The structure of the Physcomitrium patens photosystem I reveals a unique Lhca2 paralogue replacing Lhca4.

The moss Physcomitrium patens diverged from green algae shortly after the colonization of land by ancient plants. This colonization posed new environmental challenges, which drove evolutionary processes. The photosynthetic machinery of modern flowering plants is adapted to the high light conditions on land. Red-shifted Lhca4 antennae are present in the photosystem I light-harvesting complex of many green-lineage plants but absent in P. patens. The cryo-EM structure of the P. patens photosystem I light-harvesting complex I supercomplex (PSI-LHCI) at 2.8 Å reveals that Lhca4 is replaced by a unique Lhca2 paralogue in moss. This PSI-LHCI supercomplex also retains the PsaM subunit, present in Cyanobacteria and several algal species but lost in vascular plants, and the PsaO subunit responsible for binding light-harvesting complex II. The blue-shifted Lhca2 paralogue and chlorophyll b enrichment relative to flowering plants make the P. patens PSI-LHCI spectroscopically unique among other green-lineage supercomplexes. Overall, the structure represents an evolutionary intermediate PSI with the crescent-shaped LHCI common in vascular plants, and contains a unique Lhca2 paralogue that facilitates the moss's adaptation to low-light niches.

Acute neurological care in north-east Germany with telemedicine support (ANNOTeM): protocol of a multi-center, controlled, open-label, two-arm intervention study.

BACKGROUND: Both diagnosis and treatment of neurological emergencies require neurological expertise and are time-sensitive. The lack of fast neurological expertise in regions with underserved infrastructure poses a major barrier for state-of-the-art care of patients with acute neurological diseases and leads to disparity in provision of health care. The main purpose of ANNOTeM (acute neurological care in North East Germany with telemedicine support) is to establish effective and sustainable support structures for evidence based treatments for stroke and other neurological emergencies and to improve outcome for acute neurological diseases in these rural regions. METHODS: A "hub-and-spoke" network structure was implemented connecting three academic neurological centres ("hubs") and rural hospitals ("spokes") caring for neurological emergencies. The network structure includes (1) the establishment of a 24/7 telemedicine consultation service, (2) the implementation of standardized operating procedures (SOPs) in the network hospitals, (3) a multiprofessional training scheme, and (4) a quality management program. Data from three major health insurance companies as well as data from the quality management program are being collected and evaluated. Primary outcome is the composite of first time of receiving paid outpatient nursing care, first time of receiving care in a nursing home, or death within 90 days after hospital admission. DISCUSSION: Beyond stroke only few studies have assessed the effects of telemedically supported networks on diagnosis and outcome of neurological emergencies. ANNOTeM will provide information whether this approach leads to improved outcome. In addition, a health economic analysis will be performed. STUDY REGISTRATION: German Clinical Trials Register DRKS00013067, date of registration: November 16 th, 2017, URL: http://www.drks.de/DRKS00013068.

Synthesis and properties of titanomagnetite (Fe(3-x)Ti(x)O4) nanoparticles: a tunable solid-state Fe(II/III) redox system.

Titanomagnetite (Fe(3-x)Ti(x)O(4)) nanoparticles were synthesized by room temperature aqueous precipitation, in which Ti(IV) replaces Fe(III) and is charge compensated by conversion of Fe(III) to Fe(II) in the unit cell. A comprehensive suite of tools was used to probe composition, structure, and magnetic properties down to site-occupancy level, emphasizing distribution and accessibility of Fe(II) as a function of x. Synthesis of nanoparticles in the range 0≤x≤0.6 was attempted; Ti, total Fe and Fe(II) content were verified by chemical analysis. TEM indicated homogeneous spherical 9-12 nm particles. µ-XRD and Mössbauer spectroscopy on anoxic aqueous suspensions verified the inverse spinel structure and Ti(IV) incorporation in the unit cell up to x≤0.38, based on Fe(II)/Fe(III) ratio deduced from the unit cell edge and Mössbauer spectra. Nanoparticles with a higher value of x possessed a minor amorphous secondary Fe(II)/Ti(IV) phase. XANES/EXAFS indicated Ti(IV) incorporation in the octahedral sublattice (B-site) and proportional increases in Fe(II)/Fe(III) ratio. XA/XMCD indicated that increases arise from increasing B-site Fe(II), and that these charge-balancing equivalents segregate to those B-sites near particle surfaces. Dissolution studies showed that this segregation persists after release of Fe(II) into solution, in amounts systematically proportional to x and thus the Fe(II)/Fe(III) ratio. A mechanistic reaction model was developed entailing mobile B-site Fe(II) supplying a highly interactive surface phase that undergoes interfacial electron transfer with oxidants in solution, sustained by outward Fe(II) migration from particle interiors and concurrent inward migration of charge-balancing cationic vacancies in a ratio of 3:1.

Association of genotypes of the CYP3A cluster with midazolam disposition in vivo.

