Biomedical subjects
Publications and source records attributed to J Hartmann.
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The early and differential diagnosis of the clinical phenotypes of frontotemporal lobar degeneration (FTLD), including frontotemporal dementia (FTD), semantic dementia (SD) and non-fluent progressive aphasia (NFPA), can be challenging. It may be difficult not only to differentiate these conditions from normal aging, psychiatric disorders, and other dementias, but also to distinguish between them. For early diagnosis, information on the initial and presenting symptoms of the FTLD phenotypes is essential. In the present study caregivers of 78 patients with FTD, 20 patients with SD and 17 patients with PA were interviewed about initial symptoms. In patients with FTD, the most frequent initial symptoms were alterations of personality, followed by forgetfulness and word finding difficulty. Patients with SD presented with word finding difficulty and behavioral disturbances. Almost all patients with PA developed word finding difficulty as the first manifestation of their disorder. Diagnostic latency - the time from disease onset to diagnosis was 4.1 years in FTD, 4.2 years in SD and 3.1 years in PA. Caregivers, and in some cases also patients, should be educated about the likely course and mortality of FTLD. To obtain information about survival time and cause of death associated with FTLD we analyzed follow-up data on 106 patients of whom 25 had died. The median survival time from the occurrence of first symptoms was 14 years. Mortality risk was significantly higher in patients with an early disease onset. Causes of death were varied, but pneumonia and sudden unexplained deaths were particularly frequent.
BACKGROUND: Mucins are glycoproteins secreted by epithelial cells of various organ systems exerting multiple functions. MG2 as the protein transcript of the MUC7 gene has first been described as secreted by serous salivary glands in the oral cavity. We sought to explore changes of MUC7 expression in the kidney stimulated by bacterial infection of the upper urinary tract. METHODS: We investigated the gene expression of MUC7 by reverse transcriptase-polymerase chain reaction in voided urine specimens from 15 patients with acute pyelonephritis compared to 15 healthy volunteers. Furthermore, the gene and protein expression of MUC7 was studied in 15 renal tissue samples with chronic bacterial pyelonephritis versus 10 normal human kidney samples taken from tumor-bearing organs. RESULTS: MUC7 gene expression was detected in 5 of 15 voided urine samples of patients with pyelonephritis and in 2 samples from 15 healthy volunteers (Fisher's exact test p=0.39). MUC7 gene expression was detected in 7 of 15 tissue samples of kidneys with chronic pyelonephritis and in none of 10 normal renal tissue samples from tumor bearing organs (p=0.02). Immunohistochemical staining with the monoclonal antibody PANH3 revealed protein expression in 6 of the 15 tissue samples with chronic pyelonephritis, but not in normal tissue samples. CONCLUSION: Upregulated MUC7 expression in the urinary tract particularly in renal tubular epithelium can occur under inflammatory conditions. This indicates a putative role of MUC7 as an antimicrobial host defense molecule within the urogenital tract.
Chemoresistance is a biological response of cells to survive toxic stress. During cancer treatment the development of chemoresistance is a major problem. The mechanisms how cells become insensitive, and which downstream pathways are affected are not completely understood. Since it has not been well analysed which and how many regulative disorders are subsummised under the term "chemoresistance", we examined and measured arabinosylcytosine (AraC)-mediated desensitation of two mechanisms relevant for tissue homeostasis, cell cycle inhibition and apoptosis induction. MCF-7 cells harbouring ectopic mutated p53 were suitable for this investigation because they activated these mechanisms subsequently and became insensitive to AraC with regard to cell cycle inhibition and apoptosis induction. The major causal mechanism of acquired resistance against AraC was most likely through the inhibition of the first step of AraC phosphorylation within the cell, which is rate limiting for its activation. With regard to cell cycle inhibition AraC-resistant cells were also resistant against 5-fluorodeoxyuridine (5-FdUrd), but fully responsive to 5-FdUrd-induced apoptosis, evidencing that cell cycle and apoptosis are independent of each other. Apoptosis correlated with AIF-activation and was independent of Caspase 7, whereas cell cycle inhibition correlated with cyclinD1 expression but not with induction of p21 or p27. The phosphate conjugated 5-FdUrd-araC heterodimer (5-Fluoro-2'-desoxyuridylyl-(3'-->5')-Arabinocytidine), which is a prodrug of AraC-monophosphate, reactivated AIF and down-regulated cyclin D1 in AraC-resistant cells and circumvented resistance to apoptosis and to cell cycle inhibition. Also, cells which were resistant to 5-FdUrd or doxorubicin were sensitive to 5-FdUrd-araC. This investigation demonstrates that chemoresistance affects apoptosis induction and cell cycle inhibition independently and that detailed knowledge about the affected downstream pathways would enable the design of targeted intervention with small molecules to restore chemosensitivity.
