Histone deacetylase inhibitors as potential therapeutic approaches for chordoma: An immunohistochemical and functional analysis

Chordomas are rare malignancies of the axial skeleton. Therapy is mainly restricted to surgery. This study investigates histone deacetylase (HDAC) inhibitors as potential therapeutics for chordomas. Immunohistochemistry (IHC) was performed using the HDAC 1–6 antibodies on 50 chordoma samples (34 primary tumors, 16 recurrences) from 44 patients (27 male, 17 female). Pan‐HDAC‐inhibitors Vorinostat (SAHA), Panobinostat (LBH‐589), and Belinostat (PXD101) were tested for their efficacy in the chordoma cell line MUG‐Chor1 via Western blot, cell cycle analysis, caspase 3/7 activity (MUG‐Chor1, UCh‐1), cleaved caspase‐3, and PARP cleavage. p‐Values below 0.05 were considered significant. IHC was negative for HDAC1, positive for HDAC2 in most (n = 36; 72%), and for HDACs 3–6 in all specimens available (n = 43; 86%). HDAC6 expression was strongest. SAHA and LBH‐589, but not PXD101 caused a significant increase of G2/M phase cells and of cleaved caspase‐3 (p = 0.0003, and p = 0.0014 after 72 h, respectively), and a peak of caspase 3/7 activity. PARP cleavage confirmed apoptosis. The presented chordoma series expressed HDACs 2–6 with strongest expression of HDAC6. SAHA and LBH‐589 significantly increased apoptosis and changed cell cycle distribution in vitro. HDAC‐inhibitors should be further evaluated as therapeutic options for chordoma. © 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 31:1999–2005, 2013     

Assessment of executive functions in children and adolescents with acquired brain injury (ABI) using a novel complex multi-tasking computerised task: The Jansari assessment of Executive Functions for Children (JEF-C©)

ABSTRACT

Objectives: The Jansari assessment of Executive Functions for Children (JEF-C^©) is a new non-immersive computerised assessment of executive functions. The objectives of the study were to test the feasibility and validity of JEF-C^© in children and adolescents with acquired brain injury (ABI).

Methods: Twenty-nine patients with ABI aged 10–18 years and 30 age-and gender-matched controls were tested. Participants performed JEF-C^©, Wechsler Abbreviated Scale of Intelligence (WASI) and the Behavioural Assessment of the Dysexecutive Syndrome for Children (BADS-C), while parents completed the Behaviour Rating Inventory of Executive Function (BRIEF) questionnaire.

Results: The JEF-C^© task proved feasible in patients with ABI. The internal consistency was medium (Cronbach’s alpha?=?0.62 and significant intercorrelations between individual JEF-C^© constructs). Patients performed significantly worse than controls on most of the JEF-C^© subscales and total score, with 41.4% of participants with ABI classified as having severe executive dysfunction. No significant correlations were found between JEF-C^© total score, the BRIEF indices, and the BADS-C. Significant correlations were found between JEF-C^© and demographic characteristics of the sample and intellectual ability, but not with severity/medical variables.

Conclusion: JEF-C^© is a playful complex task that appears to be a sensitive and ecologically valid assessment tool, especially for relatively high-functioning individuals.     

Borrelia garinii induces CXCL13 production in human monocytes through Toll-like receptor 2

Recent studies have suggested an important role for the B-cell-attracting chemokine CXCL13 in the B-cell-dominated cerebrospinal fluid (CSF) infiltrate in patients with neuroborreliosis (NB). High levels of CXCL13 were present in the CSF of NB patients. It has not been clear, however, whether high CSF CXCL13 titers are specific for NB or are a characteristic of other spirochetal diseases as well. Furthermore, the mechanisms leading to the observed CXCL13 expression have not been identified yet. Here we describe similarly elevated CSF CXCL13 levels in patients with neurosyphilis, while pneumococcal meningitis patient CSF do not have high CXCL13 levels. In parallel, challenge of human monocytes in vitro with two of the spirochetal causative organisms, Borrelia garinii (the Borrelia species most frequently found in NB patients) and Treponema pallidum, but not challenge with pneumococci, induced CXCL13 release. This finding implies that a common spirochetal motif is a CXCL13 inducer. Accordingly, we found that the lipid moiety N-palmitoyl-S-(bis[palmitoyloxy]propyl)cystein (Pam(3)C) (three palmitoyl residues bound to N-terminal cysteine) of the spirochetal lipoproteins is critical for the CXCL13 induction in monocytes. As the Pam(3)C motif is known to signal via Toll-like receptor 2 (TLR2) and an anti-TLR2 monoclonal antibody blocked CXCL13 production of human monocytes incubated with B. garinii, this suggests that TLR2 is a major mediator of Borrelia-induced secretion of CXCL13 from human monocytes.     

CD molecules 2006--human cell differentiation molecules

The Human Leucocyte Differentiation Antigens Workshops (HLDA) have since 1984 provided a forum for the characterization and study of leucocyte surface molecules and antibodies against them. HLDA devised the CD nomenclature, which is sanctioned by IUIS. The HLDA Council reviewed and modified the objectives of HLDA in 2004, and changed the name of the organization to Human Cell Differentiation Molecules (HCDM) to reflect the broader objectives. Workshop studies under the HCDM banner proceeded during 2005 and early 2006, culminating in a meeting in May 2006. At that meeting the Council, acting as Nomenclature Committee, approved a number of new CD designations and changes to some pre-existing CD designations, which are summarized in this report.     

