Chlorophyll treatment combined with photostimulation increases glycolysis and decreases oxidative stress in the liver of type 1 diabetic rats

Photodynamic therapy (PDT) promotes cell death, and it has been successfully employed as a treatment resource for neuropathic complications of diabetes mellitus (T1DM) and hepatocellular carcinoma. The liver is the major organ involved in the regulation of energy homeostasis, and in pathological conditions such as T1DM, changes in liver metabolic pathways result in hyperglycemia, which is associated with multiple organic dysfunctions. In this context, it has been suggested that chlorophyll-a and its derivatives have anti-diabetic actions, such as reducing hyperglycemia, hyperinsulinemia, and hypertriglyceridemia, but these effects have not yet been proven. Thus, the biological action of PDT with chlorophyll-a on hepatic parameters related to energy metabolism and oxidative stress in T1DM Wistar rats was investigated. Evaluation of the acute effects of this pigment was performed by incubation of isolated hepatocytes with chlorophyll-a and the chronic effects were evaluated by oral treatment with chlorophyll-based extract, with post-analysis of the intact liver by in situ perfusion. In both experimental protocols, chlorophyll-a decreased hepatic glucose release and glycogenolysis rate and stimulated the glycolytic pathway in DM/PDT. In addition, there was a reduction in hepatic oxidative stress, noticeable by decreased lipoperoxidation, reactive oxygen species, and carbonylated proteins in livers of chlorophyll-treated T1DM rats. These are indicators of the potential capacity of chlorophyll-a in improving the status of the diabetic liver.

Chlorophyll treatment combined with photostimulation increases glycolysis and decreases oxidative stress in the liver of type 1 diabetic rats.

Photodynamic therapy (PDT) promotes cell death, and it has been successfully employed as a treatment resource for neuropathic complications of diabetes mellitus (T1DM) and hepatocellular carcinoma. The liver is the major organ involved in the regulation of energy homeostasis, and in pathological conditions such as T1DM, changes in liver metabolic pathways result in hyperglycemia, which is associated with multiple organic dysfunctions. In this context, it has been suggested that chlorophyll-a and its derivatives have anti-diabetic actions, such as reducing hyperglycemia, hyperinsulinemia, and hypertriglyceridemia, but these effects have not yet been proven. Thus, the biological action of PDT with chlorophyll-a on hepatic parameters related to energy metabolism and oxidative stress in T1DM Wistar rats was investigated. Evaluation of the acute effects of this pigment was performed by incubation of isolated hepatocytes with chlorophyll-a and the chronic effects were evaluated by oral treatment with chlorophyll-based extract, with post-analysis of the intact liver by in situ perfusion. In both experimental protocols, chlorophyll-a decreased hepatic glucose release and glycogenolysis rate and stimulated the glycolytic pathway in DM/PDT. In addition, there was a reduction in hepatic oxidative stress, noticeable by decreased lipoperoxidation, reactive oxygen species, and carbonylated proteins in livers of chlorophyll-treated T1DM rats. These are indicators of the potential capacity of chlorophyll-a in improving the status of the diabetic liver.

Parasites as bioindicators of environmental degradation in Latin America: A meta-analysis.

Unregulated economic growth in Latin America has resulted in environmental degradation, including the release of toxic compounds into the environment. One strategy to understand and prevent the outcomes of this harmful environmental degradation is the use of bioindicators. These are free-living or parasite species that respond to habitat alterations with changes in their numbers, physiology or chemical composition. The aim of this review was to determine whether there is evidence of a significant parasite response to environmental damage in Latin America. We collected 26 papers published between 2003 and 2015 and conducted a meta-analysis to test the null hypothesis that there is no significant overall effect of environmental insults on parasites. The meta-analysis showed a low but still significant negative mean overall effect (Hedges' g = -0.221; 95% CI: -0.241 to -0.200; P < 0.0001). However, the magnitudes and directions of the significant effects varied widely. These results suggest that different groups of parasites have distinct responses to various environmental insults and that the groups should be separately analysed after the accumulation of a sufficient number of studies. For future studies on this topic in Latin America, we suggest: (1) using field and experimental approaches to determine the response of parasites to environmental degradation; (2) using an interdisciplinary approach, including different types of biomarkers in both parasites and individual hosts to generate long-term datasets in polluted and reference areas; (3) conducting studies on parasites as accumulation bioindicators.

