Naringin attenuates MLC phosphorylation and NF-κB activation to protect sepsis-induced intestinal injury via RhoA/ROCK pathway

Publication date: July 2018
Source:Biomedicine & Pharmacotherapy, Volume 103
Author(s): Zhiling Li, Ming Gao, Bingchang Yang, Huali Zhang, Kangkai Wang, Zuoliang Liu, Xianzhong Xiao, Mingshi Yang
BackgroundSepsis is commonly associated with excessive stimulation of host immune system and result in multi-organ failure dysfunction. Naringin has been reported to exhibit a variety of biological effects. The present study aimed to investigate the protective effect of naringin on sepsis-induced injury of intestinal barrier function in vivo and in vitro.MethodsMice were randomly divided into 4 groups named sham (n = 20), CLP + vehicle (n = 20), CLP + NG (30 mg/kg) (n = 20) and CLP + NG (60 mg/kg) (n = 20) groups. Sepsis was induced by cecal ligation and puncture (CLP). H&E staining and transmission electron microscopy (TEM) were performed to observe intestinal mucosal morphology. ELISA was used to determine the intestinal permeability and inflammatory response in vivo and in vitro. Western blot and RhoA activity assay were performed to determine the levels of tight junction proteins and the activation of indicated signaling pathways. MTT assay was used to determine cell viability.ResultsNaringin improved survival rate of CLP mice and alleviated sepsis-induced intestinal mucosal injury. Furthermore, naringin improved impaired intestinal permeability and inhibited the release of TNF-α and IL-6, while increased IL-10 level in CLP mice and lipopolysaccharide (LPS)-stimulated MODE-K cells in a dose-dependent manner. Naringin increased the expression of tight junction proteins ZO-1 and claudin-1 via RhoA/ROCK/NF-κB/MLCK/MLC signaling pathway in vivo and in vitro.ConclusionNaringin improved sepsis-induced intestinal injury via RhoA/ROCK/NF-κB/MLCK/MLC signaling pathway in vivo and in vitro.



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Renal protective effect of SGLT2 inhibitor dapagliflozin alone and in combination with irbesartan in a rat model of diabetic nephropathy

Publication date: July 2018
Source:Biomedicine & Pharmacotherapy, Volume 103
Author(s): Ali F. Abdel-Wahab, Ghazi A. Bamagous, Randa M. Al-Harizy, Naser A. ElSawy, Naiyer Shahzad, Ibrahim A. Ibrahim, Saeed S. Al Ghamdi
Considering the complementary mechanisms of SGLT2 inhibitors and angiotensin inhibitors on kidney, it is postulated that combination of both agents could afford greater protection against diabetic renal injury. So, we investigated renal protective effects of SGLT2 inhibitor, dapagliflozin, alone and in combination with irbesartan in a rat model of diabetic nephropathy. Diabetic rats, injected with nicotinamide-streptozotocin, were treated orally for 12 weeks with either vehicle, dapagliflozin 2 mg/kg/day, irbesartan 30 mg/kg/day, or combination of both drugs; respectively. Biochemical analysis included blood glucose, HbA1c, urinary albumin excretion, creatinine clearance, TGF-β1, sRAGE, oxidative markers, and histopathological examination of kidneys. Treatment with dapagliflozin, irbesartan, and especially their combination, produced significant reduction in albuminuria, improved renal function parameters, increased sRAGE level and improved inflammatory and oxidative markers, together with amelioration of renal histopathological changes. Beside glycemic control, dapagliflozin produced higher sRAGE levels than irbesartan, suggesting that inhibition of AGE-RAGE axis is important in its renoprotective action. Combination of dapagliflozin and irbesartan produced more remarkable protective effects on renal function and structure, than use of either agent alone. It is concluded that, combination of SGLT2 inhibitor, dapagliflozin and ARB, irbesartan could offer more effective renal protection and represent a promising therapeutic option for management of diabetic nephropathy.

Graphical abstract

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Avicularin reversed multidrug-resistance in human gastric cancer through enhancing Bax and BOK expressions

Publication date: July 2018
Source:Biomedicine & Pharmacotherapy, Volume 103
Author(s): Xiang-Feng Guo, Ji-Peng Liu, Si-Quan Ma, Peng Zhang, Wen-De Sun
5-Fluorouracil (5-Fu) and cisplatin (DDP) as important therapies in treatment of human gastric cancer have been widely determined. However, the therapeutic effects are usually hampered due to drug resistance or toxicity at high concentrations for application. Avicularin (AL, quercetin-3-α-l-arabinofuranoside), a bio-active flavonol isolated from a number of plants, has been reported to display diverse pharmacological properties. In this study, we explored the hypothesis by which AL reversed 5-Fu or DDP resistance in gastric cancer and the underlying molecular mechanism. Here, in vitro, the drug-resistant cancer cells were incubated to AL or DDP alone or the combination of AL and DDP. Then, MTT, colony formation, Hoechst 33258, flow cytometry and western blot analysis were used to investigate the effects of AL in the regulation of drug-resistance gastric cancer cells. The results indicated that AL treatment markedly re-sensitizes the drug resistant cells (SGC-7901/5-Fu and SGC-7901/DDP) to cytotoxicity of 5-Fu or DDP. Molecular mechanism analysis indicated that AL and DDP combination treatment enhanced apoptosis in SGC-7901/DDP cells, accompanied with the up-regulation of cleaved Caspase-3 and PARP, as well as the activation of pro-apoptotic signals, including Bax and BOK. Significantly, down regulation of Bax or BOK expressions using Bax siRNA or BOK siRNA decreased the inhibitory role of DDP in apoptosis of SGC-7901/DDP cells pretreated with AL, demonstrating that AL-reversed DDP resistance was associated with Bax and BOK expression. In vivo, AL and DDP combination significantly reduced gastric tumor growth. Immunohistochemical analysis indicated that co-treatment of AL and DDP significantly induced apoptosis, and reduced tumor cell proliferation in tumor tissue samples. Furthermore, we also found that the Bax, BOK, cleaved Caspase-3 and PARP expression in tumor tissues were highly induced by AL and DDP co-treatment. Together, our findings may provide a novel combination therapeutic strategy in treatment of human gastric cancer.



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Betaine treatment protects liver through regulating mitochondrial function and counteracting oxidative stress in acute and chronic animal models of hepatic injury

Publication date: July 2018
Source:Biomedicine & Pharmacotherapy, Volume 103
Author(s): Reza Heidari, Hossein Niknahad, Ala Sadeghi, Hamidreza Mohammadi, Vahid Ghanbarinejad, Mohammad Mehdi Ommati, Arghavan Hosseini, Negar Azarpira, Forouzan Khodaei, Omid Farshad, Elaheh Rashidi, Asma Siavashpour, Asma Najibi, Asrin Ahmadi, Akram Jamshidzadeh
Betaine is a derivative of the amino acid glycine widely investigated for its hepatoprotective properties against alcoholism. The protective properties of betaine in different other experimental models also have been documented. On the other hand, the exact cellular mechanism of cytoprotection provided by betaine is obscure. The current study was designed to evaluate the hepatoprotective effects of betaine and its potential mechanisms of hepatoprotection in two animal models of acute and chronic liver injury. Bile duct ligation (BDL) was used as a model of chronic liver injury and thioacetamide (TAA)-induced hepatotoxicity was applied as the acute liver injury model. Severe increase in serum markers of liver tissue damage along with significant liver tissue histopathological changes were evident in both acute and chronic models of hepatic injury. It was also found that tissue markers of oxidative stress were significantly increased in BDL and TAA-treated animals. Moreover, liver mitochondrial indices of functionality were deteriorated in both investigated models. Betaine supplementation (10 and 50 mg/kg, i.p) ameliorated hepatic injury as judged by decreased liver tissue histopathological alterations, a significant decrease in tissue markers of oxidative stress, and mitigation of serum biomarkers of hepatotoxicity. On the other hand, betaine (10 and 50 mg/kg, i.p) protected hepatocytes mitochondria in both chronic and acute models of hepatotoxicity. These data indicate that the antioxidative and mitochondria regulating properties of betaine could play a primary role in its mechanisms of hepatoprotection.

Graphical abstract

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Impact of stress on female reproductive health disorders: Possible beneficial effects of shatavari (Asparagus racemosus)

Publication date: July 2018
Source:Biomedicine & Pharmacotherapy, Volume 103
Author(s): Ajai K Pandey, Anumegha Gupta, Meenakshi Tiwari, Shilpa Prasad, Ashutosh N. Pandey, Pramod K. Yadav, Alka Sharma, Kankshi Sahu, Syed Asrafuzzaman, Doyil T. Vengayil, Tulsidas G. Shrivastav, Shail K Chaube
Stress is deeply rooted in the society and women are frequently exposed to psychological, physical and physiological stressors. Psychological stress disturbs reproductive health by inducing generation of reactive oxygen species (ROS) and thereby oxidative stress (OS). The increased OS may affect physiology of ovary, oocyte quality and cause female reproductive health disorders. To overcome stress-mediated reproductive health disorders in women, shatavari (Asparagus racemosus) is frequently recommended in Ayurvedic system of medicine. Although shatavari is one of the major health tonics and most popular rasayana drugs to treat reproductive ailments of women, underlying mechanism of shatavari action at the level of ovary remains poorly understood. Based on the existing studies, we propose that shatavari may improve female reproductive health complications including hormonal imbalance, polycystic ovarian syndrome (PCOS), follicular growth and development, oocyte quality and infertility possibly by reducing OS level and increasing antioxidants level in the body. Further studies are required to elucidate the mechanism of shatavari actions at the level of ovary and oocyte that directly impacts the reproductive health of women.



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Bombesin attenuated ischemia-induced spatial cognitive and synaptic plasticity impairment associated with oxidative damage

Publication date: July 2018
Source:Biomedicine & Pharmacotherapy, Volume 103
Author(s): Yang Yao, Faqi Wang, Xuening Yang, Dawei Zang, Jiajia Yang, Zhiyun Wang
The dysfunction of spatial cognition is a character to various neurological disorders and therapeutic strategy. However, it is limited to known risk factors clinically so far. Gastrin releasing peptide (GRP) signaling is a neuropeptide system mediating emotional memory events. However, the effects of GRP agonist on spatial cognition and hippocampal synaptic plasticity are rarely investigated, especially in pathologic condition. This study was designed to investigate the long-term effects of GRPR agonist, bombesin, against cognitive impairment induced by chronic cerebral ischemia in rats and its possible mechanisms. Our results revealed that bombesin administration (30 μg/kg/day, for 14 continuous days) significantly protected the cognitive and synaptic plasticity impairments as assessed by the Morris water maze and long-term potentiation tests. The mechanism studies demonstrated that bombesin significantly alleviated the decreased activity of total superoxide dismutase (T-SOD), catalase (CAT) and altered the increased the content of malondialdehyde (MDA). Besides, the decreased expression of synapse plasticity-related proteins, calcium- calmodulin- dependent protein kinase II (CaMKII) and synaptophysin (SYP) in the hippocampus were increased with drug treatment. In conclusion, bombesin could protect the oxidative stress and expression of proteins, which were important for synaptic plasticity and cognitive function impairment induced by chronic cerebral ischemia. Our study is presented to provide novel insights into the effects of bombesin on spatial learning and memory, which should be further explored as a potential drug in disorders involving deficits in cognitive function.

