Combined oral 5-azacytidine and romidepsin are highly effective in patients with PTCL: a multicenter phase 2 study.

Peripheral T-cell lymphomas (PTCLs) are uniquely vulnerable to epigenetic modifiers. We demonstrated in vitro synergism between histone deacetylase inhibitors and DNA methyltransferase inhibitors in preclinical models of T-cell lymphoma. In a phase 1 trial, we found oral 5-azacytidine and romidepsin to be safe and effective, with lineage-selective activity among patients with relapsed/refractory (R/R) PTCL. Patients who were treatment naïve or who had R/R PTCL received azacytidine 300 mg once per day on days 1 to 14, and romidepsin 14 mg/m2 on days 8, 15, and 22 every 35 days. The primary objective was overall response rate (ORR). Targeted next-generation sequencing was performed on tumor samples to correlate mutational profiles and response. Among 25 enrolled patients, the ORR and complete response rates were 61% and 48%, respectively. However, patients with T-follicular helper cell (tTFH) phenotype exhibited higher ORR (80%) and complete remission rate (67%). The most frequent grade 3 to 4 adverse events were thrombocytopenia (48%), neutropenia (40%), lymphopenia (32%), and anemia (16%). At a median follow-up of 13.5 months, the median progression-free survival, duration of response, and overall survival were 8.0 months, 20.3 months, and not reached, respectively. The median progression-free survival and overall survival were 8.0 months and 20.6 months, respectively, in patients with R/R disease. Patients with tTFH enjoyed a particularly long median survival (median not reached). Responders harbored a higher average number of mutations in genes involved in DNA methylation and histone deacetylation. Combined azacytidine and romidepsin are highly active in PTCL patients and could serve as a platform for novel regimens in this disease. This trial was registered at www.clinicaltrials.gov as #NCT01998035.

Oral 5-azacytidine and romidepsin exhibit marked activity in patients with PTCL: a multicenter phase 1 study.

The peripheral T-cell lymphomas (PTCLs) are uniquely sensitive to epigenetic modifiers. Based on the synergism between histone deacetylase inhibitors and hypomethylating agents that we established in preclinical PTCL models, we conducted a phase 1 study of oral 5-azacytidine (AZA) and romidepsin (ROMI) in patients with advanced lymphoid malignancies, with emphasis on PTCL. According to a 3 + 3 design, patients were assigned to 1 of 7 cohorts with AZA doses ranging from 100 mg daily on days 1 to 14 to 300 mg daily on days 1 to 21, ROMI doses ranging from 10 mg/m2 on days 8 and 15 to 14 mg/m2 on days 8, 15, and 22, with cycles of 21 to 35 days. Coprimary end points included maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). We treated a total of 31 patients. The MTD was AZA 300 mg on days 1 to 14 and ROMI 14 mg/m2 on days 8, 15, and 22 on a 35-day cycle. DLTs included grade 4 thrombocytopenia, prolonged grade 3 thrombocytopenia, grade 4 neutropenia, and pleural effusion. There were no treatment-related deaths. The combination was substantially more active in patients with PTCL than in those with non-T-cell lymphoma. The overall response rate in all, non-T-cell, and T-cell lymphoma patients was 32%, 10%, and 73%, respectively, and the complete response rates were 23%, 5%, and 55%, respectively. We did not find an association between response and level of demethylation or tumor mutational profile. This study establishes that combined epigenetic modifiers are potently active in PTCL patients. This trial was registered at www.clinicaltrials.gov as NCT01998035.

A phase 1 study of romidepsin and pralatrexate reveals marked activity in relapsed and refractory T-cell lymphoma.

Peripheral T-cell lymphomas (PTCL) are a group of rare malignancies characterized by chemotherapy resistance and poor prognosis. Romidepsin and pralatrexate were approved by the US Food and Drug Administration for patients with relapsed/refractory PTCL, exhibiting response rates of 25% and 29% respectively. Based on synergy in preclinical models of PTCL, we initiated a phase 1 study of pralatrexate plus romidepsin in patients with relapsed/refractory lymphoma. This was a single institution dose-escalation study of pralatrexate plus romidepsin designed to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, pharmacokinetic profile, and response rates. Patients were treated with pralatrexate (10 to 25 mg/m2) and romidepsin (12 to 14 mg/m2) on 1 of 3 schedules: every week × 3 every 28 days, every week × 2 every 21 days, and every other week every 28 days. Treatment continued until progression, withdrawal of consent, or medical necessity. Twenty-nine patients were enrolled and evaluable for toxicity. Coadministration of pralatrexate and romidepsin was safe, well tolerated, with 3 DLTs across all schedules (grade 3 oral mucositis × 2; grade 4 sepsis × 1). The recommended phase 2 dose was defined as pralatrexate 25 mg/m2 and romidepsin 12 mg/m2 every other week. Twenty-three patients were evaluable for response. The overall response rate was 57% (13/23) across all patients and 71% (10/14) in PTCL. The phase 1 study of pralatrexate plus romidepsin resulted in a high response rate in patients with previously treated PTCL. A phase 2 study in PTCL will determine the efficacy of the combination. This trial was registered at www.clinicaltrials.gov as #NCT01947140.

