Normal colorectal mucosa exhibits sex- and segment-specific susceptibility to DNA methylation at the hMLH1 and MGMT promoters.

Silencing of gene expression by aberrant cytosine methylation is a prominent feature of human tumors, including colorectal cancers. Epigenetic changes of this type play undisputed roles in cell transformation when they involve genes that safeguard genome stability, and they can also be detected in precancerous lesions and seemingly normal peritumoral tissues. We explored physiological conditions associated with aberrant promoter methylation involving two DNA-repair genes in normal colorectal mucosa. Samples of cecal, transverse colon, sigmoid and rectal mucosa collected from 100 healthy individuals undergoing screening colonoscopy were analysed for hMLH1 and MGMT promoter methylation with a quantitative PCR assay. Positivity in at least one colon segment was common in both sexes, with methylation involving 0.1-18.8% of the alleles (median=0.49%). Samples from males showed no consistent patterns for either promoter, but there were striking age- and colon segment-specific differences in the female subgroup. Here, the prevalence of hMLH1 and MGMT methylation increased significantly with age, particularly in the right colon, where there was also an age-related increase in the percentage of alleles showing hMLH1 methylation. Concomitant methylation of both promoters was also significantly more common in the right colon of women. These findings paralleled immunohistochemical patterns of hMLH1 and MGMT protein loss in an independent series of 231 colorectal cancers and were consistent with current epigenetic profiles of colorectal cancer subsets. They suggest the intriguing possibility that the epigenetic signatures of cancers may have early-stage, normal-tissue counterparts that reflect potentially important aspects of the initial carcinogenetic process.

[Autoimmune pancreatitis: new concepts of an often overlooked disease]. / Autoimmune Pankreatitis: Aktuelle Konzepte einer häufig übersehenen Krankheit.

Autoimmune pancreatitis is characterized by a lympho-plasmacytic infiltrate centred around the pancreatic ducts along with venulitis; it can produce a mass-like fibroinflammatory lesion and often simulates pancreatic malignancy or chronic pancreatitis of other types. This may lead to unnecessary surgical interventions. Patients, who are usually over 40 years of age, show 1) mild unspecific abdominal pain, 2) increased serum immunoglobulins (specifically IgG4) and autoantibodies, and 3) diffuse or focal enlargement of the pancreas with pancreatic strictures and sometimes jaundice due to biliary obstruction (detectable by US, CT, MRI, ERCP and/or endoscopic ultrasound (EUS)). The diagnosis can be strongly supported by EUS- or US-guided biopsies showing typical histological changes and specific indirect immunohistochemistry with the patient's serum or a steroid trial showing often a dramatic decrease of pathological findings within weeks.

[Background of a new delineation of the medical profession]. / Hintergrund eines neuen Arztbildes.

The survival of mankind is jeopardized in a hitherto unprecedented manner by the three global-scale interacting worldillnesses, i.e., overpopulation, environmental deterioration, and the extermination potential of the modern arsenals of atomic, biologic and chemical weapons. These self-created hazards should appeal to new accountability, to a rethinking of our medical duties and actions. With their consequences they form the background of a new delineation of the medical profession.

[Environmental health. Medical aspects--children's unique vulnerability--perception of the environment]. / Umwelt und Gesundheit. Arztliche Aspekte--Risikogruppe Kinder--Umweltwahrnehmung.

It is recognized that humans are participants in complex ecosystems and that their potential for health is proportional to the health function of those ecosystems ("ecosystem health"). From the medical viewpoint this close connection between environment and health is outlined acknowledging that man-made environmental degradation may lead to human illness. This is the very object of the "environmental medicine" which should also take into account psycho-philosophical aspects related to the affective perception of our environment and its degradation. Data are reviewed on the special vulnerability of children as an example of groups within the population who are particularly sensitive to toxic hazards in the environment. The vulnerability of infants and children reflects the unique patterns of exposure to environmental hazards, coupled with the inherent fragility of their developmental processes. Given this example, the concept is explored that certain groups within our population, most notably children, are deserving of special protection in risk assessment, law, and regulation. As physicians, we should use prudence when counselling our patients, especially pregnant mothers, about avoidance of exposures to chemicals of unknown and untested toxic potential.

