Association between Bone marrow lesions & synovitis and symptoms in symptomatic knee osteoarthritis.

OBJECTIVE: Bone marrow lesions (BMLs) on MRI are typically subchondral in location, however, a proportion occur at knee ligament attachments and also include a cyst-like component. Our aim was to determine whether the volume of BML subtypes and synovial tissue volume (STV) was associated with symptoms in symptomatic knee OA. METHOD: Images were acquired in a sub-sample who had taken part in a randomised trial of vitamin D therapy in knee OA (UK-VIDEO). Contrast-enhanced (CE) MRI was performed annually. In those who had ≥1 follow-up and a baseline scan (N = 50), STV and BML volume was assessed. BMLs were categorised by location and by the presence/absence of a cyst-like component. WOMAC was assessed annually. We used fixed-effects panel-regression modelling to examine the association between volume and symptoms. RESULTS: There was no association between knee pain and total subchondral BML volume (b = 0.3 WOMAC units, 95% CI -0.3 to 1.0) or total ligament-based BML volume (b = 1.9, 95% CI -1.6 to 5.3). The volume of subchondral BMLs with a cyst-like component was not associated with pain (b = 0.8, 95% CI -0.5 to 2.1) however, the volume of the cyst-like component itself was associated with pain (b = 51.8, 95% CI 14.2 to 89.3). STV was associated with pain (b = 2.2, 95% CI 0.6 to 3.7). CONCLUSION: The volume of the cyst-like component from subchondral BMLs with a cyst-like component was associated with knee pain. BML location, however, did not influence symptoms. STV was also associated with knee symptoms.

The experimental Alzheimer drug phenserine: preclinical pharmacokinetics and pharmacodynamics.

Phenserine, a phenylcarbamate of physostigmine, is a new potent and highly selective acetylcholinesterase (AChE) inhibitor, with a > 50-fold activity versus butyrylcholinesterase (BChE), in clinical trials for the treatment of Alzheimer's disease (AD). Compared to physostigmine and tacrine, it is less toxic and robustly enhances cognition in animal models. To determine the time-dependent effects of phenserine on cholinergic function, AChE activity, brain and plasma drug levels and brain extracellular acetylcholine (ACh) concentrations were measured in rats before and after phenserine administration. Additionally, its maximum tolerated dose, compared to physostigmine and tacrine, was determined. Following i.v. dosing, brain drug levels were 10-fold higher than those achieved in plasma, peaked within 5 min and rapidly declined with half-lives of 8.5 and 12.6 min, respectively. In contrast, a high (> 70%) and long-lasting inhibition of AChE was achieved (half-life > 8.25 h). A comparison between the time-dependent plasma AChE inhibition achieved after similar oral and i.v. doses provided an estimate of oral bioavailability of 100%. Striatal, in vivo microdialysis in conscious, freely-moving phenserine-treated rats demonstrated > 3-fold rise in brain ACh levels. Phenserine thus is rapidly absorbed and cleared from the body, but produces a long-lasting stimulation of brain cholinergic function at well tolerated doses and hence has superior properties as a drug candidate for AD. It selectively inhibits AChE, minimizing potential BChE side effects. Its long duration of action, coupled with its short pharmacokinetic half-life, reduces dosing frequency, decreases body drug exposure and minimizes the dependence of drug action on the individual variations of drug metabolism commonly found in the elderly.

Behavioural, histochemical and biochemical consequences of selective immunolesions in discrete regions of the basal forebrain cholinergic system.

The effectiveness of a recently developed immunotoxin, 192 IgG-saporin, was evaluated for making selective lesions of subgroups of basal forebrain cholinergic neurons. Following a pilot series of injections into the nucleus basalis magnocellularis to establish the effective dose for intraparenchymal lesions, separate groups of rats received injections of the immunotoxin into the septum, into the diagonal band of Broca or into the nucleus basalis magnocellularis. The lesions produced extensive and effective loss of cholinergic neurons in the discrete areas of the basal forebrain, as identified by loss of cells staining for acetylcholinesterase and p75NGFr, with a parallel loss of acetylcholinesterase staining and choline acetyltransferase activity in the target areas associated with each injection site in the dorsolateral neocortex, cingulate cortex and hippocampus. The selectivity of the lesion for cholinergic neurons was supported by the lack of gliosis and sparing of small to medium-sized cells at the site of injection of the toxin, including the glutamate decarboxylase immunoreactive cells that contribute to the septohippocampal projection. In spite of the extensive disturbance in the cholinergic innervation of the neocortex and hippocampus, immunotoxin lesions produced no detectable deficit in the Morris water maze task in any of the lesion sites within the basal forebrain. By contrast small but significant deficits were seen on tests of nocturnal activity (septal and nucleus basalis magnocellularis lesions), open field activity (septal and diagonal band lesions), passive avoidance (nucleus basalis magnocellularis lesions) and delayed non-matching to position (septal lesions). The results indicate that the 192 IgG-saporin provides a powerful tool for making effective lesions of the basal forebrain cholinergic neurons, and that the behavioural sequelae of such lesions warrant further detailed investigation.

Tunable diode laser spectroscopy for isotope analysis--detection of isotopic carbon monoxide in exhaled breath.

A high resolution tunable infrared diode laser spectroscopy system was developed for isotope analysis with sensitivity at ppb levels. Such a system is ideally suited for detection and measurement of minute amounts of infrared active compounds present in a huge noninfrared active background such as air. The operation and capabilities of the system were demonstrated by measuring physiological levels of isotopic carbon monoxide, 12C16O and 13C16O, naturally present in exhaled human breath with essentially no sample preparation. The simplicity in obtaining such data suggests that fundamental physiological information may be derived from noninvasive measurements. This makes the system potentially useful for many biomedical applications.