Showing papers by "Charité published in 2001"

Three-dimensional structure of cyanobacterial photosystem I at 2.5 Å resolution

Abstract: Life on Earth depends on photosynthesis, the conversion of light energy from the Sun to chemical energy. In plants, green algae and cyanobacteria, this process is driven by the cooperation of two large protein-cofactor complexes, photosystems I and II, which are located in the thylakoid photosynthetic membranes. The crystal structure of photosystem I from the thermophilic cyanobacterium Synechococcus elongatus described here provides a picture at atomic detail of 12 protein subunits and 127 cofactors comprising 96 chlorophylls, 2 phylloquinones, 3 Fe4S4 clusters, 22 carotenoids, 4 lipids, a putative Ca2+ ion and 201 water molecules. The structural information on the proteins and cofactors and their interactions provides a basis for understanding how the high efficiency of photosystem I in light capturing and electron transfer is achieved.

Effect of resynchronization therapy stimulation site on the systolic function of heart failure patients.

Abstract: Background— Cardiac resynchronization therapy (CRT) improves systolic function in heart failure patients with ventricular conduction delay by stimulating the left ventricle (LV) or both ventricles (biventricular, BV). Optimal LV site selection is of major clinical interest for CRT device implantation; however, the dependence of hemodynamics on LV stimulation site has not been established. Thus, the objective of this study was to compare the hemodynamic response to CRT for 2 LV coronary vein sites: the free wall and anterior wall. Methods and Results— A total of 30 patients (mean NYHA class, 2.7; mean QRS interval, 152 ms; mean PR interval, 194 ms) enrolled in the PATH-CHF-II trial were studied. CRT was administered with LV and BV stimulation in VDD mode at 4 AV delays. LV stimulation was at the lateral free wall or anterior wall, whereas right ventricular stimulation was fixed near the apex. LV+dP/dtmax and aortic pulse pressure changes from baseline during CRT were compared for LV sites. Free wall sites ...

Receptor-targeted optical imaging of tumors with near-infrared fluorescent ligands.

Abstract: We report here the in vivo diagnostic use of a peptide-dye conjugate consisting of a cyanine dye and the somatostatin analog octreotate as a contrast agent for optical tumor imaging. When used in whole-body in vivo imaging of mouse xenografts, indotricarbocyanine-octreotate accumulated in tumor tissue. Tumor fluorescence rapidly increased and was more than threefold higher than that of normal tissue from 3 to 24 h after application. The targeting conjugate was also specifically internalized by primary human neuroendocrine tumor cells. This imaging approach, combining the specificity of ligand/receptor interaction with near-infrared fluorescence detection, may be applied in various other fields of cancer diagnosis.

Tolerance and Autoimmunity

Abstract: The immunologic specificity of the antigen receptors of T cells and B cells is the result of random shuffling of the many genes that form the DNA code for the antigen-binding site of these receptors.1–3 Theoretically, this process could generate 109 different T-cell receptors, including some that can bind to autoantigens (these cells are often called self-reactive T cells). Tolerance is the process that eliminates or neutralizes such autoreactive cells, and a breakdown in the working of this system can cause autoimmunity. B-Cell Tolerance Autoantibodies are characteristic of many autoimmune diseases and may be the direct cause of the . . .

CYP2D6 and CYP2C19 genotype-based dose recommendations for antidepressants: a first step towards subpopulation-specific dosages.

Abstract: CYP2D6 and CYP2C19 genotype-based dose recommendations for antidepressants: A first step towards subpopulation specific dosages.

Use of Intravascular Ultrasound to Compare Effects of Different Strategies of Lipid-Lowering Therapy on Plaque Volume and Composition in Patients With Coronary Artery Disease

Abstract: Background We studied whether lipid-lowering therapy with atorvastatin (target LDL cholesterol [LDL-C] <100 mg/dL) compared with a moderate treatment regimen that used other lipid-lowering drugs le...

Minimally invasive fracture stabilization of distal femoral fractures with the LISS: a prospective multicenter study. Results of a clinical study with special emphasis on difficult cases.

