Transcription Independent Stimulation of Telomerase Enzymatic Activity by HTLV-I Tax Through Stimulation of IKK.

The persistence and spreading of HTLV-I infected cells relies upon their clonal expansion through cellular replication. The development of adult T cell leukemia (ATLL) occurs decades following primary infection by HTLV-I. Moreover, identical provirus integration sites have been found in samples recovered several years apart from infected individuals. These observations suggest that infected cells persist in the host for an extended period of time. To endure long term proliferation, HTLV-I pre-leukemic cells must acquire critical oncogenic events, two of which are the bypassing of apoptosis and replicative senescence. In the early stages of disease, interleukin-2 (IL-2)/IL-2R signaling likely plays a major role in combination with activation of anti-apoptotic pathways. Avoidance of replicative senescence in HTLV-I infected cells is achieved through reactivation of human telomerase (hTERT). We have previously shown that HTLV-I viral Tax transcriptionally activates the hTERT promoter. In this study we demonstrate that Tax can stimulate hTERT enzymatic activity independently of its transcriptional effects. We further show that this occurs through Tax-mediated NF-KB activating functions. Our results suggest that in ATLL cells acquire Tax-transcriptional and post-transcriptional events to elevate telomerase activity.

Ketamine for chronic non-cancer pain: A meta-analysis and trial sequential analysis of randomized controlled trials.

BACKGROUND: Ketamine has been suggested to be efficient in relieving chronic pain. However, there is inconsistency across studies investigating the effect of ketamine for chronic pain management. We aimed to perform a meta-analysis in order to assess the efficacy of this compound during chronic non-cancer pain conditions. METHODS: The study consisted in a meta-analysis of clinical trials comparing ketamine to a placebo during chronic non-cancer pain. The primary endpoint of this study was pain relief 4 weeks after the beginning of treatment. Secondary outcomes were: pain relief 1, 2, 8 and 12 weeks after the beginning of treatment and incidence of psychedelic manifestations. RESULTS: Six studies were included in this meta-analysis. Overall, 99 patients received ketamine and 96 received placebo. Ketamine did not decrease pain intensity at 4 weeks (MD (on a 0 to 10 scale) = -1.12 [-2.33, 0.09], GRADE evidence: very low). However, analysing studies with no high-risk bias found ketamine to decrease pain intensity at 4 weeks and increased the level of GRADE evidence to moderate. Trial sequential analysis confirmed the overall result and revealed the lack of power of this meta-analysis. Ketamine also decreased pain intensity at all other evaluated points in time. Ketamine increased the incidence of psychedelic manifestations in comparison to placebo. CONCLUSION: Results of this meta-analysis found moderate evidence suggesting the efficacy of ketamine during chronic pain. Further studies are warranted to conclude about the effect of ketamine during chronic pain conditions and to determine optimal administration regimes of this agent during this condition. SIGNIFICANCE: Ketamine has been found interesting for managing chronic pain. We performed a meta-analysis aiming to confirm those results. Ketamine was found efficient in alleviating pain up to 12 weeks after the beginning of treatment. However, overall evidence favouring the use of this compound was very low.

Validation of a simple tool for anxiety trait screening in children presenting for surgery.

BACKGROUND.: Screening for preoperative anxiety is an important challenge during the preoperative period. The aim of our study was to validate the faces scale used to detect anxiety trait in children. METHODS.: Children aged 8-18 yr were asked to quantify their anxiety trait using the readily available faces scale and to respond to the trait component of the State-Trait Anxiety Inventory (STAI) for children (C) or adults (A) before the anaesthesia consultation. Using receiver operating characteristics analysis, we determined the faces scale optimal value on a construct cohort. A validation cohort was recruited to assess the accuracy of the results. RESULTS.: The construction cohort comprised 207 patients and the validation cohort 91 patients. The receiver operating characteristics analysis found an area under the curve of 0.75 [95% confidence interval (CI) 0.67, 0.83]. The optimal value for faces scale score was 4, with a sensitivity of 0.61 [95% CI 0.59, 0.62] and a specificity of 0.82 [95% CI 0.81, 0.83]. When this threshold was applied to the construction and validation cohorts, 61.3 and 44.4% of positives were true positives in the construction and validation cohorts, respectively; and 82.1 and 81.3% of negatives were true negatives, respectively. CONCLUSIONS.: Our study determined the performance of a simple faces scale to measure the preoperative anxiety trait in children aged 8-18 yr. This tool is potentially helpful for clinicians aiming to identify patients at risk of preoperative anxiety and to assign them to targeted management.