Graphical abstract

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The long non-coding RNA-DANCR exerts oncogenic functions in non-small cell lung cancer via miR-758-3p

Publication date: July 2018
Source:Biomedicine & Pharmacotherapy, Volume 103
Author(s): Sheng Wang, Ming Jiang
Long non-coding RNAs (lncRNAs) have been demonstrated to be involved in the occurrence and progression of multiple cancers. In this study, we investigated the role of the lncRNA DANCR in the development of non-small cell lung cancer (NSCLC). First, we found that DANCR was markedly upregulated in NSCLC tumor tissues and cell lines compared with related normal controls. The ectopic expression of DANCR significantly increased the proliferation, migration and invasion of SPC-A1 and NCL-H1299 cells. Furthermore, we investigated whether DANCR regulates NSCLC tumor formation in vivo. Subsequently, we concluded that DANCR promotes NSCLC cell proliferation, migration and invasion by regulating the tumor suppressor miR-758-3p. These results indicated that the DANCR/miR-758-3p axis could be a potential target in the treatment of NSCLC.

Graphical abstract

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Hinokiflavone induces apoptosis in melanoma cells through the ROS-mitochondrial apoptotic pathway and impairs cell migration and invasion

Publication date: July 2018
Source:Biomedicine & Pharmacotherapy, Volume 103
Author(s): Shuping Yang, Yange Zhang, Yi Luo, Bocheng Xu, Yuqin Yao, Yuanle Deng, Fangfang Yang, Tinghong Ye, Gang Wang, Zhiqiang Cheng, Yu Zheng, Yongmei Xie
Melanoma, the highest degree of malignancy, is one of the most common skin tumors. However, there is no effective strategy to treat melanoma in current clinical practice. Therefore, it is urgent to find an efficient drug to overcome melanoma. Here, the in vitro anticancer effects of a natural product named hinokiflavone on three melanoma carcinoma cell lines (human melanoma A375 and CHL-1 cells, murine melanoma B16-F10 cells) and mechanisms of action were explored. The results of MTT assay revealed that hinokiflavone inhibited cell proliferation of these cell lines in a dose- and time-dependent manner. Interestingly, hinokiflavone showed low toxicity to normal liver cells. Flow cytometry assay and EdU incorporation assay indicated that hinokiflavone affected A375 and B16 cells survival by inducing apoptosis and blocking cell cycle progression at S phase in a concentration-dependent manner. Moreover, hinokiflavone enhanced the reactive oxygen species (ROS) and decreased the mitochondrial membrane potential obviously. Furthermore, hinokiflavone effectively impaired A375 cells migration and invasion, and down-regulated the expression of matrix metalloproteinase (MMP) MMP2 and MMP9. The above-mentioned results demonstrated that hinokiflavone could be a novel chemotherapeutic agent in melanoma treatment by inhibiting cell proliferation, inducing apoptosis and cell cycle arresting and blocking cell migration and invasion.



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Comparison of thyroid transcription factor-1 expression by two monoclonal antibodies in Scotchwoman: the chosen clone matters—reply

Publication date: Available online 7 April 2018
Source:Human Pathology
Author(s): Dai-Zhong Wang, Li Yao, Xian-Bin Tang




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The clinicopathological significance of micropapillary pattern in colorectal cancers

Publication date: Available online 7 April 2018
Source:Human Pathology
Author(s): Jung-Soo Pyo, Mee Ja Park, Dong-Wook Kang
The aim of the present study is to elucidate the clinicopathological significance and prognostic role of micropapillary pattern (MPP) in colorectal cancer (CRC). We investigated the correlation between the presence of MPP and clinicopathological characteristics and prognosis in 266 CRCs. In addition, the clinicopathological significance of MPP in mucin pools was investigated and compared to pure MPP, which is not associated with mucin pools. MPP, regardless of its proportion in the overall tumor, was found in 74 of 266 CRCs (27.8%). The rate of MPP in proportions ≥5% was 9.4% (25 of 266 cases). CRC with MPP showed higher rates of vascular and lymphatic invasion, higher metastatic lymph node ratio, and higher pT stage compared to CRC without MPP. In addition, increasing proportion of MPP in overall tumor showed more frequent vascular and lymphatic invasions (P=.002 and P=.008, respectively). Among 74 CRCs with MPP, 25 CRCs were found in mucin pools (33.8%). These cases were more right-sided and poorly differentiated with less frequent lymphatic invasion and lymph node metastasis, compared to CRCs with pure MPP. The presence of MPP significantly correlated with worse overall survival (P=.010). In 74 CRCs with MPP, overall survival significantly differed between pure MPP and MPP in mucin pools (P=.003). Taken together, our data suggest that the presence of MPP significantly correlated with aggressive tumor behavior and worse survival in CRC. In addition, the clinicopathological significance of MPP in mucin pools differed from CRC with pure MPP.



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MET amplification, expression, and exon 14 mutations in colorectal adenocarcinoma

Publication date: Available online 8 April 2018
Source:Human Pathology
Author(s): Meng Zhang, Guichao Li, Xiangjie Sun, Shujuan Ni, Cong Tan, Midie Xu, Dan Huang, Fei Ren, Dawei Li, Ping Wei, Xiang Du
MET amplification, expression, and splice mutations at exon 14 result in dysregulation of the MET signaling pathway. The aim of this study was to identify the relationship between MET amplification, protein or mRNA expression, and mutations in colorectal cancer (CRC). MET immunohistochemistry (IHC) was used for MET protein expression analysis and fluorescence in situ hybridization (FISH) was used for MET amplification detection. Both analyses were performed in tissue microarrays (TMA) containing 294 of colorectal adenocarcinoma tissue samples and 131 samples of adjacent normal epithelial tissue. MET mRNA expression was examined by real-time quantitative polymerase chain reaction (qRT-PCR) in 72 fresh colorectal adenocarcinoma tissue samples and adjacent normal colon tissue. PCR sequencing was performed to screen for MET exon 14 splice mutations in 59 fresh CRC tissue samples. Our results showed that MET protein expression was higher in colorectal tumor tissue than in adjacent normal intestinal epithelium. Positive MET protein expression was associated with significantly poorer overall survival (OS) and disease-free survival (DFS). Multivariate analysis revealed that positive MET protein expression was an independent risk factor for DFS, but not for OS. MET mRNA expression was upregulated in tumor tissues compared with the adjacent normal tissues. The incidence of MET amplification was 4.4%. None of the patients was positive for MET mutation. Collectively, MET was overexpressed in colorectal adenocarcinoma, and its positive protein expression predicted a poorer outcome in CRC patients. Furthermore, according to our results, MET amplification and 14 exon mutation are extremely rare events in colorectal adenocarcinoma.



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Clinical implication of programmed death-ligand 1 expression in tonsillar squamous cell carcinoma in association with intratumoral heterogeneity, human papillomavirus, and epithelial-to-mesenchymal transition

Publication date: Available online 7 April 2018
Source:Human Pathology
Author(s): Mi Jung Kwon, Young-Soo Rho, Eun Sook Nam, Seong Jin Cho, Hye-Rim Park, Soo Kee Min, Jinwon Seo, Ji-Young Choe, Eun Soo Kim, Bumjung Park, Mineui Hong, Kyueng-Whan Min
Programmed death-ligand 1 (PD-L1), essential for immune evasion, is a potential candidate for pathogenesis and therapeutic target of human papillomavirus (HPV)-positive tonsillar squamous cell carcinomas (TSCCs). MET/hepatocyte growth factor (HGF) signaling and transcription factors involved in epithelial-to-mesenchymal transition (EMT) upregulate PD-L1, which can contribute to clinical outcome. Intratumoral heterogeneity of PD-L1 expression is of clinical importance in selection bias due to false-negative patient enrollment. However, the clinicopathological features, prognostic value, and co-expressed molecules of PD-L1 remain unclear in TSCCs. PD-L1 expression was evaluated via immunohistochemistry using a specific monoclonal antibody (SP142) between whole tissue and tissue microarray (TMA) sections of 79 tumors (5% cutoff value with weak staining). Expressions of EMT markers (TWIST1, Snail, and SNIP1) and MET/HGF were also analyzed. Staining of the TMA sections showed 78.5% concordance rate to the whole section. PD-L1 positivity and its intratumoral heterogeneity were 29.1% and 15.2% of TSCCs by whole section, respectively. PD-L1 positivity was prevalent in females, HPV-positive tumors without base of tongue invasion, and SNIP1-overexpressed tumors. SNIP1 overexpression, unmethylated TWIST1, smoking, and poorly-differentiated tumors were predictive for PD-L1 overexpression. PD-L1 positivity was a favorable independent prognostic factor. Subgroup analyses according to the co-expression of PD-L1 with HPV, SNIP1, or unmethylated TWIST1 indicated the best clinical outcome than any other subgroups. In conclusion, intratumoral heterogeneity of PD-L1 expression was frequent, warranting a caution in punching TMA cores. A combined analysis of PD-L1 with EMT and HPV may define a characteristic subset of patients and prognostic group.



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Comparison of thyroid transcription factor-1 expression by two monoclonal antibodies in schwannomas: the chosen clone matters

Publication date: Available online 7 April 2018
Source:Human Pathology
Author(s): David Creytens, Mieke Van Bockstal, Liesbeth Ferdinande, Jo Van Dorpe




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The association between experiences of exclusionary discipline and justice system contact: A systematic review

Publication date: Available online 8 April 2018
Source:Aggression and Violent Behavior
Author(s): Abigail Novak
The term "school-to-prison pipeline" is regularly used by policymakers and researchers alike to describe school-level policies pushing students from schools into the juvenile and adult justice systems. Though the term is widely used, its interpretation and specified components vary across disciplines. Research assessing the pipeline's existence paints a complex picture, leading to questions about the existence of a non-spurious association between exclusionary discipline and justice system contact. The purpose of this systematic review is to assess existing empirical evidence evaluating the association between experiences of exclusionary discipline and subsequent justice system involvement. This review is limited to studies using multivariate, inferential statistical techniques. A total of seven studies met specified qualifications and are included in the review. All studies found a significant association between experiences of exclusionary discipline and subsequent justice system contact, with odds ratios ranging from 1.72 to 5.17. Further research is needed to extend understanding of how this association differs according to age at first experience of exclusionary discipline and frequency of discipline. Additionally, future research should explore possible mediating and moderating factors influencing the relationship between exclusionary discipline and justice system contact.



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Re “Calcification of Thoracic and Abdominal Aneurysms is Associated with Mortality and Morbidity”. Abdominal Aortic Aneurysm Calcification: Are Biochemical Markers a Missing Piece of the Puzzle?