Abstract: The LISS-DF (Less invasive stabilization system-distal femur) is a new type of implant system for the treatment of distal femoral fractures according to the principles of "Minimally Invasive Surgery". A plate, pre-contoured to the anatomy, is inserted through a minimally invasive incision into the epiperiosteal space by means of an aiming device after indirect, closed fracture reduction. The implant is stabilized by insertion of screws which lock into the plate holes and prevent tilting. This is performed with the aid of an aiming device and through stab incisions. It is not necessary for a large area to be exposed at the fracture site. As part of an AO prospective multicenter study, the new system was applied to 112 patients with 116 fractures. The time to follow-up was on average 13.7 months (minimum 7 months, maximum 33 months). Fractures treated were distal femoral shaft and supracondylar femoral fractures. Eight patients died during the study of causes unrelated to the implant. Of the remaining 104 patients with 107 fractures, 96 patients with 99 fractures were available for complete follow-up (93% follow-up rate). In 90% of all cases treated and followed up, the fracture had consolidated during the period of observation. Twenty-three revision operations were necessary in 21 patients. In two cases, implant failure occurred as the result of a pseudarthrosis. The complications can be attributed in nearly all cases to the severity of the trauma and/or a lack of experience when applying the new style implant to a wider range of indications. The results of the study show that with a sound knowledge of the operative technique and careful preoperative planning this system represents an excellent, safe procedure for the treatment of almost all distal femoral fracture types including periprosthetic fractures of the distal femur. There is generally no need for primary cancellous bone grafting.

Systematic review and meta-analysis of antibiotic therapy for bone and joint infections

Abstract: We set out to evaluate the clinical efficacy of individual antibiotic agents for bone and joint infections in adults. Published and unpublished controlled trials reported between 1966 and 2000 were reviewed to determine if they involved random or quasi-random allocation to systemically administered antimicrobials or local antibiotic therapy for osteomyelitis and septic arthritis. Quiescence of infection after 1 year of follow-up was defined as the primary outcome measure. 22 trials containing 927 patients were eligible for final analysis. Varying proportions of the entire study population could be evaluated with respect to primary and secondary endpoints. Methodological quality was poor among most studies, and interpretability of results was further limited by small sample sizes, missing descriptions of patient populations and disease characteristics, and the frequent application of concomitant antibiotics. A trend towards improved, long-lasting infection control was observed in favour of a rifampicin-ciprofloxacin combination versus ciprofloxacin monotherapy for the treatment of staphylococcal infections related to orthopaedic devices (absolute risk difference [ARD] 28-9%; 95% CI -0.7 to 54.4%). Obviously unbalanced comparative studies showed some benefit of ticarcillin for bone infections caused by Pseudomonas species. No significant differences in therapeutic efficacy were found among trials comparing oral fluoroquinolones with intravenous beta-lactam drugs for both end-of-treatment (OR 0.8; 0.5 to 1.4) and long-term results (OR 1.3; 0.8 to 2.1). A variety of drugs was used as controls, thereby leading to inconsistent findings of drug-related side effects. Only one randomised trial was suitable to investigate the impact of polymethylmethacrylate gentamicin bead chains compared with parenteral antibiotics for skeletal infections, although this study was biased by patients receiving both combined local and systemic antibiotic therapy. Whereas intention-to-treat evaluation suggested a therapeutic advantage of systemic over local therapy, this trend diminished in the per-protocol analysis (1-year follow-up ARD -2.3;-17.5 to 10.8%). There exists little high-quality evidence on antibiotic therapy for osteomyelitis and septic arthritis. The observed heterogeneity among patient populations and medical and surgical treatment concepts preclude reliable inferences from the available data.

Expression of Cyclooxygenase 2 in Human Malignant Melanoma

Abstract: Cyclooxygenase (COX)-2 is an inducible enzyme involved in production of prostaglandins in inflammatory processes. There is now increasing evidence that a constitutive expression of COX-2 plays a role in development and progression of malignant epithelial tumors. In the present study we investigated expression and function of COX-2 in malignant melanoma. Expression of COX-2 was determined by immunohistochemistry in 28 cases of primary skin melanoma and 4 benign nevi. We show that COX-2 was expressed in 26 cases (93%) of melanomas, with a moderate to strong expression in 19 cases (68%). Benign nevi as well as normal epithelium were negative in all cases. A constitutive expression of COX-2 mRNA and protein was found in five melanoma cell lines (A375, MeWo, SK-Mel-13, SK-Mel-28, and IGR-37) by using Northern blot as well as immunoblotting. All melanoma cell lines produced prostaglandin (PG) E2 between 468 and 3500 pg/ml as determined by ELISA. Treatment with NS-398 (50 microM), a specific inhibitor of COX-2, suppressed PGE2 production of all melanoma cell lines by 50-96%. The IC50 for inhibition of PGE2 production by NS-398 was determined as 4 microM, indicating that NS-398 acts via inhibition of the COX-2 isoenzyme. We could show that proliferation of melanoma cell lines was not influenced by treatment with NS-398 in concentrations up to 100 microM. However, NS-398 reduced Matrigel invasion of all five malignant melanoma cell lines by 50-68%. Our results indicate that COX-2 is expressed in malignant melanomas and may be involved in regulation of melanoma invasion. It remains to be investigated whether selective inhibitors of COX-2 might be useful for prevention or treatment of malignant melanoma.