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In the extracorporeal adsorption system, MDS (Microspheres based Detoxification System), micro-adsorbent particles measuring 1-25 micrometers circulate in a filtrate circuit for highly specific blood purification/adsorption. The MDS circuit containing the adsorbent microparticles is linked to the patient's blood line by a hollow fiber plasma filter. When the transmembrane pressure or the shear forces due to the red blood cells in the hollow fiber filter are too high, they can be damaged and hemoglobin will be released. In order to detect free hemoglobin (fHb) by optical means, we have designed a new flow-dynamic filter system, placed in the microadsorbent circuit for continuous separation of microparticles from the filtrate. In the flow dynamic filter, we use a high velocity liquid vortex to remove sedimentation and particle plugs on the filter membrane. In our investigations, 3 and 8 micron cellulose nitrate filter membranes for particle separation are used. The obtained particle free bypass filtrate flow rates are typically 0.5 and 0.8 ml/min respectively. The typical sensitivity for fHb detection by the applied noninvasive optical method is 0.15 g/dL. Medical safety regulations require a fail-safe mechanism for fHb detection which monitors the bypass filtrate flow in the flowdynamic filter and shuts down the system in case of membrane occlusion. The bypass filtrate flow is monitored by periodically occluding and releasing the bypass line by means of a clamp. The resulting back pressure profile gives information about the actual filtration rate. This safety principle was proven by statistical analysis and shows its clear functionality.
BACKGROUND: A microsphere-based detoxification system is an adsorption system, whereby microadsorbent particles having diameters of 1-20 microm circulate in an extracorporeal filtrate circle. A thin-wall hollow-fiber membrane filter separates the microparticle-plasma suspension from the bloodstream. For patient safety, it is necessary to have a means to detect membrane ruptures that could lead to a release of microparticles into the patient's bloodstream. METHODS: An optical detection system was developed to monitor the venous bloodstream for the presence of microparticles from the filtrate circuit. For detection purposes, cellulose microspheres, both ferromagnetic and fluorescence labeled, were included with the microsphere adsorbant particles. In the case of a membrane rupture, the labeled particles would also be released into the bloodstream. By illuminating a small volume of blood with an excitation wavelength (590 nm) of the fluorescence marker, the particles can be detected by their emission light at 620 nm. The detector sensitivity is increased by collecting the ferromagnetic and fluorescently labeled microparticles using a magnetic trap. The efficiency of magnetic trap arrangements was tested by adjusting the magnet placements. RESULTS: In vitro experiments were performed by pumping whole blood and labeled microparticles through the fluorescence detector. The efficiency of a magnetic trap arrangement was determined. With an optimal trap setup, 5-10 microl of labeled microparticles can be clearly detected in streaming whole blood. CONCLUSION: An easy to handle microparticle detector was developed, ready for use in particle based blood detoxification systems. The microparticle detection system fulfills the medical and technical requirements to bring the MDS into clinical tests.
