Catheter Tract Hemorrhages and Intracerebral Hemorrhage Outcomes in the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Trial.

BACKGROUND AND OBJECTIVES: Factors associated with external ventricular catheter tract hemorrhage (CTH) are well studied; whether CTH adversely influence outcomes after intracerebral hemorrhage (sICH), however, is poorly understood. We therefore sought to evaluate the association between CTH and sICH outcomes. METHODS: We performed a post hoc analysis of the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage trial. The exposure was CTH and evaluated on serial computed tomography scans between admission and randomization (approximately 72 hours). The primary outcomes were a composite of death or major disability (modified Rankin Score >3) and mortality alone, both assessed at 6 months. Secondary outcomes were functional outcomes at 30 days, permanent cerebrospinal fluid (CSF) shunt placement, any infection, and ventriculitis. We performed logistic regression adjusted for demographics, comorbidities, sICH characteristics, and treatment assignment, for all analyses. RESULTS: Of the 500 patients included, the mean age was 59 (SD, ±11) years and 222 (44%) were female. CTH occurred in 112 (22.4%) patients and was more common in minority patients, those on prior antiplatelet therapy, and patients who had more than 1 external ventricular drain placed. The end of treatment intraventricular hemorrhage volume was higher among patients with CTH (11.7 vs 7.9 mL, P = .01), but there were no differences in other sICH characteristics or the total duration of external ventricular drain. In multivariable regression models, CTH was not associated with death or major disability (odds ratio, 0.7; 95% CI: 0.4-1.2) or death alone (odds ratio, 0.8; 95% CI, 0.5-1.4). There were no relationships between CTH and secondary outcomes including 30-day functional outcomes, permanent CSF shunt placement, any infection, or ventriculitis. CONCLUSION: Among patients with sICH and large intraventricular hemorrhage, CTH was not associated with poor sICH outcomes, permanent CSF shunt placement, or infections. A more detailed cognitive evaluation is needed to inform about the role of CTH in sICH prognosis.

Plasma Inflammatory Markers and Ventriculostomy-Related Infection in Patients With Hemorrhagic Stroke: A Retrospective and Descriptive Study.

Background: Diagnosis of ventriculostomy-related infection (VRI) remains difficult due to the various existing definitions. In patients with hemorrhagic stroke, its diagnosis might be further complicated by the presence of intraventricular blood. Furthermore, hemorrhagic stroke per se may cause symptoms compatible with VRI. This study aimed to evaluate the benefit of plasma inflammatory markers for the diagnosis of VRI and its differentiation from patients with non-cerebral infection and patients without infection in a cohort of patients with hemorrhagic stroke. Methods: A total of 329 patients with hemorrhagic stroke and an external ventricular drain (EVD) in situ were admitted to the Neurocritical Care Unit, University Hospital Zurich over a period of 6 years. Of those patients, 187 with subarachnoid hemorrhage and 76 with spontaneous intracerebral hemorrhage were included. Patients with VRI were compared to patients without any infection and to patients with non-cerebral infection, with regards to their clinical characteristics, as well as their inflammatory plasma and cerebrospinal fluid (CSF) markers. For the analysis, peak values were considered. Results: The VRI was diagnosed in 36% of patients with subarachnoid and in 17% of patients with intracerebral hemorrhage. The VRI was diagnosed on an average day 9±6.2 after EVD insertion, one day after the white blood cell count (WBC) peaked in CSF (8 ± 6.3). Plasma inflammatory markers (WBC, C-reactive protein "CRP" and procalcitonin "PCT") did not differ among patients with VRI compared to patients without infection. The CRP and PCT, however, were higher in patients with non-cerebral infection than in patients with VRI. The WBC in CSF was generally higher in patients with VRI compared to both patients without any infection and patients with non-cerebral infection. Conclusions: No differences in plasma inflammatory markers could be found between patients with VRI and patients without any infection. Conversely, CRP/PCT were higher in patients with non-cerebral infection than in patients with VRI. Altogether, CRP, PCT, and WBC are not suitable parameters for VRI diagnosis in neurocritical care unit patients.

IgE is associated with exacerbations and lung function decline in COPD.

