Der Einfluss der Nikotinsäure auf die Expression von PPARgamma, Scavenger Rezeptoren und ABCA-1 auf monozytoiden und hepatischen Zellen

Das natürliche Vitamin Nikotinsäure wird seit 1955 in pharmakologischer Dosierung als Medikament zur Behandlung von Dyslipidämien und bei arteriosklerotischen Gefäßveränderungen verwendet. Von Nikotinsäure konnte als erstem Medikament bereits 1975 im Coronary Drug Project nachgewiesen werden, dass es die Mortalität nach Myokardinfarkt signifikant und anhaltend reduziert. Nikotinsäure senkt den LDL-Plasmaspiegel und erhöht den HDL-Spiegel. Während der Nikotinsäureeffekt auf LDL vielfach untersucht wurde, ist über den Mechanismus der HDL-Erhöhung bisher wenig bekannt. Nikotinsäure stimuliert massiv die PGD2-Synthese in vivo. Der Hauptmetabolit von PGD2, das 15-deoxy-Δ12,14-Prostaglandin J2, wurde kürzlich als wichtigster endogener Aktivator des nukleären Transkriptionsfaktors PPAR erkannt. PPAR ist entscheidend an der Regulation des Scavenger Rezeptors CD36 und des zellulären Cholesterinexporters ABCA-1 beteiligt. Diese Rezeptoren dominieren die zelluläre Aufnahme modifizierter LDL-Partikel und die Ausschleusung zellulären Cholesterins auf HDL-Partikel und damit die Cholesterinhomöostase in Monozyten/Makrophagen in der Gefäßwand. Deshalb war es Ziel der Arbeit an einem Makrophagenmodell zu untersuchen, ob Nikotinsäure Scavenger-Rezeptoren und zelluläre Cholesterin-Transporter tatsächlich beeinflusst und so über einen gesteigerten reversen Cholesterintransport aus der Peripherie zur Leber seinen klinischen Nutzen vermitteln könnte. Als Modelle wurden die differenzierte humane Monozytenlinie MM6, die humane hepatische Linie HepG2 und frisch präparierte humane Monozyten verwendet. Die Expression der Scavenger Rezeptoren CD36, SR-BI, LOX-1, des LDL-R, des Cholesterinexporters ABCA-1, des Transkriptionsfaktors PPAR und von -Aktin wurden durch reverse Transkription der spezifischen mRNAs, nachfolgende PCR und Quantifizierung der Amplifikate über HPLC bestimmt. Die Proteinexpression von CD36 und PPAR wurden mittels spezifischer Antikörper nach Fluoreszenzmarkierung im FACS gemessen. Die Änderung des zellulären Cholesteringehalts durch Inkubationen mit Nikotinsäure, oxLDL und delipidiertem HDL wurde nach zellulärer Lipidextraktion in einem adaptierten enzymatischen Assay gemessen. Im Makrophagenmodell stimulierte die Inkubation der Zellen mit Nikotinsäure schon nach 3 h und mindestens bis 48 h anhaltend die Transkription von PPAR, des PPAR abhängigen Scavenger-Rezeptors CD36 und des zellulären Cholesterinexporters ABCA-1. Dagegen blieb die Transkription des ApoB-spezifischen LDL-R und des Scavenger-Rezeptors LOX-1 unverändert. Vergleichbare Effekte waren auch am Hepatozytenmodell nachweisbar. Die Effekte auf die PPAR und CD36 Expression waren tendenziell auch auf Proteinebene nachweisbar. Die Stimulation von CD36 und ABCA-1 durch Nikotinsäure konnte auf RNA-Ebene auch an frisch präparierten peripheren Monozyten von Normalpersonen nachgewiesen werden. Die funktionelle Bedeutung der Nikotinsäureeffekte wurde in einem Cholesterin-Aufnahme und Efflux-Assay überprüft. Dabei reduzierte die Inkubation mit Nikotinsäure den zellulären Cholesteringehalt basal und unter oxLDL-Exposition und steigerte den zellulären Cholesterin-Efflux auf delipidiertes HDL. Diese neuen Effekte der Nikotinsäure auf mehrere Lipid-Rezeptoren und -Transporter können Lipidablagerungen in der Gefäßintima reduzieren, der Schaumzellbildung entgegenwirken und durch vermehrte Einschleusung von zellulärem Cholesterin in den reversen Cholesterintransport zurück zur Leber die HDL-Spiegel erhöhen. Diese peripheren Effekte der Nikotinsäure ergänzen die Effekte von Statinen und liefern ein Rational für einen potentiell überadditiven klinischen Nutzen durch die Kombinationstherapie, die gegenwärtig klinisch geprüft wird

Nanostructured Nb-substituted CaMnO3 n-type thermoelectric material prepared in a continuous process by ultrasonic spray combustion