Publication date: Available online 7 April 2018
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Emirena Garrafa, Stefano Bonardelli




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Clinical Effect and Cost-Effectiveness of Screening for Asymptomatic Carotid Stenosis: A Markov Model

Publication date: Available online 7 April 2018
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Dominika Högberg, Kevin Mani, Anders Wanhainen, Sverker Svensjö
Objective/BackgroundThe cost-effectiveness of screening depends on the cost of screening, prevalence of asymptomatic carotid artery stenosis (ACAS), and the potential effect of medical intervention in reducing the risk of stroke. The aim of the study was to determine the threshold values for these parameters in order for screening for ACAS to be cost-effective.MethodsThe clinical effect and cost-effectiveness of ultrasound screening for ACAS with subsequent initiation of preventive therapy versus not screening was assessed in a Markov model with a lifetime perspective. Key parameters, including stroke risk, all cause mortality, and costs, were based on contemporary published data, population statistics, and data from an ongoing screening program in Uppsala county (population 300,000), Sweden. Prevalence of ACAS (2%) and the rate of best medical treatment (BMT; 40%) were based on data from a male Swedish population recently screened for ACAS. The required stroke risk reduction from BMT, incremental cost-efficiency ratio (ICER), absolute risk reduction for stroke (ARR), and number needed to screen (NNS) were calculated.ResultsScreening was cost-effective at an ICER of €5744 per incremental quality adjusted life year (QALY) gained. ARR was 135 per 100,000 screened, NNS was 741, and QALYs gained were 6700 per 100,000 invited. At a willingness to pay (WTP) threshold of €50,000 per QALY the minimum required stroke risk reduction from BMT was 22%. The assumed degree of stroke risk reduction was the most important determinant of cost-efficiency.ConclusionA moderate (22%) reduction in the risk of stroke was required for an ACAS screening strategy to be cost-effective at a WTP of €50,000/QALY. Targeting populations with a higher prevalence of ACAS could further improve cost-efficiency.



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Combined Impact of Chronic Kidney Disease and Contrast Induced Acute Kidney Injury on Long-term Outcomes in Patients with Acute Lower Limb Ischaemia

Publication date: Available online 7 April 2018
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Petar Zlatanovic, Igor Koncar, Marko Dragas, Nikola Ilic, Milos Sladojevic, Perica Mutavdzic, Ivan Tomic, Dusan Kostic, Lazar Davidovic
IntroductionAcute lower limb ischaemia (ALI) is the sudden onset of decreased arterial perfusion with imminent threat to limb viability. Contrast induced acute kidney injury (CI-AKI) is one of the complications that increases mortality in patients who undergo contrast imaging in coronary procedures. The goal of this study is to evaluate the impact of chronic kidney disease (CKD) and CI-AKI on long-term clinical outcomes in patients with ALI undergoing lower limb revascularisation.MethodsA total 1017 consecutive patients with acute lower limb ischaemia who were admitted between July 1, 2006, and January 1, 2017, were retrospectively reviewed. Patients who had end stage renal disease, those who had end stage heart and malignant disease and died within 7 days of limb revascularisation, and those who did not undergo angiography were excluded. Thus 546 patients were included in the final analysis. Patients were classified as with or without CKD and were then subdivided according to the presence or absence of the development of CI-AKI, defined as an increase in serum creatinine of ≥0.5 mg/dL or by ≥25% from the baseline value within the first 72 h after contrast exposure. The primary end point was all cause mortality and secondary major adverse limb event (MALE).ResultsBoth CKD and CI-AKI were associated with the highest rate of all cause mortality (chi square = 55.77, d.f. = 1, p < .01, log rank test) and MALE (chi square = 79.07, d.f. = 1, p < .01, log rank test). The presence of CKD and CI-AKI were significant risk factors associated with long-term all cause mortality (HR = 2.61, p < .01) and MALE (HR = 2.87, p < .01).ConclusionIn patients with ALI undergoing lower limb revascularisation, both CKD and CI-AKI were significantly associated with poor long-term outcomes compared with either CKD or CI-AKI alone. Further studies are required to assess this association and to confirm the combined effect of CKD and CI-AKI on long-term clinical outcomes.



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Elective Repair of Abdominal Aortic Aneurysm and the Risk of Colonic Ischaemia: Systematic Review and Meta-Analysis

Publication date: Available online 7 April 2018
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Jeremy S. Williamson, Graeme K. Ambler, Christopher P. Twine, Ian M. Williams, Gethin Ll. Williams
IntroductionColon ischaemia (CI) is a significant complication of open (OR) and endovascular (EVAR) repair of abdominal aortic aneurysm (AAA). With a rapid increase in EVAR uptake, contemporary data demonstrating the differing rates and outcomes of CI between EVAR and OR, particularly in the elective setting, are lacking. The aim was to characterise the risk and consequences of CI in elective AAA repair comparing EVAR with OR.MethodsA systematic review and meta-analysis of the literature was performed using the Cochrane collaboration protocol and reported according to the PRISMA guidelines. PubMed, MedLine, and EMBASE were searched for studies reporting CI rates after elective AAA repair. Ruptured AAAs were excluded from analysis.ResultsThirteen studies reporting specific outcomes of CI after elective AAA repair, containing 162,750 evaluable patients (78,151 EVAR and 84,599 OR) were included. All studies found a higher risk of CI with OR than with EVAR. Three studies performed confounder adjustment with CI rates of 0.5–1% versus 2.1–3.6% (EVAR vs. OR) and combined odds ratio of 2.7 (2.0–3.5) for the development of CI with OR versus EVAR. The majority of cases of CI occurred within 30 days and were associated with variable mortality (0–73%) and re-intervention rates (27–54%). GRADE assessment of evidence strength was very low for all outcomes. There was a high degree of heterogeneity between studies both methodologically and in terms of CI rates, re-intervention, mortality, and time to development of CI.ConclusionsEVAR is associated with a reduced incidence of CI compared with OR.



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Additional physical therapy services reduce length of stay and improve health outcomes in people with acute and sub-acute conditions: an updated systematic review and meta-analysis

Publication date: Available online 7 April 2018
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Casey L. Peiris, Nora Shields, Natasha K. Brusco, Jennifer J. Watts, Nicholas F. Taylor
ObjectiveTo update a previous review on whether additional physical therapy services reduce length of stay, improve health outcomes, are safe and cost effective for patients with acute or sub-acute conditions.Data sourcesElectronic database (AMED, CINAHL, EMBASE, MEDLINE, PEDro, PubMed) searches were updated from 2010 through June 2017.Study selectionRandomized controlled trials evaluating additional physical therapy services on patient health outcomes, length of stay or cost effectiveness were eligible. Searching identified 1524 potentially relevant articles, of which 11 new articles from 8 new randomized controlled trials with 1563 participants were selected. In total, 24 randomized controlled trials with 3262 participants are included in this review.Data extractionData were extracted using the form used in the original systematic review. Methodological quality was assessed using the PEDro scale and The Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach was applied to each meta-analysis.Data synthesisPost intervention data were pooled with an inverse variance, random effects model to calculate standardized mean differences (SMDs) and 95% confidence intervals (CIs). There is moderate quality evidence that additional physical therapy services reduced length of stay by 3 days in sub-acute settings (MD-2.8, 95%CI -4.6 to -0.9, I² 0%) and low quality evidence that it reduced length of stay by 0.6 days in acute settings (MD -0.6, 95%CI -1.1 to 0.0, I² 65%). Additional physical therapy led to small improvements in self-care (SMD 0.11, 95%CI 0.03 to 0.19, I² 0%), activities of daily living (SMD 0.13, 95%CI 0.02 to 0.25, I² 15%) and health-related quality of life (SMD 0.12, 95%CI 0.03 to 0.21, I² 0%), with no increases in adverse events. There was no significant change in walking ability. One trial reported that additional physical therapy was likely to be cost-effective in sub-acute rehabilitation.ConclusionsAdditional physical therapy services improve patient activity and participation outcomes, while reducing hospital length of stay for adults. These benefits are likely safe and there is preliminary evidence to suggest they may be cost effective.



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Pertussis in Africa: Findings and recommendations of the Global Pertussis Initiative (GPI)

Publication date: 25 April 2018
Source:Vaccine, Volume 36, Issue 18
Author(s): Rudzani Muloiwa, Nicole Wolter, Ezekiel Mupere, Tina Tan, A.J. Chitkara, Kevin D. Forsyth, Carl-Heinz Wirsing von König, Gregory Hussey
Pertussis remains a major cause of morbidity and mortality, particularly in infants and young children, and despite the availability of vaccines and pertinent national and international guidelines. The disease burden is more severe in low- and middle-income countries (LMICs), especially in the African continent. Pertussis is more prevalent among young infants in Africa. Poor or no pertussis surveillance, lack of disease awareness, diagnostic limitations, and competing health priorities are considered key contributory factors for this high pertussis burden in Africa. Most African countries use whole-cell pertussis (wP) vaccines, but coverage with three primary doses of diphtheria–tetanus–pertussis vaccines falls short of the World Health Organization's recommended goal of >90%. The Global Pertussis Initiative (GPI) works toward developing recommendations through systematic evaluation and prioritization of strategies to prevent pertussis-related infant and child deaths, as well as reducing global disease burden to acceptable national, regional, and local levels. For countries using wP vaccines, the GPI recommends continuing to use wP to improve primary and toddler booster vaccination coverage. Vaccination during pregnancy is the next priority when acellular pertussis (aP) vaccines and other resources are available that directly protect newborns too young to be vaccinated, followed by, in order of priority, booster doses in older children, adolescents, healthcare workers and finally, all adults. Improved surveillance should be a high priority for African LMICs assessing true disease burden and vaccine effectiveness to inform policy. More research is warranted to evaluate the safety and efficacy of wP and aP vaccines and strategies, and to determine their optimal use.



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Immune mechanisms induced by an HSV-1 mutant strain: Discrepancy analysis of the immune system gene profile in comparison with a wild-type strain

Publication date: 25 April 2018
Source:Vaccine, Volume 36, Issue 18
Author(s): Xiaolong Zhang, Quanlong Jiang, Xingli Xu, Yongrong Wang, Lei Liu, Yaru Lian, Hao Li, Lichun Wang, Ying Zhang, Guorun Jiang, Jieyuan Zeng, Han Zhang, Jing-Dong Jackie Han, Qihan Li
Herpes simplex virus is a prevalent pathogen of humans of various age groups. The fact that no prophylactic or therapeutic vaccine is currently available suggests a significant need to further investigate the immune mechanisms induced by the virus and various vaccine candidates. We previously generated an HSV-1 mutant strain, M3, with partial deletions in ul7, ul41 and LAT that produced an attenuated phenotype in mice. In the present study, we performed a comparative analysis to characterize the immune responses induced by M3 versus wild-type HSV-1 in a mouse model. Infection with wild-type HSV-1 triggered an inflammatory-dominated response and adaptive immunity suppression and was accompanied by severe pathological damage. In contrast, infection with M3 induced a systematic immune response involving full activation of both innate and adaptive immunity and was accompanied by no obvious pathological changes. Furthermore, the immune response induced by M3 protected mice from lethal challenge with wild-type strains of HSV-1 and restrained virus proliferation and impaired latency. These data are useful for further HSV-1 vaccine development using a mutant strain construction strategy.



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Delineating the serotype-specific neutralizing antibody response to a live attenuated tetravalent dengue vaccine

Publication date: 25 April 2018
Source:Vaccine, Volume 36, Issue 18
Author(s): Gregory D. Gromowski, Sandra Henein, Chandrika B. Kannadka, David A. Barvir, Stephen J. Thomas, Aravinda M. de Silva, Richard G. Jarman
The dengue virus (DENV) vaccines that are licensed or in clinical development consist of DENV serotype 1–4 tetravalent formulations given simultaneously and are not acquired sequentially like natural infections. It is unclear what effect this has on development of protective levels of immunity to all four serotypes. Serotype-specific neutralizing antibody (NAb) is considered the most relevant correlate of protection from dengue disease. Here we assessed levels of serotype-specific and cross-reactive NAb in immune sera from 10 subjects vaccinated with a live attenuated tetravalent DENV vaccine developed at the Walter Reed Army Institute of Research. The majority of subjects NAb responses to DENV-2 and DENV-4 were type-specific, while their NAb responses to DENV-1 and DENV-3 were primarily cross-reactive. Vaccine virus RNAemia has been most frequently detected for DENV-2 and DENV-4 in vaccinated subjects, strongly suggesting that replication is important for eliciting serotype-specific immunity.



