bluuebunny/crossref_metadata_2025 huggingface dataset:
Perceptions of generic medication in the general population, doctors and pharmacists: a systematic review
Authors: Colgan Sarah , Faasse Kate , Martin Leslie R , Stephens Melika H , Grey Andrew , Petrie Keith J
Published: December 2015

Objective

To investigate negative perceptions about generic medicines and evaluate the proportions of lay people, doctors and pharmacists who hold these perceptions.

Design

A systematic review of observational studies.

Data sources

MEDLINE, EMBASE, PsycInfo and Scopus.

Eligibility criteria

Quantitative data from cross-sectional and prospective studies published in English after 1980, using self-report measures to evaluate perceptions about generic medicines, presented as percentages of the total sample assessed.

Results

After screening 2737 articles, 52 articles were included in the final analysis. A high proportion of doctors, pharmacists and lay people had negative perceptions of generics. Lay people were significantly more likely to view generics as less effective than branded medication (35.6%, 95% CI 34.8% to 36.4%) compared to doctors (28.7%, 27.5% to 29.9%) and pharmacists (23.6%, 21.2% to 26.2%), p<0.0001. Pharmacists (33.4%, 31.0% to 35.9%) were significantly more likely to believe generics were of inferior quality compared to branded medication than were doctors (28.0%, 26.3% to 29.9%), p=0.0006, and lay people (25.1%, 24.2% to 26.0%), p<0.0001. Doctors believed generics caused more side effects than branded medication (24.4%, 22.2% to 26.9%), compared to pharmacists (17.6%, 15.3% to 20.1%) and lay people (18.8%, 17.8% to 19.8%), p<0.0001. Doctors (28.5%, 26.9% to 30.2%) and pharmacists (25.4%, 21.4% to 29.9%) had significantly more safety concerns about generics than did lay people (18.0%, 17.0% to 19.0%), p≤0.0002. A greater proportion of lay people felt negatively about generic substitution (34.0%, 33.2% to 34.9%), compared to doctors (24.1%, 22.0% to 26.4%) and pharmacists (11.0%, 9.6% to 12.7%), p<0.0001. Rates of negative perceptions of generics do not appear to have changed substantially over time in the general population or among physician groups, p≥0.431, but such negative beliefs show a decreasing trend in pharmacists over the study period, p=0.034.

Conclusions

A significant proportion of doctors, pharmacists and lay people hold negative perceptions of generic medicines. It is likely these attitudes present barriers to the wider use of generics.
Qualitative investigation of patients’ experience of a glaucoma virtual clinic in a specialist ophthalmic hospital in London, UK
Authors: Kotecha Aachal , Bonstein Karen , Cable Richard , Cammack Jocelyn , Clipston Jane , Foster Paul
Published: December 2015

Objectives

To explore how patients felt about delivery of care in a novel technician-delivered virtual clinic compared with delivery of care in a doctor-delivered model.

Design

A qualitative investigation using one-to-one interviews before and after patients’ appointments at either the standard outpatient glaucoma clinic or the new technician-delivered virtual glaucoma clinic (Glaucoma Screening and Stable Monitoring Service, GSMS).

Setting

A glaucoma clinic based in a tertiary ophthalmic specialist hospital in London.

Participants

43 patients (38 Caucasian, 5 African/Afro-Caribbean) were interviewed prior to their glaucoma appointment; 38 patients were interviewed between 4 and 6 weeks after their appointment. Consecutive patients were identified from patient reception lists and telephoned prior to their appointment inviting them to participate.

Results

Trust in the patient–provider relationship emerged as a key theme in patients’ acceptance of not being seen in a traditional doctor-delivered service. Patients who were well informed regarding their glaucoma status and low risk of progression to sight loss were more accepting of the GSMS. Patients valued the reassurance received through effective communication with their healthcare practitioner at the time of their appointment.

Conclusions

This study suggests that patients are accepting of moving to a model of service delivery whereby the doctor is removed from the consultation as long as they are informed about the status of their condition and reassured by the interaction with staff they meet. This study highlights the importance of patient engagement when introducing new models of service delivery.
Association between self-efficacy, career interest and rural career intent in Australian medical students with rural clinical school experience
Authors: Isaac Vivian , Walters Lucie , McLachlan Craig S
Published: December 2015

Objectives

To investigate medical student's self-efficacy at the time of finishing their rural clinical school (RCS) placement and factors associated with self-efficacy. Secondary aims are to explore whether interest levels or self-efficacy are associated with rural or remote career intentions.

Design, setting and participants

A cross-sectional study of medical students who had completed their RCS term in 17 Australian universities. Data were derived from the 2013 Federation of Rural Australian Medical Educators (FRAME) evaluation survey. Questionnaire responses were analysed from 653 medical students from regional Australia. All 732 students who completed their RCS term in 2013 were invited to participate.

Primary and secondary outcome measures

Rural self-efficacy: Six questions to measure self-efficacy beliefs in rural medical practice, based on the sources of self-efficacy described by Bandura. Rural career intention: Students were asked to identify their preferred location for future practice. The options were, Capital or Major City; Inner regional city or large town; Smaller town and very remote area.

Results

Questionnaire responses were analysed from 653 medical students from regional Australia (response rate 89.2%). 83.8% of all students recalled an increase in their interest levels for rural medicine as a result of their RCS experience. Actual career intention to work in a regional area or rural area was 60.2%. Bivariate analyses showed female gender (p=0.003), rural background (p<0.001), an RCS preference for clinical training (p<0.001) and general practice intentions (p=0.004) were factors associated with higher levels of self-efficacy. Logistic regression analyses showed that self-efficacy was independently associated with increased interest in rural medicine (OR 1.4 (95% CI 1.3 to 1.5)) and rural career intent (OR 1.2 (95% CI 1.1 to 1.3)). (Model included gender, rural background, preference for RCS, generalist intent, rural practice interest and self-efficacy).

