Quantitative structure-activity analysis of acetylcholinesterase inhibition by oxono and thiono analogues of organophosphorus compounds.

A comparison of the bimolecular rate constants (ki) for inhibition of electric eel acetylcholinesterase (AChE) by the oxono (i.e., P=O) and thiono (i.e., P=S) analogues of parathion, methylparathion, leptophos, fonofos, sarin, and soman revealed that the oxono/thiono ratios of ki values varied from 14 for soman to 1240 for parathion. Analysis of the relative importance of the dissociation equilibrium constant and the phosphorylation rate constant in producing this variation in ki values indicated that the oxono analogues and the phosphorylation rate constant values that varied in a narrow range from 8- to 14-fold greater than their thiono counterparts, while the oxono/thiono ratios for dissociation constants varied widely from 1 for soman to 82 for fonofos. The lower affinities of thiono analogues for AChE probably resulted from differences in the hydrophobic binding of oxono and thiono analogues to the active site of AChE, inasmuch as the hydrophobicities (i.e., octanol/water partition coefficients) of thiono organophosphorus compounds were much greater than the hydrophobicities of their oxono analogues. Quantitative structure--activity analysis indicated that the hydrophobic effects of oxono and thiono moieties correlated with log ki for AChE inhibition to a greater extent (r2 = 0.79) than their electronic effects (r2 less than or equal to 0.48). These observations suggest that the differences in hydrophobicity of oxono and thiono analogues of organophosphorus compounds may be as important as their electronic differences in determining their effectiveness as AChE inhibitors.     

Reactivity of isolated bovine facial vessels to electric stimulation and to drugs.

The effects of electric stimulation on isometric force generation of isolated helical strips of bovine facial arteries (BFA) and veins (BFV) were investigated. Whereas BFA always contracted, electrically stimulated BFV showed a biphasic response, i.e. a small, transient contraction followed by an intense relaxation. The findings presented suggest a neurogenic response for the vasodilator component of BFV response to electric stimulation. Exogenous catecholamines and serotonin dilated the veins; the effects were antagonized by propranolol and dihydroergotamine, respectively. Dopamine-induced relaxations were only partially inhibited by propranolol; the residual relaxations were antagonized by chlorpormazine and haloperidol. Relaxations of the veins after electric stimulation or after administration of noradrenaline were accompanied by an increase of the cAMP content. In the BFA catecholamines, serotonin and histamine increased the tension, whereas isoprenaline was ineffective. Acetylcholine contracted the veins and relaxed the arteries; both effects were antagonized by atropine.     

Der Einfluß von Änderungen der extracellulären Calciumkonzentration auf die Ermüdungskontraktur von Skeletmuskeln

Summary 1. The development of fatigue-contracture by phasic and tonic muscles is strongly influenced by the extracellular calcium concentration.2. Muscles of both types, which have been pretreated with calcium-rich Ringer's solution will remain inexcitable in maximal posttetanic after contracture after several series of tetanic stimuli.3. On the other hand, muscles of both types which have been pretreated in calcium-free Ringer's solution will remain relaxed and inexcitable after several series of tetanic stimuli (posttetanic relaxation).4. The causes of this calcium effect are not yet clear. Some aspects which seem important for the site of action of calcium ions are discussed briefly.

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Late effects in 164 patients with rhabdomyosarcoma of the bladder/prostate region: a report from the international workshop