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Human papillomavirus vaccination coverage in Luxembourg – Implications of lowering and restricting target age groups

Publication date: 25 April 2018
Source:Vaccine, Volume 36, Issue 18
Author(s): Ardashel Latsuzbaia, Marc Arbyn, Steven Weyers, Joël Mossong
BackgroundIn Luxembourg, a national Human Papillomavirus (HPV) vaccination programme was introduced in 2008, targeting 12–17 year old girls offering a choice of bivalent or quadrivalent vaccine free of charge. In 2015, the programme was changed offering the bivalent vaccine only to 11–13 year old girls. The aim of this study was to evaluate the HPV vaccination coverage, to assess the impact of age target changes and compare vaccination coverage to other European countries.MethodsAnonymous HPV vaccination records consisting of individual vaccine doses obtained free of charge in pharmacies between 2008 and 2016 were extracted from the Luxembourgish Social Security database. Additional aggregate tables by nationality and municipality were analysed.ResultsOf the target cohort of 39,610 girls born between 1991 and 2003 residing in Luxembourg, 24,550 (62.0%) subjects obtained at least one dose, 22,082 (55.7%) obtained at least two doses, and 17,197 (43.4%) obtained three doses of HPV vaccine. The mean age at first dose was 13.7 years during 2008–14 and 12.7 years in 2016 after the age target change. Coverage varied significantly by nationality (p < 0.0001): Portuguese (80%), former Yugoslavs (74%), Luxembourgish (54%), Belgian (52%), German (47%), French (39%) and other nationalities (51%). Coverage varied also by geographical region, with lower rates (<50%) noted in some Northern and Central areas of Luxembourg (range: 38% to 78%).ConclusionOverall HPV vaccination coverage in Luxembourg is moderate and varied by nationality and region. The policy changes in 2015 did not have a substantial impact except lowering age at initiating vaccination. Options to improve coverage deserve further investigation.



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Poor knowledge of vaccination recommendations and negative attitudes towards vaccinations are independently associated with poor vaccination uptake among adults – Findings of a population-based panel study in Lower Saxony, Germany

Publication date: 25 April 2018
Source:Vaccine, Volume 36, Issue 18
Author(s): Manas K. Akmatov, Nicole Rübsamen, Igor V. Deyneko, André Karch, Rafael T. Mikolajczyk
ObjectivesThe aims of this study were to (a) assess knowledge of official vaccination recommendations and attitudes towards vaccinations among adults and (b) examine their association with vaccination uptake among adults.MethodsThis study was part of the HaBIDS study (Hygiene and Behaviour Infectious Diseases Survey), which is an online panel established in March 2014 in Lower Saxony, Germany with males and females aged between 15 and 69 years (n = 2379). Every few months, participants completed questionnaires on different aspects of infectious diseases. In September 2014, knowledge of vaccination recommendations, attitudes towards vaccinations and information on uptake of vaccinations in the last 10 years (practice) were collected using a knowledge-attitude-practice (KAP) questionnaire. Multiple correspondence analysis was applied to identify underlying structures in each KAP domain and fractional polynomial regression analysis to examine the associations of knowledge and attitudes with vaccination uptake.ResultsOf the 2379 panel members, 1698 (71%) completed the KAP questionnaire on vaccinations. The majority of participants (80%) knew that the vaccine against diphtheria and tetanus should be administered every 10 years. Regarding other recommendations, the proportion of correct answers varied between 35% and 60%. 82% of participants agreed that adult vaccinations should be mandatory for selected groups such as health care workers and 40% stated that vaccinations should be mandatory for all adults. For the different vaccines, the odds of being unvaccinated were 1.5- to 5-times higher among participants with poor knowledge of vaccination recommendations compared to participants with good knowledge. Participants with negative attitudes towards vaccinations were also more likely to be unvaccinated.ConclusionsEfforts should be undertaken to improve knowledge of official vaccination recommendations in the general population and reduce common misconceptions about vaccinations. This information can be provided during general practitioner visits or through media campaigns.



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Editorial Board/Aims and Scope

Publication date: 25 April 2018
Source:Vaccine, Volume 36, Issue 18





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A single vaccination with non-replicating MVA at birth induces both immediate and long-term protective immune responses

Publication date: 25 April 2018
Source:Vaccine, Volume 36, Issue 18
Author(s): Cédric Cheminay, Jana Körner, Constanze Bernig, Michael Brückel, Markus Feigl, Martin Schletz, Mark Suter, Paul Chaplin, Ariane Volkmann
Newborns are considered difficult to protect against infections shortly after birth, due to their ineffective immune system that shows quantitative and qualitative differences compared to adults. However, here we show that a single vaccination of mice at birth with a replication-deficient live vaccine Modified Vaccinia Ankara [MVA] efficiently induces antigen-specific B- and T-cells that fully protect against a lethal Ectromelia virus challenge. Protection was induced within 2 weeks and using genetically modified mice we show that this protection was mainly T-cell dependent. Persisting immunological T-cell memory and neutralizing antibodies were obtained with the single vaccination. Thus, MVA administered as early as at birth induced immediate and long-term protection against an otherwise fatal disease and appears attractive as a new generation smallpox vaccine that is effective also in children. Moreover, it may have the potential to serve as platform for childhood vaccines as indicated by measles specific T- and B-cell responses induced in newborn mice vaccinated with recombinant MVA expressing measles antigens.



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Improving the immunogenicity and protective efficacy of the EtMIC2 protein against Eimeria tenella infection through random mutagenesis

Publication date: 25 April 2018
Source:Vaccine, Volume 36, Issue 18
Author(s): Zhengtao Chen, Xiuzhen Wang, Ningning Zhao, Linzhen Han, Fangkun Wang, Hongmei Li, Yanshun Cui, Xiaomin Zhao
In recent years, directed evolution has emerged as an efficient tool to develop and identify novel protein variants. Eimeria tenella microneme-2 (EtMIC2) is a promising vaccine candidate for use against E. tenella infection; however, it only yields partial protection. The present study aimed to improve the immunogenicity and protective efficacy of EtMIC2 through random mutagenesis. Mutagenesis gene libraries of EtMIC2 were generated using error-prone polymerase chain reaction (epPCR), and the corresponding variant proteins were displayed on the yeast cell surface. Variant EtMIC2 proteins with high immunogenicity were screened through fluorescence-activated cell sorting (FACS) based on the affinity between polyclonal antibodies and antigens. Seven effective variant proteins were screened out and heterogeneously expressed in Escherichia coli as subunit vaccines. The protective efficacy of the variant proteins against E. tenella infections was then evaluated in chicken. Two variant proteins (1130 and 2119) displayed higher immunogenicity and protective efficacy than the wild-type EtMIC2 protein against E. tenella infections, increasing body weight gains and significantly decreasing lesion scores and fecal oocyst shedding, and increasing sIgA antibody production and lymphocyte proliferation. These variants displayed potential for use in the development of subunit vaccines for coccidiosis in chickens. The present results also indicate that directed evolution technology is useful for improving the immunogenicity and protective efficacy of parasite antigens.



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Monitoring the efficacy of infant hepatitis B vaccination and revaccination in 0- to 8-year-old children: Protective anti-HBs levels and cellular immune responses

Publication date: 25 April 2018
Source:Vaccine, Volume 36, Issue 18
Author(s): Xuefen Li, Yumiao Xu, Yuejiao Dong, Xianzhi Yang, Bo Ye, Yiyin Wang, Yu Chen
Vaccination against hepatitis B virus (HBV) is recommended worldwide. The aim of this study was to assess the efficacy of infant hepatitis B vaccination and revaccination in 0- to 8-year-old children in the context of protective anti-HBs levels and cellular immune responses. Using a random questionnaire survey, 1695 pre-school children were recruited as research subjects during January 2015 to June 2017. Blood samples were obtained to measure HBV serological markers as well as peripheral immunocytes. The children were divided into non-, low- and hyper- responsive groups (NR, LR, and HR) based on the vaccination efficacy. Additionally, the effect of revaccination on the NR group was evaluated at 1 month after completion of the vaccination course. Among a total of 1695 children, 1591 (93.86%) were infants who were followed while undergoing their primary course of hepatitis B vaccination at the 0-1-6 month schedule, and 1249 (79.30%) of them developed antibodies against HBsAg (anti-HBs) titers greater than 10 IU/L. The results of immunocyte studies indicated that the CD8⁺ T cells, CD4⁺CD45RO⁺ T cells, CD8⁺CD45RA⁺ T cells, and T follicular helper (Tfh) cells increased significantly in NR compared with HR. However, lymphocytes, CD4⁺ T cells, and CD4⁺CD45RA⁺ T cells in NR were lower than that in HR. 96 of the non-response cases showed seroprotection after revaccination among 103 cases. Therefore, most of the preschool children who received hepatitis B vaccine in infancy achieved significant seroprotection. Seroconversion rates of individuals revaccinated after initial vaccination failure were significantly higher than those after primary vaccination. Different vaccination efficacy groups showed significant changes in circulating immunocytes, which might be a factor affecting the recombinant HBV vaccine's immune effectiveness.



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Japanese encephalitis virus/yellow fever virus chimera is safe and confers full protection against yellow fever virus in intracerebrally challenged mice

Publication date: 25 April 2018
Source:Vaccine, Volume 36, Issue 18
Author(s): Huiqiang Yang, Huan Yang, Zhushi Li, Lina Liu, Wei Wang, Ting He, Fengming Fan, Yan Sun, Jie Liu, Yuhua Li, Xianwu Zeng
Yellow fever (YF) is an acute viral haemorrhagic disease caused by the yellow fever virus (YFV), which remains a potential threat to public health. The live-attenuated YF vaccine (17D strain) is a safe and highly effective measure against YF. However, increasing adverse events have been associated with YF vaccinations in recent years; thus, safer, alternative vaccines are needed. In this study, using the Japanese encephalitis live vaccine strain SA14-14–2 as a backbone, a novel chimeric virus was constructed by replacing the pre-membrane (prM) and envelope (E) genes with their YFV 17D counterparts.The chimeric virus exhibited a reduced growth rate and a much smaller plaque morphology than did either parental virus. Furthermore, the chimera was much less neurovirulent than was YF17D and protected mice that were challenged with a lethal dose of the YF virus. These results suggest that this chimera has potential as a novel attenuated YF vaccine.



