Biomedical subjects
Publications and source records attributed to M Hermann.
Magnetic resonance imaging is the method of choice for examination of the inner ear and acoustic tract. In order to obtain detailed visualization of all structures the scans have to be made in three planes: axial, coronal, and sagittal.
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RNA editing in higher plant plastids alters mRNA sequences by C-to-U conversions at highly specific sites through an unknown mechanism. To elucidate how the cytidine residues to be edited are specifically recognized and distinguished from other cytidines in close proximity, we have changed in vivo the distances of two plastid RNA-editing sites from their essential upstream cis-acting sequence element. Analysis of RNA editing in transgenic chloroplasts revealed that reduction of this distance by 1 nt entirely abolishes RNA editing. Surprisingly, deletions or combinations of deletional and point mutations that shift a heterologous cytidine residue in the same distance from the upstream cis-element as the editing site in the wild type result in transfer of the RNA-editing activity to the heterologous cytidine whereas the wild-type site remains unedited. Our results suggest that the molecular identity of at least some editing sites in the chloroplast genome is defined by their distance from an essential upstream sequence element.
Simultaneously produced superoxide/nitric oxide radicals (O2*-/NO*) could form peroxynitrite (OONO-) which has been found to cause atherogenic, i.e. oxidative modification of LDL. Aromatic hydroxylation and nitration of the aspirin metabolite salicylate by OONO- has been reported. Therefore we tested if salicylate may be able to protect LDL from oxidation by O2*-/NO* by scavenging the OONO reactive decomposition products. When LDL was exposed to simultaneously produced O2*-/NO* using the sydnonimine SIN-1, salicylate exerted an inhibitory effect on LDL oxidation as measured by TBARS and lipid hydroperoxide formation and alteration in electrophoretic mobility of LDL. The cytotoxic effect of SIN-1 pre-oxidised LDL to endothelial cells was also diminished when salicylate was present during SIN-1 treatment of LDL. Spectrophotometric analysis revealed that salicylate was converted to dihydroxybenzoic acid (DHBA) derivatives in the presence of SIN-1. 2,3- and 2,5-DHBA were even more effective to protect LDL from oxidation by O2*-/NO*. Because O2*-/NO* can occur in vivo, the results may indicate that salicylate could act as an efficacious inhibitor of O2*-/NO* initiated atherogenic LDL modification, thus further supporting the rationale of aspirin medication regarding cardiovascular diseases.
The interaction of the female germ cell with somatic cells during the development of the ovarian follicle in the chicken provides a prime system to study gene expression. Here, we have uncovered the involvement of clusterin, the function(s) of which is still poorly understood, in this complex process. As revealed by molecular cloning, chicken clusterin is a 428-residue protein that migrates at 70 kDa on SDS-polyacrylamide gel electrophoresis and possesses most of the structural features of its mammalian successors. However, in contrast to mammalian clusterin, the chicken protein appears not to be cleaved intracellularly into a disulfide-linked heterodimer; possibly as a consequence thereof, it is not secreted constitutively and is absent from the circulation, where most of clusterin is found in mammals. In the ovary, clusterin is a major product of the somatic granulosa cells, in a pattern correlating with the developmental phases of individual follicles. In that, transcript levels are high not only at onset of vitellogenesis, but also in atretic follicles and in the postovulatory follicle sac, i.e. in situations characterized by apoptotic events. Yolk of growing oocytes contains a 43-kDa truncated form of clusterin that does not appear to be synthesized within the oocyte. Rather, we here show for the first time that 70-kDa clusterin interacts not only with megalin, but also with two chicken oocyte-specific members of the low density lipoprotein receptor (LDLR) gene family. These receptors, termed LDLR-related protein with eight ligand binding repeats (LR8) and LDLR-related protein (380 kDa), likely internalize granulosa cell-derived 70-kDa clusterin, which may subsequently be processed to the 43-kDa product. Thus, chicken clusterin could serve as a marker for follicular atresia and resorption, and, based on its ability to bind several other proteins, it may serve as carrier for the receptor-mediated endocytosis into oocytes of components important for embryonic development, two hitherto unknown functions of this intriguing protein.
