From inflammation to sexual dysfunctions: a journey through diabetes, obesity, and metabolic syndrome

Abstract

Metabolic diseases are associated with chronic low-grade inflammation, which has been indicated as a potential mediator of endothelial dysfunction and cardiovascular disease. Visceral adiposity is thought to be the starting condition of the inflammatory state through the release of inflammatory cytokines, including TNF-alpha, CRP, and IL-6, which in turn promote endothelial dysfunction, endothelial expression of chemokines (IL-1) and adhesion molecules (ICAM-1, VCAM-1, and P-selectin), and the inhibition of anti-atherogenic factors (adiponectin). Obesity, metabolic diseases, and diabetes, all conditions characterized by abdominal fat, are well-recognized risk factors for sexual dysfunction in both sexes. Evidence from randomized-controlled trials supports the association between inflammatory milieau and erectile dysfunction in men suffering from metabolic diseases, whereas, in women, this has to be confirmed in further studies. A healthy lifestyle based on dietary pattern with high content of whole grain, fruit, nuts and seeds, and vegetables and low in sodium and saturated fatty acids plus regular physical activity may help to modulate the pro-inflammatory state associated with metabolic diseases and the related burden of sexual dysfunctions.

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Lymph node location is a risk factor for papillary thyroid cancer-related death

Abstract

Purpose

Papillary thyroid cancer (PTC) has good prognosis with a very low chance of mortality. The prognostic role of metastatic lymph node location was judged controversial and more recently (TNM VIII ed.) was considered to have no impact on the prognosis of older patients. The aim of the study was to evaluate the role of metastasized node location on PTC-related mortality.

Methods

PTC-related mortality was analysed in a consecutive retrospective series of 1653 PTC patients followed at our Thyroid Clinic (mean follow-up 5.9 years).

Results

Sixteen out of 1653 patients (0.96%) died because of PTC. Average age was 68 years at presentation and 74.7 at death. F/M ratio was 1:1. The death rate increased in relation to the lymph node status: 0.2% in N0, 0.3% in N1a and 3.0% in N1b.

Conclusions

The presence of lymph node metastases in the N1b compartment should be considered as a risk factor for distant metastatic spread and for cancer-related death and included in post-surgery evaluation.

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Sleep and gravity

Publication date: April 2018
Source:Medical Hypotheses, Volume 113
Author(s): Alain A. Gonfalone
What is known about sleep results from years of observation at the surface of the Earth. Since a few decade man has been able to reach space, escape from the earth attraction and spend days and nights in a weightless condition. Some major physiological changes have been observed during long stays and in particular the sleep duration in space is shorter than on ground.This paper reviews a novel hypothesis proposing that sleep is partly due to gravity. Gravity is a fundamental part of our environment, but is elusive and difficult to apprehend. At the same time, all creatures on Earth undergo cycles of activity and periods of rest (although not always sleep).Careful analysis of previous research on sleep, on Earth, in space and in water, shows that gravity differs in these three situations, and sleep also varies, at least in its duration.On Earth, Rapid Eye Movement (REM) sleep is conditioned by gravity; in space, astronauts have a shorter sleep duration and this is even more striking when a test subject is immersed in water for a week. In conclusion, sleep is partly due to gravity, which acts on our body and brain during the wake period.



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Editorial Board

Publication date: April 2018
Source:Medical Hypotheses, Volume 113





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Contrast-Enhanced Color-Coded Doppler Sonography in Moyamoya Disease: A Retrospective Study

Publication date: Available online 15 March 2018
Source:Ultrasound in Medicine & Biology
Author(s): Woo-Keun Seo, Chang-Woon Choi, Chi Kyung Kim, Kyungmi Oh
The purpose of this study was to validate the feasibility of contrast-enhanced transcranial Doppler sonography (CE-TCCD) in the diagnosis of Moyamoya disease (MMD). CE-TCCD data on patients with MMD were analyzed. The CE-TCCD data were classified qualitatively into four patterns by two independent investigators: normal vascular color Doppler signal (pattern 1), augmented color Doppler signal with identifiable vascular structure (pattern 2), confluent color Doppler signal filling more than two-thirds of the display frame without identifiable vascular structure (pattern 3) and confluent color Doppler signal filling full display (pattern 4). To investigate the validity, we compared the CE-TCCD data with traditional transcranial Doppler data and Suzuki grades on cerebral angiography. A total of 32 CE-TCCD studies from 16 MMD patients (male 37.5%, median age 48) were included in this study. The CE-TCCD findings were distributed across patterns 1 (n = 3), 2 (n = 12), 3 (n = 10) and 4 (n = 7) and were correlated with the Suzuki grades (p < 0.005) and hemodynamic parameters. Inter-rater reliability was promising (Cronbach α = 0.883). The CE-TCCD test provides distinctive patterns in MMD, according to their stage of progression. CE-TCCD patterns seem to be a reliable and valid means for the evaluation of MMD.



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Substantially reduced incidence of genital warts in women and men six years after HPV vaccine availability in Sweden

Publication date: 5 April 2018
Source:Vaccine, Volume 36, Issue 15
Author(s): Eva Herweijer, Alexander Ploner, Pär Sparén
BackgroundBetween 2007 and 2011, opportunistic HPV-vaccination was available in Sweden and partially subsidized to girls aged 13–17, reaching a ∼30% overall coverage.MethodsAll Swedish women/men aged 15–44 were followed between 2006 and 2012 for condyloma. Average annual percent changes (AAPCs) in incidence were estimated.ResultsSubstantial decreases were seen in women aged 15–24 from 2008-onwards (AACP-range: −8.5% to −18.5%); similar effects were seen for men aged 15–29 (AACP-range: −7.0% to −16.6%) from 2010-onwards.DiscussionDespite low population vaccination coverage in women and no coverage in men, similar condyloma incidence reductions were observed among men and women, with delays of >1 years in men.



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Seroprevalence of anti-polio antibodies in children from polio high risk area of Afghanistan: A cross sectional survey 2017

Publication date: 5 April 2018
Source:Vaccine, Volume 36, Issue 15
Author(s): Imtiaz Hussain, Ondrej Mach, Nasir A. Hamid, Zaid S. Bhatti, Deborah D. Moore, M. Steven Oberste, Shahid Khan, Hasan Khan, William C. Weldon, Roland W. Sutter, Zulfiqar A Bhutta, Sajid B. Soofi
BackgroundAfghanistan is one of the remaining wild-poliovirus (WPV) endemic countries. We conducted a seroprevalence survey of anti-poliovirus antibodies in Kandahar Province.MethodsChildren in two age groups (6–11 months and 36–48 months) visiting Mirwais hospital in Kandahar for minor ailments unrelated to polio were enrolled. After obtaining informed consent, we collected venous blood and conducted neutralization assay to detect poliovirus neutralizing antibodies.ResultsA total of 420 children were enrolled and 409/420 (97%) were analysed. Seroprevalence to poliovirus type 1 (PV1) was 97% and 100% in the younger and older age groups respectively; it was 71% and 91% for PV2; 93% and 98% for PV3. Age group (RR = 3.6, CI 95% = 2.2–5.6) and place of residence outside of Kandahar city (RR = 1.8, CI 95% = 1.2–2.6) were found to be significant risk factors for seronegativity.ConclusionsThe polio eradication program in Kandahar achieved high serological protection, especially against PV1 and PV3. Lower PV2 seroprevalence in the younger age group is a result of a withdrawal of live type 2 vaccine in 2016 and is expected. Ability to reach all children with poliovirus vaccines is a pre-requisite for achieving poliovirus eradication.



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African horse sickness virus (AHSV) with a deletion of 77 amino acids in NS3/NS3a protein is not virulent and a safe promising AHS Disabled Infectious Single Animal (DISA) vaccine platform

Publication date: 5 April 2018
Source:Vaccine, Volume 36, Issue 15
Author(s): Piet A. van Rijn, Mieke A. Maris-Veldhuis, Christiaan A. Potgieter, René G.P. van Gennip
African horse sickness virus (AHSV) is a virus species in the genus Orbivirus of the family Reoviridae. Currently, nine serotypes have been defined showing limited cross neutralization. AHSV is transmitted by species of Culicoides biting midges and causes African Horse Sickness (AHS) in equids with a mortality up to 95% in naïve domestic horses. AHS has become a serious threat for countries outside Africa, since endemic Culicoides species in moderate climates are competent vectors of closely related bluetongue virus. AHS outbreaks cause huge economic losses in developing countries. In the developed world, outbreaks will result in losses in the equestrian industry and will have an enormous emotional impact on owners of pet horses. Live-attenuated vaccine viruses (LAVs) have been developed, however, safety of these LAVs are questionable due to residual virulence, reversion to virulence, and risk on virulent variants by reassortment between LAVs or with field AHSV. Research aims vaccines with improved profiles. Reverse genetics has recently being developed for AHSV and has opened endless possibilities including development of AHS vaccine candidates, such as Disabled Infectious Single Animal (DISA) vaccine. Here, virulent AHSV5 was recovered and its high virulence was confirmed by experimental infection of ponies. 'Synthetically derived' virulent AHSV5 with an in-frame deletion of 77 amino acids codons in genome segment 10 encoding NS3/NS3a protein resulted in similar in vitro characteristics as published NS3/NS3a knockout mutants of LAV strain AHSV4LP. In contrast to its highly virulent ancestor virus, this deletion AHSV5 mutant (DISA5) was completely safe for ponies. Two vaccinations with DISA5 as well as two vaccinations with DISA vaccine based on LAV strain AHSV4LP showed protection against lethal homologous AHSV. More research is needed to further improve efficacy, to explore the AHS DISA vaccine platform for all nine serotypes, and to study the vaccine profile in more detail.



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A large-scale field randomized trial demonstrates safety and efficacy of the vaccine LetiFend® against canine leishmaniosis

Publication date: 5 April 2018
Source:Vaccine, Volume 36, Issue 15
Author(s): Javier Fernández Cotrina, Virginia Iniesta, Isabel Monroy, Victoria Baz, Christophe Hugnet, Francisco Marañon, Mercedes Fabra, Luis Carlos Gómez-Nieto, Carlos Alonso
Canine leishmaniosis is a zoonotic disease caused by Leishmania infantum. Extensive research is currently ongoing to develop safe and effective vaccines to protect from disease development. The European Commission has granted a marketing authorization for LetiFend®, a new vaccine containing recombinant Protein Q. The efficacy of LetiFend® vaccination in a large-scale dog population of both sexes, different breeds and ages in endemic areas is reported in this multicenter, randomized, double-blind, placebo-controlled field trial.Dogs (n = 549) living in France and Spain were randomly selected to receive a single subcutaneous dose of LetiFend® or placebo per year, and were naturally exposed to two L. infantum transmission seasons. Clinical examinations, blood and lymphoid organ sampling to evaluate serological, parasitological and disease status of the dogs were performed at different time points during the study.LetiFend® was very well tolerated and clearly reduced the incidence of clinical signs related to leishmaniosis. The number of confirmed cases of leishmaniosis was statistically significantly lower in the vaccine group. The number of dogs with parasites was close to be significantly reduced in the vaccine group (p = 0.0564). Re-vaccination of seropositive dogs demonstrated to be safe and not to worsen the course of the disease. The likelihood that a dog vaccinated with LetiFend® develops a confirmed case or clinical signs of leishmaniosis in areas with high pressure is, respectively, 5 and 9.8 time less than that for an unvaccinated dog. Thus, the overall efficacy of the LetiFend® vaccine in the prevention of confirmed cases of leishmaniosis in endemic areas with high disease pressure was shown to be 72%.In conclusion, this field trial demonstrates that LetiFend® is a novel, safe and effective vaccine for the active immunization of non-infected dogs from 6 months of age in reducing the risk of developing clinical leishmaniosis after natural infection with Leishmania infantum.



