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.

[Langerhans cell histiocytoses: 50 years to histiocytosis X]. / Langerhanszell-Histiozytosen: 50 Jahre Histiozytosis X.

Histiocytoses encompass a heterogeneous group of histiocytic disorders that may be separated in a group of variable biological behaviour and in a clearly malignant group. The histopathologic diagnosis of all types of histiocytoses is always mandatory. The 50-year-old Histiocytosis X compiles a subgroup of different biological behaviour, nowadays called Langerhans cell histiocytoses--the subject of the review. It has a wide range of manifestations: self-healing cutaneous, benign solitary and malignant systemic manifestations require the staging in order to evaluate a possibly necessary therapy. Chemotherapy should be performed within international protocols.

Clinical significance of human intestinal spirochetosis--a morphologic approach.

Intestinal spirochetosis (IS) is a condition defined morphologically by the presence of spirochetal microorganisms attached to the apical cell membrane of the colonic and rectal epithelium. Intestinal spirochetes comprise a heterogeneous group of bacteria. In humans Brachyspira aalborgi and Brachyspira pilosicoli predominate. Prevalence rates of IS are low where living standards are high, in contrast to poorly developed areas where IS is common. Homosexuals and HIV-infected individuals are at high risk of being colonized. Clinical significance in individual cases has remained unclear up to now. A review of the literature reveals that invasion of spirochetes beyond the surface epithelium is associated with gastrointestinal symptoms which respond to antibiotic treatment (metronidazole), whereas patients lacking this feature are mostly asymptomatic. Homosexual and HIV-positive men are more likely to be symptomatic irrespective of invasion. Rare cases of spirochetemia and multiple organ failure have been reported in critically ill patients.

[Juvenile ossifying fibroma. Case report with diagnostic and therapeutic considerations]. / Juveniles ossifizierendes Fibrom. Fallbericht mit diagnostischen und therapeutischen Uberlegungen.

BACKGROUND: Fibro-osseous lesions of the jaws, including juvenile ossifying fibroma, pose diagnostic and therapeutic difficulties due to their clinical, radiological and histological variability. CASE REPORT: The case of an 8-year-old girl with a juvenile ossifying fibroma of the mandible is presented. Extirpation of the tumor and filling of the defect with cancellous bone was performed. After 9 months, a recurrence occurred which made a second extirpation of the tumor necessary. This was done without osteoplasty. After a 2-year follow-up the patient is free of tumor. DISCUSSION: Different classifications for fibro-osseous lesions of the jaws can be found in the literature. This makes a correct diagnosis and standardized treatment difficult. Based on the case presented here, the histological features of juvenile ossifying fibroma and the differentiation from osteosarcoma are discussed. At present, conservative surgical treatment seems to be adequate for these tumors.

Abortion in woman caused by caprine Chlamydophila abortus (Chlamydia psittaci serovar 1).

On a farm housing cattle and goats an abortion storm occurred affecting 50% of the goats during the lambing season 2000/2001. In one of three investigated caprine abortions Chlamydophila abortus could be identified as aetiology. During this time a pregnant woman (pregnancy week 19/20) had contact with aborting goats. She developed a severe generalized infection and aborted. The placenta contained Chlamydophila abortus shown by immunohistochemistry and PCR. The aim of the present case report is to alert medical doctors about the potential zoonotic risk of ovine/caprine abortions.

[Abortion in humans caused by Chlamydophila abortus (Chlamydia psittaci serovar 1)]. / Abort beim Menschen durch Chlamydophila abortus (Chlamydia psittaci serovar1).

On a farm housing cattle and goats an abortion storm occurred affecting 50% of the goats during the lambing season 2000/2001. In one of three investigated caprine abortions Chlamydophila abortus could be identified as etiology. During this time a pregnant woman (pregnancy week 19/20) had contact with aborting goats. She developed a severe generalized infection and aborted. The placenta contained Chlamydophila abortus shown by immunohistochemistry and PCR. Aim of the present case report is to alert veterinarians about the potential zoonotic risk of ovine/caprine abortions.

[The environment and autoimmunity--from external causes to inner conflicts]. / Umwelt und Autoimmunität--Von äusseren Ursachen zu inneren Konflikten.

Autoimmune disorders result from a breakdown of immunologic tolerance leading to an immune response against self-molecules. In most instances the events that initiate the immune response to self-molecules are unknown, but a number of studies suggest associations with environmental and genetic factors and certain types of infections. The concordance of autoimmune diseases among identical twins is virtually always less than 50%, often in the 25-40% range. This observation, as well as epidemic clustering of some autoimmune diseases following xenobiotic exposure, reinforces the thesis that autoimmune disease is secondary to both genetic and environmental factors. In addition, because of individual genetic susceptibilities based not only on major histocompatibility complex differences but also on differences in toxin metabolism, lifestyles, and exposure rates, individuals will react differently to the same chemicals. With these comments in mind it is important to note that there have been associations of a number of xenobiotics with human autoimmune disease, including mercury, iodine, vinyl chloride, canavanine, organic solvents, silica, L-tryptophan, particulates, ultraviolet radiation, and ozone. In addition, there is discussion in the literature that raises the possibility that xenobiotics may also exacerbate an existing autoimmune disorder. In this article these issues are discussed, in particular, the evidence for the role of environmental agents in the initiation or progression of autoimmune conditions. With the worldwide deterioration of the environment, this is a particular important subject for human health. This is best illustrated by the epidemics of eosinophilic myalgia syndrome with shared characteristics that occurred about 20 years ago. Another example is the toxic oil syndrome of Spain in 1981 involving cooking oil led to both acute and chronic disease as well as formation of auto-antibodies to collagen, DNA, and skeletal muscle. Currently the question is risen whether there is a link between environmental estrogens and autoimmune disorders, especially since these illnesses are reported possibly more frequent. Yet for the time being, an answer is not available, since the current state of science with respect to autoimmunity and environmental agents is still in the early stages of hazard identification.

[Cor bovinum: decreased incidence over the last 20 years--a therapeutic success?]. / Cor bovinum: Abnehmende Häufigkeit in den letzten 20 Jahren--ein Therapieerfolg?

BACKGROUND: The Cor bovinum (CB), a heart of > 500 g, is often found in patients with clinically unclear cause of death. Cardiomyocyte hypertrophy and increase of the interstitial connective tissue can lead to electromechanical instability and consecutive sudden heart death. METHODS: This retrospective, autopsy-protocol-based study compared the frequency of altogether 415 CB and associated pathologies in two 4-year periods (1978-1981 and 1997-2000), including only patients of the Clinic of Internal Medicine (n = 1181 autopsies). RESULTS: A CB was found in 25.3% of the patients of the first period (1978-1981) in contrast of 20.6% in the second period (1997-2000); hence, the frequency of CB is decreasing (0.05 > p > 0.02). The mean age at death was 67.7 years in 1978-1981 and 74.3 years in 1997-2000; this revealed an increasing trend (p < 0.001). The male-female proportion was 4:1. In 93% of all patients with CB, we found coronary atherosclerosis as a sign of high blood pressure and in 79% a COPD. In 84% of all cases with CB the cause of death was directly related to the CB, in 37% of these patients the cause of death was clinically unclear. CONCLUSIONS: The CB is a decreasing but still frequent autopsy-finding. We consider high blood pressure, COPD and male sex as the main risk factors. The decrease in frequency of CB and the increase in age at death might be interpreted as the effect of a successful application of new therapeutic standards in the last two decades (ACE-inhibitors, beta blockers, statins, PTCA, surgical heart interventions).