Dose-Volume Predictors for Patient-reported Late Diarrhoea, Faecal Incontinence and Urgency after Pelvic Radiotherapy.

AIMS: Pelvic radiotherapy adds significantly to the curative treatment of many pelvic malignancies. However, this cure comes at a cost for many patients, where late bowel toxicities, such as faecal incontinence, urgency and diarrhoea, adversely affect quality of life. Despite the implementation of advanced radiotherapy techniques in many centres, there are deficiencies in our knowledge of how to make best use of these techniques to minimise these late toxicities, with dose-volume constraints specifically for late effects needing definition. The aims of this study were to establish dose-volume predictors for patient-reported late bowel toxicities and derive constraints for clinical use to reduce the risk of these toxicities. MATERIALS AND METHODS: All radiotherapy patients treated in our institution between 2012 and 2014 for gynaecological and urological cancers (bladder, prostate where pelvic nodes are treated) were identified. Patients were sent patient-reported toxicity questionnaires at 12 and 24 months after treatment. Planning computed tomography scans were retrospectively contoured with different definitions of bowel as organs at risk (OARs). Dose-volume data for each OAR were collected and predictors of these toxicities found using multivariate analysis. For those dose-volume predictors found to be significant on multivariate analysis, statistically significant and clinically relevant dose-volume constraints were derived. Furthermore, data collected were used to validate constraints from published studies. RESULTS: Faecal urgency, incontinence and diarrhoea rates were found in 52, 23.5 and 18.7% of the 203 patients included at 12 months following radiotherapy. Dose-volume parameters for sigmoid colon and large bowel were significant for these toxicities, and constraints for these OARs were derived, which are promising. A previously published constraint for bowel loops was validated with our data. CONCLUSIONS: The sigmoid colon and large bowel are important OARs for the development of faecal urgency, incontinence and diarrhoea. Promising constraints for these OARs were derived, which require further validation before prospective clinical use.

Confirming improved detection of gadolinium in bone using in vivo XRF.

The safety of using Gd in MRI contrast agents has recently been questioned, due to recent evidence of the retention of Gd in individuals with healthy renal function. Bone has proven to be a storage site for Gd, as unusually high concentrations have been measured in femoral heads of patients undergoing hip replacement surgery, as well as in autopsy samples. All previous measurements of Gd in bone have been invasive and required the bone to be removed from the body. X-ray fluorescence (XRF) offers a non-invasive and non-destructive method for carrying out in vivo measurements of Gd in humans. An updated XRF system provides improved detection limits in a short measurement time of 30-min. A new four-detector system and higher activity Cd-109 excitation source of 5GBq results in minimum detection limits (MDLs) of 1.64-1.72µgGd/g plaster for an average overlaying tissue thickness of the tibia. These levels are well within the range of previous in vitro Gd measurements. Additional validation through comparison with ICP-MS measurements has confirmed the ability of the XRF system for detecting Gd further, proving it is a feasible system to carry out human measurements.

Glandular neoplasia and borderline endocervical reporting rates before and after conversion to the SurePath(TM) liquid-based cytology (LBC) system.

Reporting rates for glandular neoplasia in 464,754 cervical samples reported at six laboratories in 12-month periods before and after the implementation of Surepath™ LBC processing are compared. The introduction of LBC processing is seen to have resulted in a significant (P = 0.001) increase in the detection rate for endocervical glandular neoplasia (from 2.2 per 10,000 tests to 3.9 per 10,000) while maintaining high levels of reporting specificity. An observed fall in the number of samples reported as showing borderline glandular neoplasia falls short of statistical significance, and the reporting of possible endometrial and 'other' glandular abnormalities appears to be unaffected. The underlying reasons for the observed improvement in detection of endocervical glandular neoplasia are discussed.

The sap from Euphorbia peplus is effective against human nonmelanoma skin cancers.

