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1.  Feasibly of axitinib as first-line therapy for advanced or metastatic renal cell carcinoma: a single-institution experience in Japan 
BMC Urology  2015;15:32.
Clinical benefit of axitinib as a first line agent to treat patients with metastatic renal cell carcinoma (mRCC), or locally advanced renal cell carcinoma (RCC) have not been clearly demonstrated. The aim of this study was to evaluate the efficacy and safety of axitinib as first-line therapy in Japanese patients with locally advanced RCC or mRCC.
In this retrospective study, we focused on eighteen patients who underwent first-line therapy with axitinib between May 2012 and May 2014 at Hirosaki University. Axitinib was orally administered at a dose of 10 mg daily. Progression-free survival (PFS) was the primary endpoint, while secondary endpoints included overall response rate (ORR) and adverse events (AEs).
All patients had histologically proven clear cell RCC. The median duration of the administration of axitinib was 10.8 months. According to the response evaluation criteria for solid tumors, five patients (27.8%) achieved a partial response and nine (50%) had stable disease. The 1-year PFS rate was 84.4%, and the median PFS was 20.4 months (95% confidence interval, 17.5 – 21.7). No serious AEs were reported during the study, and there were no toxicity-related deaths.
In the current study, axitinib showed acceptable oncological outcomes and favorable safety profile as first-line therapy for locally advanced RCC or mRCC in treatment-naïve Japanese patients. Thus, first-line therapy with axitinib may provide a feasible option for treatment of advanced RCC or mRCC patients.
PMCID: PMC4417199  PMID: 25887125
Axitinib renal cell carcinoma; First-line; Vascular endothelial growth factor receptor; Advanced renal cell carcinoma; Metastatic renal cell carcinoma
2.  Tramadol for premature ejaculation: a systematic review and meta-analysis 
BMC Urology  2015;15:6.
Tramadol is a centrally acting analgesic prescribed off-label for the treatment of premature ejaculation (PE). However, tramadol may cause addiction and difficulty in breathing and the beneficial effect of tramadol in PE is yet not supported by a high level of evidence. The purpose of this study was to systematically review the evidence from randomised controlled trials (RCT) for tramadol in the management of PE.
We searched bibliographic databases including MEDLINE to August 2014 for RCTs. The primary outcome was intra-vaginal ejaculatory latency time (IELT). Methodological quality of RCTs was assessed. Between-group differences in IELT and other outcomes were pooled across RCTs in a meta-analysis. Statistical and clinical between-trial heterogeneity was assessed.
A total of eight RCTs that evaluated tramadol against a comparator were included. The majority of RCTs were of unclear methodological quality due to limited reporting. Pooled evidence (four RCTs, 721 participants), suggests that tramadol is significantly more effective than placebo at increasing IELT over eight to 12 weeks (p = 0.0007). However, a high level of statistical heterogeneity is evident (I-squared = 74%). Single RCT evidence indicates that tramadol is significantly more effective than paroxetine taken on-demand, sildenafil, lidocaine gel, or behavioural therapy on IELT in men with PE. Tramadol is associated with significantly more adverse events including: erectile dysfunction, constipation, nausea, headache, somnolence, dry mouth, dizziness, pruritus, and vomiting, than placebo or behavioural therapy over eight to 12 weeks of treatment. However, addiction problems or breathing difficulties reported by patients for PE is not assessed in the current evidence base.
Tramadol appears effective in the treatment of PE. However, these findings should be interpreted with caution given the observed levels of between-trial heterogeneity and the reporting quality of the available evidence. The variability across placebo-controlled trials in terms of the tramadol dose evaluated and the treatment duration does not permit any assessment of a safe and effective minimum daily dose. The long-term effects and side effects, including addiction potential, for men with PE have not been evaluated in the current evidence base.
Trial registration
The review is registered on PROSPERO 2013:CRD42013005289.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2490-15-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4417346  PMID: 25636495
Premature ejaculation; Tramadol; Systematic review; Meta-analysis; Efficacy; Safety
3.  Epidemiological Trends in Invasive Mechanical Ventilation in the United States: A Population-Based Study 
Journal of critical care  2015;30(6):1217-1221.
Epidemiological trends for invasive mechanical ventilation (IMV) have not been clearly defined. We sought to define trends for IMV in the US and assess for disease-specific variation for three common causes of respiratory failure: pneumonia, heart failure (HF), and chronic obstructive pulmonary disease (COPD).
We calculated national estimates for utilization of non-surgical IMV cases from the Nationwide Inpatient Sample from 1993-2009 and compared trends for COPD, HF, and pneumonia.
