Publications by authors named "Denise Johnson"

51 Publications

Developing and Implementing a Patient Behaviour Risk Screening, Communication and Care Planning Intervention for Hospital Settings.

Healthc Q 2021 Jan;23(4):53-59

An interventional cardiologist at Hamilton Health Sciences, an associate professor in cardiology in the Department of Medicine at McMaster University, a scientist at the Population Health Research Institute and the director of the Hamilton Health Sciences Centre for Evidence-Based Implementation in Hamilton, ON.

Workplace violence prevention of patient behaviours is a primary safety focus in hospital settings. In response to provincial mandates, a multi-site tertiary care hospital system developed the Behaviour Safety Risk Communication and Care Planning Program. Components include patient risk screening, communication tools and care plans that outline mitigation strategies. The program has been implemented at six sites using the following strategies: educational and planning meetings, formation of steering committees, identification of champions, educational materials/training, facilitation and consultation, and audit and feedback. Our paper can guide program development and implementation in similar contexts.
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http://dx.doi.org/10.12927/hcq.2020.26392DOI Listing
January 2021

Upper limb robotic assessment: Pilot study comparing velocity dependent resistance in individuals with acquired brain injury to healthy controls.

J Rehabil Assist Technol Eng 2020 Jan-Dec;7:2055668320929535. Epub 2020 Dec 4.

College of Physical and Engineering Science, University of Guelph, Guelph, Canada.

Introduction: Assessment of velocity dependent resistance (VDR) can provide insights into spasticity in individuals with upper motor neuron syndrome. This study investigates the relationship between Modified Ashworth scores and a biomechanical based representation of VDR using a rehabilitation robot. Comparisons in VDR are made for the upper limb (UL) between individuals with acquired brain injury and healthy controls for the para-sagittal plane.

Methods: The system manipulates the individual's limb through five flexion and extension motions at increasing speeds to obtain force profiles at different velocities. An approximation of VDR is calculated and analyzed statistically against clinical scales and tested for interactions.

Results: All individuals (aged 18-65), including healthy controls exhibited VDR greater than 0 (P < 0.05). MAS scores were found to be related to VDR (P < 0.05) with an interaction found between MAS Bicep and Tricep scores (P < 0.01). Considering this interaction, evidence of differences in VDR were found between several neighboring assessment score combinations.

Conclusion: The robot can detect and quantify VDR that captures information relevant to UL spasticity. Results suggests a better categorization of VDR is possible and supports further development of rehabilitation robotics for assisting spasticity assessment.
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http://dx.doi.org/10.1177/2055668320929535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720336PMC
December 2020

High-Sensitivity Cardiac Troponin-Optimizing the Diagnosis of Acute Myocardial Infarction/Injury in Women (CODE-MI): Rationale and design for a multicenter, stepped-wedge, cluster-randomized trial.

Am Heart J 2020 11 25;229:18-28. Epub 2020 Jun 25.

BC Centre for Improved Cardiovascular Health (ICVHealth) at Centre for Health Evaluation and Outcome Sciences (CHEOS), Vancouver, British Columbia, Canada; Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address:

Despite evidence that high-sensitivity cardiac troponin (hs-cTn) levels in women are lower than in men, a single threshold based on the 99th percentile upper reference limit of the overall reference population is commonly used to diagnose myocardial infarction in clinical practice. This trial aims to determine whether the use of a lower female-specific hs-cTn threshold would improve the diagnosis, treatment, and outcomes of women presenting to the emergency department with symptoms suggestive of myocardial ischemia. METHODS/DESIGN: CODE-MI (hs-cTn-Optimizing the Diagnosis of Acute Myocardial Infarction/Injury in Women) is a multicenter, stepped-wedge, cluster-randomized trial of 30 secondary and tertiary care hospitals across 8 Canadian provinces, with the unit of randomization being the hospital. All adults (≥20 years of age) presenting to the emergency department with symptoms suggestive of myocardial ischemia and at least 1 hs-cTn test are eligible for inclusion. Over five, 5-month intervals, hospitals will be randomized to implement lower female hs-cTn thresholds according to the assay being used at each site. Men will continue to be assessed using the overall thresholds throughout. Women with a peak hs-cTn value between the female-specific and the overall thresholds will form our primary cohort. The primary outcome, a 1-year composite of all-cause mortality or readmission for nonfatal myocardial infarction, incident heart failure, or emergent/urgent coronary revascularization, will be compared before and after the implementation of female thresholds using mixed-effects logistic regression models. The cohort and outcomes will be obtained from routinely collected administrative data. The trial is designed to detect a 20% relative risk difference in the primary outcome, or a 2.2% absolute difference, with 82% power. CONCLUSIONS: This pragmatic trial will assess whether adopting lower female hs-cTn thresholds leads to appropriate assessment of women with symptoms suggestive of myocardial infarction, thereby improving treatment and outcomes.
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http://dx.doi.org/10.1016/j.ahj.2020.06.013DOI Listing
November 2020

Interrater Reliability of Three Versions of the Chedoke Arm and Hand Activity Inventory.

Physiother Can 2018 ;70(2):133-140

School of Rehabilitation Science, McMaster University.

The purpose of this study was to estimate the interrater reliability of three shortened versions of the Chedoke Arm and Hand Activity Inventory (CAHAI-7, CAHAI-8, CAHAI-9) when used with persons with acquired brain injury (ABI). The CAHAI is an assessment of upper limb function with high reliability in the stroke and ABI populations. In the stroke population, three shortened versions of the measure have established reliability. Clinicians report time constraints as a barrier to using standardized assessments; thus, establishing the reliability of the shortened versions of the CAHAI in the ABI population may increase the use of this measure. This was an observational, parameter estimation study. The participants were recruited from an in-patient ABI rehabilitation programme. The administration of the CAHAI to six persons with ABI was video recorded, and the video recordings were assessed by six clinicians to estimate interrater reliability. A Latin square design was used to balance the order in which the raters evaluated the videos. A repeated-measures analysis of variance was performed, and the variance components were used to calculate an intra-class correlation coefficient (ICC) and standard error of measurement (SEM) with 95% confidence limits (CLs) for each of the shortened versions. Interrater reliability was high for all three versions: CAHAI-7, ICC=0.96 (95% CL: 0.89, 0.99; SEM 2.65); CAHAI-8, ICC=0.96 (95% CL: 0.90, 0.99; SEM 2.72); and CAHAI-9, ICC=0.95 (95% CL: 0.85, 0.99; SEM 3.49). These results suggest that the three shortened versions of the CAHAI demonstrate high reliability in the ABI population. These versions may be particularly useful when time constraints or patient tolerance are an issue.
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http://dx.doi.org/10.3138/ptc.2016-70DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938075PMC
January 2018

Transverse forces versus modified ashworth scale for upper limb flexion/extension in para-sagittal plane.