Noninvasive MRI-Based Liver Iron Quantification: Methodic Approaches, Practical Applicability and Significance.

Due to the dependence of transverse relaxation times T2 and T2* on tissue iron content, MRI offers different options for the determination of iron concentration. These are the time-consuming spin-echo sequence as well as the gradient-echo sequence. For the latter, several data analysis approaches have been proposed, with different requirements for acquisition and post-processing: the mathematically challenging R2* analysis and the signal-intensity ratio method with its high demand on the signal homogeneity of MR images. Furthermore, special procedures currently under evaluation are presented as future prospects: quantitative susceptibility imaging, as a third approach for analyzing gradient echo data, and multi-contrast spin-echo using repeated refocusing pulses. MR theory, as far as needed for understanding the methods, is briefly depicted. Key points: • Description of underlying technology of different MRI-based procedures for liver iron quantification• Applicability of these methods in clinical practice• Validity of the methods, i. e. positive and negative predictive value, if available Citation Format: • Wunderlich AP, Cario H, Juchems MS et al. Noninvasive MRI-Based Liver Iron Quantification: Methodic Approaches, Practical Applicability and Significance. Fortschr Röntgenstr 2016; 188: 1031 - 1036.

Individualized multimodal treatment strategy for anaplastic thyroid carcinoma-Case report of long-term remission and review of literature.

INTRODUCTION: The prognosis of anaplastic thyroid cancer (ATC) is poor with a mean survival time of six months following diagnosis. Despite various attempts to modify common treatment modalities including surgery, external beam radiation and chemotherapy, an effective treatment is not available yet. We report, here, a patient who achieved long-term survival based on multimodal treatment, including in vitro evaluation of drug response of his tumor cells. PRESENTATION OF CASE: A 42 years old male patient underwent total thyroidectomy with central and lateral neck dissection for ATC (pT4b, pN0 (0/36), L0, V0, Pn1, R0 cM0 - UICC-Stage: IV b). From the tumor tissue a primary cell culture was established. While the patient received a combined radio-chemotherapy cell viability assays were performed using Sorafenib, Vandetanib und MLN8054 (Aurora kinase inhibitor) as inhibitors. Cell viability was determined by MTT-assay after 72 and 144h of treatment. DISCUSSION: All the three compounds affected cell viability in a time- and dose dependent manner. These effects were most pronounced by Sorafenib. Based on in vitro findings, the patient was treated daily with 400mg Sorafenib for 75days. 43 months after initial diagnosis, the patient had no evidence of disease as shown by MRI, CT and FDG-PET-CT imaging. CONCLUSION: In the setting of multimodal treatment, in vitro drug evaluation of individual tumor cells of patients might be a promising tool to ameliorate the fatal prognosis of selected ATC patients.

MRI-Based Liver Iron Content Determination at 3T in Regularly Transfused Patients by Signal Intensity Ratio Using an Alternative Analysis Approach Based on R2* Theory.