So far, blood progenitor cells (BPC) expanded ex vivo in the absence of stromal cells have not been demonstrated to reconstitute hematopoiesis in myeloablated patients. To characterize the fate of early hematopoietic progenitor cells during ex vivo expansion in suspension culture, human CD34(+)-enriched BPC were cultured in serum-free medium in the presence of FLT3 ligand (FL), stem cell factor (SCF) and interleukin 3 (IL-3). Both CD34 surface expression levels and the percentage of CD34+ cells were continuously downregulated during the culture period. We observed an expansion of colony-forming units granulocyte-macrophage (CFU-GM) and BFU-E beginning on day 3 of culture, reaching an approximate 2-log increase by days 5 to 7. Limiting dilution analysis of primitive in vitro clonogenic progenitors was performed through a week 6 cobblestone-area-forming cell (CAFC) assay, which has previously been shown to detect long-term bone marrow culture-initiating cells (LTC-IC). A maintenance or a slight (threefold) increase of week 6 CAFC/LTC-IC was found after one week of culture. To analyze the presence of BPC mediating in vivo engraftment, expanded CD34+ cells were transplanted into preirradiated NOD/SCID mice at various time points. Only CD34+ cells cultured for up to four days successfully engrafted murine bone marrow with human cells expressing myeloid or lymphoid progenitor phenotypes. In contrast, five- and seven-day expanded human BPC did not detectably engraft NOD/SCID mice. When FL, SCF and IL-3-supplemented cultures were performed for seven days on fibronectin-coated plastic, or when IL-3 was replaced by thrombopoietin, colony forming cells and LTC-IC reached levels similar to those of control cultures, yet no human cell engraftment was recorded in the mice. Also, culture in U-bottom microplates resulting in locally increased CD34+ cell density had no positive effect on engraftment. These results indicate that during ex vivo expansion of human CD34+ cells, CFC and LTC-IC numbers do not correlate with the potential to repopulate NOD/SCID mice. Our results suggest that ex vivo expanded BPC should be cultured for limited time periods only, in order to preserve bone-marrow-repopulating hematopoietic stem cells.
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Intracerebral extension of Wegener's granulomatosis (WG) is rare. We present a patient with oculomotor and trochlear nerve palsy with histologically proved WG. An MR examination revealed granulomatous tissue in nasal cavity, paranasal sinuses with meningeal infiltration, and uncommon penetration into cavernous sinus and sella turcica. The MR images before and during pharmacological therapy are presented.
Growth hormone (GH) and placental lactogen (PL) gene transcription patterns in testicular germ cell tumors (GCT) and normal testicular tissue were comparatively investigated to identify GH/PL gene products associated with the development of GCT. This was done by nondiscriminative reverse transcriptase-polymerase chain reaction (RT-PCR), amplifying all major transcripts of any of the 5 GH/PL genes--GH-N(ormal), GH-V(ariant), PL-A, PL-B, PL-L(ike)--and subsequent analytical restriction enzyme analyses of 5'-end radioactively labeled cDNA. Surprisingly, all nonseminomatous GCT (NSGCT; n = 9) expressed GH-N, PL-A/B, and PL-L transcripts (9 of 9). Seminoma (n = 7) showed a distinctly unique pattern of GH-N and PL-A/B. GH-V products, which are hallmarks of the normal healthy testis, were not detected in any testicular cancer specimen (0 of 16). The fact that both seminomatous and NSGCT showed alterations in the same gene cluster indicates a pathogenetic relationship. Two choriocarcinoma cell lines of conceptus origin, BeWo and JAR, clearly differing from the male counterparts, exhibited a placental-derived pattern of PL-A/B and GH-V. Obviously, profound differences exist between conceptus and male germ cell GH/PL gene cluster transcription. In summary, the unique testicular pattern of GH/PL gene expression changes significantly and in directed ways with malignancy. Loss of GH-V gene expression in testicular GCT compared with normal testis and loss (seminoma) or mutation (NSGCT) of PLL gene products might have significance in terms of the relationship between these tumors and for testicular GCT development.