Effects of ethics education on moral sensitivity of nursing students.

BACKGROUND: While nursing ethics education is commonly provided for undergraduate nursing students in most nursing colleges, consensus on the content and teaching modules for these ethics courses have still not been established. OBJECTIVES: This study aimed to examine the effects of nursing ethics education on the moral sensitivity and critical thinking disposition of nursing students in Korea. RESEARCH DESIGN: A one-group pre- and post-test design was used. Moral sensitivity was measured using the Korean version of the Moral Sensitivity Questionnaire. Critical thinking disposition was measured using the Critical Thinking Disposition Questionnaire. Participants and research context: Participants were 70 undergraduate nursing students who were attending a university located in Seoul, Korea. The nursing ethics education was provided 7 times, from September to December 2010, and comprised 90-min sessions each week. Ethical considerations: This study was conducted in accordance with the Human Subject Research Ethics Committee guidelines. FINDINGS: After the education, the levels for the patient-oriented care, a sub-domain of moral sensitivity, and inquisitiveness, a sub-domain of critical thinking disposition, significantly improved. There were no changes in overall scores for moral sensitivity and critical thinking disposition. There were significant positive correlations between moral sensitivity and critical thinking disposition both pre- and post-intervention. CONCLUSION: These results reflect the need for ongoing efforts to develop innovative content, structure, and instructional methods for undergraduate nursing ethics education programs.

Moral sensitivity and critical thinking disposition of nursing students in Korea.

This study aimed to examine the level of moral sensitivity and critical thinking disposition among baccalaureate nursing students in Korea. A convenience sample of 142 undergraduate nursing students was surveyed on moral sensitivity using the Korean version of the Moral Sensitivity Questionnaire (K-MSQ) and on critical thinking disposition using the Critical Thinking Disposition Questionnaire (CTDQ). Data were collected from June 2009 to July 2010. Mean score was 2.83 out of 7 on the K-MSQ (relatively low) and 3.70 out of 5 on the CTDQ (relatively high), indicating the need for nursing educators to continue to develop and incorporate strategies that enhance moral sensitivity into ethics courses in undergraduate nursing programs in Korea. Nursing students who regarded nursing as a lifelong career exhibited stronger critical thinking disposition than did students who considered nursing to be a temporary or premarital job. Moral sensitivity should be further emphasized in nursing ethics courses in undergraduate nursing programs in Korea.

Association between physical activity and metabolic syndrome in older adults in Korea: analysis of data from the Korean National Health and Nutrition Examination Survey IV.

The prevalence of metabolic syndrome is consistently increasing among Korean adults and is reported to be particularly high among older adults in Korea. This paper reports the prevalence of metabolic syndrome and identifies the association between metabolic syndrome and physical activity in Korean older adults. Subjects of this study were 3653 older adults who participated in the fourth Korean National Health and Nutrition Examination Survey during the years 2007-2009. The prevalence of metabolic syndrome in the study population was 46.84%. The prevalences of abdominal obesity, elevated fasting glucose, elevated triglycerides, reduced high-density lipoprotein cholesterol, and elevated blood pressure were 39.51, 45.53, 39.55, 48.24, and 69.14%, respectively, in the study population. Compared to subjects who reported low levels of physical activity, the odds ratios of metabolic syndrome for those who were moderately active and highly active were 0.93 and 0.63, respectively. Nurses should develop metabolic syndrome management programs that are tailored to the needs of the targeted group and that include individually adapted physical activity programs to promote health.

Recognition memory impairments and amyloid-beta deposition of the retrosplenial cortex at the early stage of 5XFAD mice.

