Palladium-catalyzed cascade cyclizations involving C-C and C-X bond formation: strategic applications in natural product synthesis.

Palladium-catalyzed cascade cyclizations (PCCs) are powerful synthetic tools that enable rapid assembly of polycyclic scaffolds. Palladium complexes can promote a variety of carbon-carbon and carbon-heteroatom bond-forming reactions with high chemo-, enantio-, and diastereoselectivity. The combination of multiple ring-forming elementary steps into a single cascade sequence can allow complex structures to be accessed with high step economy. This strategy has been employed to access natural products in several distinct classes, including the mitomycins, dragmacidins, isoryanodane diterpenes, and ergot alkaloids. In this tutorial review, we demonstrate how PCCs have expedited natural product synthesis by enabling the formation of both C-C and C-X (X = O, N) bonds in a single synthetic operation.

Visuospatial impairment in Parkinson's disease.

We explored the nature of the visuospatial deficit in Parkinson's disease (PD) and its progression as a function of disease duration. We compared the performance of 183 patients with idiopathic PD and 90 control subjects matched for age and education on six visuospatial measures. We divided patients into three groups according to the disease duration: early (1 to 4 years), middle (5 to 10 years), and advanced (greater than 10 years). Performance deteriorated in five of the six visuospatial measures, as a function of disease duration. However, the pattern of visuospatial decline depended on whether dementia was present. The results were not influenced by age or anticholinergic medication. These findings support the presence of visuospatial deficits in PD patients, with a changing pattern of impairment related to dementia and progression of the disease.

Quantitation of extent, depth, and severity of planar thallium defects in patients undergoing exercise thallium-201 scintigraphy.

Previous quantitation of exercise-redistribution planar 201TI scintigraphy has shown high sensitivity and specificity in the detection of coronary artery disease and improved detection of individual coronary stenoses over visual analysis. By using similar methodology based on the circumferential profile method, we studied 133 patients to quantitatively assess the extent, depth, and severity of thallium defects compared with consensus visual analysis. These quantitative measurements are objective, requiring only three operator interactions. In comparing quantitative and visual results, a close correlation was found for measurement of extent of thallium defect (r = 0.73) and severity of defect (r = 0.79). In detecting patients with the high-risk scintigraphic pattern of a severe stress thallium defect, a quantitative depth score of greater than or equal to 36 had an 81% sensitivity and an 82% specificity. Thus, this nearly automatic, computerized quantitative method allows objective determination of extent, severity, and depth of planar 201TI defects.

Facile entry to the tetracyclic 5-7-6-3 tigliane ring system.

[figure: see text] A tandem anionic 5-exo-dig cyclization/Claisen rearrangement sequence was used to effect a facile, "one-pot" conversion of an appropriately substituted 4-alkyn-1-ol to the tetracyclic carbon core structure of phorbol. The synthesis was conducted using readily available nonracemic starting materials to provide the target structure as a single enantiomer in high chemical yield.

The effect of a cholecystokinin agonist on masseter muscle activity in the cat.

The CCK(B) agonist, pentagastrin, has been shown to induce anxiety in human subjects. Similarly, in the cat model, pentagastrin facilitates the expression of hypothalamically activated emotional behavior. Because hypothalamically mediated emotional behavior is also accompanied by increased EMG activity in the jaw muscles, these experiments were designed to examine the combined effects of administration of pentagastrin with activation of hypothalamically mediated emotional behavior upon jaw muscle EMG activity. Electrodes were carefully lowered through previously placed guide tubes overlying the hypothalamus until a behavioral site was identified. Following the establishment of a stable threshold current for eliciting an emotional behavioral response, the skin overlying the ipsilateral masseter muscle was shaved and cleaned with alcohol, and surface electrodes were attached. The EMG was recorded, amplified, digitized, and stored in a microcomputer for analysis. Mean power frequencies (MPF) and latencies for behavior were calculated for baseline prior to infusion of all drugs. Following this, the effects of intravenous administration of pentagastrin and the CCK(B) antagonist LY288513 on the MPF were determined. The infusion of the CCK(B) agonist, pentagastrin (0.77, 1.92, and 3.84 microg/kg), decreased MPF in a time-related manner. The effects of pentagastrin 1.92 microg/kg were blocked by the CCK(B) antagonist, LY288513 (6.54 microg/kg). In addition, the infusion of LY288513 alone increased MPF. These results are surprising in that pentagastrin's anxiogenic properties would appear to make it likely to facilitate motor activity, not suppress it.

Is spectral analysis of the surface electromyographic signal a clinically useful tool for evaluation of skeletal muscle fatigue?