BACKGROUND: The sap from Euphorbia peplus, commonly known as petty spurge in the U.K. or radium weed in Australia, has been used as a traditional treatment for a number of cancers. OBJECTIVE: To determine the effectiveness of E. peplus sap in a phase I/II clinical study for the topical treatment of basal cell carcinomas (BCC), squamous cell carcinomas (SCC) and intraepidermal carcinomas (IEC). METHODS: Thirty-six patients, who had refused, failed or were unsuitable for conventional treatment, were enrolled in a phase I/II clinical study. A total of 48 skin cancer lesions were treated topically with 100-300 µL of E. peplus sap once daily for 3 days. RESULTS: The complete clinical response rates at 1 month were 82% (n = 28) for BCC, 94% (n = 16) for IEC and 75% (n = 4) for SCC. After a mean follow-up of 15 months these rates were 57%, 75% and 50%, respectively. For superficial lesions < 16 mm, the response rates after follow-up were 100% for IEC (n = 10) and 78% for BCC (n = 9). CONCLUSIONS: The clinical responses for these relatively unfavourable lesions (43% had failed previous treatments, 35% were situated in the head and neck region and 30% were > 2 cm in diameter), are comparable with existing nonsurgical treatments. An active ingredient of E. peplus sap has been identified as ingenol mebutate (PEP005). This clinical study affirms community experience with E. peplus sap, and supports further clinical development of PEP005 for the treatment of BCC, SCC and IEC.

Laser beam combiner for Thomson scattering core LIDAR.

The light detection and ranging Thomson scattering (TS) diagnostic is advantageous since it only requires a single view port into the tokamak. This technique requires a short pulse laser at high energy, usually showing a limited repetition rate. Having multiple lasers will increase the repetition rate. This paper presents a scanning mirror as a laser beam combiner. Measurements of the position accuracy and jitter show that the pointing stability of the laser beam is within ±25 µrad for over tens of seconds. A control feedback loop is implemented to demonstrate the long term stability. Such a system could be applied for ITER and JET.

Regioselective acylation of 3-O-angeloylingenol by Candida antarctica Lipase B.

Acylation of 3-O-angeloylingenol (1) with vinyl acetate, vinyl decanoate and vinyl cinnamate, catalyzed by Candida antarctica Lipase B, was investigated. In each case, compound 1 was quantitatively and regioselectively acylated to afford a single product, 3-O-angeloyl-20-O-acetylingenol (1a), 3-O-angeloyl-20-O-decanoylingenol (1b) and 3-O-angeloyl-20-O-cinnamoylingenol (1c), respectively. The structures of the novel compounds 1b-1c were determined by MS and NMR, and product 1a by comparison of RP-HPLC and TLC with a standard. Compounds 1b-1c induced a bipolar morphology of MM96L melanoma cells at a similar concentration as compound 1, as well as having activity in inhibiting the growth of MM96L melanoma cells.

Plasma receptor for advanced glycation end products and clinical outcomes in acute lung injury.

OBJECTIVES: To determine whether baseline plasma levels of the receptor for advanced glycation end products (RAGE), a novel marker of alveolar type I cell injury, are associated with the severity and outcomes of acute lung injury, and whether plasma RAGE levels are affected by lower tidal volume ventilation. DESIGN, SETTING AND PARTICIPANTS: Measurement of plasma RAGE levels from 676 subjects enrolled in a large randomised controlled trial of lower tidal volume ventilation in acute lung injury. MEASUREMENTS AND MAIN RESULTS: Higher baseline plasma RAGE was associated with increased severity of lung injury. In addition, higher baseline RAGE was associated with increased mortality (OR for death 1.38 (95% CI 1.13 to 1.68) per 1 log increment in RAGE; p = 0.002) and fewer ventilator free and organ failure free days in patients randomised to higher tidal volumes. These associations persisted in multivariable models that adjusted for age, gender, severity of illness and the presence of sepsis or trauma. Plasma RAGE was not associated with outcomes in the lower tidal volume group (p = 0.09 for interaction in unadjusted analysis). In both tidal volume groups, plasma RAGE levels declined over the first 3 days; however, the decline was 15% greater in the lower tidal volume group (p = 0.02; 95% CI 2.4% to 25.0%). CONCLUSIONS: Baseline plasma RAGE levels are strongly associated with clinical outcomes in patients with acute lung injury ventilated with higher tidal volumes. Lower tidal volume ventilation may be beneficial in part by decreasing injury to the alveolar epithelium.