Early diagnosis and treatment of AD are critical for delaying its progression. The present study, therefore, examined the cognitive status and neuropathological characteristics of 4-month-old 5X familial AD (5XFAD) transgenic (Tg) mice, as an early stage of AD animal model. The novel object recognition task was performed with retention tests at varying intervals (i.e., 10 min, 1 h, 4 h, and 24 h) to measure the retention capacity of recognition memory of 5XFAD mice. At the 4h retention interval, 5XFAD mice exhibited worse performances than non-Tg control mice. Therefore, using amyloid-beta (Aß) 42- and 4G8-immunoreactive plaques, the accumulation of Aß was examined in the gray and white matter of the system that was necessary for the retention of recognition memory, with a focus on the hippocampus and retrosplenial cortex. The expression of ionized calcium-binding adapter molecule-1 (Iba-1) was also examined to measure microglial activation. The immunohistological analysis of Aß and Iba-1 revealed that the retrosplenial cortex was the most affected region in the brains of 4-month-old 5XFAD mice. These findings indicate that the cognitive and neuropathological characteristics of 4-month-old 5XFAD mice would provide a research platform for studying early diagnosis and treatment of AD.

Proteome-based plasma biomarkers for Alzheimer's disease.

Alzheimer's disease is a common and devastating disease for which there is no readily available biomarker to aid diagnosis or to monitor disease progression. Biomarkers have been sought in CSF but no previous study has used two-dimensional gel electrophoresis coupled with mass spectrometry to seek biomarkers in peripheral tissue. We performed a case-control study of plasma using this proteomics approach to identify proteins that differ in the disease state relative to aged controls. For discovery-phase proteomics analysis, 50 people with Alzheimer's dementia were recruited through secondary services and 50 normal elderly controls through primary care. For validation purposes a total of 511 subjects with Alzheimer's disease and other neurodegenerative diseases and normal elderly controls were examined. Image analysis of the protein distribution of the gels alone identifies disease cases with 56% sensitivity and 80% specificity. Mass spectrometric analysis of the changes observed in two-dimensional electrophoresis identified a number of proteins previously implicated in the disease pathology, including complement factor H (CFH) precursor and alpha-2-macroglobulin (alpha-2M). Using semi-quantitative immunoblotting, the elevation of CFH and alpha-2M was shown to be specific for Alzheimer's disease and to correlate with disease severity although alternative assays would be necessary to improve sensitivity and specificity. These findings suggest that blood may be a rich source for biomarkers of Alzheimer's disease and that CFH, together with other proteins such as alpha-2M may be a specific markers of this illness.

Plasma REST: a novel candidate biomarker of Alzheimer's disease is modified by psychological intervention in an at-risk population.

The repressor element 1-silencing transcription (REST) factor is a key regulator of the aging brain's stress response. It is reduced in conditions of stress and Alzheimer's disease (AD), which suggests that increasing REST may be neuroprotective. REST can be measured peripherally in blood plasma. Our study aimed to (1) examine plasma REST levels in relation to clinical and biological markers of neurodegeneration and (2) alter plasma REST levels through a stress-reduction intervention-mindfulness training. In study 1, REST levels were compared across the following four well-characterized groups: healthy elderly (n=65), mild cognitive impairment who remained stable (stable MCI, n=36), MCI who later converted to dementia (converter MCI, n=29) and AD (n=65) from the AddNeuroMed cohort. REST levels declined with increasing severity of risk and impairment (healthy elderly>stable MCI>converter MCI>AD, F=6.35, P<0.001). REST levels were also positively associated with magnetic resonance imaging-based hippocampal and entorhinal atrophy and other putative blood-based biomarkers of AD (Ps<0.05). In study 2, REST was measured in 81 older adults with psychiatric risk factors for AD before and after a mindfulness-based stress reduction intervention or an education-based placebo intervention. Mindfulness-based training caused an increase in REST compared with the placebo intervention (F=8.57, P=0.006), and increased REST was associated with a reduction in psychiatric symptoms associated with stress and AD risk (Ps<0.02). Our data confirm plasma REST associations with clinical severity and neurodegeneration, and originally, that REST is modifiable by a psychological intervention with clinical benefit.

An evaluation of the time for nursing activity in a hospital using a full Electronic Medical Record System (EMR).

This study was designed to analyze the time for direct and indirect nursing activity to evaluate the workload of nurses using a full Electronic Medical Record (EMR) system on practice. The result is that the mean time for nursing activity per nurse was 499.56 minutes, the mean time for direct nursing activity per nurse was 251.1 minutes (50.3%), and the mean time for indirect nursing activity per nurse was 248.42 minutes(49.7%). The time for direct nursing activity was more than the time for indirect nursing activity. There was a significant difference in the time for nursing activity according to workplace (p < 0.00*), but no difference according to nursing career. Regarding 3 duty-shifts, the time for direct nursing activity was highest in the evening shift and the time for indirect nursing activity was highest in the night shift.

Blood metabolite markers of neocortical amyloid-ß burden: discovery and enrichment using candidate proteins.