BACKGROUND: Both allergen-specific IgE and total IgE in serum play a major role in asthma. However, the role of IgE in chronic obstructive pulmonary disease (COPD) is poorly understood. It was the aim of this study to systematically analyze the relationship between serum IgE levels and disease characteristics in large COPD cohorts. METHODS: COSYCONET is a comprehensively characterized cohort of patients with COPD: total IgE and IgE specific to common aeroallergens were measured in serum of 2280 patients, and related to clinical characteristics of the patients. WISDOM is another large COPD population (2477 patients): this database contains the information whether total IgE in serum was elevated (≥ 100 IU/l) or normal in patients with COPD. RESULTS: Both in COSYCONET and WISDOM, total IgE was elevated (≥ 100 IU/l) in > 30% of the patients, higher in men than in women, and higher in currently than in not currently smoking men. In COSYCONET, total IgE was elevated in patients with a history of asthma and/or allergies. Men with at least one exacerbation in the last 12 months (50.6% of all men in COSYCONET) had higher median total IgE (71.3 IU/l) than men without exacerbations (48.3 IU/l): this difference was also observed in the subgroups of not currently smoking men and of men without a history of asthma. Surprisingly, a history of exacerbations did not impact on total IgE in women with COPD. Patients in the highest tertiles of total IgE (> 91.5 IU/ml, adjusted OR: 1.62, 95% CI 1.12-2.34) or allergen-specific IgE (> 0.19 IU/ml, adjusted OR: 2.15, 95% CI 1.32-3.51) were at risk of lung function decline (adjusted by: age, gender, body mass index, initial lung function, smoking status, history of asthma, history of allergy). CONCLUSION: These data suggest that IgE may play a role in specific COPD subgroups. Clinical trials using antibodies targeting the IgE pathway (such as omalizumab), especially in men with recurrent exacerbations and elevated serum IgE, could elucidate potential therapeutic implications of our observations.

Alcohols as Latent Hydrophobes: Entropically Driven Uptake of 1,2-Diol Functionalized Ligands by a Porous Capsule in Water.

Alcohols, with hydroxyl groups compositionally identical to water itself, are consummate hydrophiles, whose high solubilities preclude spontaneous self-assembly in water. Nevertheless, the solute-solvent interactions associated with their highly favorable solvation enthalpies impose substantial entropic costs, similar in magnitude to those that drive the hydrophobic assembly of alkanes. We now show that under nanoconfined conditions this normally dormant "hydrophobicity" can emerge as the driving force for alcohol encapsulation. Using a porous molecular capsule, the displacement of endohedrally coordinated formate ligands (HCO2-) by 1,2-hydroxyl-functionalized l-glycerate (l-gly, l-HOCH2(HO)CHCO2-) was investigated by van't Hoff analysis of variable-temperature 1H NMR in D2O. At pD 5.8, l-gly uptake is enthalpically inhibited. Upon attenuation of this unfavorable change in enthalpy by cosequestration of protons within the alcoholic environment provided by encapsulated diol-functionalized ligands, - TΔ S° dominates over Δ H°, spontaneously filling the capsule to its host capacity of 24 l-gly ligands via an entropically driven hydrophobic response.

The Incidence of Catheter Tract Hemorrhage and Catheter Placement Accuracy in the CLEAR III Trial.

BACKGROUND: Incidence of catheter tract hemorrhage (CTH) after initial ventriculostomy placement ranges from 10 to 34%. We investigated CTH incidence in the Clot Lysis: Evaluation of Accelerated Resolution of Intraventricular Hemorrhage Phase III trial. METHODS: Prospective observational analysis of 1000 computer tomography (CT) scans from all 500 patients enrolled in the trial. All catheters were evaluated on first CT post-placement and on last CT prior to randomization for placement location and CTH size, location, and severity. Clinical variables were assessed for association with CTH with multivariable logistic regression. RESULTS: Of 563 catheters, CTH was detected in 14 and 21% of patients on first and last CT (median 3.7 and 43.4 h after catheter placement, respectively). All, but one were asymptomatic. Majority of CTH (86%) occurred within 24 h after placement, were located within 1 cm of the skull, and had at least one diameter > 5 mm. Most catheters (71%) terminated in the third or lateral ventricle ipsilateral to insertion site. Factors significantly associated with CTH were pre-admission use of antiplatelet drugs, accuracy of catheter placement, non-operating room catheter placement, Asian race, and intraventricular hemorrhage expansion. CONCLUSIONS: CTH incidence on initial catheter placement and during stabilization was relatively low, despite emergent placement in a high-risk population. Catheter placement accuracy was similar or better than convenience samples from the published literature. Decreasing risk of CTH may be achieved with attention to catheter placement accuracy and placement in the operating room. Antiplatelet agent use was an independent risk factor for CTH.

