Mesoporous Silica Nanoparticles as pH-Responsive Carrier for the Immune-Activating Drug Resiquimod Enhance the Local Immune Response in Mice.

Nanoparticle-based delivery systems for cancer immunotherapies aim to improve the safety and efficacy of these treatments through local delivery to specialized antigen-presenting cells (APCs). Multifunctional mesoporous silica nanoparticles (MSNs), with their large surface areas, their tunable particle and pore sizes, and their spatially controlled functionalization, represent a safe and versatile carrier system. In this study, we demonstrate the potential of MSNs as a pH-responsive drug carrier system for the anticancer immune-stimulant R848 (resiquimod), a synthetic Toll-like receptor 7 and 8 agonist. Equipped with a biotin-avidin cap, the tailor-made nanoparticles showed efficient stimuli-responsive release of their R848 cargo in an environmental pH of 5.5 or below. We showed that the MSNs loaded with R848 were rapidly taken up by APCs into the acidic environment of the lysosome and that they potently activated the immune cells. Upon subcutaneous injection into mice, the particles accumulated in migratory dendritic cells (DCs) in the draining lymph nodes, where they strongly enhanced the activation of the DCs. Furthermore, simultaneous delivery of the model antigen OVA and the adjuvant R848 by MSNs resulted in an augmented antigen-specific T-cell response. The MSNs significantly improved the pharmacokinetic profile of R848 in mice, as the half-life of the drug was increased 6-fold, and at the same time, the systemic exposure was reduced. In summary, we demonstrate that MSNs represent a promising tool for targeted delivery of the immune modulator R848 to APCs and hold considerable potential as a carrier for cancer vaccines.

[Role of Institutional Review Boards for multi-centre studies in national health services research - a cross-sectional study of the effort to obtain secondary ethical approvals for the DACAPO study]. / Die Rolle von Ethikkommissionen für die nationale Versorgungsforschung - eine Querschnittsstudie des Aufwandes zur Erlangung von Sekundärvoten anhand der DACAPO-Studie.

BACKGROUND: Health services research (HSR) is of fundamental importance for the continuous improvement of preventive, diagnostic or therapeutic measures. The conduct of multi-centre HSR studies requires that ethical approval by Institutional review boards (IRB's) is obtained. We documented the effort, the complexity and the man power necessary to obtain secondary ethical approval for a national HSR in Germany ("Surviving the Acute Respiratory Distress Syndrome" [DACAPO-study]). METHODS: Having obtained a primary ethical approval by the IRB of Regensburg University, the time, correspondence, necessity for amendments, corrections, or additional costs by 34 IRB's for 64 participating study centers was documented. RESULTS: The complete obtainment was found to be time consuming and associated with a high workload and man power. A time span of seven month was needed to receive votes from all IRB's. The median time span was 25,5 days (25 %/75 % percentile 13 and 42 days, respectively). Requirements in terms of corrections or amendments were inhomogeneous and frequent changes were necessary. There were additional fees for secondary votes of 4328,40 €. Total costs for the study center Regensburg were 21.193,40 € (2,6 % of the grant volume). CONCLUSION: Obtaining all ethical approvals for a multi-centre observational HSR study in Germany is complex and time consuming. Various and inhomogeneous formalities may delay the plan and realization of HSR. A Homogenization and simplification of the procedure of ethics votes should be discussed.

A zinc phthalocyanine based periodic mesoporous organosilica exhibiting charge transfer to fullerenes.

Periodic mesoporous organosilica (PMO) materials offer a strategy to position molecular semiconductors within a highly defined, porous network. We developed thin films of a new semiconducting zinc phthalocyanine-bridged PMO exhibiting a face-centered orthorhombic pore structure with an average pore diameter of 11 nm. The exceptional degree of order achieved with this PMO enabled us to create thin films consisting of a single porous domain throughout their entire thickness, thus providing maximal accessibility for subsequent incorporation of a complementary phase. The phthalocyanine building blocks inside the pore walls were found to be well-aggregated, enabling electronic conductivity and extending the light-harvesting capabilities to the near IR region. Ordered 3D heterojunctions capable of promoting photo-induced charge transfer were constructed by impregnation of the PMO with a fullerene derivative. When integrated into a photovoltaic device, the infiltrated PMO is capable of producing a high open-circuit voltage and a considerable photocurrent, which represents a significant step towards potential applications of PMOs in optoelectronics.