INTRODUCTION: The mechanism of potential tumor cell spread and growth during laparoscopy is poorly understood. Nevertheless, different experimental studies reported a stimulation of tumor cell growth and an increased metastatic potential of carcinoma cells using carbon dioxide as an insufflation medium. Adhesion molecules do play an important and regulatory function in the process of metastatic spread and invasion of cancer cells. Therefore we investigated the influence of CO2 and Helium insufflation on the in-vitro expression of E-Cadherin, CD44v6 and CD54 (ICAM-1) on HT-29 colon carcinoma cells. METHODS: HT-29 carcinoma cells were exposed to either CO2 or helium insufflation. Expression of E-Cadherin, CD44v6 and CD54 (ICAM-1) on HT-29 colon carcinoma cells were measured 1, 12, 24, 48 and 96 h after CO2 and helium insufflation using flowcytometry (FACScan). Data were analyzed by Friedman-test. RESULTS: HT-29 cell line showed a short decrease in E-Cadherin expression after CO2 exposure while helium insufflation had no influence. In contrasts to these findings the expression of CD44v6 and CD54 on HT-29 cells were not influenced significantly by either CO2 or helium. CONCLUSION: CO2 seems only to have a minor influence on the expression of E-Cadherin while expression of other adhesion molecules did not change after CO2 incubation. The alternative gas helium did not cause any significant changes of the expression of either E-Cadherin, CD44v6 and CD54. Further investigations are needed to elucidate the changes of the metastatic potential of tumor cells after laparoscopic and open procedures.
G-protein-coupled metabotropic glutamate group I receptors (mGluR1s) mediate synaptic transmission and plasticity in Purkinje cells and, therefore, critically determine cerebellar motor control and learning. Purkinje cells express two members of the G-protein G(q) family, namely G(q) and G11. Although in vitro coexpression of mGluR1 with either Galpha11 or Galpha(q) produces equally well functioning signaling cascades, Galpha(q)- and Galpha11-deficient mice exhibit distinct alterations in motor coordination. By using whole-cell recordings and Ca2+ imaging in Purkinje cells, we show that Galpha(q) is required for mGluR-dependent synaptic transmission and for long-term depression (LTD). Galpha11 has no detectable contribution for synaptic transmission but also contributes to LTD. Quantitative single-cell RT-PCR analyses in Purkinje cells demonstrate a more than 10-fold stronger expression of Galpha(q) versus Galpha11. Our findings suggest an expression level-dependent action of Galpha(q) and Galpha11 for Purkinje cell signaling and assign specific roles of these two G(q) isoforms for motor coordination.
Alzheimer's disease is characterized by amyloid peptide formation and deposition, neurofibrillary tangles, central cholinergic dysfunction, and dementia; however, the relationship between these parameters is not well understood. We studied the effect of amyloid peptide formation and deposition on central cholinergic function in knock-in mice carrying the human amyloid precursor protein (APP) gene with the Swedish/London double mutation (APP-SL mice) which were crossbred with transgenic mice overexpressing normal (PS1wt) or mutated (M146L; PS1mut) human presenilin-1. APP-SLxPS1mut mice had increased levels of Abeta peptides at 10 months of age and amyloid plaques at 14 months of age while APP-SLxPS1wt mice did not have increased peptide levels and did not develop amyloid plaques. We used microdialysis in 15-27 months old mice to compare hippocampal acetylcholine (ACh) levels in the two mouse lines and found that extracellular ACh levels were slightly but significantly reduced in the APP-SLxPS1mut mice (-26%; P=0.044). Exploratory activity in the open field increased hippocampal ACh release by two-fold in both mouse lines; total and relative increases were not significantly different for the two strains under study. Similarly, infusion of scopolamine (1 microM) increased hippocampal ACh release to a similar extent (3-5-fold) in both groups. High-affinity choline uptake, a measure of the ACh turnover rate, was identical in both mouse lines. Neurons expressing choline acetyltransferase were increased in the septum of APP-SLxPS1mut mice (+26%; P=0.046). We conclude that amyloid peptide production causes a small decrease of extracellular ACh levels. The deposition of amyloid plaques, however, does not impair stimulated ACh release and proceeds without major changes of central cholinergic function.