One way to further optimize the thermoelectric properties toward a higher ZT is a temperature stable nanoengineering of materials, where the thermal conductivity is reduced by increasing the phonon scattering at the grain boundaries. To study this, Nb-substituted CaMnO3 perovskite-type material was synthesized by ultrasonic spray combustion (USC). The grain growth has been characterized by x-ray diffraction, scanning electron microscopy, and transmission electron microscopy. Finally, the thermoelectric properties of compacted and sintered bulk samples from powder prepared by a continuous scalable USC process were measured up to 1050 K. The thermoelectric legs were prepared by an adapted sintering process. Here, a compromise between enhanced porosity to reduce the thermal conductivity and securing of mechanical stability and low resistivity should be obtained. Based on the grain growth mechanisms, an advanced sintering process for additional interconnection of the particles without particle growth is needed to further increase the thermoelectric performanc

Thermoelectric oxide modules tested in a solar cavity-receiver

Four-leg thermoelectric oxide modules (TOMs) consisting of two p-type (La1.98Sr0.02CuO4) and two n-type (CaMn0.98Nb0.02O3) thermoelectric (TE) legs were produced with a manufacturing quality factor between 30 and 60%. The pressed sintered TE legs revealed 90% of the theoretical density to ensure a sufficient mechanical stability of the TE modules. The legs were connected electrically in series and sandwiched thermally in parallel between two Al2O3 plates serving as absorber and cooler, respectively. A solar cavity-receiver packed with an array of TOMs was subjected to concentrated thermal radiation with peak solar radiative flux intensities exceeding 600 kW/m2. Temperature distributions in the cavity, open-circuit voltage (VOC), and maximum output power (Pmax) were measured for different external loads and solar radiative fluxes (qin). Finally, the solar-to-electricity conversion efficiency (η) was calculate

Seminar Future Internet WS2012

Near Field Communication (NFC) is an emerging close range, low bandwidth, induction based communication standard. It is already and will be more broadly integrated tightly with modern smartphones, devices and operating systems. Payment services, setup of high-bandwidth connections, information sharing and identity verification become possible by just touching two NFC devices together. This paper tries to give an overview over how NFC technology works, what some of its current and potential applications are and which risks and exploits come along with its simplicity

Effects of Elevated beta-Estradiol Levels on the Functional Morphology of the Testis - New Insights

Elevated estradiol levels are correlated with male infertility. Causes of hyperestrogenism include diseases of the adrenal cortex, testis or medications affecting the hypothalamus-pituitary-gonadal axis. The aim of our study was to elucidate the effects of estradiol treatment on testicular cellular morphology and function, with reference to the treatment regimen received. Testes samples (n = 9) were obtained post-orchiectomy from male-to-female transsexuals within the age range of 26–52 years. Each patient had a minimum of 1–6 years estradiol treatment. For comparison, additional samples were obtained from microscopically unaltered testicular tissue surrounding tumors (n = 7). The tissues obtained were investigated by stereomicroscopy, histochemistry, scanning electron microscopy (SEM) and immunohistochemistry. Our studies revealed that estradiol treatment significantly decreased the diameter of the seminiferous tubules (p < 0.05) and induced fatty degeneration in the surrounding connective tissue. An increase in collagen fiber synthesis in the extracellular matrix (ECM) surrounding the seminiferous tubules was also induced. Spermatogenesis was impaired resulting in mainly spermatogonia being present. Sertoli cells revealed diminished expression of estrogen receptor alpha (ERα). Both Sertoli and Leydig cells showed morphological alterations and glycoprotein accumulations. These results demonstrate that increased estradiol levels drastically impact the human testis

A Nonsense Mutation in TMEM95 Encoding a Nondescript Transmembrane Protein Causes Idiopathic Male Subfertility in Cattle

Genetic variants underlying reduced male reproductive performance have been identified in humans and model organisms, most of them compromising semen quality. Occasionally, male fertility is severely compromised although semen analysis remains without any apparent pathological findings (i.e.,idiopathic subfertility). Artificial insemination (AI) in most cattle populations requires close examination of all ejaculates before insemination. Although anomalous ejaculates are rejected, insemination success varies considerably among AI bulls. In an attempt to identify genetic causes of such variation, we undertook a genome-wide association study (GWAS). Imputed genotypes of 652, 856 SNPs were available for 7962 AI bulls of the Fleckvieh (FV) population. Male reproductive ability (MRA) was assessed based on 15.3 million artificial inseminations. The GWAS uncovered a strong association signal on bovine chromosome 19 (P = 4.08x10(-59)). Subsequent autozygosity mapping revealed a common 1386 kb segment of extended homozygosity in 40 bulls with exceptionally poor reproductive performance. Only 1.7% of 35, 671 inseminations with semen samples of those bulls were successful. None of the bulls with normal reproductive performance was homozygous, indicating recessive inheritance. Exploiting whole-genome resequencing data of 43 animals revealed a candidate causal nonsense mutation (rs378652941, c. 483C>A, p.Cys161X) in the transmembrane protein 95 encoding gene TMEM95 which was subsequently validated in 1990 AI bulls. Immunohistochemical investigations evidenced that TMEM95 is located at the surface of spermatozoa of fertile animals whereas it is absent in spermatozoa of subfertile animals. These findings imply that integrity of TMEM95 is required for an undisturbed fertilisation. Our results demonstrate that deficiency of TMEM95 severely compromises male reproductive performance in cattle and reveal for the first time a phenotypic effect associated with genomic variation in TMEM95

