Growth rates of pulmonary metastases after liver transplantation for unresectable colorectal liver metastases.

BACKGROUND: The previously reported SECA study demonstrated a dramatic 5-year survival improvement in patients with unresectable colorectal liver metastases (CLM) treated with liver transplantation (LT) compared with chemotherapy. The objective of this study was to assess whether immunosuppressive therapy accelerates the growth of pulmonary metastases in patients transplanted for unresectable CLM. METHODS: Chest CT scans from 11 patients in the SECA study resected for 18 pulmonary metastases were reviewed retrospectively. Tumour diameter, volume and CT characteristics were registered and tumour volume doubling time was calculated. Findings in the SECA group were compared with those of a control group consisting of 12 patients with non-transplanted rectal cancer resected for 26 pulmonary metastases. Disease-free survival (DFS) and overall survival (OS) after first pulmonary resection were determined. RESULTS: Median doubling time based on tumour diameter and volume in the SECA and control groups were 125 and 130 days (P = 0·658) and 110 and 129 days (P = 0·632) respectively. The metastases in both groups were distributed to all lung lobes and were mostly peripheral. Median DFS after LT in the SECA group and after primary pelvic surgery in the control group was 17 (range 6-42) and 18 (2-57) months respectively (P = 0·532). In the SECA group, estimated 5-year DFS and OS rates after first pulmonary resection were 39 and 51 per cent respectively. CONCLUSION: Patients treated by LT for unresectable CLM have a good prognosis following resection of pulmonary metastases. Doubling time did not appear to be worse with the immunosuppression used after LT.

Phosphorylation of intracellular signalling molecules in peripheral blood cells from patients with psoriasis on originator or biosimilar infliximab.

BACKGROUND: Psoriasis vulgaris is a chronic, inflammatory skin disease characterized by a dysregulated immune response and it is associated with substantial systemic comorbidities. Biological drugs such as tumour necrosis factor (TNF)-α inhibitors can ameliorate the disease but are expensive. Biosimilar drugs have the same amino-acid sequence as the originator, but differences in manufacturing can affect biological activity, efficacy and tolerability. OBJECTIVES: To explore potential differences in intracellular phosphorylation of signalling molecules in peripheral blood cells from patients with psoriasis treated with the TNF-α inhibitor infliximab compared with healthy controls, and to investigate if the phosphorylation pattern was influenced by switching from the originator infliximab to the biosimilar CT-P13. METHODS: By flow cytometry, we measured phosphorylation of nuclear factor kappa B, extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase and signal transducer and activator of transcription 3, before and after TNF-α stimulation in monocytes and T, B, natural killer and CD3+  CD56+ cells from 25 patients with psoriasis treated with infliximab and 19 healthy controls. RESULTS: At inclusion, phosphorylation levels of peripheral blood mononuclear cells (PBMCs) were increased in patients with psoriasis compared with healthy controls, even though clinical remission had already been achieved. Phosphorylation levels declined in patients on both originator infliximab and biosimilar during continued treatment. No significant differences were detected between the two medications after 12 months. CONCLUSIONS: Patients with psoriasis on infliximab have higher activation levels of PBMCs than do healthy controls, possibly reflecting systemic inflammation. Switching from the originator infliximab to biosimilar CT-P13 did not affect phosphorylation levels or clinical parameters, suggesting that CT-P13 is a noninferior treatment alternative to the originator infliximab.

High number of kinome-mutations in non-small cell lung cancer is associated with reduced immune response and poor relapse-free survival.