OBJECTIVES: To evaluate the feasibility of addressing liver iron content (LIC) in regularly transfused patients by MR imaging at 3 T based on the signal intensity ratio (SIR). An innovative data analysis approach was developed for this purpose. METHODS: 47 consecutive examinations of regularly transfused patients were included. In all cases, we expected high LIC levels. Patients were scanned with MRI at 3 T with multi-echo gradient echo sequences (GRE) at four different flip angles between 20° and 90° with echo times (TE) ranging from 0.9 to 9.8 ms. Spin-echo protocols were acquired to determine the LIC with a reference MRI method working at 1.5 T. 3 T GRE data were analyzed using the liver-to-muscle SIR. Since the method known for 1.5 T was not expected to be applicable for analyzing 3 T data, theoretic dependence of the SIR on the LIC was derived from the equation describing R2* signal decay. Obtained SIR values were correlated to reference LIC to get a relation for calculating LIC from SIR quantities. LIC values and their uncertainties were determined from GRE data and correlated to LIC reference values. For two LIC thresholds, the diagnostic accuracy was determined. RESULTS: LIC was reliably determined from SIR in our patient cohort even for large LIC values. Median of LIC uncertainties was 10 %, and the diagnostic accuracy was 0.92 and 0.91, respectively. CONCLUSION: Determination of even high LIC, resulting in small SIR values, is feasible at 3 T using appropriate SIR analysis. KEY POINTS: • Determination of Liver Iron Concentration (LIC) based on GRE MRI at 3T is feasible even for high LIC levels using Signal Intensiy Ratios. • Relative uncertainty of LIC determined with 3T GRE MRI was below 13 % in most cases. • The patient-management relevant threshold (LIC = 80 µmol/g (4.5 mg/g)) yielded an accuracy of .92 in our cohort. • The proposed method is quick and simple, both in terms of data acquisition and analysis. Citation Format: • Wunderlich AP, Cario H, Bommer M et al. MRI-Based Liver Iron Content Determination at 3T in Regularly Transfused Patients by Signal Intensity Ratio Using an Alternative Analysis Approach Based on R2* Theory. Fortschr Röntgenstr 2016; 188: 846 - 852.

The bromodomain protein BRD4 regulates the KEAP1/NRF2-dependent oxidative stress response.

The epigenetic sensor BRD4 (bromodomain protein 4) is a potent target for anti-cancer therapies. To study the transcriptional impact of BRD4 in cancer, we generated an expression signature of BRD4 knockdown cells and found oxidative stress response genes significantly enriched. We integrated the RNA-Seq results with DNA-binding sites of BRD4 generated by chromatin immunoprecipitations, correlated these with gene expressions from human prostate cancers and identified 21 top BRD4 candidate genes among which the oxidative stress pathway genes KEAP1, SESN3 and HDAC6 are represented. Knock down of BRD4 or treatment with the BRD4 inhibitor JQ1 resulted in decreased reactive oxygen species (ROS) production and increased cell viability under H2O2 exposure. Consistently, a deregulation of BRD4 diminished the KEAP1/NRF2 axis and led to a disturbed regulation of the inducible heme oxygenase 1 (HMOX1). Without exogenous stress induction, we also found BRD4 directly targeting the HMOX1 promoter over the SP1-binding sites. Our findings provide insight into the transcriptional regulatory network of BRD4 and highlight BRD4 as signal transducer of the cellular response to oxidative stress.

Liver iron content determined by MRI: spin-echo vs. gradient-echo.

PURPOSE: Liver iron content (LIC) measurement plays a central role in the management of patients with transfusional iron overload. Calculating the LIC with data obtained from standardized MRI sequences represents an attractive alternative diagnostic possibility. The purpose of this study was to compare the LIC measurement obtained with gradient-echo (GRE) sequences to the mean liver proton transverse relaxation (R2) acquired with SE sequences. MATERIALS AND METHODS: 68 patients with iron overload (median age: 24, range: 3-88) underwent 1.5 T MRI for liver iron content measurement. All patients received spin-echo (SE) and gradient-echo (GRE) sequences. RESULTS: The two MRI methods revealed different liver iron content results although a significant correlation was found (r=0.85, p<0.001). Values evaluated using GRE sequences (median: 260 µmol/g dry weight [d. w.], range: 6-732) were generally higher than those obtained by SE examinations (median: 161 µmol /g d. w., range: 5-830). CONCLUSION: In conclusion, our study revealed different results for both MRI measurements, which could lead to different decisions concerning the management of chelation therapy in individual patients.

