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Exploring determinants of care-seeking behaviour of oral cancer patients in India: A qualitative content analysis

Publication date: April 2018
Source:Cancer Epidemiology, Volume 53
Author(s): Hemamalini Rath, Swikant Shah, Gaurav Sharma, Ekagrata Mishra
BackgroundA major public health concern in India is the high morbidity and mortality rates of oral cancer because of late diagnosis. Among the several determinants of this late diagnosis, the most important is the healthcare-seeking behaviour of the oral cancer patients. The aim of this study was to explore the care-seeking behaviour and its determinants among oral cancer patients.MethodsA face-to-face in-depth interview was conducted among 70 oral cancer patients using a semi-structured questionnaire, and qualitative content analysis of the results was performed.ResultsAll the patients had squamous-cell carcinoma and none had attended any screening programme. The most common site affected was the buccal mucosa with a non-healing wound. Most of the patients contacted a doctor available nearby; only 7% of patients consulted a dentist. Only one patient approached a traditional healer. The median patient delay was 30 (4–365) days and the professional delay was 40 (4–650) days. Enablers included determinants such as increasing symptoms (80%), influence of the society (74%), fear (10%), and social media (3%). The main barriers were lack of awareness (97%), hope that the lesion will heal spontaneously (90%), lack of perception of seriousness (64%), financial constraints (55%), provider switching (47%), and missed diagnosis (44%).ConclusionThe care-seeking path among oral cancer patients is complex, customised, and influenced by multiple patient-related and system-related factors.



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Effectiveness of acellular pertussis vaccine and evolution of pertussis incidence in the community of Madrid from 1998 to 2015

Publication date: Available online 10 February 2018
Source:Vaccine
Author(s): P. Latasa, L. García-Comas, A. Gil de Miguel, M.D. Barranco, I. Rodero, J.C. Sanz, M. Ordobás, A. Arce, M. Garrido-Estepa
IntroductionPertussis is a communicable disease that primarily affects infants. Vaccination has led to an important reduction in the incidence of the disease, however, resurgence of the disease has been observed. This study aimed to analyze the incidence of pertussis and assess the vaccination effectiveness (VE) of different schedules of acellular pertussis vaccination in the community of Madrid.MethodsPertussis cases notified to the Mandatory Disease Reporting System from 1998 to 2015 were analyzed. Five comparison periods were created: 1998–2001 (reference), 2002–2005, 2006–2009, 2010–2012 and 2013–2015. The incidence ratio (IR) between inter-epidemic periods was analyzed using a Poisson regression. VE was calculated using the screening method. Vaccine status data were collected from the vaccine registry.ResultsIn total, 3855 cases were notified. Inter-epidemic periods were observed every 3–4 years. The incidence increased (IR: 5.99, p < 0.05) in the 2013–2015 period, particularly among infants younger than 1 month (IR: 32.41, p < 0.05). Vaccination data were available in 89% of cases. For those receiving the last dose at ≤6-month VE was 89.9% (95% confidence interval (CI): 87.3–92.0) after one year of follow-up, and 85.5% (95% CI: 82.4–88.1) after 11 years of follow-up. For those receiving the last dose at 18-months VE decreased from 98.8% (95% CI: 98.3–99.1) to 85.1% (95% CI: 81.9–87.7) in the same period, and for those receiving the last dose at 4-year VE decreased from 99.6% (95% CI: 99.3–99.7) to 79.3% (95% CI: 74.6–83.1).ConclusionsB. pertussis is circulating in our population, as shown by the epidemic peaks and increased incidence of pertussis in recent years. VE increased with the number of doses and decreased with the follow-up period. The effect of this and other vaccination strategies must be monitored to control the disease.



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Dermaseptins as potential antirabies compounds

Publication date: Available online 10 February 2018
Source:Vaccine
Author(s): Mohamed Ben Mechlia, Afifa Belaid, Guillaume Castel, Corinne Jallet, Karen L. Mansfield, Anthony R. Fooks, Khaled Hani, Noël Tordo
Over the last 20 years, natural peptides playing a key role in defense mechanisms and innate immunity have been isolated from unicellular organisms. Amphibian skin secretes dermaseptins, 24–34 amino acids in length that have a wide antimicrobial spectrum incorporating yeast, fungi, protozoa, bacteria and enveloped viruses. The anti-rabies virus (RABV) activity of dermaseptins S3 (30aa) and S4 (28aa) from Phyllomedusa sauvagei has been investigated, and further dissected its molecular basis by comparing punctual mutation or deletion of S4 analogues. The results showed that: (1) S4 is more active than S3 against RABV infection, 89% versus 38% inhibition at 7.5 μM; (2) the 5 NH2-aa of S4 are crucial for its inhibitory potential (S46–28 lost any inhibition) but the COOH terminus stabilizes the inhibitory potential (S41–16 showed only 23% inhibition at 7.5 μM); (3) there is a correlation between viral inhibition and dermaseptin cytotoxicity, which remains however moderated for BSR cells (≤12% at 10 μM). A single mutation in position 4 (S4M4K) slightly reduced cytotoxicity while keeping its antiviral activity, 97% at 7.5 μM. S4 and S4M4K showed an antiviral activity in vitro when provided 1 h after infection. In vivo experiments in mice by intramuscular injection of non-toxic doses of dermaseptin S4M4K 1 h post-infection by a lethal dose of RABV at the same site allowed more than 50% improvement in mice survival. This study highlights the potential interest of dermaseptins as non-expansive alternatives to rabies immunoglobulins for the treatment of rabies that continues to claim about 60,000 human lives per year worldwide, almost exclusively in developing countries.



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RTS,S malaria vaccine efficacy and immunogenicity during Plasmodium falciparum challenge is associated with HLA genotype

Publication date: Available online 10 February 2018
Source:Vaccine
Author(s): C.M. Nielsen, J. Vekemans, M. Lievens, K.E. Kester, J.A. Regules, C.F. Ockenhouse
Although RTS,S remains the most advanced malaria vaccine, the factors influencing differences in vaccine immunogenicity or efficacy between individuals or populations are still poorly characterised. The analyses of genetic determinants of immunogenicity have previously been restricted by relatively small sample sizes from individual trials. Here we combine data from six Phase II RTS,S trials and evaluate the relationship between HLA allele groups and RTS,S-mediated protection in controlled human malaria infections (CHMI), using multivariate logistic or linear regression. We observed significant associations between three allele groups (HLA-A^∗01, HLA-B^∗08, and HLA-DRB1^∗15/^∗16) and protection, while another three allele groups (HLA-A^∗03, HLA-B^∗53, and HLA-DRB1^∗07) were significantly associated with lack of protection. It is noteworthy that these 'protective' allele groups are thought to be at a lower prevalence in sub-Saharan African populations than in the UK or USA where these Phase II trials occurred. Taken together, the analyses presented here give an indication that HLA genotype may influence RTS,S-mediated protective efficacy against malaria infection.



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Mass media effect on vaccines uptake during silent polio outbreak

Publication date: Available online 10 February 2018
Source:Vaccine
Author(s): Iftach Sagy, Victor Novack, Michael Gdalevich, Dan Greenberg
BackgroundDuring 2013, isolation of a wild type 1 poliovirus from routine sewage sample in Israel, led to a national OPV campaign. During this period, there was a constant cover of the outbreak by the mass media.AimsTo investigate the association of media exposure and OPV and non-OPV vaccines uptake during the 2013 silent polio outbreak in Israel.MethodsWe received data on daily immunization rates during the outbreak period from the Ministry of Health (MoH). We conducted a multivariable time trend analysis to assess the association between daily media exposure and vaccines uptake. Analysis was stratified by ethnicity and socio-economic status (SES).ResultsDuring the MoH supplemental immunization activity, 138,799 OPV vaccines were given. There was a significant association between media exposure and OPV uptake, most prominent in a lag of 3–5 days from the exposure among Jews (R.R 1.79C.I 95% 1.32–2.41) and high SES subgroups (R.R 1.71C.I 95% 1.27–2.30). These subgroups also showed increased non-OPV uptake in a lag of 3–5 days from the media exposure, in all vaccines except for MMR. Lower SES and non-Jewish subgroups did not demonstrate the same association.ConclusionOur findings expand the understanding of public behaviour during outbreaks. The public response shows high variability within specific subgroups. These findings highlight the importance of tailored communication strategies for each subgroup.



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In-depth genome analyses of viruses from vaccine-derived rabies cases and corresponding live-attenuated oral rabies vaccines

Publication date: Available online 10 February 2018
Source:Vaccine
Author(s): Florian Pfaff, Thomas Müller, Conrad M. Freuling, Christine Fehlner-Gardiner, Susan Nadin-Davis, Emmanuelle Robardet, Florence Cliquet, Vlad Vuta, Peter Hostnik, Thomas C. Mettenleiter, Martin Beer, Dirk Höper
Live-attenuated rabies virus strains such as those derived from the field isolate Street Alabama Dufferin (SAD) have been used extensively and very effectively as oral rabies vaccines for the control of fox rabies in both Europe and Canada. Although these vaccines are safe, some cases of vaccine-derived rabies have been detected during rabies surveillance accompanying these campaigns. In recent analysis it was shown that some commercial SAD vaccines consist of diverse viral populations, rather than clonal genotypes. For cases of vaccine-derived rabies, only consensus sequence data have been available to date and information concerning their population diversity was thus lacking.In our study, we used high-throughput sequencing to analyze 11 cases of vaccine-derived rabies, and compared their viral population diversity to the related oral rabies vaccines using pairwise Manhattan distances. This extensive deep sequencing analysis of vaccine-derived rabies cases observed during oral vaccination programs provided deeper insights into the effect of accidental in vivo replication of genetically diverse vaccine strains in the central nervous system of target and non-target species under field conditions. The viral population in vaccine-derived cases appeared to be clonal in contrast to their parental vaccines. The change from a state of high population diversity present in the vaccine batches to a clonal genotype in the affected animal may indicate the presence of a strong bottleneck during infection. In conclusion, it is very likely that these few cases are the consequence of host factors and not the result of the selection of a more virulent genotype. Furthermore, this type of vaccine-derived rabies leads to the selection of clonal genotypes and the selected variants were genetically very similar to potent SAD vaccines that have undergone a history of in vitro selection.