IEEE Int Conf Rehabil Robot 2017 07;2017:765-770

Spasticity is a common impairment following an upper motor neuron lesion in conditions such as stroke and brain injury. A clinical issue is how to best quantify and measure spasticity. Recently, research has been performed to develop new methods of spasticity quantification using various systems. This paper follows up on previous work taking a closer look at the role of transversal forces obtained via rehabilitation robot for motions in the para-sagittal plane. Results from 45 healthy individuals and 40 individuals with acquired brain injury demonstrate that although the passive upper motions are vertical, horizontal forces into and away from the individual's body demonstrate a relationship with the Modified Ashworth Scale. This finding leads the way to new avenues of spasticity quantification and monitoring.
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http://dx.doi.org/10.1109/ICORR.2017.8009340DOI Listing
July 2017

Inter-rater reliability of the Chedoke Arm and Hand Activity Inventory.

NeuroRehabilitation 2017 ;40(2):201-209

School of Rehabilitation Science, McMaster University, Hamilton, ON, Canada.

Background: The Chedoke Arm and Hand Activity Inventory (CAHAI) is an assessment of upper limb function designed for use in the stroke population. The CAHAI has strong reliability and validity in this population; however, it is unknown whether this measure can be used with other clinical populations such as acquired brain injury (ABI).

Purpose: The purpose of this study was to estimate the inter-rater reliability of the CAHAI when used with persons with ABI.

Methods: The research design was an observational parameter estimation study. The administration of the CAHAI was videotaped for 6 persons with ABI. To estimate inter-rater reliability each video was assessed independently by 6 clinicians yielding a total of 36 assessments. A Latin square design was used to balance the order raters evaluated the videos. Shrout and Fleiss Type 2,1 intra class correlation coefficients (ICC) and standard error of measurement (SEM) were calculated to estimate inter-rater reliability of the CAHAI.

Results: Inter-rater reliability was high ICC = 0.96 (95% CL: 0.88, 0.99) and the SEM was 3.35 (95% CL: 2.63, 4.63) CAHAI points.

Conclusions: These results suggest that the CAHAI, although designed for use in the stroke population, can be used reliably in the ABI population.
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http://dx.doi.org/10.3233/NRE-161405DOI Listing
May 2017

Association between change in cervical length and spontaneous preterm birth in twin pregnancies.

Am J Obstet Gynecol 2017 Feb 8;216(2):159.e1-159.e7. Epub 2016 Oct 8.

Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY.

Background: There is a lack of consensus on the optimal transvaginal cervical length for determining risk for spontaneous preterm birth in twin pregnancies. Change in transvaginal cervical length over time may reflect early activation of the parturition process, as has been demonstrated in singleton pregnancies. The association between change in transvaginal cervical length and the risk for spontaneous preterm birth has not yet been described in the population of women with diamniotic twin pregnancies.

Objective: Our primary objective is to determine whether rate of change in transvaginal cervical length in the midtrimester is associated with spontaneous preterm birth in twin gestations. Our secondary objective is to describe parameters for identifying patients at increased risk for spontaneous preterm birth based on change in transvaginal cervical length over time.

Study Design: This is a retrospective cohort of serial transvaginal cervical length performed for twin pregnancies at a single institution from 2008 through 2015. Women with diamniotic twin pregnancies who had transvaginal cervical length measurements at 18 and 22 weeks' gestation and outcome data available were included. Logistic regression was used to determine the relationship between the rate of change in transvaginal cervical length and the risk for the primary outcome of spontaneous preterm birth <35 weeks as well as spontaneous preterm birth <32 weeks.

Results: In all, 527 subjects met inclusion criteria for this study. The average rate of change in transvaginal cervical length for patients with spontaneous preterm birth <35 weeks was -0.21 cm/wk (SD 0.27) vs -0.10 cm/wk (SD 0.24) for patients who delivered ≥35 weeks (P < .01). The rate of change in transvaginal cervical length was associated with spontaneous preterm birth <35 weeks when controlling for initial transvaginal cervical length and other important risk factors for spontaneous preterm birth. Results for spontaneous preterm birth <32 weeks were similar. This association remained significant when the rate of weekly change was treated as a dichotomous variable based on an apparent inflection point in the risk for spontaneous preterm birth: women with rapid change in transvaginal cervical length, ≥-0.2 cm/wk, had 3.45 times the odds of spontaneous preterm birth as those with less rapid change (95% confidence interval, 2.15-5.52) when controlling for initial transvaginal cervical length.

Conclusion: Change in transvaginal cervical length in the midtrimester is associated with spontaneous preterm birth, and therefore protocols for serial transvaginal cervical length measurement can provide the clinician with information to identify at-risk patients. A decrease of ≥0.2 cm/wk of transvaginal cervical length identifies patients at increased risk for spontaneous preterm birth <35 weeks.
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http://dx.doi.org/10.1016/j.ajog.2016.10.002DOI Listing
February 2017

A comparison of prevaginal and postvaginal manipulation fetal fibronectin.

Am J Obstet Gynecol 2016 May 28;214(5):646.e1-6. Epub 2016 Feb 28.

Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, NY.

Background: Fetal fibronectin (fFN) is used as a biomarker for preterm delivery. Currently, its use is discouraged if there has been vaginal manipulation in the previous 24 hours.

Objective: Our objective is to determine if there are differences between fFN results before and after vaginal manipulation in the form of sterile vaginal exam or transvaginal ultrasound.

Study Design: This was a prospective observational cohort study at a single center of women between 22-33 6/7 weeks at risk for preterm delivery due to: (1) a history of preterm delivery, short cervix, or multifetal gestation; or (2) symptoms of preterm labor. We excluded women with vaginal bleeding or infection, placenta previa, ruptured membranes, cervical dilation >3 cm, or any form of vaginal manipulation in the previous 24 hours. Specimen A was collected prior to planned vaginal exam or transvaginal ultrasound and specimen B was collected within 4 hours. The agreement between specimens A and B was assessed using descriptive statistics. Test characteristics of specimens A and B using the outcome of preterm delivery (<37 weeks) were calculated.

