DNA flow-cytometric analysis in colorectal cancer: A comparison of metastasizing and non-metastasizing tumours

The most common cause of death in patients with colorectal cancer is metastatic liver disease. In order to identify patients at a high risk of developing hepatic secondaries from colorectal cancers, DNA content was measured in metastasizing colorectal primaries (Group I, n= 32) as well as in their subsequently resected liver secondaries and in sections of non-metastasizing colorectal cancers (Group II, n= 25). A modified interpretation system involving both a DNA index and percentage of cycling cells (those in S and G2 + M phases) was developed. DNA content was measured in paraffin-embedded sections by flow cytometry using internal controls (human peripheral blood mononuclear cells) and non-malignant tissue controls (19 patients with diverticular disease). In Group I there were significantly more tumours with both abnormal ploidy (aneuploid or abnormal tetraploid peak) and > 15% cycling cells compared with Group II (Chi-squared; P= 0.034). The combination of abnormal ploidy and > 15% cycling cells was superior to Dukes’ classification for identifying metastasizing tumours (Logistic Regression; P= 0.047). However, it was not possible to discriminate between the two groups using either DNA ploidy or the percentage of cycling cells alone. The metastasizing colorectal cancers exhibited similar DNA ploidy characteristics and had a similar percentage of cycling cells compared with their liver metastases. These results suggest that tumour DNA ploidy plus the percentage of cycling cells may predict the development of liver metastases and thus survival in patients with colorectal cancer.     

Hepatic Uptake and Metabolism of 2,3,7,8-Tetrachlorodibenzo-p-dioxin and 2,3,7,8-Tetrachlorodibenzofuran

The pharmacokinetics of TCDD and related compounds is congener,dose, and species specific, with urinary and biliary excretionbeing dependent on the metabolism of these compounds. Isolatedhepatocytes and liver slices in suspension culture and hepaticmicrosomes were used as in vitro models to assess the hepaticuptake and metabolism of [³H]- and [¹⁴C]- TCDD and [³H]TCDF(0.01–1.0 µM) in control and induced (5 µgTCDD/kg, 3 days earlier) male Sprague-Dawley rats. TCDD pretreatment,with an increase in cytochromes P450 1A1 and 1A2 (CYP1 Al, CYP1A2),produced an increase in the hepatic uptake of TCDD, while noincrease in the hepatic uptake of TCDF was observed. The resultsare consistent with CYP1A2 serving as a hepatic binding proteinfor TCDD but not for TCDF. The rates of metabolism of TCDD andTCDF were directly proportional to their concentrations, indicatingthat the reaction follows first order kinetics at concentrationsfrom 0.01 to 1.0 µM. Very limited metabolism of TCDD andTCDF was observed in control rat liver (0.45 and 3.2 pmol/hr/ghepatocyte wet wt at 0.1 µm, respectively). TCDD inducedits own rate of metabolism about two- to fivefold at 1.0 µMbut no induction was observed at 0.01 and 0.1 µM. In contrast,TCDD markedly induced the rate of TCDF metabolism at all substrateconcentrations. While the results support the role of rat CYP1A1in TCDF metabolism, the data suggest that CYP1 Al or CYP1A2may not metabolize TCDD. These results also support the hypothesisthat the more rapid metabolism and excretion of TCDF accountsfor the relative resistance of the rat to the acute toxicityof TCDF. Comparative studies in rat and human liver microsomesfound that TCDF metabolism exhibited first order kinetics inboth species. Furthermore, the rate of TCDF metabo-lism in humanliver microsomes was similar to that of control rat liver microsomes.Together the results suggest that TCDF will be far more persistentin rats, and possibly humans, following exposure at low doseswhich do not significantly induce cytochrome P450 1A1 and/or1A2.     

Sensory Responses to Fat are Not Affected by Varying Dietary Energy Intake From Fat and Saturated Fat Over Ranges Common in the American Diet

