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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.  Future healthcare professionals’ knowledge about the Argentinean abortion law 
We assessed healthcare students’ knowledge and opinions on Argentinian abortion law and identified differences between first- and final-year healthcare students.
In this cross-sectional study, self-administered anonymous questionnaires were administered to 760 first- and 695 final-year students from different fields of study (medicine, midwifery, nursing, radiology, nutrition, speech therapy, and physiotherapy) of the School of Medicine at the University of Buenos Aires, in 2011-2013.
Compared to first-year students, a higher percentage of final-year students knew that abortion is legally restricted in Argentina (p < 0.001). A significantly higher percentage of final-year students could correctly identify the circumstances in which abortion is legal: woman´s life risk (87.4% last vs. 79.1% first year), rape of a woman with developmental disability (66.2% first vs. 85.4% last-year; p < 0.001). More final-year students chose severe foetal malformations (37.3% first year vs. 57.3% final year) despite its being illegal.
Although most final-year students knew that abortion is legally restricted in Argentina, misconceptions regarding circumstances of legal abortion were observed; this may be due to the fact that abortion is inadequately covered in the medical curricula. Medical schools should ensure that sexual and reproductive health topics are an integral part of their curricula. Healthcare providers who are aware of the legality of abortion are more likely to provide the public with sound information and ensure abortions are appropriately performed.
PMCID: PMC4809747  PMID: 27018552
Healthcare students; abortion law; knowledge; personal opinion; Argentina
4.  Supporting Treatment Adherence Readiness through Training (START) for patients with HIV on antiretroviral therapy: study protocol for a randomized controlled trial 
Trials  2016;17:162.
Few HIV antiretroviral adherence interventions target patients before they start treatment, assess adherence readiness to determine the timing of treatment initiation, or tailor the amount of adherence support. The Supporting Treatment Adherence Readiness through Training (START) intervention, based on the information-motivation-behavioral skills model of behavior change, is designed to address these gaps with the inclusion of (1) brief pill-taking practice trials for enhancing pretreatment adherence counseling and providing a behavioral criterion for determining adherence readiness and the timing of treatment initiation and (2) a performance-driven dose regulation mechanism to tailor the amount of counseling to the individual needs of the patient and conserve resources. The primary aim of this randomized controlled trial is to examine the effects of START on antiretroviral adherence and HIV virologic suppression.
A sample of 240 patients will be randomized to receive START or usual care at one of two HIV clinics. Primary outcomes will be optimal dose-taking adherence (>85 % prescribed doses taken), as measured with electronic monitoring caps, and undetectable HIV viral load. Secondary outcomes will include dose-timing adherence (>85 % prescribed doses taken on time) and CD4 count. Primary endpoints will be month 6 (short-term effect) and month 24 (to test durability of effect), though electronic monitoring will be continuous and a fully battery of assessments will be administered every 6 months for 24 months.
If efficacious and cost-effective, START will provide clinicians with a model for assessing patient adherence readiness and helping patients to achieve and sustain readiness and optimal treatment benefits.
Trial registration identifier NCT02329782. Registered on 22 December 2014.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-016-1287-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4806419  PMID: 27009061
HIV; Antiretroviral; Adherence; Readiness; Intervention; Randomized controlled trial
5.  Evaluation of the validity of the Psychology Experiment Building Language tests of vigilance, auditory memory, and decision making 
PeerJ  2016;4:e1772.
Background. The Psychology Experimental Building Language (PEBL) test battery ( is a popular application for neurobehavioral investigations. This study evaluated the correspondence between the PEBL and the non-PEBL versions of four executive function tests.
Methods. In one cohort, young-adults (N = 44) completed both the Conner’s Continuous Performance Test (CCPT) and the PEBL CPT (PCPT) with the order counter-balanced. In a second cohort, participants (N = 47) completed a non-computerized (Wechsler) and a computerized (PEBL) Digit Span (WDS or PDS) both Forward and Backward. Participants also completed the Psychological Assessment Resources or the PEBL versions of the Iowa Gambling Task (PARIGT or PEBLIGT).