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Molecular characteristics of Streptococcus agalactiae in a mother-baby prospective cohort study: Implication for vaccine development and insights into vertical transmission

Publication date: 5 April 2018
Source:Vaccine, Volume 36, Issue 15
Author(s): Shunming Li, Guoming Wen, Xuelian Cao, Dan Guo, Zhenjiang Yao, Chuan'an Wu, Xiaohua Ye
BackgroundStreptococcus agalactiae (GBS) is a leading cause of neonatal sepsis and meningitis in many countries. This study aimed to determine the molecular characteristics of GBS colonized in mothers and their infants so as to provide implication for vaccine strategies and confirm vertical transmission.MethodsA prospective cohort study was conducted to recruit 1815 mother-neonate pairs. All GBS isolates from pregnant women and her infants were tested for serotypes, multilocus sequence types and virulence genes. The relationship between multiple molecular characteristics of GBS isolates was tested by the correspondence analysis, and the agreement between mother-neonate paired data in molecular characteristics was analyzed using Kappa tests.ResultsThe predominant serotypes were III, Ia and V, and the most prevalent sequence types (STs) were ST19, ST17, ST10, and ST12. All isolates carried at least one pilus island (PI). The most common combination of PIs was PI-2b alone, followed by PI-1+PI-2a and PI-2a alone, and the most prevalent alpha-like protein (alp) genes were rib, epsilon and alphaC. Moreover, a strong relationship was noted between STs, serotypes, alp genes and PIs, including ST17 associated with serotype-III/rib/PI-2b, ST19 with serotype-III/rib/PI-1+PI-2a, and ST485 with serotype-Ia/epsilon/PI-2b. The rate of GBS vertical transmission was 14.1%, and the kappa test revealed good agreement in multiple molecular characteristics among GBS-positive mother-neonate pairs. Notably, the switching of molecular characteristics was found during vertical transmission.ConclusionsOur findings underscore the value of monitoring multiple molecular characteristics so as to provide implication for multivalent strategies and gain insights into GBS vertical transmission and vertical characteristic switching.



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Editorial Board/Aims and Scope

Publication date: 5 April 2018
Source:Vaccine, Volume 36, Issue 15





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No effect of an additional early dose of measles vaccine on hospitalization or mortality in children: A randomized controlled trial

Publication date: 5 April 2018
Source:Vaccine, Volume 36, Issue 15
Author(s): Anja Schoeps, Eric Nebié, Ane Baerent Fisker, Ali Sié, Alphonse Zakane, Olaf Müller, Peter Aaby, Heiko Becher
BackgroundNon-specific effects (NSEs) of vaccines have increasingly gained attention in recent years. Recent studies suggest that live vaccines, such as measles vaccine (MV), have beneficial effects on health, while inactivated vaccines, such as the diphtheria-tetanus-pertussis (DTP) vaccine, may have harmful effects. If this is the case, it should improve child health to move MV closer to the last vaccination with DTP. The objective of this study was to investigate the NSEs of an additional early dose of MV on hospitalization or mortality.MethodsChildren were randomized to receive either the standard MV at 9 months (control) or an additional early dose of MV 4 weeks after the third dose of DTP-containing Pentavalent vaccine and the standard MV at 9 months (intervention). In this analysis of a secondary outcome in the trial, we investigated the effect of the intervention on a composite endpoint of over-night hospitalization with or without recovery, or death without previous hospitalization, in children between 4.5 and 36 months of age in the Nouna HDSS in Burkina Faso. We used Cox proportional hazards regression with repeated events and time since study enrolment as underlying time-scale.ResultsAmong 2258 children in the intervention and 2238 children in the control group we observed a total of 464 episodes of hospitalization or mortality. There was no difference between intervention and control group (HR = 1.00, 95% Confidence Interval (CI) 0.83–1.20). Results from the per-protocol and intention-to-treat analysis were similar. Although no significant, results suggest a possible beneficial effect of early MV in children that had not been exposed to an OPV campaign after enrolment (HR = 0.83, 95% CI 0.55–1.29).ConclusionsWe did not detect any effect of early MV on subsequent hospitalization or mortality. However, possible effects of early MV could have been obscured by NSEs of the frequent OPV campaigns.Registration: The trial was registered at ClinicalTrials.gov, NCT01644721



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Prevalence and genetic characteristics of 4CMenB and rLP2086 vaccine candidates among Neisseria meningitidis serogroup B strains, China

Publication date: 5 April 2018
Source:Vaccine, Volume 36, Issue 15
Author(s): Bingqing Zhu, Fenglin Shi, Aiyu Zhang, Xiaofang Sun, Zheng Xu, Li Xu, Yuan Gao, Jing Lv, Zhujun Shao
ObjectiveTo systematically investigate the prevalence and genetic characteristics of 4CMenB and rLP2086 vaccine candidates among Neisseria meningitidis serogroup B (NmB) in China.MethodsA total of 485 NmB strains isolated in 29 provinces of China between 1968 and 2016 were selected from the culture collection of the national reference laboratory according to the isolation year, location, and source. Multi-locus sequence typing (MLST) and porA gene sequencing were performed on all 485 study strains; PCR was used to detect the fHbp, nadA, and nhba gene of 432 strains; positive amplification products from the fHbp and nadA genes from all strains, as well as those of the nhba gene from 172 representative strains, were sequenced.ResultsMLST results showed that the predominant (putative) clonal complexes (CCs) of NmB isolates have changed over time in China. While strains that could not be assigned to existing (p)CCs were the biggest proportion, CC4821 was the most prevalent lineage (36.0%) since 2005. PCR and sequence analysis revealed that the 4CMenB and rLP2086 vaccine candidates were highly diverse. Respectively, 152 PorA genotypes and 83 VR2 sequences were identified with significant diversity within a single CC; the complete nadA gene was found in ten of 432 study strains; fHbp was present in most strains (422/432) with variant 2 predominating (82.9%) in both patient- and carrier- derived isolates; almost all strains harbored the nhba gene while sequences were diverse.ConclusionsWith regards to clonal lineages and vaccine candidate proteins, NmB isolates from China were generally diverse. Further studies should be performed to evaluate the cross-protection of present vaccines against Chinese NmB strains.



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Assessment of the safety of Bacillus Calmette-Guérin vaccine administered orally to badgers (Meles meles)

Publication date: 5 April 2018
Source:Vaccine, Volume 36, Issue 15
Author(s): Simon Perrett, Sandrine Lesellier, Fiona Rogers, Gareth A. Williams, Sonya Gowtage, Si Palmer, Deanna Dalley, Dipesh Davé, Ute Weyer, Emma Wood, Francisco J. Salguero, Alex Nunez, Nick Reed, Mark A. Chambers
European badgers (Meles meles) are a wildlife reservoir for Mycobacterium bovis (M. bovis) in parts of England, Wales and Ireland, constituting a potential source of tuberculosis (TB) infection for cattle. Vaccination of badgers against TB is one of the tools available for helping reduce the prevalence of bovine TB in badgers, made possible by the licensing in 2010 of Bacillus Calmette-Guérin (BCG) vaccine for intramuscular administration to badgers (BadgerBCG). However, practical limitations associated with administering an injected vaccine to wild animals make an oral, bait-delivered form of the vaccine highly desirable. Evaluation of the safety of oral BCG to badgers and the environment is a mandatory step on the road to licensing an oral vaccine. This study had the following objectives: (a) to determine whether adverse effects followed the oral administration of BCG vaccine to badgers; (b) to measure the quantity and frequency of BCG excreted in the faeces of vaccinated badgers; and (c) to assess whether there was evidence of the vaccine spreading to unvaccinated, 'sentinel' badgers sharing the same environment as vaccinated animals. We report here that the oral administration per badger of ≥6.4 × 10⁹ cfu BCG, followed 14 days later by a single oral dose of ≥6.4 × 10⁷ cfu BCG caused no adverse physical effects and did not affect the social behaviour and feeding habits of the vaccinated animals. BCG was cultured from the faeces of two of nine vaccinated animals (372 cfu/g and 996 cfu/g, respectively) approximately 48 h after the higher dose of BCG was administered and by one of the nine vaccinated animal (80 cfu/g) approximately 24 h after receiving the lower dose of BCG. We found no evidence for the transmission of BCG to unvaccinated, sentinel, badgers housed with the vaccinated animals despite the occasional excretion of BCG in faeces.



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Effectiveness of parental cocooning as a vaccination strategy to prevent pertussis infection in infants: A case-control study

Publication date: 5 April 2018
Source:Vaccine, Volume 36, Issue 15
Author(s): Stacey L. Rowe, Ee Laine Tay, Lucinda J. Franklin, Nicola Stephens, Robert S. Ware, Marlena C. Kaczmarek, Rosemary A. Lester, Stephen B. Lambert
BackgroundDuring a pertussis epidemic in 2009, the Department of Health, Victoria, Australia, implemented a cocoon program offering parents of new babies a funded-dose of pertussis-containing vaccine. We assessed vaccine effectiveness (VE) of the program in reducing pertussis infection in infants.MethodsUsing a matched case-control design, infants aged <12 months that were notified with pertussis between 1 January 2010 and 31 December 2011, and born during the time that the cocoon program was in place, were identified. Controls were matched by area of residence and date of birth. Telephone interviews we conducted to ascertain parents' vaccination status, and if vaccinated, timing of vaccination receipt relative to the birth of their baby. Odds ratios (ORs) were calculated for the association between vaccination and pertussis infection, with VE calculated as (1 – OR) × 100%.ResultsThe study recruited 215 cases and 240 controls (response rates 67% and 25% of eligible participants, respectively). Vaccination of both parents after delivery of the infant and ≥28 days prior to illness onset reduced pertussis infection by 77% (Vaccine Effectiveness [VE] = 77% (confidence interval [95% CI], 18–93%). After adjusting for maternal education, presence of a sibling within the household, and the infants' primary course vaccination status, the adjusted VE was 64% (95% CI, −58–92%).ConclusionsAlthough not reaching statistical significance, our results demonstrated that cocoon immunisation – where both parents are vaccinated in the post-partum period – may offer some protection again infant pertussis infection. Cocoon immunisation could be considered in circumstances where antenatal vaccination of the mother has not occurred.



