Effect of smoking cessation counseling within a randomised study on early detection of lung cancer in Germany.

INTRODUCTION: In the German lung cancer screening trial LUSI, smoking cessation counseling (SCC) was offered to all participants at time of randomization, and smoking habits were asked for within annual questionnaire inquiries. We analyzed the smoking habits of the participants within the first 2 years of follow-up and especially the potential effect of the SCC on these habits. MATERIALS AND METHODS: We used the smoking data of the initial inquiry on which the decision on invitation to the study was based, the socio-economic data of the questionnaire filled-in at time of randomization, the psycho-social data obtained during the SCC, and the annual questionnaire data of the first two annual follow-up screening rounds. RESULTS: Smoking prevalence decreased in the entire cohort significantly by 4 %, whereby the decrease was with 4.5 % statistically not significantly higher in the control arm than in the screening arm with 3.4 %. The decline was much stronger in the subgroup of attendees to stop-smoking counseling and mounted up therein to 10 %. In some participants, an increase of readiness to quit smoking was observed during the counseling hour, but did not show effects on smoking status 2 years later. DISCUSSION: We did not see a tendency to increased smoking among participants of the intervention arm or the entire study. The decline of smoking prevalence among the attendees of the counseling might be due to self-selection. Since the issue of effectiveness of smoking cessation counseling is important, further research with randomization into offering counseling or no intervention should be taken into consideration.

Randomized Study on Early Detection of Lung Cancer with MSCT in Germany: Results of the First 3 Years of Follow-up After Randomization.

INTRODUCTION: The German Lung Cancer Screening Intervention Trial (LUSI) is one of the European randomized trials investigating the efficacy of low-dose multislice computed tomography (MSCT) as a screening tool for lung cancer. In the evaluation of the first (prevalence) screening round, we observed exceptionally high early recall rates, which made the routine application of MSCT screening questionable. Because screening may behave differently in subsequent (incidence) screening rounds, we analyzed (a) basic characteristics for the annual rounds 2 to 4, which have now also been completed, and (b) the first 3 years with complete follow-up since time of randomization. METHODS: Data material was the data record of LUSI after the fourth screening round and the 3-year follow-up had been completed. Basic characteristics of screening, e.g., early recall rate, detection rate, and interval cancers as well of proportion of advanced cancers, were descriptively evaluated and, if informative, group differences were tested for statistical significance. RESULTS: Early recall rates were significantly lower in the subsequent screening rounds than in the first one if the MSCT information from the previous screening rounds was available. Detection and biopsy rates were approximately 1% or lower, ratio of benign:malignant biopsies: 1:1.6 to 1:3. CONCLUSION: Our recent data may not only settle one concern regarding high recall rates in routine MSCT screening but also indicate that screening must be strictly organized to be effective. Performance indicators are similar to those in mammography screening. Nevertheless, possible consequences for the participants (diagnostic workup of suspicious findings, biopsies) are more invasive than in mammography screening.

Randomized study on early detection of lung cancer with MSCT in Germany: study design and results of the first screening round.

PURPOSE: Low-dose multislice-CT (MSCT) detects many early-stage lung cancers with good prognosis, but whether it decreases lung cancer mortality and at which costs is yet insufficiently explored. Scope of the present study is to examine within a common European effort whether MSCT screening is capable to reduce the lung cancer mortality by at least 20 % and at which amount of undesired side effects this could be achieved. METHODS: Overall 4,052 heavy smoking men and women were recruited by a population-based approach and randomized into a screening arm with five annual MSCT screens and an initial quit-smoking counseling, and a control arm with initial quit-smoking counseling and five annual questionnaire inquiries. RESULTS: In the first screening round, 2,029 participants received a MSCT providing 1,488 negative and 540 suspicious screens with early recalls (early recall rate 26.6 %) leading to 31 biopsies (biopsy rate 1.5 %) and 22 confirmed lung cancers (detection rate 1.1 %). Among the lung cancers, 15 were adenocarcinomas, 3 squamous cell carcinomas, one small-cell lung cancer, and 3 others, whereby 18 were in clinical stage I, one in stage II, and 3 in stage III. One interval cancer occurred. CONCLUSIONS: The indicated performance indicators fit into the range observed in comparable trials. The study continues finalizing the second screening round and for the first participants even the last screening round. The unresolved issue of the precise amount of side effects and the high early recall rate precludes currently the recommendation of MSCT as screening tool for lung cancer.