Results. The between-test correlations were moderately high (reaction time r = 0.78, omission errors r = 0.65, commission errors r = 0.66) on the CPT. DS Forward was significantly greater than DS Backward on the WDS (p < .0005) and the PDS (p < .0005). The total WDS score was moderately correlated with the PDS (r = 0.56). The PARIGT and the PEBLIGTs showed a very similar pattern for response times across blocks, development of preference for Advantageous over Disadvantageous Decks, and Deck selections. However, the amount of money earned (score–loan) was significantly higher in the PEBLIGT during the last Block.
Conclusions. These findings are broadly supportive of the criterion validity of the PEBL measures of sustained attention, short-term memory, and decision making. Select differences between workalike versions of the same test highlight how detailed aspects of implementation may have more important consequences for computerized testing than has been previously acknowledged.
PMCID: PMC4806597  PMID: 27014512
Attention; Decision making; Iowa Gambling Task; Short-term memory
6.  Comparison of Guided and Unguided Ocriplasmin Injection for the Treatment of Vitreomacular Traction: A Preliminary Study 
Journal of Ophthalmology  2016;2016:6521304.
This retrospective quality control study aimed at comparing resolution in patients treated with intravitreal ocriplasmin (IVO) using two injection techniques, classical injection procedure (unguided) and targeted injection using a surgical microscope with a 30-gauge 1-inch needle (guided) for the treatment of focal VMT without macular hole. The two groups presented a statistically significant difference in terms of resolution of VMT within the first month following treatment: 1/7 for the unguided group versus 6/7 for the guided group (p = 0.0291). The majority of the guided group presented an earlier resolution than the single resolved case in the unguided group. The results of this preliminary study indicate that the injection of ocriplasmin closer to the site of VMT results in the resolution in a higher number of cases and that this resolution occurs in a short time interval.
PMCID: PMC4811109  PMID: 27066269
7.  Acceleration of Acetal Hydrolysis by Remote Alkoxy Groups: Evidence for Electrostatic Effects on the Formation of Oxocarbenium Ions** 
In contrast to observations with carbohydrates, experiments with 4-alkoxy-substituted acetals indicate that an alkoxy group can accelerate acetal hydrolysis by up to 20-fold compared to substrates without an alkoxy group. The acceleration of ionization in more flexible acetals can be up to 200-fold when compensated for inductive effects.
PMCID: PMC4480982  PMID: 25614209
Electrostatic Effects; Kinetics; Carbocations; Carbohydrates
9.  Abbreviations/Acronyms 
The Ochsner Journal  2016;16(Spec AIAMC Iss):7.
PMCID: PMC4806439  PMID: 27026790
10.  Pregnant women’s perceptions of weight gain, physical activity, and nutrition using Theory of Planned Behavior constructs 
Journal of behavioral medicine  2015;39(1):41-54.
A better understanding of women’s perceptions of weight gain and related behaviors during pregnancy is necessary to inform behavioral interventions. We used the Theory of Planned Behavior (TPB) to examine pregnant women’s perceptions and intentions toward weight gain, physical activity (PA), and nutrition using a mixed methods study design. Women between 20 and 30 weeks gestation (n = 189) were recruited to complete an Internet-based survey. Salient beliefs toward weight gain, PA, and nutrition were captured through open-ended responses and content analyzed into themes. TPB constructs (attitude, subjective norm, perceived behavioral control, intentions) were examined using Pearson correlations and hierarchical linear regression models. Salient beliefs were consistent with the existing literature in non-pregnant populations, with the addition of many pregnancy-specific beliefs. TPB constructs accounted for 23–39 % of the variance in weight gain, PA, and nutrition intentions, and made varying contributions across outcomes. The TPB is a useful framework for examining women’s weight-related intentions during pregnancy. Study implications for intervention development are discussed.
PMCID: PMC4753045  PMID: 26335313
Theory of Planned Behavior; Pregnancy; Weight; Physical activity; Nutrition
11.  The Autophagic Machinery in Enterovirus Infection 
Viruses  2016;8(2):32.
