Mice with heterozygous deficiency of manganese superoxide dismutase (SOD2) have a skin immune system with features of "inflamm-aging".

Dendritic cells (DC) are central in regulating skin immunity. Immunosenescence is associated with a chronic inflammatory state. Little is known about the contribution of DC to "inflamm-aging". When determining langerhans cell (LC) numbers, we found a 60 % reduction of LC in aged epidermis. Reactive oxygen species(ROS) are linked with aging. The mitochondrial manganese superoxide dismutase (SOD2) is in the first line of antioxidant defense. We investigated the function of DC from SOD2 heterozygous mice (SOD2+/-) and found that at 4 months of age LC numbers are not altered, but activated LC have impaired expression of MHC-II and CD44. Immature SOD2+/- DC produced increased proinflammatory IL-6 and chemokines CXCL1 and CXCL2. Upon challenge SOD2+/- DC accumulated ROS. When activating SOD2+/- DC by LPS they less efficiently upregulated MHC-II, CD86 and CD44. Surprisingly, in vivo contact hypersensitivity (CHS) was enhanced in SOD2+/- mice although SOD2+/- DC were less potent in stimulating wt T cells. However, SOD2+/- T cells showed increased proliferation, even when stimulated with SOD2+/- DC, possibly explaining the increased CHS. Our findings suggest that SOD2 is a molecular candidate in the regulation of "inflamm-aging" conveying both immunosuppressive and proinflammatory signals through alteration of DC and T cell functions.

Amyloid aggregation inhibitory mechanism of arginine-rich D-peptides.

It is widely believed that Alzheimer's disease pathogenesis is driven by the production and deposition of the amyloid-ß peptide (Aß) in the brain. In this study, we employ a combination of in silico and in vitro approaches to investigate the inhibitory properties of selected arginine-rich D-enantiomeric peptides (D-peptides) against amyloid aggregation. The D-peptides include D3, a 12-residue peptide with anti-amyloid potencies demonstrated in vitro and in vivo, RD2, a scrambled sequence of D3, as well as truncated RD2 variants. Using a global optimization method together with binding free energy calculations followed by molecular dynamics simulations, we perform a detailed analysis of D-peptide binding to Aß monomer and a fibrillar Aß structure. Results obtained from both molecular simulations and surface plasmon resonance experiments reveal a strong binding of D3 and RD2 to Aß, leading to a significant reduction in the amount of ß structures in both monomer and fibril, which was also demonstrated in Thioflavin T assays. The binding of the D-peptides to Aß is driven by electrostatic interactions, mostly involving the D-arginine residues and Glu11, Glu22 and Asp23 of Aß. Furthermore, we show that the anti-amyloid activities of the D-peptides depend on the length and sequence of the Dpeptide, its ability to form multiple weak hydrophobic interactions with Aß, as well as the Aß oligomer size.

Nanosuspension formulations for low-soluble drugs: pharmacokinetic evaluation using spironolactone as model compound.

Various particle sizes of spironolactone as a model low solubility drug were formulated to yield micro-and nanosuspensions of the type solid lipid nanoparticles and DissoCubes. Seven oral and one i.v. formulations were tested in an in vivo pharmacokinetic study in rats with the aim of characterizing the bioavailability of spironolactone on the basis of its metabolites canrenone and 7-alpha-thiomethylspirolactone. In addition, a dose escalation study was carried out using nonmicronized spironolactone suspension as well as a nanosuspension type DissoCubes. On the basis of AUC as well as Cmax ratios, three groups of formulations were distinguished. The biggest improvement was seen with a solid lipid nanoparticle formulation yielding a 5.7-fold increase in AUC for canrenone and a similar improvement based on the Cmax metric, followed by a group of three formulations containing nanosized, micronized, and coarse drug material and surfactant. The DissoCubes nanosuspension yielded highly significant improvements in bioavailability averaging 3.3-fold in AUC and 3.0-fold in terms of Cmax for canrenone. The third class encompasses all other formulations, which showed very little to no improvement in bioavailability. The results show that the particle size minimization was not the major determining factor in the bioavailability improvement. Rather, the type of surfactant used as stabilizer in the formulations was of greater importance. Improvement in drug solubility in the intestine as well as in dissolution rate of spironolactone are the most likely mechanisms responsible for the observed effect, although additional mechanisms such as permeability enhancement may also be involved.

[Appearance of choroidal melanoma on high resolution MRI using 1.5T with a dedicated surface coil in 200 consecutive patients]. / Erscheinungsbild von Aderhautmelanomen in der hochauflösenden 1,5-T-MRT mit einer Oberflächenspule anhand von 200 konsekutiven Patienten.

PURPOSE: Choroidal melanomas usually present a characteristic appearance in MRI. Differing characteristics can cause problems in differential diagnosis between melanomas and other masses in the globe. The purpose of this study was to evaluate the appearance of choroidal melanomas with MRI in a large consecutive patient group. METHODS: In a prospective study, 200 patients with choroidal melanomas were investigated with MRI using a 1.5 T scanner and a 5 cm surface coil. Both quantitative and qualitative evaluation of the resulting images was performed. RESULTS: 78.5% of the melanomas presented with homogeneous signal intensities within the tumor due to a homogeneous pigmentation whereas 21.5% of the melanomas demonstrated a mixed pigmentation. Signal intensities of the homogeneous melanomas in the plain T1-WI were moderately or markedly hyperintense compared to the vitreous in 29.3% and moderately or markedly hypointense in the T2-WI in 37.1%. An accompanying retinal detachment was found in 65.5% and an extraocular growth in 7.0%. CONCLUSIONS: In 10% to 37% we observed the typical well known MR appearance, including homogeneous high signal in the T1-WI and low signals in the T2-WI. For further differentiation, morphological criteria (e.g. shape, size, and position) were used, which are also discussed.

[Ambulatory versus inpatient laparoscopy: decision aids for choice of management]. / Ambulante versus stationäre Laparoskopie: Beratungshilfen zur Versorgungswahl.

319 Patients are retrospectively competed, which underwent an inpatient or outpatient gynecological laparoscopy in 1992. Equality exists for martial status, education degree, nationality, anesthesiological risk and social structure. Outpatients are older, more rarely private assured, more often abdominal preoperated, have more children and live closer to the providing clinic. The satisfaction with the chosen medical care was outpatiently higher than inpatiently (97% vs 86%). In this context hesitation of security, quality of care and involvement at home are important. The inpatient group is characterized by patients with infertility, endometriosis and extrauterine gravidity, distance to employment and intensity of troubles have been important for the decision of medical providing. Outpatients were less anxious, sterilization and adhesions were main diagnoses. Here decisive factors for the choice of medical care have been care requiring relatives and financial aspects. By mean of these characteristics predictors are diverted for both kinds of care for being help to the advising doctor.