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Safety and tolerability of a liquid bovine rotavirus pentavalent vaccine (LBRV-PV) in adults

Publication date: Available online 10 February 2018
Source:Vaccine
Author(s): K. Anil, Sajjad Desai, Chetanraj Bhamare, Abhijeet Dharmadhikari, R.L. Madhusudhan, Jaya Patel, Prasad S. Kulkarni
BackgroundRotavirus Gastroenteritis (RVGE) is an important global public health problem. Recently a Lyophilized Pentavalent Human Bovine Reassortant Rotavirus vaccine (BRV-PV, Rotasiil) was licensed in India. A Liquid formulation of the same vaccine (LBRV-PV) was tested in a Phase I clinical trial.MethodsTotal 20 healthy adults were given a single oral dose of LBRV-PV and were followed for one month for safety outcomes: immediate reactions, solicited reactions, unsolicited adverse events and serious adverse events.ResultsAll 20 adults completed the study without any major protocol deviations. No immediate reaction, solicited reactions and unsolicited adverse events were reported during the study. No clinically significant changes were seen in the vital parameters and safety laboratory test results.ConclusionsLBRV-PV developed in India was safe and well tolerated in adults. Further clinical development of this vaccine in infants should be undertaken.Trial Registration – CTRI/2015/11/006,384.



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Immunization with an adjuvanted low-energy electron irradiation inactivated respiratory syncytial virus vaccine shows immunoprotective activity in mice

Publication date: Available online 10 February 2018
Source:Vaccine
Author(s): Lea Bayer, Jasmin Fertey, Sebastian Ulbert, Thomas Grunwald
Respiratory syncytial virus (RSV) is a pathogen causing severe lower respiratory tract disease in infants and the elderly. In spite of the great need for a vaccine against RSV, currently there is no licensed product on the market. A very early vaccine candidate developed in the 1960s based on formaldehyde inactivation (FI) turned out to instead enhance the disease. Our novel inactivation method applied low-energy electron irradiation (LEEI) to produce a killed RSV vaccine. LEEI yielded inactivated virus particles with a reproducible virus antigen conservation above 70%, while FI resulted in highly variable antigen conservation. Immunization of mice with LEEI-RSV elicited a strong immune response, resulting in a drastic reduction in viral load upon challenge in two independent studies. These results have implications for the development of an RSV vaccine and should be validated in further preclinical and clinical studies.



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13-Valent vaccine serotype pneumococcal community acquired pneumonia in adults in high clinical risk groups

Publication date: Available online 10 February 2018
Source:Vaccine
Author(s): Priya Daniel, Chamira Rodrigo, Thomas Bewick, Carmen Sheppard, Sonia Greenwood, Tricia M. McKeever, Caroline Trotter, Wei Shen Lim
There is debate regarding the value of vaccinating adults with the 13-valent pneumococcal conjugate vaccine (PCV-13). This analysis was conducted to investigate the risk of PCV-13 serotype community acquired pneumonia (CAP) in hospitalised adults with co-morbid disease and risk factors for pneumococcal disease in the UK.Consecutive adults hospitalised (2008–2013) with a primary diagnosis of CAP, were recruited. Pneumococcal aetiology disease was identified by use of pneumococcal urinary antigen detection and serotype identification using a validated multiplex immunoassay or serum latex agglutination. Adults with PCV-13 serotype CAP were compared to those with non-PCV-13 serotype CAP.Of 2224 patients, PCV-13 serotype CAP was identified in 337 (15.2%) and non-PCV-13 serotype CAP in 250 (11.2%) individuals. Adults aged ≥65 years with one or more clinical risk factors had a significantly lower risk of PCV-13 serotype CAP compared to those aged 16–64 years without clinical risk factors (aOR 0.61, 95%CI 0.41–0.92, p = .018). In a stacked-risk analysis, the presence of incremental clinical risk factors was associated with lower odds of PCV-13 disease (p for trend = .029) Adults with underlying chronic respiratory disease (aOR) 0.56, 95% CI 0.36–0.85, p = .007) and chronic kidney disease (aOR 0.48, 95% CI 0.25–0.92, p = .028) had significantly lower adjusted odds of PCV-13 compared to non-PCV-13 serotype CAP.This analysis suggests that in the UK, the burden of PCV13 disease is greater in adults outside the traditional 'at-risk' groups compared to adults in 'at-risk' groups.



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Incidence and epidemiology of intussusception among children under 2 years of age in Chenzhou and Kaifeng, China, 2009–2013

Publication date: Available online 10 February 2018
Source:Vaccine
Author(s): Na Liu, Catherine Yen, Tao Huang, Pengwei Cui, Jacqueline E. Tate, Baoming Jiang, Umesh D. Parashar, Zhao-jun Duan
IntroductionIn China, rotavirus is the leading cause of diarrhea hospitalizations among children aged <5 years. A locally manufactured rotavirus vaccine is available for private market use, but little is known about its coverage. Given the impending availability of newer rotavirus vaccines, we evaluated intussusception rates among children aged <2 years to better understand intussusception epidemiology for future vaccine safety monitoring.MethodsWe conducted a retrospective review at 4 hospitals in Chenzhou City of Hunan Province and Kaifeng City of Henan Province. We identified intussusception cases admitted during 2009–2013 by reviewing medical records with the ICD-10 discharge code for intussusception and extracting demographic and clinical information from the electronic clinical record systems.ResultsDuring 2009–2013, 1715 intussusception hospitalizations among 1,487,215 children aged <2 years occurred in both cities. The average annual intussusception hospitalization incidence was 112.9 per 100,000 children aged <2 years (181.8 per 100,000 children <1 year; 56 per 100,000 children 1 to <2 years). Intussusception incidence was low among infants aged <3 months and peaked at age 6–8 months. No clear seasonality was observed. Ultrasound was used to diagnose 95.9% of cases. Enema reduction was performed in 80% cases; 25% of cases in Chenzhou and 16% in Kaifeng required surgical intervention. No deaths were reported. The median time between symptom onset and admission was 1 day.ConclusionsThis study provides information on intussusception incidence and epidemiology in two cities of China during 2009–2013. Monitoring intussusception rates in this population will be important in the post-rotavirus vaccine era.



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Examination of the twinning activity in additively manufactured Ti-6Al-4V

Publication date: 15 April 2018
Source:Materials & Design, Volume 144
Author(s): H.Z. Zhong, X.Y. Zhang, S.X. Wang, J.F. Gu
This present paper investigates the dominant twinning mode and secondary twin via transmission electron microscopy at different positions of additively manufactured (AM) Ti-6Al-4V deposition wall fabricated by laser metal deposition (LMD). {10−11} 〈−1012〉 twinning system is observed as the dominant twinning mode. Secondary twins, including the inserting secondary twin and neighboring secondary twin, are characterized at position with sufficient thermal cycle history. These twinning morphologies can be rationalized to some degree from the standpoint of the twinning effect and thermal condition in additive manufacturing. This work gets insight into the twinning evolution in additively manufactured Ti alloys.

Graphical abstract

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A systematic investigation of cycle number, temperature and electric field strength effects on Si anode

Publication date: 15 April 2018
Source:Materials & Design, Volume 144
Author(s): Qihong Fang, Qiong Wang, Jia Li, Eenze Chen, Bin Liu, Pihua Wen
Cycling number, crystal orientation, temperature and electric field strength play key roles in affecting the capacity and cycling ability of Li-ion battery. However, the detailed dynamic and continuous process of capacity decline mechanism from above factors need to be further understood at nanoscale. Herein, we report deformation behavior and microstructure evolution of Si anode under electric field using molecular dynamics simulations. The results show larger cycling number and electric field strength cause larger volume expansion of Si electrode, leading to the capacity loss and the reducing cycling ability as well as the decreasing structural stability. The phase transformation from diamond cubic structure to body-centred tetragonal structure and the amorphous formation depend on lithiated and delithiated depths. The crystal orientation [100] Si anode produces the volume expansion owing to a large number of nanoscale void. The various temperatures strongly affect the number and radius of nanovoid. The associated transition in the nanovoid nucleation due to the involuntary diffusion process is driven by larger cycling number or electric field strength, resulting in the irreversible capacity loss of Li-ion battery. An established analytical model suggests that diffusion-induced stress not only relies on the position of Si anode but depends upon the cycling time.

Graphical abstract

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3D printing of Fe-based bulk metallic glass composites with combined high strength and fracture toughness

Publication date: 5 April 2018
Source:Materials & Design, Volume 143
Author(s): Ning Li, Jianji Zhang, Wei Xing, Di Ouyang, Lin Liu
Additive manufacturing is a promising technique for the production of bulk metallic glass (BMG) components without size limitations. However, the current additive manufacturing technique encounters the challenge of micro-cracking induced by huge thermal stress during the process, which significantly degrades the mechanical performance of the components. Based on systematic experiments combined with finite element simulation, we revealed that micro-cracks in inherently brittle Fe-based metallic glass during selective laser melting (SLM) are triggered by highly concentrated thermal stress around micro-pores, which is difficult to avoid during SLM even by careful process optimization. To suppress these micro-cracks, Cu and Cu-Ni alloys with high toughness as second phases were introduced to form BMG composites. The results revealed that the generation of high-density dislocations in second phases during SLM drastically reduce thermal stress by releasing strain energy and thus suppress micro-crack formation. Further investigation has shown that the introduction the second phase improves the fracture toughness of Fe-based BMGs to 47MPam^1/2, which is approximately 20 times higher than that of the Fe-based BMG (2.2MPam^1/2). Our findings provide general guidelines for the SLM fabrication of bulk metallic glass composites with tunable mechanical performances, as well as large sizes and freeform geometries.