Glycated and carbamylated albumin are more "nephrotoxic" than unmodified albumin in the amphibian kidney.

There is increasing evidence that proteins in tubular fluid are "nephrotoxic." In vivo it is difficult to study protein loading of tubular epithelial cells in isolation, i.e., without concomitant glomerular damage or changes of renal hemodynamics, etc. Recently, a unique amphibian model has been described which takes advantage of the special anatomy of the amphibian kidney in which a subset of nephrons drains the peritoneal cavity (open nephrons) so that intraperitoneal injection of protein selectively causes protein storage in and peritubular fibrosis around open but not around closed tubules. There is an ongoing debate as to what degree albumin per se is nephrotoxic and whether modification of albumin alters its nephrotoxicity. We tested the hypothesis that carbamylation and glycation render albumin more nephrotoxic compared with native albumin and alternative albumin modifications, e.g., lipid oxidation and lipid depletion. Preparations of native and modified albumin were injected into the axolotl peritoneum. The kidneys were retrieved after 10 days and studied by light microscopy as well as by immunohistochemistry [transforming growth factor (TGF)-ß, PDGF, NF-κB, collagen I and IV, RAGE], nonradioactive in situ hybridization, and Western blotting. Two investigators unaware of the animal groups evaluated and scored renal histology. Compared with unmodified albumin, glycated and carbamylated albumin caused more pronounced protein storage. After no more than 10 days, selective peritubular fibrosis was seen around nephrons draining the peritoneal cavity (open nephrons), but not around closed nephrons. Additionally, more intense expression of RAGE, NF-κB, as well as PDGF, TGF-ß, EGF, ET-1, and others was noted by histochemistry and confirmed by RT-PCR for fibronectin and TGF-ß as well as nonradioactive in situ hybridization for TGF-ß and fibronectin. The data indicate that carbamylation and glycation increase the capacity of albumin to cause tubular cell damage and peritubular fibrosis.

Treatment of an asymptomatic penetrating aortic ulcer in a young patient.

We want to report and discuss the indication for open surgery for an asymptomatic penetrating aortic ulcer (PAU) in the era of thoracic endovascular aortic repair (TEVAR). A 31-year-old female presented with the diagnosis of an aneurysm in the distal aortic arch. With respect to the patients young age, the controversial status of connective tissue disorders and in the absence of concomitant disease, open repair was indicated. There was no proof of a mycotic plaque or connective tissue disease in the microbiological-, pathological analysis and at electron-microscopy. The patient was discharged on the thirteenth postoperative day. In spite of good preliminary results of TEVAR in PAU, in selective cases there is still an indication for open surgery.

Renal toxicity mediated by glucose degradation products in a rat model of advanced renal failure.

BACKGROUND: In peritoneal dialysis (PD) residual renal function contributes to improved patient survival and quality of life. Glucose degradation products (GDP) generated by heat sterilization of PD fluids do not only impair the peritoneal membrane, but also appear in the systemic circulation with the potential for organ toxicity. Here we show that in a rat model of advanced renal failure, GDP affect the structure and function of the remnant kidney. MATERIALS AND METHODS: Sprague-Dawley rats were randomly assigned to a two stage subtotal nephrectomy (SNX) or sham operation and were left untreated for 3 weeks. The SNX + GDP group continuously received chemically defined GDP intravenously for 4 weeks; the SNX and the sham-operated rats remained without GDP. The complete follow-up for all groups was 7 weeks postoperatively. We analysed renal damage using urinary albumin excretion as well as a semiquantitative score for glomerulosclerosis and tubulointerstitial damage, as well as for immunohistochemical analyses. RESULTS: The SNX + GDP rats developed significantly more albuminuria and showed a significantly higher score of glomerulosclerosis index (GSI) and tubulointerstitial damage index (TII) as compared to SNX or control rats. In the SNX + GDP group the expression of carboxymethyllysine and methylglyoxal was significantly higher in the tubulointerstitium and the glomeruli compared to the SNX rats. Caspase 3 staining and TUNEL assay were more pronounced in the tubulointerstitium and the glomeruli of the SNX + GDP group. In SNX + GDP animals, the expression of the slit diaphragm protein nephrin, was significantly lower compared to SNX or control animals. CONCLUSION: In summary, our data suggests that GDP can significantly advance chronic kidney disease and argues that PD solutions containing high GDP might deteriorate residual renal function in PD.