We identified 8,309,344 cases of IMV from 1993-2009. Utilization of IMV for non-surgical indications increased from 178.9/100,000 in 1993 to 310.9/100,000 US adults in 2009. Pneumonia cases requiring IMV showed the largest increase (103.6%), whereas COPD cases remained relatively stable (2.5% increase) and HF cases decreased by 55.4%. Similar demographic and clinical changes were observed for pneumonia, COPD, and HF, with cases of IMV becoming younger, more ethnically diverse, and more frequently insured by Medicaid. Outcome trends for patients differed based on diagnosis. Adjusted hospital mortality decreased over time for cases of pneumonia (OR per 5 years=0.89, 95% CI 0.88-0.90) and COPD (OR per 5 years=0.97, 95% CI 0.97-0.98) but increased for HF (OR per 5 years=1.10, 95% CI 1.09-1.12).
Utilization of IMV in the US increased from 1993-2009 with a decrease in overall mortality. However, trends in utilization and outcomes of IMV differed markedly based on diagnosis. Unlike favorable outcome trends in pneumonia and COPD, hospital mortality for HF has not improved. Further studies to investigate the outcome gap between HF and other causes of respiratory failure are needed.
PMCID: PMC4628853  PMID: 26271686
Mortality/Trends; Epidemiology; Respiratory Insufficiency/Mortality; Respiratory Insufficiency/epidemiology; United States/epidemiology
4.  EGF as a New Therapeutic Target for Medulloblastoma Metastasis 
Medulloblastoma (MB) is a malignant pediatric brain tumor known for its aggressive metastatic potential. Despite the well-documented migration of MB cells to other parts of the brain and spinal column, MB chemotaxis is poorly understood. Herein, we examined the in vitro migratory and cellular responses of MB-derived cells to external signaling of Epidermal Growth Factor (EGF), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF-BB), and the stromal cell-derived factors 1-alpha (SDF-1). Experiments utilized transwell assays and immunocytochemistry to identify receptor activation in MB migration, and used a microfluidic platform to examine directionality, trajectory, and gradient-dependence of motile cells. Data illustrates that MB-derived cells respond strongly to EGF in a dosage and gradient-dependent manner with increased EGF-R activation, and show that high EGF gradient fields cause an increased number of cells to migrate longer directed distances. Our results provide evidence that EGF and its receptor play an important role than previously documented in MB chemotactic migration than previously documented and should be considered for developing migration-target therapies against MB metastasis.
PMCID: PMC4648625  PMID: 26594253
Pediatric cancer; chemotaxis; microfluidics; gradients
5.  Stroke Literature Synopses: Basic Science (2015/October) 
PMCID: PMC4659724  PMID: 26534972
6.  B Cell Responses during Secondary Dengue Virus Infection Are Dominated by Highly Cross-Reactive, Memory-Derived Plasmablasts 
Journal of Virology  2016;90(12):5574-5585.
Dengue virus (DENV) infection results in the production of both type-specific and cross-neutralizing antibodies. While immunity to the infecting serotype is long-lived, heterotypic immunity wanes a few months after infection. Epidemiological studies link secondary heterotypic infections with more severe symptoms, and cross-reactive, poorly neutralizing antibodies have been implicated in this increased disease severity. To understand the cellular and functional properties of the acute dengue virus B cell response and its role in protection and immunopathology, we characterized the plasmablast response in four secondary DENV type 2 (DENV2) patients. Dengue plasmablasts had high degrees of somatic hypermutation, with a clear preference for replacement mutations. Clonal expansions were also present in each donor, strongly supporting a memory origin for these acutely induced cells. We generated 53 monoclonal antibodies (MAbs) from sorted patient plasmablasts and found that DENV-reactive MAbs were largely envelope specific and cross neutralizing. Many more MAbs neutralized DENV than reacted to envelope protein, emphasizing the significance of virion-dependent B cell epitopes and the limitations of envelope protein-based antibody screening. A majority of DENV-reactive MAbs, irrespective of neutralization potency, enhanced infection by antibody-dependent enhancement (ADE). Interestingly, even though DENV2 was the infecting serotype in all four patients, several MAbs from two patients neutralized DENV1 more potently than DENV2. Further, half of all type-specific neutralizing MAbs were also DENV1 biased in binding. Taken together, these findings are reminiscent of original antigenic sin (OAS), given that the patients had prior dengue virus exposures. These data describe the ongoing B cell response in secondary patients and may further our understanding of the impact of antibodies in dengue virus pathogenesis.
IMPORTANCE In addition to their role in protection, antibody responses have been hypothesized to contribute to the pathology of dengue. Recent studies characterizing memory B cell (MBC)-derived MAbs have provided valuable insight into the targets and functions of B cell responses generated after DENV exposure. However, in the case of secondary infections, such MBC-based approaches fail to distinguish acutely induced cells from the preexisting MBC pool. Our characterization of plasmablasts and plasmablast-derived MAbs provides a focused analysis of B cell responses activated during ongoing infection. Additionally, our studies provide evidence of OAS in the acute-phase dengue virus immune response, providing a basis for future work examining the impact of OAS phenotype antibodies on protective immunity and disease severity in secondary infections.
PMCID: PMC4886779  PMID: 27030262
7.  Amygdala functional connectivity, HPA axis genetic variation, and life stress in children and relations to anxiety and emotion regulation 
Journal of abnormal psychology  2015;124(4):817-833.
