The expression of surface markers on dendritic cells as indicators for the sensitizing potential of chemicals

Novel approaches to testing of skin sensitizing chemicals have made use of immature dendritic cells (DCs) cultured from different hematopoietic progenitors. These cells resemble Langerhans cells (LCs), which are the most potent antigen presenting cells in the skin. Former research has focused on the phenotypic and functional changes of LCs after application of skin sensitizers. But it has proven difficult to isolate sufficient numbers of LCs from skin. This disadvantage is overcome by cultures of immature DCs providing high numbers of reactive cells. The aim of the present investigation was to test the response of DC cultures established from different blood donors to known sensitizers, an irritant and a vehicle. The sensitizers NiSO₄, dinitrochlorobenzene (DNCB), 2,4,6 trinitrobenzene sulfonic acid (TNBS), -hexylcinnamaldehyde (Cinn) and eugenol (Eu) induced the up-regulation of the co-stimulatory molecule CD86, of intercellular adhesion molecule CD54 and of the HLA-DR antigen. The irritant sodium dodecyl sulfate (SDS) and the vehicle dimethyl sulfoxide (DMSO) had no effect. A high rate of responders within blood donors was found for NiSO₄, TNBS, Cinn and Eu, while DNCB was less effective. The augmentation of surface marker expression in dendritic cells obtained from peripheral human blood seems to be a promising readout in prescreening for strong and moderate sensitizers. This test could thus help to reduce animal numbers for in vivo testing.     

Impact of insulin resistance on the developmental potential of immature oocytes retrieved from human chorionic gonadotropin-primed women with polycystic ovary syndrome undergoing in vitro maturation

In a homeostasis model assessment-insulin resistance (HOMA-IR)-positive group of women with polycystic ovary syndrome undergoing in vitro maturation (IVM), the maturation rate of immature oocytes was significantly lower compared with a HOMA-IR negative group of women (47% vs. 59%). The results of our study showed that IR and hyperinsulinemia have an adverse effect on the developmental potential of immature oocytes retrieved in the IVM procedure.     

Neuropeptides in epilepsy

Neuropeptides play an important role in modulating seizures and epilepsy. Unlike neurotransmitters which operate on a millisecond time-scale, neuropeptides have longer half lives; this leads to modulation of neuronal and network activity over prolonged periods, so contributing to setting the seizure threshold. Most neuropeptides are stored in large dense vesicles and co-localize with inhibitory interneurons. They are released upon high frequency stimulation making them attractive targets for modulation of seizures, during which high frequency discharges occur. Numerous neuropeptides have been implicated in epilepsy; one, ACTH, is already used in clinical practice to suppress seizures. Here, we concentrate on neuropeptides that have a direct effect on seizures, and for which therapeutic interventions are being developed. We have thus reviewed the abundant reports that support a role for neuropeptide Y (NPY), galanin, ghrelin, somatostatin and dynorphin in suppressing seizures and epileptogenesis, and for tachykinins having pro-epileptic effects. Most in vitro and in vivo studies are performed in hippocampal tissue in which receptor expression is usually high, making translation to other brain areas less clear. We highlight recent therapeutic strategies to treat epilepsy with neuropeptides, which are based on viral vector technology, and outline how such interventions need to be refined in order to address human disease.     

A simple and efficient automated cGMP‐compliant radiosynthesis of [11C]metomidate using solid phase extraction cartridge purification

[¹¹C]metomidate ([¹¹C]MTO) is a radiotracer widely used to detect disorders of adrenocortical origin by positron emission tomography (PET) imaging. [¹¹C]MTO PET/computed tomography (PET/CT) is considered a sensitive and specific noninvasive alternative to adrenal vein sampling (AVS) in the management of primary hyperaldosteronism (PHA). Herein, we report a reliable automated procedure for the routine manufacturing of [¹¹C]MTO in current good manufacturing practice (cGMP) conditions on the commercial Synthra MeI_Plus Loop Vessel synthesizer. The method is based on a combination of the captive‐solvent ¹¹C‐methylation of the carboxylate salt 1b of the MTO precursor 1a followed by solid phase extraction (SPE) cartridge purification methodology, which substitutes HPLC purification of the crude reaction mixture. Starting from 45 GBq [¹¹C]CO₂ at the end of bombardment (EOB), 3 GBq of pure [¹¹C]MTO was produced in 18 minutes with 12% decay corrected radiochemical yield (RCY) at the end of synthesis (EOS) and with the modest molar activity of 13 GBq/μmol at the time of application. Each dose produced met all established quality control (QC) criteria. The method can easily be implemented into other commercial automated radiosynthesizers for manufacturing carbon‐11 labeled radiotracers.     

Determination of regional rate of glucose metabolism in lumbar muscles in patients with generalized tendomyopathy using dynamic 18F-FDG PET]

Generalized tendomyopathy (GTM), or fibromyalgia (FM), is a disease characterized by wide-spread pain in the musculoskeletal system which usually begins at a single site, e.g., as low-back pain or cervical syndrome, and develops into generalized pain over months or years. The disorder affects primarily women, beginning around the age of 35 and reaching its peak during or after the menopause. Its etiology is still unknown. Secondary forms are observed particularly in rheumatoid arthritis. In order to get more information on FM we determined the local metabolic rate of glucose in vivo in the skeletal muscle (lumbar region) with dynamic 18F-FDG positron emission tomography (PET). 2 healthy volunteers and 6 female patients with FM reaching in age from 31 to 53 years were scanned. As 18F-FDG PET scanning is a metabolic tool, it is crucial to observe standardized conditions of metabolic steady-state. We used, therefore, the hyperinsulinemic euglycemic insulin clamp technique to stimulate the myogenic glucose uptake under stable plasma-glucose levels. The local metabolic rates of glucose utilization were estimated with a non-linear least squares fit on the 3 compartment 18F-FDG-model. A lumped constant of 0.67 was assumed. Under glucose clamp conditions patients with FM showed a significantly (p < 0.001) lower metabolic rate of glucose (4.3 +/- 1.1) mumol/100 g tissue/min compared with normal volunteers (8.5 +/- 2.3 mumol/100 g/min). Due to a significantly (p < 0.005) increased glucose backflow from tissue into the vascular space (k2 in the kinetic model) the rate of phosphorylation was markedly reduced in patients with FM.(ABSTRACT TRUNCATED AT 250 WORDS)     

Guidelines to determine the role of laparoscopically assisted vaginal hysterectomy

Copyright © 1998 by Mosby, Inc.