Perception and suppression of thermally induced pain: a fMRI study.

Two neuroimaging studies using functional magnetic resonance imaging (fMRI) and thermally induced pain are presented. Fifteen healthy right-handed subjects were imaged while they had to discern different levels of thermal stimuli in the first study and while they disengaged from the feeling of pain during constant stimulation in the second study. In the first experiment, during painful phasic stimuli, right-sided anterior insular activation as well as bilateral posterior insular activation could be shown regardless of stimulation side, as well as right-sided activation of sensory association areas in the superior parietal lobule. Also, activation of the ipsilateral sensorimotor cortex could be shown. In the second experiment, all subjects succeeded in suppressing the feeling of pain during previously painful levels of stimulation. During the early part of the tonic painful stimulation, bilateral activation of caudate head and dorsolateral prefrontal cortex (DLPFC) as well as insular cortex and dorsal anterior cingulated cortex (dACC) was observed. During the late part of the tonic painful stimulation, anterior insular activation as well as dACC and bilateral prefrontal cortical activation could be shown. Taken together, the activation of PFC and caudate nucleus hints at an important role in the initiation (caudate) and maintenance (PFC) of suppression of the feeling of pain. No ipsilateral sensorimotor activation could be shown in the second experiment. The possible import of unwanted sensorimotor activation due to the simultaneous rating process in the first experiment is discussed.

Differential effects of cetuximab and AEE 788 on epidermal growth factor receptor (EGF-R) and vascular endothelial growth factor receptor (VEGF-R) in thyroid cancer cell lines.

This study evaluated the role of EGF and the effects of EGF-targeting drugs (Cetuximab, AEE 788) on growth, apoptosis, and autocrine VEGF-secretion of thyroid cancer (TC) cells. Autocrine activation of the epidermal growth factor receptor (EGF-R) is commonly regarded to contribute to the malignant phenotype of TC cells and may therefore represent a rational therapeutic target. Out of a number of TC cell lines two anaplastic (Hth74, C643), one follicular (FTC133), and one papillary thyroid cancer cell line (TPC1) were analyzed in depth for VEGF-R-and EGF-R-expression, basal and EGF-stimulated (1-100 ng/ml) VEGF protein secretion and proliferation. Subsequently the antiprolifereative and antiangiogenic effect of cetuximab (Erbitux), a monoclonal antibody that blocks the EGF-R and AEE 788, a novel dual-kinase inhibitor of EGF-R and VEGF-R were assessed, and the downstream EGF-R signal transduction was analyzed by means of detecting phosphorylated pEGF-R, pVEGF-R, pAkt, and p-MAPK. EGF stimulated VEGF-mRNA expression and protein secretion in all TC cell lines. The EGF-R antagonist Cetuximab consistently decreased VEGF secretion in all TC cell lines (min. 15%, n.s. in C643 cells and max. 90% in Hth74 cells, P < 0.05), but did not affect tumor cell proliferation in vitro. In contrast, the EGF-R- and VEGF-R-kinase inhibitor AEE 788 not only reduced VEGF secretion (min. 55%, P < 0.05 in C643 and max. 75%, P < 0.05, in FTC133), but also exhibited a dose-dependent inhibition of tumor cell proliferation (min. 75%, P < 0.05 in C643 and max. 95%, P < 0.05 in Hth74) and was a potent inductor of apoptosis in two of four TC cell lines. These effects were always accompanied by reduced levels of pEGF-R, pVEGF-R, pAkt, and pMAPK. Although inhibition of the EGF-receptor by Cetuximab potently disrupts autocrine secretion of VEGF, only the concurrent inhibition of the VEGF- and EGF receptor, e.g., by AEE 788 induces reduced proliferation and apoptosis in vitro. This suggests a particular rationale for the use of tyrosine kinase inhibitors with dual modes of action such as AEE 788 in thyroid cancer.

Functional thyrotropin receptor attenuates malignant phenotype of follicular thyroid cancer cells.