Value of p63 and cytokeratin 5/6 as immunohistochemical markers for the differential diagnosis of poorly differentiated and undifferentiated carcinomas.

Abstract: To facilitate the differential diagnosis of poorly differentiated metastatic carcinomas of unknown primary site, we evaluated p63 and cytokeratin (CK) 5/6 as immunohistochemical markers for squamous cell carcinomas. The study cases were as follows: squamous cell carcinoma of the lungs, head/neck, esophagus, cervix uteri, or anal canal, 73; non-squamous cell carcinomas of various primary sites, 141; and urothelial carcinoma, 20. We also tested 14 malignant mesotheliomas. Immunoreactivity for p63 was as follows: squamous cell carcinomas, 59 (81%); urothelial carcinoma, 14 (70%), most often with diffuse staining patterns; non-squamous cell carcinomas, 20 (14.2%), resulting in a specificity of 0.86 of p63 for squamous cell carcinomas. Coexpression of p63 and CK5/6 had a sensitivity of 0.77 and a specificity of 0.96 for squamous cell carcinomas. Increasing the minimal criterion of positive immunostaining for both markers to more than 50% of immunoreactive tumor cells resulted in a specificity of 0.99, although the sensitivity diminished to 0.66. All malignant mesotheliomas were negative for p63. Our data suggest that positive immunostaining for both p63 and CK5/6 in poorly differentiated metastatic carcinomas is highly predictive of a primary tumor of squamous epithelial origin.

Nutrition in the elderly

Abstract: Malnutrition is more common in elderly persons than in younger adults. Ageing itself, however, neither leads to malabsorption nor to malnutrition with the exception of a higher frequency of atrophic gastritis in older persons. Malnutrition in elderly people is therefore a consequence of somatic, psychic or social problems. Typical causes are chewing or swallowing disorders, cardiac insufficiency, depression, social deprivation and loneliness. Undernutrition is associated with a worse prognosis and is an independent risk factor for morbidity and mortality. Awareness of this problem is therefore important. For the evaluation of nutritional status, it must be remembered that most normal values are derived from younger adults and may not necessarily be suitable for elderly persons. Suitable tools for evaluating the nutritional status of elderly persons are e.g. the body mass index, weight loss within the last 6 months, the Mini Nutritional Assessment (MNA) or the Subjective Global Assessment (SGA). An improvement in the nutritional status can be achieved by simple methods such as the preparation of an adequate diet, hand feeding, additional sip feeding or enteral nutrition.

MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation.

Abstract: The gene MID1, the mutation of which causes X-linked Opitz G/BBB syndrome (OS, MIM 300000), encodes a microtubule-associated protein (MAP) We show that mutation of MID1 leads to a marked accumulation of the catalytic subunit of protein phosphatase 2A (PP2Ac), a central cellular regulator PP2Ac accumulation is caused by an impairment of a newly identified E3 ubiquitin ligase activity of the MID1 protein that normally targets PP2Ac for degradation through binding to its alpha4 regulatory subunit in an embryonic fibroblast line derived from a fetus with OS Elevated PP2Ac causes hypophosphorylation of MAPs, a pathological mechanism that is consistent with the OS phenotype

Determining changes in NIR absorption using a layered model of the human head.

Abstract: A theoretical approach is presented to determine absorption changes in different compartments of a layered structure from distributions of times of flight of photons. In addition resulting changes in spatial profiles of time-integrated intensity and mean time of flight are calculated. The capability of a single-distance, time-domain method to determine absorption changes with depth resolution is tested on a layered phantom. We apply this method to in vivo measurements on the human head (motor stimulation, Valsalva manoeuvre) and introduce a small-sized time-domain experimental set-up suitable for bedside monitoring.

Mechanisms and modulation of intestinal epithelial repair.