Conclusions

Self-efficacy is associated with increased interest levels for rural medicine and rural medical career intent.
The effectiveness of buprenorphine for treating cancer pain: an abridged Cochrane review
Authors: Schmidt-Hansen Mia , Taubert Mark , Bromham Nathan , Hilgart Jennifer S , Arnold Stephanie
Published: December 2015

Objectives

To assess the effectiveness and tolerability of buprenorphine for cancer pain in adults and children.

Methods

We searched CENTRAL, MEDLINE, EMBASE, ISI Web of Science, ISI BIOSIS, ClinicalTrials.gov,metaRegister of Controlled Trials, WHO International Clinical Trials Registry Platform and the Proceedings of the Congress of the European Federation of International Association for the Study of Pain to early 2015.

Results

We included 19 randomised controlled trials comparing buprenorphine with placebo, buprenorphine or another active drug for cancer pain. The trials included 1421 patients and examined 16 different intervention comparisons. Of the 11 studies that compared buprenorphine to another drug, 5, 3 and 3 studies, respectively, found that buprenorphine was superior, no different or inferior to the alternative treatment in side effects profile or patient preference/acceptability. Pain intensity ratings did not differ significantly between intramuscular buprenorphine and buprenorphine suppository, although intramuscular treatment was associated with more adverse events (1 study). One study found faster onset of pain relief after sublingual than subdermal buprenorphine, with similar analgesia duration and adverse event rates. 2 studies found transdermal buprenorphine superior to placebo, whereas a third study found no difference between placebo and different doses of transdermal buprenorphine. No clear dose–response relationship was found for transdermal buprenorphine. The quality of this evidence base was limited by under-reporting, small sample sizes and attrition.

Conclusions

Buprenorphine might be considered as a fourth-line option compared with the more standard therapies of morphine, oxycodone and fentanyl, and even then it would only be suitable for some patients.
ZEB1 expression is associated with prognosis of intrahepatic cholangiocarcinoma
Authors: Terashita Katsumi , Chuma Makoto , Hatanaka Yutaka , Hatanaka Kanako , Mitsuhashi Tomoko , Yokoo Hideki , Ohmura Takumi , Ishizu Hiroyuki , Muraoka Shunji , Nagasaka Atsushi , Tsuji Takahiro , Yamamoto Yoshiya , Kurauchi Nobuaki , Shimoyama Norihiko , Toyoda Hidenori , Kumada Takashi , Kaneoka Yuji , Maeda Atsuyuki , Ogawa Koji , Natsuizaka Mitsuteru , Kamachi Hirofumi , Kakisaka Tatsuhiko , Kamiyama Toshiya , Taketomi Akinobu , Matsuno Yoshihiro , Sakamoto Naoya
Published: December 2015

Background/Aim

Intrahepatic cholangiocarcinoma (ICC) is one of the most aggressive malignant tumours, so the identification of molecular targets for ICC is an important issue. Zinc finger E-box binding homeobox 1 (ZEB1) is a key inducer of epithelial–mesenchymal transition (EMT). The aim of the present study was to clarify the clinical significance of ZEB1 in ICC and the associations between ZEB1 expression and EMT-related proteins.

Methods

We immunohistochemically examined the expression of EMT-related proteins, namely ZEB1, vimentin and E-cadherin, in ICC specimens from 102 patients. The clinicopathological and prognostic values of these markers were evaluated.

Results

ZEB1 and vimentin were expressed in 46.1% and 43.1% of tumours, respectively, and E-cadherin expression was lost in 44.1% of tumours. ZEB1 expression showed a significant inverse correlation with E-cadherin expression (p=0.004) and a positive correlation with vimentin expression (p=0.022). Altered expression of ZEB1 was associated with aggressive tumour characteristics, including advanced tumour stage (p=0.037), undifferentiated-type histology (p=0.017), lymph node metastasis (p=0.024) and portal vein invasion (p=0.037). Moreover, overall survival rates were significantly lower for patients with high ZEB1 expression than for patients with low ZEB1 expression (p=0.027). Kaplan–Meier analysis also identified E-cadherin expression (p=0.041) and vimentin expression (p=0.049) as prognostic indicators for overall survival.

Conclusions

ZEB1 expression is associated with tumour progression and poor prognosis in patients with ICC through positive correlations with vimentin and negative correlations with E-cadherin. ZEB1 expression is associated with a poor prognosis and might be an attractive target for the treatment of ICC.
Clinician-educators in emerging graduate medical education systems: description, roles and perceptions
Authors: Ibrahim Halah , Stadler Dora J , Archuleta Sophia , Shah Nina G , Bertram Amanda , Chandrasekhar Nair Satish , Alkhal Abdullatif , Ali Al-Mohammed Ahmed , Cofrancesco Joseph
Published: December 2015

Objectives

To describe clinician-educators (CEs) in new graduate medical education (GME) systems and characterize perception of preparedness, roles and rewards, and factors affecting job satisfaction and retention.

Methods

A cross-sectional survey of all CEs of institutions using competency-based GME and accredited by the Accreditation Council for Graduate Medical Education-International (ACGME-I).