Internalizing pathology is related to alterations in amygdala resting state functional connectivity, potentially implicating altered emotional reactivity and/or emotion regulation in the etiological pathway. Importantly, there is accumulating evidence that stress exposure and genetic vulnerability impact amygdala structure/function and risk for internalizing pathology. The present study examined whether early life stress and genetic profile scores (10 single nucleotide polymorphisms within four hypothalamic-pituitary-adrenal axis genes: CRHR1, NR3C2, NR3C1, and FKBP5) predicted individual differences in amygdala functional connectivity in school-age children (9–14 year olds; N=120). Whole-brain regression analyses indicated that increasing genetic ‘risk’ predicted alterations in amygdala connectivity to the caudate and postcentral gyrus. Experience of more stressful and traumatic life events predicted weakened amygdala-anterior cingulate cortex connectivity. Genetic ‘risk’ and stress exposure interacted to predict weakened connectivity between the amygdala and the inferior and middle frontal gyri, caudate, and parahippocampal gyrus in those children with the greatest genetic and environmental risk load. Furthermore, amygdala connectivity longitudinally predicted anxiety symptoms and emotion regulation skills at a later follow-up. Amygdala connectivity mediated effects of life stress on anxiety and of genetic variants on emotion regulation. The current results suggest that considering the unique and interacting effects of biological vulnerability and environmental risk factors may be key to understanding the development of altered amygdala functional connectivity, a potential factor in the risk trajectory for internalizing pathology.
PMCID: PMC4662045  PMID: 26595470
amygdala; functional connectivity; stress; genetics; anxiety
8.  Antioxidant and anti-inflammatory action of melatonin in an experimental model of secondary biliary cirrhosis induced by bile duct ligation 
World Journal of Gastroenterology  2016;22(40):8918-8928.
To evaluate the effects of melatonin (Mel) on oxidative stress in an experimental model of bile duct ligation (BDL).
Male Wistar rats (n = 32, weight ± 300 g) were allocated across four groups: CO (sham BDL), BDL (BDL surgery), CO + Mel (sham BDL and Mel administration) and BDL + Mel (BDL surgery and Mel administration). Mel was administered intraperitoneally for 2 wk, starting on postoperative day 15, at a dose of 20 mg/kg.
Mel was effective at the different standards, reestablishing normal liver enzyme levels, reducing the hepatosomatic and splenosomatic indices, restoring lipoperoxidation and antioxidant enzyme concentrations, reducing fibrosis and inflammation, and thereby reducing liver tissue injury in the treated animals.
The results of this study suggest a protective effect of Mel when administered to rats with secondary biliary cirrhosis induced by BDL.
PMCID: PMC5083797  PMID: 27833383
Antioxidant; Cirrhosis; Fibrosis; Melatonin; Oxidative stress
10.  Clinical nomogram to predict bone-only metastasis in patients with early breast carcinoma 
British Journal of Cancer  2015;113(7):1003-1009.
Bone is one of the most common sites of distant metastasis in breast cancer. The purpose of this study was to combine selected clinical and pathologic variables to develop a nomogram that can predict the likelihood of bone-only metastasis (BOM) as the first site of recurrence in patients with early breast cancer.
Medical records of patients with non-metastatic breast cancer were retrospectively collected. On the basis of the analysis of patient and tumour characteristics using the Cox proportional hazards regression model, a nomogram to predict BOM was constructed for a 4175-patient-training cohort. The nomogram was validated in an independent cohort of 579 patients.
Among 4175 patients with non-metastatic breast cancer, 314 developed subsequent BOM. Age, T classification, lymph node status, lymphovascular space invasion, and hormone receptor status were significantly and independently associated with subsequent BOM. The nomogram had a concordance index of 0.69 in the training set and 0.73 in the validation set.
We have developed a clinical nomogram to predict subsequent BOM in patients with non-metastatic breast cancer. Selection of a patient population at high risk for BOM could facilitate research of more specific staging approaches or the selective use of bone-targeted therapy.
PMCID: PMC4651124  PMID: 26393887
bone metastasis; nomogram; ER+ breast cancer; prediction
11.  mouseTube – a database to collaboratively unravel mouse ultrasonic communication 
F1000Research  2016;5:2332.
Ultrasonic vocalisation is a broadly used proxy to evaluate social communication in mouse models of neuropsychiatric disorders. The efficacy and robustness of testing these models suffer from limited knowledge of the structure and functions of these vocalisations as well as of the way to analyse the data. We created mouseTube, an open database with a web interface, to facilitate sharing and comparison of ultrasonic vocalisations data and metadata attached to a recording file. Metadata describe 1) the acquisition procedure, e.g., hardware, software, sampling frequency, bit depth; 2) the biological protocol used to elicit ultrasonic vocalisations; 3) the characteristics of the individual emitting ultrasonic vocalisations ( e.g., strain, sex, age). To promote open science and enable reproducibility, data are made freely available. The website provides searching functions to facilitate the retrieval of recording files of interest. It is designed to enable comparisons of ultrasonic vocalisation emission between strains, protocols or laboratories, as well as to test different analysis algorithms and to search for protocols established to elicit mouse ultrasonic vocalisations. Over the long term, users will be able to download and compare different analysis results for each data file. Such application will boost the knowledge on mouse ultrasonic communication and stimulate sharing and comparison of automatic analysis methods to refine phenotyping techniques in mouse models of neuropsychiatric disorders.