Objective To examine the effects of manipulating dietary fat in foods on sensitivity and hedonic response to fat in selected foods.Design Twenty subjects were randomly assigned to a sequence of three 8-week experimental diets (average American diet, step 1 diet, low-saturated-fat diet) that varied in energy from fat (37%, 30%, and 26%, respectively) and saturated fat (17%, 10%, and 6%, respectively). Subjects participated in sensory tests designed to assess their sensitivity to and liking for fat in several foods, before the study (baseline), after consumption of each diet, and after the study (washout).Subjects/setting Subjects were participants in the Dietary Effects on Lipoprotein and Thrombogenic Activity (DELTA) study.Results No significant differences were found among diets for difference thresholds (ie, just noticeable differences) for fat in milk and pudding, ad libitum mixing of low- and high-fat samples of milk and soup, and hedonic scaling of fat concentrations in milk and muffins and of cheese, mayonnaise, hot dog, and pastry samples.Applications/conclusions Within the dietary fat ranges and for the fat stimuli tested in this study, dietary fat as percentage of energy from fat and saturated fat was not a significant determinant of sensitivity to and/or liking for fat. Sensory factors should not be a barrier to the implementation of low-fat diets such as the step 1 and low-saturated-fat diets. J Am Diet Assoc. 1999;99:690–696.     

The Translocation of Inhaled Silicon Dioxide: An Empirically Derived Compartmental Model

The Translocation of Inhaled Silicon Dioxide: An EmpiricallyDerived Compartmental Model. VACEK, P. M., HEMENWAY, D. R.,ABSHER, M. P., AND GOODWIN, G. D. (1991). Fundam. Appl Toxicol.17, 614–626. The movement of inhaled silicon dioxide particleswas studied by measuring the amounts in alveolar fluid and cells,lung tissue, and lymphoid tissue during the 6 months followingshort-term aerosol exposure of Fischer 344 rats. A variety offirst-order compartmental models were fit to data from nineexposure experiments to identify the most feasible biologicpathways for the transfer of material among these sites andout of the body. A multivariate least-squares approach was usedto simultaneously fit the data from several compartments. Theresults indicate that transfer between alveolar cells and lungtissue occurs in both directions, suggesting that silica canreenter the alveolar space from the lung tissue. This featurehas not been included in previously published models. The resultsalso indicate that transfer from lung tissue to the mediastinallymph nodes and thymus is indirect; there are one or more unidentifiedextrapulmonary compartments that receive silica from the lung.Rates of transfer among compartments were dependent on mineraltype (quartz or cristobalite), heat treatment, and exposuredose. There was no evidence for direct clearance from the alveolarspace via the tracheobronchial tract.     

Postoperative Heart Block in Children with Common Forms of Congenital Heart Disease: Results from the KID Database

Postoperative Heart Block in Congenital Heart Disease. Introduction: Cardiac conduction system injury is a cause of postoperative cardiac morbidity following repair of congenital heart disease (CHD). The national occurrence of postoperative complete heart block (CHB) following surgical repair of CHD is unknown. We sought to describe the occurrence of and costs related to postoperative CHB following surgical repair of common forms of CHD using a large national database. Methods and Results: Retrospective, observational analysis performed over a 10‐year period (2000–2009) using the Kids’ Inpatient Database (KID). Visits for patients ≤24 months of age were identified who underwent surgical repair of ventricular septal defects (VSD), atrioventricular canal defects (AVC), and tetralogy of Fallot (TOF). Patients were identified who were diagnosed with postoperative CHB, further identifying those requiring a new pacemaker placement during the same hospitalization. Costs associated with visits were calculated. There were 16,105 surgical visits: 7,146 VSD, 3,480 AVC, and 5,480 TOF. There was a decrease in postoperative mortality (P = 0.0001) with no significant change in postoperative CHB. Hospital stay and cost were higher with CHB and placement of a permanent pacemaker. Repair of AVC (OR 1.77; [1.32–2.38]) was associated with a higher rate of postoperative CHB. Length of hospital stay and total cost were significantly increased with the development of postoperative CHB and increased further with placement of a permanent pacemaker. Conclusion: There has been little change over time in the frequency of postoperative CHB in patients undergoing repair of VSD, AVC, and TOF. Postoperative CHB results in major added cost to the healthcare system. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1349‐1354, December 2012)     

Long‐Term Care Financing: Lessons From France

Context

An aging population leads to a growing demand for long-term services and supports (LTSS). In 2002, France introduced universal, income-adjusted, public long-term care coverage for adults 60 and older, whereas the United States funds means-tested benefits only. Both countries have private long-term care insurance (LTCI) markets: American policies create alternatives to out-of-pocket spending and protect purchasers from relying on Medicaid. Sales, however, have stagnated, and the market''s viability is uncertain. In France, private LTCI supplements public coverage, and sales are growing, although its potential to alleviate the long-term care financing problem is unclear. We explore whether France''s very different approach to structuring public and private financing for long-term care could inform the United States’ long-term care financing reform efforts.