Results: In all, 310 specimen pairs from 237 women were collected. Specimen A was positive in 37 (12%) instances and negative in 273 (88%) while specimen B was positive in 39 (13%) and negative in 271 (87%). There were discordant results in 26 specimen pairs. Of these, 14 (5%) negative specimen A results subsequently became positive for specimen B, and 12 (32%) positive specimen A results became negative for specimen B. Overall, there was a 92% agreement between specimens A and B (confidence interval, 88-94%). The specificity of specimens A and B for preterm birth was 90% vs 89%, respectively, with a negative predictive value of 87% for both. The false-negative rate was 12.8% for specimen A and 13.3% for specimen B.

Conclusion: There is a moderately high degree of agreement between prevaginal and postvaginal manipulation fFN results. Their test characteristics for evaluating preterm birth are similar with strong specificity and negative predictive values, and their false-negative rates are not clinically different. Consideration should be made to the utilization of postvaginal manipulation fFN when a prevaginal manipulation specimen is not available.
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http://dx.doi.org/10.1016/j.ajog.2016.01.160DOI Listing
May 2016

Robotic pilot study for analysing spasticity: clinical data versus healthy controls.

J Neuroeng Rehabil 2015 Dec 2;12:109. Epub 2015 Dec 2.

University of Guelph, 50 Stone Road East, N1G 2W1, Guelph, ON, Canada.

Background: Spasticity is a motor disorder that causes significant disability and impairs function. There are no definitive parameters that assess spasticity and there is no universally accepted definition. Spasticity evaluation is important in determining stages of recovery. It can determine treatment effectiveness as well as how treatment should proceed. This paper presents a novel cross sectional robotic pilot study for the primary purpose of assessment. The system collects force and position data to quantify spasticity through similar motions of the Modified Ashworth Scale (MAS) assessment in the Sagittal plane. Validity of the system is determined based on its ability to measure velocity dependent resistance.

Methods: Forty individuals with Acquired Brain Injury (ABI) and 45 healthy individuals participated in a robotic pilot study. A linear regression model was applied to determine the effect an ABI has on force data obtained through the robotic system in an effort to validate it. Parameters from the model were compared for both groups. Two techniques were performed in an attempt to classify between healthy and patients. Dynamic Time Warping (DTW) with k-nearest neighbour (KNN) classification is compared to a time-series algorithm using position and force data in a linear discriminant analysis (LDA).

Results: The system is capable of detecting a velocity dependent resistance (p<0.05). Differences were found between healthy individuals and those with MAS 0 who are considered to be healthy. DTW with KNN is shown to improve classification between healthy and patients by approximately 20 % compared to that of an LDA.

Conclusions: Quantitative methods of spasticity evaluation demonstrate that differences can be observed between healthy individuals and those with MAS of 0 who are often clinically considered to be healthy. Exploiting the time-series nature of the collected data demonstrates that position and force together are an accurate predictor of patient health.
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http://dx.doi.org/10.1186/s12984-015-0103-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667530PMC
December 2015

Aberrant lymphatic drainage and risk for melanoma recurrence after negative sentinel node biopsy in middle-aged and older men.

Head Neck 2016 04 14;38 Suppl 1:E754-60. Epub 2015 Jul 14.

Department of Dermatology, Pigmented Lesion and Melanoma Program, Stanford University School of Medicine, Stanford, California.

Background: Aberrant lymphatic drainage is believed to contribute to the high recurrence rate of head and neck melanomas. The purpose of this study was to identify the clinical significance of unexpected lymphatic drainage patterns.

Methods: A single institution retrospective analysis was performed of middle-aged and older men (mean age, 66.2 years; range, 41-87 years) who underwent successful lymphoscintigraphy with sentinel lymph node biopsy (SLNB) from 1997 through 2012. Node status, distribution, and recurrence were assessed comparing patients with expected and unexpected drainage patterns.

Results: Sixty-six patients were identified with 55.8 months median follow-up (range, 5.6-206.1 months). Unexpected sentinel lymph node drainage was associated with multiple basin drainage (p < .01) and greater recurrence after negative SLNB (p = .03). Both groups had similar anatomic distribution, sentinel lymph node sampling, histopathologic characteristics, follow-up, and survival.

Conclusion: Lymphatic drainage differing from expected patterns is associated with greater recurrence after negative SLNB in middle-aged and older men. © 2015 Wiley Periodicals, Inc. Head Neck 38: E754-E760, 2016.
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http://dx.doi.org/10.1002/hed.24094DOI Listing
April 2016

Tuberculin skin test reversion following isoniazid preventive therapy reflects diversity of immune response to primary Mycobacterium tuberculosis infection.

PLoS One 2014 5;9(5):e96613. Epub 2014 May 5.

Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, United States of America.

Rationale: Healthy household contacts (HHC) of individuals with Tuberculosis (TB) with Tuberculin Skin Test (TST) conversions are considered to harbor latent Mycobacterium tuberculosis (Mtb), and at risk for TB. The immunologic, clinical, and public health implications of TST reversions that occur following Isoniazid preventive therapy (IPT) remain controversial.

Objectives: To measure frequency of TST reversion following IPT, and variation in interferon-gamma (IFN-γ) responses to Mtb, in healthy Ugandan TB HHC with primary Mtb infection evidenced by TST conversion.

Methods: Prospective cohort study of healthy, HIV-uninfected, TST-negative TB HHC with TST conversions. Repeat TST was performed 12 months following conversion (3 months following completion of 9 month IPT course) to assess for stable conversion vs. reversion. Whole blood IFN-γ responses to Mtb antigen 85B (MtbA85B) and whole Mtb bacilli (wMtb) were measured in a subset (n = 27 and n = 42, respectively) at enrollment and TST conversion, prior to initiation of IPT.

Results: Of 122 subjects, TST reversion was noted in 25 (20.5%). There were no significant differences in demographic, clinical, or exposure variables between reverters and stable converters. At conversion, reverters had significantly smaller TST compared to stable converters (13.7 mm vs 16.4 mm, respectively; p = 0.003). At enrollment, there were no significant differences in IFN-γ responses to MtbA85B or wMTB between groups. At conversion, stable converters demonstrated significant increases in IFN-γ responses to Ag85B and wMtb compared to enrollment (p = 0.001, p<0.001, respectively), while there were no significant changes among reverters.

Conclusions: TST reversion following IPT is common following primary Mtb infection and associated with unique patterns of Mtb-induced IFN-γ production. We have demonstrated that immune responses to primary Mtb infection are heterogeneous, and submit that prospective longitudinal studies of cell mediated immune responses to Mtb infection be prioritized to identify immune phenotypes protective against development of TB disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0096613PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4010490PMC
January 2015

Mycobacterium tuberculosis specific CD8(+) T cells rapidly decline with antituberculosis treatment.