New cysteine derivatives with antiproliferative activity on melanoma cells.

Here we describe the rational design, computer-aided virtual ligand docking and synthesis of 19 nonpeptidic compounds designed to inhibit histone deacetylases and kill melanoma cells. Compounds were derived from cysteine, fused at the S-terminus to 4-butanoyl hydroxamate, and at the N-terminus to 4-(dimethylamino)benzoic acid. The latter was extended by coupling to amines to form a small library of prospective anti-cancer compounds. Four compounds were cytotoxic at sub-micromolar concentrations against cells of a particularly aggressive human melanoma (MM96L), and nine compounds showed selectivities of >or=5:1 for killing human melanoma instead of normal human fibroblast cells. The most active compounds were shown to cause hyperacetylation of histones due to inhibition of histone deacetylases. Further refinement of these compounds may produce an anti-tumor drug suitable for treating melanoma.

Deformation of press-fitted metallic resurfacing cups. Part 1: Experimental simulation.

The interference press fit of a metallic one-piece acetabular cup employed for metal-on-metal hip resurfacing procedures was investigated experimentally under laboratory conditions in the present study, in particular regarding the cup deformation. Tests were carried out in cadavers as well as polyurethane foams of various grades with different elastic moduli to represent different cancellous bone qualities. The cadaver test was used to establish the most suitable configuration of the foam model representing realistic support and geometrical conditions at the pelvis. It was found that a spherical cavity, with two identical areas relieved on opposite sides, was capable of creating a two-point pinching action of the ischeal and ilial columns on the cup as the worst-case scenario. Furthermore, the cup deformation produced from such a two-point loading model with a grade 30 foam was similar to that measured from the cadaver test. Therefore, such a protocol was employed in subsequent experimental tests. For a given size of the outside diameter of the cup of 60 mm, the cup deflection was shown to be dependent largely on the cup wall thickness and the diametral interference between cup and prepared cavity at implantation. For a relatively thin cup with a wall thickness between 2.3 mm (equator) and 4 mm (pole) and with a modest nominal diametral interference of 1 mm, which corresponds to an actual interference of approximately 0.5 mm, the maximum diametral cup deflection (at the rim) was around 60 microm, compared with a diametral clearance of 80-120 microm between the femoral head and the acetabular cup, generally required for fluid-film lubrication and tribological performances. Stiffening of the cup, by both thickening and lateralizing by 1 mm, reduced the cup deformation to between 30 and 50 microm with actual diametral interferences between 0.5 and 1 mm.

Factors influencing the difference between maternal and cord blood lead.

AIMS: To determine the factors that affect why some infants receive higher exposures relative to the mother's body burden than do others. METHODS: A total of 159 mother-infant pairs from a cohort of women receiving prenatal care at Magee-Womens Hospital in Pittsburgh, PA from 1992 to 1995 provided blood samples at delivery for lead determination. The difference between cord and maternal blood lead concentration (PbB) and a dichotomous variable indicator of higher cord than maternal PbB, were examined as indicators of relative transfer. Women were interviewed twice during the pregnancy about lifestyle, medical history, calcium nutrition, and physical activity. RESULTS: Higher blood pressure was associated with relatively greater cord compared with maternal PbB, as was maternal alcohol use. Sickle cell trait and higher haemoglobin were associated with a lower cord relative to maternal blood lead PbB. No association was seen with smoking, physical exertion, or calcium consumption. CONCLUSION: While reduction in maternal exposure will reduce fetal exposure, it may also be possible to mitigate infant lead exposure by reducing transfer from the pregnant woman. Interventions aimed at reducing blood pressure and alcohol consumption during pregnancy may be useful in this regard.

Plasma surfactant protein levels and clinical outcomes in patients with acute lung injury.