Normal values for initial median frequency (IMF) of the electromyographic (EMG) power-density spectrum must be determined before EMG spectral analysis can be used to evaluate clinically muscle fatigue. This study attempts to establish normal values in four muscles. Thirty-one healthy subjects performed isometric contractions of the biceps brachii, triceps, deltoid, and tibialis anterior muscles at 50% maximum voluntary contraction. Linear regression analysis was used to compute the IMF and the slope of the median frequency as it decayed with fatigue over 45 seconds. The IMF of the tibialis anterior (mean +/- standard deviation, 116 +/- 20 Hz) was significantly higher (p < 0.001) than that of the biceps (90 +/- 18 Hz), triceps (85 +/- 18 Hz), and deltoid (87 +/- 15 Hz). The deltoid and tibialis anterior had the steepest slopes. The IMF of all muscles was greater in men than in women, but gender did not affect the slope. This study attempted to establish normal values for IMF and slope in specific muscles. However, the range of normal values is so broad that it may preclude the clinical use of spectral analysis to evaluate muscle fatigue.

Effects of stress and tranylcypromine on amphetamine-induced locomotor activity and GABA(B) receptor function in rat brain.

Modification in gamma-aminobutyric acid-B (GABA(B)) receptors may contribute to the symptoms of some neurological and psychiatric disorders and to the clinical response to psychotherapeutics. The present study was undertaken to determine whether chronic administration of tranylcypromine (TCP), an antidepressant, and chronic stress influence GABA(B) receptor function in rat brain. The results indicate that TCP treatment, but not stress, increases GABA(B) receptor activity in the cerebral cortex, as measured by baclofen-stimulated GTPgammaS binding. In addition, chronic administration of TCP enhances significantly the locomotor response to a single dose of amphetamine, an effect that is abolished by restraint stress. These results indicate that although TCP administration modifies brain GABA(B) receptor activity, which may contribute to the antidepressant response to this agent, this effect is unrelated to the interaction of stress and TCP treatment on the locomotor response to amphetamine.

CT fan beam reconstruction with a nonstationary axis of rotation.

To reconstruct an image using computed tomography (CT), the axis of rotation must pivot at the same point on the reconstruction plane that the X-ray source and the CT detector assembly rotate about around the imaged object. This pivot point is used as a reference point for backprojecting pixel values to their proper coordinates. Reconstructing an image with a nonstationary axis of rotation would backproject pixel values to incorrect coordinate points. A convolution filtered backprojection algorithm has been derived for correcting images that were acquired with a nonstationary axis of rotation using the fan beam geometry with a collinear (flat) detector. The correction method accounts for the vertical displacements of the axis of rotation as the CT scanner rotates around the imaged object, as may be the case when sagging occurs. Software simulations are performed to show how the algorithm corrects for the shift in the axis of rotation.

Variable threshold R wave detector: use in automated ECG processing.

Reliable R wave detection is difficult under many commonly found conditions of varying baseline and changing morphology such as varying R wave amplitude and reduced R/T ratio. An instrument has been developed which overcomes many of these problems. The device employs a variable detection threshold which is based on the amplitude of the last occurring R wave. For large R wave amplitudes, the threshold is raised, thus providing good noise immunity. For low R wave amplitudes, the threshold is lowered, thus providing continued detection. An R wave filter de-emphasizes noise as well as P and T waves, and an adjustable refractory period following R wave detection prevents false detection during this period. The variable threshold R wave detector has been used to process ECG in a heart rate study in nearly 100 diabetic patients as well as in healthy controls. The detector provides much improved automatic R wave detection over fixed level detectors and can be constructed with parts costing under 100 dollars.

Respiration response curve analysis of heart rate variability.

A noninvasive study was conducted on intact awake humans to characterize the dynamic response of the heart to the vagus during slow-, comfortable-, and fast-paced respiration (8, 12, and 18 breaths/min), under both sitting and standing conditions. The respiration response curve (RRC) of respiration-associated vagal effects on the heart was estimated, and characteristics of entrainment and frequency dependence on respiration were demonstrated. It was shown that the degree of entrainment and magnitude of phase resetting decrease with increase of pacing rate from 8 to 18 breaths/min. Further, the RRC was examined by overlapping equivalent phase shifts in different respiration cycles. This examination of the RRC can help us not only to find the common pattern underlying the RRC during different respiration cycles but also to perceive its variation related to degree of entrainment.

Assessment of autonomic regulation of heart rate variability by the method of complex demodulation.

Complex demodulation was used to examine the effect of both divisions of the autonomic nervous system (sympathetic and parasympathetic) on heart rate. Data were analyzed from dogs during classical conditioning procedures which caused different changes in the autonomic regulation of heart rate. Two significant peaks in the heart rate variability spectrum were examined by this technique. The amplitude of the peak at the respiration frequency showed parasympathetic changes, while the amplitude of the low frequency peak (0-0.124 Hz) showed both sympathetic and parasympathetic effects. Complex demodulation results at these frequencies clearly showed the activities of both branches of the autonomic nervous system in regulating heart rate. During the CS+ period, when trained dogs were presented with a tone predicting a subsequent shock, the observed tachycardia was due to decreased parasympathetic activity and a transient increase in sympathetic activity. During the CS- period where a different tone predicts no shock, parasympathetic and sympathetic activities were unchanged from the baseline condition. The use of complex demodulation enables us to examine autonomic contributions to heart rate regulation in conditioning and a variety of other physiological and environmental conditions where autonomic input can be expected to change rapidly.