The Enterovirus genus of the Picornaviridae family comprises many important human pathogens, including polioviruses, rhinovirus, enterovirus A71, and enterovirus D68. They cause a wide variety of diseases, ranging from mild to severe life-threatening diseases. Currently, no effective vaccine is available against enteroviruses except for poliovirus. Enteroviruses subvert the autophagic machinery to benefit their assembly, maturation, and exit from host. Some enteroviruses spread between cells via a process described as autophagosome-mediated exit without lysis (AWOL). The early and late phases of autophagy are regulated through various lipids and their metabolizing enzymes. Some of these lipids and enzymes are specifically regulated by enteroviruses. In the present review, we summarize the current understanding of the regulation of autophagic machinery by enteroviruses, and provide updates on recent developments in this field.
PMCID: PMC4776187  PMID: 26828514
picornavirus; enterovirus; replication; antiviral; autophagy; lipids; autophagosome maturation
12.  Logistic analysis of epidemiologic studies with augmentation sampling involving re-stratification and population expansion 
Biostatistics (Oxford, England)  2014;16(1):169-178.
Epidemiologic cross-sectional, case-cohort, or case–control studies often select augmentation samples to supplement an existing (baseline) sample, primarily for the two reasons: (1) to increase the sample sizes from certain subdomains of interest that were not originally considered in the design of the baseline study and (2) to obtain samples from an extension of the target population. To address these two objectives, two-stage stratified sample designs are considered, where the stratification based on the expanded population at the second stage is not nested in the first stage strata. The sample weighting and Taylor linearization variance estimation for the two-stage stratified sample designs, involving re-stratification and population expansion, are provided for estimating population totals and logistic regression coefficients. Results from limited simulation studies and a logistic regression analysis of a study of human papillomavirus serology are provided.
PMCID: PMC4263221  PMID: 24907707
Pseudo-likelihood function; Sample weighting; Taylor linearization variance estimation; Two-stage stratified sampling
13.  Naproxen Induces Type X Collagen Expression in Human Bone-Marrow-Derived Mesenchymal Stem Cells Through the Upregulation of 5-Lipoxygenase 
Tissue Engineering. Part A  2014;21(1-2):234-245.
Several studies have shown that type X collagen (COL X), a marker of late-stage chondrocyte hypertrophy, is expressed in mesenchymal stem cells (MSCs) from osteoarthritis (OA) patients. We recently found that Naproxen, but not other nonsteroidal anti-inflammatory drugs (NSAIDs) (Ibuprofen, Celebrex, Diclofenac), can induce type X collagen gene (COL10A1) expression in bone-marrow-derived MSCs from healthy and OA donors. In this study we determined the effect of Naproxen on COL X protein expression and investigated the intracellular signaling pathways that mediate Naproxen-induced COL10A1 expression in normal and OA hMSCs. MSCs of OA patients were isolated from aspirates from the intramedullary canal of donors (50–80 years of age) undergoing hip replacement surgery for OA and were treated with or without Naproxen (100 μg/mL). Protein expression and phosphorylation were determined by immunoblotting using specific antibodies (COL X, p38 mitogen-activated protein kinase [p38], phosphorylated-p38, c-Jun N-terminal kinase [JNK], phosphorylated-JNK, extracellular signal-regulated kinase [ERK], and phosphorylated-ERK). Real-time reverse transcription polymerase chain reaction (RT-PCR) was performed to determine the expression of COL10A1 and Runt-related transcription factor 2 gene (Runx2). Our results show that Naproxen significantly stimulated COL X protein expression after 72 h of exposure both in normal and OA hMSCs. The basal phosphorylation of mitogen-activated protein kinases (MAPKs) (ERK, JNK, and p38) in OA hMSCs was significantly higher than in normal. Naproxen significantly increased the MAPK phosphorylation in normal and OA hMSCs. NSAID cellular effects include cyclooxygenase, 5-lipoxygenase, and p38 MAPK signaling pathways. To investigate the involvement of these pathways in the Naproxen-induced COL10A1 expression, we incubated normal and OA hMSCs with Naproxen with and without inhibitors of ERK (U0126), JNK (BI-78D3), p38 (SB203580), and 5-lipoxygenase (MK-886). Our results showed that increased basal COL10A1 expression in OA hMSCs was significantly suppressed in the presence of JNK and p38 inhibitors, whereas Naproxen-induced COL10A1 expression was suppressed by 5-lipoxygenase inhibitor. This study shows that Naproxen induces COL X both at transcriptional and translational levels in normal and OA hMSCs. Elevated basal COL10A1 expression in OA hMSCs is probably through the activation of MAPK pathway and Naproxen-induced COL10A1 expression is through the increased 5-lipoxygenase signaling.