Abstract: The mucosal epithelium of the alimentary tract represents a crucial barrier to a broad spectrum of noxious and immunogenic substances within the intestinal lumen. An impairment of the integrity of the mucosal epithelial barrier is observed in the course of various intestinal disorders including inflammatory bowel diseases (IBD), celiac disease, intestinal infections, and various other diseases. Furthermore, even under physiologic conditions temporary damage of the epithelial surface mucosa may be caused by proteases, residential flora, dietary compounds, or other factors. Generally, the integrity of the intestinal mucosal surface barrier is rapidly reestablished even after extensive destruction because of an enormous regenerative capability of the mucosal surface epithelium. Rapid resealing of the surface epithelium is accomplished by epithelial cell migration, also termed epithelial restitution, epithelial cell proliferation, and differentiation. Healing of the intestinal surface epithelium is regulated by a complex network of highly divergent factors, among them a broad spectrum of structurally distinct regulatory peptides that have been identified within the mucosa of the intestinal tract. These regulatory peptides, conventionally designated as growth factors and cytokines, play an essential role in regulating differential epithelial cell functions to preserve normal homeostasis and integrity of the intestinal mucosa. In addition, a number of other peptide molecules such as extracellular matrix factors and blood clotting factors, and also nonpeptide molecules including phospholipids, shortchain fatty acids, adenine nucleotides, trace elements, and pharmacological agents, have been demonstrated to modulate intestinal epithelial repair mechanisms. Some of these molecules may be released by platelets, adjacent stromal cells, inflammatory cells, or injured epithelial and nonepithelial cells and may play an important role in the modulation of intestinal injury. Repeated damage and injury of the intestinal surface are key features of various intestinal disorders including IBD and require constant repair of the epithelium. Enhancement of intestinal repair mechanisms by regulatory peptides or other modulatory factors may provide future approaches for the treatment of diseases that are characterized by injuries of the epithelial surface.

IL-5-induced airway eosinophilia--the key to asthma?

Abstract: Bronchial asthma is a chronic inflammatory airway disease defined by reversible airway obstruction and non-specific airway hyper-responsiveness (AHR). Although profound insights have been made into the pathophysiology of asthma, the exact mechanisms inducing and regulating the disease are still not fully understood. Yet, it is generally accepted that the pathological changes in asthma are induced by a chronic inflammatory process which is characterized by infiltration of the bronchial mucosa with lymphocytes and eosinophils, increased mucus production and submucosal edema. There is increasing evidence that an imbalance in the T-helper (Th) cell response of genetically predisposed individuals to common environmental antigens plays a pivotal role in the pathogenesis of allergic bronchial asthma and other atopic disorders. Following allergic sensitization, T cells from atopic patients tend to produce elevated levels of Th2-type cytokines, especially interleukin (IL)-4, IL-13, IL-5 and IL-6, which induce and regulate IgE production and eosinophil airway infiltration. In this review, the role of Th2-type cytokines, IgE and airway eosinophils in the induction of airway inflammation and AHR is discussed, and animal studies of asthma and AHR, mainly in rodents will be considered. A better understanding of the underlying mechanisms leading to asthma pathology may yield more specific immunological strategies for the treatment of this disease which is increasing worldwide.

The pregnancy hormone relaxin is a player in human heart failure

Abstract: Human congestive heart failure is characterized by complex neurohumoral activation associated with the up-regulation of vasoconstricting and salt-retaining mediators and the compensatory rise of counter-regulatory hormones. In the present study, we provide the first evidence that relaxin (RLX), known as a pregnancy hormone, represents a potential compensatory mediator in human heart failure: plasma concentrations of RLX and myocardial expression of the two RLX genes (H1 and H2) correlate with the severity of disease and RLX responds to therapy. The failing human heart is a relevant source of circulating RLX peptides, and myocytes as well as interstitial cells produce RLX. Elevation of ventricular filling pressure up-regulates RLX expression and the hormone acts as a potent inhibitor of endothelin 1, the most powerful vasoconstrictor in heart failure. Furthermore, RLX modulates effects of angiotensin II, another crucial mediator. Our data identify RLX as a new player in human heart failure with potential diagnostic and therapeutic relevance.

Functional cardiac MR imaging with steady-state free precession (SSFP) significantly improves endocardial border delineation without contrast agents.

Abstract: Contrast between blood and myocardium in standard turbo gradient echo MR techniques (TFE) used routinely in clinical practice is mainly caused by unsaturated inflowing blood. Steady-state free precession (SSFP) has excellent contrast even in the absence of inflow effects. In 45 subjects cardiac cine loops in two long axis projections were acquired using TFE and compared with SSFP. A visual score (range 0 worst – 3 best) was assigned for endocardial border delineation for six myocardial segments in two long axis views. Endocardial border delineation score for TFE was 1.3 ± 0.3 per segment and 2.4 ± 0.3 for SSFP (P < 0.0001). Signal intensity blood/signal intensity myocardium was 1.5 ± 0.4 at enddiastole and 1.4 ± 0.3 at systole for TFE and 3.5 ± 1.1 and 3.2 ± 1.3 for SSFP, respectively (P < 0.0001). SSFP increases contrast between blood and myocardium more than twofold, resulting in an improved endocardial border definition. This may reduce variability for the determination of cardiac volumes and ejection fraction. J. Magn. Reson. Imaging 2001;14:362–367. ©2001 Wiley-Liss, Inc.