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A safety and immunogenicity study of immunization with hVEGF26-104/RFASE in cynomolgus monkeys

Publication date: 5 April 2018
Source:Vaccine, Volume 36, Issue 15
Author(s): Madelon Q. Wentink, Henk M.W. Verheul, Arjan W. Griffioen, Kenneth A. Schafer, Susan McPherson, Richard J. Early, Hans J. van der Vliet, Tanja D. de Gruijl
IntroductionVascular endothelial growth factor (VEGF) is pivotal in tumor angiogenesis and therapies targeting the VEGF axis are widely used in the clinic for the treatment of cancer. We have developed a therapeutic vaccine targeting human (h)VEGF165. hVEGF26-104/RFASE is based on the truncated protein hVEGF26-104 as antigen formulated in an oil-in-water emulsion containing the sulpholipopolysaccharide RFASE as adjuvant. Here we describe the toxicity and immunogenicity of this therapeutic vaccine in cynomolgus monkeys.MethodsIn total 54 cynomolgus monkeys were used and divided in 7 groups. Groups 1–3 were control groups, either receiving PBS alone (group 1), RFASE alone (group 2) or hVEGF26-104 alone (group 3). Animals allocated to groups 4–7 received hVEGF26-104 together with RFASE, but with varying doses of the antigen or the adjuvant. All animals were immunized four times with 2-week intervals and safety and immunogenicity were monitored until 3 days after the final immunization.ResultsImmunization induced an RFASE adjuvant dependent acute phase response. High titers of antibodies against hVEGF26-104 and cross-reactive with hVEGF165, were found in monkey sera, 28 days after primer immunization. These antibodies were able to inhibit the binding of the monoclonal antibody bevacizumab with hVEGF165 in a competition ELISA. Moreover, the biological activity of hVEGF165 could be inhibited by the addition of immunized monkey serum in a VEGF specific bioassay. Importantly, no adverse events commonly observed with VEGF neutralization were observed throughout the study.ConclusionThese data show that hVEGF26-104/RFASE can be safely administered in cynomolgus monkeys, induces the desired immune response and therefore support the clinical development of this vaccine.



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Safety and immunogenicity of investigational recombinant botulinum vaccine, rBV A/B, in volunteers with pre-existing botulinum toxoid immunity

Publication date: 5 April 2018
Source:Vaccine, Volume 36, Issue 15
Author(s): Jessica M. Khouri, Ruth N. Motter, Stephen S. Arnon
ObjectivesWe undertook an open-label, uncontrolled study of investigational recombinant botulinum vaccine for botulinum neurotoxin (BoNT) serotypes A and B (rBV A/B) to assess its safety and immunogenicity in healthy volunteers who had been previously immunized with investigational pentavalent botulinum toxoid. Study participants who wished to do so could donate their hyperimmune plasma for production of Human Botulism Immune Globulin Intravenous (BIG-IV, BabyBIG®).Study designA single 0.5 ml (mL), 40-microgram intramuscular injection of rBV A/B was administered to study participants. Post-vaccination sera collected at approximately 2-week intervals were evaluated for anti-BoNT/A and anti-BoNT/B neutralizing antibody concentrations (NAC). Local and systemic treatment-emergent adverse events (TEAEs) were identified by clinical and laboratory monitoring for 12 weeks post-vaccination with a final telephone follow-up for additional safety assessment at 6 months. The primary endpoint for immunogenicity was a ≥4-fold rise in NAC in ≥50% of participants by Week 4 post-vaccination.ResultsAll 45 enrolled participants completed the study. Forty-two of 45 participants (93.3%) experienced at least one TEAE. Overall, 138 of 218 (63.3%) reported TEAEs were treatment-related, the majority of which were mild injection-site reactions. No serious or unexpected adverse events occurred. The study achieved its primary immunogenicity endpoint with 37/45 (82.2%) participants and 39/45 (86.7%) participants having a ≥4-fold rise in NAC to anti-BoNT/A and to anti-BoNT/B, respectively, by Week 4 post-vaccination.ConclusionA single 0.5 mL dose of rBV A/B was safe, well-tolerated and immunogenic in participants previously immunized with pentavalent botulinum toxoid. The tolerability and immunogenicity characteristics of rBV A/B vaccination of individuals with existing BoNT immunity support its potential future use to provide occupational protection to botulism laboratory workers. Almost all study participants donated hyperimmune plasma for production of BIG-IV.ClinicalTrials.gov registration number: NCT01701999.



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Characterization of the immune response elicited by the vaccinia virus L3 protein delivered as naked DNA

Publication date: 5 April 2018
Source:Vaccine, Volume 36, Issue 15
Author(s): Maite Ramírez, Saritza Santos, Osmarie Martínez, Ricardo Rodríguez, Eric Miranda, Willy D. Ramos-Perez, Miguel Otero
Poxviruses are complex dsDNA viruses with over 200 genes, many of them with unknown role in the stimulation of immune responses. Among these, the vaccinia virus (VACV) L3L ORF encodes an essential protein for the transcription of the VACV early genes. To the best of our knowledge, the immune response elicited by L3 has not been characterized. In this regard, our data describes a DNA L3-coding plasmid (pL3L) that stimulates both, humoral- and cell-mediated immune responses in a mouse model. Cell-mediated immune responses were measured by IFN-γ and IL-4 ELISPOT assays. We performed CD8⁺ cells depletion and flow cytometry analysis to account for the contribution of cytotoxic T lymphocytes in the IFN-γ production. Moreover, results from ELISPOT were confirmed by measuring the concentration of IL-4 and IFN-γ in supernatant of antigen-stimulated splenocytes by cytokine ELISA. Additionally, dominant antigenic regions of L3 protein were identified by epitope mapping analysis. Humoral immune responses were assessed by ELISA. Specifically, the production of total IgG, IgG1 (TH-2) and IgG2a (TH-1) were determined one week after the final immunization. Our ELISPOT data shows pL3L-immunized animals to produce significantly higher frequencies of IFN-γ Spot-Forming Cells (SFC) versus controls. IL-4 levels remained unchanged in all three groups, demonstrating the increase in antigen-specific IFN-γ releasing cells. Flow cytometry assay results showed that CD8⁺ T cells are a major contributor to the production of IFN-γ. Moreover, our formulation enhances the production of total IgG, predominantly IgG2a isotype. Immunization with pL3L promotes a robust cytotoxic immune response, crucial against viral pathogens. In addition, our vaccine candidate promotes an increase in IgG levels, especially IgG2a (TH-1 type). Our data encourages further studies of L3 as a novel antigen in vaccine development against poxviruses.



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Methylene blue internalization and photodynamic action against clinical and ATCC Pseudomonas aeruginosa and Staphyloccocus aureus strains

Publication date: June 2018
Source:Photodiagnosis and Photodynamic Therapy, Volume 22
Author(s): André Henrique Correia Pereira, Juliana Guerra Pinto, Mirian Aparecida Alves Freitas, Letícia Corrêa Fontana, Cristina Pacheco Soares, Juliana Ferreira-Strixino
Bacterial infections have been a major challenge to health. Increasing resistance to antimicrobial agents, according to World Health Organization, could be the major cause of death until 2050. Photodynamic therapy emerges as an alternative in microbial inactivation, due to its selectivity and to decreasing or dismissing antibiotic use. This study aimed at evaluating, in vitro, the internalization of the Methylene Blue and its photodynamic activity against a clinical and ATCC strain of Pseudomonas aeruginosa and Staphyloccocus aureus. Thus, the strains were incubated with MB in concentrations of 100, 300 e 500 μg/ml and then irradiated with a LED (±660 nm) at fluence of 10 and 25 J/cm². The MB internalization was evaluated using a confocal microscope (Zeiss LSM 700), to capture the MB and the DAPI (for DNA staining). It was possible to observe that the MB was internalized by the bacterial cells, in all concentrations tested. The CFU/ml count demonstrated significant reduction (p ≤ 0,01) at the average 5.0 logs comparing with control group for the two species in all the tested concentrations. In conclusion, the strains tested were capable of internalizing the MB. PDT with MB was able to decrease the growth of the tested strains in vitro, being a promising alternative to the future treatment of infections caused by these species.



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Apoptotic Caspases: Multiple or Mistaken Identities?

Publication date: Available online 15 March 2018
Source:Trends in Cell Biology
Author(s): Kate McArthur, Benjamin T. Kile
The mitochondrial caspase cascade was originally thought to be required for apoptotic death driven by Bak/Bax-mediated intrinsic apoptosis. It has also been ascribed several 'non-apoptotic' functions, including differentiation, proliferation, and cellular reprogramming. Recent work has demonstrated that, during apoptosis, the caspase cascade suppresses damage-associated molecular pattern (DAMP)-initiated production of cytokines such as type I interferon by the dying cell. The caspase cascade is not required for death to occur; instead, it shapes the immunogenic properties of the apoptotic cell. This raises questions about the role of apoptotic caspases in regulating DAMP signaling more generally, puts a new perspective on their non-apoptotic functions, and suggests that pharmacological caspase inhibitors might find new applications as antiviral or anticancer agents.



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Once-weekly versus every-other-day stereotactic body radiotherapy in patients with prostate cancer (PATRIOT): A phase 2 randomized trial

Publication date: Available online 15 March 2018
Source:Radiotherapy and Oncology
Author(s): Harvey C. Quon, Aldrich Ong, Patrick Cheung, William Chu, Hans T. Chung, Danny Vesprini, Amit Chowdhury, Dilip Panjwani, Geordi Pang, Renee Korol, Melanie Davidson, Ananth Ravi, Boyd McCurdy, Liying Zhang, Alexandre Mamedov, Andrea Deabreu, Andrew Loblaw
Background and purposeProstate stereotactic body radiotherapy (SBRT) regimens differ in time, dose, and fractionation. We completed a multicentre, randomized phase II study to investigate the impact of overall treatment time on quality of life (QOL).Material and methodsMen with low and intermediate-risk prostate cancer were randomly assigned to 40 Gy in 5 fractions delivered once per week (QW) vs. every other day (EOD). QOL was assessed using the Expanded Prostate Cancer Index Composite. The primary endpoint was the proportion with a minimum clinically important change (MCIC) in bowel QOL during the acute (≤12 week) period, and analysis was by intention-to-treat. ClinicalTrials.gov NCT01423474.Results152 men from 3 centres were randomized with median follow-up of 47 months. Patients treated QW had superior acute bowel QOL with 47/69 (68%) reporting a MCIC compared to 63/70 (90%) treated EOD (p = 0.002). Fewer patients treated QW reported moderate–severe problems with bowel QOL during the acute period compared with EOD (14/70 [20%] vs. 40/70 [57%], p < 0.001). Acute urinary QOL was also better in the QW arm, with 52/67 (78%) vs 65/69 (94%) experiencing a MCIC (p = 0.006). There were no significant differences in late urinary or bowel QOL at 2 years or last follow-up.ConclusionProstate SBRT delivered QW improved acute bowel and urinary QOL compared to EOD. Patients should be counselled regarding the potential for reduced short-term toxicity and improved QOL with QW prostate SBRT.



http://ift.tt/2pinbIt

Bi-hemispheric repetitive transcranial magnetic stimulation for upper limb motor recovery in chronic stroke: A feasibility study

Publication date: Available online 15 March 2018
Source:Brain Stimulation
Author(s): Raffaella Chieffo, Giuseppe Scopelliti, Mario Fichera, Roberto Santangelo, Simone Guerrieri, Abraham Zangen, Giancarlo Comi, Letizia Leocani




http://ift.tt/2tW8WPo

A response to comments by Dr. Mohammad Alwardat on “Safety of repeated sessions of transcranial direct current stimulation: A systematic review”

Publication date: Available online 15 March 2018
Source:Brain Stimulation
Author(s): Stevan Nikolin, Colleen K. Loo, Donel M. Martin




http://ift.tt/2GxuS5Z

Short-interval and long-interval intracortical inhibition of TMS-evoked EEG potentials