PLoS One 2013 4;8(12):e81564. Epub 2013 Dec 4.

Department of Medicine, Oregon Health and Science University, Portland, Oregon, United States of America.

Rationale: Biomarkers associated with response to therapy in tuberculosis could have broad clinical utility. We postulated that the frequency of Mycobacterium tuberculosis (Mtb) specific CD8(+) T cells, by virtue of detecting intracellular infection, could be a surrogate marker of response to therapy and would decrease during effective antituberculosis treatment.

Objectives: We sought to determine the relationship of Mtb specific CD4(+) T cells and CD8(+) T cells with duration of antituberculosis treatment.

Materials And Methods: We performed a prospective cohort study, enrolling between June 2008 and August 2010, of HIV-uninfected Ugandan adults (n = 50) with acid-fast bacillus smear-positive, culture confirmed pulmonary TB at the onset of antituberculosis treatment and the Mtb specific CD4(+) and CD8(+) T cell responses to ESAT-6 and CFP-10 were measured by IFN-γ ELISPOT at enrollment, week 8 and 24.

Results: There was a significant difference in the Mtb specific CD8(+) T response, but not the CD4(+) T cell response, over 24 weeks of antituberculosis treatment (p<0.0001), with an early difference observed at 8 weeks of therapy (p = 0.023). At 24 weeks, the estimated Mtb specific CD8(+) T cell response decreased by 58%. In contrast, there was no significant difference in the Mtb specific CD4(+) T cell during the treatment. The Mtb specific CD4(+) T cell response, but not the CD8(+) response, was negatively impacted by the body mass index.

Conclusions: Our data provide evidence that the Mtb specific CD8(+) T cell response declines with antituberculosis treatment and could be a surrogate marker of response to therapy. Additional research is needed to determine if the Mtb specific CD8(+) T cell response can detect early treatment failure, relapse, or to predict disease progression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0081564PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3852504PMC
September 2014

Clinical evaluation of a novel intraoperative handheld gamma camera for sentinel lymph node biopsy.

Phys Med 2014 May 14;30(3):340-5. Epub 2013 Nov 14.

Department of Bioengineering, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA; Department of Radiology-Nuclear Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA; Molecular Imaging Program at Stanford (MIPS), Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA. Electronic address:

Objective: Preoperative lymphoscintigraphy (PLS) combined with intraoperative gamma probe (GP) localization is standard procedure for localizing the sentinel lymph nodes (SLN) in melanoma and breast cancer. In this study, we evaluated the ability of a novel intraoperative handheld gamma camera (IHGC) to image SLNs during surgery.

Methods: The IHGC is a small-field-of-view camera optimized for real-time imaging of lymphatic drainage patterns. Unlike conventional cameras, the IHGC can acquire useful images in a few seconds in a free-running fashion and be moved manually around the patient to find a suitable view of the node. Thirty-nine melanoma and eleven breast cancer patients underwent a modified SLN biopsy protocol in which nodes localized with the GP were imaged with the IHGC. The IHGC was also used to localize additional nodes that could not be found with the GP.

Results: The removal of 104 radioactive SLNs was confirmed ex vivo by GP counting. In vivo, the relative node detection sensitivity was 88.5 (82.3, 94.6)% for the IHGC (used in conjunction with the GP) and 94.2 (89.7, 98.7)% for the GP alone, a difference not found to be statistically significant (McNemar test, p = 0.24).

Conclusion: Small radioactive SLNs can be visualized intraoperatively using the IHGC with exposure time of 20 s or less, with no significant difference in node detection sensitivity compared to a GP. The IHGC is a useful complement to the GP, especially for SLNs that are difficult to locate with the GP alone.
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http://dx.doi.org/10.1016/j.ejmp.2013.10.005DOI Listing
May 2014

Using the Science of Psychology to Target Perpetrators of Racism and Race-Based Discrimination For Intervention Efforts: Preventing Another Trayvon Martin Tragedy.

J Soc Action Couns Psychol 2013 Mar;5(1):11-36

University of California, Los Angeles, Departments of Psychology and Health Policy and Management and UCLA Center for Bridging Research Innovation, Training and Education in Minority Health Disparities Solutions.

Psychological science offers a variety of methods to both understand and intervene when acts of potential racial or ethnic racism, bias or prejudice occur. The Trayvon Martin killing is a reminder of how vulnerable African American men and boys, especially young African American men, are to becoming victims of social inequities in our society. We examine several historical events of racial bias (the Los Angeles civil disturbance after the Rodney King verdict, the federal government's launch of a "War on Drugs" and the killing of Trayvon Martin) to illustrate the ways in which behaviors of racism and race-based discrimination can be viewed from a psychological science lens in the hopes of eliminating and preventing these behaviors. If society is to help end the genocide of African American men and boys then we must broaden our focus from simply understanding instances of victimization to a larger concern with determining how policies, laws, and societal norms serve as the foundation for maintaining implicit biases that are at the root of race-based discrimination, prejudice, bias and inequity. In our call to action, we highlight the contributions that psychologists, particularly racial and ethnic minority professionals, can make to reduce the negative impact of racial and ethnic bias through their volunteer/pro bono clinical efforts.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3718570PMC
March 2013

Systemic immune activation and microbial translocation in dual HIV/tuberculosis-infected subjects.

J Infect Dis 2013 Jun 11;207(12):1841-9. Epub 2013 Mar 11.

Case Western Reserve University, Cleveland, Ohio, USA.

Background: Systemic immune activation is a strong predictor of progression of human immunodeficiency virus type 1 (HIV-1) disease and a prominent feature of infection with Mycobacterium tuberculosis.

Objective: To understand the role of systemic immune activation and microbial translocation in HIV/tuberculosis dually infected patients over the full spectrum of HIV-1 immunodeficiency, we studied circulating sCD14 and lipopolysaccharide (LPS) and their relationship to HIV-1 activity.

Methods: Two cohorts of HIV/tuberculosis subjects defined by CD4 T-cell count at time of diagnosis of tuberculosis were studied: those with low (<350/μL) and those with high (≥ 350/μL) CD4 T-cell count. Circulating soluble CD14 (sCD14) and LPS were assessed.

Results: Levels of sCD14 were higher in HIV/tuberculosis with high (≥ 350/μL) as compared to low CD4 T-cell count (P < .001). Whereas sCD14 levels remained elevated in HIV/tuberculosis subjects with lower CD4 T-cell counts despite treatment of tuberculosis, in HIV/tuberculosis patients with higher CD4 T-cell count (≥ 350/μL), levels declined regardless of whether highly active antiretroviral therapy (HAART) was included with the anti-tuberculosis regimen. Circulating LPS levels in HIV/tuberculosis patients with CD4 T-cell count ≥ 350/μL were unaffected by treatment of tuberculosis with or without HAART.