Photodynamic therapy for the treatment of complex anal fistula.

BACKGROUND: Photodynamic therapy (PDT) is a new procedure for the treatment of anal fistula. This preliminary study was designed to investigate the safety and effectiveness of this new technique in the treatment of anal fistula. METHODS: Ten patients were treated with PDT. Intralesional 5-aminolevulinic acid (ALA) 2% was directly injected into the fistula. The internal and external orifices were closed. After an incubation period of 2 h, the fistula was irradiated using an optical fibre connected to a red laser (MULTIDIODE 630 PDT, INTERmedic, Spain) operating at 1 W/cm for 3 min (180 Joules). Patient demographics, operation notes and complications were recorded. RESULTS: There were no complications. The average length of patient follow-up was 14.9 months (range 12-20 months). We could observe primary healing in eight patients (80%). Two patients (20%) showed persistence of suppuration after the operation. No patient reported incontinence postoperatively. CONCLUSIONS: PDT is a potential sphincter-saving procedure that is safe, simple and minimally invasive and has a high success rate.

The "E" word: epilepsy and perceptions of unfair treatment from the 2010 Australian Epilepsy Longitudinal Survey.

AIM: The aim of the current study was to examine self-report data on perceptions of unfair treatment due to epilepsy. METHOD: We analyzed data from the 2010 Australian Epilepsy Longitudinal Survey, distributed to 621 registrants on the Australian Epilepsy Research Register. A total of 343 responses were received (55% response rate), providing insight into experiences of life with epilepsy in Australia. Responses relating to perceptions of unfair treatment in areas of employment, education and community participation as a result of epilepsy are reported in this article. RESULTS: Forty-eight percent of respondents reported perceptions of unfair treatment as a result of their epilepsy, with most providing details of their experiences. Discrimination in the workplace remains of key concern, with 47% citing examples of unfair treatment in this setting. CONCLUSIONS: In spite of Australian anti-discrimination laws, findings indicate that full-time employment rates for people with epilepsy are lower than previously reported, with further mechanisms for support required to improve education and reduce experiences of stigma.

Commissioning of the Varian TrueBeam linear accelerator: a multi-institutional study.

PURPOSE: Latest generation linear accelerators (linacs), i.e., TrueBeam (Varian Medical Systems, Palo Alto, CA) and its stereotactic counterpart, TrueBeam STx, have several unique features, including high-dose-rate flattening-filter-free (FFF) photon modes, reengineered electron modes with new scattering foil geometries, updated imaging hardware/software, and a novel control system. An evaluation of five TrueBeam linacs at three different institutions has been performed and this work reports on the commissioning experience. METHODS: Acceptance and commissioning data were analyzed for five TrueBeam linacs equipped with 120 leaf (5 mm width) MLCs at three different institutions. Dosimetric data and mechanical parameters were compared. These included measurements of photon beam profiles (6X, 6XFFF, 10X, 10XFFF, 15X), photon and electron percent depth dose (PDD) curves (6, 9, 12 MeV), relative photon output factors (Scp), electron cone factors, mechanical isocenter accuracy, MLC transmission, and dosimetric leaf gap (DLG). End-to-end testing and IMRT commissioning were also conducted. RESULTS: Gantry/collimator isocentricity measurements were similar (0.27-0.28 mm), with overall couch/gantry/collimator values of 0.46-0.68 mm across the three institutions. Dosimetric data showed good agreement between machines. The average MLC DLGs for 6, 10, and 15 MV photons were 1.33 ± 0.23, 1.57 ± 0.24, and 1.61 ± 0.26 mm, respectively. 6XFFF and 10XFFF modes had average DLGs of 1.16 ± 0.22 and 1.44 ± 0.30 mm, respectively. MLC transmission showed minimal variation across the three institutions, with the standard deviation <0.2% for all linacs. Photon and electron PDDs were comparable for all energies. 6, 10, and 15 MV photon beam quality, %dd(10)x varied less than 0.3% for all linacs. Output factors (Scp) and electron cone factors agreed within 0.27%, on average; largest variations were observed for small field sizes (1.2% coefficient of variation, 10 MV, 2 × 2 cm(2)) and small cone sizes (<1% coefficient of variation, 6 × 6 cm(2) cone), respectively. CONCLUSIONS: Overall, excellent agreement was observed in TrueBeam commissioning data. This set of multi-institutional data can provide comparison data to others embarking on TrueBeam commissioning, ultimately improving the safety and quality of beam commissioning.