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The effectiveness of influenza vaccination among nursery school children in China during the 2016/17 influenza season

Publication date: 25 April 2018
Source:Vaccine, Volume 36, Issue 18
Author(s): Yin Wang, Liling Chen, Jia Yu, Yuanyuan Pang, Jun Zhang, Tao Zhang, Genming Zhao
BackgroundThe effectiveness of influenza vaccine among nursery school children has not been systematically studied. We conducted a cohort study of children from 13 nursery schools in Suzhou, China, to estimate the effectiveness of influenza vaccine against laboratory-confirmed influenza during 2016–17.MethodsChildren aged 36–72 months were chosen from 13 nursery schools from 3 District in Suzhou. The surveillance started 2 weeks after vaccination during October 2016–February 2017. Class teachers reported the names of students with ILI (influenza-like illness) to study clinicians on each school day. Further, local physicians collected the student's nasopharyngeal swab or throat swab, either at a study clinic or at the child's home. The swabs were sent to the National Influenza Network Laboratory in Suzhou Center for Disease Control and Prevention for influenza testing by RT-PCR.ResultA total of 4614 children were enrolled, of which 15 children (vaccinated: 2; unvaccinated: 13) were lost to follow-up. Of the remaining 4599 children, 558 swabs were collected. Among these swabs, 70 samples tested positive for influenza virus; 17 in the vaccinated group (B Victoria: 2; H3N2: 15) and 53 in the unvaccinated group (B Victoria: 14; A(H1N1)pdm09: 1; H3N2: 38). The overall influenza vaccine effectiveness (VE) during the influenza season of 2016–2017 was 20.6%. The incidence of developing ILI symptoms and healthcare seeking behavior through clinical visits was significantly lower in vaccinated children than in the unvaccinated group.ConclusionInfluenza vaccine protection in vaccinated and unvaccinated children showed no statistical difference and the VE percentage varied for different virus subtypes. However, the incidence rate of developing ILI and healthcare seeking behavior was significant lower in the vaccinated group than in the unvaccinated children. Larger studies are required to estimate the VE according to the influenza type, subtype, and lineage during influenza seasons in China in the future.



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Sequential pulmonary immunization with heterologous recombinant influenza A virus tuberculosis vaccines protects against murine M. tuberculosis infection

Publication date: 25 April 2018
Source:Vaccine, Volume 36, Issue 18
Author(s): H. Muflihah, M. Flórido, L.C.W. Lin, Y. Xia, J.A. Triccas, J. Stambas, W.J. Britton
Tuberculosis (TB) infection affects a quarter of the global population resulting in a large burden of TB disease and mortality. The long-term control of TB requires vaccines with greater efficacy and durability than the current Mycobacterium bovis Bacille Calmette-Guérin (BCG). Pulmonary immunization may increase and prolong immunity at the site of Mycobacterium tuberculosis infection. We have investigated recombinant influenza A viruses (rIAVs) expressing the p25 CD4⁺ T cell epitope of M. tuberculosis Ag85B240–254 for single and sequential immunization against M. tuberculosis infection. Intranasal immunization with single dose of rIAV X31 (H3N2 strain) expressing the p25 epitope (X31-p25), induced p25-specific CD4⁺ T cells and conferred protection against aerosol delivery of M. tuberculosis infection in the lungs. To enhance this effect, prime-boost immunization with hetero-subtypic rIAVs was examined. Sequential immunization with X31-p25 and a second rIAV, PR8 (H1N1 strain) expressing the same epitope (PR8-p25), increased the frequency of p25-specific IFN-γ T cell responses and polyfunctional CD4⁺ T cells producing IFN-γ, IL-2, and TNF, compared to immunization with each rIAV alone. This combination resulted in protection against M. tuberculosis in both the lungs and spleen. Therefore, our study revealed that rIAV is not only an efficient vector to induce protective immunity in the lungs, but also has a potential use for sequential immunization with heterologous rIAV to boost the immunogenicity and improve the protection against M. tuberculosis.



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Intranasal but not subcutaneous vaccination with LaAg allows rapid expansion of protective immunity against cutaneous leishmaniasis

Publication date: 25 April 2018
Source:Vaccine, Volume 36, Issue 18
Author(s): Izabella Pereira Silva Bezerra, Marina Amaral Abib, Bartira Rossi-Bergmann
Mucosal but not parenteral vaccination with whole Leishmania amazonensis promastigotes antigens (LaAg) is known to increase host resistance to infection by an as yet unknown immune mechanism. Since early immune responses are critical for infection establishment, in the present study the differential responses elicited by subcutaneous (s.c.) and intranasal (i.n.) vaccination with LaAg were investigated during the initial stages of infection. For that, BALB/c mice were given two LaAg doses by i.n. or s.c. route prior to L. amazonensis infection in the footpad. It was found that mucosal vaccination prevented both T helper (Th) 2-associated cutaneous hypersensitivity and local interleukin (IL)-4 production in the first days after parasite challenge in the footpad. That was accompanied by increased Th1 (T-bet and IL-12) and Treg (Foxp3 and IL-10) transcription factor and cytokine expression in the lesion draining lymph nodes. In contrast, s.c. LaAg predominantly led to higher Th2 (GATA3) and transforming growth factor (TGF)-β expression. Prior i.n. vaccination was able to prevent the disease-exacerbating effect of s.c. vaccination. Although both CD4⁺ and CD8⁺ T cells were transiently increased in the cervical lymph nodes (cLN), the numbers of CD4⁺Foxp3⁺ regulatory T (Treg) cells decreased within 48 h of i.n. vaccination as compared to non-vaccinated mice. Adoptive transfer of such cLN cells conferred increased resistance to infected mice, mimicking the effect of i.n. vaccination. Altogether, these data indicate that i.n. vaccination with LaAg may prevent early peripheral expansion of detrimental cells normally elicited by active infection or s.c. vaccination, thus allowing full expansion of protective responses.



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Evaluation of Mycoplasma gallisepticum (MG) ts-304 vaccine as a live attenuated vaccine in turkeys

Publication date: 25 April 2018
Source:Vaccine, Volume 36, Issue 18
Author(s): Anna Kanci, Dinidu S. Wijesurendra, Nadeeka K. Wawegama, Gregory J. Underwood, Amir H. Noormohammadi, Philip F. Markham, Glenn F. Browning
Mycoplasma gallisepticum (MG) is an important pathogen of poultry worldwide that causes chronic respiratory disease (CRD) in chickens and infectious sinusitis in turkeys. Vaxsafe MG (strain ts-11) is a live attenuated temperature sensitive vaccine that has been proven to be effective in controlling CRD in chickens, but it is not efficacious in turkeys. The gapA gene, which encodes a mature cytadhesin protein with a molecular weight of approximately 105 kDa, is not expressed in strain ts-11 because a 20 base pair reiterated sequence introduces a frame shift and causes premature truncation of the translated peptide. A GapA positive clone, MG ts-304, isolated from strain ts-11 has been shown to have enhanced efficacy in chickens. Here we describe studies we conducted to assess the safety and efficacy of the MG ts-304 vaccine candidate in turkeys. We found that MG ts-304 was able to colonise the trachea of 3-week-old turkeys and was safe, even at a tenfold overdose, inducing no adverse clinical signs of respiratory disease or significant gross lesions in the respiratory tract (air sacs or trachea), and was poorly transmissible to in-contact birds. We also showed that it was efficacious when administered to 3-week-old turkeys, inducing protective immunity against challenge with the M.gallisepticum wild-type strain Ap3AS. MG ts-304 is therefore a promising live attenuated vaccine candidate for use in turkeys.



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Cancer-salient messaging for Human Papillomavirus vaccine uptake: A randomized controlled trial

Publication date: 25 April 2018
Source:Vaccine, Volume 36, Issue 18
Author(s): Rachael M. Porter, Avnika B. Amin, Robert A. Bednarczyk, Saad B. Omer
Background and objectivesVaccination with Human Papillomavirus (HPV) vaccine is recommended for 11–12 years-old, but uptake is suboptimal. Current messaging focuses on HPV infection transmission and prevention. Parents and providers are often uncomfortable discussing sexual practices of adolescents, contributing to the delay/refusal of vaccine. We created a cervical cancer-salient message encouraging HPV vaccination, emphasizing disease salience and disease threat, while promoting self-efficacy. We hypothesized this message would have greater effects on vaccine confidence and intent to vaccinate compared to Centers for Disease Control and Prevention (CDC) and non-vaccine control messages.MethodsA 3-arm randomized trial was conducted. Parents of girls aged 9–17 were eligible for the study. We measured participants' vaccine confidence and intent to vaccinate at baseline and post intervention message. Recruitment and surveys were administered online through Amazon Mechanical Turk.Results762 participants completed both surveys. We saw modest increases in vaccine confidence when comparing cervical cancer arm and control arm, and CDC arm and control arm; estimates were not statistically significant. The odds of reporting intent to vaccinate among the cervical cancer message arm were 1.13 times the odds of reporting intent to vaccinate in the control arm (95% CI: 0.30. 4.29). Intent to vaccinate was also not statistically significantly different between CDC message arm and control arm (OR = 1.25, 95%CI: 0.66, 2.37).ConclusionNeither message had effect on intent to vaccinate, highlighting need for research to identify successful messaging strategies for HPV. Exploratory analyses suggest among parents with 'Low' vaccine confidence at baseline, the cervical cancer framed message may be more effective in changing intention than the CDC message or non-vaccine control. Future work should target groups with 'Low' or 'Medium' vaccine confidence at baseline - they may be more amenable to change, and more receptive to disease-salient messaging.Clinical Trial Registration:Clinicaltrials.gov, Reference #: NCT03002324.



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Obstrucción de la vena cava superior por seminoma testicular con metástasis en el mediastino. Imagen de vías colaterales durante la gammagrafía por hemorragia intestinal con hematíes marcados con 99mTc

Publication date: Available online 7 April 2018
Source:Revista Española de Medicina Nuclear e Imagen Molecular
Author(s): V. Valotassiou, S. Alexiou, A. Manolakis, F. Tsiopoulos, S. Potamianos, P. Georgoulias




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Valor de la PET/TC con 68Ga-DOTATOC en la detección de recidiva de un tumor fibroso solitario de la pleura

Publication date: Available online 7 April 2018
Source:Revista Española de Medicina Nuclear e Imagen Molecular
Author(s): F. Lococo, C. Rapicetta, A. Filice, M.C. Mengoli, T. Ricchetti, R. Borrelli, M. Paci




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Utilidad de la gammagrafía con hematíes desnaturalizados por calor marcados con 99mTc en el diagnóstico de una esplenosis intramuscular

Publication date: Available online 7 April 2018
Source:Revista Española de Medicina Nuclear e Imagen Molecular
Author(s): E. Noriega, J. Suils, M.T. Bajén, A. Benítez, J. Rodríguez-Rubio, J. Mora Salvadó




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Linfoma de Burkitt etmoidal y extranodal en un niño con lesiones renales bilaterales de linfoma de Burkitt detectadas por 18F-FDG PET/TC

Publication date: Available online 7 April 2018
Source:Revista Española de Medicina Nuclear e Imagen Molecular
Author(s): M. Bonacina, M. Bertoli, D. Albano, F. Bertagna, F. Laffranchi, R. Giubbini




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RNAi-mediated SYT14 knockdown inhibits the growth of human glioma cell line U87MG

Publication date: Available online 7 April 2018
Source:Brain Research Bulletin
Author(s): Bin Sheng, Yuxin Jiang, Degang Wu, Niansheng Lai, Zhennan Ye, Bingbing Zhang, Xinggen Fang, Shanshui Xu
SYT14 (Synaptotagmin 14) participates in pathomechanical neurodegeneration and contributes to abnormal neurodevelopment. However, the functional mechanism of SYT14 in human glioma tumorigenesis remains unclear. In the present study, we measured the expression levels of SYT14 mRNA in human glioma cell lines, U373MG, U178, and U87MG and neural stem cells (NSC) cell line by RT-PCR, and used lentivirus-mediated small hairpin RNAs (shRNAs) to knock down SYT14 expression in U87MG cells. Changes in SYT14 expression were determined by real-time PCR. Cell proliferation and colony formation assays were used to analyze the role of SYT14 in U87MG cell proliferation, and cell apoptosis was assessed by flow cytometry. SYT14 mRNA expression was detected in the three glioma cell lines, and was highest in the U87MG cell line. The RNAi-mediated knockdown of SYT14 significantly decreased cell proliferation and colony formation in U87MG cells, and caused a moderate increase in apoptosis. Fewer S phase cells and more G2/M phase cells were observed. These data indicate that SYT14 is highly expressed in glioma cells, and may participate in glioma cell proliferation, apoptosis, and colony formation.