Thyrotropin (TSH) is a thyroid-specific growth factor inducing differentiated function and growth of thyrocytes in vitro. In thyroid cancer, loss of TSH-receptor (TSHR) expression is a sign of de-differentiation and is believed to contribute to the malignant phenotype. The present studies aimed to determine the in vitro and in vivo effects of functioning TSHR in the follicular thyroid cancer cell line HTC, a subclone of FTC133 cells, lacking endogenous expression of TSHR, and HTCtshr+ cells transfected with human TSHR-cDNA. HTCtshr+ cells grew faster in vitro (doubling time 1.15 vs 1.56 d, p < 0.05) and TSH caused a dose-dependent growth response. Adhesion to and invasion through reconstituted basement membrane were reduced in HTCtshr+ cells, but when stimulated with TSH increased to levels comparable to naïve HTC cells. In vivo, tumor latency was 11 d for naïve HTC as compared to 21 d for HTCtshr+ xenografts. Smaller tumor volumes were registered for HTCtshr+ cells (250 +/- 217 vs 869 +/- 427 mm3, p < 0.05). Angiogenesis, as determined by vascular surface density (VSD) of experimental tumors, was enhanced in naïve HTC tumors (VSD 0.87 +/- 0.1 microm-1 vs 0.55 +/- 0.2 microm-1 in HTCtshr+, p < 0.05). VEGF secretion was more pronounced in naïve HTC cells stimulated with EGF, than in HTCtshr+ cells stimulated with either TSH or EGF. In conclusion, regained expression of functional TSHR in the follicular thyroid cancer cell line HTC alters in vitro features commonly associated with the malignant phenotype. Smaller tumors and reduced angiogenesis of xenotransplanted HTC cells with functioning TSHR suggest a less aggressive in vivo phenotype. The present data highlight the pivotal role of TSHR to affect transformed thyrocytes in vitro and in vivo. They also suggest a role for EGF as a modulator of angiogenesis in thyrocytes devoid of TSHR.

Internal radionuclide therapy: software for treatment planning using tomographic data.

AIM: Accurate dosimetry must be performed for each patient before therapy with unsealed radionuclides. Recently, the software tool ULMDOS was developed to facilitate planar dosimetric calculations and to support traceability and documentation as a prerequisite for good clinical practice. Here, the extended version of ULMDOS for processing of tomographic data is presented. METHODS: ULMDOS is developed in IDL 6.1 (Interactive Data Language) under Windows XP/2000. Serial tomographic data can be loaded in an ECAT7 or DICOM format, and presented as maximum intensity projection. The definition of volumes of interest is supported by various tools (e.g., freehand, isocontour, polygon), region growing, and cluster analysis. Residence times are calculated from fits of the time activity data to exponential functions. RESULTS, DISCUSSION: Quantitative 3-dimensional data allow performing a more individualized dosimetry, as problems due to organ overlay, insufficient attenuation and scatter correction in the planar approach can be avoided. For traceability, documentation, retrospective examination and later processing all data can be saved in binary or ASCII format. Dosimetric calculations can be conducted within a single environment, thus it spares the time-consuming transfer of data between different software tools.

Targeting the EGF/VEGF-R system by tyrosine-kinase inhibitors--a novel antiproliferative/antiangiogenic strategy in thyroid cancer.