Results

274 of 359 eligible participants (76.3%) responded, representing 47 residency programs across 17 specialties. CEs were predominantly married men aged in their 40s, employed at their current institution 9.3 years (±6.4 years). CEs judged themselves competent or expert in teaching skills (91.5%), trainee assessment (82%) and mentoring (75%); less so in curriculum development (44%) and educational research skills (32%). Clinical productivity was perceived by the majority (62%) as the item most valued by their institutions, with little or no perceived value for teaching or educational efforts. Overall, 58.3% were satisfied or very satisfied with their roles, and 77% expected to remain in academic medicine for 5 years. A strong negative correlation was found between being a program or associate program director and likelihood of staying in academic medicine (aOR 0.42; 0.22 to 0.80).

Conclusions

In the GME systems studied, CEs, regardless of country or programme, report working in environments that value clinical productivity over educational efforts. CEs feel competent and prepared for many aspects of their roles, have positive attitudes towards teaching, and report overall job satisfaction, with most likely to remain in academic medicine. As medical training advances internationally, the impact on and by CEs requires ongoing attention.
Dynamic analysis of an extraordinarily mobile rock avalanche in the Northwest Territories, Canada
Authors: Aaron Jordan , Hungr Oldrich
Published: December 2015

The pre-historic rock avalanche at Avalanche Lake was a spectacularly mobile rock avalanche that resulted in the largest documented runup of any landslide on earth. The runout of the 200 Mm3 event was a complex and three-dimensional process that created three distinct depositional lobes. There is some controversy as to whether the presence of glacial ice played an important role in the dynamics of this event. To investigate this hypothesis an advanced, three-dimensional numerical landslide runout model was used to reconstruct the dynamics of this event. It was found that a conventional runout model is able to reproduce the bulk characteristics of this event, including its spectacular runup, without accounting for glacial ice. A sensitivity analysis was performed to determine the factors that control the mobility of this event. It was found that low strength in the source zone, as well as the presence of significant internal strength, is required to reproduce the 600 m runup. This has important implications for the hazard analysis of rock avalanches. It appears as though large-volume rock avalanches can move with a friction angle lower than that expected for dry fragmented rock, and the runout process can be strongly influenced by internal strength. These important factors must be accounted for when performing forward analyses of this type of natural disaster.
Vegetation changes in boreo–nemoral forest stands depending on soil factors and past land use during an 80 year period of no human impact
Authors: Kokarēviča Ilze , Brūmelis Guntis , Kasparinskis Raimonds , Rolava Arta , Nikodemus Oļģerts , Grods John , Elferts Didzis
Published: December 2015

Information on the long-term changes in plant communities that occur without human interference is limited, due to insufficient studies where vegetation can be resurveyed. In 1912, a strict nature protection reserve, with non-intervention management, was established on Moricsala Island in Latvia, located in the boreo–nemoral forest zone. Prior to establishment of the nature reserve, part of the island area was used for agriculture. The island is now covered almost entirely by forest dominated by Quercus robur L. and Tilia cordata Mill. on sandy soils. Resurvey was conducted in 2011 in 17 plots in which tree layers and the understory vegetation had been described in 1930. The plots were classified into two groups based on tree species composition in 1930 to determine changes in species composition. Differences in understory and tree canopy composition between these groups persisted over the period between the studies, in relation to soil factors and past stand history. Considerable turnover of species occurred, with a decrease of species typical of open habitats and replacement by species typical of nemoral (temperate deciduous) forest plant communities. In the past, Q. robur had likely established in open habitats created by agricultural land use or past fire but is presently not regenerating in the understory.
A food-grade fimbrial adhesin FaeG expression system inLactococcus lactisandLactobacillus casei
Authors: Lu W.W. , Wang T. , Wang Y. , Xin M. , Kong J.
Published: December 2015

Enterotoxigenic Escherichia coli (ETEC) infection is the major cause of diarrhea in neonatal piglets. The fimbriae as colonizing factor in the pathogenesis of ETEC constitute a primary target for vaccination against ETEC. Lactic acid bacteria (LAB) are attractive tools to deliver antigens at the mucosal level. With the safety of genetically modified LAB in mind, a food-grade secretion vector (pALRc or pALRb) was constructed with DNA entirely from LAB, including the replicon, promoter, signal peptide, and selection marker alanine racemase gene (alr). To evaluate the feasibility of the system, the nuclease gene (nuc) from Staphylococcus aureus was used as a reporter to be expressed in both Lactococcus lactis and Lactobacillus casei. Subsequently, the extracellular secretion of the fimbrial adhesin FaeG of ETEC was confirmed by Western blot analysis. These results showed that this food-grade expression system has potential as the delivery vehicle for the safe use of genetically modified LAB for the development of vaccines against ETEC infection.
Efficacy of oral Bifidobacterium bifidum ATCC 29521 on microflora and antioxidant in mice
Authors: Wang Bao-gui , Xu Hai-bo , Xu Feng , Zeng Zhe-ling , Wei Hua
Published: December 2015