We believe this is the first study to investigate associations between blood metabolites and neocortical amyloid burden (NAB) in the search for a blood-based biomarker for Alzheimer's disease (AD). Further, we present the first multi-modal analysis of blood markers in this field. We used blood plasma samples from 91 subjects enrolled in the University of California, San Francisco Alzheimer's Disease Research Centre. Non-targeted metabolomic analysis was used to look for associations with NAB using both single and multiple metabolic feature models. Five metabolic features identified subjects with high NAB, with 72% accuracy. We were able to putatively identify four metabolites from this panel and improve the model further by adding fibrinogen gamma chain protein measures (accuracy=79%). One of the five metabolic features was studied in the Alzheimer's Disease Neuroimaging Initiative cohort, but results were inconclusive. If replicated in larger, independent studies, these metabolic features and proteins could form the basis of a blood test with potential for enrichment of amyloid pathology in anti-amyloid trials.

Predictors of patient satisfaction with tertiary hospitals in Korea.

This study examined the general and system-related predictors of outpatient satisfaction with tertiary health care institutions in Korea. A cross-sectional descriptive study design was employed. The subjects were 1,194 outpatients recruited from 29 outpatient clinics of a university medical center in Korea. Measurements included 5 outpatient service domains (i.e., doctor service, nurse service, technician service, convenience, and physical environment of facility) and patient satisfaction. Of the five domains, nurse service was the domain with the highest mean score (M = 4.21) and convenience was the domain with the lowest mean score (M = 3.77). The most significant predictor of patient satisfaction was the constructs of convenience (ß = 0.21). The results of this study suggest that the concept of patient satisfaction with health care institutions in modern hospitals reflects an integrative process that includes not only the concerned health care personnel but also improved convenience such as user-friendly reservation system and comfortable waiting areas.

Factors affecting mobility in community-dwelling older Koreans with chronic illnesses.

PURPOSE: This descriptive study aims to describe the levels of mobility in community-dwelling older Koreans with chronic illnesses, and to examine the associations of their mobility with sleep patterns, physical activity and physical symptoms including fatigue and pain. METHODS: The participants were a total of 384 community-dwelling older adults recruited from three senior centers in Seoul, Korea. Measures included mobility assessed using 6-minute walk test (6MWT), physical activity behavior, sleep profiles, fatigue and pain. Data were collected from July to December 2012. RESULTS: The mean 6MWT distance was 212.68 meters. Over 90% of the study participants (n = 373) were classified as having impaired mobility using 400 meters as the cutoff point diagnostic criteria of normal mobility in 6MWT. The 6MWT distance was 246.68 meters for participants in their 60s, 212.32 meters for those in their 70s, and 175.54 meters for those in their 80s. Significant predictors of mobility included younger age, taking mediation, regular physical activity, female gender, higher income, higher fatigue and better perception on sleep duration, which explained 18% of the total variance of mobility. CONCLUSIONS: A high-risk group for mobility limitation includes low income, sedentary older men who are at risk for increased fatigue and sleep deficit. Further research should incorporate other psychological and lifestyle factors such as depression, smoking, drinking behavior, and/or obesity into the prediction model of mobility to generate specific intervention strategies for mobility enhancement recommendations for older adults.

Reproducibility of sputum smear examination for acid-fast bacilli: practical problems met during cross-checking.

SETTING: A TB control programme in Bangladesh with proficiency testing of sputum smears for acid-fast bacilli (AFB) using cross-checking of routine smears. OBJECTIVE: To document factors that may adversely affect repeatability of the AFB smear, and which should be taken into account for interpretation of cross-checking. DESIGN: A number of simple experiments falling within the scope of small routine laboratories in a developing country. RESULTS: Fuchsin staining is not stable, fading quickly in direct sunlight and combinations of high temperature and humidity. Diffuse daylight, immersion oil or xylene did not have the same effect. Contamination of smears by saprophytic mycobacteria may occur during staining or rinsing, with contaminants becoming visible only after restaining and cross-checking. Finally, AFB may be dislodged from smears during soaking in xylene or restaining, especially if the smears are made from thin, liquefied sputum. CONCLUSIONS: These possible interfering factors should be taken into account when organizing proficiency testing and interpreting its results.

Conclusions about differences in linear growth between Bangladeshi boys and girls depend on the growth reference used.