Publication date: Available online 15 March 2018
Source:Brain Stimulation
Author(s): Isabella Premoli, Julia Király, Florian Müller-Dahlhaus, Carl M. Zipser, Pierre Rossini, Christoph Zrenner, Ulf Ziemann, Paolo Belardinelli
BackgroundInhibition in the human motor cortex can be probed by means of paired-pulse transcranial magnetic stimulation (ppTMS) at interstimulus intervals of 2–3 ms (short-interval intracortical inhibition, SICI) or ∼100 ms (long-interval intracortical inhibition, LICI). Conventionally, SICI and LICI are recorded as motor evoked potential (MEP) inhibition in the hand muscle. Pharmacological experiments indicate that they are mediated by GABAA and GABAB receptors, respectively.Objective/Hypothesis: SICI and LICI of TMS-evoked EEG potentials (TEPs) and their pharmacological properties have not been systematically studied. Here, we sought to examine SICI by ppTMS-evoked compared to single-pulse TMS-evoked TEPs, to investigate its pharmacological manipulation and to compare SICI with our previous results on LICI.MethodsPpTMS-EEG was applied to the left motor cortex in 16 healthy subjects in a randomized, double-blind placebo-controlled crossover design, testing the effects of a single oral dose 20 mg of diazepam, a positive modulator at the GABAA receptor, vs. 50 mg of the GABAB receptor agonist baclofen on SICI of TEPs.ResultsWe found significant SICI of the N100 and P180 TEPs prior to drug intake. Diazepam reduced SICI of the N100 TEP, while baclofen enhanced it. Compared to our previous ppTMS-EEG results on LICI, the SICI effects on TEPs, including their drug modulation, were largely analogous.ConclusionsFindings suggest a similar interaction of paired-pulse effects on TEPs irrespective of the interstimulus interval. Therefore, SICI and LICI as measured with TEPs cannot be directly derived from SICI and LICI measured with MEPs, but may offer novel insight into paired-pulse responses recorded directly from the brain rather than muscle.



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Novel application of virtual reality in patient engagement for Deep Brain Stimulation: A Pilot study

Publication date: Available online 15 March 2018
Source:Brain Stimulation
Author(s): Malie K. Collins, Victoria Y. Ding, Robyn L. Ball, Dana L. Dolce, Jaimie M. Henderson, Casey H. Halpern




http://ift.tt/2GwAQnu

Dualistic effect of pallidal deep brain stimulation on motor speech disorders in dystonia

Publication date: Available online 15 March 2018
Source:Brain Stimulation
Author(s): Jan Rusz, Tereza Tykalová, Anna Fečíková, Daniela Šťastná, Dušan Urgošík, Robert Jech
BackgroundAlthough pallidal deep brain stimulation (GPi-DBS) is an effective treatment for dystonia, it may cause important stimulation-induced side-effects such as hypokinetic dysarthria or stuttering. However, the reasons behind the occurrence of these side-effects remain unknown.ObjectiveTo objectively investigate the impact of GPi-DBS on patients with dystonia on speech fluency, intelligibility, and key aspects of hyperkinetic and hypokinetic dysarthria.MethodsSpeech was systematically evaluated in 19 dystonic patients with GPi-DBS. Each patient was tested twice within one day in both the GPi-DBS ON and GPi-DBS OFF stimulation conditions. A control sample of 19 matched healthy speakers underwent the same speech assessment.ResultsWe observed an improvement of hyperkinetic dysarthria symptoms in 47% and an aggravation of hypokinetic dysarthria symptoms in 26% of patients with the GPi-DBS switched ON. A higher stimulus intensity was found in a group of patients in whom the hypokinetic dysarthria worsened with the GPi-DBS ON when compared to other dystonic patients (p = 0.02). Furthermore, we revealed a significant increase of dysfluent words in the GPi-DBS ON when compared to OFF condition (p = 0.001) associated with the shorter distance of the active contact localization along the medio-lateral direction (r = −0.70, p = 0.005).ConclusionThis study provides evidence of dualistic effects of GPi-DBS on speech in dystonia manifested as an improvement of hyperkinetic or a deterioration of hypokinetic dysarthria. Our findings suggest that lower stimulation parameters and placement of active contacts more laterally in the internal globus pallidus should be preferred to avoid the possible side effects of hypokinetic dysarthria and dysfluency.



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Crustacean cardioactive peptide (CCAP) of the oriental fruit fly, Bactrocera dorsalis (Diptera: Tephritidae): Molecular characterization, distribution and its potential roles in larva-pupa ecdysis

Publication date: Available online 15 March 2018
Source:Peptides
Author(s): Yan Shi, Tian-Yuan Liu, Yu-Xia Pei, Hong-Bo Jiang, Wei Dou, Guy Smagghe, Jin-Jun Wang
Insects must undergo ecdysis for successful development and growth, and the crustacean cardioactive peptide (CCAP) is one of the most important hormone in this process. Here we reported a cDNA encoding for the CCAP precursor cloned from the oriental fruit fly, Bactrocera dorsalis, a most destructive insect pest of agriculture. The CCAP mature peptide (PFCNAFTGC-NH2) of B. dorsalis was generated by post-translational processing and found to be highly comparable with other insects. RT-qPCR showed that mRNA of CCAP in B. dorsalis (BdCCAP) was predominantly expressed in the central nervous system (CNS) and midgut of 3rd-instar larvae. By using immunohistochemical analysis, we also localized the endocrine cells that produce CCAP in the CNS, ring gland and midgut of 3rd-instar larvae of B. dorsalis. The synthetic CCAP mature peptide could induce the expression of mRNA of adipokinetic hormone (AKH), the metabolic neuropeptides in insects. The expression of BdCCAP mRNA in the CNS, but not in the midgut, could be upregulated in the response to the challenge of insect molting hormone, 20-hydroxyecdysone.



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Lumbar Gout Tophus Mimicking Epidural Abscess with Magnetic Resonance Imaging, Bone, and Gallium Scans

Justo Serrano Vicente, Alejandro Lorente Gómez, Rafael Lorente Moreno, Jose Rafael Infante Torre, Lucía García Bernardo, Juan Ignacio Rayo Madrid

Indian Journal of Nuclear Medicine 2018 33(2):158-160

Gout is a common metabolic disorder, typically diagnosed in peripheral joints. Tophaceous deposits in lumbar spine are a very rare condition with very few cases reported in literature. The following is a case report of a 52-year-old patient with low back pain, left leg pain, and numbness. Serum uric acid level was in normal range. magnetic resonance imaging, bone scan, and gallium-67 images suggested an inflammatory-infectious process focus at L4. After a decompressive laminectomy at L4–L5 level, histological examination showed a chalky material with extensive deposition of amorphous gouty material surrounded by macrophages and foreign-body giant cells (tophaceous deposits).

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The Radioprotective Effects of Curcumin and Trehalose Against Genetic Damage Caused By I-131

Seyed Masoud Jafarpour, Mehdi Safaei, Mehran Mohseni, Morteza Salimian, Akbar Aliasgharzadeh, Bagher Fahood

Indian Journal of Nuclear Medicine 2018 33(2):99-104

Background: Thyroid cancer has been growing rapidly during the last decades. Radioiodine-131 (I-131) as an appropriate therapy modality is currently using in the treatment of cancer and hyperthyroidism diseases. This radiotracer is considered as a cause of oxidative DNA damage in nontarget cells and tissues. The aim of this study was to investigate the effects of curcumin and trehalose on the level of DNA double-strand breaks (DSBs) caused by I-131 in human lymphocytes. Materials and Methods: First, 6-mL blood samples were taken from each of the five volunteers. After 1 h of preincubation with the antioxidants, a total of 20 μCi I-131/2 mL (blood + NaCl) was added to each sample, and then, the samples were reincubated for 1 h. Lymphocytes were separated and the mean DSB levels were measured for each sample through γ-H2AX assay to evaluate the effects of antioxidants. Results: After 1-h incubation with I-131, the DSBs increased by 102.9% compared to the control group (0.343 vs. 0.169 DSB/cell; P = 0.00). Furthermore, compared to the control + I-131 group, curcumin and trehalose reduced the DSBs by 42% and 38%, respectively. There was a significant decrement (P = 0.00) in the levels of DSBs of the curcumin + I-131 and trehalose + I-131 subgroups compared to the control + I-131 subgroup. Furthermore, there was no significant relationship between the radioprotective effect of curcumin and trehalose (P = 0.95). Conclusion: The use of curcumin and trehalose as antioxidant can reduce the numbers of DSBs caused by I-131. Meanwhile, the radioprotective effect of curcumin was more than trehalose.

http://ift.tt/2FT7nXd

Which is Better - A Standalone Ventilation or Perfusion Scan or Combined Imaging to Predict Postoperative FEV1in One Seconds in Patients Posted for Lung Surgeries with Borderline Pulmonary Reserve

Padma Subramanyam, P Shanmuga Sundaram

Indian Journal of Nuclear Medicine 2018 33(2):105-111

Introduction: Forced expiratory volume in one second (FEV1) is an independent predictor for respiratory morbidity. Reports are varied and controversial substantiating the use of either lung perfusion (Q) or ventilation (V) scintigraphy as a single stage investigation to predict postoperative (ppo) FEV1in patients scheduled for lung resection surgeries. It is said that there is no additional benefit by performing both V/Q scan. As per one of the recommendations, no further respiratory function tests are required for a lobectomy if the postbronchodilator FEV1is >1.5 l. We wanted to study the ppo FEV1in patients with FEV1of <1.5 L scheduled for lung surgeries. Being a high-risk population, we wanted to assess (a) whether the ppo changes by this combined V/Q imaging and (b) whether the incidence of respiratory complication in the postoperative setting of this subgroup is different, (c) and study the short- and long-term clinical outcome. Materials and Methods: Fifty-two high-risk patients (with comorbidities) and borderline preoperative FEV1of 1.5 L or less planned for lung resection were enroled in this prospective study. V and Q scans were performed, and tracer uptake percentage was tabulated. Results: Tracer uptake in each lung was quantitated. Manual method of ROI drawing is preferred in high risk patients with reduced pulmonary reserve over the automatic method. Based on uptake patterns by V/Q scans, 4 different types of patterns were tabulated. Eighty-eight percentage of centrally placed tumors showed the difference in uptake patterns. Chronic obstructive pulmonary disease patients usually showed more modest ventilatory defects (categorised as type 2 or 3). Lung tumours produce erratic uptake patterns (Type 4) which depend heavily on their location and extent. The range of FEV1predicted was 0.6–1.38 L/min Conclusion: We recommend that combined imaging should be performed in patients with borderline pulmonary reserve to derive the benefit of surgery as it provides a realistic ppo FEV1in patients with moderate to severely damaged lung. Centrally placed hilar or bronchial tumors (even those <2 cm in size), produce discrepancies in V/Q distribution pattern. Patient who was thought ineligible for surgery due to low baseline FEV1may be actually be operable by this combined imaging if uptake pattern is better in V or Q scan with a good outcome. Accurate estimation of postop FEV1in fact helps the surgical team to implement measures to prepare high risk patients to reduce postoperative complications, enable faster weaning from ventilatory support and ensure favourable prognosis.

http://ift.tt/2GwGcit

Fluorodeoxyglucose Positron Emission Tomography-computed Tomography Evaluation of an Interesting Case of Uterine Carcinosarcoma with Isolated Appendicular Skeletal Metastases

Chidambaram Natrajan Balasubramanian Harisankar

Indian Journal of Nuclear Medicine 2018 33(2):152-153

Uterine carcinosarcomas, also known as malignant mixed mullerian tumors, are one of the rare and most aggressive neoplasms of the uterus. They have an aggressive course and can spread to distant organs. Owing to the low incidence of these tumors, the optimal adjuvant management after surgery is not well established. Many patients develop distant metastases during follow-up. An interesting case of uterine carcinosarcoma who developed metastases to the femur, tibia, and calcaneum during follow is presented.