BACKGROUND: Because injury to the alveolar epithelial barrier is a characteristic feature of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS), plasma surfactant protein levels may have prognostic value. To test this hypothesis plasma surfactant proteins A and D (SP-A and SP-D) levels were measured in patients with ALI or ARDS enrolled in the NHLBI sponsored multicentre ARDS Network randomised controlled trial of a 6 ml/kg v 12 ml/kg tidal volume strategy. METHODS: Data from 565 participants in the clinical trial were used. Plasma levels of SP-A and SP-D were measured at baseline and on day 3 after the start of the mechanical ventilation protocol. The longitudinal impact of baseline plasma surfactant protein levels on clinical outcomes was examined by multivariate analysis, controlling for mechanical ventilation group, APACHE III score, and other clinical covariates. The effect of 6 ml/kg tidal volume ventilation on plasma SP-A and SP-D levels was evaluated using analysis of covariance. RESULTS: Baseline plasma SP-A levels were not related to any clinical outcome. In contrast, higher baseline plasma SP-D levels were associated with a greater risk of death (OR 1.21 per 100 ng/ml increment; 95% CI 1.08 to 1.35), fewer ventilator-free days (mean decrease -0.88 days; p=0.001), and fewer organ failure-free days (mean decrease -1.06 days; p<0.0001). The 6 ml/kg tidal volume strategy had no effect on the rise in plasma SP-A levels (p=0.91) but attenuated the rise in plasma SP-D levels (p=0.0006). CONCLUSIONS: Early in the course of ALI/ARDS an increased level of plasma SP-D is associated with a worse clinical outcome. The 6 ml/kg tidal volume strategy attenuated the rise of SP-D early in the clinical course. Taken together, these observations indicate that plasma SP-D, a product of alveolar type II cells, is a valuable biomarker in ALI/ARDS.

Associations of lead biomarkers with renal function in Korean lead workers.

AIMS: To compare associations of lead biomarkers with renal function in current and former lead workers. METHODS: Cross sectional analysis of first year results from a longitudinal study of 803 lead workers and 135 controls in South Korea. Clinical renal function was assessed by blood urea nitrogen (BUN), serum creatinine, and measured and calculated creatinine clearance. Urinary N-acetyl-beta-D-glucosaminidase (NAG) and retinol-binding protein were also measured. RESULTS: Mean (SD) tibia lead, blood lead, and DMSA chelatable lead levels in lead workers were 37.2 (40.4) micro g/g bone mineral, 32.0 (15.0) micro g/dl, and 767.8 (862.1) micro g/g creatinine, respectively. Higher lead measures were associated with worse renal function in 16/42 models. When influential outliers were removed, higher lead measures remained associated with worse renal function in nine models. An additional five associations were in the opposite direction. Effect modification by age was observed. In 3/16 models, associations between higher lead measures and worse clinical renal function in participants in the oldest age tertile were significantly different from associations in those in the youngest age tertile which were in the opposite direction. Mean urinary cadmium (CdU) was 1.1 micro g/g creatinine (n = 191). Higher CdU levels were associated with higher NAG. CONCLUSIONS: These data suggest that lead has an adverse effect on renal function in the moderate dose range, particularly in older workers. Associations between higher lead measures and lower BUN and serum creatinine and higher creatinine clearances may represent lead induced hyperfiltration. Environmental cadmium may also have an adverse renal impact, at least on NAG.

Individual variability in human tibia lead concentration.

Our aims in this study were to determine proximal-distal variability in adult human tibia lead concentration via electrothermal atomization atomic absorption spectrometry (ETAAS) and to determine whether there were any differences between core and surface tibia lead concentrations. We analyzed duplicate core and surface tibia samples for lead at multiple proximal-distal sections on 10 adult human cadaver legs. Dried bone samples were digested in nitric acid using microwave-assisted heating, and lead content was determined by ETAAS with Zeeman background correction. Lead concentrations in nine tibiae (one tibia was excluded because some of the data were compromised) ranged from 3.1 to 27.9 microg lead/g of dry bone. Both core and surface tibia lead concentrations were lower at the proximal and distal ends of the tibia. Surface tibia lead was approximately 5 microg/g greater than core tibia lead in six tibiae with relatively low lead concentration, and 8 microg/g greater in three tibiae with relatively high lead concentration. The difference between core and surface tibia lead was independent of proximal-distal tibia location. We conclude that these nine human tibiae showed a greater surface tibia lead concentration than core tibia lead concentration. This observation has consequences for the noninvasive measurement of tibia lead via K-shell and L-shell X-ray fluorescence.