AIM: In thyroid cancer (TC), endothelial growth factor (EGF) has been associated with dedifferentiation, tumor cell proliferation, and angiogenesis. Vascular endothelial growth factor (VEGF) has been documented to be the main stimulator of angiogenesis in the thyroid gland. Patients with undifferentiated thyroid cancer are in desperate need of new therapeutic strategies because common protocols of therapy usually fail. The aim of this study, therefore, was to evaluate two tyrosine-kinase inhibitors (TKI, ZD 1839 gefitinib and ZD 6474 vandetanib), directed against the EGF/VEGF receptor for possible antitumor therapy in thyroid cancer. METHODS: EGF/VEGF-R was documented in anaplastic (Hth74, C643), follicular (FTC133), and papillary (TPC1) thyroid cancer cell lines by Western blot analysis. The antiproliferative effect of two TKI (0.1-10 microM) on thyroid cancer cell lines in vitro was quantified by MTT assay, the antiangiogenic effect by assessing secretion of VEGF by enzyme-linked immunosorbent assay (R&D Systems). ZD 1839 is mainly directed against EGF-R and ZD 6474 against VEGF-R (AstraZeneca, UK), single applications and combinations of compounds were evaluated. RESULTS: EGF-R and VEGF-R as well as the phosphorylated receptor were documented in all of the cell lines. Administration of ZD1839 led to an up to 90% reduction of cell number in Hth74, 80% in C643, 50% in FTC133, and 90% in TPC1 (p < 0.05). ZD1839 induced a decrease of VEGF secretion between 30% in C643 and 90% in Hth74. Administration of ZD6474 led to an up to 95% reduction of cell number in Hth74, 85% in C643, 90% in FTC133, and 90% in TPC1 (p < 0.05). The ZD6474 induced decrease of VEGF secretion ranged between 20% (FTC133) and 60% (TPC1). Combinations of IC50 concentrations of TKI showed synergistic effects, resulting in additional inhibition of proliferation between 50 and 90% compared to single drug administration. CONCLUSION: The EGF/EGF-R system resembles a powerful VEGF-stimulating pathway in all histiotypes of TC and can be inhibited by TKI. TKI directed against EGF-R as well as VEGF-R inhibit tumor cell proliferation and VEGF secretion in vitro. Combinations of TKI are more effective than strategies using single agents. It is suggested that targeting EGF-R/VEGF-R-mediated pathways may have therapeutic potential in some undifferentiated thyroid cancers.

Antisense p53 decreases production of VEGF in follicular thyroid cancer cells.

Inactivating mutations of wild-type p53 (WTp53) tumor suppressor gene are common in anaplastic thyroid cancer (ATC) and are associated with poor prognosis. Mutated p53 (MTp53) has been implicated with angiogenesis. Therefore, the potential of MTp53 knockout by oligodeoxyribonucleotide phosphorothioates (ODNs) to affect VEGF production of undifferentiated thyroid cancer cells with a recessive MTp53 mutation was evaluated. Transient transfection with 20 bp ODNs complementary to portions of exon 10 of p53 and a negative control ODN (HIV-RT) were carried out in FTC-133 cells. In vitro secretion of VEGF protein was quantified by EIA and correlated to cell numbers, which was evaluated by in vitro MTT assay. Transfection of undifferentiated thyroid cancer cells with ODN reduced VEGF secretion of FTC-133 cells following transfection by 34% as compared to the negative control (cells transfected with ODN-HIV; p = 0.03). These results suggest that transient MTp53 knockout with ODNs complementary to p53 nucleotide sequences impair secretion of VEGF in the undifferentiated thyroid cancer cell line FTC-133.

Antisense p53 oligonucleotides inhibit proliferation and induce chemosensitivity in follicular thyroid cancer cells.

BACKGROUND: The potential of MTp53 knockout by oligodesoxyribonucleotide phosphothioates (ODNs) to affect proliferation, apoptosis and chemosensitivity in undifferentiated thyroid cancer (UTC) cells with a recessive MTp53 mutation was evaluated. MATERIALS AND METHODS: Transient transfections with ODNs complementary to p53 and control ODN (HIV-RT) were carried out in FTC 133 cells. In vitro proliferation was evaluated by cell counting of 10 random fields and by the MTT assay. A single pulse of 100 microg/ml Cytarabine was added to each well and the cells were incubated for an additional day. Chemosensitivity was calculated as the ratio of apoptotic and necrotic cells versus viable cells by flow cytometry (FACS). RESULTS: Transfection of UTC cells with ODN decreased the cell number by up to 70% (p < 0.002). The proliferation rate also decreased up to 35% (p < 0.03), without inducing apoptosis. ODNs rendered FTC cells sensitive to treatment with Cytarabine, inducing apoptosis in 35% of cells, as compared to 17% of cells transfected with the reverse transcriptase gene of HIV (ODN-HIV) and less than 10% of non-transfected cells (p < 0.05). CONCLUSION: Transient MTp53 knockout with ODNs complementary to p53 nucleotide sequences inhibited proliferation and increased chemosensitivity in the UTC cell line FTC133.