A 48-year-old woman presented with bloody diarrhea, exsiccosis, abdominal pain and fever. A CT-scan showed air inclusions and thickening of the colonic wall. Laparotomy revealed partial necrosis of the colonic wall from the cecum to the rectosigmoid junction. After colectomy with ileorectostomy recovery was uneventful. The histological examination showed erosions, ulcerations, necrosis and some abscesses along the colonic wall which were not typical for ulcerative colitis or Crohn's disease. The patient reported medication with diclofenac for rheumatoid arthritis. The most probable diagnosis was NSAID-induced colitis. That NSAID may cause colitis has often been described in literature, but there have been only few records on nearly total colon necrosis.
Single modality bladder-sparing therapy for muscle-invasive bladder cancer, including transurethral resection (TUR), partial cystectomy, systemic chemotherapy or radiotherapy, have been demonstrated to result in insufficient local control of the primary tumour, as well as decreased long-term survival in the patients when compared to radical cystectomy. Therefore, multimodality treatment protocols that aim at bladder preservation and involve all of the aforementioned approaches have been established. Arguments for combining systemic chemotherapy with radiation are to sensitise tumour tissue to radiotherapy and to eradicate occult metastases that have already developed in as many as 50% of patients at the time of first diagnosis. It has been shown that the clinical outcome observed with this approach approximates that after radical cystectomy. Additionally, a substantial number of patients survive with an intact bladder. However, bladder-sparing approaches are costly, and require close co-operation between different clinical specialists as well as careful follow-up. The good long-term results that are observed after cystectomy and the creation of an orthotopic neobladder make the substantial advantage of a bladder preservation strategy questionable when the patient's quality of life is addressed. Additionally, bladder-sparing therapy-related side effects might result in an increased morbidity and mortality in those patients who need to undergo surgery due to recurrent or progressive disease. Multimodality bladder-sparing treatment is a therapeutic option that can be offered to the patient at centres that have a dedicated multidisciplinary team at their disposal. However, radical cystectomy remains the standard of care for muscle-invasive bladder cancer.
OBJECTIVES: To further clarify the need for routine adrenalectomy during the surgical treatment of renal cell cancer, as in the absence of clinically overt metastatic disease, tumorous lesions within the adrenal gland are found in only 2-10% of patients, with most being over-treated by adrenalectomy. PATIENTS AND METHODS: The medical records of 819 patients undergoing adrenalectomy combined with nephrectomy, irrespective of the local extension of the primary tumour or the clinical stage at first diagnosis, were reviewed to determine the reliability of currently available imaging methods in predicting adrenal gland metastases. Several patient and tumour characteristics were correlated with the presence of intra-adrenal metastases, and their possible independent prognostic value was determined by a multivariate logistic regression model. RESULTS: There was metastatic spread into the adrenal gland in 27 of 819 (3.3%) patients. In only three of eight patients in whom the adrenal was identified as the only metastatic site were preoperative abdominal computed tomography scans interpreted as false-negative. On multivariate statistical analysis only the presence of distant metastases, vascular invasion within the primary tumour and multifocal growth of renal cell cancer within the tumour-bearing kidney were identified as independent predictors of the presence of intra-adrenal metastases. CONCLUSIONS: None of the patient or tumour characteristics evaluated reliably predicted the likelihood of adrenal metastases in patients with no evidence of disseminated metastatic spread. However, previously published data indicate that the frequency of metachronous metastases within the contralateral kidney (1.8-3.8%) is significantly higher than the risk of a preoperatively undetected isolated intra-adrenal metastatic lesion when currently available imaging modalities are applied. Therefore, routine adrenalectomy should not be recommended if the preoperative radiological examinations are normal.