Graphical abstract

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Three-dimensional imaging assessment of anatomic invasion and volumetric considerations for chemo/radiotherapy-based laryngeal preservation in T3 larynx cancer

Publication date: April 2018
Source:Oral Oncology, Volume 79
Author(s): Mona Kamal, Sweet Ping Ng, Salman A. Eraj, Crosby D. Rock, Brian Pham, Jay A. Messer, Adam S. Garden, William H. Morrison, Jack Phan, Steven J. Frank, Adel K. El-Naggar, Jason M. Johnson, Lawrence E. Ginsberg, Renata Ferrarotto, Jan S. Lewin, Katherine A. Hutcheson, Carlos E. Cardenas, Mark E. Zafereo, Stephen Y. Lai, Amy C. Hessel, Randal S. Weber, G. Brandon Gunn, Clifton D. Fuller, Abdallah S.R. Mohamed, David I. Rosenthal
ObjectivesTo investigate the impact of 3-Diminsional (3D) tumor volume (TV) and extent of involvement of primary tumor on treatment outcomes in a large uniform cohort of T3 laryngeal carcinoma patients treated with nonsurgical laryngeal preservation strategies.Materials and MethodsThe pretreatment contrast-enhanced computed tomography images of 90 patients with T3 laryngeal carcinoma were reviewed. Primary gross tumor volume (GTVp) was delineated to calculate the 3D TV and define the extent of invasion. Cartilage and soft tissue involvement was coded. The extent of invasion was dichotomized into non/limited invasion versus multiple invasion extension (MIE), and was subsequently correlated with survival outcomes.ResultsThe median TV was 6.6 cm³. Sixty-five patients had non/limited invasion, and 25 had MIE. Median follow-up for surviving patients was 52 months. The 5-year local control and overall survival rates for the whole cohort were 88% and 68%, respectively. There was no correlation between TV and survival outcomes. However, patients with non/limited invasion had better 5-year local control (LC) than those with MIE (95% vs 72%, p = .009) but did not have a significantly higher rate of overall survival (OS) (74% vs 67%, p = .327). In multivariate correlates of LC, MIE maintained statistical significance whereas baseline airway status showed a statistically significance trend with poor LC (p = .0087 and 0.06, respectively). Baseline good performance status was an independent predictor of improved OS (p = .03) in multivariate analysis.ConclusionThe extent of primary tumor invasion is an independent prognostic factor of LC of the disease after definitive radiotherapy in T3 larynx cancer.



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Dual-responsive polyplexes with enhanced disassembly and endosomal escape for efficient delivery of siRNA

Publication date: April 2018
Source:Biomaterials, Volume 162
Author(s): Jia Zhu, Mingxi Qiao, Qi Wang, Yuqing Ye, Shuang Ba, Jingjing Ma, Haiyang Hu, Xiuli Zhao, Dawei Chen
Despite the extracellular barriers for siRNA delivery have been overcome by utilizing advanced nanoparticle delivery systems, the key intracellular barriers after internalization including efficient disassembly of siRNA and endosomal escape still remains challenging. To address the issues, we developed a unique pH- and redox potential-responsive polyplex delivery system based on the copolymer of mPEG-b-PLA-PHis-ssPEI1.8 k, which is composed of a pH-responsive copolymer of PEG-b-PLA-PHis (Mw 5 k) and a branched PEI (Mw1.8 k) linked with redox cleavable disulfide bond. The copolymer showed excellent siRNA complexation and protection abilities against endogenous substances at the relatively low N/P ratio of 6. The siRNA release from the polyplexes (N/P 6) was markedly increased from 13.62% to 58.67% under conditions simulating the endosomal microenvironment. Fluorescence resonance energy transfer (FRET) test also indicated a higher disassembly extent of siRNA from the copolymer. The accelerated siRNA release from the polyplexes was markedly restrained when the N/P ratio was raised above 10 due to the increasing of electrostatic interactions. The efficient endosomal escape of siRNA after internalization was confirmed by confocal microscopy, which was attributed to the cleavaged PEI chains inducing membrane destabilization, the "proton sponge effect" of PHis and PEI as well as the relative small size of after disassembly. The enhanced disassembly and endosomal escape were elucidated as the leading cause for polyplexes (N/P 6) showed more efficient Bcl-2 silencing (85.45%) than those polyplexes with higher N/P ratios (N/P 10 and 15). In vivo results further demonstrated that polyplexes (N/P 6) delivery of siBcl-2 significantly inhibited the MCF-7 breast tumor growth as compared to its counterparts. The incorporation of convertible non-electrical interactions at a balance with electrostatic interactions in complexation siRNA has been demonstrated as an effective strategy to achieve efficient disassembly from stable polyplexes. Moreover, polyplexes equipped with the enhanced disassembly and endosomal escape provides a new potential way to tackle the intracellular delivery bottleneck for siRNA delivery.



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Gradient nano-engineered in situ forming composite hydrogel for osteochondral regeneration

Publication date: April 2018
Source:Biomaterials, Volume 162
Author(s): Janani Radhakrishnan, Amrutha Manigandan, Prabu Chinnaswamy, Anuradha Subramanian, Swaminathan Sethuraman
Fabrication of anisotropic osteochondral-mimetic scaffold with mineralized subchondral zone and gradient interface remains challenging. We have developed an injectable semi-interpenetrating network hydrogel construct with chondroitin sulfate nanoparticles (ChS-NPs) and nanohydroxyapatite (nHA) (∼30–90 nm) in chondral and subchondral hydrogel zones respectively. Mineralized subchondral hydrogel exhibited significantly higher osteoblast proliferation and alkaline phosphatase activity (p < 0.05). Osteochondral hydrogel exhibited interconnected porous structure and spatial variation with gradient interface of nHA and ChS–NPs. Microcomputed tomography (μCT) demonstrated nHA gradation while rheology showed predominant elastic modulus (∼930 Pa) at the interface. Co–culture of osteoblasts and chondrocytes in gradient hydrogels showed layer–specific retention of cells and cell-cell interaction at the interface. In vivo osteochondral regeneration by biphasic (nHA or ChS) and gradient (nHA + ChS) hydrogels was compared with control using rabbit osteochondral defect after 3 and 8 weeks. Complete closure of defect was observed in gradient (8 weeks) while defect remained in other groups. Histology demonstrated collagen and glycosaminoglycan deposition in neo–matrix and presence of hyaline cartilage–characteristic matrix, chondrocytes and osteoblasts. μCT showed mineralized neo–tissue formation, which was confined within the defect with higher bone mineral density in gradient (chondral: 0.42 ± 0.07 g/cc, osteal: 0.64 ± 0.08 g/cc) group. Further, biomechanical push-out studies showed significantly higher load for gradient group (378 ± 56 N) compared to others. Thus, the developed nano-engineered gradient hydrogel enhanced hyaline cartilage regeneration with subchondral bone formation and lateral host-tissue integration.



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Glucose & oxygen exhausting liposomes for combined cancer starvation and hypoxia-activated therapy

Publication date: April 2018
Source:Biomaterials, Volume 162
Author(s): Rui Zhang, Liangzhu Feng, Ziliang Dong, Li Wang, Chao Liang, Jiawen Chen, Qingxi Ma, Rui Zhang, Qian Chen, Yucai Wang, Zhuang Liu
Starvation therapy to slow down the tumor growth by cutting off its energy supply has been proposed to be an alternative therapeutic strategy for cancer treatment. Herein, glucose oxidase (GOx) is loaded into stealth liposomes and act as the glucose and oxygen elimination agent to trigger the conversion of glucose and oxygen into gluconic acid and H2O2. Such liposome-GOx after intravenous injection with effective tumor retention is able to exhaust glucose and oxygen within the tumor, producing cytotoxic H2O2 and enhancing hypoxia, as vividly visualized by non-invasive in vivo photoacoustic imaging. By further combination treatment with stealth liposomes loaded with banoxantrone dihydrochloride (AQ4N), a hypoxia-activated pro-drug, a synergistically enhanced tumor growth inhibition effect is achieved in the mouse model of 4T1 tumor. Hence, by combining starvation therapy and hypoxia-activated therapy tactfully utilizing liposomal nanocarriers to co-deliver both enzymes and prodrugs, an innovative strategy is presented in this study for effective cancer treatment.



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Influence of heading perception in the control of posture

Publication date: Available online 10 February 2018
Source:Journal of Electromyography and Kinesiology
Author(s): Alessandro Piras, Milena Raffi, Monica Perazzolo, Salvatore Squatrito
The optic flow visual input directly influences the postural control. The aim of the present study was to examine the relationship between visually induced heading perception and postural stability, using optic flow stimulation. The dots were accelerated to simulate a heading direction to the left or to the right of the vertical midline. The participants were instructed to indicate the perceived optic flow direction by making a saccade to the simulated heading direction. We simultaneously acquired electromyographyc and center of pressure (COP) signals. We analysed the postural sway during three different epochs: i) the first 500 ms after the stimulus onset, ii) 500 ms before saccade onset, epoch in which the perception is achieved and, iii) 500 ms after saccade onset. Participants exhibited a greater postural instability before the saccade, when the perception of heading was achieved, and the sway increased further after the saccade. These results indicate that the conscious representation of the self-motion affects the neural control of posture more than the mere visual motion, producing more instability when visual signals are contrasting with eye movements. It could be that part of these effects are due to the interactions between gaze shift and optic flow.