Immune-compromised state in the rat pancreas after chronic alcohol exposure: the role of peroxisome proliferator-activated receptor gamma.

Alcohol exposure is known to sensitize acinar cells to various insults but the pathophysiological mechanisms of alcoholic pancreatitis remain unknown. Alcohol abuse has been shown to mediate an anti-inflammatory response and periods of immune suppression seem to be associated with organ injury and mortality. The purpose of this study was to determine the mechanisms by which alcohol exerts transcriptional activities in the rat pancreas and how alcohol alters the inflammatory response. Using the Lieber-DeCarli alcohol/control diet, rats that were fed with alcohol over 14 weeks demonstrated a decrease of inflammatory cells in pancreatic tissue compared to controls. The anti-inflammatory effects of alcohol were confirmed by decreased expression of pro-inflammatory cytokines including TNFalpha, IL-1beta, IL-18, TGFbeta, and MCP-1. In addition, alcohol significantly increased the activity of PPARgamma, which is a known anti-inflammatory transcription factor, while pro-inflammatory factors including AP-2 and EGR-1 were significantly suppressed. NFkappaB binding showed a tendency towards a reduction. Electron microscopy studies revealed enlarged and injured mitochondria and lysosomes, accompanied by peri-cellular fibrosis. Furthermore, alcohol exposure increased the activities of trypsin and cathepsin B, both known to be critical in initiating acinar cell injury and pancreatitis. Despite the known alcohol-mediated acinar cell and mitochondrial injury, the mitochondrial-mediated apoptotic pathway was attenuated. These data demonstrate that the pancreas exposed to alcohol maintains an anti-inflammatory state by activating PPARgamma. Intracellular mitochondrial and lysosomal damage after chronic alcohol exposure induces premature activation of digestive enzymes and establishment of peri-cellular fibrosis in the absence of inflammation.

An unusual cause of peripheral artery embolism: floating thrombus of the thoracic aorta surgically removed.

Intraluminal mobile thrombus of the descending aorta are rare disorders. They are at high risk for peripheral embolism and therefore indication for treatment is mandatory. We report on a 54-year-old patient with peripheral arterial embolization who was treated by surgical thrombus removement by thoracotomy and staged peripheral bypass grafting. New diagnostic tools are presented, therapy and prognosis are discussed.

Growth hormone treatment prevents osteoporosis in uremic rats.

INTRODUCTION: Growth hormone (GH) is responsible for longitudinal bone growth. GH-receptor in the growth plate was found to be decreased in chronic renal insufficiency. A therapeutic use of GH in chronic renal insufficiency is not established. The current study aims to clarify the effects of GH treatment on bone metabolism in a uremic rat model. METHODS: Sprague Dawley rats were subjected to subtotal surgical renal ablation (SNX) or sham operation. SNX rats were randomized into 4 groups: treated with different doses of GH (1.5, 4.0, or 10.0 mg/kg) or vehicle after 10 weeks of uremia and treated for 6 weeks. Bone and renal morphology was evaluated: bone density, thickness of spongiosa, osteoblast surface, osteoid volume, osteoclast quantity, and resorptive volume. RESULTS: GH treatment resulted in a decrease of resorption area and lower number of osteoclasts. Osteoid volume, number of osteoblasts, percentage of active osteoblasts, thickness of the growth plate and mean cortical width increased. GH receptor (GHR) protein expression increased in GH treated rats. IGF-1 expression was decreased in osteoblasts and chondroblasts of SNX-V rats and increased following GH treatment. The TGF-beta expression was down regulated in SNX+V group in osteocytes and chondroblasts as compared to sham operated animals. The down regulation was prevented in treated animals irrespective of the dose given. CONCLUSIONS: Treatment with GH in uremic animals increased bone density to the levels of non-uremic controls. Thus GH seems to have a potential of preventing renal osteodystrophy.

[Primary metastatic renal metastatic carcinoid tumor in a young male patient: a contribution to the differential diagnosis of neuroendocrine tumors]. / Primärer renaler Karzinoidtumor mit ausgedehnter lymphogener und hämatogener Metastasierung. Ein Beitrag zur Differenzialdiagnose neuroendokriner Tumoren.