Lung cancer is the leading cause of cancer related death, and the past years' improved insight into underlying molecular events has significantly improved outcome for specific subsets of patients. In particular, several new therapies that target protein kinases have been implemented, and many more are becoming available. We have investigated lung cancer specimens for somatic mutations in a targeted panel of 612 human genes, the majority being protein kinases. The somatic mutation profiles were correlated to profiles of immune cell infiltration as well as relapse-free survival. Targeted deep sequencing was performed on 117 tumour/normal pairs using the SureSelect Human Kinome kit (Agilent Technologies), with capture probes targeting 3.2 Mb of the human genome, including exons and untranslated regions of all known kinases, kinase receptors and selected cancer-related genes (612 genes in total). CD8 staining was determined using Ventana Benchmark. Survival analyses were performed using SPSS. The number of mutations per sample ranged from 0 to 50 (within the 612 genes tested), with a median of nine. The prognosis was worse for patients with more than the median number of mutations. A significant correlation was found between mutations in one of selected DNA-repair genes and the total number of mutations in that tumour (p < 0.001). There was a significant inverse correlation between the number of infiltrating stromal CD8+ lymphocytes and the presence of EGFR mutations.

Assays for Infliximab Drug Levels and Antibodies: A Matter of Scales and Categories.

Immunogenicity is a frequent cause of secondary non-response to tumour necrosis factor (TNF) inhibitors. Drug level measurement and detection of antidrug antibodies have been shown to be cost effective and clinically relevant, and a large number of assays are available for these purposes. It is, however, difficult to compare assays and translate results into clinical meaningful information due to different methodological approaches and a lack of assay standardization. We have analysed infliximab drug levels and antidrug antibodies in 107 patient samples using enzyme-linked immunoassays (ELISA), immunofluorometric assays (IFMA) and reporter-gene assays (RGA). The RGA gave the lowest results for drug levels, whereas the IFMA detected the highest number of antidrug antibody positive sera. Applying individualized therapeutic ranges to each assay resulted in agreement among all three assays in 74% of samples for drug levels and 98% of samples for antidrug antibodies. We found that TNF inhibitor monitoring assays measure on different scales and that the agreement between quantitative results is limited. However, interassay differences can partially be overcome by assay-individualized translations of quantities into categories, which also is necessary for a meaningful clinical application. Our data demonstrate that assays should not be used interchangeably and that direct comparison of quantitative drug levels obtained with different assays should be avoided.

Strategies for clinical implementation of TNM-Immunoscore in resected nonsmall-cell lung cancer.

Immunoscore is a prognostic tool defined to quantify in situ immune cell infiltrates and appears highly promising as a supplement to the tumor-node-metastasis (TNM) classification of various tumors. In colorectal cancer, an international task force has initiated prospective multicenter studies aiming to implement TNM-Immunoscore (TNM-I) in a routine clinical setting. In breast cancer, recommendations for the evaluation of tumor-infiltrating lymphocytes (TILs) have been proposed by an international working group. Regardless of promising results, there are potential obstacles related to implementing TNM-I into the clinic. Diverse methods may be needed for different malignancies and even within each cancer entity. Nevertheless, a uniform approach across malignancies would be advantageous. In nonsmall-cell lung cancer (NSCLC), there are several previous reports indicating an apparent prognostic importance of TILs, but studies on TILs in a TNM-I setting are sparse and no general recommendations are made. However, recently published data is promising, evoking a realistic hope of a clinical useful NSCLC TNM-I. This review will focus on the TNM-I potential in NSCLC and propose strategies for clinical implementation of a TNM-I in resected NSCLC.

Carotid atherosclerosis and relation to growth of infrarenal aortic diameter and follow-up diameter: the Tromsø Study.