Conclusion: During HIV/tuberculosis, systemic immune activation is dissociated from microbial translocation. Changes in circulating sCD14 and LPS are dependent on CD4 T-cell count.
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http://dx.doi.org/10.1093/infdis/jit092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654743PMC
June 2013

PRC2/EED-EZH2 complex is up-regulated in breast cancer lymph node metastasis compared to primary tumor and correlates with tumor proliferation in situ.

PLoS One 2012 10;7(12):e51239. Epub 2012 Dec 10.

Division of Hematology, Department of Medicine, Stanford University, Stanford, CA, USA.

Background: Lymph node metastasis is a key event in the progression of breast cancer. Therefore it is important to understand the underlying mechanisms which facilitate regional lymph node metastatic progression.

Methodology/principal Findings: We performed gene expression profiling of purified tumor cells from human breast tumor and lymph node metastasis. By microarray network analysis, we found an increased expression of polycomb repression complex 2 (PRC2) core subunits EED and EZH2 in lymph node metastatic tumor cells over primary tumor cells which were validated through real-time PCR. Additionally, immunohistochemical (IHC) staining and quantitative image analysis of whole tissue sections showed a significant increase of EZH2 expressing tumor cells in lymph nodes over paired primary breast tumors, which strongly correlated with tumor cell proliferation in situ. We further explored the mechanisms of PRC2 gene up-regulation in metastatic tumor cells and found up-regulation of E2F genes, MYC targets and down-regulation of tumor suppressor gene E-cadherin targets in lymph node metastasis through GSEA analyses. Using IHC, the expression of potential EZH2 target, E-cadherin was examined in paired primary/lymph node samples and was found to be significantly decreased in lymph node metastases over paired primary tumors.

Conclusions/significance: This study identified an over expression of the epigenetic silencing complex PRC2/EED-EZH2 in breast cancer lymph node metastasis as compared to primary tumor and its positive association with tumor cell proliferation in situ. Concurrently, PRC2 target protein E-cadherin was significant decreased in lymph node metastases, suggesting PRC2 promotes epithelial mesenchymal transition (EMT) in lymph node metastatic process through repression of E-cadherin. These results indicate that epigenetic regulation mediated by PRC2 proteins may provide additional advantage for the outgrowth of metastatic tumor cells in lymph nodes. This opens up epigenetic drug development possibilities for the treatment and prevention of lymph node metastasis in breast cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0051239PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3519681PMC
June 2013

Altered local and systemic immune profiles underlie lymph node metastasis in breast cancer patients.

Int J Cancer 2013 Jun 26;132(11):2537-47. Epub 2012 Nov 26.

Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA.

Cancer-mediated immune dysfunction contributes to tumor progression and correlates with patient outcome. Metastasis to tumor draining lymph nodes (TDLNs) is an important step in breast cancer progression and is used to predict patient outcome and survival. Although lymph nodes are important immune organs, the role of immune cells in TDLNs has not been thoroughly investigated. We hypothesized that the host immune response in node negative (NN) patients is more intact and thereby can resist tumor invasion compared to node positive (NP) patients. As such, lymph node metastasis requires breakdown of the host immune response in addition to escape of cancer cells from the tumor. To investigate the immunological differences between NN and NP breast cancer patients, we purified and profiled immune cells from the three major compartments where cancer and immune cells interact: tumor, TDLNs and peripheral blood. Significant down-regulation of genes associated with immune-related pathways and up-regulation of genes associated with tumor-promoting pathways was consistently observed in NP patients' TDLNs compared to NN patients. Importantly, these signatures were seen even in NP patients' tumor-free TDLNs, suggesting that such immune changes are not driven solely by local tumor invasion. Furthermore, similar patterns were also observed in NP patients' tumor and blood immune cells, suggesting that immunological differences between NN and NP patients are systemic. Together, these findings suggest that alterations in overall immune function may underlie risk for LN metastasis in breast cancer patients.
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http://dx.doi.org/10.1002/ijc.27933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609917PMC
June 2013

CD8+ T cells provide an immunologic signature of tuberculosis in young children.

Am J Respir Crit Care Med 2012 Jan 27;185(2):206-12. Epub 2011 Oct 27.

Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio, USA.

Rationale: The immunologic events surrounding primary Mycobacterium tuberculosis infection and development of tuberculosis remain controversial. Young children who develop tuberculosis do so quickly after first exposure, thus permitting study of immune response to primary infection and disease. We hypothesized that M. tuberculosis-specific CD8(+) T cells are generated in response to high bacillary loads occurring during tuberculosis.

Objectives: To determine if M. tuberculosis-specific T cells are generated among healthy children exposed to M. tuberculosis and children with tuberculosis.

Methods: Enzyme-linked immunosorbent spot assays were used to measure IFN-γ production in response to M. tuberculosis-specific proteins ESAT-6/CFP-10 by peripheral blood mononuclear cells and CD8(+) T cells isolated from Ugandan children hospitalized with tuberculosis (n = 96) or healthy tuberculosis contacts (n = 62).

Measurements And Main Results: The proportion of positive CD8(+) T-cell assays and magnitude of CD8(+) T-cell responses were significantly greater among young (<5 yr) tuberculosis cases compared with young contacts (P = 0.02, Fisher exact test, P = 0.01, Wilcoxon rank-sum, respectively). M. tuberculosis-specific T-cell responses measured in peripheral blood mononuclear cells were equivalent between groups.

Conclusions: Among young children, M. tuberculosis-specific CD8(+) T cells develop in response to high bacillary loads, as occurs during tuberculosis, and are unlikely to be found after M. tuberculosis exposure. T-cell responses measured in peripheral blood mononuclear cells are generated after M. tuberculosis exposure alone, and thus cannot distinguish exposure from disease. In young children, IFN-γ-producing M. tuberculosis-specific CD8(+) T cells provide an immunologic signature of primary M. tuberculosis infection resulting in disease.
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http://dx.doi.org/10.1164/rccm.201107-1355OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297089PMC
January 2012

Effects of antiretroviral therapy on immune function of HIV-infected adults with pulmonary tuberculosis and CD4+ >350 cells/mm3.

J Infect Dis 2011 Apr;203(7):992-1001

Division of Pediatric Infectious Disease, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.

Background: Human immunodeficiency virus (HIV)-tuberculosis coinfection is associated with heightened immune activation, viral replication, and T cell dysfunction. We compared changes in T cell activation and function between patients receiving concurrent treatment for HIV-tuberculosis coinfection and those receiving treatment for tuberculosis alone.