Densely Packed Hydrophobic Clustering: Encapsulated Valerates Form a High-Temperature-Stable {Mo132 } Capsule System.

Porous molecular nanocontainers of {Mo132 }-type Keplerates offer unique opportunities to study a wide variety of relevant phenomena. An impressive example is provided by the highly reactive {Mo132 -CO3 } capsule, the reaction of which with valeric acid results in the very easy release of carbon dioxide and the uptake of 24 valerate ions/ligands that are integrated as a densely packed aggregate, thus indicating the unique possibility of hydrophobic clustering inside the cavity. Two-dimensional NMR techniques were used to demonstrate the presence of the 24 valerates and the stability of the capsule up to ca. 100 °C. Increasing the number of hydrophobic parts enhances the stability of the whole system. This situation also occurs in biological systems, such as globular proteins or protein pockets.

The Uptake and Assembly of Alkanes within a Porous Nanocapsule in Water: New Information about Hydrophobic Confinement.

In Nature, enzymes provide hydrophobic cavities and channels for sequestering small alkanes or long-chain alkyl groups from water. Similarly, the porous metal oxide capsule [{Mo(VI) 6 O21 (H2 O)6 }12 {(Mo(V) 2 O4 )30 (L)29 (H2 O)2 }](41-) (L=propionate ligand) features distinct domains for sequestering differently sized alkanes (as in Nature) as well as internal dimensions suitable for multi-alkane clustering. The ethyl tails of the 29 endohedrally coordinated ligands, L, form a spherical, hydrophobic "shell", while their methyl end groups generate a hydrophobic cavity with a diameter of 11 Šat the center of the capsule. As such, C7 to C3 straight-chain alkanes are tightly intercalated between the ethyl tails, giving assemblies containing 90 to 110 methyl and methylene units, whereas two or three ethane molecules reside in the central cavity of the capsule, where they are free to rotate rapidly, a phenomenon never before observed for the uptake of alkanes from water by molecular cages or containers.

Safety and efficacy of tiotropium Respimat versus HandiHaler in patients naive to treatment with inhaled anticholinergics: a post hoc analysis of the TIOSPIR trial.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) who were naive to anticholinergics before the TIOtropium Safety and Performance In Respimat (TIOSPIR) trial may reflect patients seen in practice, in particular in primary care. In addition, investigating safety in these patients avoids the potential bias in patients who previously received anticholinergics and may be tolerant of their effects. AIMS: The aim of this study was to evaluate whether patients naive to anticholinergic therapy who were treated with tiotropium Respimat 2.5 or 5 µg had different safety and efficacy outcomes than patients treated with tiotropium HandiHaler 18 µg. METHODS: A post hoc analysis of patients who were not receiving anticholinergics before TIOSPIR (N=6,966/17,135) was conducted. Primary end points were risk of death from any cause and risk of COPD exacerbation. Secondary outcomes included severe exacerbation and major adverse cardiovascular events (MACE). Additional analysis of exacerbations was carried out in anticholinergic-naive patients with moderate (GOLD II) disease. RESULTS: Anticholinergic-naive patients had less severe disease than the total TIOSPIR population. Discontinuations because of anticholinergic side effects were infrequent (0.9% overall). Similar to the primary study, patients in the tiotropium Respimat groups had no difference in the risk of death or risk of any or severe exacerbation than patients treated with tiotropium HandiHaler. Risk of MACE was similar across the Respimat and HandiHaler groups. Rates of exacerbations in the subgroup of patients with moderate disease were similar across the Respimat and HandiHaler groups. CONCLUSIONS: Tiotropium Respimat and HandiHaler have similar safety and efficacy profiles in patients who are naive to anticholinergic therapy.