OBJECTIVES: This research aims to study how carotid atherosclerosis is related to growth of infrarenal aortic diameter and aneurysmal formation. DESIGN: Population-based follow-up study. MATERIALS AND METHODS: At baseline, ultrasound examination of the carotid artery and the abdominal aorta was performed in 4241 persons from a general population with no evidence of abdominal aortic aneurysm (AAA). The burden of atherosclerosis was assessed as carotid total plaque area (TPA). After a mean follow-up of 6.3 years, a new ultrasound examination was performed and measurements of the aortic diameter and carotid TPA were repeated. The effects on aortic diameter progression, follow-up diameter and risk for AAA were assessed in multiple linear and logistic regression models according to carotid TPA, adjusted for known risk factors. RESULTS: When analysing AAA as a dichotomous variable, a borderline association between atherosclerosis and AAA could be demonstrated. When modelling aortic diameter as a continuous variable, a 1-SD increase in 5 years' carotid plaque area (ΔTPA) was associated with a 0.12-mm growth in infrarenal aortic diameter (standard error (SE) 0.04) and a 0.20-mm wider aorta at follow-up (SE 0.06). No independent relation was seen for baseline atherosclerosis. CONCLUSIONS: Carotid plaque progression was positively related to growth in infrarenal aortic diameter and aortic diameter at follow-up. Whether this co-variation between plaque growth and aortic diameter growth is causally related or independent events is still an open question.

Diameter of the infrarenal aorta as a risk factor for abdominal aortic aneurysm: the Tromsø Study, 1994-2001.

OBJECTIVES: We aim to study whether the diameter of the non-aneurysmatic infrarenal aorta influences the risk for abdominal aortic aneurysm (AAA) and whether the larger diameter in men can explain the male predominance in AAA. DESIGN: This is a population-based follow-up study. MATERIALS AND METHODS: In 4265 men and women with a normal-sized aorta in 1994-1995, 116 incident cases of AAA were diagnosed 7 years later. The risk of an incident AAA was analysed in a multiple logistic regression model according to baseline maximal infrarenal aortic diameter, adjusted for known risk factors. RESULTS: Compared with subjects with aortic diameter in the 21-23 mm bracket, men and women with a diameter <18mm and > or =27mm had an adjusted odds ratio (OR) of 0.30 (95% confidence interval (CI): 0.10-0.88) and 4.22 (95% CI: 1.94-9.19), respectively, for an incident AAA. When adjusted for age and baseline aortic diameter, male sex was not statistically significantly associated with the incidence of AAA (OR=1.45, 95% CI: 0.93-2.30, P=0.10). CONCLUSIONS: Increased baseline diameter of the infrarenal aorta was a highly significant, strong and independent risk factor for developing an AAA. The larger aortic diameter in men than in women may be the most important explanation for the higher AAA risk in men.

Modelling atmospheric oxidation of 2-aminoethanol (MEA) emitted from post-combustion capture using WRF-Chem.

Carbon capture and storage (CCS) is a technological solution that can reduce the amount of carbon dioxide (CO2) emissions from the use of fossil fuel in power plants and other industries. A leading method today is amine based post-combustion capture, in which 2-aminoethanol (MEA) is one of the most studied absorption solvents. In this process, amines are released to the atmosphere through evaporation and entrainment from the CO2 absorber column. Modelling is a key instrument for simulating the atmospheric dispersion and chemical transformation of MEA, and for projections of ground-level air concentrations and deposition rates. In this study, the Weather Research and Forecasting model inline coupled with chemistry, WRF-Chem, was applied to quantify the impact of using a comprehensive MEA photo-oxidation sequence compared to using a simplified MEA scheme. Main discrepancies were found for iminoethanol (roughly doubled in the detailed scheme) and 2-nitro aminoethanol, short MEA-nitramine (reduced by factor of two in the detailed scheme). The study indicates that MEA emissions from a full-scale capture plant can modify regional background levels of isocyanic acid. Predicted atmospheric concentrations of isocyanic acid were however below the limit value of 1 ppbv for ambient exposure. The dependence of the formation of hazardous compounds in the OH-initiated oxidation of MEA on ambient level of nitrogen oxides (NOx) was studied in a scenario without NOx emissions from a refinery area in the vicinity of the capture plant. Hourly MEA-nitramine peak concentrations higher than 40 pg m(-3) did only occur when NOx mixing ratios were above 2 ppbv. Therefore, the spatial variability and temporal variability of levels of OH and NOx need to be taken into account in the health risk assessment. The health risk due to direct emissions of nitrosamines and nitramines from full-scale CO2 capture should be investigated in future studies.

