Synthesis of C-prenylated analogues of stilbenoid methyl ethers and their cyclic dihydrobenzopyranyl derivatives as potential anti-inflammatory agents

An efficient and versatile synthesis of the naturally occurring C-prenylated stilbenoid methyl ethers and their synthetic analogues is presented. The synthesis represents a six step convergent process including an optimised C-prenylation method. Furthermore, during the demethylation process, six new dihydro-benzopyranyl derivatives were obtained and isolated.

An efficient and versatile synthesis of the naturally occurring C-prenylated stilbenoid methyl ethers and synthetic analogs has been developed.     

Narcolepsy and pregnancy: a retrospective European evaluation of 249 pregnancies

In a retrospective cohort study undertaken in 12 European countries, 249 female narcoleptic patients with cataplexy (n = 216) and without cataplexy (n = 33) completed a self‐administrated questionnaire regarding pregnancy and childbirth. The cohort was divided further into patients whose symptoms of narcolepsy started before or during pregnancy (308 pregnancies) and those in whom the first symptoms of narcolepsy appeared after delivery (106 pregnancies). Patients with narcolepsy during pregnancy were older during their first pregnancy (P < 0.001) and had a higher body mass index (BMI) prior to pregnancy (P < 0.01). Weight gain during pregnancy was higher in narcoleptic patients with cataplexy (P < 0.01). More patients with narcolepsy–cataplexy during pregnancy had impaired glucose metabolism and anaemia. Three patients experienced cataplexy during delivery. The rate of caesarean sections was higher in the narcolepsy–cataplexy group compared to the narcolepsy group (P < 0.05). The mean birth weight and gestational age of neonates were within the normal range and did not differ across groups. Neonatal care was affected adversely by symptoms of narcolepsy in 60.1% of those with narcolepsy during pregnancy. This study reports more obstetric complications in patients with narcolepsy–cataplexy during pregnancy; however, these were not severe. This group also had a higher BMI and higher incidence of impaired glucose metabolism during pregnancy. Caesarian section was conducted more frequently in narcolepsy–cataplexy patients, despite cataplexy being a rare event during delivery. Furthermore, symptoms of narcolepsy may render care of the infant more difficult.     

Incidence and hemodynamic characteristics of near-fainting in healthy 6- to 16-year old subjects

Objectives. We studied the incidence and hemodynamic characteristics of near-fainting under orthostatic stress in healthy children and teenagers.

Background. Orthostatic stress testing is increasingly used to identify young subjects with unexplained syncope. However, the associated incidence of syncope and hemodynamic responses in normal young subjects are not well known.

Methods. Eighty-four healthy subjects 6 to 16 years old performed forced breathing, stand-up and 70° tilt-up tests. An intravenous line to sample blood for biochemical assessment of sympathetic function was introduced between the stand-up and tilt-up tests. Finger arterial pressure was measured continuously. Left ventricular stroke volume was computed from the pressure pulsations.

Results. Sixteen of the 84 subjects were excluded because of technical problems. The incidence of a near-fainting response in the remaining 68 subjects was 10% (7 of 68) for the stand-up test and 40% (29 of 68) for the tilt-up test. Baseline parasympathetic and sympathetic activity of nonfainting and near-fainting subjects was not different. Near-fainting was characterized by attenuated systemic vasoconstriction and exaggerated tachycardia that occurred as early as 1 min after return to the upright position. On tilt-up, plasma adrenaline levels increased by a factor of 2, with slightly higher increments in the near-fainting subjects.

Conclusions. Inadequate vasoconstriction is the common underlying mechanism of near-fainting in young subjects. The remarkably high incidence of near-fainting during the tilt-up test after intravascular instrumentation raises serious doubts about the utility of this procedure in evaluating syncope of unknown origin in young subjects.     