The mechanism of CO2 hydration: a porous metal oxide nanocapsule catalyst can mimic the biological carbonic anhydrase role.

The mechanism for the hydration of CO2 within a Keplerate nanocapsule is presented. A network of hydrogen bonds across the water layers in the first metal coordination sphere facilitates the proton abstraction and nucleophilic addition of water. The highly acidic properties of the polyoxometalate cluster are crucial for explaining the catalysed hydration.

Amplified Rate Acceleration by Simultaneous Up-Regulation of Multiple Active Sites in an Endo-Functionalized Porous Capsule.

Using the hydrolysis of epoxides in water as a model reaction, the effect of multiple active sites on Michaelis-Menten compliant rate accelerations in a porous capsule is demonstrated. The capsule is a water-soluble Ih-symmetry Keplerate-type complex of the form, [{Mo(VI)6O21(H2O)6}12{Mo(V)2O4(L)}30](42-), in which 12 pentagonal "ligands," {(Mo(VI))Mo(VI)5O21(H2O)6}(6-), are coordinated to 30 dimolybdenum sites, {Mo(V)2O4L}(1+) (L = an endohedrally coordinated η(2)-bound carboxylate anion), resulting in 20 Mo9O9 pores. When "up-regulated" by removal of ca. one-third of the blocking ligands, L, an equal number of dimolybdenum sites are activated, and the newly freed-up space allows for encapsulation of nearly twice as many substrate guests, leading to a larger effective molarity (amplification), and an increase in the rate acceleration (k(cat)/k(uncat)) from 16,000 to an enzyme-like value of 182,800.

Biomimetic Approach for Ion Channels Based on Surfactant Encapsulated Spherical Porous Metal-Oxide Capsules.

Distinguished hybrid clusters with hydrophilic and hydrophobic interiors embedded within cationic surfactant shells are spontaneously inserted into lipid bilayers, showing well-defined ionic conductance behaviors. The transport via the narrow pore gates acting as selectivity filters is controlled by the dehydration energy of the cations.

Process Development of Adenoviral Vector Production in Fixed Bed Bioreactor: From Bench to Commercial Scale.

Large-scale vector manufacturing for phase III and beyond has proven to be challenging. Upscaling the process with suspension cells is increasingly feasible, but many viral production applications are still applicable only in adherent settings. Scaling up the adherent system has proven to be troublesome. The iCELLis(®) disposable fixed-bed bioreactors offer a possible option for viral vector manufacturing in large quantities in an adherent environment. In this study, we have optimized adenovirus serotype 5 manufacturing using iCELLis Nano with a cultivation area up to 4 m(2). HEK293 cell cultivation, infection, and harvest of the virus (by lysing the cells inside the bioreactor) proved possible, reaching total yield of up to 1.6×10(14) viral particles (vp)/batch. The iCELLis 500 is designed to satisfy demand for large-scale requirements. Inoculating a large quantity of cell mass into the iCELLis 500 was achieved by first expanding the cell mass in suspension. Upscaling the process into an iCELLis 500/100 m(2) cultivation area cassette was practical and produced up to 6.1×10(15) vp. Flask productivity per cm(2) in iCELLis Nano and iCELLis 500 was in the same range. As a conclusion, we showed for the first time that iCELLis 500 equipment has provided an effective way to manufacture large batches of adenoviral vectors.

A unique fluoride nanocontainer: porous molecular capsules can accommodate an unusually high number of "rather labile" fluoride anions.

The present work refers to the challenging issue of fluoride anion recognition/binding in water by taking advantage of the unique possibilities offered by the porous molecular nanocontainers of the {Mo132} Keplerate type allowing the study of a variety of new phenomena. Reaction of the highly reactive carbonate-type capsule with aqueous HF results in the release of carbon dioxide and integration of an unprecedentedly large number of fluoride anions--partly as coordinated ligands at both the pentagonal units and the linkers, partly as a disordered water/fluoride assembly inside the cavity. The internal assembly and some of the fluoride ligands are easily released, which provides interesting options for future studies regarding coordination chemistry and catalysis under confined conditions.