A longitudinal MRI study of histopathologically defined hypointense multiple sclerosis lesions.

Abstract: Severe tissue destruction is the presumed histopathological correlate of hypointense multiple sclerosis (MS) lesions. In this study we correlated changes of lesion hypointensity over time with initial histopathological features in 14 biopsied MS lesions. The extent of hypointensity increased in initially demyelinated plaques and decreased in remyelinating lesions. The initial axonal loss determined the increase of hypointensity over time. In conclusion, both axonal loss and demyelinating activity determine the evolution of hypointensity over time.

The kiss of death: promises and failures of death receptors and ligands in cancer therapy.

Abstract: Death receptors and their ligands exert important regulatory functions in the maintenance of tissue homeostasis and the physiological regulation of programmed cell death. Currently, six different death receptors are known including tumor necrosis factor (TNF) receptor-1, CD95 (Fas/APO-1), TNF receptor-related apoptosis-mediating protein (TRAMP), TNF-related apoptosis-inducing ligand (TRAIL) receptor-1 and -2, and death receptor-6 (DR6). The signaling pathways by which these receptors induce apoptosis are similar and rely on oligomerization of the receptor by death ligand binding, recruitment of an adapter protein through homophilic interaction of cytoplasmic domains, and subsequent activation of an inducer caspase which initiates execution of the cell death programme. The ability of these receptors and their ligands to kill malignant cells was discovered early and helped to coin the term 'tumor necrosis factor' for the first identified death ligand. This review summarizes the current and rapidly expanding knowledge about the signaling pathways triggered by death receptor/ligand systems, their potency in experimental cancer therapy, and their therapeutic limitations, especially regarding their toxicity for non-malignant cells.

Peptide growth factors in the intestine.

Abstract: A continuously increasing number of regulatory peptides has been demonstrated to be expressed in the intestine and to modulate several functional properties of various intestinal cell populations, including the intestinal epithelium and lamina propria cell populations. These regulatory peptides include members of the epidermal growth factor (EGF) family, the transforming growth factor beta (TGF-beta) family, the insulin-like growth factor (IGF) family, the fibroblast growth factor (FGF) family, the trefoil factor (TFF) family, the colony-stimulating factor (CSF) family, and a few other seemingly unrelated regulatory peptides, such as hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), and various interleukins, interferons and tumour necrosis factor-related proteins. In addition to the well-known effects on cell proliferation, these regulatory peptide factors regulate several other functional properties of epithelial and other cell populations, such as differentiation, migration, and extracellular matrix deposition and degradation. This review is designed not to discuss all the identified factors in detail but to highlight some of the basic principles of growth factor action in the intestine. It focuses mainly on classical growth factors rather than interleukins and interferons.

Age-related changes in protein oxidation and proteolysis in mammalian cells.

Abstract: Reactive oxygen species generated as by-products of oxidative metabolism, or from environmental sources, frequently damage cellular macromolecules. Proteins are recognized as major targets of oxidative modification, and the accumulation of oxidized proteins is a characteristic feature of aging cells. An increase in the amount of oxidized proteins has been reported in many experimental aging models, as measured by the level of intracellular protein carbonyls or dityrosine, or by the accumulation of protein-containing pigments such as lipofuscin and ceroid bodies. In younger individuals, moderately oxidized soluble cell proteins appear to be selectively recognized and rapidly degraded by the proteasome. An age-related accumulation of oxidized proteins could, therefore, be a result of declining activity of the proteasome. Previous research to investigate the notion of an age-related decline in the content and/or activity of the proteasome has generated contradictory results. The latest evidence, including our own recent findings, indicates that proteasome activity does, indeed, decline during aging as the enzyme complex is progressively inhibited by oxidized and cross-linked protein aggregates. We propose that cellular aging involves both an increase in (mitochondrial) oxidant production and a progressive decline in proteasome activity. Eventually so much proteasome is inactivated that oxidized proteins begin to accumulate rapidly and contribute to cellular dysfunction and senescence.