This study aimed to examine whether Bifidobacterium bifidum ATCC 29521, a species of colonic microflora in humans, is involved in the intestinal tract of mice. This study was also conducted to determine the antioxidant activity of this species by evaluating different microbial populations and reactive oxygen species isolated from feces and intestinal contents for 28 days of oral administration. Microbial diversities were assessed through bacterial culture techniques, PCR–DGGE, and real-time PCR. This study showed that the intake of B. bifidum ATCC 29521 significantly (p < 0.05) improved the ecosystem of the intestinal tract of BALB/c mice by increasing the amount of probiotics (Lactobacillus intestinalis and Lactobacillus crispatus) and by reducing unwanted bacterial populations (Enterobacter, Escherichia coli). Antioxidative activities of incubated cell-free extracts were evaluated through various assays, including the scavenging ability of DPPH radical (64.5% and 67.54% (p < 0.05), respectively, at 21 days in nutrients and 28 days in MRS broth), superoxide anion, and hydroxyl radical (85% and 61.5% (p < 0.05), respectively, at intestinal contents in nutrients and 21 days in MRS broth). Total reducing power (231.5 μmol/L (p < 0.05), 14 days in MRS broth) and mRNA level of genes related to oxidative stress were also determined. Results indicated that B. bifidum ATCC 29521 elicits a beneficial effect on murine gut microbiota and antioxidant activities compared with the control samples. This species can be considered as a potential bioresource antioxidant to promote health. Bifidobacterium bifidum ATCC 29521 may also be used as a promising material in microbiological and food applications.
Electrocortical activity distinguishes between uphill and level walking in humans
Authors: Bradford J. Cortney , Lukos Jamie R. , Ferris Daniel P.
Published: December 2015

The objective of this study was to determine if electrocortical activity is different between walking on an incline compared with level surface. Subjects walked on a treadmill at 0% and 15% grades for 30 min while we recorded electroencephalography (EEG). We used independent component (IC) analysis to parse EEG signals into maximally independent sources and then computed dipole estimations for each IC. We clustered cortical source ICs and analyzed event-related spectral perturbations synchronized to gait events. Theta power fluctuated across the gait cycle for both conditions, but was greater during incline walking in the anterior cingulate, sensorimotor and posterior parietal clusters. We found greater gamma power during level walking in the left sensorimotor and anterior cingulate clusters. We also found distinct alpha and beta fluctuations, depending on the phase of the gait cycle for the left and right sensorimotor cortices, indicating cortical lateralization for both walking conditions. We validated the results by isolating movement artifact. We found that the frequency activation patterns of the artifact were different than the actual EEG data, providing evidence that the differences between walking conditions were cortically driven rather than a residual artifact of the experiment. These findings suggest that the locomotor pattern adjustments necessary to walk on an incline compared with level surface may require supraspinal input, especially from the left sensorimotor cortex, anterior cingulate, and posterior parietal areas. These results are a promising step toward the use of EEG as a feed-forward control signal for ambulatory brain-computer interface technologies.
Oscillatory neural responses evoked by natural vestibular stimuli in humans
Authors: Gale Steven , Prsa Mario , Schurger Aaron , Gay Annietta , Paillard Aurore , Herbelin Bruno , Guyot Jean-Philippe , Lopez Christophe , Blanke Olaf
Published: December 2015

While there have been numerous studies of the vestibular system in mammals, less is known about the brain mechanisms of vestibular processing in humans. In particular, of the studies that have been carried out in humans over the last 30 years, none has investigated how vestibular stimulation (VS) affects cortical oscillations. Here we recorded high-density electroencephalography (EEG) in healthy human subjects and a group of bilateral vestibular loss patients (BVPs) undergoing transient and constant-velocity passive whole body yaw rotations, focusing our analyses on the modulation of cortical oscillations in response to natural VS. The present approach overcame significant technical challenges associated with combining natural VS with human electrophysiology and reveals that both transient and constant-velocity VS are associated with a prominent suppression of alpha power (8–13 Hz). Alpha band suppression was localized over bilateral temporo-parietal scalp regions, and these alpha modulations were significantly smaller in BVPs. We propose that suppression of oscillations in the alpha band over temporo-parietal scalp regions reflects cortical vestibular processing, potentially comparable with alpha and mu oscillations in the visual and sensorimotor systems, respectively, opening the door to the investigation of human cortical processing under various experimental conditions during natural VS.
Modulation of impulsivity and reward sensitivity in intertemporal choice by striatal and midbrain dopamine synthesis in healthy adults
Authors: Smith Christopher T. , Wallace Deanna L. , Dang Linh C. , Aarts Esther , Jagust William J. , D'Esposito Mark , Boettiger Charlotte A.
Published: December 2015

Converging evidence links individual differences in mesolimbic and mesocortical dopamine (DA) to variation in the tendency to choose immediate rewards (“ Now”) over larger, delayed rewards (“ Later”), or “ Now bias.” However, to date, no study of healthy young adults has evaluated the relationship between Now bias and DA with positron emission tomography (PET). Sixteen healthy adults (ages 24–34 yr; 50% women) completed a delay-discounting task that quantified aspects of intertemporal reward choice, including Now bias and reward magnitude sensitivity. Participants also underwent PET scanning with 6-[18F]fluoro-l- m-tyrosine (FMT), a radiotracer that measures DA synthesis capacity. Lower putamen FMT signal predicted elevated Now bias, a more rapidly declining discount rate with increasing delay time, and reduced willingness to accept low-interest-rate delayed rewards. In contrast, lower FMT signal in the midbrain predicted greater sensitivity to increasing magnitude of the Later reward. These data demonstrate that intertemporal reward choice in healthy humans varies with region-specific measures of DA processing, with regionally distinct associations with sensitivity to delay and to reward magnitude.
Vestibular contribution to balance control in the medial gastrocnemius and soleus
Authors: Dakin Christopher J. , Héroux Martin E. , Luu Billy L. , Inglis John Timothy , Blouin Jean-Sébastien
Published: December 2015