Sonographic Characteristics of Rectal Sensations in Healthy Females

Purpose This study was designed to characterize rectal sensations by visualizing the internal and external anal sphincter and intra-anal transport of bolus during elicited rectal sensations. Methods The anal canal was visualized with real-time transperineal ultrasonography in 13 healthy female volunteers. Rectal sensations were elicited by injecting water into the rectum. The ultrasound images were recorded on a videotape and analyzed offline. Results The median time between an injection of water and the events studied was calculated in 105 rectal sensations. A relaxation in the internal anal sphincter (4 seconds after the injection of water), an antegrade transport of bolus (4 seconds) into the anal canal, and a contraction in the external anal sphincter (5 seconds) were observed before a sensation (6 seconds) was reported. The antegrade flow continued until the distal internal anal sphincter contracted (18 seconds) and the bolus moved in a retrograde transport direction (17 seconds) thereafter the sensation disappeared (18 seconds) and the external anal sphincter relaxed (22 seconds). A significant correlation in time between the end of the sensation, contraction in the internal anal sphincter, reversed flow of anal contents, and relaxation of the external anal sphincter was found (Pearson, P<0.01). Conclusions The results verified that the internal anal sphincter contributes to the perception of rectal sensations by a relaxation allowing intra-anal bolus to increase the pressure on the anoderm during rectal contraction. A new observation is presented on the time relation between contraction in the distal internal anal sphincter, reversed flow in the anal canal, and the end of rectal sensations. Presented at the meeting of the International Continence Society, Christchurch, New Zealand, November 27 to December 1, 2006. Supported by Hitachi Ultrasound, Supfstrasse 24, 6300 Zug Switzerland provided the sonography system. Reprints are not available.     

Abrupt reoxygenation of microvascular endothelial cells after hypoxia activates ERK1/2 and JNK1, leading to NADPH oxidase-dependent oxidant production

OBJECTIVE: Mitogen-activated protein kinases (MAPK) in microvascular endothelial cells (EC) may participate in organ pathophysiology following hypoxia/reoxygenation (H/R). The authors aimed to determine the role of MAPK in H/R-induced reactive oxygen species (ROS) generation in mouse microvascular EC. METHODS: Cultured EC derived from skeletal muscle of male wild-type (WT), gp91phox-/- or p47phox-/- mice were subjected to hypoxia (0.1% O2, 1 h) followed by abrupt reoxygenation, H/RA (hypoxic medium quickly replaced by normoxic medium), or slow reoxygenation, H/RS (O2 diffused to cells through hypoxic medium). Cells were analyzed for ERK, JNK, and p38 MAPK phosphorylation, NADPH oxidase activation, and ROS generation. RESULTS: In WT cells, H/RA but not H/RS rapidly phosphorylated ERK1/2 and JNK1 and subsequently increased ROS production. H/RA did not affect p38. MAPK phosphorylation persisted despite inhibition of NADPH oxidase, mitochondrial respiration, protein tyrosine kinase, or PKC. ROS increase during H/RA was prevented by deletion of gp91phox or p47phox, or MAPK inhibition. CONCLUSIONS: Abrupt reoxygenation after hypoxia activates ERK1/2 and JNK1 in mouse microvascular endothelial cells via a tyrosine kinase-, PKC-, and NADPH oxidase-insensitive mechanism, leading to increased NADPH oxidase-dependent ROS production. The results suggest that MAPK activation in the microvascular endothelium is O2-sensitive, contributing critically to tissue pathophysiology after H/R.     

Analysis of Surface State after Turning of High Tempered Bearing Steel

This paper investigates surface state after turning of the high tempered bearing steel 100Cr6 with a hardness of 40 HRC. White layer (WL) thickness and its microhardness, as well as surface roughness, are investigated as a function of tool flank wear VB as well as cutting speed v_c. The mechanical and thermal load of the machined surface were analysed in order to provide a deeper insight into their superimposing contribution. Cutting energy expressed in terms of cutting force was analyses as that consumed for chip formation F_γ and consumed in the flank wear land F_α. It was found that the mechanical energy expressed in terms of the shear components of the F_α grows with VB, converts to the heat and strongly affects the thickness of the re-hardened layer. Furthermore, the superimposing contribution of the heat generation and its duration in the VB region should also be taken into account. It was also found that the influence of VB predominates over the variable cutting speed.     