Lack of ability to synthesize tissue factor by endothelial cells in intact human saphenous veins.

It is well established that cultured endothelial cells are induced to generate tissue factor activity when incubated with either endotoxin or thrombin. In this study a perfusion system was used on 3-4 cm long human saphenous veins. The veins were perfused with thrombin (2.5 U/ml), endotoxin (30 ng/ml) or just medium for 3 h at 37 degrees C. After the perfusion, the veins were treated with collagenase, and EC were collected and subjected to tissue factor activity measurements. Some perfused veins were examined for tissue factor activity on the vessel wall by allowing factor VII and factor X to interact with the lumen of the intact vessels, followed by quantitation of generated factor Xa in a chromogenic assay. No formation of tissue factor activity could be found after perfusion in either collagenase-dissolved endothelial cells or in the coupled chromogenic assay for tissue factor activity performed in the lumen of the vessel. Our data strongly suggest that endothelial cells in intact endothelium may behave quite differently from isolated endothelial cells stimulated in cell cultures.

Crown condition of Norway spruce in relation to sulphur and nitrogen deposition and soil properties in southeast Norway.

Atmospheric deposition of sulphur and nitrogen compounds may lead to enhanced leaching of base cations, accumulation of nitrogen in organic matter, lowered pH and increased concentration of toxic aluminium in soil, which in turn may affect the vitality of forest trees. A general monitoring of forest condition has been initiated in many European countries, partly in order to reveal stresses caused by acidification. However, forest condition is also affected by many other factors. This paper examines a seven-year series of crown-condition data from Local County Monitoring Plots in Norway spruce stands in Norway. Average, time trend and lability variables were calculated for crown density and crown colour for each plot. Wet deposition of sulphate, ammonium and nitrate for each plot were estimated using data from the national air and precipitation monitoring programmes. Soil data are based on soil sampling within the plots. The analysis gave no evident support for the hypothesized negative effect on crown condition from sulphur and nitrogen deposition and related alterations in soil.

Time series study of concentrations of SO4(2-) and H+ in precipitation and soil waters in Norway.

Along with a steady reduction of acid inputs during 14 years of intensive forest monitoring in Norway, the influence of acid deposition upon soil water acidity is gradually reduced in favour of other and internal sources of H+ and sulphate, in particular from processes in the upper soil layer. We used statistical analyses in two steps for precipitation, throughfall and soil water at 5, 15 and 40 cm depths. Firstly, we employed time series analyses to model the temporal variation as a long-term linear trend and a monthly variation, and by this filtered out residual, weekly variation. Secondly, we used the parameter estimates and the residuals from this to show that the long term, the monthly and the weekly variation in one layer were correlated to similar temporal variation in the above, adjacent layer. This was strongly evident for throughfall correlated to precipitation, but much weaker for soil water. Continued acidification in soil water on many plots suggests that the combined effects of anthropogenic and natural acid inputs exceed in places the buffering capacity of the soil.

Cold induced endothelial cell detachment in human saphenous vein grafts.

The effect of profound (4 degrees C) and moderate cooling (20 degrees C) on the endothelium of human saphenous vein grafts for aortocoronary bypass was studied. When harvesting the vein, a piece (5-6 cm) was taken for the study and divided in two equal parts. The segments were incubated in cell culture medium for 45 minutes at 4 degrees C and 20 degrees C respectively. They were then perfused with cell culture medium at a flow rate of 100 ml/min, with a pressure of 85 mmHg and a temperature of 20 degrees C. After termination of perfusion the percentage of luminal surface without endothelial cells was determined by morphometry with scanning electron microscopy. The veins that were exposed to 4 degrees C had a significantly higher degree of endothelial cell detachment than those exposed to 20 degrees C (p less than 0.003). This study indicates that cooling to 4 degrees C may be harmful to the endothelial lining of veins which are prepared for grafting into the arterial system. Such cooling should therefore probably be avoided.