Clinicians' approaches to mechanical ventilation in acute lung injury and ARDS.

STUDY OBJECTIVES: To examine clinicians' approaches to mechanical ventilation in patients with acute lung injury (ALI; PaO(2)/fraction of inspired oxygen [FIO(2)] 35 cm H(2)O in 26% of patients. Seventy-eight percent of patients with ARDS received

Exposure to lead during critical windows of embryonic development: differential immunotoxic outcome based on stage of exposure and gender.

Previous rat studies with lead (Pb) have shown that exposure throughout the full gestational period results in persistent immunotoxicity detectable in both juvenile and adult offspring. Gender differences are also evident. However, little is known about the persistent immunotoxic effects of Pb when administered during specific stages of embryonic development. Adult Sprague-Dawley female rats were administered Pb acetate (or control acetate) in their drinking water early in gestation (days 3-9) or late in gestation (days 15-21). Significantly depressed delayed type hypersensitivity (DTH) responses as well as elevated IL-10 production, relative monocyte numbers, and increased relative thymic weights were observed in late-gestation Pb-exposed female offspring assessed as adults. In contrast, late-gestation Pb-treated male offspring had significantly increased IL-12 production and decreased IL-10 production, while the DTH response, relative monocyte numbers and thymic weights were unchanged. With early exposure, the primary alteration was decreased nitric oxide production in Pb-treated males, whereas in Pb-treated females nitrite production was unaltered. These results suggest that at the Pb dosage employed, the embryo may be more sensitive to the full range of Pb-induced immunotoxic effects with late gestational Pb exposure, and the effects of Pb on DTH function are more pronounced in females. The data also indicate that adherent splenocytes (probably macrophages) and T lymphocytes are the primary immune cells affected during fetal Pb exposure, and that gender may influence the impact of Pb exposure on these cells. Therefore, additional developmental immunotoxicity studies are needed to examine critical windows of immune development for immunotoxicity and differential susceptibility based on gender.

Gender-based profiles of developmental immunotoxicity to lead in the rat: assessment in juveniles and adults.

Gender-based differences in immunotoxicity induced by the heavy metal lead (Pb) have been observed both in the juvenile chicken and the adult rat following low-level exposure during embryonic development. To better define the gender-based differences, as related to dose following in utero exposure to Pb, potential differential sensitivities were examined after exposure of F344 rats to low concentrations of Pb (0, 50, 100, or 250 ppm Pb) ad libitum throughout gestation. Immune assessment was performed in juveniles (5 wk old) and young adults (13 wk old). At the highest (250 ppm) Pb concentration examined, the delayed-type hypersensitivity (DTH) response was depressed in females relative to gender-matched controls at both ages; relative spleen weights and relative neutrophil numbers were increased while relative and absolute monocyte numbers and relative basophil numbers were decreased at 13 but not 5 wk of age. In contrast, 250 ppm Pb-treated males did not differ in these endpoints. With in utero exposure to 100 ppm Pb, 13-wk-old females again had decreased relative and absolute monocyte numbers and increased relative neutrophil numbers, although the DTH response was unchanged. Males (with 100 ppm Pb) had increased relative neutrophil numbers, decreased relative lymphocytes, and transiently increased nitrite production seen at 5, but not 13, wk of age. After gestational exposure to 50 ppm Pb, minimal immunotoxic effects were observed in either males or females at either developmental age assessed. These results suggest that differential gender-based immunotoxicity profiles exist after gestational Pb exposure depending on the concentration of Pb administered to the dam. In utero exposure of dams to 250 ppm Pb results in more profound immunotoxicity in females than males. Males arenot more sensitive to lower concentrations of Pb than females. Since the 50 ppm exposure produced minimal changes, these data may provide information to establish a no-observed-adverse-effect level (NOAEL) for in utero exposure to Pb. Additionally, while most effects were evident at both juvenile and adult ages, some changes were not fully evident until measured in the adult. Most changes were persistent with only one exception (male nitrite levels at 100 ppm).