Mesoporous structures confined in anodic alumina membranes.

The synthesis of nanoporous membranes based on different concepts and materials is a field of active research. This review focuses on the synthesis strategies, mesophase evolution mechanisms and potential applications of mesoporous materials confined within anodic alumina membranes (AAM). Following a rapid evolution of synthetic techniques, a significant number of different mesoporous materials (e.g., silica, titania, and carbon) with highly regular structures can now be prepared within these membranes. In recent years, efforts have also been made to understand the formation mechanisms of these hierarchical mesophases. The resulting organized nanoporous membranes open up a wide range of potential applications in fields such as templating oriented nanowires and controlled separation and release of molecules. For example, while various synthesis strategies can be used for the preparation of membrane-embedded nanowires, the latter can also be obtained as isolated objects after dissolution of the alumina host matrix. The review also discusses issues such as control of structural defects or integrity of interfaces that should be addressed in future research in order to fully exploit the potential of these hierarchical mesoporous channel structures.

Acupuncture in critically ill patients improves delayed gastric emptying: a randomized controlled trial.

BACKGROUND: Malnutrition remains a severe problem in the recovery of critically ill patients and leads to increased in-hospital morbidity and in-hospital stay. Even though early enteral nutrition has been shown to improve overall patient outcomes in the intensive care unit (ICU), tubefeed administration is often complicated by delayed gastric emptying and gastroesophageal reflux. Acupuncture has been successfully used in the treatment and prevention of perioperative nausea and vomiting. In this study we evaluated whether acupuncture can improve gastric emptying in comparison with standard promotility drugs in critically ill patients receiving enteral feeding. METHODS: Thirty mechanically ventilated neurosurgical ICU patients with delayed gastric emptying, defined as a gastric residual volume (GRV) >500 mL for ≥ 2 days, were prospectively and randomly assigned to either the acupoint stimulation group (ASG; bilateral transcutaneous electrical acupoint stimulation at Neiguan, PC-6) or the conventional promotility drug treatment group (DTG) over a period of 6 days (metoclopramide, cisapride, erythromycin). Patients in the ASG group did not receive any conventional promotility drugs. Successful treatment (feeding tolerance) was defined as GRV <200 mL per 24 hours. RESULTS: Demographic and hemodynamic data were similar in both groups. After 5 days of treatment, 80% of patients in the ASG group successfully developed feeding tolerance versus 60% in the DTG group. On treatment day 1, GRV decreased from 970 ± 87 mL to 346 ± 71 mL with acupoint stimulation (P = 0.003), whereas patients in the DTG group showed a significant increase in GRV from 903 ± 60 mL to 1040 ± 211 mL (P = 0.015). In addition, GRV decreased and feeding balance (defined as enteral feeding volume minus GRV) increased in more patients in the ASG group (14 of 15) than in the DTG group (7 of 15; P = 0.014). On treatment day 1, the mean feeding balance was significantly higher in the ASG group (121 ± 128 mL) than in the DTG group (-727 ± 259 mL) (P = 0.005). Overall, the feeding balance improved significantly on all days of treatment in comparison with the DTG group. Patients in the DTG group did not show an increase in feeding balance until day 6. CONCLUSIONS: We introduce a new protocol for acupuncture administration in the critical care setting. We demonstrated that this protocol was more effective than standard promotility medication in the treatment of delayed gastric emptying in critically ill patients. Acupoint stimulation at Neiguan (PC-6) may be a convenient and inexpensive option (with few side effects) for the prevention and treatment of malnutrition in critically ill patients.

Multiple nanowire species synthesized on a single chip by selectively addressable horizontal nanochannels.

The synthesis of horizontal porous anodic alumina (PAA) structures with individually addressable channel systems is demonstrated. This was achieved by developing a multicontact design of aluminum finger structures (two to five contacts) on silicon wafers. These aluminum contacts were electrically isolated from each other, allowing the individual anodization of each contact at different conditions. This way it is possible to synthesize different pore diameters, pore densities, and channel lengths on a single chip. Scanning electron microscopy (SEM) characterization revealed that the neighboring contacts are not significantly altered during the anodization procedure. After successful barrier-layer thinning, the individual finger structures of each contact were filled by electrodeposition and thermal chemical vapor deposition. The resulting metal (Au, Cu, Ni, Co) and semiconductor (Te, Si) nanowires embedded within the porous anodic alumina mold were characterized by SEM and energy dispersive X-ray measurements. The multicontact fabrication results open a new route toward complex nanoelectronic and sensing applications.