The effects of two different crystalloid cardioplegic solutions on cultured human endothelial cells.

The effects on cultured human endothelial cells of incubation with two standard crystalloid cardioplegic solutions (St. Thomas' and Bretschneider's) for one or five hours at 10 degrees C or 20 degrees C were studied. The cells were prelabelled with 51Cr and cell injury was measured by release of 51Cr, cell detachment, and by electron microscopy. The injury was also studied after a rewarming period of 35 minutes in cell culture medium at 37 degrees C. Endothelial cells incubated with cell culture medium, but otherwise treated in a similar way, served as controls. Both cardioplegic solutions caused significantly greater release of 51Cr than cell culture medium when incubated at 10 degrees C or 20 degrees C. The Bretschneider's solution induced slightly more release of 51Cr than did the St. Thomas' solution. The cells did not become detached during incubation. Electron microscopy of the cells after 5 hours with the cardioplegic solutions at 10 degrees C revealed contraction of the cells, mild intracellular oedema, swelling of mitochondria, and blebs or craters on the luminal surface of the cells. After rewarming in culture medium for 35 min the cells were not contracted and showed only minimal signs of injury, indicating a rapid and nearly complete reversibility of the changes. The present observations indicate that cultured endothelial cells get some protection, albeit not optimal, from the two crystalloid cardioplegic solutions tested. The presence of procaine-CL increased the injurious effect of the solutions.

Concepts of caring and caring as a concept.

If caring is to be retained as the "essence" of nursing, and if research in this area is to advance, then the various perspectives of caring must be clarified, the strengths and the limitations of these conceptualizations examined, and the applicability of caring as a concept and theory to the practice of nursing identified. Examination of the concept of caring resulted in the identification of five epistemological perspectives: caring as a human state, caring as a moral imperative or ideal, caring as an affect, caring as an interpersonal relationship, and caring as a nursing intervention. Two outcomes of caring were identified: caring as the subjective experience and as the physiologic responses in patients. The authors concluded that knowledge development related to caring in nursing is limited by the lack of refinement of caring theory, the lack of definitions of caring attributes, the neglect to examine caring from the dialectic perspective, and the focus of theorists and researchers on the nurse to the exclusion of the patient.

Dose-response relationships for traffic noise and annoyance.

The annoyance due to road traffic noise was studied in 18 areas in five countries. A total of 1379 interviews was performed and noise measurements were made in each area. The relation between Leq and the extent of the population expressing that they were "very annoyed" was poor (rxy = 0.03). An augmentation of the number of heavy vehicles from 1000/24 hr up to greater than 3000/24 hr did not increase the extent of annoyance. The highest correlation was obtained for the maximum noise level. The dose-response relationship implies that the number of events above a certain limit will not increase the extent of annoyance: it is determined by the highest noise level from single vehicles. It is suggested that this model for the human reaction to environmental noise, which has now been demonstrated for aircraft, train, and traffic noise, should be considered for the establishment of standards.

The comforting behaviors of caregivers toward distressed postoperative neonates.

The comforting behaviors of nurses caring for four postoperative neonates were examined by analyzing 40 hours of videotaped caregiving. Using the techniques of qualitative ethology, 30 periods of distress were identified. During these periods, 98 episodes of direct tactile and verbal comforting occurred. The types and patterns of comforting touch are delineated. Observations revealed that comforting occurs in response to infant cues, comfort touch had limited effect in settling the infants, infants were often distressed for long periods without being comforted, and the infants were handled as normal infants without regard for their incisions. Suggestions for further research are presented.

Increased growth rate of abdominal aortic aneurysms in women. The Tromsø study.

