Oscillations of Hes7 caused by negative autoregulation and ubiquitination.

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.

Longitudinal stability of CSF tau levels in Alzheimer patients.

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.

Physostigmine challenge before and after chronic cholinergic blockade in elderly volunteers.

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.

Combining serotonin reuptake inhibitors and bupropion in partial responders to antidepressant monotherapy.

BACKGROUND: Many patients with affective illness show partial or otherwise unsatisfactory responses to standard treatments, encouraging trials of combinations of pharmacologically dissimilar antidepressants. METHOD: Records of consecutive outpatients with affective disorders only partially responsive to treatment with a serotonin reuptake inhibitor (SRI) or bupropion, alone, were reviewed for changes in specific symptoms and risks of adverse events when an SRI and bupropion were combined. RESULTS: Greater symptomatic improvement was found in 19 (70%) of 27 subjects during a mean +/- SD of 11 +/- 14 months of combined daily use of bupropion (243 +/- 99 mg) with an SRI (31 +/- 16 mg fluoxetine-equivalents) than with either agent alone. Adverse effect risks were similar to those associated with each monotherapy, with a > 10% incidence of sexual dysfunction (N = 11, 41%), insomnia (N = 6, 22%), anergy (N = 4, 15%), and tremor (N = 3, 11%) during combined therapy; there were no seizures. CONCLUSION: With conservative dosing and close monitoring, combinations of SRIs with bupropion in this uncontrolled clinical series appeared to be safe and often more effective than monotherapy.

Newer psychotropic medication use in nursing home residents.

OBJECTIVE: To evaluate the use of newer psychotropic agents in nursing home residents in the era of new Health Care Financing Administration (HCFA) guidelines. DESIGN: Retrospective chart review of referrals to an on-site geriatric psychiatry service in seven Eastern Massachusetts facilities during 1995-1996. SUBJECTS: The 298 patients examined included 226 women and 72 men with a mean (SD) age of 81.9 (9.4) years. MEASUREMENTS: Patient demographics, psychiatric history and medical diagnoses, prescribed medication information, and mental status examination results were recorded systematically. Descriptive statistics of demographics, medication use, and dosing were generated, and comparative analyses were performed by chi-square, ANOVA, and Tukey's tests. RESULTS: Overall, 69% of subjects were taking at least one psychotropic medication. Although benzodiazepines (32%) and antipsychotics (42%) were used by a large portion of subjects, antidepressants (61%) were the most commonly prescribed psychotropic, with 53% taking serotonin reuptake inhibitors. The atypical antipsychotic, risperidone, accounted for more than 30% of antipsychotic prescriptions. Low rates of anticholinergic use and low doses and rates of tricyclic antidepressant use were found in Alzheimer's disease patients. Mean dosing of the psychotropic agents fell within HCFA guidelines. CONCLUSIONS: Newer-generation psychotropics have had a significant impact on the prescribing practices of primary physicians in treating nursing home residents. Of clinical importance is the high rate of antidepressant use in a population that has traditionally received inadequate pharmacotherapy for depression. More studies are needed to examine a shift to the use of other psychotropic drugs in this population in the post-HCFA area.

Discriminant power of combined cerebrospinal fluid tau protein and of the soluble interleukin-6 receptor complex in the diagnosis of Alzheimer's disease.

Alzheimer's disease (AD) still can only be definitively diagnosed with certainty by examination of brain tissue. There is a great need for a noninvasive, sensitive and specific in vivo test for AD. We combined cerebrospinal fluid analyses of tau protein (levels were significantly increased in AD patients [p=0.0001]), a putative marker of neuronal degeneration, with components of the soluble interleukin-6 receptor complex (sIL-6RC: IL-6, soluble IL-6 receptor and soluble gp130), putative markers of neuroregulatory and inflammatory processes in the brain. A stepwise multivariate discriminant analysis revealed that tau protein and soluble gp130 (levels were significantly reduced in AD subjects [p=0.007]), the affinity converting and signal-transducing receptor of neuropoietic cytokines, maximized separation between the investigated groups. The discriminant function predicted 23 of 25 clinically diagnosed AD patients (sensitivity 92%) with mild to moderate dementia correctly as having AD. Furthermore, 17 of 19 physically and cognitively healthy age-matched control subjects (specificity 90%) were accurately distinguished by this test. Later predicting with the jackknife procedure each case in turn through the remaining patient group, the discriminant function remained stable. Our data suggest that multivariate discriminant analysis of combined CSF tau protein and sIL-6RC components may add more certainty to the diagnosis of AD, however, the method will need to be extended to an independent group of patients, comparisons and control subjects to assess the true applicability.

Interleukin-6 and the soluble IL-6 receptor are decreased in cerebrospinal fluid of geriatric patients with major depression: no alteration of soluble gp130.