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New mechanistic insights into memory processes

Publication date: Available online 7 April 2018
Source:Brain Research Bulletin
Author(s): K.P. Giese, S. Kida




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Journal Article Tag Suite Conference (JATS-Con) Proceedings 2018 [Internet].

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The NET-effect of combining rituximab with belimumab in severe systemic lupus erythematosus

Publication date: Available online 7 April 2018
Source:Journal of Autoimmunity
Author(s): Tineke Kraaij, Sylvia W.A. Kamerling, Esther N.M. de Rooij, Paul L.A. van Daele, Obbo W. Bredewold, Jaap A. Bakker, Ingeborg M. Bajema, Hans U. Scherer, Rene E.M. Toes, Tom J.W. Huizinga, Ton J. Rabelink, Cees van Kooten, Y.K. Onno Teng
ObjectiveIn systemic lupus erythematosus (SLE) patients, excessive formation of neutrophil extracellular traps (NETs) is observed and their degradation is impaired. In vitro, immune complexes (ICx) trigger NET formation while NET-derived DNA is a postulated autoantigen for anti-nuclear autoantibodies (ANAs), found in SLE. Based on these self-perpetuating mechanisms in SLE, this study investigates whether interfering with ICx formation using a combination of rituximab (RTX) and belimumab (BLM) could decrease NET formation and ameliorate disease.MethodsA phase 2A, open-label, single arm proof-of-concept study was performed wherein 16 SLE patients with severe, refractory disease were treated with a combination of CD20-mediated B-cell depletion with rituximab and sustained inhibition of B-cell activating factor BlyS with belimumab. Besides safety, the study's endpoints were chosen to address the concept of autoantibodies in relation to excessive NET formation.ResultsWe demonstrated a surge of BlyS levels upon RTX-mediated B-cell depletion which was abrogated by subsequent BLM treatment. As such, therapeutic intervention with RTX + BLM led to specific reductions in ANAs and regression of excessive NET formation. RTX + BLM appeared to be safe and achieved clinically significant responses: low lupus disease activity state was achieved in 10 patients, renal responses in 11 patients and concomitant immunosuppressive medication was tapered in 14 out of the 16 patients.ConclusionsThis study provides novel insights into clinical beneficence of reducing excessive NET formation in SLE by therapeutic targeting ANA production with RTX + BLM. Altogether putting forward a new treatment concept that specifically ameliorates underlying SLE pathophysiology.Trial registrationClinicalTrials.gov NCT02284984.



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Biocontrol of Sclerotinia sclerotiorum (Lib.) de Bary on common bean by native lipopeptide-producer Bacillus strains

Publication date: Available online 7 April 2018
Source:Microbiological Research
Author(s): Daniela C. Sabaté, Carolina Pérez Brandan, Gabriela Petroselli, Rosa Erra-Balsells, M.Carina Audisio
Bacillus sp. B19, Bacillus sp. P12 and B. amyloliquefaciens B14 were isolated from soils of Salta province, and PGPR properties on the common bean (Phaseolus vulgaris L.) cv. Alubia and antagonistic activity against Sclerotinia sclerotiorum were studied.It was determined that B19 and P12 increased crop germination potential (GP) from the common bean by 14.5% compared to control seeds; these strains also increased root length (10.4 and 15%, respectively) and stem length (20.2 and 30%, respectively) compared to the control; however, as for the B14 strain, no increases in growth parameters were detected. In addition, all the treatments that combined two bacilli: B14 + B19, B14 + P12 and B19 + P12, generated beneficial effects on GP and seedling growth compared to control seeds, but not compared to a single inoculant. B19 and P12 strains synthesized auxins at concentrations of 5.71 and 4.90 mg/mL, respectively, and it was qualitatively determined that they synthesize siderophores. In addition, previous studies have determined that B14 produces auxins in a concentration of 10.10 mg/ml, and qualitatively synthesizes siderophores.The phytosanitary state of the white bean cv. Alubia control seeds revealed bacterial contamination in 87% of all the evaluated seeds and different fungi such as Cladosporium sp., Fusarium sp., and Rhizopus sp. Bean seeds treated with B14, B19 or P12 showed no growth of contaminating bacteria or of pathogenic fungi; in fact, bacilli inoculum development was observed in all seeds. Additionally, B19, P12 and B14 strains inhibited in vitro the development of 9 native S. sclerotiorum strains isolated from the Salta region, with FI ranging between 60 and 100%. The three Bacillus strains synthesized different isoforms of the lipopeptides: surfactin, iturin, and fengycin in the presence of S. sclerotiorum, as determined by MALDI-TOF.In the in vivo trials, when common bean seeds were grown in soils contaminated with S. sclerotiorum, an incidence of 100% was determined when the seeds were not treated with any Bacillus. Seeds treated with the chemical fungicide and sown in S. sclerotiorum-infested soil did not produce seed emergence, while the inoculation of the seeds with B14 + P12, B14 + B19 or B19 + P12 reduced the effect of the pathogen by 46, 43 and 25%, respectively. Disease progression in B14 + P12 and B14 + B19 treatments was significantly lower than in the remaining treatments, with an AUDPC of 873.75 and 1071, respectively.



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An investigation on the seasonal variations of the biomarkers of oxidative stress response and their correlations to Polonium-210 in mussel (Mytilus galloprovincialis) and common sole (Solea solea) from İzmir Bay, Turkey

Publication date: September 2018
Source:Journal of Environmental Radioactivity, Volume 189
Author(s): Ersan Aslan, Aysun Uğur Görgün, Selma Katalay, Işık Filizok, Seda Becerik, Tülin Aydemir
It is well known that the marine organisms are used as biological indicators for environmental pollution studies. Among these studies, the research on oxidative stress has been increasing in recent years. In this study, mussels (Mytilus galloprovincialis) and fish (Solea solea) samples were collected seasonally from İnciraltı, İzmir, Turkey. This station was in an area where fishing is carried out for human consumption. The relationship between ²¹⁰Po and oxidative stress markers (lipid peroxidation (LPO), H2O2 and proline) was investigated in the mussel tissue (digestive gland, gills) and fish tissue (liver, gills) samples. The present study indicated that H2O2 accumulated with increasing ²¹⁰Po concentration in mussel samples. Statistically significant correlation were found between H2O2 and ²¹⁰Po and LPO and proline in mussel samples. This correlation between LPO and proline can be attributed to common environmental parameters (other than ²¹⁰Po) affecting expression of both LPO and proline levels. There was not a significant correlation between ²¹⁰Po and LPO levels. Similarly, a significant correlation was not found between ²¹⁰Po and proline.



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NDUFA4 (Renamed COXFA4) Is a Cytochrome-c Oxidase Subunit

Publication date: Available online 7 April 2018
Source:Trends in Endocrinology & Metabolism
Author(s): Robert D.S. Pitceathly, Jan-Willem Taanman
Groundbreaking work by Kadenbach and colleagues in the 1980s revealed the presence of 13 subunits in the mammalian mitochondrial cytochrome-c oxidase (COX; Complex IV). This observation stood the test of time until 2012 when it was demonstrated that NDUFA4, a polypeptide previously attributed to mitochondrial Complex I, was a 14th subunit of COX. In his recent opinion article, Kadenbach argued that NDUFA4 is not a subunit of COX. However, based on the findings that NDUFA4 deficiency results in a severe loss of COX activity and that NDUFA4 represents a stoichiometric component of the individual COX complex, we reason that NDUFA4 is a bona fide COX subunit and propose renaming it as COX subunit FA4 (COXFA4).



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A density gradient of VAPG peptides on a cell-resisting surface achieves selective adhesion and directional migration of smooth muscle cells over fibroblasts

Publication date: Available online 7 April 2018
Source:Acta Biomaterialia
Author(s): Shan Yu, Xingang Zuo, Tao Shen, Yiyuan Duan, Zhengwei Mao, Changyou Gao
Selective adhesion and migration of smooth muscle cells (SMCs) over fibroblasts (FIBs) is required to prevent adventitia fibrosis in vascular regeneration. In this study, a uniform cell-resisting layer of poly(ethylene glycol) (PEG) with a density gradient of azide groups was generated on a substrate by immobilizing two kinds of PEG molecules in a gradient manner. A density gradient of alkynyl-functionalized Val-Ala-Pro-Gly (VAPG) peptides was then prepared on the PEG layer via click chemistry. The VAPG density gradient was characterized by fluorescence imaging, revealing the gradual enhancement of the fluorescent intensity along the substrate direction. The adhesion and mobility of SMCs were selectively enhanced on the VAPG density gradient, leading to directional migration toward the higher peptide density (up to 84%). In contrast, the adhesion and mobility of FIBs were significantly weakened. The net displacement of SMCs also significantly increased compared with that on tissue culture polystyrene (TCPS) and that of FIBs on the gradient. The mitogen-activated protein kinase (MAPK) signaling pathways related to cell migration were studied, showing higher expressions of functional proteins from SMCs on the VAPG-modified surface in a density-dependent manner. For the first time the selective adhesion and directional migration of SMCs over FIBs was achieved by an elaborative design of a gradient surface, leading to a new insight in design of novel vascular regenerative materials.Selective cell adhesion and migration guided by regenerative biomaterials are extremely important for the regeneration of targeted tissues, which can avoid the drawbacks of incorrect and uncontrolled responses of tissue cells to implants. For example, selectivity of smooth muscle cells (SMCs) over fibroblasts (FIBs) is required to prevent adventitia fibrosis in vascular regeneration. Herein we prepare a uniform cell-repelling layer, on which SMCs-selective Val-Ala-Pro-Gly (VAPG) peptides are immobilized in a continuous manner. Selective adhesion and enhanced and directional migration of SMCs over FIBs are achieved by the interplay of cell-repelling layer and gradient SMCs-selective VAPG peptides, paving a new way for the design of novel vascular grafts with enhanced biological performance.

Graphical abstract

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Enabling physical activity participation for children and youth with disabilities following a goal-directed, family-centred intervention

Publication date: June 2018
Source:Research in Developmental Disabilities, Volume 77
Author(s): Claire Willis, Astrid Nyquist, Reidun Jahnsen, Catherine Elliott, Anna Ullenhag
BackgroundThere is a paucity of research demonstrating the optimisation and maintenance of participation outcomes following physical activity interventions for children and youth with disabilities.AimTo evaluate changes in physical activity participation in children with disabilities following a goal-directed, family-centred intervention at a healthsports centre, and to identify factors influencing participation following the intervention.Methods and proceduresA mixed methods pre-test post-test cohort design was applied. Recruitment occurred over a 12 month period during standard clinical service provision. The Canadian Occupational Performance Measure (COPM) was administered to children and parents pre (T1) and post-intervention (T2), and at 12 weeks follow-up (T3). Goal Attainment Scaling (GAS) was applied to assess outcomes at 12 weeks follow-up (T2–T3). Qualitative inquiry described barriers to goal attainment at T3.Outcomes and resultsNinety two children with a range of disabilities (mean age 11.1yr; 49 males) were included in the study. Statistically significant and clinically meaningful improvements in parent ratings of COPM performance and satisfaction of participation goals were observed following intervention. Ratings at 12 weeks follow-up remained significantly higher than baseline, and 32% of children attained their COPM-derived GAS goal. Environmental factors were the most frequent barrier to goal attainment following intervention.Conclusion and implicationsThese results provide preliminary evidence for goal-directed, family-centred interventions to optimise physical activity participation outcomes for children with disabilities.