Alternative technologies for extracorporeal blood purification systems based on microadsorbents in suspension are discussed. Principally, microadsorbents offer higher efficiency and flexibility when compared to conventional column-based adsorption systems. Systems already clinically employed (e.g., BioLogic DT) or close to clinical application (e.g., the microspheres-based detoxification system, MDS) are described. The MDS technology, in particular, is characterized by efficiency and a high degree of flexibility with respect to both the use of different adsorbents as well as the combination with hemodialysis/hemofiltration therapy. It was designed for continuous use in intensive-care units, but enables also the removal of low-density lipoprotein, fibrinogen, autoimmune antibodies, immune complexes, and other pathophysiologically relevant substances. Alternative anticoagulation regimes and safety systems on fluorescence sensor technology have recently been developed for the MDS and are presented in this paper.
PURPOSE: To study and test the impact of modern MRI techniques in diagnostic imaging in the evaluation of intra-osseous fistulous systems and sequesters. MATERIALS AND METHODS: In a prospective study, nine patients with chronic osteomyelitis of the legs were examined by MRI. Patients with clinical signs of osteomyelitis requiring surgery were included in the study. T1-weighted spin echo (SE) sequences, proton density (PD) and T2-weighted fast spin echo (FSE) sequences, water- and fat-selective FSE sequences, and diffusion weighted (DW) PSIF sequences were used preoperatively. Furthermore, magnetizing transfer (MT) with gradient echo (GRE) sequences was evaluated. RESULTS: Water selective sequences revealed the highest sensitivity for the detection of fistulas (100%), providing the best delineation of the extent of the entire fistulous systems. Fat-selective sequences (sensitivity 55.6%) and T1-weighted sequences (sensitivity 77.8%) displayed fistulas as hypointense bands, which, however, cannot be well differentiated from cortical bone in the transcortical areas. PD and T2-weighted images were found to have a poor sensitivity (55.6% and 66.7%) for fistulas in any location. The sensitivity of water-selective sequences to demonstrate intraosseous sequesters was 100%. The sensitivity was low for the other sequences. In 4 of 5 patients with surgically proven infection, DW and MT revealed an abnormal spatial distribution, with high diffusion in the central parts of the fistulas and high MT effect peripherally surrounding a weak MT effect centrally. CONCLUSION: Water-selective sequences are superior when demonstrating fistulous systems and intraosseous sequesters. The combined use of MT and DW sequences seems to allow a differentiation between solid granulation tissue and liquid pus.
Data on possible acute effects of today's relevant low-level exposure to toluene are contradictory, and information on possible effects of exposure under occupational conditions is largely lacking. In a controlled, multi-center, blinded field trial, effects possibly associated with acute toluene exposure were evaluated in workers of 12 German rotogravure factories. Medical examinations (inquiries on subjective symptoms, and standard tests of psycho-physiological and psycho-motor functions) were performed on almost 1500 volunteers, of whom 1290 were toluene-exposed (1178 men and 112 women), and about 200 participants served as references (157 men and 37 women), but the main aim of the trial was to reveal dose-response relationships. All volunteers were of the morning work-shift (6 h exposure). Both individual ambient air concentrations (time-weighted average) during the work-shift, as well as blood toluene concentrations after the work-shift were measured. Therefore, the medical data could for the first time be correlated with the actual individual body burden (blood toluene level) at the time of testing. In order to largely exclude confounding by chronic toluene exposure, kinetic measurements as well as the psycho-physiological and psycho-motoric tests were performed before and after the work-shift. Except for minor statistical deviations, neither convincing dose-dependent acute effects could be demonstrated with regression analyses in male volunteers at the exposure levels evaluated, nor were significant differences found when applying group statistics (highly toluene-exposed group versus volunteers with negligible exposure). Due to the rather large number of participants, the predictive power of the study is high, especially when compared with previous publications. In two psycho-physiological tests, a few more female volunteers with quite low toluene body burdens (<340 microg/l blood) showed relatively low scores when compared with participants of the reference group. Although evidence for a medical relevance is meager, the small numbers of participants, in both the exposure and the reference groups, hamper a reliable interpretation of the results concerning exposure levels above 85 microg toluene/l blood, and it is difficult to take confounding factors adequately into account. For the end points evaluated and under occupational conditions, neither blood toluene levels of 850 to 1700 microg/l (in the highest exposure group [EXPO-IV] with 56 participants), as measured 1/2 (+/-1/2) h after the work-shift, nor ambient air concentrations (time-weighted average over 6 h) between 50 and 100 ppm (188-375 mg/m(3)) were convincingly associated with alterations in psycho-physiological and psycho-motoric performances or increased the frequency of subjective complaints in male volunteers. For higher dose ranges of toluene exposure (i.e. >1700 microg toluene/l blood [or >100 ppm in ambient air]), our data set is too small for far reaching conclusions. Our data are insufficient for conclusions on a possibly higher susceptibility to toluene of some female workers. Results of kinetic studies and possible effects of long-term exposure are discussed in two accompanying publications (Neubert et al., 2001; Gericke et al., 2001).