Methods

We consulted insurance experts and conducted a detailed review of public reports, academic studies, and other documents to understand the public and private LTCI systems in France, their advantages and disadvantages, and the factors affecting their development.

Findings

France provides universal public coverage for paid assistance with functional dependency for people 60 and older. Benefits are steeply income adjusted and amounts are low. Nevertheless, expenditures have exceeded projections, burdening local governments. Private supplemental insurance covers 11% of French, mostly middle-income adults (versus 3% of Americans 18 and older). Whether policyholders will maintain employer-sponsored coverage after retirement is not known. The government''s interest in pursuing an explicit public/private partnership has waned under President François Hollande, a centrist socialist, in contrast to the previous center-right leader, President Nicolas Sarkozy, thereby reducing the prospects of a coordinated public/private strategy.

Conclusions

American private insurers are showing increasing interest in long-term care financing approaches that combine public and private elements. The French example shows how a simple, cheap, cash-based product can gain traction among middle-income individuals when offered by employers and combined with a steeply income-adjusted universal public program. The adequacy of such coverage, however, is a concern.     

The effect of hypotonicity on the mean platelet volume of patients with thrombo-embolism

Summary When dipotassium EDTA anticoagulated platelet rich plasma was incubated against a range of hypotonic saline concentrations, platelet volume was seen to change in a particular and rcproducible fashion. When platelets taken from patients suffering a thromboembolic episode were tested in the same manner, a different pattern of response was observed the platelets being far less tolerant to osmotic stress. Similar changes occurred in platelets from ante-natal subjects. Platelets from both groups regained their tolerance to hypotonicity following either the thromboembolic incident or parturition respectively.     

THE NATURE OF ARTHRITIS PAIN

A modified version of the McGill Pain Questionnaire in visualanalogue format was used to evaluate the sensory, affectiveand evaluative intensities of pain experienced by 40 patientswith rheumatoid arthritis and 20 patients with degenerativearthritis. The affective component of the pain was found tobe more intense than the sensory component in all patients indicatingthe importance of emotional factors in the pain experience.The sensory aspects of the pain were more complex than the affectiveones reflecting the varied sources and combinations of somaticpathology. There were no significant differences found in theoverall pain experience between rheumatoid and degenerativearthritis. No differences were noted in the evaluative categoryof pain. Overall pain intensity increased with disease durationin both rheumatoid and degenerative arthritis. The relationshipof affective and sensory components of the pain experience didnot alter with duration of disease. KEY WORDS: Arthritis, Pain     

Image Integration Using Intracardiac Ultrasound and 3D Reconstruction for Scar Mapping and Ablation of Ventricular Tachycardia

Background: Ablation of ventricular tachycardia (VT) reduces implantable cardioverter defibrillator shocks. Intracardiac ultrasound (ICE) can visualize and quantify the function of all left ventricular wall segments. We thus hypothesized that ICE could identify scar tissue and provide a guide to facilitate substrate‐guided VT ablation. Methods: Eighteen patients underwent VT ablation with real time ICE mapping from the right atrium and ventricle with online 3D‐image reconstruction of scar segments. The left ventricle was also scar mapped by traditional electroanatomic mapping (CARTO) for comparison. Images from these 2 scar mapping techniques were compared to each other as well as to a preprocedure transthoracic echocardiogram. Results: The average age was 65 ± 12 years and 12 (67%) were male (15 [83%] had ischemic cardiomyopathy). Two patients (12%) had recurrence of their clinical VT (1 remained on an antiarrhythmic medication, the other had a repeat ablation) over a follow‐up of 127 ± 33 days. No periprocedural or long‐term adverse events occurred. A total of 248 wall segments were analyzed. All 3 modalities were concordant in scar identification in 193 (78%) segments. The ICE segments correlated with the electroanatomic map in 213 (86%) segments versus 198 (80%), which correlated with transthoracic echocardiography and electroanatomic mapping (P = 0.046). Specifically, the ICE wall motion scores were closer to the electroanatomic mapping in the basal segments and showed a higher accuracy in ischemic heart disease. Conclusion: These data demonstrate that real time ICE images provide accurate chamber geometries and scar boundaries of the left ventricle. These scar borders were more accurate than transthoracic echocardiography and illustrate the feasibility of ICE for substrate‐based ablation for VT. (J Cardiovasc Electrophysiol, Vol. 21, pp. 678‐684, June 2010)