OBJECTIVE: To examine sex differences in height-for-age z-scores and the percentage stunting among Bangladeshi children estimated using three growth references. DESIGN, SETTING AND SUBJECTS: Data collected between 1990 and 1999 by Helen Keller International's nutritional surveillance system in rural Bangladesh were analyzed for 504 358 children aged 6-59 months. Height-for-age z-scores were estimated using the 1977 NCHS, 2000 CDC and 1990 British growth references. RESULTS: The shape of the growth curves for Bangladeshi boys and girls, and their positions relative to one another, depend on which of the three growth references is used. At 6 months of age the British reference showed no sex difference whereas the NCHS and CDC showed girls to have higher average z-scores than boys by 0.14 and 0.28 s.d., respectively. While all references showed a faster deterioration of girls' z-scores from 6 to 24 months, the magnitude and direction of the sex differences, and how they changed with age, were different. There was greater disagreement about girls' z-scores than boys. Discontinuities at 24 months in the NCHS and CDC produced jagged curves whereas the British curves were smooth. CONCLUSIONS: The assessment of sex differences in linear growth depends on the growth reference used. Reasons for the different results need to be determined and may aid the final development of the new WHO international growth reference and the guidelines for its use. The findings suggest that anthropometry as a tool to explore the effects of societal gender inequality must be used with caution.

Mechanisms of drug photobinding to proteins: photobinding of suprofen to human serum albumin.

Photobinding of drugs to biomolecules constitutes an important early event in the onset of photoallergy. In the present work, UV irradiation of human serum albumin in the presence of either suprofen (SUP) or its major photoproduct, decarboxylated suprofen (DSUP), has been studied as a model system for drug-photosensitised protein binding. Both dark binding and binding in the presence of light were investigated since this will affect the mode, site and mechanism of drug interaction with the protein. In order to determine the binding features of SUP to albumin, competitive binding experiments were carried out using fluorescent probes specific for site I and II. Suprofen was found to selectively dark bind to site II on HSA. Photobinding of DSUP to HSA was more efficient than SUP. Parallel to this, the intrinsic tryptophan fluorescence of HSA decreased when the protein was previously irradiated in the presence of the photoactive compounds, again being DSUP more efficient compared with SUP. As fluorescence quenching involves electron transfer from the excited Trp to the ground state DSUP, it follows that the photoactive compound binding to HSA must be on (or in close proximity to) site I Trp(214) residue. It appears that photobinding of SUP is largely preceded by its photodecomposition to DSUP which, in turn, associates and photobinds to HSA.

Photobinding of carprofen to protein.

Carprofen is a non-steroidal antiinflammatory drug with marked photosensitising properties. In order to elucidate the mechanisms underlying the phenomenon of drug-protein photobinding, mixtures of the drug and human serum albumin were irradiated under different experimental conditions. After irradiation and subsequent gel-filtration chromatography of the photomixture, the eluting protein fraction was analysed by means of fluorescence spectroscopy. The formation of drug-protein photoadducts could be evidenced by the characteristic emission properties of the carbazole chromophore. The photobinding of the drug to human serum albumin appears to involve the formation of aryl radicals resulting from carbon-halogen photocleavage. This mechanistic interpretation is supported by the observed variations in the intensity of the fluorescence spectra, which can be correlated with the lower quantum yield emission of chlorocarbazoles as compared to non-halogenated analogues. The results from laser flash photolysis studies are also in agreement with this proposal.

Stress and coping strategies of patients with cancer. A Korean study.

Cancer is a potential life-threatening illness that engenders considerable psychologic distress, requiring persistent coping for the treatment procedures. In this cross-sectional descriptive study stress levels and coping strategies of 257 cancer patients residing in South Korea are addressed. Lazarus and Folkman's theory of stress and coping was used as the theoretical framework. The data were collected from November 1999 to March 2000 by face-to-face interviews. Study participants were primarily male (62.6%) and married (91.4%). Cancer of the gastrointestinal system was the most prevalent type of cancer (31.3%). Women and the patients in the third-stage of cancer showed higher stress but less coping than other groups. Stress was negatively correlated with both problem-focused coping and emotion-focused coping. Korean patients with cancer used emotion-focused coping strategies more than problem-focused coping strategies.

The effects of aromatherapy on pruritus in patients undergoing hemodialysis.

This study was designed to investigate the effects of aromatherapy on pruritus in patients with chronic renal failure undergoing hemodialysis. The participants were 29 adult patients living in Seoul, Korea. Thirteen patients were assigned to the experimental group and received the aromatherapy massage on the arm 3 times a week for 4 weeks. Pruritus score, skin pH, stratum corneum hydration, and pruritus-related biochemical markers were measured before and after the treatment. The results showed that pruritus score was significantly decreased after aromatherapy. Skin pH showed no significant changes in either group while stratum corneum hydration increased significantly in the experimental group after aromatherapy. The results support the use aromatherapy as a useful and effective method of managing pruritus in patients undergoing hemodialysis.