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Role of Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Various Orbital Malignancies

Aravintho Natarajan, Piyush Chandra, Nilendu Purandare, Archi Agrawal, Sneha Shah, Ameya Puranik, Venkatesh Rangarajan

Indian Journal of Nuclear Medicine 2018 33(2):118-124

Orbital swelling comprises wide spectrum of pseudotumors, benign and malignant tumor. Malignant tumor may be primary or secondary tumor, and they constitute about 36% of orbital tumors in adult. Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scan is extensively used in hematological malignancies and in solid tumors for staging, treatment response, and restaging. Recently, the use of FDG-PET/CT in orbital malignancies has gained importance. The aim of this pictorial essay is to illustrate few important orbital malignancies detected in F-18 FDG-PET/CT and discuss its role in assessing the primary lesion and associated systemic finding.

http://ift.tt/2GBjndT

Simultaneous 18F- FDG PET/MRI in Autoimmune Limbic Encephalitis

Sangeeta Taneja, Vinit Suri, Aashim Ahuja, Amarnath Jena

Indian Journal of Nuclear Medicine 2018 33(2):174-176

Limbic encephalitis is an autoimmune disorder characterized by inflammation of the brain with rapidly progressing dementia which requires definitive neurological evaluation. We describe both clinical as well as imaging findings in a case of limbic encephalitis using positron emission tomography/magnetic resonance imaging.

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An Interesting Case of Retropharyngeal Lymph Nodal Metastases in a Case of Iodine-Refractory Thyroid Cancer

Chidambaram Natrajan Balasubramanian Harisankar, Ramakrishnan Vijayabhaskar

Indian Journal of Nuclear Medicine 2018 33(2):125-127

Metastases to cervical lymph node are fairly common in differentiated thyroid cancer. In iodine-refractory disease, the disease may persist in the thyroid bed, cervical lymph nodes, lungs, or the bones commonly. Retropharyngeal lymph nodal involvement in thyroid cancer is unusual and may even be the presenting complaint. We represent a case of iodine-refractory thyroid cancer with retropharyngeal lymph nodal involvement in addition to lung metastases.

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Role of Preablative Stimulated Thyroglobulin in Prediction of Nodal and Distant Metastasis on Iodine Whole-Body Scan

Meghana Prabhu, Sanju Samson, Avinash Reddy, Sunil Hejaji Venkataramanarao, Naveen Hedne Chandrasekhar, Vijay Pillai, Vivek Shetty, Moni Abraham Koriokose, Bushan Vaidhya, Subramanian Kannan

Indian Journal of Nuclear Medicine 2018 33(2):93-98

Background: Preablative stimulated thyroglobulin (ps-Tg) is an important investigation in the follow-up of patients with Differentiated thyroid cancer(DTC) after surgery. Levels of ps-Tg >2–10 ng/ml have been suggested to predict metastasis to cervical and extracervical sites. There is still debate on the need for routine iodine whole-body scan (131I WBS) in the management of low-to-intermediate-risk DTC patients. Objective: We analyzed our data of patients with DTC who underwent total thyroidectomy to discuss the predictability of ps-Tg on metastatic disease on the 131I WBS. Materials and Methods: Retrospective analysis of patient records. Results: One hundred and seventeen patients with DTC (95 papillary thyroid cancer [71 had classic histology, 8 had tall cell variant, 16 had follicular variant] and 22 follicular thyroid cancer [18 minimally invasive, 2 hurtle cell, and 2 widely invasive cancers]) had undergone total thyroidectomy. All these patients underwent ps-Tg assessment and an 131I WBS. About 65% of them went on to have radioiodine ablation along with a posttherapy 131I WBS. We divided the cohort into four groups based on their ps-Tg levels: Group 1 (ps-Tg <1), Group 2 (ps-Tg 1–1.9), Group 3 (ps-Tg 2–5), and Group 4 (ps-Tg >5). None of the patients in Group 1, 7% of those combined in Groups 2 and 3 (2 out of 28 patients), and 26% (12 out of 47) of those in Group 4 had either cervical or extracervical metastasis. Those with extracervical metastatic disease to lungs and bones had a mean (standard deviation) ps-Tg value of 436 (130) and median of 500 ng/ml and those with cervical metastatic disease had a mean Tg value of 31 (64) and median 6.6 ng/ml. Conclusions: A ps-Tg value in the absence of anti-Tg antibodies <1 ng/ml reliably excludes metastatic disease in DTC, while a value >5 ng/ml has a 26% risk of having either cervical or extracervical metastasis.

http://ift.tt/2tR1KUr

Mismatch in Brain Perfusion and Metabolism Detected with 99mTc-Hexamethyl Propylene Amine Oxime Single Photon Emission Computed Tomography and 18F-Fluorodeoxyglucose Positron Emission Tomography in Moyamoya Disease

Justo Serrano Vicente, Luis Fernández Prudencio, José Rafael Infante Torre, Juan Ignacio Rayo Madrid

Indian Journal of Nuclear Medicine 2018 33(2):154-157

We report a 47-year-old woman who developed an ischemic stroke with diplopia and dysarthria. Emergency computed tomography (CT) showed no pathological findings, and magnetic resonance (MR) showed mild ischemic-degenerative lesions. MR angiography and angiogram showed severe stenosis of both internal carotid and main intracranial arteries with plenty collateral vessels with "puff of smoke" suggesting a moyamoya disease (MMD). Brain perfusion single-photon emission CT showed global diminished perfusion in the brain lobes and a marked relative hyperperfusion in the cerebellum. However, brain 18F-fluorodeoxyglucose-positron emission tomography showed physiological metabolism in the brain cortex with only slightly relative cerebellar hypermetabolism. MMD is a well-known arterial pathology that frequently develops with only mild symptoms until the middle age. Functional neuroimaging findings indicate a mismatch between brain glucose metabolism and brain perfusion, probably due to neuronal subclinical chronic ischemia in the brain cortex with preserved viability of neurons.

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Serendipitous Unearthing of Silent Multiple Giant Rasmussen's Aneurysms by Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography/Computerized Tomography

Vatturi Venkata Satya Prabhakar Rao, Sujatha Naidu, Gangireddy Venkateshwar Reddy, Swetha Hanumanthu

Indian Journal of Nuclear Medicine 2018 33(2):136-139

The authors report multiple giant bilateral pseudoaneurysms of pulmonary artery, also known as Rasmussen's aneurysms, which remained silent and unrevealed despite the large size and multiplicity unearthed by fluorine-18 fluorodeoxyglucose positron emission tomography/computerized tomography.

http://ift.tt/2G00HX2

Postrenal Transplant Allograft “Page Kidney” Identified and Salvaged using 99mTc-diethylenetriaminepentaacetic acid Renogram and Single-photon Emission-computed Tomography

Aashish Gambhir, Indirani Elangovan, Shelley Simon, Avani Jain

Indian Journal of Nuclear Medicine 2018 33(2):161-164

99mTc diethylenetriaminepentaacetic acid (DTPA) renogram is a commonly performed evaluation postrenal transplant to assess graft function and for early detection of suspected immediate and late transplant-associated complications. Although several modalities can be utilized to detect perinephric collection in posttransplant period, the utility of 99mTc DTPA single-photon emission-computed tomography (SPECT-CT) is not recognized. Herein, we discuss the incremental role of seldom considered SPECT-CT in early detection, leading to timely appropriate management and graft salvage in a case of posttransplant deteriorating renal allograft as a result of subcapsular hematoma.

http://ift.tt/2tQqUTn

Discordant Primary Resistance to Imatinib Mesylate in the Same Individual and Splenic Involvement in Recurring Gastric Gastrointestinal Stromal Tumors: Assessment by Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography

Preeti Fargose, Sandip Basu

Indian Journal of Nuclear Medicine 2018 33(2):140-142

Discordant primary resistance and response of the metastatic lesions in the same individual coupled with splenic involvement in gastrointestinal stromal tumors (GISTs) are relatively uncommon. We herein report such a case of recurring GIST of the stomach that presented with the involvement of spleen with 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) imaging documentation. Ultrasonography-guided fine needle aspiration cytology from the splenic and paravesical lesions demonstrated metastatic spindle cell tumor consistent with diagnosis of metastasis from GIST of the stomach. The splenic and the paravesical lesions appeared resistant to the conventional 400 mg of imatinib mesylate, while most other abdominopelvic metastatic lesions demonstrated good metabolic response on FDG-PET/CT, with the noteworthy findings of interlesional heterogeneity of the metastatic lesions in terms of differential primary response in the same individual.

http://ift.tt/2GAU0J6

Parent perspectives on the clinician-client relationship in speech-language treatment for children

Publication date: Available online 15 March 2018
Source:Journal of Communication Disorders
Author(s): Kerry Danahy Ebert
Few studies have explored clinician-client relationships in speech-language treatment for children, although evidence indicates that these relationships may be important. Parents play a unique role in clinician-client relationships and their views have yet to be considered in the speech-language pathology literature. This study explored parents' perspectives on the clinician-client relationship in speech-language treatment for children using both quantitative and qualitative information. An online survey collected responses from 159 parents with children enrolled in speech-language services. Respondents were asked to complete a rating of the clinician-client relationship, provide information on length of treatment and treatment setting, and respond to open-ended questions about what enhances the clinician-client relationship. Length of treatment was unrelated to the parent rating of the clinician-client relationship. However, ratings did vary by treatment setting; parents of children enrolled in treatment services in schools provided lower ratings than parents with children enrolled in other settings. Thematic analysis of parent views on what enhances the clinician-client relationship yielded four main themes: qualities of the speech-language pathologist (SLP), session characteristics, the child-SLP bond, and communication. The most frequent subthemes in the analysis related to characteristics of the sessions: the integration of play and fun, and a child-oriented approach to sessions. These results provide insight into the development of clinician-client relationships in children's speech-language treatment, with implications for both clinicians and researchers.



http://ift.tt/2FG89aI

Chinese herb medicine matrine induce apoptosis in human esophageal squamous cancer KYSE-150 cells through increasing reactive oxygen species and inhibiting mitochondrial function

Publication date: Available online 15 March 2018
Source:Pathology - Research and Practice
Author(s): Jin-Huan Jiang, Jiang Pi, Hua Jin, Fen Yang, Ji-Ye Cai
Matrine, as a natural alkaloid isolated from the traditional herb medicine sophora flavescens, has been proved to possess excellent biological activities, including anticancer effects. Now, this research aims to assess the anticancer activities and the mechanism of matrine against esophageal cancer cells, we investigated the proliferative inhibition, apoptosis induction, as well as the underlying mechanism of matrine on esophageal cancer KYSE-150 cells. It was found that matrine could suppress KYSE-150 cell proliferation and significantly mediate cell apoptosis in a dose-dependent relation by increasing intracellular reactive oxygen species level and triggering mitochondrial membrane potential disruption. More precise mechanism studies demonstrated that matrine could up-regulate the expression of Bax proteins and down-regulate the expression of Bcl-2 proteins, as well as the activation about caspase-3, 8 and 9 in KYSE-150 cells. The morphological analysis of KYSE-150 cells exhibited that matrine could destroy the F-actin and nuclei structures and induce morphological damage with increased surface height distribution and roughness of cell membrane. These results not only demonstrated the potential anticancer activity mechanism of matrine at nanoscale, but also provide preliminary guidance for the treatment of esophageal cancer using matrine.