The soleus (Sol) and medial gastrocnemius (mGas) muscles have different patterns of activity during standing balance and may have distinct functional roles. Using surface electromyography we previously observed larger responses to galvanic vestibular stimulation (GVS) in the mGas compared with the Sol muscle. However, it is unclear whether this difference is an artifact that reflects limitations associated with surface electromyography recordings or whether a compensatory balance response to a vestibular error signal activates the mGas to a greater extent than the Sol. In the present study, we compared the effect of GVS on the discharge behavior of 9 Sol and 21 mGas motor units from freely standing subjects. In both Sol and mGas motor units, vestibular stimulation induced biphasic responses in measures of discharge timing [11 ± 5.0 (mGas) and 5.6 ± 3.8 (Sol) counts relative to the sham (mean ± SD)], and frequency [0.86 ± 0.6 Hz (mGas), 0.34 ± 0.2 Hz (Sol) change relative to the sham]. Peak-to-trough response amplitudes were significantly larger in the mGas (62% in the probability-based measure and 160% in the frequency-based measure) compared with the Sol (multiple P < 0.05). Our results provide direct evidence that vestibular signals have a larger influence on the discharge activity of motor units in the mGas compared with the Sol. More tentatively, these results indicate the mGas plays a greater role in vestibular-driven balance corrections during standing balance.
Noninvasive Quantification of 2-Hydroxyglutarate in Human Gliomas with IDH1 and IDH2 Mutations
Authors: Emir Uzay E. , Larkin Sarah J. , de Pennington Nick , Voets Natalie , Plaha Puneet , Stacey Richard , Al-Qahtani Khalid , Mccullagh James , Schofield Christopher J. , Clare Stuart , Jezzard Peter , Cadoux-Hudson Tom , Ansorge Olaf
Published: December 2015

Mutations in the isocitrate dehydrogenase genes (IDH1/2) occur often in diffuse gliomas, where they are associated with abnormal accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). Monitoring 2-HG levels could provide prognostic information in this disease, but detection strategies that are noninvasive and sufficiently quantitative have yet to be developed. In this study, we address this need by presenting a proton magnetic resonance spectroscopy (1H-MRS) acquisition scheme that uses an ultrahigh magnetic field (≥7T) capable of noninvasively detecting 2-HG with quantitative measurements sufficient to differentiate mutant cytosolic IDH1 and mitochondrial IDH2 in human brain tumors. Untargeted metabolomics analysis of in vivo 1H-MRS spectra discriminated between IDH-mutant tumors and healthy tissue, and separated IDH1 from IDH2 mutations. High-quality spectra enabled the quantification of neurochemical profiles consisting of at least eight metabolites, including 2-HG, glutamate, lactate, and glutathione in both tumor and healthy tissue voxels. Notably, IDH2 mutation produced more 2-HG than IDH1 mutation, consistent with previous findings in cell culture. By offering enhanced sensitivity and specificity, this scheme can quantitatively detect 2-HG and associated metabolites that may accumulate during tumor progression, with implications to better monitor patient responses to therapy. Cancer Res; 76(1); 43–49. ©2015 AACR.
The Initial Detection and Partial Characterization of Circulating Tumor Cells in Neuroendocrine Prostate Cancer
Authors: Beltran Himisha , Jendrisak Adam , Landers Mark , Mosquera Juan Miguel , Kossai Myriam , Louw Jessica , Krupa Rachel , Graf Ryon P. , Schreiber Nicole A. , Nanus David M. , Tagawa Scott T. , Marrinucci Dena , Dittamore Ryan , Scher Howard I.
Published: December 2015

Purpose: The transition of prostate adenocarcinoma to a predominantly androgen receptor (AR) signaling independent phenotype can occur in the later stages of the disease and is associated with low AR expression +/− the development of small-cell or neuroendocrine tumor characteristics. As metastatic tumor biopsies are not always feasible and are difficult to repeat, we sought to evaluate noninvasive methods to identify patients transitioning toward a neuroendocrine phenotype (NEPC).

Experimental Design: We prospectively studied a metastatic tumor biopsy, serum biomarkers, and circulating tumor cells (CTC, Epic Sciences) from patients with castration-resistant prostate cancer (CRPC) including those with pure or mixed NEPC histology present on biopsy. CTCs labeled with the patient's clinical status were used to learn features that discriminate NEPC patients, which was then applied to an independent cohort.

Results: Twenty-seven patients with CRPC including 12 NEPC and 5 with atypical clinical features suggestive of NEPC transition were studied. CTCs from NEPC patients demonstrated frequent clusters, low or absent AR expression, lower cytokeratin expression, and smaller morphology relative to typical CRPC. A multivariate analysis of protein and morphologic variables enabled distinguishing CTCs of NEPC from CRPC. This CTC classifier was applied to an independent prospective cohort of 159 metastatic CRPC patients and identified in 17/159 (10.7%) of cases, enriched in patients with high CTC burden (P < 0.01) and visceral metastases (P = 0.04).

Conclusions: CTCs from patients with NEPC have unique morphologic characteristics, which were also identified in a subset of CRPC patients with aggressive clinical features potentially undergoing NEPC transition. Clin Cancer Res; 22(6); 1510–9. ©2015 AACR.
Serum Protein Thiol Levels in Patients with Hospital-Acquired Acute Kidney Injury
Authors: Qian Jing , Fang Junyan , Zhu Qiuyu , Ma Shuai , Wang Wenji , Zheng Ying , Hao Guihua , Deng Bo , Zhao Xiaojiao , Ding Feng
Published: December 2015