PMCID: PMC4292866  PMID: 25091567
14.  Neonatal Brain Tissue Classification with Morphological Adaptation and Unified Segmentation 
Measuring the distribution of brain tissue types (tissue classification) in neonates is necessary for studying typical and atypical brain development, such as that associated with preterm birth, and may provide biomarkers for neurodevelopmental outcomes. Compared with magnetic resonance images of adults, neonatal images present specific challenges that require the development of specialized, population-specific methods. This paper introduces MANTiS (Morphologically Adaptive Neonatal Tissue Segmentation), which extends the unified segmentation approach to tissue classification implemented in Statistical Parametric Mapping (SPM) software to neonates. MANTiS utilizes a combination of unified segmentation, template adaptation via morphological segmentation tools and topological filtering, to segment the neonatal brain into eight tissue classes: cortical gray matter, white matter, deep nuclear gray matter, cerebellum, brainstem, cerebrospinal fluid (CSF), hippocampus and amygdala. We evaluated the performance of MANTiS using two independent datasets. The first dataset, provided by the NeoBrainS12 challenge, consisted of coronal T2-weighted images of preterm infants (born ≤30 weeks' gestation) acquired at 30 weeks' corrected gestational age (n = 5), coronal T2-weighted images of preterm infants acquired at 40 weeks' corrected gestational age (n = 5) and axial T2-weighted images of preterm infants acquired at 40 weeks' corrected gestational age (n = 5). The second dataset, provided by the Washington University NeuroDevelopmental Research (WUNDeR) group, consisted of T2-weighted images of preterm infants (born <30 weeks' gestation) acquired shortly after birth (n = 12), preterm infants acquired at term-equivalent age (n = 12), and healthy term-born infants (born ≥38 weeks' gestation) acquired within the first 9 days of life (n = 12). For the NeoBrainS12 dataset, mean Dice scores comparing MANTiS with manual segmentations were all above 0.7, except for the cortical gray matter for coronal images acquired at 30 weeks. This demonstrates that MANTiS' performance is competitive with existing techniques. For the WUNDeR dataset, mean Dice scores comparing MANTiS with manually edited segmentations demonstrated good agreement, where all scores were above 0.75, except for the hippocampus and amygdala. The results show that MANTiS is able to segment neonatal brain tissues well, even in images that have brain abnormalities common in preterm infants. MANTiS is available for download as an SPM toolbox from
PMCID: PMC4809890  PMID: 27065840
magnetic resonance imaging; tissue classification; statistical parametric mapping; neonate; preterm birth
15.  Iron Deposition Is Positively Related to Cognitive Impairment in Patients with Chronic Mild Traumatic Brain Injury: Assessment with Susceptibility Weighted Imaging 
BioMed Research International  2015;2015:470676.
Background. This study aimed to evaluate the usability of SWI in assessment of brain iron to detect cognitive dysfunction in patients with chronic mild traumatic brain injury (mTBI). Methods. 39 patients with mTBI and 37 normal controls were given the Mini-Mental State Examination (MMSE) and underwent SWI scanning at least 6 months after injury. Angle radian values were calculated with phase images. The angle radian values were compared between groups using analysis of covariance, and their association with MMSE scores was analyzed using Spearman correlations. Results. Significantly higher angle radian values (p < 0.05) were found in the head of the caudate nucleus, the lenticular nucleus, the hippocampus, the thalamus, the right substantia nigra, the red nucleus, and the splenium of the corpus callosum (SCC) in the mTBI group, compared to the control group. MMSE scores were negatively correlated with angle radian values in the right substantia nigra (r = −0.685, p < 0.001). Conclusions. Patients with chronic mTBI might have abnormally high accumulations of iron, and their MMSE scores are negatively associated with angle radian values in the right substantia nigra, suggesting a role of SWI in the assessment of cognitive impairments of these patients.