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Axillary motor nerve conduction study: description of technique and provision of normative data

Publication date: Available online 10 February 2018
Source:Journal of Electromyography and Kinesiology
Author(s): Panagiotis Zis, Marios Hadjivassiliou, Dasappaiah Ganesh Rao
BackgroundAxillary nerve lesions can commonly occur secondary to trauma or brachial plexopathy. Our aim was to describe our technique of axillary nerve motor conduction studies and provide the respective normal values.MethodsActive electrode was positioned over the most prominent portion of the middle deltoid, approximately 5-7cm distal to the acromion. Reference electrode was positioned over the acromion. Ground electrode was placed between the active and the reference electrodes. Supramaximal stimulation was at the Erb's point.ResultsA total of 154 participants (61% male, age range 18-84) were included. There was a significant positive correlation between the subjects' age and the onset latency Spearman's rho 0.312, p<0.001) and a significant negative correlation between the participants' age and the CMAP (Spearman's rho -0.481, p<0.001).For the total male population the lower normal value for the CMAP was 7.6mV and the higher normal value for the onset latency was 5.0msec. For the total female population the respective normal values were 6.5mV and 3.5msec.In order to detect an axillary nerve lesion, asymmetry of >40% in the CMAPS between the symptomatic and the asymptomatic side show a sensitivity of 95.2% and a specificity of 96.6%.ConclusionWe described our technique of axillary nerve motor conduction studies and provided the respective normal values stratified for age and gender. When suspecting an axillary nerve lesion it is always worth performing axillary motor NCS bilaterally and compare the CMAPs.



http://ift.tt/2Eh3v21

A dual tracer ratio method for comparative emission measurements in an experimental dairy housing

Publication date: April 2018
Source:Atmospheric Environment, Volume 179
Author(s): Joachim Mohn, Kerstin Zeyer, Margret Keck, Markus Keller, Michael Zähner, Jernej Poteko, Lukas Emmenegger, Sabine Schrade
Agriculture, and in particular dairy farming, is an important source of ammonia (NH3) and non-carbon dioxide greenhouse gas (GHG) emissions. This calls for the development and quantification of effective mitigation strategies. Our study presents the implementation of a dual tracer ratio method in a novel experimental dairy housing with two identical, but spatially separated housing areas. Modular design and flexible floor elements allow the assessment of structural, process engineering and organisational abatement measures at practical scale. Thereby, the emission reduction potential of specific abatement measures can be quantified in relation to a reference system. Emissions in the naturally ventilated housing are determined by continuous dosing of two artificial tracers (sulphur hexafluoride SF6, trifluoromethylsulphur pentafluoride SF5CF3) and their real-time detection in the ppt range with an optimized GC-ECD method. The two tracers are dosed into different experimental sections, which enables the independent assessment of both housing areas. Mass flow emissions of NH3 and GHGs are quantified by areal dosing of tracer gases and multipoint sampling as well as real-time analysis of both tracer and target gases. Validation experiments demonstrate that the technique is suitable for both areal and point emission sources and achieves an uncertainty of less than 10% for the mass emissions of NH3, methane (CH4) and carbon dioxide (CO2), which is superior to other currently available methods. Comparative emission measurements in this experimental dairy housing will provide reliable, currently unavailable information on emissions for Swiss dairy farming and demonstrate the reduction potential of mitigation measures for NH3, GHGs and potentially other pollutants.

Graphical abstract

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Summertime diurnal variations in the isotopic composition of atmospheric nitrogen dioxide at a small midwestern United States city

Publication date: April 2018
Source:Atmospheric Environment, Volume 179
Author(s): Wendell W. Walters, Huan Fang, Greg Michalski
The nitrogen and oxygen stable isotopes (δ¹⁵N & δ¹⁸O) of nitrogen oxides (NOx = nitric oxide (NO) + nitrogen dioxide (NO2)) may be a useful tool for partitioning NOx emission sources and for evaluating NOx photochemical cycling, but few measurements of in situ NOx exist. In this study, we have collected and characterized the diurnal variability in δ¹⁵N and δ¹⁸O of NO2 from ambient air at a small Midwestern city (West Lafayette, IN, USA, 40.426° N, 86.908° W) between July 7 to August 5, 2016, using an active sampling technique. Large variations were observed in both δ¹⁵N(NO2) and δ¹⁸O(NO2) that ranged from −31.4 to 0.4‰ and 41.5–112.5‰, respectively. Daytime averages were −9.2 ± 5.7‰ (x̅ ± 1σ) and 86.5 ± 14.1‰ (n = 11), while nighttime averages were −13.4 ± 7.3‰ and 56.3 ± 7.1‰ (n = 12) for δ¹⁵N(NO2) and δ¹⁸O(NO2), respectively. The large variability observed in δ¹⁵N(NO2) is predicted to be driven by changing contributions of local NOx emission sources, as calculated isotope effects predict a minor impact on δ¹⁵N(NO2) relative to δ¹⁵N(NOx) that is generally less than 2.5‰ under the sample collection conditions of high ozone concentration ([O3]) relative to [NOx]. A statistical δ¹⁵N mass-balance model suggests that traffic-derived NOx is the main contributor to the sampling site (0.52 ± 0.22) with higher relative contribution during the daytime (0.58 ± 0.19) likely due to higher traffic volume than during the nighttime (0.47 ± 0.22). The diurnal cycle observed in δ¹⁸O(NO2) is hypothesized to be a result of the photochemical cycling of NOx that elevates δ¹⁸O(NO2) during the daytime relative to the nighttime. Overall, this data suggests the potential to use δ¹⁵N(NO2) for NOx source partitioning under environmental conditions of high [O3] relative to [NOx] and δ¹⁸O(NO2) for evaluating VOC-NOx-O3 chemistry.



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Michelangelo Buonarroti (1475–1564) had the deconditioning syndrome while painting the Sistine Chapel ceiling

Publication date: April 2018
Source:Medical Hypotheses, Volume 113
Author(s): R. Bianucci, D. Lippi, A. Perciaccante, P. Charlier, O. Appenzeller




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Vitamin D3 signaling and breast cancer: Insights from transgenic mouse models

Publication date: Available online 10 February 2018
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Lei Sheng, David F. Callen, Andrew G. Turner
The biologically active form of vitamin D3 (1,25(OH)2D) regulates epithelial cell differentiation, proliferation, and apoptosis, lending weight to clinical evidence linking vitamin D3 insufficiency to breast cancer incidence and mortality. Local dysregulation of vitamin D3metabolism has been identified in patients with breast cancer, implying that disruption of 1,25(OH)2D signaling may contribute to breast cancer development in an autocrine or paracrine manner. Mouse mammary glands express the critical enzymes responsible for 1,25(OH)2D synthesis (Cyp2r1 and Cyp27b1), degradation (Cyp24a1), as well as the vitamin D3 receptor (Vdr), and genetically modified mouse models have revealed a great deal about the role of vitamin D3 in cancer initiation and progression. Ablation of Vdr or Cyp27b1 in murine models of mammary cancer reduces the anti-tumor effects of vitamin D3, while elevation of Cyp24a1 levels increases degradation of 1,25(OH)2D, leading to diminished anti-tumor effects. This review discusses the recent transgenic mouse models of vitamin D3 metabolism and the Vdr signaling network, and how these contribute to mammary gland development, and cancer tumorigenesis and progression. Collectively, these mouse models have helped clarify mechanisms of action of the vitamin D3 signaling and suggest that activation or restoration of the vitamin D3 regulated pathway is a potential approach for human breast cancer prevention.



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Discovery and Development of ODM-204: A Novel Nonsteroidal Compound for the Treatment of Castration-Resistant Prostate Cancer by blocking the Androgen Receptor and Inhibiting CYP17A1

Publication date: Available online 10 February 2018
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Riikka Oksala, Anu Moilanen, Reetta Riikonen, Petteri Rummakko, Arja Karjalainen, Mikko Passiniemi, Gerd Wohlfahrt, Päivi Taavitsainen, Chira Malmström, Meri Ramela, Hanna-Maija Metsänkylä, Riikka Huhtaniemi, Pekka J. Kallio, Mika VJ. Mustonen
We report the discovery of a novel nonsteroidal dual-action compound, ODM-204, that holds promise for treating patients with castration-resistant prostate cancer (CRPC), an advanced form of prostate cancer characterised by high androgen receptor (AR) expression and persistent activation of the AR signaling axis by residual tissue androgens. For ODM-204, has a dual mechanism of action. The compound is anticipated to efficiently dampen androgenic stimuli in the body by inhibiting CYP17A1, the prerequisite enzyme for the formation of dihydrotestosterone (DHT) and testosterone (T), and by blocking AR with high affinity and specificity. In our study, ODM-204 inhibited the proliferation of androgen-dependent VCaP and LNCaP cells in vitro and reduced significantly tumour growth in a murine VCaP xenograft model in vivo. Intriguingly, after a single oral dose of 10-30 mg/kg, ODM-204 dose-dependently inhibited adrenal and testicular steroid production in sexually mature male cynomolgus monkeys. Similar results were obtained in human chorionic gonadotropin-treated male rats. In rats, leuprolide acetate-mediated (LHRH agonist) suppression of the circulating testosterone levels and decrease in weights of androgen-sensitive organs was significantly and dose-dependently potentiated by the co-administration of ODM-204. ODM-204 was well tolerated in both rodents and primates. Based on our data, ODM-204 could provide an effective therapeutic option for men with CRPC.



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Food insecurity, diet quality and body mass index of women participating in the Supplemental Nutrition Assistance Program: The role of intrapersonal, home environment, community and social factors

Publication date: 1 June 2018
Source:Appetite, Volume 125
Author(s): Namrata Sanjeevi, Jeanne Freeland-Graves, Matthew Hersh
Obesity is a public health problem that disproportionately affects low-income populations. Moreover, participation in Supplemental Nutrition Assistance Program (SNAP) has been associated with obesity among low-income women. The goal of this study was to determine the impact of intrapersonal, home environment, community and social factors on diet quality and body mass index (BMI) of low-income women participating in SNAP. This study also aimed to examine the role of these factors in mediating the relationship between food insecurity and diet quality, and BMI. A total of 152 women receiving SNAP benefits were recruited from low-income neighborhood centers and housing communities, and administered a demographics questionnaire, the United States adult food security scale, food frequency questionnaire, and multi-dimensional home environment scale (MHES). They also were measured for height and weight to calculate BMI. The Dietary Guidelines Adherence Index 2015 was used to measure diet quality. Regression analyses were conducted to determine the MHES subscales that were significant predictors of diet quality and BMI. The Preacher and Hayes mediation model was used to evaluate the mediation of the relationship between food insecurity and diet quality, and BMI by the MHES. Emotional eating resistance and favorable social eating behaviors were positively associated with diet quality; whereas emotional eating resistance, lower availability of unhealthy food at home, neighborhood safety and favorable social eating behaviors were inversely associated with BMI in women participating in SNAP. The MHES significantly mediated the relationship between food insecurity and BMI. These results emphasize the importance of intrapersonal, home environment, community and social factors in mediating the relationship between food insecurity and BMI in low-income women.



http://ift.tt/2G4BHKy

The buffer effect of body compassion on the association between shame and body and eating difficulties

Publication date: 1 June 2018
Source:Appetite, Volume 125
Author(s): Sara Oliveira, Inês A. Trindade, Cláudia Ferreira
Body compassion is a new construct which incorporates two multidimensional concepts: body image and self-compassion. Self-compassion has been revealed as a protective mechanism against body image and eating-related-related disturbances, including eating disorders. However, the study of this compassionate competence specifically focused on the domain of the body is still largely unexplored.This study aims to test whether body compassion moderate the impact of external shame on body image shame and disordered eating, in a sample of 354 women from the Portuguese general population.Correlation analyses showed that body compassion was negatively associated with experiences of shame and disordered eating. Path analysis results demonstrated the existence of a moderator effect of body compassion on the relationship between general feelings of shame and both body image shame and related behaviours, and disordered eating symptomatology. In fact, results suggested that body compassion buffered the impact of general feelings of shame on these psychopathological indices, with the tested model accounting for 46% and 39% of the variance of body image shame and disordered eating, respectively.This study contributes to a better understanding of the role of body compassion in body image and eating difficulties. Body compassion seems to be an important protector of these difficulties in women by buffering the effects of general shame on body image shame and related body concealment behaviours, as well as disordered eating. The findings from this study thus appear to offer important research and clinical implications, supporting the relevance of promoting body compassion in prevention and treatment programs for body image difficulties and disordered eating.