OBJECTIVES: The present study was undertaken in order to assess the effect of gender on the growth rate of abdominal aortic aneurysms (AAAs). METHODS: One hundred and eighty-five men and 49 women with AAAs were studied, mean follow-up 62 months, giving 14,544 patient-months of follow-up. A mean of 16 ultrasound examinations was performed on each patient. RESULTS: The mean growth rate was 1.82; 1.65 and 2.43 mm per year in men and women, respectively. In a weighted linear regression analysis, high initial diameter and female gender were independent and significant (p < 0.001 and p = 0.003, respectively) predictors for increased growth rate of AAAs. None of the other considered risk factors predicted the growth rate. CONCLUSIONS: This is the first study to report a significantly different growth rate of AAAs in females compared to males. It, thus, adds evidence to the view that AAA is a more malignant condition in females than in males and could have implications for the frequency of follow-up in women.

Anabolic steroids and Norwegian weightlifters.

The mean bodyweight, in kilograms, and mean weightlifting result, in points, for the ten best weightlifters at the annual Norwegian championships 1962-82 have been studied. During the 21 years, the mean bodyweight for these ten increased by 18 kg, probably due to the effect of androgens. The weightlifting results improved rapidly from 1968 onwards, probably reflecting an increasingly widespread use of anabolic steroids by Norwegian weightlifters. In 1977 doping tests were introduced, and from then on, rate of improvement has increased much more slowly. The annual sale of anabolic steroids 1963-81 and testosterone 1974-81, in Norway have been recorded. The sale of anabolic steroids increased irregularly until 1974-75, and has since shown a 42% decrease. The sale of testosterone 1974-81 showed a slight reduction, thus giving no support to the suggestion that doping tests for anabolic steroids would lead to a transfer to testosterone abuse.

[Curriculum vitae aortae]. / Curriculum vitae aortae.

The Greek word aorta means lifter. The vessel was so termed because Aristotle, who first described it, assumed that the heart was lifted by/hanging in aorta. Leonardo da Vinci described the detailed anatomy of aorta. During the 17th century our present understanding of the aorta and the circulation of blood took form due to the descriptions given by William Harvey. The first known operation for abdominal aortic aneurysm was performed in London in 1817 by Sir Astley Cooper who ligated the infrarenal aorta above the aneurysm. Puncture with needles and application of electricity were later tried in order to induce thromboses in the aneurysm. In 1948 Albert Einstein was operated with wrapping of his abdominal aneurysm with cellophane. In 1955 he suffered rupture and died after having refused operation. In 1951 the first successful operation for abdominal aortic aneurysm was performed in Paris by Charles Dubost. With slight modifications, the same operative technique is used today.

Differences in reactivity of confluent and nonconfluent cultures of human endothelial cells toward thrombin-stimulated platelets or heparinized salt solution.

This study examined whether nonconfluent endothelial cell cultures reacted differently than confluent ones toward thrombin-stimulated platelets or a heparinized salt solution. The adherence to the endothelial cell cultures of 51Cr-labeled human platelets stimulated at different thrombin concentrations was studied. There was significantly higher adherence of stimulated platelets to nonconfluent cultures compared with confluent ones. This was confirmed by scanning electron microscopy, which also revealed a tendency for the platelets to adhere at the cell periphery. Electron microscopy also showed that thrombin-stimulated platelets induced endothelial cell contraction. Part of the peripheral endothelial cell surface toward the bottom of the culture dish was inverted, facing the lumen of the dish. This phenomenon was particularly seen in nonconfluent cultures. When 51Cr-labeled endothelial cultures were incubated with a mildly injurious fluid as heparinized sodium acetate and 20% serum, at 20 degrees C for 30 min, the nonconfluent cultures showed significantly more cell detachment and release of 51Cr than the confluent ones. We conclude that under the conditions of the present experiments there are differences in the reactivity of confluent and nonconfluent endothelial cell cultures. These differences probably reflect biological dissimilarities. In experiments where properties of cultured endothelium are studied, care should be taken that the degree of confluency is standardized.