PMCID: PMC4698517  PMID: 26798636
16.  Mammal survival at the Cretaceous–Palaeogene boundary: metabolic homeostasis in prolonged tropical hibernation in tenrecs 
Free-ranging common tenrecs, Tenrec ecaudatus, from sub-tropical Madagascar, displayed long-term (nine months) hibernation which lacked any evidence of periodic interbout arousals (IBAs). IBAs are the dominant feature of the mammalian hibernation phenotype and are thought to periodically restore long-term ischaemia damage and/or metabolic imbalances (depletions and accumulations). However, the lack of IBAs in tenrecs suggests no such pathology at hibernation Tbs > 22°C. The long period of tropical hibernation that we report might explain how the ancestral placental mammal survived the global devastation that drove the dinosaurs and many other vertebrates to extinction at the Cretaceous–Palaeogene boundary following a meteorite impact. The genetics and biochemistry of IBAs are of immense interest to biomedical researchers and space exploration scientists, in the latter case, those envisioning a hibernating state in astronauts for deep space travel. Unravelling the physiological thresholds and temperature dependence of IBAs will provide new impetus to these research quests.
PMCID: PMC4213634  PMID: 25339721
mammals; hibernation; Cretaceous–Palaeogene boundary; Madagascar; Tenrec ecaudatus
17.  Thalamic inflammation after brain trauma is associated with thalamo-cortical white matter damage 
Traumatic brain injury can trigger chronic neuroinflammation, which may predispose to neurodegeneration. Animal models and human pathological studies demonstrate persistent inflammation in the thalamus associated with axonal injury, but this relationship has never been shown in vivo.
Using [11C]-PK11195 positron emission tomography, a marker of microglial activation, we previously demonstrated thalamic inflammation up to 17 years after traumatic brain injury. Here, we use diffusion MRI to estimate axonal injury and show that thalamic inflammation is correlated with thalamo-cortical tract damage.
These findings support a link between axonal damage and persistent inflammation after brain injury.
PMCID: PMC4666189  PMID: 26627199
Microglia; Translocator protein; Positron emission tomography; Traumatic brain injury; Traumatic axonal injury; PK11195; Thalamus
18.  Determinants of acceptance of end-of-life interventions: a comparison between withdrawing life-prolonging treatment and euthanasia in Austria 
BMC Medical Ethics  2015;16:81.
End-of-life decisions remain a hotly debated issue in many European countries and the acceptance in the general population can act as an important anchor point in these discussions. Previous studies on determinants of the acceptance of end-of-life interventions in the general population have not systematically assessed whether determinants differ between withdrawal of life-prolonging treatment (WLPT) and euthanasia (EUT).
A large, representative survey of the Austrian adult population conducted in 2014 (n = 1,971) included items on WLPT and EUT. We constructed the following categorical outcome: (1) rejection of both WLPT and EUT, (2) approval of WLPT but rejection of EUT, and (3) approval of both WLPT and EUT. The influence of socio-demographics, personal experiences, and religious and socio-cultural orientations on the three levels of approval were assessed via multinomial logistic regression analysis.
Higher education and stronger socio-cultural liberal orientations increased the likelihood of approving both WLPT and EUT; personal experience with end-of-life care increased only the likelihood of approval of WLPT; and religiosity decreased approval of EUT only.
This study found evidence for both shared (education, liberalism) and different (religiosity, care experiences) determinants for the acceptance of WLPT and EUT.
PMCID: PMC4666202  PMID: 26625908
Withdrawal of life-prolonging treatment; Euthanasia; Acceptance; Determinants
19.  A randomized pilot study on the effect of niacin on pulmonary arterial pressure 
Trials  2015;16:530.