Multiple core-shell functionalized colloidal mesoporous silica nanoparticles.

The selective functionalization of the inner and outer surfaces of colloidal mesoporous silica (CMS) nanoparticles with different trialkoxysilanes, following a newly developed delayed co-condensation approach, results in bifunctional CMS. Complementary CMS nanoparticles were prepared with two different functional groups located either on the outer shell or in the inner core of the particle. The identification and localization of the functional groups was achieved by means of different techniques including zeta potential, nitrogen sorption measurements, and fluorescence spectroscopy. This last technique was applied to fluorescein isothiocyanate (FITC)-labeled CMS featuring aminopropyl functional groups on the periphery or the internal pore surface of the particles. Fluorescence quenching experiments were carried out with dodecanethiolate-stabilized gold nanoparticles having a diameter greater than the pore size of the CMS. It could be shown that fluorescence quenching occurs only when the FITC is positioned on the outer surface of the CMS nanoparticles, whereas no quenching was observed for FITC located in the inner core of the nanoparticle. These results clearly confirm the controlled localization of the aminopropyl groups in the nanometer space of the CMS particles. Our approach thus offers the opportunity to synthesize, in a novel multistep co-condensation strategy, various bifunctional mesoporous nanoparticles with controlled localization of different functional groups in the inner core or on the outer shell of the nanoparticle.

Periodic mesoporous organosilica in confined environments.

Periodic mesoporous organosilica (PMO) mesophases based on bis(triethoxysilyl)ethane (BTSE) were synthesized within the confined tubular environment of anodic alumina membrane (AAM) channels. The resulting mesophases were investigated by transmission small angle X-ray scattering (SAXS), nuclear magnetic resonance (NMR), nitrogen sorption, and transmission electron microscopy (TEM). Two different surfactants--nonionic Brij 56 and ionic cetyltrimethylammonium bromide (CTAB)--were used in an acid-catalyzed evaporation-induced self-assembly (EISA) process. Brij 56 as the structure-directing agent (SDA) resulted in the formation of either the hexagonal circular or the cubic mesophase. While the hexagonal circular mesophase is common for such kinds of composites, the cubic mesophase has never been reported before. The template could be removed from the mesophases by template extraction and calcination after annealing the samples. When using CTAB as the SDA during EISA, the only mesophase observed was the hexagonal circular structure. This is in contrast to previous experiments and reports on pure silica mesophases, where the only mesophase formed with CTAB is hexagonal columnar.

The impact of acoustic stimulation on the AEP monitor/2 derived composite auditory evoked potential index under awake and anesthetized conditions.

UNLABELLED: The AEP Monitor/2 features an auditory evoked potential (AEP) and electroencephalogram (EEG)-derived hybrid index of the patient's hypnotic state. The composite AEP index (AAI) is preferably calculated from the AEP, but in case of low signal quality it is based entirely on the spontaneous EEG. We investigated the impact of auditory input on the AAI in 16 patients with correctly positioned headphones for acoustic stimulation and headphones disconnected from the patient's ears under awake and anesthetized conditions. The AAI and the Narcotrend Index (NI), another EEG-based measure of hypnotic depth, were recorded simultaneously. AAI values under awake and anesthetized conditions were higher with correctly positioned headphones than with headphones disconnected from the patient's ears (P < 0.05) but remained within the range indicating the patient's actual hypnotic state as given by the manufacturer of the monitor. Under awake conditions with correctly positioned headphones we observed frequent fluctuations between AEP-derived and EEG-derived AAI, whereas with headphones disconnected from the patient's ears the AAI calculation was completely EEG based. Acoustic stimulation had no impact on the Narcotrend Index. Although relevant misinterpretations of the patient's hypnotic state as a consequence of a turnover from AEP-derived to EEG-derived AAI values should not occur, an improved harmonization of the two methods of indexing would be desirable. IMPLICATIONS: The AEP Monitor/2 generates an Index (AAITM) indicating the patient's hypnotic state by analyzing either auditory evoked potentials (AEP) or spontaneous electroencephalographic (EEG) activity. We demonstrate that, though significantly different under AEP-derived or EEG-derived conditions, AAI values remain within the range indicating the patient's actual hypnotic state as given by the manufacturer of the device.