PMCID: PMC5081159  PMID: 27830061
Mouse; ultrasonic vocalisations; mouse communication; database; mouseTube; mouse behaviour; open data; open analysis
12.  MYB-related transcription factors function as regulators of the circadian clock and anthocyanin biosynthesis in Arabidopsis 
Plant Signaling & Behavior  2016;11(3):e1139278.
In Arabidopsis, the MYB (myeloblastosis) gene family contains more than 190 members, which play a number of roles in plant growth and development. Based on their protein structure, this gene family was divided into several subclasses, including the MYB-related class. Currently, an MYB-related gene designated as MYB-like Domain (AtMYBD) has been shown to function as a positive regulator of anthocyanin biosynthesis in Arabidopsis. This gene was found to belong to the CCA1-like (circadian clock-associated 1) group, which represents several genes that are master regulators of the circadian clocks of plants. Here, we speculate that AtMYBD is able to regulate anthocyanin biosynthesis in Arabidopsis thaliana in a circadian clock-related manner.
PMCID: PMC4883932  PMID: 26905954
Anthocyanin; Arabidopsis; AtMYBD (AT1G70000), circadian clock; MYB-related
13.  Tract-Based Analysis of White Matter Degeneration in Alzheimer’s Disease 
Neuroscience  2015;301:79-89.
Although much prior work has focused on the known cortical pathology that defines Alzheimer’s disease (AD) histologically, recent work has additionally demonstrated substantial damage to the cerebral white matter in this condition. While there is large evidence of diffuse damage to the white matter in AD, it is unclear whether specific white matter tracts exhibit a more accelerated pattern of damage and whether the damage is associated with the classical neurodegenerative changes of AD. In this study, we investigated physiological differences in the large fascicular bundles of the cerebral white matter of individuals with AD and mild cognitive impairment (MCI), using recently developed automated diffusion tractography procedures in the Alzheimer’s disease Neuroimaging Initiative (ADNI) dataset. Eighteen major fiber bundles in a total of 36 individuals with AD, 81 MCI and 60 control participants were examined with the TRActs Constrained by UnderLying Anatomy (TRACULA) procedure available as part of the FreeSurfer image processing software package. For each fiber bundle, the mean fractional anisotropy (FA), and mean, radial and axial diffusivities were calculated. Individuals with AD had increased diffusivities in both left and right cingulum-angular bundles compared to control participants (p<0.001). Individuals with MCI also had increased axial and mean diffusivities and increased FA in both cingulum-angular bundles compared to control participants (p<0.05) and decreased radial diffusivity compared to individuals with AD (p<0.05). We additionally examined how white matter deterioration relates to hippocampal volume, a traditional imaging measure of AD pathology, and found the strongest negative correlations in AD patients between hippocampal volume and the diffusivities of the cingulum-angular and cingulum-cingulate gyrus bundles and of the corticospinal tracts (p<0.05). However, statistically controlling for hippocampal volume did not remove all group differences in white matter measures, suggesting a unique contribution of white matter damage to AD unexplained by this disease biomarker. These results suggest that 1) AD-associated deterioration of white matter fibers is greatest in tracts known to be connected to areas of pathology in AD and 2) lower white matter tract integrity is more diffusely associated with lower hippocampal volume indicating that the pathology in the white matter follows to some degree the neurodegenerative staging and progression of this condition.
PMCID: PMC4505932  PMID: 26026680
Alzheimer’s disease; mild cognitive impairment; white matter; hippocampus; cingulum and angular bundle
14.  General practitioners’ perceptions of COPD treatment: thematic analysis of qualitative interviews 
In Denmark, the treatment of COPD is mainly managed by general practitioners (GPs). Pulmonary rehabilitation (PR) is available to patients with COPD in the local community by GP referral, but in practice, many patients do not participate in rehabilitation. The aim of our study was to explore 1) GPs’ perceptions of their role and responsibility in the rehabilitation of patients with COPD, and 2) GPs’ perceptions of how patients manage their COPD.
The study was based on a qualitative design with semi-structured key-informant interviews with GPs. Investigator triangulation was applied during data generation, and analysis was done using thematic analysis methodology.
Our main findings were that GPs relied on patients themselves to take the initiative to make clinic appointments and on professionals at health centers to provide the PR including consultations on lifestyle changes. The GPs experienced that patients chose to come to the clinic when they were in distress and that patients either declined or had poor adherence to rehabilitation when offered. The GPs were relieved that the health centers had taken over the responsibility of rehabilitation as GPs lacked the resources to discuss rehabilitation and follow up on individual plans.