Brain tumour surgery in the vicinity of short-term memory representation--results of neuronavigation using fMRI images.

OBJECTIVE: Functional information concerning the surrounding brain is mandatory for a good clinical outcome in brain tumour surgery. The value of fMRI to detect the motorcortex and Broca's area is widely accepted today. If an appropriate paradigm is used, short-term memory areas can be visualized as well. Obviously this information must be integrated into cranial neuronavigation for an appropriate intra-operative use. We report our first experiences with the direct integration of short-term memory fMRI into cranial neuronavigation. METHOD: From January 2001 to March 2002 14 patients were operated on for intracranial tumours with short-term memory fMRI imaging, using the "two-back-paradigm". Both pre- and postoperatively, the short-term memory of all patients was tested additionally by a standardized test battery including 16 different verbal and visuo-spatial items. RESULTS: In all 14 patients the general level of working memory capacity was preserved after surgery. The visuo-spatial performance was kept unchanged or deteriorated slightly, the alertness slightly worsened as well, but we found an improvement in verbal test items. CONCLUSION: The two-back paradigm is able to visualize verbal memory tasks in fMRI. For visuo-spatial items, a new paradigm has to be designed. In contrast to deep seated brain lesions, focal cortical impairments do not lead to obvious and serious memory deficits. Therefore, the aim of gross total tumour removal has to be balanced against the aim of preservation of short-term memory fields. Nevertheless, the knowledge of the localization of cortical short-term memory fields may combine both aims during navigated brain tumour surgery, thus preserving the patient with a better quality of life.

Inhibition of hippocampal function in mild cognitive impairment: targeting the cholinergic hypothesis.

Mild cognitive impairment (MCI) is a condition with an increased risk of developing Alzheimer's disease. Chief complaint and diagnostic criterion in subjects with mild cognitive impairment is memory failure. We hypothesized that cholinergic malfunction may underlie memory impairment in these subjects and applied a low dosage of an acetylcholinesterase inhibitor and modulator of nicotinic acetylcholine receptors, galantamine (4 mg bid), for 7 days. We used neuropsychological tests to investigate attention, cognitive flexibility, verbal and visual short-term and working memory, susceptibility to interference and episodic memory and functional magnetic resonance imaging to assess spatial navigation both prior to and after treatment. Late episodic learning and delayed recall improved on treatment as did recruitment of the hippocampal region during spatial navigation. Performance in all other neuropsychological measures remained unchanged. We show that an increase of cholinergic neurotransmission in subjects with MCI specifically improves hippocampal function and thus that a cholinergic deficit is functionally relevant in subjects with MCI. Malfunction of the cholinergic system may be tackled pharmacologically via the inhibition of acetylcholinesterase even when the impairment is slight.

Differential pattern of integrin receptor expression in differentiated and anaplastic thyroid cancer cell lines.