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Opposing Effects of CREBBP Mutations Govern the Phenotype of Rubinstein-Taybi Syndrome and Adult SHH Medulloblastoma

Publication date: Available online 15 March 2018
Source:Developmental Cell
Author(s): Daniel J. Merk, Jasmin Ohli, Natalie D. Merk, Venu Thatikonda, Sorana Morrissy, Melanie Schoof, Susanne N. Schmid, Luke Harrison, Severin Filser, Julia Ahlfeld, Serap Erkek, Kaamini Raithatha, Thomas Andreska, Marc Weißhaar, Michael Launspach, Julia E. Neumann, Mehdi Shakarami, Dennis Plenker, Marco A. Marra, Yisu Li, Andrew J. Mungall, Richard A. Moore, Yussanne Ma, Steven J.M. Jones, Beat Lutz, Birgit Ertl-Wagner, Andrea Rossi, Rabea Wagener, Reiner Siebert, Andreas Jung, Charles G. Eberhart, Boleslaw Lach, Michael Sendtner, Stefan M. Pfister, Michael D. Taylor, Lukas Chavez, Marcel Kool, Ulrich Schüller
Recurrent mutations in chromatin modifiers are specifically prevalent in adolescent or adult patients with Sonic hedgehog-associated medulloblastoma (SHH MB). Here, we report that mutations in the acetyltransferase CREBBP have opposing effects during the development of the cerebellum, the primary site of origin of SHH MB. Our data reveal that loss of Crebbp in cerebellar granule neuron progenitors (GNPs) during embryonic development of mice compromises GNP development, in part by downregulation of brain-derived neurotrophic factor (Bdnf). Interestingly, concomitant cerebellar hypoplasia was also observed in patients with Rubinstein-Taybi syndrome, a congenital disorder caused by germline mutations of CREBBP. By contrast, loss of Crebbp in GNPs during postnatal development synergizes with oncogenic activation of SHH signaling to drive MB growth, thereby explaining the enrichment of somatic CREBBP mutations in SHH MB of adult patients. Together, our data provide insights into time-sensitive consequences of CREBBP mutations and corresponding associations with human diseases.

Graphical abstract

Teaser

Merk et al. show that the developmental time frame of CREBBP mutation acquisition in cerebellar granule neurons determines the pathogenic effect of these alterations in the cerebellum. These time-sensitive consequences explain phenotypic differences seen in patients with germline (Rubinstein-Taybi syndrome) or somatic mutations (adult SHH medulloblastoma) of CREBBP.


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Herpesvirus-encoded microRNAs detected in human gingiva alter host cell transcriptome and regulate viral infection

Publication date: Available online 15 March 2018
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Afsar R. Naqvi, Alexandra Seal, Jennifer Shango, Maria Brambila Navarette, Gloria Martinez, Gabriela Chapa, Shirin Hasan, Tejabhiram Yadavalli, Dinesh Jaishankar, Deepak Shukla, Salvador Nares
MicroRNAs (miRNAs) are small, non-coding RNAs of ~18-25 nucleotides that have gained extensive attention as critical regulators in complex gene networks including immune cell lineage commitment, differentiation, maturation, and maintenance of immune homeostasis and function. Many viruses encode miRNAs that directly downregulate the expression of factors of the innate immune system, which includes proteins involved in promoting apoptosis and recruitment. In this study, we examined the expression profiles of three previously identified viral miRNAs (v-miRs) from the human herpesvirus (HHV) family, HSV-1 (miR-H1), KSHV (miR-K12-3-3p), and HCMV (miR-US4) in healthy and diseased periodontal tissues and observed increased levels of v-miRs in diseased tissues. To understand the significance of this increase, we overexpressed v-miRs in human oral keratinocytes (HOK), a common target for various HHV, and analyzed the impact of miR-H1 and miR-K12-3-3p on the host transcriptome. More than 1300 genes were altered in HOK overexpressing miR-H1 and miR-K12-3-3p. Global pathway analysis of deregulated genes identified several key cellular pathways that may favor viral persistence. Using bioinformatic analysis, we predicted hundreds of potential v-miR binding sites on genes downregulated by miR-H1 and miR-K12-3-3p and validated three novel target v-miR sites suggesting widespread direct and indirect modualtion of numerous host genes/pathways by a single v-miR. Finally, in vitro HSV-1 infection assays showed that miR-H1 can regulate viral entry and infection in human oral keratinocytes (HOK). Overall, our results demonstrate clinical and functional relevance of pathogenic viral molecules viz., v-miRs that regulate both host and viral functions and may contribute to the pathogenesis of inflammatory oral diseases.



http://ift.tt/2FU9yK3

Impairing L-Threonine Catabolism Promotes Healthspan through Methylglyoxal-Mediated Proteohormesis

Publication date: Available online 15 March 2018
Source:Cell Metabolism
Author(s): Meenakshi Ravichandran, Steffen Priebe, Giovanna Grigolon, Leonid Rozanov, Marco Groth, Beate Laube, Reinhard Guthke, Matthias Platzer, Kim Zarse, Michael Ristow
Whether and how regulation of genes and pathways contributes to physiological aging is topic of intense scientific debate. By performing an RNA expression-based screen for genes downregulated during aging of three different species, we identified glycine-C-acetyltransferase (GCAT, EC 2.3.1.29). Impairing gcat expression promotes the lifespan of C. elegans by interfering with threonine catabolism to promote methylglyoxal (MGO; CAS 78-98-8) formation in an amine oxidase-dependent manner. MGO is a reactive dicarbonyl inducing diabetic complications in mammals by causing oxidative stress and damaging cellular components, including proteins. While high concentrations of MGO consistently exert toxicity in nematodes, we unexpectedly find that low-dose MGO promotes lifespan, resembling key mediators of gcat impairment. These were executed by the ubiquitin-proteasome system, namely PBS-3 and RPN-6.1 subunits, regulated by the stress-responsive transcriptional regulators SKN-1/NRF2 and HSF-1. Taken together, GCAT acts as an evolutionary conserved aging-related gene by orchestrating an unexpected nonlinear impact of proteotoxic MGO on longevity.

Graphical abstract

Teaser

Ravichandran et al. show that the gcat gene is downregulated during normal aging in different species, and show that impairment of GCAT delays aging by promoting formation of methylglyoxal. This diabetes-related and toxic compound unexpectedly also extends healthspan at low concentrations. Both interventions converge at stress-response and proteostasis pathways.


http://ift.tt/2GwH0UG

Elevated Levels of the Reactive Metabolite Methylglyoxal Recapitulate Progression of Type 2 Diabetes

Publication date: Available online 15 March 2018
Source:Cell Metabolism
Author(s): Alexandra Moraru, Janica Wiederstein, Daniel Pfaff, Thomas Fleming, Aubry K. Miller, Peter Nawroth, Aurelio A. Teleman
The molecular causes of type 2 diabetes (T2D) are not well understood. Both type 1 diabetes (T1D) and T2D are characterized by impaired insulin signaling and hyperglycemia. From analogy to T1D, insulin resistance and hyperglycemia are thought to also play causal roles in T2D. Recent clinical studies, however, found that T2D patients treated to maintain glycemia below the diabetes definition threshold (HbA1c < 6.5%) still develop diabetic complications. This suggests additional insulin- and glucose-independent mechanisms could be involved in T2D progression and/or initiation. T2D patients have elevated levels of the metabolite methylglyoxal (MG). We show here, using Drosophila glyoxalase 1 knockouts, that animals with elevated methylglyoxal recapitulate several core aspects of T2D: insulin resistance, obesity, and hyperglycemia. Thus elevated MG could constitute one root cause of T2D, suggesting that the molecular causes of elevated MG warrant further study.

Graphical abstract

Teaser

Moraru et al. find that elevated levels of the reactive metabolite methylglyoxal in a Drosophila model recapitulate the progression of type 2 diabetes, causing flies to become obese, insulin resistant, and hyperglycemic. This raises the question of whether elevated methylglyoxal might be a cause of type 2 diabetes.


http://ift.tt/2tSqCuX

Confucian Culture as Determinants of Consumers' Food Leftover Generation: Evidence from Chengdu, China

Abstract

Food waste is a worldwide problem due to its effects on carbon emission, water pollution, and arable lands. Previous studies of food waste generation and reduction focus on demographic, psychological, and situational factors, whereas the effects of culture in different countries have been ignored. This paper investigates the influence of Confucian culture on behaviors that waste food, considering additional factors of face saving and group conformity. We used an integrated behavioral intention model combining the TPB model and Lee's modified Fishbein model. The results show that including the constructors of Confucian culture increases the predictive power of the model. Face saving and group conformity are found to significantly influence attitude toward food waste reduction. Face saving can greatly reduce the intention to pack leftovers, and group conformity has a significant effect on the ordering of small portion sizes. Based on these results, we give a discussion and put forward with suggestions to the government and the catering industry. Limitations and implications for future research are provided accordingly.

http://ift.tt/2FXjTVi

Production-scale fibronectin nanofibers promote wound closure and tissue repair in a dermal mouse model

Publication date: June 2018
Source:Biomaterials, Volume 166
Author(s): Christophe O. Chantre, Patrick H. Campbell, Holly M. Golecki, Adrian T. Buganza, Andrew K. Capulli, Leila F. Deravi, Stephanie Dauth, Sean P. Sheehy, Jeffrey A. Paten, Karl Gledhill, Yanne S. Doucet, Hasan E. Abaci, Seungkuk Ahn, Benjamin D. Pope, Jeffrey W. Ruberti, Simon P. Hoerstrup, Angela M. Christiano, Kevin Kit Parker
Wounds in the fetus can heal without scarring. Consequently, biomaterials that attempt to recapitulate the biophysical and biochemical properties of fetal skin have emerged as promising pro-regenerative strategies. The extracellular matrix (ECM) protein fibronectin (Fn) in particular is believed to play a crucial role in directing this regenerative phenotype. Accordingly, Fn has been implicated in numerous wound healing studies, yet remains untested in its fibrillar conformation as found in fetal skin. Here, we show that high extensional (∼1.2 ×10⁵ s⁻¹) and shear (∼3 ×10⁵ s⁻¹) strain rates in rotary jet spinning (RJS) can drive high throughput Fn fibrillogenesis (∼10 mL/min), thus producing nanofiber scaffolds that are used to effectively enhance wound healing. When tested on a full-thickness wound mouse model, Fn nanofiber dressings not only accelerated wound closure, but also significantly improved tissue restoration, recovering dermal and epidermal structures as well as skin appendages and adipose tissue. Together, these results suggest that bioprotein nanofiber fabrication via RJS could set a new paradigm for enhancing wound healing and may thus find use in a variety of regenerative medicine applications.