Our study suggested a potential self-reinforcing problem with the treatment of COPD being mainly focused on medication rather than on PR. Neither GPs nor patients used a proactive approach. Further, GPs were not fully committed to discuss non-pharmacological treatment and perceived the patients as unmotivated for PR. As such, there is a need for optimizing non-pharmacological treatment of COPD and in particular the referral process to PR.
Video abstract
PMCID: PMC4994802  PMID: 27574417
non-pharmacological treatment; motivation theory; primary care; treatment approach; pulmonary rehabilitation; qualitative research
15.  Intranasal Introduction of Fc-Fused Interleukin-7 Provides Long-Lasting Prophylaxis against Lethal Influenza Virus Infection 
Journal of Virology  2016;90(5):2273-2284.
Influenza A virus (IAV) infection frequently causes hospitalization and mortality due to severe immunopathology. Annual vaccination and antiviral drugs are the current countermeasures against IAV infection, but they have a limited efficacy against new IAV variants. Here, we show that intranasal pretreatment with Fc-fused interleukin-7 (IL-7–mFc) protects mice from lethal IAV infections. The protective activity of IL-7–mFc relies on transcytosis via neonatal Fc receptor (FcRn) in the lung and lasts for several weeks. Introduction of IL-7–mFc alters pulmonary immune environments, leading to recruitment of T cells from circulation and their subsequent residency as tissue-resident memory-like T (TRM-like) cells. IL-7–mFc-primed pulmonary TRM-like cells contribute to protection upon IAV infection by dual modes. First, TRM-like cells, although not antigen specific but polyclonal, attenuate viral replication at the early phase of IAV infection. Second, TRM-like cells augment expansion of IAV-specific cytotoxic T lymphocytes (CTLs), in particular at the late phase of infection, which directly control viruses. Thus, accelerated viral clearance facilitated by pulmonary T cells, which are either antigen specific or not, alleviates immunopathology in the lung and mortality from IAV infection. Depleting a subset of pulmonary T cells indicates that both CD4 and CD8 T cells contribute to protection from IAV, although IL-7-primed CD4 T cells have a more prominent role. Collectively, we propose intranasal IL-7–mFc pretreatment as an effective means for generating protective immunity against IAV infections, which could be applied to a potential prophylaxis for influenza pandemics in the future.
IMPORTANCE The major consequence of a highly pathogenic IAV infection is severe pulmonary inflammation, which can result in organ failure and death at worst. Although vaccines for seasonal IAVs are effective, frequent variation of surface viral proteins hampers development of protective immunity. In this study, we demonstrated that intranasal IL-7–mFc pretreatment protected immunologically naive mice from lethal IAV infections. Intranasal pretreatment with IL-7–mFc induced an infiltration of T cells in the lung, which reside as effector/memory T cells with lung-retentive markers. Those IL-7-primed pulmonary T cells contributed to development of protective immunity upon IAV infection, reducing pulmonary immunopathology while increasing IAV-specific cytotoxic T lymphocytes. Since a single treatment with IL-7–mFc was effective in the protection against multiple strains of IAV for an extended period of time, our findings suggest a possibility that IL-7–mFc treatment, as a potential prophylaxis, can be developed for controlling highly pathogenic IAV infections.
PMCID: PMC4810684  PMID: 26656713
16.  DHA but Not EPA Emulsions Preserve Neurological and Mitochondrial Function after Brain Hypoxia-Ischemia in Neonatal Mice 
PLoS ONE  2016;11(8):e0160870.
Background and Purpose
Treatment with triglyceride emulsions of docosahexaenoic acid (tri-DHA) protected neonatal mice against hypoxia-ischemia (HI) brain injury. The mechanism of this neuroprotection remains unclear. We hypothesized that administration of tri-DHA enriches HI-brains with DHA/DHA metabolites. This reduces Ca2+-induced mitochondrial membrane permeabilization and attenuates brain injury.
10-day-old C57BL/6J mice following HI-brain injury received tri-DHA, tri-EPA or vehicle. At 4–5 hours of reperfusion, mitochondrial fatty acid composition and Ca2+ buffering capacity were analyzed. At 24 hours and at 8–9 weeks of recovery, oxidative injury, neurofunctional and neuropathological outcomes were evaluated. In vitro, hyperoxia-induced mitochondrial generation of reactive oxygen species (ROS) and Ca2+ buffering capacity were measured in the presence or absence of DHA or EPA.
Only post-treatment with tri-DHA reduced oxidative damage and improved short- and long-term neurological outcomes. This was associated with increased content of DHA in brain mitochondria and DHA-derived bioactive metabolites in cerebral tissue. After tri-DHA administration HI mitochondria were resistant to Ca2+-induced membrane permeabilization. In vitro, hyperoxia increased mitochondrial ROS production and reduced Ca2+ buffering capacity; DHA, but not EPA, significantly attenuated these effects of hyperoxia.