Primary renal carcinoid tumors originating in normal kidney are extremely rare. We report a case of primary renal carcinoid tumor with an aggressive clinical course and multiple metastases in the paraaortal lymph nodes and the liver as well as a pulmonary metastasis, in a 30-year-old patient. A CT scan of the abdomen revealed a large mass in the right kidney and multiple tumor suspect areas in the liver and paraaortal lymph nodes. The patient did not have clinical manifestations of carcinoid syndrome. Histologically, the tumor was composed of trabecular, solid or anastomosing ribbon-like nests, identical to the features of neuroendocrine tumors from other locations. Immunohistochemical staining was positive for cytokeratin, neurospecific enolase, and chromogranin. Electron microscopically, tonofibrils, primitive desmosomes, and dense-core granules with a neuroendocrine appearance were present. The pathological features of this case are briefly reviewed in comparison with those of previously reportet in terms of certain clinical aspects, prognostic factors and the WHO-classification (2004) of this rare neoplasia.

Renal failure and ACE inhibition: how much is too much?

The dose-response relationship between pharmacological blockade of the renin-angiotensin system (RAS) and angiotensin II concentration in the circulation, on the one hand, and decrease of blood pressure, on the other hand, has been well established. In contrast it is currently unclear which dose of ACE inhibitors and/or angiotensin receptor blockers is optimal for nephroprotection. Clinical studies are rendered quite complex by an early decrease of glomerular filtration after RAS blockade and by side effects at higher doses such as renal sodium loss, hyperkalemia, anemia, etc. Animal experiments and recent clinical studies suggest that the doses of ACE inhibitors or angiotensin receptor blockers required for maximal reduction of proteinuria (as a surrogate marker) and for optimal nephroprotection (retardation of the loss of glomerular filtration) exceed those required for maximal lowering of blood pressure. Ongoing studies try to define the relative merits of high dose monotherapy (ACE inhibitors or angiotensin receptor blockers) versus a combination therapy of the two.

Treating competent patients by force: the limits and lessons of Israel's Patient's Rights Act.

Competent patients who refuse life saving medical treatment present a dilemma for healthcare professionals. On one hand, respect for autonomy and liberty demand that physicians respect a patient's decision to refuse treatment. However, it is often apparent that such patients are not fully competent. They may not adequately comprehend the benefits of medical care, be overly anxious about pain, or discount the value of their future state of health. Although most bioethicists are convinced that partial autonomy or marginal competence of this kind demands the same respect as full autonomy, Israeli legislators created a mechanism to allow ethics committees to override patients' informed refusal and treat them against their will. To do so, three conditions must be satisfied: physicians must make every effort to ensure the patient understands the risks of non-treatment, the treatment physicians propose must offer a realistic chance of significant improvement, and there are reasonable expectations that the patient will consent retroactively. Although not all of these conditions are equally cogent, they offer a way forward to assure care for certain classes of competent patients without abandoning the principle of autonomy altogether. These concerns reach past Israel and should engage healthcare professionals wary that respect for autonomy may sometimes cause avoidable harm.

Comparison of renal morphology in the Streptozotocin and the SHR/N-cp models of diabetes.

The Streptozotocin (STZ) model of diabetes is commonly used for studies of diabetic nephropathy although the histological lesions of the kidney are mild and do not resemble those seen in diabetic patients. The SHR/N-cp rat model of type II diabetes spontaneously develops pronounced abnormalities in renal histology. In the present study, we compared renal morphology in the STZ rat and the diabetic SHR/N-cp rat. Sprague-Dawley rats received STZ, developed diabetes after 2 days and were treated with insulin. In the SHR/N-cp rat, obesity is inherited as an autosomal recessive trait. The progeny are either lean (used as controls) or obese and diabetic. After 6 months of observation, STZ and SHR/N-cp rats were killed. The renal damage was evaluated by assessing damage indices and by using stereological techniques. In addition, immunohistochemistry and electron microscopy were performed. The glomerular and tubulointerstitial changes were much more pronounced in the diabetic SHR/N-cp compared to the STZ model. In parallel glomerular PCNA+cells were significantly more frequent and expression of TGF-beta and PDGF by immunohistochemistry in glomeruli and in the tubulointerstitial space was more pronounced in SHR/N-cp compared to STZ rats. The glomeruli of SHR/N-cp contained less and larger podocytes as well as smaller mesangial cells embedded in more mesangial matrix compared to STZ. Similarly, less, but larger endothelial cells were found in SHR/N-cp than in STZ rats. The mean glomerular volume was similarly increased in the two models. Albumin excretion was only modestly increased in STZ diabetes, but pronounced in the SHR/N-cp rat. Although the STZ model of diabetes exhibits numerous biochemical sequelae of hyperglycemia, the morphological lesions are unimpressive. In contrast, the diabetic SHR/N-cp exhibits marked structural lesions, particularly podocyte damage and mesangial expansion that promise to make it a more suitable model for investigation of diabetic glomerulosclerosis.