Long-term kinetics of Zika virus RNA and antibodies in body fluids of a vasectomized traveller returning from Martinique: a case report

BACKGROUND: The magnitude of the current Zika virus (ZIKV) epidemic has led to a declaration of a Public Health Emergency of International Concern by the WHO. Findings of viable viral particles in semen for several weeks are corroborating reports of sexual transmission of ZIKV. Serious consequences of a positive diagnostic result particularly in the pregnant patient are calling for precise diagnostic tools also at later time points after infection. Currently, recommendations suggest a diagnostic period of direct viral detection of 5 to 7 days after onset of symptoms in serum or plasma, and up to 3 weeks in urine samples. CASE PRESENTATION: A vasectomized 41-year-old German returning from Martinique presented at the outpatient clinic of the Department for Infectious Diseases and Tropical Medicine, Munich, with subfebrile temperature, rash, malaise, severe retro-orbital pain and occipital lymphadenopathy. The main complaints resolved after ten days without specific treatment. We are reporting on clinical course and results of direct and indirect detection methods of ZIKV in different sample types including whole blood, ejaculate, urine, serum, plasma and saliva samples up to 119 days post symptom onset. Ejaculate samples remained PCR positive for ZIKV until day 77, whole blood samples until day 101. CONCLUSIONS: The case presentation adds to the still limited knowledge of kinetics of detection of ZIKV by direct as well as indirect methods. Here, a complete data set including results from PCR, serology and cell culture is provided allowing an improved evaluation of optimum diagnostic periods for testing a variety of sample types. Moreover, a high viral load of ZIKV RNA was detected in ejaculate of the vasectomized patient. This finding sheds new light on the possible localizations of ZIKV replication in the human male reproductive tract

Impact of the 'Repositioning Test' on Postoperative Outcome of Retroluminar Transobturator Male Sling Implantation

OBJECTIVE: To evaluate prospectively the value of the ‘repositioning test’ (RT) in preoperative patient selection for the efficacy of male stress urinary incontinence (SUI) treatment using a retroluminar transobturator male sling (AdVance sling). PATIENTS AND METHODS: 65 consecutive patients with SUI after radical prostatectomy were included in this singlecenter prospective study. Preoperatively, patients were classified into those with ‘positive’ and ‘negative’ RT. Postoperative results were analyzed and the association between the result of the RT and postoperative outcome was evaluated. RESULTS: 53 patients (81.5%) showed preoperatively a positive RT and 12 patients (18.5%) a negative RT. After a followup of 12 months, patients with positive RT showed a cure rate (0 pads/day) of 83% and patients with a negative RT showed only a cure rate of 25%. A positive RT significantly correlated with cure in outcome (p < 0.001). CONCLUSIONS: Patients with positive RT have a significantly better hance for successful AdVance sling implantation. The RT is minimally invasive, easy to learn and easy to perform. Therefore, the RT is a very useful tool for preoperative patient selection

Scaling Up electrodes for photoelectrochemical water splitting : fabrication process and performance of 40cm2 LaTiO2N photoanodes

A scalable process for fabrication of particlebased photoanodes is developed. The electrodes are versatilely made of photocatalytically active semiconductor particles, in this case LaTiO2N, and optionally coated with cocatalysts and protecting components, all immobilized on a conducting substrate. The involved fabrication steps are restricted to scalable processes such as electrophoretic deposition, annealing in air, and dip coating. Special care is taken to ensure efficient charge transport inbetween particles and to the substrate by incorporating conducting connectors. By adapting the fabrication steps, the electrode geometrical dimension is increased from the size of a typical lab electrode of 1 to 40cm2. The quality of the scaleup process is characterized by comparing the photoanodes in terms of thickness, lightabsorption properties, and morphology. For several compositions, the electrochemical performance of both electrode sizes is assessed by measuring the photocurrents and faradaic efficiencies. The comparison revealed a complex upscaling behavior and showed that the photoelectrode size affects performance already on the 0.1m scale.(VLID)460373