Background/Aims: This study aimed to examine antioxidants in patients with acute kidney injury (AKI) and determine whether serum protein thiol levels are associated with all-cause 90-day mortality in patients with hospital-acquired AKI. Methods: According to the RIFLE criteria, 160 patients with hospital-acquired AKI were enrolled in our prospective cohort study. As controls, 72 critically ill patients without AKI and 72 age and sex-matched healthy subjects were also recruited. Serum protein thiol levels were analyzed in relation to all-cause mortality of patients with AKI. Results: Serum protein thiol levels in AKI patients were lower than those in healthy people (p=0.010). Protein thiol levels showed a weak but significant positive correlation with serum albumin levels. The 90-day overall mortality rate was higher in AKI patients with high serum protein thiol levels than in those with low levels (p=0.032 by log rank test). In multivariate analysis (Cox regression), serum protein thiol levels (p=0.031) were independently associated with 90-day overall mortality after adjustment for age, sex, sepsis, and the Acute Physiology and Chronic Health Evaluation II score. Conclusions: Patients with hospital-acquired AKI have remarkably low serum protein thiol levels. Elevated protein thiol levels are associated with 90-day overall mortality in hospital-acquired AKI.
Bladder Leiomyosarcoma 25 Years after Treatment with Cyclophosphamide in Patient with History of Retinoblastoma
Authors: Ramírez Sevilla Cristóbal , Admella-Salvador Carme , Romero-Martin Jose-Antonio , Llopis-Manzanera Juan , Barranco-Sanz Miguel-Angel
Published: December 2015

The objective of this case report is to present a rare bladder tumour in a young patient 25 years after the treatment with cyclophosphamide because of a neuroblastoma of the right eye. The first symptom of the tumour was macroscopic haematuria with dysuria and pollakiuria. The final diagnosis was dictaminated by the pathologist and the best treatment option was radical cystoprostatectomy. Leiomyosarcoma was presented in a 26-year-old patient like the third different tumour, the second was an esphenoidal meningioma. At the 8th year of follow-up after the radical surgery, the patient is free of bladder disease. Bladder leiomyosarcoma is a rare tumour of the bladder and its early diagnosis and treatment are mandatory for best prognosis.
Long-Term Evaluation of Colestilan in Chronic Kidney Disease Stage 5 Dialysis Patients with Hyperphosphataemia
Authors: Locatelli Francesco , Spasovski Goce , Dimkovic Nada , Wanner Christoph
Published: December 2015

Background: This study investigated in a North American patient population the longer-term treatment effects of the phosphate binder, colestilan, in patients with CKD Stage 5D and hyperphosphataemia. Methods: One hundred and sixteen CKD Stage 5D patients with hyperphosphataemia were entered into a multi-centre, open-label study where they received flexible dose colestilan (6-15 g/day) to maintain serum phosphorus levels between 3.5 and 5.5 mg/dl. The primary endpoint was safety, assessed by treatment-emergent adverse events. Efficacy was assessed by changes in serum phosphorus, mineral metabolism, lipids, HbA1c, uric acid and bone markers. Results: Serum phosphorus was significantly reduced by 1.18 mg/dl (p < 0.001), from 6.99 mg/dl at baseline to 5.80 mg/dl at week 52. LDL-cholesterol was also significantly reduced as well as uric acid. Significant change was observed only for one bone marker - PINP. Most adverse events were of mild or moderate intensity. Nausea (22.4%), vomiting (21.6%), and diarrhoea (19.8%) were most commonly reported. Conclusions: Long-term flexible dosing with colestilan reduces serum phosphorus and demonstrates an acceptable safety and tolerability profile.
Modulation of Hyperosmotic and Immune-Induced Disruption of the Blood-Brain Barrier by the Nitric Oxide System
Authors: Hasarmeh Malik , Itzik Anna , Weidenfeld Joseph , Ovadia Haim
Published: December 2015

Objectives: The role of nitric oxide (NO) in modulating the blood-brain barrier (BBB) is not entirely clear. We examined the effect of different NO synthase (NOS) inhibitors and NO donors on the permeability of the BBB in animals with normally functioning brain blood vessels, following disruption by hyperosmotic mannitol and during immune inflammation. Methods: We administered L-NAME, aminoguanidine, S-methyl-thiocitrulline (SMT) and 7-indazole (NOS inhibitors) and NOR-4 (an NO donor) into the cerebral ventricle of rats. Disruption of the BBB was induced by intracarotid injection of mannitol (25%). Experimental autoimmune encephalomyelitis (EAE) was induced by brain homogenate. The extent of disruption was evaluated by Evans blue (2%) dye extravasation. Results: L-NAME (a nonspecific NOS inhibitor) and SMT (a neuronal and endothelial NOS inhibitor) increased mannitol-induced disruption of BBB. This effect was inhibited by NO donors. In animals with a normally functioning BBB, none of these inhibitors or NO donors caused a change in the permeability. 7-indazole (a specific neuronal NOS inhibitor) and aminoguanidine (an inducible NOS inhibitor) had no facilitatory effect on BBB permeability, either alone or in combination with hyperosmotic mannitol. Administration of L-NAME and SMT to rats with EAE significantly aggravated the clinical outcome. In contrast, the administration of NOR-4 diminished clinical signs of EAE. Conclusion: The NOS system does not play a role in BBB permeability in naïve animals. Only endothelial NOS takes part in the facilitation of BBB compromised by mannitol and EAE. Extrinsic NO decreases this facilitatory effect.
Early Hemodynamic Changes during Head-Up Tilt Table Testing Can Predict a Neurocardiogenic Response in an African-American Patient Population
Authors: Ho David , Ghods Michael , Kumar Sanjay , Warrier Nikhil , Ilias Basha Haseeb , Budzikowski Adam S. , Kassotis John
Published: December 2015

