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Loss of Hes7 function leads to irregular somite formation demonstrating that Hes7 is a crucial component of the segmentation clock during somitogenesis. Experiments revealed that not only the repressor functionality but also the half-life of the protein is crucial for oscillatory expression of Hes7 and regular somite formation. Numerical integration of a delay equation system supported this finding. However, in a recent paper it was shown that the number of binding sites is also decisive for damped or undamped oscillations. It was shown that for more than one binding site the Hill coefficient increases. This leads to a completely different behavior. The oscillations are undamped and thus the mathematical model can no longer explain the results observed in the experiments. In this paper we propose a more sophisticated model for the Hes7 oscillator. Since Hes7 is degraded by the ubiquitin-proteasome pathway we include Michaelis-Menten kinetics for the ubiquitination of Hes7. We identify the Michaelis-Menten constant as an additional model parameter for oscillatory behavior. By increasing the Michaelis-Menten constant we found damped oscillations even if the Hill coefficient is increased.

Background: Antemortem levels of tau in the cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients have repeatedly been demonstrated to be elevated when compared to controls. Although CSF tau has been reported to be elevated even in very mild AD, it is unknown how tau levels change during the course of the disease., Methods: We have followed 29 mild-to-moderately affected AD subjects over 2 years with repeated CSF taps. Clinical measures of dementia severity (Clinical Dementia Rating Scale, Global Deterioration Scale and Mini-Mental Status Examination) were obtained at the start and conclusion of the observation period, and CSF tau was measured with a standard enzyme-linked immunoabsorbent assay (ELISA) using two monoclonal antibodies., Results: Despite significant changes in the clinical measures consistent with progression of the disease, no significant overall change in CSF tau levels (548 +/- 355 vs. 557 +/- 275 pg/mL, NS) was observed. None of the clinical variables was significantly correlated with either baseline measures of CSF tau or delta CSF tau (last-first). Similarly, CSF tau at baseline and changes over time were not significantly related to Apolipoprotein E (APO E) phenotype., Conclusions: These data suggest that CSF tau levels are stable over extended periods of time in a group of mild-to-moderately demented AD subjects and that CSF tau levels do not predict the severity or rate of progression of AD, at least not during the middle stages of the illness.

Background: As a test of possible muscarinic up-regulation, the cortisol response to intravenous (i.v.) physostigmine (an anticholinesterase) was measured in 9 elderly volunteers before and after chronic cholinergic blockade with the muscarinic cholinergic antagonist scopolamine., Methods: Each of the 9 elderly control subjects was given two physostigmine (0.5 mg i.v.) infusions separated by 21 doses of nightly scopolamine (1.2 mg p.o.). No scopolamine was administered the night before infusions, and glycopyrrolate (0.2 mg i.v.) was administered prior to physostigmine, to block its peripheral effects. Vital signs were monitored and blood samples were collected at six time points surrounding the physostigmine infusion (-10, +10, +20, +30, +50, and +70 min). Behavioral measures and cognitive tests were administered prior to and 30 min after the physostigmine., Results: The cortisol response to physostigmine was greater after the second (post-chronic scopolamine) infusion study compared to the first (p < .05) as measured by an area under the curve analysis of all time points. When individual time points were compared, the mean cortisol response was significantly increased after the second physostigmine infusion at the +50- and +70-min time points (p < .05). There were no significant changes in behavioral rating scales, cognitive tests, or vital signs between the two physostigmine infusion study days., Conclusions: This study demonstrates increased hypothalamic-pituitary-adrenocortical axis responsivity to a central nervous system cholinergic stimulus after chronic muscarinic blockade in 9 elderly control subjects. It also gives further evidence to support previous suggestions of muscarinic plasticity, specifically postsynaptic up-regulation, in the aging brain following exposure to chronic anticholinergic treatment.

The clinical relevance of platelet function assessment with stagnation point flow adhesio-aggregometry (SPAA) has been verified. Quantitative analysis of platelet adhesion and aggregation is possible by means of mathematical analysis of the dark-field, light intensity curves (growth curves) obtained during the SPAA experiment. We present a computational procedure for evaluating these curves, which was necessitated by, and is based on, actual clinical application. A qualitative growth curve classification, corresponding to a basic and distinct pattern of platelet deposition and characteristic of a regularly occurring clinical state is also presented.