Post-treatment with tri-DHA resulted in significant accumulation of DHA and DHA derived bioactive metabolites in the HI-brain. This was associated with improved mitochondrial tolerance to Ca2+-induced permeabilization, reduced oxidative brain injury and permanent neuroprotection. Interaction of DHA with mitochondria alters ROS release and improves Ca2+ buffering capacity. This may account for neuroprotective action of post-HI administration of tri-DHA.
PMCID: PMC4981459  PMID: 27513579
17.  Comparison of Salivary pH, Buffering Capacity and Alkaline Phosphatase in Smokers and Healthy Non-Smokers 
Saliva contains alkaline phosphatase (ALP)—a key intracellular enzyme related to destructive processes and cellular damage—and has buffering capacity (BC) against acids due to the presence of bicarbonate and phosphate ions. Smoking may have deleterious effects on the oral environment due to pH changes which can affect ALP activity. This study aimed to evaluate the salivary pH, BC and ALP activity of male smokers and healthy non-smokers.
This retrospective cohort study took place between August 2012 and December 2013. A total of 251 healthy male non-smokers and 259 male smokers from Hamadan, Iran, were selected. Unstimulated whole saliva was collected from each participant and pH and BC were determined using a pH meter. Salivary enzymes were measured by spectrophotometric assay.
Mean salivary pH (7.42 ± 0.48 and 7.52 ± 0.43, respectively; P = 0.018) and BC (3.41 ± 0.54 and 4.17 ± 0.71; P = 0.001) was significantly lower in smokers compared to non-smokers. Mean ALP levels were 49.58 ± 23.33 IU/L among smokers and 55.11 ± 27.85 IU/L among non-smokers (P = 0.015).
Significantly lower pH, BC and ALP levels were observed among smokers in comparison to a healthy control group. These salivary alterations could potentially be utilised as biochemical markers for the evaluation of oral tissue function and side-effects among smokers. Further longitudinal studies are recommended to evaluate the effects of smoking on salivary components.
PMCID: PMC4996294  PMID: 27606111
Saliva; Alkaline Phosphatase; Acids; Buffers; Smoking
18.  Coupled RNA-SIP and metatranscriptomics of active chemolithoautotrophic communities at a deep-sea hydrothermal vent 
The ISME Journal  2016;10(8):1925-1938.
The chemolithoautotrophic microbial community of the rocky subseafloor potentially provides a large amount of organic carbon to the deep ocean, yet our understanding of the activity and metabolic complexity of subseafloor organisms remains poorly described. A combination of metagenomic, metatranscriptomic, and RNA stable isotope probing (RNA-SIP) analyses were used to identify the metabolic potential, expression patterns, and active autotrophic bacteria and archaea and their pathways present in low-temperature hydrothermal fluids from Axial Seamount, an active submarine volcano. Metagenomic and metatranscriptomic results showed the presence of genes and transcripts for sulfur, hydrogen, and ammonium oxidation, oxygen respiration, denitrification, and methanogenesis, as well as multiple carbon fixation pathways. In RNA-SIP experiments across a range of temperatures under reducing conditions, the enriched 13C fractions showed differences in taxonomic and functional diversity. At 30 °C and 55 °C, Epsilonproteobacteria were dominant, oxidizing hydrogen and primarily reducing nitrate. Methanogenic archaea were also present at 55 °C, and were the only autotrophs present at 80 °C. Correspondingly, the predominant CO2 fixation pathways changed from the reductive tricarboxylic acid (rTCA) cycle to the reductive acetyl-CoA pathway with increasing temperature. By coupling RNA-SIP with meta-omics, this study demonstrates the presence and activity of distinct chemolithoautotrophic communities across a thermal gradient of a deep-sea hydrothermal vent.
PMCID: PMC5029171  PMID: 26872039
19.  Spatial heterogeneity in repeated measures of perceived stress among car commuters in Scania, Sweden 
Long commutes by car are stressful. Most research studying health effects of commuting have summarized cross-sectional data for large regions. This study investigated whether the levels of stress and individual characteristics among 30–60 min car commuters were similar across different places within the county of Scania, Sweden, and if there were changes over time.
The study population was drawn from a public health survey conducted in 2000, with follow-ups in 2005 and 2010. The study population was selected from the 8206 study participants that completed the questionnaire at all three time points. Commuting questions in the 2010 questionnaire assessed exposure concurrently for that year and retrospectively for 2000 and 2005. In total, 997 persons aged 18–65 and working 15–60 h/week had commuted by car 30–60 min at least at one time point. Geographically weighted proportions of stress among 30–60 min car commuters were calculated for each year and classified into geographically continuous groups based on Wards algorithm. Stress levels, sociodemographic characteristics and commuting characteristics were compared for areas with high and low stress in relation to the rest of the county. This novel methodology can be adapted to other study settings where individual-level data are available over time.