Niacin induces the release of vasodilating prostaglandins, for which receptors are present within the pulmonary arterial circulation. We hypothesized that immediate-release niacin would reduce right ventricular systolic pressure in patients with pulmonary hypertension in a randomized, double-blinded, single-dose provocation study.
We recruited inpatient subjects with a Doppler echocardiogram showing a peak tricuspid regurgitation (TR) jet velocity of 2.7 m/s or greater, and who were free of known pulmonary vascular disease. Subjects were randomized in a 1:2:2 ratio to receive a single dose of either placebo, niacin 100 mg or niacin 500 mg, respectively. TR jet velocities were measured immediately before, and 1 hour post dose, corresponding to peak niacin absorption and prostaglandin release. The primary endpoint was the change in mean TR jet velocity measured over ten successive cardiac cycles.
The baseline mean estimated right ventricular systolic pressure (RVSP) for all 49 subjects (25 male) was 51.9 ± 12.1 mm Hg. The primary endpoint of mean change in TR jet velocity was 0.016 ± 0.065 m/s in the placebo group, compared to −0.017 ± 0.065 m/s with niacin 100 mg, and −0.063 ± 0.038 m/s with niacin 500 mg (P = 0.63). The change in maximum estimated RVSP across the three drug groups was 0.2 ± 1.6 mm Hg, −1.3 ± 1.8 mm Hg and −2.2 ± 1.2 mm Hg (P = 0.62). In exploratory pairwise analysis in the high-dose niacin group (500 mg), the reduction in mean RVSP was from 50.9 ± 9.4 mm Hg to 48.7 ± 10.0 mm Hg (P = 0.09).
A single dose of immediate-release niacin (100 mg or 500 mg) had no significant effect on RVSP 1 hour post administration. A nonsignificant dose-dependent trend for a modest reduction in RVSP, most notable in the 500 mg group, was noted.
(ISRCTN number 12353191, registered April 23, 2015).
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-1013-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4654874  PMID: 26590128
20.  Clinical trial designs for rare diseases: Studies developed and discussed by the International Rare Cancers Initiative 
The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research.
The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional – usually randomised – clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed.
The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design.
Trials can be designed using a wide array of possibilities. There is no ‘one size fits all’ solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases.
PMCID: PMC4639696  PMID: 25542058
Rare cancers; Clinical trials; Randomised controlled; trials; Methodology; Frequentist; Bayesian; Multi-arm
21.  Cationic surface modification of gold nanoparticles for enhanced cellular uptake and X-ray radiation therapy 
A challenge of X-ray radiation therapy is that high dose X-ray can damage normal cells and cause side effects. This paper describes a new nanoparticle-based method to reduce X-ray dose in radiation therapy by internalization of gold nanoparticles that are modified with cationic molecules into cancer cells. A cationic thiol molecule is synthesized and used to modify gold nanoparticles in a one-step reaction. The modified nanoparticles can penetrate cell membranes at high yield. By bring radio-sensitizing gold nanoparticles closer to nuclei where DNA is stored, the total X-ray dose needed to kill cancer cells has been reduced. The simulation of X-ray-gold nanoparticle interaction also indicates that Auger electrons contribute more than photoelectrons.
Graphical abstract
Gold nanoparticles with cationic surface modification can enhance X-ray radiation therapy by enhancing cellular uptake.
PMCID: PMC4620571  PMID: 26512323
22.  Convenient methods for ingestion of molecular hydrogen: drinking, injection, and inhalation 
Medical Gas Research  2015;5:13.
Molecular hydrogen (H2) is clinically administered; however, in some hospitals, H2 is given to patients without consideration of its safe use. In the present study, we prepared convenient and safe devices for the drinking of super-saturated H2 water, for intravenous drip infusion of H2-rich saline, and for the inhalation of H2 gas. In order to provide useful information for researchers using these devices, the changes in H2 concentration were studied. Our experimental results should contribute to the advance of non-clinical and clinical research in H2 medicine.
PMCID: PMC4620630  PMID: 26504515
Hydrogen water; Hydrogen-rich saline; Hydrogen gas
23.  Markers of Bone Metabolism in Patients With Chronic Pancreatitis and Pancreatic Ductal Adenocarcinoma 
Medicine  2015;94(42):e1754.