Sleep duration as a risk factor for diabetes incidence in a large U.S. sample

STUDY OBJECTIVES: To explore the relationship between sleep duration and diabetes incidence over an 8- to 10-year follow-up period in data from the First National Health and Nutrition Examination Survey (NHANES I). We hypothesized that prolonged short sleep duration is associated with diabetes and that obesity and hypertension act as partial mediators of this relationship. The increased load on the pancreas from insulin resistance induced by chronically short sleep durations can, over time, compromise beta-cell function and lead to type 2 diabetes. No plausible mechanism has been identified by which long sleep duration could lead to diabetes. DESIGN: Multivariate longitudinal analyses of the NHANES I using logistic regression models. SETTING: Probability sample (n=8992) of the noninstitutionalized population of the United States between 1982 and 1992. PARTICIPANTS: Subjects between the ages of 32 and 86 years. MEASUREMENTS AND RESULTS: Between 1982 and 1992, 4.8% of the sample (n=430) were determined by physician diagnosis, hospital record, or cause of death to be incident cases of diabetes. Subjects with sleep durations of 5 or fewer hours (odds ratio = 1.47, 95% confidence interval 1.03-2.09) and subjects with sleep durations of 9 or more hours (odds ratio = 1.52, 95% confidence interval 1.06-2.18) were significantly more likely to have incident diabetes over the follow-up period after controlling for covariates. CONCLUSIONS: Short sleep duration could be a significant risk factor for diabetes. The association between long sleep duration and diabetes incidence is more likely to be due to some unmeasured confounder such as poor sleep quality.     

Nurses’ perceptions of mental healthcare in primary-care settings in Kenya

Kenya maintains an extraordinary treatment gap for mental health services because the need for and availability of mental health services are extraordinarily misaligned. One way to narrow the treatment gap is task-sharing, where specialists rationally distribute tasks across the health system, with many responsibilities falling upon frontline health workers, including nurses. Yet, little is known about how nurses perceive task-sharing mental health services. This article investigates nurses’ perceptions of mental healthcare delivery within primary-care settings in Kenya. We conducted a cross-sectional study of 60 nurses from a public urban (n?=?20), private urban (n?=?20), and public rural (n?=?20) hospitals. Nurses participated in a one-hour interview about their perceptions of mental healthcare delivery. Nurses viewed mental health services as a priority and believed integrating it into a basic package of primary care would protect it from competing health priorities, financial barriers, stigma, and social problems. Many nurses believed that integrating mental healthcare into primary care was acceptable and feasible, but low levels of knowledge of healthcare providers, especially in rural areas, and few specialists, would be barriers. These data underscore the need for task-sharing mental health services into existing primary healthcare in Kenya.     

Tympanic temperature measurements: are they reliable in the critically ill? A clinical study of measures of agreement

OBJECTIVE: Accurate measurement of temperature is vital in the intensive care setting. A prospective trial was performed to compare the accuracy of tympanic, urinary, and axillary temperatures with that of pulmonary artery (PA) core temperature measurements. DESIGN: A total of 110 patients were enrolled in a prospective observational cohort study. SETTING: Multidisciplinary intensive care unit of a university teaching hospital. PATIENTS: The cohort was (mean +/- sd) 65 +/- 16 yrs of age, Acute Physiology and Chronic Health Evaluation (APACHE) II score was 25 +/- 9, 58% of the patients were men, and 76% were mechanically ventilated. The accuracy of tympanic (averaged over both ears), axillary (averaged over both sides), and urinary temperatures was referenced (as mean difference, Delta degrees centigrade) to PA temperatures as standard in 6,703 recordings. Lin concordance correlation (pc) and Bland-Altman 95% limits of agreement (degrees centigrade) described the relationship between paired measurements. Regression analysis (linear mixed model) assessed covariate confounding with respect to temperature modes and reliability formulated as an intraclass correlation coefficient. MEASUREMENTS AND MAIN RESULTS: Concordance of PA temperatures with tympanic, urinary, and axillary was 0.77, 0.92, and 0.83, respectively. Compared with PA temperatures, Delta (limits of agreement) were 0.36 degrees C (-0.56 degrees C, 1.28 degrees C), -0.05 degrees C (-0.69 degrees C, 0.59 degrees C), and 0.30 degrees C (-0.42 degrees C, 1.01 degrees C) for tympanic, urinary, and axillary temperatures, respectively. Temperature measurement mode effect, estimated via regression analysis, was consistent with concordance and Delta (PA vs. urinary, p = .98). Patient age (p = .03), sedation score (p = .0001), and dialysis (p = .0001) had modest negative relations with temperature; quadratic relationships were identified with adrenaline and dobutamine. No interactions with particular temperature modes were identified (p > or = .12 for all comparisons) and no relationship was identified with either mean arterial pressure or APACHE II score (p > or = .64). The average temperature mode intraclass correlation coefficient for test-retest reliability was 0.72. CONCLUSION: Agreement of tympanic with pulmonary temperature was inferior to that of urinary temperature, which, on overall assessment, seemed more likely to reflect PA core temperature.