Adhesion of tumor cells to the extracellular matrix (ECM) is a crucial step for the development of metastatic disease and is mediated by specific integrin receptor molecules (IRM). The pattern of metastatic spread differs substantially among the various histotypes of thyroid cancer (TC). However, IRM have only occasionally been characterized in TC until now. IRM expression was investigated in 10 differentiated (FTC133, 236, 238, HTC, HTC TSHr, XTC, PTC4.0/4.2, TPC1, Kat5) and two anaplastic TC cell lines (ATC, C643, Hth74), primary cultures of normal thyroid tissue (Thy1,3), and thyroid cancer specimens (TCS). Expression of 16 IRM (beta1-4, beta7, alpha1-6, alphaV, alphaIIb, alphaL, alphaM, alphaX) and of four IRM heterodimers (alpha2beta1, alpha5beta1, alphaVbeta3, alphaVbeta5), was analyzed by fluorescent-activated cell sorter (FACS) and immunohistochemical staining. Thyroid tumor cell adhesion to ECM proteins and their IRM expression in response to thyrotropin (TSH) was assessed. Follicular TC cell lines presented high levels of integrins alpha2, alpha3, alpha5, beta1, beta3 and low levels of alpha1, whereas papillary lines expressed a heterogenous pattern of IRM, dominated by alpha5 and beta1. ATC mainly displayed integrins alpha2, alpha3, alpha5, alpha6, beta1 and low levels of alpha1, alpha4 and alphaV. Integrin heterodimers correlated with monomer expression. Evaluation of TCS largely confirmed these results with few exceptions, namely alpha4, alpha6, and beta3. The ability of TC cell lines to adhere to purified ECM proteins correlated with IRM expression. TSH induced TC cell adhesion in a dose-dependent fashion, despite an unchanged array of IRM expression or level of a particular IRM. Thyroid carcinoma cell lines of different histogenetic background display profoundly different patterns of IRM expression that appear to correlate with tumor aggressiveness. In vitro adhesion to ECM proteins and IRM expression concur. Finally, TSH-stimulated adhesion of thyroid tumor cell lines to ECM may not be associated with altered IRM expression.

[Measurement of noise protection in functional magnetic resonance imaging]. / Messungen zum Lärmschutz bei der funktionellen MR-Tomographie.

BACKGROUND: Functional magnetic resonance imaging (fMRI) can detect changes in oxygen saturation of the brain. Fast changing high gradient fields are necessary which produce high levels of noise. In studies of the auditory cortex, auditory stimuli have to be perceived and discriminated against the noise level of the activated tomograph. MATERIAL AND METHODS: The generated frequency bands and their intensities during fMRI with a Siemens Magnetom Vision, 1.5 T, EPI sequence were measured in the outer ear canal of a dummy head. Noise attenuation was evaluated with four different noise muffs (simple/inexpensive products, quality product, specialized fMRI muffs). RESULTS: Without protection, peak noise levels reached up to 111 dB(A) near 1000 Hz in the dummy ear canal. Major noise attenuation was only found at higher frequencies (4000 Hz by about 25 dB; 8000 Hz by about 35 dB) with the quality product and the specialized fMRI muffs. CONCLUSION: Only quality noise products can sufficiently protect patients from high sound pressure levels of tomograph noise. If in the future higher gradient fields are applied at faster slew rates, acoustic stimuli can safely be applied only in combination with increased hearing protection systems in order to minimize the risk of noise trauma.

Quasi-automatic 3D finite element model generation for individual single-rooted teeth and periodontal ligament.

The paper demonstrates how to generate an individual 3D volume model of a human single-rooted tooth using an automatic workflow. It can be implemented into finite element simulation. In several computational steps, computed tomography data of patients are used to obtain the global coordinates of the tooth's surface. First, the large number of geometric data is processed with several self-developed algorithms for a significant reduction. The most important task is to keep geometrical information of the real tooth. The second main part includes the creation of the volume model for tooth and periodontal ligament (PDL). This is realized with a continuous free form surface of the tooth based on the remaining points. Generating such irregular objects for numerical use in biomechanical research normally requires enormous manual effort and time. The finite element mesh of the tooth, consisting of hexahedral elements, is composed of different materials: dentin, PDL and surrounding alveolar bone. It is capable of simulating tooth movement in a finite element analysis and may give valuable information for a clinical approach without the restrictions of tetrahedral elements. The mesh generator of FE software ANSYS executed the mesh process for hexahedral elements successfully.