Seizure-related injuries and hospitalizations: self-report data from the 2010 Australian Epilepsy Longitudinal Survey.

AIM: To examine self-report data on seizure-related injuries and hospitalizations. METHOD: We analyzed data from the 2010 Australian Epilepsy Longitudinal Survey, distributed to registrants on the Australian Epilepsy Research Register. 343 responses were received (55% response rate), providing insight into experiences of living with seizures. This article examines self-report data on injuries related to seizures and hospitalizations. RESULTS: 64% of those reporting injuries required hospital treatment. Respondents with seizure-related injuries had significantly earlier seizure onset, with risk of injury related to myoclonic and atonic seizures and currently taking 3 or more AEDs. Soft tissue injuries were the most frequently reported (85%), with 27% indicating facial injuries. CONCLUSIONS: The high rate of hospitalizations largely for soft tissue injuries suggests that access to more appropriate care was not available. Further research into care-seeking behavior by Australians suffering injury following seizure is required. Additionally, awareness of injury risks is important for appropriate self-management of epilepsy.

Nuclear export and expression of human T-cell leukemia virus type 1 tax/rex mRNA are RxRE/Rex dependent.

Human T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus associated with the lymphoproliferative disease adult T-cell leukemia/lymphoma (ATL) and the neurodegenerative disorder tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). Replication of HTLV-1 is under the control of two major trans-acting proteins, Tax and Rex. Previous studies suggested that Tax activates transcription from the viral long terminal repeat (LTR) through recruitment of cellular CREB and transcriptional coactivators. Other studies reported that Rex acts posttranscriptionally and allows the cytoplasmic export of unspliced or incompletely spliced viral mRNAs carrying gag/pol and env only. As opposed to HIV's Rev-responsive element (RRE), the Rex-responsive element (RxRE) is present in all viral mRNAs in HTLV-1. However, based on indirect observations, it is believed that nuclear export and expression of the doubly spliced tax/rex RNA are Rex independent. In this study, we demonstrate that Rex does stimulate Tax expression, through nuclear-cytoplasmic export of the tax/rex RNA, even though a Rex-independent basal export mechanism exists. This effect was dependent upon the RxRE element and the RNA-binding activity of Rex. In addition, Rex-mediated export of tax/rex RNA was CRM1 dependent and inhibited by leptomycin B treatment. RNA immunoprecipitation (RNA-IP) experiments confirmed Rex binding to the tax/rex RNA in both transfected cells with HTLV-1 molecular clones and HTLV-1-infected T cells. Since both Rex and p30 interact with the tax/rex RNA and with one another, this may offer a temporal and dynamic regulation of HTLV-1 replication. Our results shed light on HTLV-1 replication and reveal a more complex regulatory network than previously anticipated.

SU-E-T-107: Uncertainty Estimate of a Practical EBT-2 Film Dosimetry Approach: Transpose-And-Scan Technique.

PURPOSE: To estimate the uncertainty of a practical EBT2 film dosimetry approach that has been established at our institution and used for routine patient-specific plan verifications, particularly for SBRT and RapidArc, as well as planning system commissioning. Our technique is unique from other common dosimetry protocols with respect to calibration, irradiation and scanning. METHODS: Film dosimetry for patient-specific quality assurance of 29 patient plans were retrospectively reviewed. For each case, four films were irradiated; two for calibration and two for treatment plan. Each pair of two films were irradiated together in a phantom with one film transposed (rotated 180 degrees relative to the other) to compensate for asymmetric film response. After a minimum of 12 hrs post-irradiation, each film was scanned in four different orientations to mitigate non-uniform response of the scanner light and detector elements. The scanned 8 calibration and 8 plan images were averaged into one calibration and one plan film image, respectively. Each color channel of the calibration film was correlated to the reference dose matrix to produce a 3rd order polynomial calibration curve. Finally, each color channel of the plan film was converted to a dose map using the corresponding calibration curve. Average dose maps of the red and green channels were correlated to the treatment planning dose matrix, and the mean dose differences at the center of dose distributions (5×5mm̂2 area) as well as a gamma analysis were evaluated. RESULTS: The absolute dose differences were -0.8±1.7% (range=-4.5-3.0%). The gamma pass-rates (3%/3mm) were 94±7% (min.=74%). The pass rate increased to 99±3%(min.=87%) with the film scaled relatively to the plan doses. CONCLUSIONS: Based on a large number of cases, our approach appears to be robust to non-uniform film and scanner responses, and is shown to have an uncertainty (1SD) of less than 2% for absolute film dosimetry.