Methods: HIV-infected adults with tuberculosis and CD4(+) T cell counts >350 cells/mm(3) were randomized to receive tuberculosis treatment alone (control arm; n = 36) or 6 months of antiretroviral therapy (ART) concurrent with tuberculosis treatment (intervention arm; n = 38). HIV viral load, T cell subsets, T cell activation, and cytokine production were measured at enrollment and every 3 months for 12 months.

Results: Differences in absolute CD4(+) and CD8(+) T cell counts were not observed between arms. Viral load was reduced while participants received ART; control patients maintained viral load at baseline levels. Both arms had significant reductions in T cell expression of CD38 and HLA-DR. Interferon-γ production in response to mitogen increased significantly in the intervention arm.

Conclusions: In HIV-infected adults with tuberculosis and CD4(+) T cell counts >350 cells/mm(3), both tuberculosis treatment and concurrent HIV-tuberculosis treatment reduce T cell activation and stabilize T cell counts. Concurrent ART with tuberculosis treatment does not provide additional, sustained reductions in T cell activation among individuals with preserved immunologic function.
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http://dx.doi.org/10.1093/infdis/jiq141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068037PMC
April 2011

Melanoma of the penis with scintigraphically-guided sentinel node biopsy.

Indian J Urol 2010 Jul;26(3):429-30

Department of Urology, USA.

Melanoma of the penis is an uncommon cancer. We present the case of a 73-year-old male with penile melanoma and non palpable lymph nodes. Lymphoscintigraphy was applied to locate the sentinel lymph nodes for dissection. His lymph nodes were negative for melanoma and he has been disease-free for 1 year with careful surveillance.
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http://dx.doi.org/10.4103/0970-1591.70587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2978448PMC
July 2010

Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271.

Nature 2010 Jul;466(7302):133-7

Institute for Stem Cell Biology and Regenerative Medicine, Stanford Cancer Center, Stanford University School of Medicine, Stanford, California 94304-5542, USA.

The question of whether tumorigenic cancer stem cells exist in human melanomas has arisen in the last few years. Here we show that in melanomas, tumour stem cells (MTSCs, for melanoma tumour stem cells) can be isolated prospectively as a highly enriched CD271(+) MTSC population using a process that maximizes viable cell transplantation. The tumours sampled in this study were taken from a broad spectrum of sites and stages. High-viability cells isolated by fluorescence-activated cell sorting and re-suspended in a matrigel vehicle were implanted into T-, B- and natural-killer-deficient Rag2(-/-)gammac(-/-) mice. The CD271(+) subset of cells was the tumour-initiating population in 90% (nine out of ten) of melanomas tested. Transplantation of isolated CD271(+) melanoma cells into engrafted human skin or bone in Rag2(-/-)gammac(-/-) mice resulted in melanoma; however, melanoma did not develop after transplantation of isolated CD271(-) cells. We also show that in mice, tumours derived from transplanted human CD271(+) melanoma cells were capable of metastatsis in vivo. CD271(+) melanoma cells lacked expression of TYR, MART1 and MAGE in 86%, 69% and 68% of melanoma patients, respectively, which helps to explain why T-cell therapies directed at these antigens usually result in only temporary tumour shrinkage.
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http://dx.doi.org/10.1038/nature09161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2898751PMC
July 2010

Melanoma and melanocytic tumors of uncertain malignant potential in children, adolescents and young adults--the Stanford experience 1995-2008.

Pediatr Dermatol 2010 May-Jun;27(3):244-54. Epub 2010 Apr 9.

Department of Dermatology, Pigmented Lesion and Melanoma Program, Stanford University Medical Center, Stanford, California 94063, USA.

Pediatric melanoma is difficult to study because of its rarity, possible biological differences in preadolescents compared with adolescents, and challenges of differentiating true melanoma from atypical spitzoid neoplasms. Indeterminant lesions are sometimes designated as melanocytic tumors of uncertain malignant potential (MelTUMPs). We performed a retrospective, single-institution review of melanomas, MelTUMPs and Spitz nevi with atypical features (SNAFs) in patients at 21 years of age and younger from 1995 to 2008. We identified 13 patients with melanoma, seven with MelTUMPs, and five with SNAFs. The median age for melanoma patients was 17 years, 10 for MelTUMPs, and six for SNAFs. Of the 13 melanoma patients, only four were younger than 15 years, while six were adolescents, and three were young adults. Nine melanoma patients (69%) were female. The most common histologic subtype was superficial spreading. The median depth for melanomas was 1.2 mm, and 3.4 mm for MelTUMPs. Microscopic regional nodal involvement detected on elective or sentinel lymph node (SLN) dissection was present in 2/10 (20%) of primary melanomas and 2/6 (33%) of Mel-TUMPs. Complete lymphadenectomy was performed on four melanoma patients, with three positive cases. Patient outcome through March 31, 2009 revealed no in-transit or visceral metastasis in patients with MelTUMPs or SNAFs. One SLN-positive patient (8%) with melanoma developed recurrent lymph node and liver metastasis and died 15 months after primary diagnosis. Our data highlight the rarity, female predominance, and significant rate of SLN positivity of pediatric melanoma. The high rate of MelTUMPs with regional nodal disease reinforces the need for close follow-up.
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http://dx.doi.org/10.1111/j.1525-1470.2009.01078.xDOI Listing
October 2010

Tuberculosis treatment in HIV infected Ugandans with CD4 counts>350 cells/mm reduces immune activation with no effect on HIV load or CD4 count.

PLoS One 2010 Feb 22;5(2):e9138. Epub 2010 Feb 22.

Tuberculosis Research Unit, Case Western Reserve University School of Medicine, and University Hospitals-Case Medical Center, Cleveland, Ohio, United States of America.

Background: Both HIV and TB cause a state of heightened immune activation. Immune activation in HIV is associated with progression to AIDS. Prior studies, focusing on persons with advanced HIV, have shown no decline in markers of cellular activation in response to TB therapy alone.

Methodology: This prospective cohort study, composed of participants within a larger phase 3 open-label randomized controlled clinical trial, measured the impact of TB treatment on immune activation in persons with non-advanced HIV infection (CD4>350 cells/mm3) and pulmonary TB. HIV load, CD4 count, and markers of immune activation (CD38 and HLA-DR on CD4 and CD8 T cells) were measured prior to starting, during, and for 6 months after completion of standard 6 month anti-tuberculosis (TB) therapy in 38 HIV infected Ugandans with smear and culture confirmed pulmonary TB.