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Practice Management: Successfully Guiding Your Group into the Future

Publication date: Available online 7 April 2018
Source:Anesthesiology Clinics
Author(s): Lee A. Fleisher




https://ift.tt/2qgrlC3

Conformation Polymorphism of Polyglutamine Proteins

Publication date: Available online 7 April 2018
Source:Trends in Biochemical Sciences
Author(s): Xinran Feng, Shouqing Luo, Boxun Lu
Expanded polyglutamine (polyQ) stretches within endogenous proteins cause at least nine human diseases. The structural basis of polyQ pathogenesis is the key to understanding fundamental mechanisms of these diseases, but it remains unclear and controversial due to a lack of polyQ protein structures at the single-atom level. Various hypotheses have been proposed to explain the structure–cytotoxicity relationship of pathogenic proteins with polyQ expansion, largely based on indirect evidence. Here we review these hypotheses and their supporting evidence, along with additional insights from recent structural biology and chemical biology studies, with a focus on Huntingtin (HTT), the most extensively studied polyQ disease protein. Lastly, we propose potential novel strategies that may further clarify the conformation–cytotoxicity relationship of polyQ proteins.



https://ift.tt/2uYkYbr

Structural Basis of Arrestin-Dependent Signal Transduction

Publication date: Available online 7 April 2018
Source:Trends in Biochemical Sciences
Author(s): Qiuyan Chen, Tina M. Iverson, Vsevolod V. Gurevich
Arrestins are a small family of proteins with four isoforms in humans. Remarkably, two arrestins regulate signaling from >800 G protein-coupled receptors (GPCRs) or nonreceptor activators by simultaneously binding an activator and one out of hundreds of other signaling proteins. When arrestins are bound to GPCRs or other activators, the affinity for these signaling partners changes. Thus, it is proposed that an activator alters arrestin's ability to transduce a signal. The comparison of all available arrestin structures identifies several common conformational rearrangements associated with activation. In particular, it identifies elements that are directly involved in binding to GPCRs or other activators, elements that likely engage distinct downstream effectors, and elements that likely link the activator-binding sites with the effector-binding sites.



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ERPs differentiate the sensitivity to statistical probabilities and the learning of sequential structures during procedural learning

Publication date: Available online 7 April 2018
Source:Biological Psychology
Author(s): Andrea Kóbor, Ádám Takács, Zsófia Kardos, Karolina Janacsek, Kata Horváth, Valéria Csépe, Dezso Nemeth
Procedural learning facilitates the efficient processing of complex environmental stimuli and contributes to the acquisition of automatic behaviors. Although earlier findings suggest different temporal trajectories of the multiple learning processes within procedural learning, this has not been clarified at the level of neurocognitive correlates. Therefore, we investigated whether two prominent learning processes – statistical learning and sequence learning – can be distinguished using event-related brain potentials (ERPs) within the same experimental setting. Healthy young adults (N = 40) performed the Alternating Serial Reaction Time task while RTs and ERPs were measured time-locked to the onset of the task's stimuli. Both RT and N2 effects reflected the rapid acquisition of statistical probabilities. At the same time, these effects reflected the gradual learning of sequential structures. The amplitude change of the P3 reflected only gradual sequence learning. The P1 component was sensitive to both learning processes, which did not change as the task progressed. Our results altogether indicate that statistical learning and sequence learning develop differently at the level of both ERPs and overt responses. These findings could provide insight to the dynamic change of multiple parallel learning processes that occur during procedural memory formation.



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The relationship between mismatch response and the acoustic change complex in normal hearing infants

Publication date: June 2018
Source:Clinical Neurophysiology, Volume 129, Issue 6
Author(s): Kristin M. Uhler, Sharon K. Hunter, Elyse Tierney, Phillip M. Gilley
ObjectiveTo examine the utility of the mismatch response (MMR) and acoustic change complex (ACC) for assessing speech discrimination in infants.MethodsContinuous EEG was recorded during sleep from 48 (24 male, 20 female) normally hearing aged 1.77 to –4.57 months in response to two auditory discrimination tasks. ACC was recorded in response to a three-vowel sequence (/i/-/a/-/i/). MMR was recorded in response to a standard vowel, /a/, (probability 85%), and to a deviant vowel, /i/, (probability of 15%). A priori comparisons included: age, sex, and sleep state. These were conducted separately for each of the three bandpass filter settings were compared (1–18, 1–30, and 1–40 Hz).ResultsA priori tests revealed no differences in MMR or ACC for age, sex, or sleep state for any of the three filter settings. ACC and MMR responses were prominently observed in all 44 sleeping infants (data from four infants were excluded). Significant differences observed for ACC were to the onset and offset of stimuli. However, neither group nor individual differences were observed to changes in speech stimuli in the ACC. MMR revealed two prominent peaks occurring at the stimulus onset and at the stimulus offset. Permutation t-tests revealed significant differences between the standard and deviant stimuli for both the onset and offset MMR peaks (p < 0.01). The 1–18 Hz filter setting revealed significant differences for all participants in the MMR paradigm.ConclusionBoth ACC and MMR responses were observed to auditory stimulation suggesting that infants perceive and process speech information even during sleep. Significant differences between the standard and deviant responses were observed in the MMR, but not ACC paradigm. These findings suggest that the MMR is sensitive to detecting auditory/speech discrimination processing.SignificanceThis paper identified that MMR can be used to identify discrimination in normal hearing infants. This suggests that MMR has potential for use in infants with hearing loss to validate hearing aid fittings.



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Eyeball pressure stimulation induces subtle sympathetic activation in patients with a history of moderate or severe traumatic brain injury

Publication date: June 2018
Source:Clinical Neurophysiology, Volume 129, Issue 6
Author(s): Ruihao Wang, Katharina M. Hösl, Fabian Ammon, Jörg Markus, Julia Koehn, Sankanika Roy, Mao Liu, Carmen de Rojas Leal, Dafin Muresanu, Steven R. Flanagan, Max J. Hilz
ObjectiveAfter traumatic brain injury (TBI), there may be persistent central-autonomic-network (CAN) dysfunction causing cardiovascular-autonomic dysregulation. Eyeball-pressure-stimulation (EPS) normally induces cardiovagal activation. In patients with a history of moderate or severe TBI (post-moderate-severe-TBI), we determined whether EPS unveils cardiovascular-autonomic dysregulation.MethodsIn 51 post-moderate-severe-TBI patients (32.7 ± 10.5 years old, 43.1 ± 33.4 months post-injury), and 30 controls (29.1 ± 9.8 years), we recorded respiration, RR-intervals (RRI), systolic and diastolic blood-pressure (BPsys, BPdia), before and during EPS (120 sec; 30 mmHg), using an ocular-pressure-device (Okulopressor®). We calculated spectral-powers of mainly sympathetic low (LF: 0.04–0.15 Hz) and parasympathetic high (HF: 0.15–0.5 Hz) frequency RRI-fluctuations, sympathetically mediated LF-powers of BPsys, and calculated normalized (nu) LF- and HF-powers of RRI. We compared parameters between groups before and during EPS by repeated-measurement-analysis-of-variance with post-hoc analysis (significance: p < 0.05).ResultsAt rest, sympathetically mediated LF-BPsys-powers were significantly lower in the patients than the controls. During EPS, only controls significantly increased RRIs and parasympathetically mediated HFnu-RRI-powers, but decreased LF-RRI-powers, LFnu-RRI-powers, and LF-BPsys-powers; in contrast, the patients slightly though significantly increased BPsys upon EPS, without changing any other parameter.ConclusionsIn post-moderate-severe-TBI patients, autonomic BP-modulation was already compromised at rest. During EPS, our patients failed to activate cardiovagal modulation but slightly increased BPsys, indicating persistent CAN dysregulation.SignificanceOur findings unveil persistence of subtle cardiovascular-autonomic dysregulation even years after TBI.



https://ift.tt/2GKbkuc

Immunotherapy phase I trials in patients Older than 70 years with advanced solid tumours

Publication date: May 2018
Source:European Journal of Cancer, Volume 95
Author(s): H. Herin, S. Aspeslagh, E. Castanon, V. Dyevre, A. Marabelle, A. Varga, S. Postel Vinay, J.M. Michot, V. Ribrag, A. Gazzah, R. Bahleda, O. Mir, C. Massard, A. Hollebecque, J.C. Soria, C. Baldini
BackgroundThe development of immune checkpoint blocker development brings new hope in older patients (OPs) because of clinical efficacy and low toxicity. Clinical indications are rising steadily, but very few data are available in the geriatric population where comorbidities, reduced functional reserve and immunosenescence may affect efficacy and tolerance.MethodsAll cases of patients enrolled in immunotherapy phase I trials between January 2012 and December 2016 in the Drug Development Department (DITEP) at Gustave Roussy were retrospectively reviewed. Case–control analysis was performed in OPs (patients ≥ 70 years) matched to younger patients (YPs) (patients < 70 years) by trial and treatment dose. We compared cumulative incidence, grade and type of immune-related adverse events (IrAEs) and survival outcomes.ResultsAmong the 46 OPs and the 174 YPs enrolled in 14 phase I/II trials, 10 (22%) and 23 (13%) patients experienced grade III–IV IrAEs. Cumulative incidence of grade I–II IrAEs was significantly higher in OPs than YPs (p < 0.05). No significant difference was observed between the two groups for grade III–IV IrAEs (p = 0.50). Older age was not associated with lower dose intensity of treatment (p = 0.14). No significant difference was observed between OPs and YPs in median progression-free survival (hazards ratio 1.41, 95% confidence interval [CI] [0.94–2.11] p = 0.09) or median overall survival (HR 0.92, 95% CI [0.61–1.39] p = 0.77).ConclusionImmune checkpoint blockade appears to be an acceptable treatment option for OPs in the setting of phase I trials.