Porous capsules with a large number of active sites: nucleation/growth under confined conditions.

This work deals with the generation of large numbers of active sites and with ensuing nucleation/ growth processes on the inside wall of the cavity of porous nanocapsules of the type (pentagon)12(linker)30≡{(Mo(VI))Mo(VI)5}12{Mo(V)2(ligand)}30. A first example refers to sulfur dioxide capture through displacement of acetate ligands, while the grafted sulfite ligands are able to trap {MoO3H}(+) units thereby forming unusual {(O2SO)3MoO3H}(5-) assemblies. A second example relates to the generation of open coordination sites through release of carbon dioxide upon mild acidification of a carbonate-type capsule. When the reaction is performed in the presence of heptamolybdate ions, MoO4(2-) ions enter the cavity where they bind to the inside wall while forming new types of polyoxomolybdate architectures, thereby extending the molybdenum oxide skeleton of the capsule. Parallels can be drawn with Mo-storage proteins and supported MoO3 catalysts, making the results relevant to molybdenum biochemistry and to catalysis.

Hedgehog-shaped {Mo368} cluster: unique electronic/structural properties, surfactant encapsulation and related self-assembly into vesicles and films.

The hedgehog-shaped {Mo368} cluster shows unique electronic (extremely high extinction coefficient) and structural features, especially regarding its size, the high number of delocalized electrons which allows to measure the surface enhanced Raman scattering (SERS) spectrum and the option for coordination chemistry inside the cavity. Its relative instability in aqueous solution can be overcome by embedment in a hydrophobic shell of dimethyldioctadecylammonium cations. The resulting hybrid self-assembles into spherical vesicles in acetone-water mixtures, according to a process directed by hydrophobic-hydrophilic interactions. It also forms rather stable Langmuir monolayers while a second layer evolves under higher surface pressure, in accordance with a rather low alkyl surface density.

Keplerate cluster (Mo-132) mediated electrostatic assembly of nanoparticles.

The electrostatic assembly between a series of differently charged Mo-132-type Keplerates present in the compounds (NH4)42[{(Mo(VI))Mo(VI)5O21(H2O)6}12 {Mo(V)2O4(CH3COO)}30].ca. {300 H2O+10 CH3COONH4} (Mo-132a), (NH4)72-n[{(H2O)81-n+(NH4)n} {(Mo(VI))Mo(VI)5O21(H2O)6}12 {Mo(V)2O4(SO4)}30].ca. 200 H2O (Mo-132b), and Na10(NH4)62[{(Mo(VI))Mo(VI)5O21(H2O)6}12 {Mo(V)2O4(HPO4)}30]. ca. {300H2O+2Na(+)+2NH4(+)+4H2PO4(-)} (Mo-132c) with cationic gold nanoparticles (AuNPs) was investigated for the first time. The rapid electrostatic assembly from nanoscopic entities to micron scale aggregates was observed upon precipitation, which closely matched the point of aggregate electroneutrality. Successful assembly was demonstrated using UV-vis, DLS, TEM, and zeta-potential analysis. Results indicate that the point at which precipitation occurs is related to charge balance or electroneutrality, and that counterions at both the Mo-132 and AuNP play a significant role in assembly.

Risk of thromboembolic events with endovascular cooling catheters in patients with subarachnoid hemorrhage.

INTRODUCTION: Endovascular cooling is currently used for hypothermia treatment and fever reduction therapy. At the same time, little is known about the risks associated to endovascular cooling in patients treated with an endovascular cooling catheter (ECC). METHODS: A retrospective chart review of 122 patients with subarachnoid hemorrhage (SAH) treated with an ECC either for therapeutic hypothermia or for fever reduction was performed. ECC-associated thromboembolic events (TEE) such as pulmonary embolism and thrombosis were recorded and compared between patients treated with an ECC and patients treated only with a central venous line (CVL). Additionally, various laboratory parameters were recorded to determine if they might be related to the frequency of TEE's. RESULTS: 43 Patients were treated with an ECC and 79 with a CVL. Patients in the ECC group suffered more frequently from TEE (37 %) than those with a CVL (5 %). None of the laboratory parameters was associated with an increased TEE risk. The treatment with an ECC alone was a risk factor for a TEE, independent from age as well as from Hunt and Hess grade. CONCLUSION: Our data show that the treatment with ECC increases the risk of TEE in SAH patients. Therefore, especially when considered for fever reduction, non-invasive devices for surface cooling should be the first choice.