Interleukin-6 (IL-6) is hypothesized to play an important role in the interaction between immune mechanisms and the central nervous system. We investigated whether cerebrospinal fluid (CSF) concentrations of interleukin-6 (IL-6), the soluble IL-6 receptor (sIL-6R) and the soluble form of the signal transducing and affinity converting receptor gp130 (sgp130) are altered in geriatric patients with major depression (MD). In 20 geriatric patients with MD and 20 age-matched healthy control subjects CSF concentrations of the three components of the sIL-6R complex were analyzed by enzyme-linked immunosorbent assays (ELISA). All patients except one were treated with psychotropic drugs. We found statistically significant decreased CSF concentrations of IL-6 (P<0.001) and of the sIL-6R (P<0.001) of patients with MD. Levels of sgp130 showed no statistically significant difference between patients and controls.

Platelet response to vascular surgery--a preliminary study on the effect of aspirin and heparin.

Patients with peripheral arterial disease (PAD) demonstrate high cardiovascular mortality, which is further increased after arterial reconstruction. Enhanced platelet reactivity has been postulated for these patients. The effect of surgery and of periprocedural aspirin and heparin therapy on platelet reactivity was assessed with the Stagnation Point Flow Adhesio-Aggregometer (SPAA). The platelet adhesivity and aggregability of 44 PAD patients was quantitated perioperatively. Aspirin was administered during the entire course, low molecular weight heparin (LMWH) preoperatively and as of the fourth postoperative (pOP) day and unfractionated heparin (UH) upon surgery and three days thereafter. A group of 15 aspirin-free general surgical patients receiving LMWH and with no evidence of PAD served as controls. Plasma fibrinogen levels and platelet count were determined. The heparin-induced platelet activation (HIPA) assay for detection of heparin-associated thrombocytopenia (HAT) antibodies was also performed. Baseline values of SPAA-measured platelet reactivity (p < 0.001) and plasma fibrinogen (p < 0.01) were higher for patients as compared to controls and increased markedly after surgery. In the PAD group maximum platelet activation and fibrinogen levels coincided with a marked drop in platelet count and were concomitant to administration of unfractionated heparin. Thereby, a drop in platelet count of > 30% was observed in 25 patients (57%). The HIPA test verified HAT antibodies in 3 (12%) of these patients, two of which suffered postoperative thrombosis. In the control group significant pOP increases were noted only for plasma fibrinogen. Changes in platelet count and reactivity were minimal and nonsignificant. No thrombosis occurred and no HAT antibodies were detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Platelets of patients with peripheral arterial disease are hypersensitive to heparin.

We sought to verify earlier reports of increased platelet reactivity in patients with peripheral arterial disease (PAD) during perioperative heparin administration, and to test the hypothesis of platelet hypersensitivity to heparin in these patients. Before and after incubation of platelet rich plasma with unfractionated (UH), low molecular weight heparin (LMWH), and a low molecular weight heparinoid, real-time quantitative assessment of platelet function was performed by stagnation point flow adhesio-aggregometry (SPAA) in 21 patients with PAD and 14 healthy volunteers. With SPAA the occurrence of spontaneous aggregation is pathological. In the 15 patients requiring operation, platelet function and count were measured at regular intervals. To detect heparin dependent antibodies, the heparin induced platelet activation assay (HIPA) was performed preoperatively and after 10 days of heparin therapy. Mean baseline platelet adhesion in patients was double that observed in controls (p < 0.001). Spontaneous aggregation was seen in 9 (43%) patients and no controls (p < 0.001). In controls heparinoid reduced, whereas UH and LMWH slightly increased adhesion. Spontaneous aggregation was observed once with UH. Platelets from patients showed significantly enhanced adhesiveness and aggregability (p < 0.05) with UH and LMWH when compared to controls. Effects with the heparinoid were less pronounced and non-significant. In patients requiring operation, postoperative increases in platelet function and reductions in count were significant (p < 0.001). Ten (67%) experienced a fall in platelet count of > 50%. Preoperatively the HIPA assay showed no evidence of antibodies, whereas after heparin administration antibodies were verified in 4 (32%) patients and could not be ruled out in 6 (40%). Three developed postoperative thrombosis, in one case fatal. A hypersensitive in vitro and in vivo platelet response to heparin was verified in patients with PAD and a large number developed the immunological type of heparin-associated thrombocytopenia. Our findings suggest that a thrombin antagonist which does not interact with platelets may give the best perioperative protection in these patients.

Depression in the elderly: biologic considerations.

Although support for the biologic basis and effective somatic therapy of geriatric depression is increasing, both patients and clinicians are reluctant to identify and treat the symptoms associated with late-life depression, a broad-based problem in the geriatric population. There is much clinical and biologic overlap between depression and other organic brain disorders such as dementia, with evidence that late-onset depression may sometimes be a prodrome for other organic disorders. These and other issues surrounding geriatric depression are reviewed with a focus on future research questions.

Thyroid hormones in depressive disorders: a reappraisal of clinical utility.