Up-regulation of p21(WAF1/CIP1) by histone deacetylase inhibitors reduces their cytotoxicity.

Histone deacetylase inhibitors show promise as chemotherapeutic agents and have been demonstrated to block proliferation in a wide range of tumor cell lines. Much of this antiproliferative effect has been ascribed to the up-regulated expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1). In this article, we report that p21 expression was up-regulated by relatively low doses of the histone deacetylase inhibitor azelaic bishydroxamic acid (ABHA) and correlated with a proliferative arrest. Higher doses of ABHA were cytotoxic. Cells that did not up-regulate p21 expression were hypersensitive to killing by ABHA and died via apoptosis, whereas up-regulation of p21 correlated with reduced sensitivity and a block in the apoptotic mechanism, and these cells seemed to die by necrosis. Using isogenic p21(+/+) and p21(-/-) cell lines and direct inhibition of caspase activity, we demonstrate that the reduced sensitivity to killing by ABHA is a consequence of inhibition of apoptosis by up-regulated p21 expression. These data indicate the enormous potential of therapeutic strategies that bypass the cytoprotective effect of p21 and act on the same molecular targets as the histone deacetylase inhibitors.

Radiation hormesis: an ecological and energetic perspective.

Organisms in natural habitats are exposed to an array of environmental stresses, which all have energetic costs. Under this ecological scenario, hormesis for ionizing radiation becomes an evolutionary expectation at exposures substantially exceeding background. This conclusion implies that some relaxation of radiation protection criteria is worthy of serious consideration.

Photosensitization of the sunscreen octyl p-dimethylaminobenzoate by UVA in human melanocytes but not in keratinocytes.

Sunscreens penetrate human epidermis and modify the biology of proliferating cells. This study addressed the question whether the UV response of cultured human cells is affected by direct treatment with nontoxic levels of sunscreens. Cell survival following exposure to UVC or unfiltered UBV was not altered by preincubation with 25 micrograms/mL of octyl p-dimethylaminobenzoate (o-PABA), 2-ethylhexyl p-methoxycinnamate (EHMC) or oxybenzone. However, UVA or UVB filtered to reproduce the solar UV spectrum penetrating to the basal layer of the epidermis, highly sensitized cells to killing by o-PABA but not by its hydrolysis product, 4-dimethylaminobenzoic acid. Sensitization was found in all cell types tested, except normal keratinocytes, and could be prevented by certain antioxidants particularly pyruvate and the hydroxyl radical scavenger mannitol. o-PABA and EHMC applied without UV reduced the adherence of cells. The results indicate that sunscreens may increase cell mobility and the combination of o-PABA with solar UV may selectively damage melanocytes in the skin.

Histone hyperacetylation induced by histone deacetylase inhibitors is not sufficient to cause growth inhibition in human dermal fibroblasts.

Use of specific histone deacetylase inhibitors has revealed critical roles for the histone deacetylases (HDAC) in controlling proliferation. Although many studies have correlated the function of HDAC inhibitors with the hyperacetylation of histones, few studies have specifically addressed whether the accumulation of acetylated histones, caused by HDAC inhibitor treatment, is responsible for growth inhibition. In the present study we show that HDAC inhibitors cause growth inhibition in normal and transformed keratinocytes but not in normal dermal fibroblasts. This was despite the observation that the HDAC inhibitor, suberic bishydroxamate (SBHA), caused a kinetically similar accumulation of hyperacetylated histones. This cell type-specific response to SBHA was not due to the inactivation of SBHA by fibroblasts, nor was it due to differences in the expression of specific HDAC family members. Remarkably, overexpression of HDACs 1, 4, and 6 in normal human fibroblasts resulted in cells that could be growth-inhibited by SBHA. These data suggest that, although histone acetylation is a major target for HDAC inhibitors, the accumulation of hyperacetylated histones is not sufficient to cause growth inhibition in all cell types. This suggests that growth inhibition, caused by HDAC inhibitors, may be the culmination of histone hyperacetylation acting in concert with other growth regulatory pathways.