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Phase I feasibility study for intrathecal administration of trastuzumab in patients with HER2 positive breast carcinomatous meningitis

Publication date: May 2018
Source:European Journal of Cancer, Volume 95
Author(s): Claire Bonneau, Gilles Paintaud, Olivier Trédan, Coraline Dubot, Céline Desvignes, Véronique Dieras, Sophie Taillibert, Patricia Tresca, Isabelle Turbiez, Jacques Li, Christophe Passot, Fawzia Mefti, Emmanuelle Mouret-Fourme, Emilie Le Rhun, Maya Gutierrez
PurposeLeptomeningeal carcinomatosis (MC) is commonly associated with HER2-positive breast cancer (HER2-BC), with a poor prognosis and no standardised treatment. We conducted a phase I dose-escalation study of intrathecal (IT) administration of trastuzumab in HER2-BC patients with MC to determine the maximum tolerated dose (MTD), which was based on both the achievement of a trastuzumab intra-cerebrospinal fluid concentration close to a conventional therapeutic plasma concentration (30 mg/L) and/or dose-limiting toxicity (DLT).MethodsThe protocol planned IT administration of trastuzumab (30 mg, 60 mg, 100 mg or 150 mg dose levels) once a week, over the course of at least 4 weeks. Sixteen patients with MC from HER2-BC received IT trastuzumab. Intra-cerebrospinal fluid samples were obtained before each injection for pharmacokinetics.ResultsWe did not observe DLT of IT trastuzumab. Eleven patients had no toxicity attributed to IT trastuzumab. For 60 mg or higher dose levels, minor toxicities attributed to IT trastuzumab included headache (2 patients), nausea (2 patients), vomiting (1 patient), cervical pain (1 patient) and peripheral neuropathy (1 patient). Two patients experienced immediate toxicity including headache or vomiting. The mean residual intra-cerebrospinal fluid concentration of trastuzumab was 27.9 mg/L for the 150 mg dose level. Three patients achieved a clinical response, seven patients had stable disease and four patients had progressive disease.ConclusionsThe MTD and recommended phase II weekly dose of IT trastuzumab in patients with HER2-BC and MC is 150 mg. A phase II trial using this dose regimen in MC from HER2-BC is ongoing.Registration identificationClinicalTrials.gov Identifier: NCT01373710 (https://ift.tt/2IAB1Op).



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Treatment decisions and the impact of adverse events before and during extended endocrine therapy in postmenopausal early breast cancer

Publication date: May 2018
Source:European Journal of Cancer, Volume 95
Author(s): Erik J. Blok, Judith R. Kroep, Elma Meershoek-Klein Kranenbarg, Marjolijn Duijm-de Carpentier, Hein Putter, Gerrit-Jan Liefers, Johan W.R. Nortier, Emiel J.Th. Rutgers, Caroline M. Seynaeve, Cornelis J.H. van de Velde
BackgroundExtended endocrine therapy beyond 5 years for postmenopausal breast cancer has been studied within multiple phase III trials. Treatment compliance in these trials is generally poor. In this analysis, we aimed to determine factors that were associated with participation in the phase III Investigation on the Duration of Extended Adjuvant Letrozole (IDEAL) trial and with early treatment discontinuation, and how this influenced survival outcome.MethodsIn the IDEAL trial, postmenopausal patients were randomised between 2.5 or 5 years of extended letrozole, after completing 5 years of endocrine therapy for hormone receptor-positive early breast cancer. A subgroup of this population participated earlier in the Tamoxifen Exemestane Adjuvant Multinational trial (5 years of exemestane or 2.5 years of tamoxifen followed by exemestane as primary adjuvant therapy) in which we explored which factors were determinative for enrolment in the IDEAL study. In the IDEAL cohort, we evaluated which factors predicted for early treatment discontinuation and the effect of early treatment discontinuation on disease-free survival (DFS).ResultsNodal status, younger age and adjuvant chemotherapy were significantly associated with higher enrolment in the IDEAL trial. In the IDEAL cohort, adverse events (AEs), the type of primary endocrine therapy and the interval between primary and extended therapy were associated with early treatment discontinuation. Among the reported AEs, depressive feelings (56%) were most frequently associated with early treatment discontinuation. Early treatment discontinuation was not associated with worse DFS (hazard ratio [HR] = 1.02, 95% confidence interval = 0.76–1.37).ConclusionsIn this analysis, we found that risk factors were most strongly associated enrolment in the IDEAL trial. In contrast, patient experiences were the most significant factors leading to early treatment discontinuation, with no effect on DFS.



https://ift.tt/2H6eXyc

Bladder cancer survival: Women better off in the long run

Publication date: May 2018
Source:European Journal of Cancer, Volume 95
Author(s): Bettina Kulle Andreassen, Tom Kristian Grimsrud, Erik Skaaheim Haug
AimMortality among patients with bladder cancer is usually reported to be higher for women than men, but how the risk differs and why remain largely unexplained. We also described gender-specific differences in survival for patients with bladder cancer and estimated to what extent they can be explained by differences in T-stage distribution at the first diagnosis.MethodsThe present study comprised all 15,129 new cases of histologically verified invasive and non-invasive urothelial carcinoma of the urinary bladder diagnosed between 1997 and 2011 as registered in the Cancer Registry of Norway. Gender-specific excess mortality risk rates and risk ratios were calculated based on a flexible parametric relative survival model adjusting for T-stage and age, allowing the effect of gender to vary over time. We also present gender-specific relative survival curves for different T-stage patterns adjusted for age.ResultsRisk rates were significantly higher for women than men up to 2 years after bladder cancer diagnosis, particularly for muscle-invasive cancers. Thereafter, risk rates appeared to be higher in men. Adverse T-Stage distribution in women explained half of the unfavourable survival difference in female patients 2 years after diagnosis.ConclusionThe common view of worse bladder cancer prognosis in women than in men needs to be revised. Norwegian women have a less favourable prognosis solely within the first 2 years after diagnosis, particularly when diagnosed with a muscle-invasive tumour; parts of this discrepancy can be attributed to more severe initial diagnoses in women.



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Efficacy of cabazitaxel rechallenge in heavily treated patients with metastatic castration-resistant prostate cancer

Publication date: Available online 7 April 2018
Source:European Journal of Cancer
Author(s): Constance Thibault, Jean-Christophe Eymard, Alison Birtle, Michael Krainer, Giulia Baciarello, Aude Fléchon, Sylvestre Le Moulec, Dominique Spaeth, Brigitte Laguerre, Orazio Caffo, Jean-Laurent Deville, Phillipe Beuzeboc, Ali Hasbini, Marine Gross-Goupil, Carole Helissey, Mostefa Bennamoun, Anne-Claire Hardy-Bessard, Stéphane Oudard
BackgroundTreatment option in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel (DOC), cabazitaxel (CABA) and new hormone therapy (NHT) is limited. Rechallenge with DOC is limited because of cumulative toxicities. This study investigated the activity and safety of CABA rechallenge in mCRPC.Patients and methodsClinical data were collected retrospectively in 17 centres in Europe. Eligible patients had undergone rechallenge with cabazitaxel after three previous lines of treatment (DOC, NHT and CABA, in any order). Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan–Meier method. Data on toxicities were collected.ResultsA total of 69 of 562 patients (Eastern Cooperative Oncology Group performance status 0–1 69%) were rechallenged with CABA (25 mg/m² q3w, 58%; 20 mg/m² q3w, 27.5%; other, 14.5%) for 1–10 (median 6) cycles; 76.8% received prophylactic granulocyte colony-stimulating factor. Median radiological or clinical PFS with CABA rechallenge was 7.8 months and 11.9 months with initial CABA therapy. OS was 13.7 months (95% confidence interval [CI]: 9.3–15.7) from the first CABA rechallenge cycle, 59.9 months (47.8–67.1) from the first life-extending therapy in mCRPC and 78.3 months (66.4–90.7) from mCRPC diagnosis. Best clinical benefit was improved (34.3%) or stable (47.8%). Lack of response to rechallenge occurred in 17.9% of patients (3.1% with initial CABA). The level of prostate-specific antigen decreased by ≥ 50% in 24% of patients at rechallenge (71% with initial CABA). There was no grade ≥III peripheral neuropathy or nail disorders.ConclusionsCABA rechallenge may be a treatment option without cumulative toxicity in heavily pretreated patients with mCRPC who are still fit and had a progression >3 months after the last CABA injections.



https://ift.tt/2H83Kx8

Micro-nano-bio acoustic system for the detection of foodborne pathogens in real samples

Publication date: 15 July 2018
Source:Biosensors and Bioelectronics, Volume 111
Author(s): George Papadakis, Pavla Murasova, Audrey Hamiot, Katerina Tsougeni, Georgia Kaprou, Michael Eck, David Rabus, Zuzana Bilkova, Bruno Dupuy, Gerhard Jobst, Angeliki Tserepi, Evangelos Gogolides, Electra Gizeli
The fast and efficient detection of foodborne pathogens is a societal priority, given the large number of food-poisoning outbreaks, and a scientific and technological challenge, given the need to detect as little as 1 viable cell in 25 gr of food. Here, we present the first approach that achieves the above goal, thanks to the use of a micro/nano-technology and the detection capability of acoustic wave sensors. Starting from 1 Salmonella cell in 25 ml of milk, we employ immuno-magnetic beads to capture cells after only 3 h of pre-enrichment and subsequently demonstrate efficient DNA amplification using the Loop Mediated Isothermal Amplification method (LAMP) and acoustic detection in an integrated platform, within an additional ½ h. The demonstrated 4 h sample-to-analysis time comes as a huge improvement to the current need of few days to obtain the same result. In addition, the work presents the first reported Lab-on-Chip platform that comprises an acoustic device as the sensing element, exhibiting impressive analytical features, namely, an acoustic limit of detection of 2 cells/μl or 3 aM of the DNA target and ability to detect in a label-free manner dsDNA amplicons in impure samples. The use of food samples together with the incorporation of the necessary pre-enrichment step and ability for multiple analysis with an internal control, make the proposed methodology highly relevant to real-world applications. Moreover, the work suggests that acoustic wave devices can be used as an attractive alternative to electrochemical sensors in integrated platforms for applications in food safety and the point-of-care diagnostics.



https://ift.tt/2uTYc4e

Highly sensitive label-free amperometric immunoassay of prostate specific antigen using hollow dendritic AuPtAg alloyed nanocrystals

Publication date: 15 July 2018
Source:Biosensors and Bioelectronics, Volume 111
Author(s): Ya-Cheng Shi, Ai-Jun Wang, Pei-Xin Yuan, Lu Zhang, Xiliang Luo, Jiu-Ju Feng
Herein, well-defined hollow dendritic AuPtAg alloyed nanocrystals (ANCs) were synthesized by a simple L-proline-mediated one-pot aqueous method. More importantly, the synthesized hollow dendritic architectures provide a suitable platform for immobilization of anti-prostate specific antigen (PSA). The resultant label-free immunosensor exhibited the improved performance for highly sensitive detection of PSA based on the enhanced catalytic currents of K3[Fe(CN)6] as a signal probe. Impressively, the immunosensor showed the wide linear range of 0.05–50 ng mL^–1 and low detection limit of 0.017 ng mL^–1 under optimal conditions for the assay of PSA, couple with the improved stability, reproducibility and selectivity. It provides a promising platform for clinical research and diagnosis.



https://ift.tt/2Hj4Aoa

A brief history of sex determination

Publication date: Available online 7 April 2018
Source:Molecular and Cellular Endocrinology
Author(s): Isabelle Stévant, Marilena D. Papaioannou, Serge Nef
A fundamental biological question that has puzzled, but also fascinated mankind since antiquity is the one pertaining to the differences between sexes. Ancient cultures and mythologies poetically intended to explain the origin of the two sexes; philosophy offered insightful albeit occasionally paradoxical perceptions about men and women; and society as a whole put forward numerous intuitive observations about the traits that distinguish the two sexes. However, it was only through meticulous scientific research that began in the 16th century, and gradual technical improvements that followed over the next centuries, that the study of sex determination bore fruit. Here, we present a brief history of sex determination studies from ancient times until today, by selectively interviewing some of the milestones in the field. We complete our review by outlining some yet unanswered questions and proposing future experimental directions.



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