The genes that encode for CYP3A4 and CYP3A5 are located in the same region (CYP3A cluster) on chromosome 7. Midazolam (MDZ) is a substrate for both CYP3A4 and CYP3A5. We hypothesize that MDZ disposition in vivo is associated with genotypes of the CYP3A cluster. A meta-analysis of the pharmacokinetic (PK) parameters from seven clinical trials was carried out, in which MDZ was administered both intravenously and orally. DNA samples were available from 116 patients. There were significant ethnic differences in the allelic frequencies of these four common single-nucleotide polymorphisms (SNPs) in the CYP3A cluster. Significant linkage disequilibrium was found between CYP3A5(*)3 and CYP3A4(*)1A in Caucasians, and between CYP3A5(*)1 and CYP3A4(*)1B in African Americans. There were no differences in MDZ disposition in vivo between different genotypes, haplotypes and diplotypes in the CYP3A cluster (P>0.05). No significant differences in MDZ PK parameters were observed between Caucasians and African Americans. Women had higher weight-corrected systemic and oral clearance than men, but dose-adjusted AUC and bioavailability differences were not observed between sexes. The clinical importance of elevated CYP3A activity in women remains to be determined. The r(GC)'s of MDZ PK parameters were between 0.3 and 13.6%. In conclusion, the meta-analysis of seven studies suggests that environmental factors explain the majority of CYP3A activity variation. Further studies are necessary to define the functional significance of SNPs in the CYP3A cluster and the effects of CYP3A genotypes on MDZ disposition in vivo.

[Postoperative disorders of hemostasis caused by antifactor V circulating anticoagulant]. / Trouble postopératoire de l'hémostase par anticoagulant circulant anti-facteur V.

The case of a 34-year-old woman who experienced a biological haemostasis disorder, without clinical manifestations, is reported. The disorder was caused by a factor V inhibitor induced by a prolonged administration of antibiotics required by a postoperative biliary peritonitis. Therapeutic strategies in patients with an acquired factor V inhibitor are reviewed.

A phase I trial of weekly lomustine in patients with advanced cancer.

BACKGROUND: Lomustine is a commercially available chloroethyl nitrosourea compound whose antitumor activity in vitro and in animal tumor models exceeds its activity in humans. Part of the poor clinical performance of this drug may be explained by dose-limiting subjective toxicity observed with the standard schedule of one oral dose of approximately 130 mg/m2 every 6-8 weeks. METHODS: Twenty patients were enrolled in a Phase I clinical trial of weekly oral lomustine. The first dose level was 24 mg/m2, with subsequent dose increases in increments of 6 mg/m2. Intrapatient dose escalations were allowed if there were no toxic reactions noted after 12 weekly doses. RESULTS: The dose-limiting toxic effect was the development of thrombocytopenia in 35% of patients (6 of 17) treated at 30 mg/m2 after a median of 12 weekly doses (range, 5-20 weeks), whereas in 18% of patients (3 of 17), neutropenia developed after a median of 12 weeks (range, 9-22 weeks). Grade 3 or Grade 4 hematologic toxicity developed in three of three patients whose doses were escalated to 36 mg/m2/week after showing no evidence of toxicity for 12-16 weeks at 30 mg/m2/week. Partial remission was observed in two patients with malignant melanoma, and stable disease was observed in two patients with hypernephroma. Nausea, vomiting, and malaise were not significant complications of treatment. CONCLUSION: Lomustine can be administered at a dose of 30 mg/m2/week for 12+ weeks to patients with cancer who have received previous treatment with minimal toxicity while retaining antitumor activity.

Phase I clinical trial and pharmacokinetic evaluation of 4'-0-tetrahydropyranyladriamycin (THP-adriamycin).

Tetrahydropyranyladriamycin (THP-adriamycin) is an anthracycline analogue currently under development in Europe and Japan. Preclinical studies suggest that it may have greater activity and less cardiac toxicity than doxorubicin. We conducted a phase I clinical and pharmacologic study of THP-adriamycin given as a weekly 15-min infusion for 3 weeks, followed by 1 week of observation. Therapy was associated with minimal acute toxicity. The dose-limiting toxicity was neutropenia, usually maximal during the 4th week after treatment; alopecia was rare. The maximum tolerated dose was 25 mg/m2; for phase II studies using this schedule, a dose of 20 mg/m2 weekly for 3 weeks is recommended. Pharmacokinetic studies revealed a triphasic elimination of the parent compound with alpha, beta, and gamma half-lives of 5.6 min, 1.4 h, and 9.3 h, respectively. THP-adriamycin was rapidly taken up by blood cell components, with concentrations in red blood cells (RBCs), lymphocytes, and polymorphonuclear cells exceeding those in plasma. In all, less than 10% of the compound was eliminated in the urine within 24 h.

The porosity of amosite and chrysotile asbestos.

A computer program has been set up in Fortran language to calculate pore size distribution using the Cranston-Inkley method of calculation. Nitrogen adsorption isotherms were determined on amosite and chrysotile asbestos at - 195 degrees C. Size reduction had a major effect on increasing pore volumes of both asbestos materials.

The adsorption of water and benzene on amosite and chrysotile asbestos.

In previous work the authors showed that chrysoltile is more porous than amostie and consequentd benzene with a high molecular cross-section are used as adsorbates. Benzene adsorption is extremely slow on both adsorbents with each point taking from 4 to 24 hours for equilibration. Evidently, the larger benzene molecule has a more difficult ime working its way thrugh the small pores. The water adsorption is predominait. In both cases hysteresis was found. Benzene adsorption on amosite resembled Type IV which relfects capillary condensation phenomena. With chrysotile some chemisorption may have occurred. BET surface areas and heats of adsorption are calculated.