ACE-inhibition is superior to endothelin A receptor blockade in preventing abnormal capillary supply and fibrosis of the heart in experimental diabetes.

AIMS/HYPOTHESIS: There is little information whether cardiac capillary supply is deranged in diabetes. Hyperglycaemia is a potent stimulus for endothelin-1 (ET-1) production. We therefore hypothesised that increased ET-1 production in Streptozotocin-induced Type 1 diabetes causes abnormalities of cardiac capillaries and the aorta. To this end we compared the effects of an ET receptor A blocker (ETA-RB) with that of an ACE-inhibitor (ACE-i) or their combination in rats with Streptozotocin (STZ) diabetes. METHODS: Sprague Dawley rats were injected with 65 mg STZ i.v. and subsequently developed diabetes. Rats were left untreated or received daily either the ACE-i Trandolapril, the ETA-RB Darusentan or a combination of both. After 6 months the experiment was terminated and the heart and the aorta were investigated using quantitative morphological techniques. RESULTS: ACE-i but not ETA-RB lowered blood pressure in STZ Type 1 diabetic rats. Capillary length density was lower in untreated STZ diabetic rats (2932+/-128 mm/mm3) compared to non-diabetic control rats (3410+/-252 mm/mm3). Treatment with ACE-i (3568+/-431 mm/mm3), but not with ETA-RB (2893+/-192 mm/mm3), prevented the decrease in capillary supply. Volume density of the myocardial interstitium was higher in untreated STZ diabetic rats (0.86+/-0.04%) compared to non-diabetic control rats (0.36+/-0.06%). In all three intervention groups the values were lower (ACE-i: 0.53+/-0.05%, ETA-RB: 0.7+/-0.08% and combination: 0.69+/-0.1). CONCLUSION/INTERPRETATION: Our study identifies a capillary defect of the heart in STZ diabetes, i.e. decreased capillary supply. This abnormality was reversed by ACE-i, but not by ETA-R blockade. A similar trend, although not complete normalisation, was seen in cardiac fibrosis.

Special characteristics of atherosclerosis in chronic renal failure.

Cardiovascular complications are a major clinical problem in patients with chronic kidney disease and end stage renal failure. Death from cardiac causes accounts for 40%-50% of all deaths in these patients and is thus up to 20 times more common in uremic patients than in the general population. Cardiovascular pathology in patients with renal failure is complex, but accelerated atherosclerosis has repeatedly been discussed as one major cause. The prevalence of coronary atheroma in uremic patients is approximately 30% by autopsy and coronary angiography studies. Not only is the prevalence of atherosclerotic lesions very high, but also the case fatality rate of myocardial infarction. Recently, excess mortality in uremic patients having had a myocardial infarct was noted; the one year mortality was 55.4% and 62.3% in uremic patients with and without diabetes, respectively, compared to about 10-15% in non-uremic patients. This study goes beyond the well-known notion that urea is associated with more severe atherosclerosis and shows that, in addition, the adaptation to coronary perfusion deficits is inappropriate. Recent clinical and autoptical studies in pre-dialysis and dialysis cohorts have documented increased intima and media thickness which appear early in the course of renal disease; Vascular wall thickening in renal failure seems to be modified at least in part by parathyroidhormone (PTH) and endothelin-1 (ET-1) which are both elevated in patients with renal failure. In experimental renal failure a direct effect of high phosphorus diet in arterial wall thickening was also documented. In addition to thickening of the vascular wall marked structural alterations were noted in renal failure i.e. a decrease in elastic fibre content and an increase in extracellular matrix. Furthermore, increased calcification of coronary atherosclerotic plaques and of the media of the aorta and some peripheral arteries has been documented in patients with renal failure. Factors contributing to this increased calcification process may be deposition of abundant circulating calcium, microinflammation, oxidative stress, de novo expression of bone morphogenous proteins and lack of inhibitors of calcifcation. These changes in vascular wall composition may alter vessel elasticity and thus contribute to impaired vessel function in renal failure. It is obvious from the above mentioned facts that cardiovascular disease in the renal patient is certainly multifaetorial in origin. There are, however, important issues to adress in the future, like (I) the characterization of vascular morphology in the different vascular beds, (II) the pathomechanisms of vascular and plaque calcification as well as the potential beneficial effect of rigorous control of non-classical risk factors (i.e. high P or Ca x P, inflammation, oxidative stress, etc.), (III) an additive or supraadditive effect of various classical and non-classical risk factors and (IV) the role of diabetes mellitus in modifying these vascular alterations.