The majority of elderly men is affected by benign and malignant diseases of the prostate. Both proliferative disorders, i.e., benign hyperplasia of the prostate (BPH) and prostate cancer (PCa)-which has recently emerged as the most common male malignancy in industrialized countries-seem to be governed by endocrine factors such as sex steroid hormones, but auto/paracrine factors are involved as well. Age-related changes in levels and ratios of endocrine factors as androgens, estrogens, gonadotropins, and prolactin (PRL) and changes in the balance between auto/paracrine growth-stimulatory and growth-inhibitory factors such as insulin-like growth factors (IGFs), epidermal growth factor (EGF), nerve growth factor (NGF), IGF-binding proteins (IGFBPs), and transforming growth factor beta (TGFbeta) are meant to be responsible for abnormal prostatic growth. We investigated the existence of putative local regulatory circuits involving the protein hormones, human growth hormone (hGH), human placental lactogen (hPL), and hPRL, and their corresponding receptors in prostatic tissue specimens (transurethral resections of the prostate, TURP; n = 11), in the prostatic cancer cell lines PC3, Du145, LnCap, a virus-transformed BPH cell line (BPH-1), and in a normal healthy prostate by RT-PCRs and highly specific and sensitive immunofluorometric assays (IFMA). Neither hPRL nor hGH was detected at the mRNA or protein levels in prostatic tissue and cell lines, with the exception of 2 of 11 prostatic TURP-samples, which showed weak expression of the PL-A/B genes. PRL- and GH-receptors were expressed in all normal and pathological prostatic specimens. Surprisingly, PRL-receptor expression was not detectable in prostatic cancer cell lines. The trophic effects of exogenous hGH, hPL, and hPRL were investigated by cell proliferation assays (WST-I) in prostatic primary cell cultures and PCa cell lines. hGH significantly (p < 0.005) increased cell proliferation up to 138+/-3.2% (1 nM hGH), while hPL and hPRL revealed only moderate effects. Our data suggest that local auto/paracrine networks of protein hormone actions are not involved in the pathology of BPH or prostatic cancer. On the other hand, systemic pituitary-derived hGH can increase the proliferative response of BPH and PCa, acting directly on the target organ prostate, via the hGH-R. In this case, envisaged GH substitution in elderly people must be viewed at with caution because age-related declines in GH/IGF-I could act as a protective mechanism against abnormal cell growth.
The recent increase in the elderly population, current health trends, and awareness of age-related changes in the male endocrine system have led to discussions about the endocrine system being a "pacemaker" of male aging. Better prevention and treatment of "non-beneficial states of health" in aging men, such as generally decreased well-being and virility, increased visceral fat, osteopenia, atherosclerosis, and impaired cognitive function, is based on improved understanding of aging, particularly the significance of age-associated hormonal changes. Although not as dramatic as in women, men also show declining hormone serum concentrations with aging (Vermeulen and Kaufman, 1995). Because aging is associated with deleterious effects resembling the clinical signs of hypogonadism or states of subnormal hormone concentrations, the potential role of hormone supplementation in aging men paralleling hormone replacement therapy in postmenopausal women is the topic of discussion. The goal of hormone replacement would be to improve body composition and increase muscle strength and quality of life in men, thereby reducing mortality and morbidity. The findings so far support the need for long-term studies of hormonal supplementation in older males showing decreased hormone serum levels. Nevertheless, to date, such a use outside the context of a clinical trial is not justified.
The oxidative modification of low density lipoprotein (LDL) may play a significant role in atherogenesis. Tyrosyl radicals generated by myeloperoxidase (MPO) can act as prooxidants of LDL oxidation. Taking into consideration, that monophenolic compounds are able to form phenoxyl radicals in presence of peroxidases, we have tested salicylate, in its ability to act as a prooxidant in the MPO system. Measurement of conjugated dienes and lipid hydroperoxides were taken as indicators of lipid oxidation. Exposure of LDL preparations to MPO in presence of salicylate revealed that the drug could act as a catalyst of lipid oxidation in LDL. The radical scavenger ascorbic acid as well as heme poisons (cyanide, azide) and catalase were inhibitory. The main metabolite of salicylic acid, gentisic acid, showed inhibitory action in the MPO system. Even when lipid oxidation was maximally stimulated by salicylate the LDL oxidation was efficaciously counteracted in presence of gentisic acid at salicylate/gentisic acid ratios that could be reached in plasma of patients receiving aspirin medication. Gentisic acid was also able to impair the tyrosyl radical catalyzed LDL peroxidation. The results suggest that salicylate could act like tyrosine via a phenoxyl radical as a catalyst of LDL oxidative modification by MPO. But the prooxidant activity of this radical species is effectively counteracted by the salicylate metabolite gentisic acid.