Gastric emptying of a liquid nutrient meal in the critically ill: relationship between scintigraphic and carbon breath test measurement.

OBJECTIVE: It is assumed that delayed gastric emptying (GE) occurs frequently in critical illness; however, the prevalence of slow GE has not previously been assessed using scintigraphy. Furthermore, breath tests could potentially provide a convenient method of quantifying GE, but have not been validated in this setting. The aims of this study were to (i) determine the prevalence of delayed GE in unselected, critically ill patients and (ii) evaluate the relationships between GE as measured by scintigraphy and carbon breath test. DESIGN: Prospective observational study. SETTING: Mixed medical/surgical intensive care unit. PATIENTS: 25 unselected, mechanically ventilated patients (age 66 years (49-72); and 14 healthy subjects (age 62 years (19-84)). INTERVENTIONS: GE was measured using scintigraphy and (14)C-breath test. A test meal of 100 ml Ensure (standard liquid feed) labelled with (14)C octanoic acid and (99m)Technetium sulphur colloid was placed in the stomach via a nasogastric tube. MAIN OUTCOME MEASURES: Gastric 'meal' retention (scintigraphy) at 60, 120, 180 and 240 min, breath test t(50) (BTt(50)), and GE coefficient were determined. RESULTS: Of the 24 patients with scintigraphic data, GE was delayed at 120 min in 12 (50%). Breath tests correlated well with scintigraphy in both patients and healthy subjects (% retention at 120 min vs BTt(50); r(2)=0.57 healthy; r(2)=0.56 patients; p≤0.002 for both). CONCLUSIONS: GE of liquid nutrient is delayed in approximately 50% of critically ill patients. Breath tests correlate well with scintigraphy and are a valid method of GE measurement in this group.

[Hospital nursing: its own functions]. / Enfermería hospitalaria. Funciones propias.

The author investigates the degree of compliance of nursing functions in hospitals, the manner and the attitudes with which a nurse carries out these functions, and their degree of interdependence and mutual conditioning. To these ends, the author has carried out a theoretical analysis and a field investigation which have helped obtain diverse conclusions.

Fracture rates as a function of forearm mineral density in normal postmenopausal women: retrospective and prospective data.

Fracture histories were obtained from 492 normal postmenopausal women in 1983 and again in 1988, and related to forearm mineral content and density determined in 1983. All peripheral fractures, except those attributable to road traffic accidents, were included. There was only one hip fracture in the series. The total number of postmenopausal fractures was 183 in 149 subjects. In both the retrospective and prospective studies, fracture rates were inversely related to bone status and more significantly to bone density than to bone mass. In the pooled data, the fracture rate was three times as high in women with bone densities more than 4 standard deviations below the young normal mean as in those with bone densities above the mean. On logistic regression, the adjusted relative risk of fracture (odds ratio) in subjects more than 4 standard deviations below the young mean compared with those above the mean was 5.5 (2.7-11.4).

The relation between forearm and vertebral mineral density and fractures in postmenopausal women.

Vertebral and forearm mineral density (VMD and FMD, respectively) were determined in 124 postmenopausal women with no crushed vertebrae or peripheral fractures, 51 who had sustained peripheral fractures only since the menopause, 62 with vertebral compression(s) only and 75 with both types of fracture. There was a very significant correlation between the two measurements in the whole set. The scatter could not be accounted for by methodological error but was partly accounted for by body weight, since VMD was related to body weight and FMD was not. Whatever criterion was used for the diagnosis of osteoporosis (whether fracture or density) the percentage of misclassified cases was very similar by the two methods. However, VMD was relatively more reduced than FMD in vertebral fracture cases and FMD was marginally more reduced than VMD in peripheral fracture cases. There is little to choose between vertebral and forearm density in the diagnosis of osteoporosis but vertebral densitometry is slightly superior to forearm densitometry in describing the severity of osteoporosis in vertebral fracture patients.