The serine protease inhibitor Maspin has been reported to inhibit the invasiveness and motility of prostate cancer tumor cells. Additionally, a p53-dependent regulatory pathway of Maspin in prostate cancer cell lines has been indicated. The first aim of our study was to determine the prognostic value of Maspin protein expression for the recurrence-free survival of patients undergoing radical prostatectomy for the treatment of clinically localized prostate cancer. Secondly, Maspin expression was correlated to p53 protein expression in order to gain additional information on a possible and previously suggested regulatory influence of the wild-type p53 protein on the Maspin protein expression. Tumor specimens obtained from 84 patients undergoing radical prostatectomy for localized prostate cancer were investigated for the expression of the Maspin and p53 protein by an immunohistochemic approach. Maspin protein expression was correlated with further patients' and tumor characteristics such as tumor stage, histologic grading, regional lymph node status, p53 protein expression and recurrence-free survival of the patients following radical prostatectomy. After a median follow-up of 64 months (24-197 months), 23 of 40 patients (58%) with a negative or decreased Maspin expression (group 1) developed local recurrence or systemic tumor progression in contrast to 8 of 44 patients (18%) with a retained expression of the Maspin protein (group 2) (p = 0.02; log-rank test). The median recurrence-free survival following radical prostatectomy was 26 months (12-37 months) for group 1 patients and 41 months (5-134 months) for patients from group 2 (p = 0.04). A positive immunohistochemic staining reaction for the p53 protein was significantly correlated with a decreased expression of the Maspin protein (p = 0.015; Spearman correlation coefficient). Additionally, loss of Maspin protein expression was correlated to higher tumor stages (p = 0.002) and an increasing histologic dedifferentiation (p = 0.03). This is the first study to indicate that Maspin protein possibly functions as a clinically relevant inhibitor of tumor progression, preventing the local invasiveness and further systemic progression of prostate cancer. Our investigation delivers first hints for a p53-dependent regulatory pathway of the Maspin protein in human prostate cancer.
In 1980, the Hare Psychopathy Checklist (PCL), an operationalised rating scale for the quantitative assessment of "psychopathy" as seen in the Anglo-American literature, was developed by R.D. Hare in Canada. It proved to be the most valid prognostic instrument for assessing relapse of criminals in English-speaking countries. This study was aimed at verifying the applicability of a German version of the revised PCL (PCL-R) on carefully selected subjects from the Forensic Psychiatric Department of the Psychiatric University Hospital in Munich. Two groups with an equal number of different forensic-psychiatric reports were evaluated retrospectively using the PCL-R. The results confirm the applicability of the PCL-R for the assessment of psychopathy in our sample population. One can expect that the positive experiences with the PCL-R abroad can be transferred to German conditions. The results are encouraging as to the practicability of the PCL-R as a prognostic instrument in routine forensic assessment.