Results: Expression of CD38, and co-expression of CD38 and HLA-DR, on CD8 cells declined significantly within 3 months of starting standard TB therapy in the absence of anti-retroviral therapy, and remained suppressed for 6 months after completion of therapy. In contrast, HIV load and CD4 count remained unchanged throughout the study period.

Conclusion: TB therapy leads to measurable decreases in immune activation in persons with HIV/TB co-infection and CD4 counts>350 cells/mm3.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0009138PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2825253PMC
February 2010

Low risk sexual and drug-using behaviors among Latina women with AIDS in Los Angeles County.

J Immigr Minor Health 2010 Dec;12(6):882-93

HIV Epidemiology Program, Los Angeles County Department of Public Health, Los Angeles, CA 90005, USA.

Latina women represent nearly half of all females diagnosed with AIDS in Los Angeles County, yet little is known about their risk behaviors compared to women of other race/ethnicities. Compared to white and African American women with AIDS, Latinas with AIDS had fewer lifetime male sexual partners (P < .0001); reported fewer sexually transmitted diseases (OR = 0.24; 95% CI: 0.1, 0.5); were less likely to trade sex for drugs/money (OR = 0.18; 95% CI: 0.07, 0.5); and were less likely to report exposure to HIV via injection drug use (OR = 0.3; 95% CI: 0.09, 0.99). Latinas were also more likely to be single mothers (OR = 3.02; 95% CI: 1.4, 6.4); less likely to receive public assistance (OR = 0.33; 95% CI: 0.16, 0.70); were less likely to have completed high-school (OR = 0.11; 95% CI: .04, .31) and were more likely to never have had health insurance (OR = 2.44; 95% CI: 1.15, 5.18). The data demonstrate low-risk behaviors for Latinas and underscores the challenge of delivering effective HIV prevention to women without traditional risk profiles.
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http://dx.doi.org/10.1007/s10903-009-9294-zDOI Listing
December 2010

Impaired interferon signaling is a common immune defect in human cancer.

Proc Natl Acad Sci U S A 2009 Jun 18;106(22):9010-5. Epub 2009 May 18.

Division of Hematology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.

Immune dysfunction develops in patients with many cancer types and may contribute to tumor progression and failure of immunotherapy. Mechanisms underlying cancer-associated immune dysfunction are not fully understood. Efficient IFN signaling is critical to lymphocyte function; animals rendered deficient in IFN signaling develop cancer at higher rates. We hypothesized that altered IFN signaling may be a key mechanism of immune dysfunction common to cancer. To address this, we assessed the functional responses to IFN in peripheral blood lymphocytes from patients with 3 major cancers: breast cancer, melanoma, and gastrointestinal cancer. Type-I IFN (IFN-alpha)-induced signaling was reduced in T cells and B cells from all 3 cancer-patient groups compared to healthy controls. Type-II IFN (IFN-gamma)-induced signaling was reduced in B cells from all 3 cancer patient groups, but not in T cells or natural killer cells. Impaired-IFN signaling was equally evident in stage II, III, and IV breast cancer patients, and downstream functional defects in T cell activation were identified. Taken together, these findings indicate that defects in lymphocyte IFN signaling arise in patients with breast cancer, melanoma, and gastrointestinal cancer, and these defects may represent a common cancer-associated mechanism of immune dysfunction.
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http://dx.doi.org/10.1073/pnas.0901329106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690021PMC
June 2009

Transgenic expression of aflatoxin aldehyde reductase (AKR7A1) modulates aflatoxin B1 metabolism but not hepatic carcinogenesis in the rat.

Toxicol Sci 2009 May 23;109(1):41-9. Epub 2009 Jan 23.

Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.

In both experimental animals and humans, aflatoxin B(1) (AFB(1)) is a potent hepatic toxin and carcinogen against which a variety of antioxidants and experimental or therapeutic drugs (e.g., oltipraz, related dithiolethiones, and various triterpenoids) protect from both acute toxicity and carcinogenesis. These agents induce several hepatic glutathione S-transferases (GST) as well as aldo-keto reductases (AKR) which are thought to contribute to protection. Studies were undertaken in transgenic rats to examine the role of one inducible enzyme, AKR7A1, for protection against acute and chronic actions of AFB(1) by enhancing detoxication of a reactive metabolite, AFB(1) dialdehyde, by reduction to alcohols. The AFB(1) dialdehyde forms adducts with protein amino groups by a Schiff base mechanism and these adducts have been theorized to be at least one cause of the acute toxicity of AFB(1) and to enhance carcinogenesis. A liver-specific AKR7A1 transgenic rat was constructed in the Sprague-Dawley strain and two lines, AKR7A1(Tg2) and AKR7A1(Tg5), were found to overexpress AKR7A1 by 18- and 8-fold, respectively. Rates of formation of AFB(1) alcohols, both in hepatic cytosols and as urinary excretion products, increased in the transgenic lines with AKR7A1(Tg2) being the highest. Neither line offered protection against acute AFB(1)-induced bile duct proliferation, a functional assessment of acute hepatotoxicity by AFB(1), nor did they protect against the formation of GST-P positive putative preneoplastic foci as a result of chronic exposure to AFB(1). These results imply that the prevention of protein adducts mediated by AKR are not critical to protection against AFB(1) tumorigenicity.
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http://dx.doi.org/10.1093/toxsci/kfp003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2675636PMC
May 2009

Role for nanomaterial-autophagy interaction in neurodegenerative disease.

Autophagy 2008 Nov 6;4(8):1097-100. Epub 2008 Nov 6.

Nanotechnology Characterization Laboratory, Advanced Technology Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 21702, USA.

Nanotechnology is the control and manipulation of materials in the size range of 1-100 nm. Due to increasing research into the potential beneficial applications of nanotechnology, there is an urgent need for the study of possible health risks. Several researchers, including those in our laboratory, have demonstrated elevated levels of autophagic vacuoles upon exposure of cells to certain nanomaterials, including carbon- and metal-based nanoparticles. While this apparent increase in autophagic activity may be an appropriate cellular response toward nanomaterial clearance, often the interaction between nanomaterials and the autophagy pathway is disruptive, resulting in severe morphological changes and coincident cell death. Interestingly, epidemiological studies have identified an association between exposure to combustion-derived ambient particles (which are predominantly nanoscale) and neurological conditions with Alzheimer's and Parkinson's disease-like pathologies. Becuse impaired autophagy may play an important role in the pathogenesis of these and other diseases, it is intriguing to speculate about the plausible involvement of nanoscale particulates in this process. The interaction of nanomaterials with the autophagy pathway, and the potential negative consequences of resulting autophagy dysfunction, should be explored further.
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http://dx.doi.org/10.4161/auto.7142DOI Listing
November 2008

Early and extended early bactericidal activity of linezolid in pulmonary tuberculosis.