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Effects of sewage sludge modified by coal gasification slag and electron beam irradiation on the growth of Alhagi sparsifolia Shap. and transfer of heavy metals

Abstract

A greenhouse experiment was performed to investigate the feasibility of sewage sludge modified by coal gasification slag pretreatment and electron beam irradiation in soil application for cultivation of Alhagi sparsifolia Shap. The results showed that modified sewage sludge had an active effect on the growth of Alhagi sparsifolia Shap. The sandy soil and modified sludge at the volume ratio of 2:1 were optimal, and the growth potential of Alhagi sparsifolia Shap. was highest. In the sandy soil, the values of bioconcentration factor of most heavy metals were below 1.0 except for Zn and Cu. The average bioconcentration factor values of heavy metals in Alhagi sparsifolia Shap. decreased in a sequence of Zn>Cu>Ni> Mn>Co>Pb>Cr>Fe>V>Cd>Mo for all treatments. Alhagi sparsifolia Shap. could decrease the eco-toxicity and bioavailability of Ni, Fe, and Mo in all mixed soil, and Alhagi sparsifolia Shap. could reduce the eco-toxicity and bioavailability of all heavy metals discussed in this study (except for Mn) in the mixed soil of SS:MSS = 2:1.

http://ift.tt/2ExnetH

Role of residence time on the transformation of Zn, Cu, Pb and Cd attached to road dust in different land uses

Publication date: 30 May 2018
Source:Ecotoxicology and Environmental Safety, Volume 153
Author(s): Ayomi Jayarathne, Prasanna Egodawatta, Godwin A. Ayoko, Ashantha Goonetilleke
The adsorption behaviour of metals deposited on road surfaces undergo changes during dry weather periods, with the bioavailability varying compared to the original species, prior to incorporation in stormwater runoff. This study investigated the role of antecedent dry days on the transformation characteristics of Zn, Cu, Pb and Cd attached to different geochemical forms of road dust, in order to predict potential stormwater quality impacts. The study outcomes showed that the exchangeable fraction generally decreased with the increase in antecedent dry days, but the reducible, oxidisable and residual fractions increased. This implies that there is a time-dependent transformation of weakly bound metals in road dust to more persistent chemical forms. The transformation rate of metals was found to be in the order of Pb > Cu > Zn > Cd. Significant changes in metal distribution among the geochemical fractions were observed up to seven dry days, suggesting that during the initial antecedent dry days, the transformations can be relatively more significant. Among the analysed metals, Cd present on road surfaces has a higher potential for being bioavailable during the antecedent dry days.

Graphical abstract

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Signaling pathways regulating pituitary functions

Publication date: 5 March 2018
Source:Molecular and Cellular Endocrinology, Volume 463
Author(s): Stanko S. Stojilkovic




http://ift.tt/2G0t04b

Editorial Board

Publication date: 5 March 2018
Source:Molecular and Cellular Endocrinology, Volume 463





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Low CD25 on autoreactive Tregs impairs tolerance via low dose IL-2 and antigen delivery

Publication date: Available online 10 February 2018
Source:Journal of Autoimmunity
Author(s): Chie Hotta-Iwamura, Charles Benck, William D. Coley, Yi Liu, Yongge Zhao, Juan A. Quiel, Kristin V. Tarbell
Dendritic cell (DC)-mediated T cell tolerance deficiencies contribute to the pathogenesis of autoimmune diseases such as type 1 diabetes. Delivering self-antigen to dendritic-cell inhibitory receptor-2 (DCIR2)⁺ DCs can delay but not completely block diabetes development in NOD mice. These DCIR2-targeting antibodies induce tolerance via deletion and anergy, but do not increase islet-specific Tregs. Because low-dose IL-2 (LD-IL-2) administration can preferentially expand Tregs, we tested whether delivering islet-antigen to tolerogenic DCIR2⁺ DCs along with LD-IL-2 would boost islet-specific Tregs and further block autoimmunity. But, surprisingly, adding LD-IL-2 did not increase efficacy of DC-targeted antigen to inhibit diabetes. Here we show the effects of LD-IL-2, with or without antigen delivery to DCIR2⁺ DCs, on both polyclonal and autoreactive Treg and conventional T cells (Tconv). As expected, LD-IL-2 increased total Tregs, but autoreactive Tregs required both antigen and IL-2 stimulation for optimal expansion. Also, islet-specific Tregs had lower CD25 expression and IL-2 sensitivity, while islet-specific Tconv had higher CD25 expression, compared to polyclonal populations. LD-IL-2 increased activation and expansion of Tconv, and was more pronounced for autoreactive cells after treatment with IL-2 + islet-antigen. Therefore, LD-IL-2 therapy, especially when combined with antigen stimulation, may not optimally activate and expand antigen-specific Tregs in chronic autoimmune settings.



http://ift.tt/2EevtLM

Inhibition of non-homologous end joining in Fanconi Anemia cells results in rescue of survival after interstrand crosslinks but sensitization to replication associated double-strand breaks

Publication date: Available online 10 February 2018
Source:DNA Repair
Author(s): Laura J. Eccles, Andrew C. Bell, Simon N. Powell
When Fanconi Anemia (FA) proteins were depleted in human U2OS cells with integrated DNA repair reporters, we observed decreases in homologous recombination (HR), decreases in mutagenic non-homologous end joining (m-NHEJ) and increases in canonical NHEJ, which was independently confirmed by measuring V(D)J recombination. Furthermore, depletion of FA proteins resulted in reduced HR protein foci and increased NHEJ protein recruitment to replication-associated DSBs, consistent with our observation that the use of canonical NHEJ increases after depletion of FA proteins in cycling cells. FA-depleted cells and FA-mutant cells were exquisitely sensitive to a DNA-PKcs inhibitor (DNA-PKi) after sustaining replication-associated double strand breaks (DSBs). By contrast, after DNA interstrand crosslinks, DNA-PKi resulted in increased survival in FA-deficient cells, implying that NHEJ is contributing to lethality after crosslink repair. Our results suggest FA proteins inhibit NHEJ, since repair intermediates from crosslinks are rendered lethal by NHEJ. The implication is that bone marrow failure in FA could be triggered by naturally occurring DNA crosslinks, and DNA-PK inhibitors would be protective. Since some sporadic cancers have been shown to have deficiencies in the FA-pathway, these tumors should be vulnerable to NHEJ inhibitors with replication stress, but not with crosslinking agents, which could be tested in future clinical trials.



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

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print


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Ectopic impulse generation in peripheral nerve hyperexcitability syndromes and amyotrophic lateral sclerosis

Publication date: Available online 10 February 2018
Source:Clinical Neurophysiology
Author(s): Yu-ichi Noto, Neil G. Simon, Alexis Selby, Nidhi Garg, Kazumoto Shibuya, Nortina Shahrizaila, William Huynh, José M. Matamala, Thanuja Dharmadasa, Susanna B. Park, Steve Vucic, Matthew C. Kiernan
ObjectiveTo elucidate differences in the distribution and firing frequency of fasciculations between peripheral nerve hyperexcitability syndromes and amyotrophic lateral sclerosis (ALS) and to explore the generator site of fasciculations.MethodsUltrasound of 14 preselected muscles was performed in patients with peripheral hyperexcitability and ALS. The distribution and firing frequency of fasciculations were calculated. Cortical excitability assessment was also done by threshold tracking transcranial magnetic stimulation.ResultsIn total, 518 muscles from 37 peripheral hyperexcitability patients and 756 muscles from 54 ALS patients were examined. Regarding the detection rate, 74% of muscles in ALS patients demonstrated fasciculations, compared with 34% of muscles in peripheral hyperexcitability patients (P <0.001). The number of unique repeating focal muscle fasciculation movements per muscle and firing frequency of individual fasciculations in ALS were both significantly higher than those in peripheral hyperexcitability (P <0.001). Furthermore, cortical silent period duration negatively correlated with the number and firing frequency of fasciculations in ALS (P <0.05). A similar relationship was not evident in peripheral hyperexcitability.ConclusionsALS patients exhibited a widespread distribution of fasciculations, whereas peripheral hyperexcitability patients had a lower limb-dominant pattern.SignificanceA significant proportion of fasciculations in ALS may be influenced by changes in central excitability.