Centuries of clinical observation suggest a connection between thyroid function and behavior. Advances in neuroendocrinology of the hypothalamic-pituitary-thyroid (HPT) axis provide many techniques for examining the role of thyroid function in psychiatric disorders. HPT hypofunctioning may be especially relevant to the pathophysiology of major mood disorders, although the diagnostic specificity and prognostic value of its assessment remain tentative. Evidence that synthesis and actions of thyroid hormones in the brain may not parallel those in the periphery further complicates such assessments. Nevertheless, measures of HPT function show some promise of contributing to the clinical evaluation and treatment of depression. Research findings include an association of subclinical hypothyroidism with unsatisfactory responses to antidepressant treatment, evidence that triiodothyronine and thyroid-stimulating hormone may speed recovery in acute depression, and limited and inconsistent support for the effectiveness of exogenous thyroid hormones to augment antidepressants. Additional systematic and controlled studies comparing various types and doses of thyroid hormones are needed to establish their efficacy and safety. Of special interest would be studies that use contemporary diagnostic methods, assess thyroid function, and employ the newer, safer antidepressants.

Platelets of patients with peripheral arterial disease demonstrate a hypersensitive response to heparin.

We sought to verify earlier reports of increased platelet reactivity in patients with peripheral arterial disease (PAD) during perioperative heparin administration, and to test the hypothesis of platelet hypersensitivity to heparin in these patients. Before and after incubation of platelet rich plasma with unfractionated (UH), low molecular weight heparin (LMWH), and a low molecular weight heparinoid, real-time quantitative assessment of platelet function was performed by stagnation point flow adhesio-aggregometry (SPAA) in 21 patients with PAD and 14 healthy volunteers. With SPAA the occurrence of spontaneous aggregation is pathological. In the 15 patients requiring operation, platelet function and count were measured at regular intervals. To detect heparin dependent antibodies, the heparin induced platelet activation assay (HIPA) was performed preoperatively and after 10 days of heparin therapy. Mean baseline platelet adhesion in patients was double that observed in controls (p < 0.001). Spontaneous aggregation was seen in 9 (43%) patients and no controls (p < 0.001). In controls heparinoid reduced, whereas UH and LMWH slightly increased adhesion. Spontaneous aggregation was observed once with UH. Platelets from patients showed significantly enhanced adhesiveness and aggregability (p < 0.05) with UH and LMWH when compared to controls. Effects with the heparinoid were less pronounced and nonsignificant. In patients requiring operation, postoperative increases in platelet function and reductions in count were significant (p < 0.001). Ten (67%) experienced a fall in platelet count of > 50%. Preoperatively the HIPA assay showed no evidence of antibodies, whereas after heparin administration antibodies were verified in 4 (32%) patients and could not be ruled out in 6 (40%). Three developed postoperative thrombosis, in one case fatal. A hypersensitive in vitro and in vivo platelet response to heparin was verified in patients with PAD and a large number developed the immunological type of heparin-associated thrombocytopenia. Our findings suggest that a thrombin antagonist which does not interact with platelets may give the best perioperative protection in these patients.

[Increased pre- and postoperative thrombocyte activity in vascular surgery patients]. / Gesteigerte prä- und postoperative Thrombozyten-Aktivität bei gefässchirurgischen Patienten.

To determine the effect of vascular surgery on platelet function, a perioperative investigation of 37 patients with peripheral arterial disease (PAD) was performed using the Stagnation Point Adhesio-Aggregometer (SPAA). The SPAA provides well defined flow conditions. By means of dark field microscopy platelet microthrombus formation can be directly observed and measured continuously. Mathematical evaluation of resulting growth curves renders the constants for adhesion and aggregation, Kpw and Kpp, respectively. The PAD patients were divided into 2 groups: diabetics (n = 9) and nondiabetics (n = 28), and were examined perioperatively at regular intervals (average: n = 8). Preoperatively all patients received aspirin and low molecular weight heparin (LMWH). As of surgery and up to the third postoperative day all patients received unfractionated heparin (UH), at which time LMWH was resumed. Plasma fibrinogen concentration was also determined. Data obtained preoperatively were compared to those of 40 healthy volunteers (without medications). In the present study a significant increase (p < 0.001) in platelet reactivity was verified in PAD patients in spite of aspirin and LMWH administration. As of the first and up to the 8th day after surgery, a marked increase in platelet adhesivity and aggregability as well as plasma fibrinogen concentration and a concomitant decrease in platelet count was observed. Maximum values were obtained during intravenous administration of UH. Thrombocytopenia (< 150,000/ml) was observed in 12 patients. The hypercoagulability response to vascular surgery observed in the present study occurred in spite of therapy with aspirin and heparin. Our findings indicate the need for further improvement in conventional therapy and the SPAA as a useful tool in monitoring the effectiveness of current as well as of future inhibitors of platelet function.

Computational analysis of platelet adhesion and aggregation under stagnation point flow conditions.

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.