PURPOSE: We determined the late sequelae in children and adolescents with rhabdomyosarcoma of the bladder/prostate treated in the United States, Canada and selected Western European countries, primarily France, Germany, Italy and the United Kingdom, from 1979 to 1998. MATERIALS AND METHODS: We used a data collection form to record data from patient records available at the group statistical centers. RESULTS: A total of 164 patient charts had sufficient data available to be included in the study. Median patient age at diagnosis was 2.4 years. Median length of followup was approximately 8 years (range 3 to 24). Of the patients with available data 78 did not undergo cystectomy, 49 underwent partial cystectomy and 34 underwent complete cystectomy. Urinary continence was assessed at age 6 years or older in 62 patients who did not undergo cystectomy. Of these patients 43 (69%) were continent, 16 had nocturnal incontinence and 9 had diurnal incontinence. Of 44 patients who underwent partial cystectomy and had pertinent followup data 32 (73%) were continent, and 12 had nocturnal and/or diurnal incontinence. Only 11 patients underwent urodynamic investigation. Other nephrourological complications consisted of 3 or more urinary tract infections in 29 of 53 patients, abnormal renal function in 19 of 48 (tubulopathy 14, increased creatinine/blood urea nitrogen 5), chronic hematuria in 13 of 51 and hydronephrosis in 8 of 54 with available data. Vesicoureteral reflux, urinary stones and bowel problems were infrequent. CONCLUSIONS: Of the patients 48% had a relatively intact bladder after biopsy only. However, 31% of patients 6 years or older had some urinary incontinence, as did 27% of patients who had undergone partial cystectomy. In addition, 55% of all patients had 3 or more urinary tract infections, 40% had decreased renal function and 25% had chronic hematuria. Other complications were present in 15% or less of the patients with available data.     

Vergleichende experimentelle Untersuchungen photoelektrisch und mechanoelektrisch registrierter Venenpulskurven

Zusammenfassung 1. Die Behauptung vonAltmann, die Registrierung mit dem Infratonabnehmer entstelle die normale Venenpulskurve, ist auf Grund der vorliegenden Untersuchungen nicht gerechtfertigt. Der Vergleich zwischen den mit dem Infratonsystem und dem photoelektrischen Verfahren nachCollatz-Weber registrierten Venenpulskurven zeigt eine bis in den Bereich der Meßungenauigkeit gehende Übereinstimmung.2. Bei jeder Analyse von Venenpulskurven muß die physiologische Streubreite hinsichtlich der zeitlichen Verhältnisse und der Form berücksichtigt werden. In besonderem Maße gilt dies für die Beurteilung der Lage vonx, die diagnostisch verwendet wird und deren Festlegung durch die im systolischen Kollaps auftretende forminkonstantez-Welle schwierig werden kann.Herrn Prof. Dr.A. Kohlrausch, Tübingen, zum 75. Geburtstag.     

Friction-based stabilization of juxtacellular recordings in freely moving rats

Virtually nothing is known about the activity of morphologically identified neurons in freely moving mammals. Here we describe stabilization and positioning techniques that allow juxtacellular recordings from labeled single neurons in awake, freely moving animals. This method involves the use of a friction-based device that allows stabilization of the recording pipette by friction forces. Friction is generated by a clamplike mechanism that tightens a sliding pipette holder to a preimplanted pipette guide. The interacting surfaces are smoothed to optical quality (<5-nm roughness) to enable micrometer stepping precision of the device during operation. Our method allows recordings from identified neurons in freely moving animals, and thus opens new perspectives for analyzing the role of identified neurons in the control of behavior.     

Whisker movements evoked by stimulation of single motor neurons in the facial nucleus of the rat

The lateral facial nucleus is the sole output structure whose neuronal activity leads to whisker movements. To understand how single facial nucleus neurons contribute to whisker movement we combined single-cell stimulation and high-precision whisker tracking. Half of the 44 stimulated neurons gave rise to fast whisker protraction or retraction movement, whereas no stimulation-evoked movements could be detected for the remainder. Direction, speed, and amplitude of evoked movements varied across neurons. Protraction movements were more common than retraction movements (n = 16 vs. n = 4), had larger amplitudes (1.8 vs. 0.3 degrees for single spike events), and most protraction movements involved only a single whisker, whereas most retraction movements involved multiple whiskers. We found a large range in the amplitude of single spike-evoked whisker movements (0.06-5.6 degrees ). Onset of the movement occurred at 7.6 (SD 2.5) ms after the spike and the time to peak deflection was 18.2 (SD 4.3) ms. Each spike reliably evoked a stereotyped movement. In two of five cases peak whisker deflection resulting from consecutive spikes was larger than expected when based on linear summation of single spike-evoked movement profiles. Our data suggest the following coding scheme for whisker movements in the facial nucleus. 1) Evoked movement characteristics depend on the identity of the stimulated neuron (a labeled line code). 2) The facial nucleus neurons are heterogeneous with respect to the movement properties they encode. 3) Facial nucleus spikes are translated in a one-to-one manner into whisker movements.