ACE-inhibitors but not endothelin receptor blockers prevent podocyte loss in early diabetic nephropathy.

AIMS/HYPOTHESIS: It was the aim of our study to investigate the influence of a selective ET-A receptor antagonist LU 135252 alone and in combination with the ACE-inhibitor, trandolapril on podocyte number and morphology in streptozotocin diabetic rats. METHODS: Male Sprague-Dawley rats were injected with 65 mg streptozotocin i.v. and subsequently developed diabetes. Animals were left untreated or received daily either trandolapril (0.3 mg/kg body weight), LU 135252 (50 mg/kg body weight) or a combination of both. After 6 months the experiment was terminated. Glomerular geometry and cellularity were assessed by stereological techniques. Protein expression of TGF-beta, ET-1, PDGF-AB, fibronectin, desmin and alpha-smooth muscle cell actin was investigated by immunohistochemistry. RESULTS: The mean number of podocytes per glomerulus was lower (86+/-17 vs. 138+/-25; p<0.05) and mean podocyte volume was higher in untreated diabetic animals than in non-diabetic controls. Only ACE-i alone and in combination, but not ET(A)-RB alone prevented loss of podocytes and podocyte hypertrophy. In diabetic rats, increased numbers of PCNA positive and p27(kip1) positive cells (mainly podocytes) were reduced by all treatments, but only ACE-i decreased numbers of desmin positive podocytes and tubulointerstitial expression of TGF-beta. Albuminuria was increased in untreated diabetes and was prevented only by ACE-i and combination treatment. CONCLUSION/INTERPRETATION: Podocyte hypertrophy and degeneration is an early event in diabetic nephropathy leading to a loss of podocytes. Treatment with an ACE-i, but not with an ET(A)-RB, prevented the development of albuminuria as well as damage and loss of podocytes. The well known anti-proteinuric effect of ACE-i is presumably due at least in part to conservation of podocyte structure. Increased plasma endothelin-1 (ET-1) concentrations and urine excretion of ET-1 have been documented in patients with diabetes and proteinuria [1]. It has been shown that experimental diabetes mellitus increases renal ET-1 gene transcription [2]. To assess the relevance of the ET-system in the pathogenesis of renal structural changes in the model of the STZ-induced diabetic rat we compared the effect of an ET(A)-receptor specific antagonist with the well known beneficial effect of an ACE-i, especially on podocyte cell number and morphology.

Anorectal functional disorders in the absence of anorectal inflammation in patients with Crohn's disease.

BACKGROUND: Histological alterations in the enteric nervous system (ENS) have been described in patients suffering from Crohn's disease (CD). The aim of this study was to investigate whether patients with CD without rectal inflammation have abnormal anorectal function compared with healthy volunteers. METHODS: Fifty-four patients with CD and 26 healthy volunteers were examined by anorectal manometry and answered a standardized questionnaire. No patient had active CD in the rectum as determined by endoscopy. RESULTS: Maximum anal resting and squeeze pressures did not differ between patients and healthy volunteers. The rectoanal inhibitory reflex was absent in 24 of 54 patients and two of 26 healthy volunteers (P < 0.05). The first sensation to distension of the rectal balloon was reported at mean(s.e.m.) 57.9(4.4) ml by patients and 37.5(2.2) ml by healthy volunteers (P < 0.01). The standardized interview revealed additional disorders of anorectal function in patients with CD. CONCLUSION: Anorectal function appears to be altered in many patients with CD even in the absence of macroscopic anorectal disease. This may be due to a disorder of the ENS.