There are no studies comparing some of the most important markers, such as vitamin D, parathormone, osteocalcin, bone alkaline phosphatase, and calcium, in patients with chronic benign and malignant pancreatic diseases. Our objective was to comparatively evaluate serum markers of bone metabolism in patients with chronic pancreatitis and in those with ductal pancreatic adenocarcinoma. Sixty-three consecutive subjects were studied: 30 patients with a firm diagnosis of chronic pancreatitis and 33 having histologically confirmed pancreatic adenocarcinoma. Serum 25-hydroxyvitamin D, bone alkaline phosphatase, osteocalcin, parathormone, and calcium were determined using commercially available kits. Taking into consideration the clinical variables of all 63 patients studied, 25-hydroxyvitamin D was inversely correlated with only the body mass index (P = 0.007), whereas it was not correlated with age (P = 0.583) or fecal elastase-1 concentrations (P = 0.556). Regarding the other substances studied, parathormone was positively correlated with only the age of the patients (P = 0.015). Of the 5 substances studied, only bone alkaline phosphates were significantly different (P < 0.001) between patients with chronic pancreatitis and those with pancreatic ductal adenocarcinoma. Within the 2 groups of patients, the 23 patients with chronic pancreatitis without diabetes mellitus had serum concentrations of 25-hydroxyvitamin D significantly lower (P = 0.045) than those with chronic pancreatitis having diabetes mellitus, whereas smokers with pancreatic ductal adenocarcinoma had serum concentrations of calcium significantly higher (P < 0.001) as compared to nonsmokers. Altered bone metabolism seems to be associated with chronic diseases of the pancreas; however, the mechanism should be better elucidated.
PMCID: PMC4620801  PMID: 26496293
24.  Inflammatory Myofibroblastic Tumor of Genitourinary Tract Beyond Collecting System 
Medicine  2015;94(42):e1706.
Inflammatory myofibroblastic tumor (IMT) rarely arises in genitourinary tract especially beyond collecting system, which determines the unspecific clinic symptoms and sometimes can mimic malignancy. Therefore, IMT's diagnosis may usually be a pitfall. This case report characterizes a 35-year-old woman with a history of lower quadrant lasting pain followed by fever. Furthermore, radiologic examinations revealed that there were 2 lesions located in left adrenal area and left renalis. Owing to the anatomic complexity, the surgical resection was not complete. The pathologic diagnosis of the lesions was IMT. Adjuvant nonsteroids anti-inflammatory drugs were administrated after the operation. The symptoms were controlled finally and no further growing lesion was observed during a 1-year follow-up.
Inflammatory myofibroblastic tumor is rare in genitourinary tract beyond the collecting system. Diagnosis should be based on histopathology. Presently, the authors report this rare case with the aim to share the experience regarding differential diagnosis and therapy.
PMCID: PMC4620822  PMID: 26496281
25.  Vancomycin-induced thrombocytopaenia in a patient with severe pancreatitis 
BMJ Case Reports  2013;2013:bcr2013200830.
Vancomycin-induced thrombocytopenia is a rare side effect of a commonly used drug that may cause life-threatening disease. A 51-year-old man was treated for an episode of acute severe alcohol-induced pancreatitis complicated by development of a peripancreatic fluid collection. He developed fever of unknown origin and was treated with intravenous vancomycin and piperacillin with tazobactam. On day 6 of vancomycin therapy his platelet count dropped to 46×109/L (237×109/L on day 1 of treatment) and by day 8 of therapy platelets had fallen to a nadir of 9×109/L. The patient at this stage displayed a florid purpuric rash and haematoma formation on attempted intravenous cannulation. A clinical diagnosis of vancomycin-induced thrombocytopaenia was made and the drug withdrawn. After 3 days a significant improvement in the platelet count was noted, rising to 56 × 109/L. Immunofluorescence testing (PIFT) ruled out teicoplanin and heparin as causes of drug-induced thrombocytopenia.
PMCID: PMC3822161  PMID: 24132444

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