Pattern recognition and interpretation of electromyogram data from cat jaw muscle.

This study investigates the effect of emotional behavior on the masseteric muscle EMG response patterns. Two experimental protocols are utilized: (1) does not elicit emotional behavior (stick chewing) and (2) elicits emotional behavior (hypothalamic stimulation). The Karhunen-Loève transform is used to compute features which exactly represent the correlated patterns of mean-zero observations, with data compression and noise immunity. Using nonparametric tests, it is found that the populations of biting and hissing features are significantly different (p < 0.05), with increased statistical significance as the size of the training set is increased. No statistically significant difference is seen in a test of the two biting populations.

Bioelectrical impedance changes in regional extracellular fluid alterations.

The purpose of this study was to determine whether changes in bioelectrical impedance (BI) can reveal regional extracellular fluid (ECF) alterations. ECF changes were induced by holding various arm positions for ten minutes, and they were evaluated through the measurement of BI in eight normal adult subjects. A low frequency current (100 Hz, 0.50 mA) was applied using an electromyography machine through two current electrodes, and the voltage signals were recorded by two amplitude electrodes. The corresponding BI was calculated by Ohm's law, resistance = voltage/current (R = V/I). There was no significant difference between BI and time interval, but between BI and arm position (two-way ANOVA with replicate, p = 0.954, p < 0.001). BI has a negative correlation with wrist circumference. These results show that this experimental method can be used as reflection of ECF changes and that both position and wrist circumference are major factors for BI in the upper extremity.

Vergence variability: a key to understanding oculomotor adaptability?

Vergence eye movements were recorded from three different populations: healthy young (ages 18-35 years), adaptive presbyopic and non-adaptive presbyopic(the presbyopic groups aged above 45 years) to determine how the variability of the eye movements made by the populations differs. The variability was determined using Shannon Entropy calculations of Wavelet transform coefficients, to yield a non-linear analysis of the vergence movement variability. The data were then fed through a k-means clustering algorithm to classify each subject, with no a priori knowledge of true subject classification. The results indicate a highly significant difference in the total entropy values between the three groups, indicating a difference in the level of information content, and thus hypothetically the oculomotor adaptability, between the three groups.Further, the frequency distribution of the entropy varied across groups.

Elder consumer preferences of marketing strategies in the human services.

The marketing of health and social services to the aged is a relatively recent phenomenon. To explore the role of the older consumer in service marketing, a national analysis of preferred marketing methods in gerontological programs was carried out. Eighteen focus groups comprised of senior center participants (mean = 73.8 years) in six metropolitan areas was conducted (n = 220). Findings document considerable consensus across gender, ethnic, socio-economic, and racial cohorts. Preference was expressed for personal/direct forms of marketing. Regardless of age or level of infirmity, subjects identified with images of active and healthy elders. Sharp distinctions were drawn between marketing conducted by for-profit and not-for-profit organizations, as well as between marketing with a "selling" purpose versus that which is primarily informational. Results lead to recommendations for elder service providers on mounting a meaningful program of marketing initiatives. Supported by a grant from the AARP Andrus Foundation.

Vagal withdrawal as a function of audience.

This investigation examined the effects of psychosocial influences upon vagal cardiac activity. In this crossover, counter-balanced study, 15 subjects were assessed for vagal cardiac activity before and during a presentation in the presence and/or absence of an audience. Electrocardiograms (ECG) were collected throughout the epochs of interest, using a portable holter monitor system. Power spectral density analyses were used to decompose autonomic rhythmicities of heart rate variability. Significantly diminished vagal power was noted before and during presentation episodes with an audience compared with vagal power during a presentation without an audience (P < 0.05). Because respiration modulates autonomic outflow, ECG-derived respiration was derived and compared for all epochs, and no significant differences were noted. The real-life findings in the current investigation are strongly suggestive of the modulating effects of psychosocial interactions upon vagal cardiac electrophysiology and should be considered when assessing autonomic status.

A retrospective analysis of the effects of anticholinergic medication on memory performance in Parkinson's disease.

We examined the effects of anticholinergic medication on memory function in 113 patients with idiopathic Parkinson's disease (PD). Subjects were divided into three disease duration groups: early, middle, and advanced. The battery consisted of three tasks assessing memory of logical discourse, semantically related words, and figural material. We found no evidence of anticholinergic-induced memory dysfunction in any of the three groups. Analysis of covariance indicated that age was not a significant variable; however, dementia may have influenced the relationship between anticholinergic medication and memory scores. Our results indicate that anticholinergic medication does not uniformly compromise memory function in PD patients.