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Reply to “10-10 Electrode System for EEG Recording”

Publication date: Available online 10 February 2018
Source:Clinical Neurophysiology
Author(s): Margitta Seeck, Thomas Bast, Frans Leijten, Bin He, Sándor Beniczky




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Vastus lateralis motor unit firing rate is higher in females with patellofemoral pain

Publication date: Available online 10 February 2018
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Alessio Gallina, Michael A. Hunt, Paul Hodges, S. Jayne Garland
ObjectiveTo compare neural drive, determined from motor unit firing rate, to the vastus medialis and lateralis in females with and without patellofemoral pain.DesignCross-sectional study.SettingUniversity research laboratory.ParticipantsFemales (N=56) 19-35 years old, 36 with patellofemoral pain and 20 controls. Interventions: Not applicable.Main Outcome Measure(s)Participants sustained an isometric knee extension contraction at 10% of their maximal voluntary effort for 70s. Motor units (N=414) were identified using high-density surface electromyography. Average firing rate was calculated between 5 and 35s after recruitment for each motor unit. Initial firing rate was the inverse of the first three motor unit inter-spike intervals.ResultsIn control participants, vastus medialis motor units discharged at higher rates than vastus lateralis (p=0.001). This was not observed in females with patellofemoral pain (p=0.78) due to a higher discharge rate of vastus lateralis compared to control participants (p=0.002). No between-group differences were observed for vastus medialis (p=0.93). Similar results were obtained for the initial motor unit firing rate.ConclusionsThese findings suggest that females with patellofemoral pain have a higher neural drive to vastus lateralis but not vastus medialis, which may be a contributor of the altered patellar kinematics observed in some studies. The different neural drive may be an adaptation to patellofemoral pain, possibly to compensate for decreased quadriceps force production, or a precursor of patellofemoral pain.



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The clinical assessment of spasticity in people with spinal cord damage: recommendations from the Ability Network, an international initiative

Publication date: Available online 10 February 2018
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Anand V. Nene, Alexandre Rainha Campos, Klemen Grabljevec, Arminda Lopes, Bengt Skoog, Anthony S. Burns
A thorough assessment of the extent and severity of spasticity, and its impact on functioning, is central to the effective management of spasticity in persons with spinal cord damage (SCD). These individuals, however, do not always receive adequate assessment of their spasticity. Inadequate assessment compromises management when the impact of spasticity and/or need for intervention are not fully recognized. Assessment is also central to determining treatment efficacy. A barrier to spasticity assessment has been the lack of consensus on clinical and functional measures suitable for routine clinical practice. To extend upon existing work, a working group of the Ability Network identified and consolidated information on possible measures, then synthesized and formulated findings into practical recommendations for assessing spasticity and its impact on function in persons with SCD. Sixteen clinical and functional measures that have been used for this purpose were identified using a targeted literature review. These were mapped to the relevant domains of the International Classification of Functioning, Disability and Health (ICF) to assess the breadth of their coverage; coverage of many domains was found to be lacking, suggesting a focus for future work. The advantages, disadvantages and usefulness of the measures were assessed using a range of criteria, with a focus on usefulness and feasibility in routine clinical practice. Based on this evaluation, a selection of measures suitable for initial and follow-up assessments are recommended. The recommendations are intended to have broad applicability to a variety of healthcare settings where people with SCD are managed.



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Screening for Abdominal Aortic Aneurysm During Transthoracic Echocardiography: A Systematic Review and Meta-analysis

Publication date: Available online 9 February 2018
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Christos Argyriou, George S. Georgiadis, Nikolaos Kontopodis, Arun D. Pherwani, Joost A. Van Herwaarden, Constantijn E.V.B. Hazenberg, George A. Antoniou
BackgroundScreening for abdominal aortic aneurysm (AAA) during transthoracic echocardiography (TTE) may be an effective targeted screening strategy.ObjectiveThe aim was to assess the feasibility of AAA screening during TTE and to estimate the prevalence of AAA in patients undergoing TTE.MethodsElectronic bibliographic sources were interrogated using a combination of free text and controlled vocabulary searches to identify studies reporting on AAA screening during TTE. The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement standards. Fixed effect or random effects models were used to calculate pooled prevalence estimates.ResultsTwenty observational cohort studies were identified reporting a total of 43,341 participants (23,291 men and 20,050 women). Hypertension was reported in 41% (95% CI 38–43), hypercholesterolemia in 31% (95% CI 29–32), diabetes mellitus in 20% (95% CI 19–22), and tobacco use in 37% (95% CI 35–38). The aorta was visualised in 86% (95% CI 84–88) of the screened population. The pooled prevalence of AAA in the entire screened population was 0.033 (95% CI 0.024–0.044). The pooled prevalence of AAA in men was 0.046 (95% CI 0.032–0.065) and in women it was 0.014 (95% CI 0.008–0.022). The mean age of participants in whom an AAA was detected ranged across the studies from 66 to 85 years. The mean diameter of the aneurysm identified ranged across the studies from 35 mm to 45 mm. Clinical outcomes in participants with a detected AAA were poorly reported.ConclusionsScreening for AAA during TTE may identify a population group with a high risk of AAA in whom targeted screening may be beneficial. Further research is required to investigate the cost-effectiveness and clinical benefits of AAA screening in this setting.



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The Marburg-Münster Affective Disorders Cohort Study (MACS): A quality assurance protocol for MR neuroimaging data

Publication date: 15 May 2018
Source:NeuroImage, Volume 172
Author(s): Christoph Vogelbacher, Thomas W.D. Möbius, Jens Sommer, Verena Schuster, Udo Dannlowski, Tilo Kircher, Astrid Dempfle, Andreas Jansen, Miriam H.A. Bopp
Large, longitudinal, multi-center MR neuroimaging studies require comprehensive quality assurance (QA) protocols for assessing the general quality of the compiled data, indicating potential malfunctions in the scanning equipment, and evaluating inter-site differences that need to be accounted for in subsequent analyses.We describe the implementation of a QA protocol for functional magnet resonance imaging (fMRI) data based on the regular measurement of an MRI phantom and an extensive variety of currently published QA statistics. The protocol is implemented in the MACS (Marburg-Münster Affective Disorders Cohort Study, http://for2107.de/), a two-center research consortium studying the neurobiological foundations of affective disorders. Between February 2015 and October 2016, 1214 phantom measurements have been acquired using a standard fMRI protocol. Using 444 healthy control subjects which have been measured between 2014 and 2016 in the cohort, we investigate the extent of between-site differences in contrast to the dependence on subject-specific covariates (age and sex) for structural MRI, fMRI, and diffusion tensor imaging (DTI) data.We show that most of the presented QA statistics differ severely not only between the two scanners used for the cohort but also between experimental settings (e.g. hardware and software changes), demonstrate that some of these statistics depend on external variables (e.g. time of day, temperature), highlight their strong dependence on proper handling of the MRI phantom, and show how the use of a phantom holder may balance this dependence. Site effects, however, do not only exist for the phantom data, but also for human MRI data. Using T1-weighted structural images, we show that total intracranial (TIV), grey matter (GMV), and white matter (WMV) volumes significantly differ between the MR scanners, showing large effect sizes. Voxel-based morphometry (VBM) analyses show that these structural differences observed between scanners are most pronounced in the bilateral basal ganglia, thalamus, and posterior regions. Using DTI data, we also show that fractional anisotropy (FA) differs between sites in almost all regions assessed. When pooling data from multiple centers, our data show that it is a necessity to account not only for inter-site differences but also for hardware and software changes of the scanning equipment. Also, the strong dependence of the QA statistics on the reliable placement of the MRI phantom shows that the use of a phantom holder is recommended to reduce the variance of the QA statistics and thus to increase the probability of detecting potential scanner malfunctions.



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Triple representation of language, working memory, social and emotion processing in the cerebellum: convergent evidence from task and seed-based resting-state fMRI analyses in a single large cohort

Publication date: 15 May 2018
Source:NeuroImage, Volume 172
Author(s): Xavier Guell, John D.E. Gabrieli, Jeremy D. Schmahmann
Delineation of functional topography is critical to the evolving understanding of the cerebellum's role in a wide range of nervous system functions. We used data from the Human Connectome Project (n = 787) to analyze cerebellar fMRI task activation (motor, working memory, language, social and emotion processing) and resting-state functional connectivity calculated from cerebral cortical seeds corresponding to the peak Cohen's d of each task contrast. The combination of exceptional statistical power, activation from both motor and multiple non-motor tasks in the same participants, and convergent resting-state networks in the same participants revealed novel aspects of the functional topography of the human cerebellum. Consistent with prior studies there were two distinct representations of motor activation. Newly revealed were three distinct representations each for working memory, language, social, and emotional task processing that were largely separate for these four cognitive and affective domains. In most cases, the task-based activations and the corresponding resting-network correlations were congruent in identifying the two motor representations and the three non-motor representations that were unique to working memory, language, social cognition, and emotion. The definitive localization and characterization of distinct triple representations for cognition and emotion task processing in the cerebellum opens up new basic science questions as to why there are triple representations (what different functions are enabled by the different representations?) and new clinical questions (what are the differing consequences of lesions to the different representations?).



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Alter spontaneous activity in amygdala and vmPFC during fear consolidation following 24 h sleep deprivation

Publication date: 15 May 2018
Source:NeuroImage, Volume 172
Author(s): Pan Feng, Benjamin Becker, Tingyong Feng, Yong Zheng
Sleep deprivation (SD) has been associated with cognitive and emotional disruptions, however its impact on the acquisition of fear and subsequent fear memory consolidation remain unknown. To address this question, we measured human brain activity before and after fear acquisition under conditions of 24 h sleep deprivation versus normal sleep using resting-state functional magnetic resonance imaging (rs-fMRI). Additionally, we explored whether the fear acquisition-induced change of brain activity during the fear memory consolidation window can be predicted by subjective fear ratings and autonomic fear response, assessed by skin conductance responses (SCR) during acquisition. Behaviorally, the SD group demonstrated increased subjective and autonomic fear responses compared to controls at the stage of fear acquisition. During the stage of fear consolidation, the SD group displayed decreased ventromedial prefrontal cortex (vmPFC) activity and concomitantly increased amygdala activity. Moreover, in the SD group fear acquisition-induced brain activity changes in amygdala were positively correlated with both, subjective and autonomic fear indices during acquisition, whereas in controls changes vmPFC activity were positively correlated with fear indices during acquisition. Together, the present findings suggested that SD may weaken the top-down ability of the vmPFC to regulate amygdala activity during fear memory consolidation. Moreover, subjective and objective fear at fear acquisition stage can predict the change of brain activity in amygdala in fear memory consolidation following SD.