Medical ethics education: to what ends?

The goals of medical ethics education comprise several dimensions: legal duties to secure informed consent, tell the truth and protect confidentiality; objective competencies that include an understanding of DNR regulations and surrogate decision-making procedures; discursive moral skills such as moral sensitivity, reciprocity and moral development that combine into the capacity for moral dialogue and debate; and finally, behavioural goals that challenge moral education to nurture a more humane, sensitive and communicative physician. Part one of this paper describes each of these goals, together with some of the inherent difficulties affecting implementation. Part two presents survey data from medical ethics instructors (n = 126) who were asked about the importance of each goal and their ability to successfully achieve each aim. While each goal is highly rated, only those goals associated with legal duties and objective competencies are thought to be achieved with any degree of relative success. Goals associated with character transformation, unique to medical ethics education, are among the most difficult to achieve. Additional empirical data corroborate these impressions. Moreover, it is not clear that medical ethics education has much to do with good care. Empirical data are scarce and the conceptual relationship between ethics and care remains highly problematic. Part three offers a number of divergent interpretations of care and concludes that they have little to do with medical ethics. There is no reason to expect that medical competence should be affected by moral competence. Medical ethics therefore might then be viewed as an educational enhancement: unnecessary for healthy doctoring but desirable among a small percentage of the profession who maintain an interest in ethical problems.

Evidence that a burst of DNA depurination in SENCAR mouse skin induces error-prone repair and forms mutations in the H-ras gene.

Treatment of SENCAR mouse skin with dibenzo[a,l]pyrene results in abundant formation of abasic sites that undergo error-prone excision repair, forming oncogenic H-ras mutations in the early preneoplastic period. To examine whether the abundance of abasic sites causes repair infidelity, we treated SENCAR mouse skin with estradiol-3,4-quinone (E(2)-3,4-Q) and determined adduct levels 1 h after treatment, as well as mutation spectra in the H-ras gene between 6 h and 3 days after treatment. E(2)-3,4-Q formed predominantly (> or =99%) the rapidly-depurinating 4-hydroxy estradiol (4-OHE(2))-1-N3Ade adduct and the slower-depurinating 4-OHE(2)-1-N7Gua adduct. Between 6 h and 3 days, E(2)-3,4-Q induced abundant A to G mutations in H-ras DNA, frequently in the context of a 3'-G residue. Using a T.G-DNA glycosylase (TDG)-PCR assay, we determined that the early A to G mutations (6 and 12 h) were in the form of G.T heteroduplexes, suggesting misrepair at A-specific depurination sites. Since G-specific mutations were infrequent in the spectra, it appears that the slow rate of depurination of the N7Gua adducts during active repair may not generate a threshold level of G-specific abasic sites to affect repair fidelity. These results also suggest that E(2)-3,4-Q, a suspected endogenous carcinogen, is a genotoxic compound and could cause mutations.

Fragmentation of photomodified oligodeoxynucleotides adducted with metal ions in an electrospray-ionization ion-trap mass spectrometer.

We report the effect of metal-ion adduction on the fragmentation of oligodeoxynucleotides (ODNs) bearing DNA photoproducts. When protons on backbone phosphates of ODNs are completely replaced with metal ions, cleavages occur readily within the photoproduct moiety, whereas those cleavages do not occur in photomodified ODNs in which the phosphates are associated with protons. For example, thymine/adenine (TA*) photoproducts revert to their undamaged precursors upon collisional activation, the pyrimidine(6-4)pyrimidone product and its Dewar valence isomer show a characteristic neutral loss of C4H3NO3, and dimeric adenine photoproducts show a distinctive loss of NH2CN from the adenine six-membered ring. The product-ion mass spectra of photodamaged ODNs that are adducted to metal ions are complementary in terms of structure information to those spectra of ODNs in which the phosphates are associated with protons. The results also demonstrate that the energy required for strand cleavages is higher for ODNs adducted with metal ions than that for ODNs bound with protons. Furthermore, the loss of a pyrimidine is more favorable than the loss of a purine in the fragmentation of ODNs associated with metal ions.