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Physical evolution of the Three Gorges Reservoir using advanced SVM on Landsat images and SRTM DEM data

Abstract

The Three Gorges Reservoir (TGR) is one of the largest hydropower reservoirs in the world. However, changes of the important physical characteristics of the reservoir covering pre-, during-, and post- dam have not been well studied. This study analyzed the lengths and water surface areas of the TGR using advanced support vector machine method (SVM) combined Landsat images with the Shuttle Radar Topography Mission (SRTM) digital elevation model (DEM), which showed an increasing trend of lengths and surface areas with variable growth rates from pre-dam period to post-dam period. The highest water level (ca. 171.5 m) was reported in 1st Jan, 2015, with the longest length of 687.8 km and largest water surface area of 1106.2 km² during the study period. The lowest increasing magnitude of the reservoir length occurred in the first stage (2000–2005) but with the fastest magnitude of water surface area increase. The third stage (2010–2015) showed highest increase magnitude of length and lowest increase magnitude of water surface area. Meanwhile, the increased reservoir areas were mainly from cultivated land, forest land, and building land, with the biggest increase rate of cultivated land regardless of periods. Specifically, cultivated land contributed 39.1–46.0% to increased reservoir water area; the proportions were 22.6–29.6%, 22.1–24.1%, and 5.6–9.4% for forest, building land, and grassland, respectively. The study provides important data for the TGR physical evolution in the Holocene.

http://ift.tt/2pdFaka

Magnetically actuated mechanical stimuli on Fe3O4/mineralized collagen coatings to enhance osteogenic differentiation of the MC3T3-E1 cells

Publication date: Available online 15 March 2018
Source:Acta Biomaterialia
Author(s): Junjun Zhuang, Suya Lin, Lingqing Dong, Kui Cheng, Wenjian Weng
Mechanical stimuli at the bone–implant interface are considered to activate the mechanotransduction pathway of the cell to improve the initial osseointegration establishment and to guarantee clinical success of the implant. However, control of the mechanical stimuli at the bone–implant interface still remains a challenge. In this study, we have designed a strategy of a magnetically responsive coating on which the mechanical stimuli is controlled because of coating deformation under static magnetic field (SMF). The iron oxide nanoparticle/mineralized collagen (IOP-MC) coatings were electrochemically codeposited on titanium substrates in different quantities of IOPs and distributions; the resulting coatings were verified to possess swelling behavior with flexibility same as that of hydrogel. The relative quantity of IOP to collagen and the IOP distribution in the coatings were demonstrated to play a critical role in mediating cell behavior. The cells present on the outer layer of the distributed IOP-MC (O-IOP-MC) coating with a mass ratio of 0.67 revealed the most distinct osteogenic differentiation activity being promoted, which could be attributed to the maximized mechanical stimuli with exposure to SMF. Furthermore, the enhanced osteogenic differentiation of the stimulated MC3T3-E1 cells originated from magnetically actuated mechanotransduction signaling pathway, embodying the upregulated expression of osteogenic-related and mechanotransduction-related genes. This work therefore provides a promising strategy for implementing mechanical stimuli to activate mechanotransduction on the bone–implant interface and thus to promote osseointegration.Statement of significanceThe magnetically actuated coating is designed to produce mechanical stimuli to cells for promoting osteogenic differentiation based on the coating deformation. Iron oxide nanoparticles (IOPs) were incorporated into the mineralized collagen coatings (MC) forming the composite coatings (IOP-MC) with spatially distributed IOPs, and the IOP-MC coatings with outer distributed IOPs (O-IOPs-MC) shows the maximized mechanical stimuli to cells with enhanced osteogenic differentiation under static magnetic field. The upregulated expression of the associated genes reveals that the enabled mechanotransduction signaling pathway is responsible for the promoted cellular osteogenic differentiation. This work therefore provides a promising strategy for implementing mechanical stimuli to activate mechanotransduction on the bone–implant interface to promote osseointegration.

Graphical abstract

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Fatigue of soft fibrous tissues: multi-scale mechanics and constitutive modeling

Publication date: Available online 15 March 2018
Source:Acta Biomaterialia
Author(s): Kevin Linka, Markus Hillgärtner, Mikhail Itskov
In recent experimental studies a possible damage mechanism of collagenous tissues mainly caused by fatigue was disclosed. In this contribution, a multi-scale constitutive model ranging from the tropocollagen (TC) molecule level up to bundles of collagen fibers is proposed and utilized to predict the elastic and inelastic long-term tissue response. Material failure of collagen fibrils is elucidated by a permanent opening of the triple helical collagen molecule conformation, triggered either by overstretching or reaction kinetics of non-covalent bonds. This kinetics is described within a probabilistic framework of adhesive detachments of molecular linkages providing collagen fiber integrity. Both intramolecular and interfibrillar linkages are considered. The final constitutive equations are validated against recent experimental data available in literature for both uniaxial tension to failure and the evolution of fatigue for subsequent loading cycles. All material parameters of the proposed model have a clear physical interpretation.Statement of significanceIrreversible changes take place at different length scales of soft fibrous tissues tissues under supra-physiological loading and alter their macroscopic mechanical properties. Understanding the evolution of those histologic pathologies under loading and incorporating them into a continuum mechanical framework appears to be crucial in order to predict long-term evolution of various diseases and to support the development of tissue engineering.

Graphical abstract

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Cutaneous Barriers and Skin Immunity: Differentiating A Connected Network

Publication date: Available online 15 March 2018
Source:Trends in Immunology
Author(s): Stefanie Eyerich, Kilian Eyerich, Claudia Traidl-Hoffmann, Tilo Biedermann
The skin is the outermost barrier of the organism that ensures protection from external harm. Lately, our view of the skin has evolved from an inert mechanical barrier to an active organ that can sense danger signals and mount perfectly adapted defense measures in response to invading pathogens. This Review highlights the different levels of the cutaneous barrier (the microbiome, chemical, physical, and immune barriers), their characteristics, and functional, highly interconnected network of cells and mediators that allow balanced defense measures to protect the body and maintain barrier integrity.



http://ift.tt/2IrhQr6

Excitation energy dependence of the life time of orange emission from Mn-doped ZnS nanocrystals

Publication date: July 2018
Source:Journal of Luminescence, Volume 199
Author(s): N.T. Tuan, D.Q. Trung, N.V. Quang, N.D. Hung, N.T. Khoi, P.T. Huy, Philippe F. Smet, Katrien W. Meert, Dirk Poelman
Mn-doped ZnS nanocrystals were prepared by co-precipitation method. X-ray diffraction analysis indicates pure cubic zinc blende structure. We report for the first time experimental observation of the dependence of the decay time of Mn²⁺ emission from Mn-doped ZnS nanocrystals on excitation energy. Photon energy smaller than the ZnS bandgap induces faster decay time compared to the one equal to the bandgap energy. In addition, while the decay spectra of orange emission indicate both sub μs and ms, the time-resolved luminescence measurement suggests that the sub μs component belongs to the tail of the blue emission.

Graphical abstract

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Assessment of biochemical alterations in the neotropical fish species Phalloceros harpagos after acute and chronic exposure to the drugs paracetamol and propranolol

Abstract

Over time, many pollutants of anthropogenic origin have caused the contamination of aquatic ecosystems. Among several characteristics, these compounds can reach the trophic chain, causing deleterious interactions with the biota. Pharmaceutical substances can be included in this scenario as emerging contaminants that reach the aquatic environment because of direct human and veterinary usage, and release by industrial effluents, as well as through domestic dumping of surplus drugs. The effects of these compounds on exposed organisms have been studied since the 1990s, but ecotoxicological data for such chemicals are still scarce especially concerning aquatic organisms from tropical regions. Paracetamol and propranolol were selected for this study since they are frequently found in surface waters. Paracetamol is a drug used as analgesic and antipyretic, while propranolol, a β-blocker, is used in the treatment of hypertension. The objective of this study was to assess the toxic effects of these substances on the neotropical freshwater fish Phalloceros harpagos after acute (96 h) and chronic (28 days) exposures. In order to understand the effects of these drugs on P. harpagos, biochemical markers were selected, including the enzymes involved in oxidative stress, xenobiotic metabolism, and neurotransmission (catalase, glutathione-S-transferase, and cholinesterase activities, respectively). After acute exposure, no significant alterations were observed for catalase activity, suggesting the absence of oxidative stress. On the contrary, significant alterations in glutathione-S-transferases activity were described for the higher concentrations of both pharmaceuticals after acute exposure. In addition, acute exposure to paracetamol caused a significant increase of cholinesterase activity. None of the tested pharmaceuticals caused significant changes in catalase or cholinesterase activities after chronic exposure. Glutathione S-transferases activity was significantly increased for propranolol following chronic exposure, indicating the potential involvement of phase II detoxification pathway.

http://ift.tt/2tQjsYf

Hydroxychavicol, a key ingredient of Piper betle induces bacterial cell death by DNA damage and inhibition of cell division

Publication date: Available online 15 March 2018
Source:Free Radical Biology and Medicine
Author(s): Deepti Singh, Shwetha Narayanamoorthy, Sunita Gamre, Ananda Guha Majumdar, Manish Goswami, Umesh Gami, Susan Cherian, Mahesh Subramanian
Antibiotic resistance is a global problem and there is an urgent need to augment the arsenal against pathogenic bacteria. The emergence of different drug resistant bacteria is threatening human lives to be pushed towards the pre-antibiotic era. Botanical sources remain a vital source of diverse organic molecules that possess antibacterial property as well as augment existing antibacterial molecules. Piper betle, a climber, is widely used in south and south-east Asia whose leaves and nuts are consumed regularly. Hydroxychavicol (HC) isolated from Piper betle has been reported to possess antibacterial activity. It is currently not clear how the antibacterial activity of HC is manifested. In this investigation we show HC generates superoxide in E. coli cells. Antioxidants protected E. coli against HC induced cell death while gshA mutant was more sensitive to HC than wild type. DNA damage repair deficient mutants are hypersensitive to HC and HC induces the expression of DNA damage repair genes that repair oxidative DNA damage. HC treated E. coli cells are inhibited from growth and undergo DNA condensation. In vitro HC binds to DNA and cleaves it in presence of copper. Our data strongly indicates HC mediates bacterial cell death by ROS generation and DNA damage. Damage to iron sulfur proteins in the cells contribute to amplification of oxidative stress initiated by HC. Further HC is active against a number of Gram negative bacteria isolated from patients with a wide range of clinical symptoms and varied antibiotic resistance profiles.