Spatial heterogeneity in stress levels was observed and the locations of high and low stress areas changed over time. Local differences in stress among participants were only partly explained by sociodemographic characteristics. Stressed commuters in the high stress area in 2000 were more likely to maintain their commuting mode and time than those not stressed. Stressed commuters in the high stress area in 2000 were also more likely to have the same workplace location in 2010, while stressed commuters in the high stress area in 2010 were more likely to have the same residential location as in 2000.
The relationship between commuting mode and time and stress is variable in place and time. Better understanding of commuting contexts such as congestion is needed in research on the health effects of commuting.
PMCID: PMC4964024  PMID: 27465506
Stress; Commuting; Cross-sectional; Repeated measures; Spatial heterogeneity; Geographically weighted proportions; Sweden
20.  Durable intermediate-to long-term outcomes after minimally invasive transiliac sacroiliac joint fusion using triangular titanium implants 
Sacroiliac joint (SIJ) fusion (SIJF), first performed 95 years ago, has become an increasingly accepted surgical option for chronic SIJ dysfunction. Few studies have reported intermediate- or long-term outcomes after SIJF.
The objective of this study is to determine patient-based outcomes after SIJF for chronic SIJ dysfunction due to degenerative sacroiliitis or SIJ disruption at ≥3 years of follow-up.
Consecutive patients who underwent SIJF prior to December 2012 were contacted over phone or through email. Participants completed questionnaires in clinic, over phone or by email, regarding SIJ pain, activities related to SIJ dysfunction, and the Oswestry Disability Index. Charts were reviewed to extract baseline parameters and the clinical course of follow-up.
One hundred seven patients were eligible and participated in this study. Mean (standard deviation) preoperative SIJ pain score was 7.5 (1.7). At mean follow-up of 3.7 years, the mean SIJ pain score was 2.6 (representing a 4.8-point improvement from baseline, P<0.0001) and the mean Oswestry Disability Index was 28.2. The ability to perform activities commonly impaired by SIJ dysfunction showed positive improvements in most patients. SIJ revision surgery was uncommon (five patients, 4.7%). Fourteen patients (13.1%) underwent contralateral SIJF during follow-up, 25.2% of patients had additional non-SIJ-related lumbar spine or hip surgeries during follow-up.
In intermediate- to long-term follow-up, minimally invasive transiliac SIJF was associated with improved pain, low disability scores, and improved ability to perform activities of daily living.
PMCID: PMC4948694  PMID: 27471413
sacroiliac joint fusion; chronic low back pain; multicenter study
21.  Effects of combined sunitinib and extracranial stereotactic radiotherapy on bone marrow hematopoiesis 
Oncology Letters  2016;12(3):2139-2144.
There is considerable interest in deploying stereotactic body radiotherapy in combination with immune therapy for patients with extracranial oligometastases. In addition to angiogenesis inhibition, sunitinib appears to mediate antitumor immunity through effects on circulating monocytic cells. The current study investigated the effects of combined sunitinib and stereotactic radiotherapy on hematopoiesis. As part of a phase I/II clinical trial utilizing concurrent sunitinib (25–50 mg on days 1–28) and image-guided radiation therapy (40–50 Gy in 10 fractions starting on days 8–19) for patients with metastatic cancer, the complete blood count, platelet count and automatic differential were performed pretreatment and on days 8 and 19. On average, sunitinib monotherapy for 7 days resulted in a 33% decrease in monocytes and an 18% decrease in neutrophils (P<0.01 for all). Compared to sunitinib alone, combined sunitinib and radiation resulted in a further decrease in neutrophils, lymphocytes and platelets (P<0.05). Following sunitinib and radiation treatment, a greater than average decrease in monocytes (≥200/µl) was associated with a significant increase in progression-free and overall survival times. This exploratory study provides further evidence that monocytes represent a potential biomarker in patients with solid tumors treated with sunitinib.
PMCID: PMC4998656  PMID: 27602153
stereotactic radiotherapy; sunitinib; hematopoiesis; monocytes; tumor immunology
22.  Aripiprazole and Acute Extrapyramidal Symptoms in Children and Adolescents: A Meta-Analysis 
CNS Drugs  2016;30(9):807-818.
Both the US FDA and the European Medicines Agency (EMA) have approved aripiprazole for use in adolescents for specific indications. Given the assumed favorable side-effect profile of aripiprazole, its use in children and adolescents has increased for both official and off-label indications (anxiety disorders, eating disorders, personality disorders). However, several cases of children and adolescents with new-onset extrapyramidal symptoms (EPS) after commencing treatment with aripiprazole have been reported, and a more systematic appraisal of this possible risk is lacking.
We conducted a systematic review and a meta-analysis to assess the evidence for acute EPS (acute dystonia, akathisia, Parkinsonism) associated with the use of aripiprazole in children and adolescents.