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Probing biological activity through structural modelling of ligand-receptor interactions of 2,4-disubstituted thiazole retinoids

Publication date: Available online 10 February 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Hesham Haffez, David R. Chisholm, Natalie J. Tatum, Roy Valentine, Christopher Redfern, Ehmke Pohl, Andrew Whiting, Stefan Przyborski
Retinoids, such as all-trans-retinoic acid (ATRA), regulate cellular differentiation and signalling pathways in chordates by binding to nuclear retinoic acid receptors (RARα/β/γ). Polar interactions between receptor and ligand are important for binding and facilitating the non-polar interactions and conformational changes necessary for RAR-mediated transcriptional regulation. The constraints on activity and RAR-type specificity with respect to the structural link between the polar and non-polar functions of synthetic retinoids are poorly understood. To address this, predictions from in silico ligand-RAR docking calculations and molecular dynamics simulations for a small library of stable, synthetic retinoids (designated GZ series) containing a central thiazole linker structure and different hydrophobic region substituents, were tested using a ligand binding assay and a range of cellular biological assays. The docking analysis showed that these thiazole-containing retinoids were well suited to the binding pocket of RARα, particularly via a favorable hydrogen bonding interaction between the thiazole and Ser232 of RARα. A bulky hydrophobic region (i.e., present in compounds GZ23 and GZ25) was important for interaction with the RAR binding pockets. Ligand binding assays generally reflected the findings from in silico docking, and showed that GZ25 was a particularly strongly binding ligand for RARα/β. GZ25 also exhibited higher activity as an inducer of neuronal differentiation than ATRA and other GZ derivatives. These data demonstrate that GZ25 is a stable synthetic retinoid with improved activity which efficiently regulates neuronal differentiation and help to define the key structural requirements for retinoid activity enabling the design and development of the next generation of more active, selective synthetic retinoids as potential therapeutic regulators of neurogenesis.

Graphical abstract

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Design and synthesis of estrogen receptor ligands with a 4-heterocycle-4-phenylheptane skeleton

Publication date: Available online 9 February 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Ryo Eto, Takashi Misawa, Tomomi Noguchi-Yachide, Nobumichi Ohoka, Masaaki Kurihara, Mikihiko Naito, Masakazu Tanaka, Yosuke Demizu
The estrogen receptor (ER), a member of the nuclear receptor (NR) family, is involved in the regulation of physiological effects such as reproduction and bone homeostasis. Approximately 70% of human breast cancers are hormone-dependent and ERα-positive, and, thus, ER antagonists are broadly used in breast cancer therapy. We herein designed and synthesized a set of ER antagonists with a 4-heterocycle-4-phenylheptane skeleton.

Graphical abstract

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Design and Synthesis of 1-(1-Benzothiophen-7-yl)-1H-Pyrazole, a Novel Series of G Protein-coupled Receptor 52 (GPR52) Agonists

Publication date: Available online 10 February 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Takashi Nakahata, Kazuyuki Tokumaru, Yoshiteru Ito, Naoki Ishii, Masaki Setoh, Yuji Shimizu, Toshiya Harasawa, Kazunobu Aoyama, Teruki Hamada, Masakuni Kori, Kazuyoshi Aso
G-protein-coupled receptor 52 (GPR52) is classified as an orphan Gs-coupled G-protein-coupled receptor. GPR52 cancels dopamine D2 receptor signaling and activates dopamine D1/N-methyl-D-aspartate receptors via intracellular cAMP accumulation. Therefore, GPR52 agonists are expected to alleviate symptoms of psychotic disorders. A novel series of 1-(benzothiophen-7-yl)-1H-pyrazole as GPR52 agonists was designed and synthesized based on compound 1b. Compound 1b has been reported by our group as the first orally active GPR52 agonist, but high lipophilicity and poor aqueous solubility still remained as issues for candidate selection. To resolve these issues, replacement of the benzene ring at the 7-positon of compound 1b with heterocylic rings, such as pyrazole and pyridine, was greatly expected to reduce lipophilicity to levels for which calculated logD values were lower than that of compound 1b. While evaluating the pyrazole derivatives, introduction of a methyl substituent at the 3-position of the pyrazole ring led to increased GPR52 agonistic activity. Moreover, additional methyl substituent at the 5-position of the pyrazole and further introduction of hydroxy group to lower logD led to significant improvement of solubility while maintaining the activity. As a result, we identified 3-methyl-5-hydroxymethyl-1H-pyrazole derivative 17 (GPR52 EC50 = 21 nM, Emax = 103%, logD = 2.21, Solubility at pH 6.8 = 21 μg/mL) with potent GPR52 agonistic activity and good solubility compared to compound 1b. Furthermore, this compound 17 dose-dependently suppressed methamphetamine-induced hyperlocomotion in mice.

Graphical abstract

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Suspended particulate matter determines physical speciation of Fe, Mn , and trace metals in surface waters of Loire watershed

Abstract

This study investigates the spatiotemporal variability of major and trace elements, dissolved organic carbon (DOC), total dissolved solids (TDS), and suspended particulate matter (SPM) in surface waters of several hydrosystems of the Loire River watershed in France. In particular, this study aims to delineate the impact of the abovementioned water physicochemical parameters on natural iron and manganese physical speciation (homoaggregation/heteroaggregation) among fine colloidal and dissolved (< 10 nm), colloidal (10–450 nm) and particulate (> 450 nm) phases in Loire River watershed. Results show that the chemistry of the Loire River watershed is controlled by two end members: magmatic and metamorphic petrographic context on the upper part of the watershed; and sedimentary rocks for the middle and low part of the Loire. The percentage of particulate Fe and Mn increased downstream concurrent with the increase in SPM and major cations concentration, whereas the percentage of colloidal Fe and Mn decreased downstream. Transmission electron microscopy analyses of the colloidal and particulate fractions (from the non-filtered water sample) revealed that heteroaggregation of Fe and Mn rich natural nanoparticles and natural organic matter to the particulate phase is the dominant mechanism. The heteroaggregation controls the partitioning of Fe and Mn in the different fractions, potentially due to the increase in the ionic strength, and divalent cations concentration downstream, and SPM concentration. These findings imply that SPM concentration plays an important role in controlling the fate and behavior of Fe and Mn in various sized fractions.

Graphical abstract

Physical speciation by heteroaggregation of (Fe-Mn) compounds: high [SPM] → [Fe-Mn] particulate faction; low {SPM] → [Fe-Mn] colloid-dissolved fraction.

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Use of meta-analyses and joint analyses to select variants in whole genome sequences for genomic evaluation: An application in milk production of French dairy cattle breeds

Publication date: Available online 7 February 2018
Source:Journal of Dairy Science
Author(s): M. Teissier, M.P. Sanchez, M. Boussaha, A. Barbat, C. Hoze, C. Robert-Granie, P. Croiseau
As a result of the 1000 Bull Genome Project, it has become possible to impute millions of variants, with many of these potentially causative for traits of interest, for thousands of animals that have been genotyped with medium-density chips. This enormous source of data opens up very interesting possibilities for the inclusion of these variants in genomic evaluations. However, for computational reasons, it is not possible to include all variants in genomic evaluation procedures. One potential approach could be to select the most relevant variants based on the results of genome-wide association studies (GWAS); however, the identification of causative mutations is still difficult with this method, partly because of weak imputation accuracy for rare variants. To address this problem, this study assesses the ability of different approaches based on multi-breed GWAS (joint and meta-analyses) to identify single-nucleotide polymorphisms (SNP) for use in genomic evaluation in the 3 main French dairy cattle breeds. A total of 6,262 Holstein bulls, 2,434 Montbéliarde bulls, and 2,175 Normande bulls with daughter yield deviations for 5 milk production traits were imputed for 27 million variants. Within-breed and joint (including all 3 breeds) GWAS were performed and 3 models of meta-analysis were tested: fixed effect, random effect, and Z-score. Comparison of the results of within- and multi-breed GWAS showed that most of the quantitative trait loci identified using within-breed approaches were also found with multi-breed methods. However, the most significant variants identified in each region differed depending on the method used. To determine which approach highlighted the most predictive SNP for each trait, we used a marker-assisted best unbiased linear prediction model to evaluate lists of SNP generated by the different GWAS methods; each list contained between 25 and 2,000 candidate variants per trait, which were identified using a single within- or multi-breed GWAS approach. Among all the multi-breed methods tested in this study, variant selection based on meta-analysis (fixed effect) resulted in the most-accurate genomic evaluation (+1 to +3 points compared with other multi-breed approaches). However, the accuracies of genomic evaluation were always better when variants were selected using the results of within-breed GWAS. As has generally been found in studies of quantitative trait loci, these results suggest that part of the genetic variance of milk production traits is breed specific in Holstein, Montbéliarde, and Normande cattle.



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An Overview of the Emerging Interface Between Cardiac Metabolism, Redox Biology and the Circadian Clock

Publication date: Available online 10 February 2018
Source:Free Radical Biology and Medicine
Author(s): Rodrigo A. Peliciari-Garcia, Victor Darley-Usmar, Martin E. Young
At various biological levels, mammals must integrate with 24-hr rhythms in their environment. Daily fluctuations in stimuli/stressors of cardiac metabolism and oxidation-reduction (redox) status have been reported over the course of the day. It is therefore not surprising that the heart exhibits dramatic oscillations in various cellular processes over the course of the day, including transcription, translation, ion homeostasis, metabolism, and redox signaling. This temporal partitioning of cardiac processes is governed by a complex interplay between intracellular (e.g., circadian clocks) and extracellular (e.g., neurohumoral factors) influences, thus ensuring appropriate responses to daily stimuli/stresses. The purpose of the current article is to review knowledge regarding control of metabolism and redox biology in the heart over the course of the day, and to highlight whether disruption of these daily rhythms contribute towards cardiac dysfunction observed in various disease states.