Background: Head-up tilt table testing (HUTT) is time-consuming and associated with increased patient morbidity. Hemodynamic changes that occur during the early phase of HUTT may be predictive of neurocardiogenic syncope. Methods: A retrospective chart review was performed in 119 consecutive African Americans ( 57 ± 19) who underwent HUTT for evaluation of syncope of unknown etiology. Positive responses were defined as the development of symptoms linked with a systolic blood pressure (BP) <90 mm Hg, heart rate <50 b.p.m. or sinus arrest >3 s. Hemodynamic variables during the passive phase of HUTT were analyzed and results were then classified as a function of various predictors. Results: Sixty-two subjects (52%) had positive HUTT, and 57 (48%) had negative HUTT. Early changes in BP variables from baseline significantly predicted HUTT responses (p < 0.05). There was also a significant interaction between age and BP. An algorithm based on age and BP was developed which had positive and negative predictive values of 67.7 and 93%, respectively, with an accuracy of 79.8%. Conclusion: A novel algorithm utilizing the patients' age and changes in both systolic and diastolic BP during the early phase of HUTT enables the prediction of HUTT results without the use of vasoactive stimulation, allowing for rapid diagnosis, decreased patient morbidity and reduction in costs.
Hypercalcaemia in a Patient with 2p13.2-p16.1 Duplication
Authors: Lodefalk Maria , Frykholm Carina , Esbjörner Elisabeth , Ljunggren Östen
Published: December 2015

Background: Partial duplication of 2p is a rare condition that causes facial anomalies, psychomotor delay, and growth failure. Hypercalcaemia is rare in children. So far, duplication of 2p has never been associated with hypercalcaemia. Methods: Here, we report a girl with a partial duplication of 2p presenting with moderate to severe hypercalcaemia at the age of 2 years. She also had hypercalciuria, nephrocalcinosis, decreased renal function, and secondary hyperparathyroidism at presentation. She was thoroughly investigated, including genetic testing of the CYP24A1, CASR, ALPL, and NOD2 genes, to determine the cause of hypercalcaemia. Results: 1,25-dihydroxyvitamin D levels were increased. Hypercalcaemia and hypercalciuria responded well to glucocorticoids but not to cinacalcet. Hyperparathyroidism resolved with improving renal function. Apart from the known duplication of 2p, no pathogenic variants were detected in the studied genes. The duplication of 2p contains the PPP3R1 gene, which encodes for the calcineurin B subunit. Conclusion: We conclude that partial duplication of 2p can be associated with hypercalcaemia and hypercalciuria and hypothesise that the underlying mechanism is an increased extra-renal, parathyroid hormone-independent 25-hydroxyvitamin D 1α-hydroxylase activity, leading to raised amounts of 1,25-dihydroxyvitamin D. The increased enzymatic activity could possibly be caused by calcineurin B subunit-related macrophage stimulation.
Novel Therapies to Inhibit Mucus Synthesis and Secretion in Airway Hypersecretory Diseases
Authors: Ha Emily V.S. , Rogers Duncan F.
Published: December 2015

Background: In asthma and chronic obstructive pulmonary disease (COPD), airway mucus hypersecretion contributes to impaired mucociliary clearance, mucostasis and, potentially, the development of mucus plugging of the airways. Summary: Excess mucus production can be targeted via therapies that focus on inhibition mucin synthesis, via reducing expression of mucin (MUC) genes, and/or inhibition of mucin secretion into the airways. Key Messages: This review discusses a number of therapeutic approaches to reduce airway mucus in asthma and COPD, including the use of synthetic and natural products. In particular, it highlights areas where clinical trials of inhibitors of particular target molecules are lacking. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are an example of a targeted therapy that has been researched to reduce mucus synthesis, as have inhibitors of EGFR's downstream signalling pathways, for example, mitogen-activated protein kinase-13 and hypoxia inducible factor-1. However, their efficacy and safety profiles are currently not up to the mark. There is clinical potential in Bio-11006, which reduces mucus secretion via the inhibition of myristoylated alanine-rich C-kinase substrate and is currently in Phase IIb trial.
Early Neurodegeneration of the Inner Retinal Layers in Type 1 Diabetes Mellitus
Authors: Gundogan Fatih C. , Akay Fahrettin , Uzun Salih , Yolcu Umit , Çağıltay Eylem , Toyran Sami
Published: December 2015

Purpose: This study explores retinal structural changes in type 1 diabetes without clinically diagnosed diabetic retinopathy (DR). Methods: Peripapillary retinal nerve fiber layer (RNFL) thickness, macular ganglion cell complex (GCC) thickness, and macular thickness (MT) were measured in 90 type 1 diabetic patients by using spectral domain optical coherence tomography. The values were compared with 100 sex- and age-matched healthy controls. The independent t test was used to assess differences in the mean age, mean diabetic and ocular parameters, and the thickness values between the diabetic and control groups. Multiple linear regression analysis was performed to investigate the correlation between the thickness values and diabetic and ocular parameters. Results: Whole-RNFL, the superior and inferior quadrants, and the superior half of the peripapillary RNFL thicknesses were significantly thinner in diabetic patients compared with controls (p < 0.05). GCC thicknesses in the average macular, outer temporal superior and outer temporal inferior sectors were significantly thinner in diabetic patients (p < 0.05). Central and average MTs were similar in both groups (p > 0.05). There were significant negative correlations of the duration of type 1 diabetes with the inner nasal MT, inner temporal superior GCC thickness, inner nasal inferior GCC thickness, and outer nasal superior GCC thickness (p < 0.05). Similarly, there were significant negative correlations of the level of HbA1c with the whole-RNFL thickness, superior-half-RNFL thickness, and superior-quadrant-RNFL thickness (p < 0.05). Conclusions: Type 1 diabetic patients without clinically diagnosed DR had neurodegeneration in the inner retinal layers compared with healthy controls.
Mnesic Profiles According to the Size of Pericerebral Hematoma in Patients with Traumatic Brain Injury
Authors: Rolet Alice , Binetruy Mickael , Chopard Gilles , Tio Gregory , Moulin Thierry , Vandel Pierre , Galmiche Jean , Magnin Eloi
Published: December 2015