We searched the MEDLINE and Embase databases (2003–10 April 2016) for clinical trials in pediatric patients (aged 0–18 years) using the keywords ‘aripiprazole’ (regardless of the formulation) and ‘extrapyramidal symptoms’. We evaluated the abstracts of papers using the following exclusion criteria: (1) study design: case report, letter to the editor, editorial, or poster presentation data; (2) unrelated PICOS (population, intervention, comparators, outcomes, study) structure. We performed a meta-analysis, in which we used effect sizes with 95 % confidence intervals (CIs). To examine the homogeneity of the effect size distribution, we used a Q-statistic. When we observed heterogeneity in effect sizes, we assessed the possible influence of moderator variables (age and sex, mean dose, study duration, and method of measuring EPS incidence) and evaluated the suitability of either a fixed or a random model. Finally, we assessed the incidence of EPS in children and adolescents treated with aripiprazole compared with placebo.
An initial search via PubMed and Embase yielded 328 hits. A manual search of the reference lists of review papers revealed seven additional relevant articles. We included 41 studies, with 2114 pediatric patients, in the meta-analysis. For the analysis of the mean incidence of EPS, data were provided by 24 studies, with a total of 1446 pediatric patients. Meta-analysis revealed a mean EPS incidence of 17.1 % (95 % CI 0.128–0.223). In terms of the incidence of various extrapyramidal side effects, overall, no significant effects of age, sex, mean dose, study duration, or measuring method could be demonstrated. The side effects ‘EPS’, ‘parkinsonism’, and ‘tremor’ were significantly more common in children and adolescents treated with aripiprazole than in those treated with placebo.
Our meta-analysis provides evidence for a non-negligible incidence of acute EPS in children and adolescents treated with aripiprazole. Although the study has several limitations and further investigation is needed, these findings may help clinicians make more balanced treatment choices and more closely monitor the use of this drug in youth.
Electronic supplementary material
The online version of this article (doi:10.1007/s40263-016-0367-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4996892  PMID: 27395403
23.  Association of two Common Single Nucleotide Polymorphisms (+45T/G and +276G/T) of ADIPOQ Gene with Coronary Artery Disease in Type 2 Diabetic Patients 
Iranian Biomedical Journal  2016;20(3):152-160.
Adiponectin, an adipocyte-secreted hormone, is known to have anti-atherogenic, anti-inflammatory, and anti-diabetic properties. In the present study, the association between two common single nucleotide polymorphisms (SNPs) (+45T/G and +276G/T) of ADIOPQ gene and coronary artery disease (CAD) was assessed in the subjects with type 2 diabetes (T2DM).
Genotypes of two SNPs were determined by polymerase chain reaction-restriction fragment length polymorphism in 200 subjects with T2DM (100 subjects with CAD and 100 without CAD).
The frequency of TT genotype of +276G/T was significantly elevated in CAD compared to controls (χ2=7.967, P=0.019). A similar difference was found in the allele frequency of +276G/T between two groups (χ2=3.895, P=0.048). The increased risk of CAD was associated with +276 TT genotype when compared to reference GG genotype (OR=5.158; 95% CI=1.016-26.182, P=0.048). However, no similar difference was found in genotype and allele frequencies of SNP +45T/G between two groups. There was a CAD protective haplotype combination of +276 wild-type and +45 mutant-type allele (276G-45G) (OR=0.37, 95% CI=0.16-0.86, P=0.022) in the subject population.
Our findings indicated that T allele of SNP +276G/T is more associated with the increased risk of CAD in subjects with T2DM. Also, a haplotype combination of +45G/+276G of these two SNPs has a protective effect on the risk of CAD.
PMCID: PMC4949979  PMID: 26781170
Adiponectin; Type 2 diabetes; Cronary artery disease; Single nucleotide polymorphisms
25.  The Influence of Mimicry on the Reduction of Infra-Humanization 
The paper investigates the role of mimicry in the reduction of infra-humanization. Mimicry as an automatic imitation of a partner’s behavior (this is known as “social glue”) connects people (Miles et al., 2010). Empirical findings have confirmed that mimicry leads to favorable treatment of the mimicker (Van Baaren et al., 2003). The mechanism is reciprocal: the mimicker is more positively inclined towards the person mimicked (Chartrand and Bargh, 1999). Mimicry increases the sense of interpersonal closeness, reciprocal similarity, and facilitates the flow of interaction and helping behavior (Stel et al., 2008). At the same time, results point to a spontaneous inhibition of mimicry in the contact with members of negatively stereotyped groups (Bourgeois and Hess, 2008). So than, there are reasons to believe that purposeful activation of mimicry may reduce manifestations of negative attitudes towards others, i.e., infra-humanization. It was expected that imitating a model shown on video would lower the level of infra-humanization, i.e., perceiving another individual as less capable than the Self of experiencing exclusively human (secondary) emotions. The study sample consisted of 117 female students. The study followed an experimental design and was conducted individually. It employed questionnaires and a purpose-made video recording showing a model whose facial expressions were to be mimicked by the participants. The results confirmed the predictions. Mimicking facial expressions reduced the level of infra-humanization compared to the no mimicking and control conditions [F(2,114) = 3.39, p = 0.037, η2 = 0.06].
PMCID: PMC4923061  PMID: 27445935
mimicry; imitating; infra-humanization; emotions; attitudes; embodiment

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