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It has long been believed that food restriction leads to psychological disturbances, including depression, preoccupation with food, and binge eating. However, recent studies suggest that comprehensive weight loss programs that incorporate behavioral treatment, diet change, and encouragement of physical activity in fact can improve the psychological state, including mood. A study conducted on subjects participating in the Weight Watchers program demonstrated positive psychological changes and improved quality of life. These changes may help motivate overweight people to maintain the physical activity and nutritional practices necessary to lose and maintain weight. Programs that include group support, like Weight Watchers, have been associated with psychological benefits independent of the amount of weight lost. Furthermore, dieters who regain lost weight do not appear to experience adverse psychological consequences. The development or exacerbation of bulimia has been linked by some authors to strict dieting, but more moderate weight control programs do not appear to produce disordered eating and may help reduce binge eating among overweight people. Individuals who successfully lose and maintain weight have been shown to experience improved mood, self-confidence, and quality of life. Additionally, decreasing levels of psychological and behavioral symptoms have been associated with increasing duration of weight loss maintenance. It can be concluded that quality of life and other psychological measures improve in individuals on comprehensive weight management programs.
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New antibiotic compounds, melithiazols, were isolated from the culture broth of strains of the myxobacteria Melittangium lichenicola, Archangium gephyra, and Myxococcus stipitatus. The compounds belong to the group of beta-methoxyacrylate (MOA) inhibitors and are related to the myxothiazols. The melithiazols show high antifungal activity, but are less toxic than myxothiazol A and its methyl ester in a growth inhibition assay with mouse cell cultures. The melithiazols inhibit NADH oxidation by submitochondrial particles from beef heart. Melithiazol A blocks the electron transport within the bc1-segment (complex III) and causes a red shift in the reduced spectrum of cytochrome b.
BACKGROUND AND METHODS: In Graves' disease radioiodine is the recommended treatment for relapses after subtotal thyroidectomy. If patients reject radioiodine, hyperthyroidism is managed with antithyroid drugs; surgery is generally not considered as an alternative. Here we retrospectively analyzed 30 consecutive patients with Graves' disease who had recurrent hyperthyroidism after subtotal thyroidectomy. RESULTS: On relapse after the first operation, the patients were initially treated by medication; 25 opted for definitive treatment (19 for reoperation and 6 for radioiodine). Operations consisted of 10 unilateral and 8 bilateral resections (total or near-total with capsular remnants of < 1 g) and 1 transsternal approach (because of dystopic intrathoracic thyroid tissue). The decision between a unilateral and a bilateral reintervention was based on the ultrasonographic determination of remnant volumes. These size estimates were valid because they were significantly correlated to the weight of the resected remnants (r = 0.92, slope = 0.95). Eighteen of the 19 patients were adequately treated by this approach. Unilateral resection was performed in 1 patient with a remaining contralateral remnant of 5.4 mL; this patient had a second relapse. The complication rate was low (2 cases of transient recurrent nerve injury and 1 of transient hypocalcemia). CONCLUSION: Provided that no contraindication is present, reoperation is safe, effective, and expeditious in recurrent hyperthyroidism. Because the likelihood of a recurrence depends on the total remnant size, the goal is to keep it below 2 g. Preoperative ultrasonography can effectively guide the decision between a unilateral and a bilateral resection.
BACKGROUND: Benign prostatic hyperplasia (BPH) affects the majority of elderly men, and prostate cancer is the most common male cancer. Prostatic growth and function are thought to be regulated by steroid hormones, primarily androgens and estrogens, but nonandrogenic hormones must also be considered. The increasing evidence of para/autocrine functions of the gonadotropic glycoprotein-hormones (GPH), their allocation to the superfamily of cystine-knot growth factors, and luteinizing hormone (LH)/chorionic gonadotropin (CG)-receptor (R) gene expression in nongonadal tissues led us to investigate intraprostatic GPH and GPH-R gene expression. METHODS AND RESULTS: RT-PCR and subsequent Southern hybridization and/or restriction enzyme analysis of BPH and prostatic adenocarcinoma demonstrated that all three human (h) gonadotropic hormones, i.e., follicle-stimulating hormone (FSH), LH, and CG, as well as the corresponding FSH-R and LH/CG-R, are transcribed intraprostatically. Significant amounts of the alpha and beta subunits of hCG were secreted by short-term primary cultures of human BPH tissues, as detected by highly sensitive and specific time-resolved immunofluorometric assays (IFMAs). CONCLUSIONS: Our data suggest that prostatic- and pituitary-derived GPH act directly on the prostatic gland, particularly FSH via the FSH-R, thereby possibly modulating locally acting key hormones and growth factors involved in BPH development.