Objective: The study aims to assess mnesic performances of patients, following a head injury with pericerebral hematoma, according to the size of the hematoma. Methods: Cognitive performances of a group of 25 patients with large (≥10 mm) pericerebral hematomas were compared with those of a matched group of 25 patients with small (<10 mm) ones and a matched group of patient with moderate-severe traumatic brain injury with no pericerebral hematoma. Results: Executive function and information processing speed were not significantly different. Mnesic performances of the large hematomas group were more impaired: cuing effect (63.5 vs. 80% and 83%; p = 0.002; η2 = 0.183) and total recall (37.5/48 vs. 43.2 and 44.2; p = 0.022; η2 = 0.65) of the Free and Cued Recall Test. Conclusion: Memory of those in the large hematomas group was impaired with probable storage/consolidation disorders. To identify specific cognitive disorders resulting from large hematomas, it is justified to systematically screen these disorders and to adapt their management.
Mandibular Osteolytic Lesion Associated with Exuberant Hyaline Ring Granuloma Reaction
Authors: Almeida Luciana Yamamoto , Trindade Paulo Alceu Kiemle , Sverzut Alexander Tadeu , Sverzut Cassio Edvard , Trivellato Alexandre Elias , Oliveira-Santos Christiano , León Jorge Esquiche
Published: December 2015

Objective: To report an unusual case of oral hyaline ring granuloma (HRG) that caused an extensive osteolytic lesion. Clinical Presentation and Intervention: A 22-year-old female was referred to our hospital with a large expansile cystic lesion in the left mandibular ramus associated with a clinically visible, partially erupted third molar. A diagnosis of paradental cyst was made. After marsupialization of the lesion, histopathological analysis of the surgical specimen showed an unusual exuberant HRG reaction supported by scarce fibrous stroma. Conclusion: This was a case of exuberant HRG reaction that caused extensive bone destruction.
Outcomes of Argatroban Treatment in Patients With Atherothrombotic Stroke
Authors: Wada Tomoki , Yasunaga Hideo , Horiguchi Hiromasa , Matsubara Takehiro , Fushimi Kiyohide , Nakajima Susumu , Yahagi Naoki
Published: December 2015

Background and Purpose—

Argatroban, a selective thrombin inhibitor, is recommended for the use in patients with atherothrombotic stroke by the Japanese Guidelines for the Management of Patients with Acute Ischemic Stroke. We performed a nationwide Japanese study to investigate whether argatroban improved early stroke outcomes in patients with acute atherothrombotic stroke.

Methods—

This retrospective observational study, using the Diagnosis Procedure Combination database in Japan, included patients who were hospitalized from July 1, 2010, to March 31, 2012, with a diagnosis of atherothrombotic stroke within 1 day of stroke onset. Patients were divided into 2 groups: those receiving argatroban on admission (argatroban group), and those who did not receive argatroban during hospitalization (control group). To balance the baseline characteristics and concomitant treatments during hospitalization between the 2 groups, one-to-one propensity-score matching analyses were performed. The main outcomes were the modified Rankin Scale score at discharge and the occurrence of hemorrhagic complications during hospitalization. An ordinal logistic regression analysis evaluated the association between argatroban use and modified Rankin Scale at discharge.

Results—

After propensity-score matching, 2289 pairs of patients were analyzed. There were no significant differences in modified Rankin Scale at discharge between the argatroban and the control groups (adjusted odds ratio, 1.01; 95% confidence interval, 0.88–1.16). The occurrence of hemorrhagic complications did not differ significantly between the argatroban and the control groups (3.5% versus 3.8%;
P
=0.58).

Conclusions—

The present study suggested that argatroban was safe, but had no added benefit in early outcomes after acute atherothrombotic stroke.
Nonaspirin Nonsteroidal Anti-Inflammatory Drugs and Risk of Hemorrhagic Stroke
Authors: Ungprasert Patompong , Matteson Eric L. , Thongprayoon Charat
Published: December 2015

Background and Purpose—

The association between hemorrhagic stroke and use of nonsteroidal anti-inflammatory drugs (NSAIDs) is not well established. We conducted a systematic review and meta-analysis of observation studies to further characterize this possible association.

Methods—

Case–control and cohort studies that reported odds ratio, relative risk, hazard ratio, or standardized incidence ratio comparing risk of hemorrhagic stroke among NSAIDs users versus nonusers were systematically searched. Point estimates from each study were extracted. Pooled risk ratios (RR) and 95% confidence intervals (CI) for all NSAIDs and individual NSAIDs were calculated using random-effect, generic inverse variance method.

Results—

Ten studies were identified and included in our data analysis. As a single group, NSAIDs use was associated with a small but insignificant risk of hemorrhagic stroke with the pooled RR of 1.09 (95% CI, 0.98–1.22). Individual NSAIDs analysis revealed a significantly increased risk among diclofenac and meloxicam users (RR 1.27; 95% CI, 1.02–1.59 and RR 1.27; 95% CI, 1.08–1.50, respectively). The risk estimate for rofecoxib users was higher, but statistically nonsignificant (RR 1.35; 95% CI, 0.88–2.06).

Conclusions—

Overall, the use of NSAIDs is not associated with an increased risk of hemorrhagic stroke, although this risk was modestly significantly elevated in diclofenac and meloxicam users.