Am J Respir Crit Care Med 2008 Dec 11;178(11):1180-5. Epub 2008 Sep 11.

Núcleo de Doenças Infecciosas Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Av. Marechal Campos, 1468 Maruípe,Vitória-ES Brazil, CEP 29040-091.

Rationale: Linezolid, the first oxazolidinone approved for clinical use, has effective in vitro and promising in vivo activity against Mycobacterium tuberculosis.

Objectives: To evaluate the early and extended early bactericidal activity of linezolid in patients with pulmonary tuberculosis.

Methods: Randomized open label trial. Thirty patients with newly diagnosed smear-positive pulmonary tuberculosis (10 per arm) were assigned to receive isoniazid (300 mg daily) and linezolid (600 mg twice daily or 600 mg once daily) for 7 days. Sputum for quantitative culture was collected for 2 days before and then daily during 7 days of study drug administration. Bactericidal activity was estimated by measuring the decline in bacilli during the first 2 days (early bactericidal activity) and the last 5 days of study drug administration (extended early bactericidal activity).

Measurements And Main Results: The mean early bactericidal activity of isoniazid (0.67 log10 cfu/ml/d) was greater than that of linezolid twice and once daily (0.26 and 0.18 log10 cfu/ml/d, respectively). The extended early bactericidal activity of linezolid between Days 2 and 7 was minimal.

Conclusions: Linezolid has modest early bactericidal activity against rapidly dividing tubercle bacilli in patients with cavitary pulmonary tuberculosis during the first 2 days of administration, but little extended early bactericidal activity. Clinical trial registered with www.clinicaltrials.gov (NCT00396084).
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http://dx.doi.org/10.1164/rccm.200806-892OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2588492PMC
December 2008

New models and online calculator for predicting non-sentinel lymph node status in sentinel lymph node positive breast cancer patients.

BMC Cancer 2008 Mar 4;8:66. Epub 2008 Mar 4.

Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.

Background: Current practice is to perform a completion axillary lymph node dissection (ALND) for breast cancer patients with tumor-involved sentinel lymph nodes (SLNs), although fewer than half will have non-sentinel node (NSLN) metastasis. Our goal was to develop new models to quantify the risk of NSLN metastasis in SLN-positive patients and to compare predictive capabilities to another widely used model.

Methods: We constructed three models to predict NSLN status: recursive partitioning with receiver operating characteristic curves (RP-ROC), boosted Classification and Regression Trees (CART), and multivariate logistic regression (MLR) informed by CART. Data were compiled from a multicenter Northern California and Oregon database of 784 patients who prospectively underwent SLN biopsy and completion ALND. We compared the predictive abilities of our best model and the Memorial Sloan-Kettering Breast Cancer Nomogram (Nomogram) in our dataset and an independent dataset from Northwestern University.

Results: 285 patients had positive SLNs, of which 213 had known angiolymphatic invasion status and 171 had complete pathologic data including hormone receptor status. 264 (93%) patients had limited SLN disease (micrometastasis, 70%, or isolated tumor cells, 23%). 101 (35%) of all SLN-positive patients had tumor-involved NSLNs. Three variables (tumor size, angiolymphatic invasion, and SLN metastasis size) predicted risk in all our models. RP-ROC and boosted CART stratified patients into four risk levels. MLR informed by CART was most accurate. Using two composite predictors calculated from three variables, MLR informed by CART was more accurate than the Nomogram computed using eight predictors. In our dataset, area under ROC curve (AUC) was 0.83/0.85 for MLR (n = 213/n = 171) and 0.77 for Nomogram (n = 171). When applied to an independent dataset (n = 77), AUC was 0.74 for our model and 0.62 for Nomogram. The composite predictors in our model were the product of angiolymphatic invasion and size of SLN metastasis, and the product of tumor size and square of SLN metastasis size.

Conclusion: We present a new model developed from a community-based SLN database that uses only three rather than eight variables to achieve higher accuracy than the Nomogram for predicting NSLN status in two different datasets.
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http://dx.doi.org/10.1186/1471-2407-8-66DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2311316PMC
March 2008

Quantification of urinary aflatoxin B1 dialdehyde metabolites formed by aflatoxin aldehyde reductase using isotope dilution tandem mass spectrometry.

Chem Res Toxicol 2008 Mar 12;21(3):752-60. Epub 2008 Feb 12.

Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA.

The aflatoxin B 1 aldehyde reductases (AFARs), inducible members of the aldo-keto reductase superfamily, convert aflatoxin B 1 dialdehyde derived from the exo- and endo-8,9-epoxides into a number of reduced alcohol products that might be less capable of forming covalent adducts with proteins. An isotope dilution tandem mass spectrometry method for quantification of the metabolites, C-8 monoalcohol, dialcohol, and C-6a monoalcohol, was developed to ascertain their possible role as urinary biomarkers for application to chemoprevention investigations. This method uses a novel (13)C 17-aflatoxin B 1 dialcohol internal standard, synthesized from (13)C 17-aflatoxin B 1 biologically produced by Aspergillus flavus. Chromatographic standards of the alcohols were generated through sodium borohydride reduction of the aflatoxin B 1 dialdehyde. This method was then explored for sensitivity and specificity in urine samples of aflatoxin B 1-dosed rats that were pretreated with 3 H-1,2-dithiole-3-thione to induce the expression of AKR7A1, a rat isoform of AFAR. One of the two known monoalcohols and the dialcohol metabolite were detected in all urine samples. The concentrations were 203.5 +/- 39.0 ng of monoalcohol C-6a/mg of urinary creatinine and 10.0 +/- 1.0 ng of dialcohol/mg of creatinine (mean +/- standard error). These levels represented about 8.0 and 0.4% of the administered aflatoxin B 1 dose that was found in the urine at 24 h, respectively. Thus, this highly sensitive and specific isotope dilution method is applicable to in vivo quantification of urinary alcohol products produced by AFAR. Heretofore, the metabolic fate of the 8,9-epoxides that are critical for aflatoxin toxicities has been measured by biomarkers of lysine-albumin adducts, hepatic and urinary DNA adducts, and urinary mercapturic acids. This urinary detection of the alcohol products directly contributes to the goal of mass balancing the fate of the bioreactive 8,9-epoxides of AFB 1 in vivo.
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http://dx.doi.org/10.1021/tx700397nDOI Listing
March 2008