The use of PBPK modeling across the pediatric age range using propofol as a case

The project SAFEPEDRUG aims to provide guidelines for drug research in children, based on bottom-up and top-down approaches. Propofol, one of the studied model compounds, was selected because it is extensively metabolized in liver and kidney, with an important role for the glucuronidation pathway. Besides, being a lipophilic molecule, it is distributed into fat tissues, from where it redistributes into the systemic circulation. In the past, both bottom-up (Physiologically based pharmacokinetic, PBPK) and top-down approaches (population pharmacokinetic, popPK) were applied to describe its pharmacokinetics (PK). In this work, a combination of the two was used to check their performance to describe PK in children and neonates (both term and preterm) using propofol as a case compound. First, in vitro data was generated in human liver microsomes and recombinant enzymes and used to develop an adult PBPK model in Simcyp^®. Activity adjustment factors (AAFs) were calculated to account for differences between in vitro and in vivo enzyme activity. Clinical data were analyzed using a 3-compartment model in NONMEM. These data were used to construct a retrograde PBPK model and for qualification of the PBPK models. Once an accurate in vivo clearance was obtained accounting for the contribution of the different metabolic pathways, the resulting PBPK models were challenged with new data for qualification. After that, the constructed adult PPBK model for propofol was extrapolated to the pediatric population. Both the default built-in and in vivo derived ontogeny functions were used to do so. The models were qualified by comparing their predicted PK parameters to published values, and by comparison of predicted concentration–time profiles to available clinical data. Clearance values were predicted well, especially when compared with values obtained from trials where long-term sampling was applied, whereas volume of distribution was lower compared to the most common popPK model predictions. Concentration–time profiles were predicted well up until and including the preterm neonatal population. In this work, it was thus shown that PBPK can be used to predict the PK up to and including the preterm neonatal population without the use of pediatric in vivo data. This work adds weight to the need for further development of PBPK models, especially regarding distribution modeling and the use of in vivo derived ontogeny functions.     

Radioiodinated Hypericin: Its Biodistribution, Necrosis Avidity and Therapeutic Efficacy are Influenced by Formulation

Purpose

To study whether formulation influences biodistribution, necrosis avidity and tumoricidal effects of the radioiodinated hypericin, a necrosis avid agent for a dual-targeting anticancer radiotherapy.

Methods

Iodine-123- and 131-labeled hypericin (¹²³I-Hyp and ¹³¹I-Hyp) were prepared with Iodogen as oxidant, and formulated in dimethyl sulfoxide (DMSO)/PEG400 (polyethylene glycol 400)/water (25/60/15, v/v/v) or DMSO/saline (20:80, v/v). The formulations with excessive Hyp were optically characterized. Biodistribution, necrosis avidity and tumoricidal effects were studied in rats (n?=?42) without and with reperfused liver infarction and implanted rhabdomyosarcomas (R1). To induce tumor necrosis, R1-rats were pre-treated with a vascular disrupting agent. Magnetic resonance imaging, tissue-gamma counting, autoradiography and histology were used.

Results

The two formulations differed significantly in fluorescence and precipitation. ¹²³I-Hyp/Hyp in DMSO/PEG400/water exhibited high uptake in necrosis but lower concentration in the lung, spleen and liver (p?<?0.01). Tumor volumes of 0.9?±?0.3 cm³ with high radioactivity (3.1?±?0.3% ID/g) were detected 6 days post-treatment. By contrast, ¹³¹I-Hyp/Hypin DMSO/saline showed low uptake in necrosis but high retention in the spleen and liver (p?<?0.01). Tumor volumes reached 2.6?±?0.7 cm³ with low tracer accumulation (0.1?±?0.04%ID/g).

Conclusions

The formulation of radioiodinated hypericin/hypericin appears crucial for its physical property, biodistribution, necrosis avidity and tumoricidal effects.     

Come,join, lead: Attracting students to careers in aging and promoting involvement in gerontological societies

Geriatric educators face the challenge of attracting more clinicians, scientists, and educators into geriatrics and gerontology, and promoting involvement in gerontological societies. A survey of psychologists (N = 100) examined factors that attract students in clinical/counseling psychology to practice with older adults, as well as experiences in organizational service. For 58%, interest in aging began at the undergraduate level, but for others interest developed later. About one half cited academic exposure such as mentorship (51%), research (47%), or coursework (45%) as sparking interest, along with family (68%) or work experience (61%). Involvement in professional organizations lags (58%), in part owing to misperceptions about what those activities require. A continued targeted effort at the undergraduate and graduate level is essential to attract students to careers in aging. To preserve vital professional organizations, enhanced outreach may be useful to dispel myths about service and encourage engagement.