Osteosclerotic bone dysplasia (melorheostosis) of the mandible.

Melorheostosis is a linear bone dysplasia of unknown origin that may be associated with soft-tissue alterations. Although any part of the skeleton can be affected, this condition is rarely observed in the craniofacial region. Only seven cases of melorheostosis with craniofacial involvement have been reported and cranial manifestation only is even rarer. To the authors' knowledge, manifestation in the mandible only has not yet been documented. A patient with isolated melorheostosis of the mandible with characteristic symptomatic bone pain is presented. The clinical, radiological and histological findings are described and possible therapeutic options are discussed.

Synergy of gene-mediated immunoprophylaxis and microbeam radiation therapy for advanced intracerebral rat 9L gliosarcomas.

PURPOSE: Microbeam radiation therapy (MRT), a novel experimental radiosurgery that largely spares the developing CNS and other normal tissues, is tolerated well by developing animals and palliates advanced 9LGS tumors. This report, to our knowledge, is the first demonstration that gene-mediated immunotherapy (GMIMPR) enhances the efficacy of MRT for advanced 9LGS tumors. METHODS: Seventy-six male Fischer 344 rats were implanted ic with 10(4)9LGS cells on d0. By d14, the cells had generated approximately approximately 40 mm3 ic 9LGS tumours, experimental models for therapy of moderately aggressive human malignant astrocytomas. Each of the 14 untreated (control) rats died from a large (>100 mg) ic tumor before d29 (median, d21). On d14, the remaining 62 rats were given deliberately suboptimal microbeam radiation therapy (MRT) by a single lateral exposure of the tumor-bearing zone of the head to a 10.1 mm-wide, approximately approximately 11 mm-high array of 20-39 microm-wide, nearly parallel beams of synchrotron wiggler-generated radiation (mainly approximately 50-150 keV X-rays) that delivered 625 Gy peak skin doses at approximately approximately 211 microm ctc intervals in approximately approximately 300 ms either without additional treatments (MRT-only, 25 rats), with post-MRT GMIMPR (MRT+GMIMPR, 23 rats: multiple sc injections of irradiated (clonogenically-disabled) GM-CSF gene-transfected 9LGS cells), or with post-MRT IMPR (MRT+IMPR, 14 rats: multiple sc injections of irradiated (clonogenically-disabled) 9LGS cells. RESULTS: The median post-implantation survivals of rats in the MRT-only, MRT+GMIMPR and MRT+IMPR groups were over twice that of controls; further, approximately approximately 20% of rats in MRT-only and MRT+IMPR groups survived >1 yr with no obvious disabilities. Moreover, over 40% of MRT+GMIMPR rats survived >1 yr with no obvious disabilities, a significant (P<0.04) increase over the MRT-only and MRT+IMPR groups. SIGNIFICANCE: These data suggest that the combination of MRT+GMIMPR might be better than MRT only for unifocal CNS tumors, particularly in infants and young children.

[Barrett's esophagus: diagnosis and therapy]. / Barrett-Osophagus: Diagnostik und Therapie.

Barrett's esophagus is usually diagnosed by the endoscopic and histological finding of columnar epithelium with intestinal metaplasia in the distal esophagus. The prevalence of Barrett's esophagus (long segment) is <2% in the general population and 3-5% in patients with chronic reflux symptoms. Barrett mucosa predisposes patients to adenocarcinoma that develops in approximately 0.5% of these patients per year (Barrett mucosa --> dysplasia --> cancer sequence). The incidence of esophageal adenocarcinoma over the past few decades; the present incidence, however, is still rather low and is reported to be approximately 4 and approximately 0.5 per 100,000 in males and females, respectively. The malignant potential of the Barrett mucosa increases with dysplastic changes. Guidelines for surveillance and therapy are based on the presence and the degree of dysplastic lesions. Long-term studies on cost-effectiveness of these guidelines are, however, still missing.