Water repellency in hydrophobic nanocapsules--molecular view on dewetting.

The hydrophobic effect plays a major role in a variety of important phenomena in chemistry, materials science and biology, for instance in protein folding and protein-ligand interactions. Studies--performed within cavities of the unique metal oxide based porous capsules of the type {(pentagon)12(linker)30}≡{(W)W5}12{Mo2(ligand)}30 with different acetate/water ligand ratios--have provided unprecedented results revealing segregation/repellency of the encapsulated "water" from the internal hydrophobic ligand walls of the capsules, while the disordered water molecules, interacting strongly with each other via hydrogen bonding, form in all investigated cases the same type of spherical shell. The present results can be (formally) compared--but only regarding the repellency effect--with the amazing "action" of the (super)hydrophobic Lotus (Nelumbo) leaves, which are self-cleaning based on water repellency resulting in the formation of water droplets picking up dirt. The present results were obtained by constructing deliberately suitable hydrophobic interiors within the mentioned capsules.

Capsules with highly active pores and interiors: versatile platforms at the nanoscale.

Spherical porous capsules offer new exciting approaches in chemistry, materials sciences, and in context of physical and biological phenomena. The underlying concepts are reported with particular emphasis on metal oxide based capsules of the {M132 } Keplerate type which display-due to their exceptional structural features and easy variation/derivatization as well as exchange of building units-an unmatched range of properties and offer unique opportunities for investigating a variety of basic aspects of nanoscience, including the discovery of some new phenomena, especially those related to hydrophobicity issues that are of significance for everyday life. This relies in particular on the existence of a large number of flexible crown ether type pores/channels and the possibility of changing the interior from completely hydrophilic to completely hydrophobic due to the presence of numerous easily exchangeable internal ligands/functionalities; the capsules can even be constructed so that they enclose a large number of highly active Lewis and Brønsted acid sites. The manifold of possible applications/uses are outlined as subtitles with reference to results as well as possible future studies. There are, among many others, options to control passing cations under different internal frames allowing also their separations, to conduct studies about hydrophobic recognitions and clustering of biological interest in water, controlled internal ion transport, nanoscale dewetting, and to carry out basic as well as new types of reactions under confined conditions.

Tracking "apolar" NMe4+ ions within two polyoxothiomolybdates that have the same pores: smaller clathrate and larger highly porous clusters in action.

Two nanosized polyoxothiometalates were synthesized based on linking oxomolybdate building blocks with {Mo2O2S2}(2+) groups. Remarkably, both compounds are formed selectively primarily upon changing the related concentrations in a logical way; they exhibit common structural features based on the same {Mo9O6S3}-type pores, which result in connections between {Mo6O21} pentagons and {Mo2O2S2}(2+) linkers. Whereas the much larger spherical Mo132-type Keplerate contains twenty pores, the smaller Mo63 -type cluster remarkably contains only two. The two compounds and a similar Keplerate exhibit interesting supramolecular properties related to interactions with the unusual predominantly apolar NMe4(+) cations. Structural characterization of the Mo63 -type compound reveals in the solid state a clathrate-like species that contains four NMe4(+) cations embedded in two types of structurally well-adapted pockets. Related NMR spectroscopic investigations in solution using NMe4(+) as the NMR spectroscopic probe are in agreement with the solid-state description. (1)H NMR spectroscopic experiments (1D variable-temperature, 2D total correlation spectroscopy (TOCSY), exchange spectroscopy (EXSY), and diffusion-ordered spectroscopy (DOSY)) feature firmly immobilized and mobile NMe4(+) ions in relationship with the type of host-guest arrangements. The use of the (1)H NMR DOSY spectroscopic methodology has been successfully applied to track the interactions of the NMe4(+) cations with the {Mo9O6S3} pores of a sulfurated Keplerate, thereby allowing the first quantitative analysis of this type of plugging process. The stability constant K=(210±20) mol(-1) L is discussed related to the character of the process.