Graphical abstract

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Mitochondrial protein S-nitrosation protects against ischemia reperfusion-induced denervation at neuromuscular junction in skeletal muscle

Publication date: Available online 9 February 2018
Source:Free Radical Biology and Medicine
Author(s): Rebecca J. Wilson, Joshua C. Drake, Di Cui, Bevan M. Lewellen, Carleigh C. Fisher, Mei Zhang, David F. Kashatus, Lisa A. Palmer, Michael P. Murphy, Zhen Yan
Deterioration of neuromuscular junction (NMJ) integrity and function is causal to muscle atrophy and frailty, ultimately hindering quality of life and increasing the risk of death. In particular, NMJ is vulnerable to ischemia reperfusion (IR) injury when blood flow is restricted followed by restoration. However, little is known about the underlying mechanism(s) and hence the lack of effective interventions. New evidence suggests that mitochondrial oxidative stress plays a causal role in IR injury, which can be precluded by enhancing mitochondrial protein S-nitrosation (SNO). To elucidate the role of IR and mitochondrial protein SNO in skeletal muscle, we utilized a clinically relevant model and showed that IR resulted in significant muscle and motor nerve injuries with evidence of elevated muscle creatine kinase in the serum, denervation at NMJ, myofiber degeneration and regeneration, as well as muscle atrophy. Interestingly, we observed that neuromuscular transmission improved prior to muscle recovery, suggesting the importance of the motor nerve in muscle functional recovery. Injection of a mitochondria-targeted S-nitrosation enhancing agent, MitoSNO, into ischemic muscle prior to reperfusion reduced mitochondrial oxidative stress in the motor nerve and NMJ, attenuated denervation at NMJ, and resulted in accelerated functional recovery of the muscle. These findings demonstrate that enhancing mitochondrial protein SNO protects against IR-induced denervation at NMJ in skeletal muscle and accelerates functional regeneration. This could be an efficacious intervention for protecting neuromuscular injury under the condition of IR and other related pathological conditions.

Graphical abstract

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Health risk assessment of drinking arsenic-containing groundwater in Hasilpur, Pakistan: effect of sampling area, depth, and source

Abstract

Currently, several news channels and research publications have highlighted the dilemma of arsenic (As)-contaminated groundwater in Pakistan. However, there is lack of data regarding groundwater As content of various areas in Pakistan. The present study evaluated As contamination and associated health risks in previously unexplored groundwater of Hasilpur-Pakistan. Total of 61 groundwater samples were collected from different areas (rural and urban), sources (electric pump, hand pump, and tubewell) and depths (35–430 ft or 11–131 m). The water samples were analyzed for As level and other parameters such as pH, electrical conductivity, total dissolved solids, cations, and anions. It was found that 41% (25 out of 61) water samples contained As (≥ 5 μg/L). Out of 25 As-contaminated water samples, 13 water samples exceeded the permissible level of WHO (10 μg/L). High As contents have been found in tubewell samples and at high sampling depths (> 300 ft). The major As-contaminated groundwater in Hasilpur is found in urban areas. Furthermore, health risk and cancer risk due to As contamination were also assessed with respect to average daily dose (ADD), hazard quotient (HQ), and carcinogenic risk (CR). The values of HQ and CR of As in Hasilpur were up to 58 and 0.00231, respectively. Multivariate analysis revealed a positive correlation between groundwater As contents, pH, and depth in Hasilpur. The current study proposed the proper monitoring and management of well water in Hasilpur to minimize the As-associated health hazards.

http://ift.tt/2BQxCM9

Glucosensing capacity of rainbow trout telencephalon

Abstract

To assess the hypothesis of glucosensing systems present in fish telencephalon, we first demonstrated in rainbow trout by in situ hybridization the presence of glucokinase (GK). Then, we assessed the response of glucosensing markers in rainbow trout telencephalon 6h after ICV treatment with glucose or 2-deoxyglucose (inducing glucoprivation). We evaluated the response of parameters related to the mechanisms dependent on GK, liver X receptor (LXR), mitochondrial activity, sweet taste receptor, and sodium-glucose linked transporter 1 (SGLT-1). We also assessed mRNA abundance of neuropeptides involved in the metabolic control of food intake (NPY, AgRP, POMC, and CART) as well as abundance and phosphorylation status of proteins possibly involved in linking glucosensing with neuropeptide expression such as Akt, AMPK, mTOR, and CREB. The responses obtained support the presence in telencephalon of a glucosensing mechanism based on GK and maybe one based on LXR, but do not support the presence of mechanisms dependent on mitochondrial activity and SGLT-1. The mechanism based on sweet taste receptor responded to glucose, but in a converse way to that characterized previously in hypothalamus. In general, systems responded only to glucose, but not to glucoprivation. Neuropeptides did not respond to glucose or glucoprivation. In contrast, the presence of glucose activates Akt and inhibits AMPK, CREB, and FoxO1. This is the first study in any vertebrate species in which the response to glucose of putative glucosensing mechanisms is demonstrated in telencephalon. Their role might relate to processes other than homeostatic control of food intake such as the hedonic and reward system.

This article is protected by copyright. All rights reserved.

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Hepatic heterogeneity and attenuation on contrast-enhanced CT in patients with the hypovolemic shock complex: Objective classification using a contemporary cohort

Publication date: Available online 10 February 2018
Source:Current Problems in Diagnostic Radiology
Author(s): Benjamin Wildman-Tobriner, Michael S. Enslow, Rendon C. Nelson
ObjectiveWhen objectively measured on computed tomography (CT), does either hepatic heterogeneity or overall liver attenuation predict the presence of shock?MethodsThis retrospective study included 73 patients (mean age 33 years) with the hypoperfusion shock complex (HSC) on CT (cases) and 100 patients (mean age 43 years) with negative trauma CT scans (controls). Liver heterogeneity was calculated by using consistently sized regions of interest (ROIs) to measure the 2 highest and 2 lowest areas of hepatic density (in Hounsfield units [HU]). The difference between the means of the 2 highest and 2 lowest ROIs was considered the heterogeneity. Attenuation was calculated using the mean of 3 randomly placed ROIs. Both heterogeneity and attenuation were then compared between cases and controls.ResultsMedian hepatic heterogeneity was 16.8 HU (IQR 10.7–23.4) for the HSC group and 9.0 HU (IQR 7.0–10.4) for the controls (p<0.001). The area under the curve was 0.79, and a threshold of 30 HU yielded a specificity of 100%. Median hepatic attenuation was not significantly different between the HSC and control groups, with an area under the curve of 0.56.ConclusionsIncreased hepatic heterogeneity may represent an objective marker of the HSC that performs similarly to other established signs. By comparison, overall hepatic hypoattenuation is a poor indicator of the HSC.



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A case of a primary hepatic so-called adenosarcoma with heterotopic ossification: possibly of biliary adenofibroma origin

Publication date: March 2018
Source:Human Pathology, Volume 73
Author(s): Shiori Meguro, Satoru Yamazaki, Sayomi Matsushima, Kazuhito Kawata, Hideya Kawasaki, Takashi Tsuchida, Isao Kosugi, Yoshimasa Kobayashi, Satoshi Baba, Toshihide Iwashita
We present an autopsy case of a "so-called adenosarcoma with ossification of the liver" in a 63-year-old man. Macroscopically, the well-circumscribed tumor with portal vein invasion was observed in the right lobe of the liver. The cut surface of the tumor had a solid and microcystic appearance. Microscopically, the tumor was characterized by a benign epithelial component and a malignant mesenchymal component. We believe the presence of biliary adenofibroma–like areas and the von Meyenburg complexes suggests that the tumor is possibly associated with a biliary adenofibroma. In addition, the present tumor was unique in that it showed scattered heterotopic ossification. Immunohistochemical study showed that the mesenchymal atypical spindle cells had characteristics of undifferentiated mesenchymal cells. This is the first report of a primary hepatic so-called adenosarcoma.



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Expression of MDM2 and p16 in Angiomyolipoma

Publication date: Available online 10 February 2018
Source:Human Pathology
Author(s): Xiaoqi Lin, William B. Laskin, Xinyan Lu, Yaxia Zhang
Angiomyolipoma (AML) arises primarily from the kidney, but may grow into the retroperitoneal space mimicking a primary retroperitoneal tumor. Fine needle aspiration (FNA) and core needle biopsy (CNB) of AML, particularly the fat-predominant variant, may be difficult to distinguish from retroperitoneal well-differentiated liposarcoma (WDLS) or lipoma. Commonly used immunomarkers, MDM2 and p16, have proven useful in diagnosing WDLS and dedifferentiated liposarcoma (DDLS), while HMB45 and Melan-A are melanocyte-related markers characteristically expressed in AML. In this study, we investigated the utility of MDM2 and p16 along with HMB45 and Melan-A immunohistochemical analysis in distinguishing AML from WDL/DDLS or lipoma. Immunohistochemically, AMLs demonstrated focal MDM2 expression (40% of cases) and focal/diffuse expression of p16 (60%). AMLs marked focally or diffusely with HMB45 (76% of cases) and Melan-A (96%). These latter two immunomarkers were not expressed in any of the WDLS/DDLSs or lipomas tested. WDLS/DDLSs showed focal/diffuse expression of MDM2 (91% of cases) and p16 (97%). While focal expression of MDM2 and p16 was observed in14% and 67% of lipomas, respectively, no lipoma exhibited diffuse MDM2 positivity. In our hands, MDM2 expression by itself cannot exclude the diagnosis of AML or lipoma, and p16 alone is not helpful in separating AML and conventional lipoma from WDLS/DDLS. However, along with morphology, an immunohistochemical battery including HMB45, Melan-A, MDM2 and p16 are useful in distinguishing AML from WDLS/DDLS or lipoma. For equivocal cases, fluorescence in situ hybridization for MDM2 should be performed.



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Scholar : These new articles for Amyloid are available online

The online platform for Taylor & Francis Online content New for Amyloid and online now on Taylor & Francis Online: Original Article Monoclonal gammopathy of undetermined significance in systemic transthyretin amyloidosis (ATTR) Pooja Phull, Vaishali Sanchorawala, Lawreen H. Connors, Gheorghe Doros, Frederick L. Ruberg, John L. Berk & Shayna Sarosiek Pages: 1-6 | DOI: 10.1080/13506129.2018.1436048 To update which email alerts you receive, manage your alerts within the My Account area. Unsubscribe from new content alerts for this journal (both new issue and latest article notifications) with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.