Graphical abstract

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The dual role of ROS in autoimmune and inflammatory diseases: evidence from preclinical models

Publication date: Available online 15 March 2018
Source:Free Radical Biology and Medicine
Author(s): Markus H. Hoffmann, Helen Griffiths
Reactive oxygen species (ROS) are created in cells during oxidative phosphorylation by the respiratory chain in the mitochondria or by the family of NADPH oxidase (NOX) complexes. The first discovered and most studied of these complexes, NOX2, mediates the oxidative burst in phagocytes. ROS generated by NOX2 are dreadful weapons: while being essential to kill ingested pathogens they can also cause degenerative changes on tissue if production and release are not balanced by sufficient detoxification. In the last fifteen years evidence has been accumulating that ROS are also integral signalling molecules and are important for regulating autoimmunity and immune-mediated inflammatory diseases. It seems that an accurate redox balance is necessary to sustain an immune state that both prevents the development of overt autoimmunity (the bright side of ROS) and minimizes collateral tissue damage (the dark side of ROS). Herein, we review studies from rodent models of arthritis, lupus, and neurodegenerative diseases that show that low NOX2-derived ROS production is linked to disease and elaborate on the underlying cellular and molecular mechanisms and the translation of these results to disease in humans.



http://ift.tt/2GyqPXa

The bilingual language network: Differential involvement of anterior cingulate, basal ganglia and prefrontal cortex in preparation, monitoring, and execution

Publication date: 1 July 2018
Source:NeuroImage, Volume 174
Author(s): Roy Seo, Andrea Stocco, Chantel S. Prat
Research on the neural bases of bilingual language control has largely overlooked the role of preparatory processes, which are central to cognitive control. Additionally, little is known about how the processes involved in global language selection may differ from those involved in the selection of words and morpho-syntactic rules for manipulating them. These processes were examined separately in an fMRI experiment, with an emphasis on understanding how and when general cognitive control regions become activated. Results of region-of-interest analyses on 23 early Spanish-English bilinguals showed that the anterior cingulate cortex (ACC) was primarily engaged during the language preparation phase of the task, whereas the left prefrontal (DLPFC) and pre-supplementary motor areas showed increasing activation from preparation to execution. Activation in the basal ganglia (BG), left middle temporal lobe, and right precentral cortical regions did not significantly differ throughout the task. These results suggest that three core cognitive control regions, the ACC, DLPFC, and BG, which have been previously implicated in bilingual language control, engage in distinct neurocognitive processes. Specifically, the results are consistent with the view that the BG "keep track" of the target language in use throughout various levels of language selection, that the ACC is particularly important for top-down target language preparation, and that the left prefrontal cortex is increasingly involved in selection processes from preparation through task execution.



http://ift.tt/2tRemLb

Maturation trajectories of cortical resting-state networks depend on the mediating frequency band

Publication date: 1 July 2018
Source:NeuroImage, Volume 174
Author(s): Sheraz Khan, Javeria A. Hashmi, Fahimeh Mamashli, Konstantinos Michmizos, Manfred G. Kitzbichler, Hari Bharadwaj, Yousra Bekhti, Santosh Ganesan, Keri-Lee A. Garel, Susan Whitfield-Gabrieli, Randy L. Gollub, Jian Kong, Lucia M. Vaina, Kunjan D. Rana, Steven M. Stufflebeam, Matti S. Hämäläinen, Tal Kenet
The functional significance of resting state networks and their abnormal manifestations in psychiatric disorders are firmly established, as is the importance of the cortical rhythms in mediating these networks. Resting state networks are known to undergo substantial reorganization from childhood to adulthood, but whether distinct cortical rhythms, which are generated by separable neural mechanisms and are often manifested abnormally in psychiatric conditions, mediate maturation differentially, remains unknown. Using magnetoencephalography (MEG) to map frequency band specific maturation of resting state networks from age 7 to 29 in 162 participants (31 independent), we found significant changes with age in networks mediated by the beta (13–30 Hz) and gamma (31–80 Hz) bands. More specifically, gamma band mediated networks followed an expected asymptotic trajectory, but beta band mediated networks followed a linear trajectory. Network integration increased with age in gamma band mediated networks, while local segregation increased with age in beta band mediated networks. Spatially, the hubs that changed in importance with age in the beta band mediated networks had relatively little overlap with those that showed the greatest changes in the gamma band mediated networks. These findings are relevant for our understanding of the neural mechanisms of cortical maturation, in both typical and atypical development.



http://ift.tt/2FTBcXB

Cortical and subcortical responses to biological motion

Publication date: 1 July 2018
Source:NeuroImage, Volume 174
Author(s): Dorita H.F. Chang, Hiroshi Ban, Yuji Ikegaya, Ichiro Fujita, Nikolaus F. Troje
Using fMRI and multivariate analyses we sought to understand the neural representations of articulated body shape and local kinematics in biological motion. We show that in addition to a cortical network that includes areas identified previously for biological motion perception, including the posterior superior temporal sulcus, inferior frontal gyrus, and ventral body areas, the ventral lateral nucleus, a presumably motoric thalamic area is sensitive to both form and kinematic information in biological motion. Our findings suggest that biological motion perception is not achieved as an end-point of segregated cortical form and motion networks as often suggested, but instead involves earlier parts in the visual system including a subcortical network.



http://ift.tt/2FXBKvC

Dissecting the Functional Consequences of De Novo DNA Methylation Dynamics in Human Motor Neuron Differentiation and Physiology

Publication date: Available online 15 March 2018
Source:Cell Stem Cell
Author(s): Michael J. Ziller, Juan A. Ortega, Katharina A. Quinlan, David P. Santos, Hongcang Gu, Eric J. Martin, Christina Galonska, Ramona Pop, Susanne Maidl, Alba Di Pardo, Mei Huang, Herbert Y. Meltzer, Andreas Gnirke, C.J. Heckman, Alexander Meissner, Evangelos Kiskinis
The somatic DNA methylation (DNAme) landscape is established early in development but remains highly dynamic within focal regions that overlap with gene regulatory elements. The significance of these dynamic changes, particularly in the central nervous system, remains unresolved. Here, we utilize a powerful human embryonic stem cell differentiation model for the generation of motor neurons (MNs) in combination with genetic mutations in the de novo DNAme machinery. We quantitatively dissect the role of DNAme in directing somatic cell fate with high-resolution genome-wide bisulfite-, bulk-, and single-cell-RNA sequencing. We find defects in neuralization and MN differentiation in DNMT3A knockouts (KO) that can be rescued by the targeting of DNAme to key developmental loci using catalytically inactive dCas9. We also find decreased dendritic arborization and altered electrophysiological properties in DNMT3A KO MNs. Our work provides a list of DNMT3A-regulated targets and a mechanistic link between de novo DNAme, cellular differentiation, and human MN function.

Graphical abstract

Teaser

Kiskinis and colleagues demonstrate that DNA methylation dynamics play a central role in the differentiation of human pluripotent stem cells toward highly specialized motor neurons. Through a combination of molecular and functional analysis they identify key transcriptional mediators of these effects and link DNA methylation to neuronal patterning and function.


http://ift.tt/2pgDLIU

Adiposity Results in Metabolic and Inflammation Differences in Premenopausal and Postmenopausal Women Consistent with the Difference in Breast Cancer Risk

Abstract

Obesity is associated with increased risk of breast cancer in postmenopausal but not in premenopausal women. Many factors may be responsible for this difference. The aim of this study was to determine the mechanisms by which the genes related to the AMPK pathway, inflammation, and estrogen actions are affected by adiposity in breast tissue with the objective of identifying differences that may explain the different breast cancer risk in premenopausal and postmenopausal women. Random fine needle aspirates (rFNAs) of breast tissue were collected from 57 premenopausal and 55 postmenopausal women and were classified as normal weight, overweight, or obese. Expression levels of 21 target genes were determined using a TaqMan Low Density Array procedure. Breast tissue estradiol levels were measured by a liquid chromatography-tandem mass spectrometry procedure, and serum estradiol and follicle-stimulating hormone (FSH) were measured by a radioimmunoassay and an enzyme-linked immunosorbent assay, respectively. We found that in postmenopausal women, serum and tissue estradiol levels were increased in those who were overweight, and serum FSH levels were decreased in obese status. Interestingly, RPS6KB1, an AMPK downstream-responsive gene for protein synthesis and cell growth, and estrogen receptor α (encoded by the ESR1 gene) and its target gene GATA3 were significantly decreased in rFNA of premenopausal, obese women. In postmenopausal women, RPS6KB1, ESR1, and GATA3 expression remained unchanged in relation to adiposity. However, prostaglandin-endoperoxide synthase 2 (PTGS2), cyclin D1 (CCND1), and another ESR1 target gene, TFF1, were elevated in rFNA of obese postmenopausal women. Thus, as bodyweight increases, gene expression is indicative of increased proliferation in postmenopausal women but decreased proliferation in premenopausal women. Overall, our data reveal a novel process by which obesity promotes the risk of breast cancer in postmenopausal but not premenopausal women.

http://ift.tt/2FWmSxr

Intravenous injection of artificial red cells and subsequent dye laser irradiation causes deep vessel impairment in an animal model of port-wine stain

Abstract

Our previous study proposed using artificial blood cells (hemoglobin vesicles, Hb-Vs) as photosensitizers in dye laser treatment for port-wine stains (PWSs). Dye laser photons are absorbed by red blood cells (RBCs) and hemoglobin (Hb) mixture, which potentially produce more heat and photocoagulation and effectively destroy endothelial cells. Hb-Vs combination therapy will improve clinical outcomes of dye laser treatment for PWSs because very small vessels do not contain sufficient RBCs and they are poor absorbers/heaters of lasers. In the present study, we analyzed the relationship between vessel depth from the skin surface and vessel distraction through dye laser irradiation following intravenous Hb-Vs injection using a chicken wattle model. Hb-Vs were administered and chicken wattles underwent high-energy irradiation at energy higher than in the previous experiments. Hb-Vs location in the vessel lumen was identified to explain its photosensitizer effect using human Hb immunostaining of the irradiated wattles. Laser irradiation with Hb-Vs can effectively destroy deep vessels in animal models. Hb-Vs tend to flow in the marginal zone of both small and large vessels. Increasing laser power combined with Hb-Vs injection contributed for deep vessel impairment because of the synergetic effect of both methods. Newly added Hb tended to flow near the target endothelial cells of the laser treatment. In Hb-Vs and RBC mixture, heat transfer to endothelial cells from absorbers/heater may increase. Hb-Vs function as photosensitizers to destroy deep vessels within a restricted distance that the photon can reach.

http://ift.tt/2FFsc9e

LED session prior incremental step test enhance VO 2max in running

Abstract

This study aimed to investigate the effect of prior LED sessions on the responses of cardiorespiratory parameters during the running incremental step test. Twenty-six healthy, physically active, young men, aged between 20 and 30 years, took part in this study. Participants performed two incremental load tests after placebo (PLA) and light-emitting diode application (LED), and had their gas exchange, heart rate (HR), blood lactate, and rating of perceived exertion (RPE) monitored during all tests. The PLA and LED conditions were compared using the dependent Student t test with significance set at 5%. The T test showed higher maximum oxygen uptake (VO_2max) (PLA = 47.2 ± 5.7; LED = 48.0 ± 5.4 ml kg⁻¹ min⁻¹, trivial effect size), peak velocity (V_peak) (PLA = 13.4 ± 1.2; LED = 13.6 ± 1.2 km h⁻¹, trivial effect size), and lower maximum HR (PLA = 195.3 ± 3.4; LED = 193.3 ± 3.9 b min⁻¹, moderate effect size) for LED compared to PLA conditions. Furthermore, submaximal values of HR and RPE were lower, and submaximal VO₂ values were higher when LED sessions prior to the incremental step test were applied. A positive response of the previous LED application in the blood lactate disappearance was also demonstrated, especially 13 and 15 min after the test. It is concluded that LED sessions prior to exercise modify cardiorespiratory response by affecting running tolerance during the incremental step test, metabolite clearance, and RPE. Therefore, LED could be used as a prior exercise strategy to modulate oxidative response acutely in targeted muscle and enhance exercise tolerance.

http://ift.tt/2DuN6C0