MODES OF INACTIVATION OF NEUROHYPOPHYSIAL HORMONES: SIGNIFICANCE OF PLASMA DISAPPEARANCE RATE FOR THEIR PHYSIOLOGICAL RESPONSES

Analogues of oxytocin and deaminooxytocin with 4-glutamine replaced by 4-glutamic acid methyl ester readily lose their uterotonic activity when incubated with rat serum, presumably by hydrolysis to the much less active 4-glutamic acid derivatives. On the other hand, inactivation of the deaminooxytocin analogue in the rat uterus, as demonstrated by the 'oil-bath'technique, is only slightly more rapid than that of deaminooxytocin and distinctly slower than that of oxytocin. Its in situ/in vitro ratio of uterotonic activity is less than 0.1 whereas that for deaminooxytocin is about 3 and also the persistence of the uterotonic effect in situ is slightly less than that of deaminooxytocin. The results with these 'rapidly inactivated'analogues can be used as proof of some predictions of the three-compartment model for tissue distribution of neurohypophysial hormones and its influence upon the time course of a biological response published earlier. The potential use of analogues of neurohypophysial hormones as probes for inactivation mechanisms and the results thus far obtained are discussed.     

Rescue of menotrophin cycles prone to develop ovarian hyperstimulation

Summary. In an attempt to prevent the loss of'overstimulated cycles' associated with human menopausal gonadotrophin (hMG)-induced ovulation, oestradiol levels and ovarian follicular state were monitored in 12 women with'overstimulated cycles' after withholding hMG for several days. Human chorionic gonadotrophin (hCG) was administered when oestradiol levels were 1700 pg/ml and the leading follicles between 17 and 22 mm in diameter. During the withholding period follicular growth continued in all patients, while oestradiol levels declined in all but three. These three patients conceived. Ovulation was observed in six additional women. Ovarian hyperstimulation did not occur in any of the 12 patients. We conclude that a rescue of'overstimulated cycles' is sometimes possible. Conception seems to depend on a continuing rise of E2 levels and early detection of'overstimulation'.     

Stridor is not a scientifically valid outcome measure for assessing airway injury

Since about a decade cuffed intubation is becoming more popular in pediatric anesthesia. Studies supporting cuffed intubation compared cuffed and uncuffed intubation by using stridor as main outcome measure after extubation. No differentiations were made between benign (oedema) and severe (ulceration of mucosa) lesions. Stridor was considered to represent all relevant injuries. Far reaching conclusions for daily practice were drawn from these studies. Pediatric endoscopists and – ENT-surgeons with extensive experience in this field have warned against this opinion because significant injury of the airway is not always accompanied by stridor! The symptom of stridor might develop weeks and months after injury when silent ulcerations of the mucosa retract to significant stenosis. Only endoscopy can evidently detect all airway injuries. Studies describing airway injury by endoscopic control are urgently needed to find the best way of preventing airway injury by intubation.     

Determinants of Subsidiary Ventricular Pacemaker Suppression in Man

To investigate the relative contribution of the duration and rate of overdrive to subsidiary ventricular pacemaker suppression, in six patients with complete heart block after His-bundle ablation, ventricular overdrive stimulation studies were performed. The studies, which were spread over a mean follow-up period of 745 days, were carried out invasively with a temporary lead (one patient) as well as nonin-vasively with the implanted pacemakers and chest wall inhibition (five patients). The overdrive pacing rate was increased in steps of 10 beats/min, and the pacing duration was 15, 30, 60, 90, and 120 seconds at each level. A recovery period of 2 minutes was allowed after each overdrive stimulation. Incremental ventricular overdrive stimulation at increasing pacing durations consistently caused progressive suppression of ventricular impulse formation. Nonparamelric variance analysis demonstrated a significant (P < 0.0001) influence of both the pacing rate and duration on ventricular recovery time. Nonlinear regression showed an exponential increase in recovery time with incremental pacing rate and a biphasic increase in recovery time with incremental pacing duration. Beyond a pacing duration of 60 seconds ventricular impulse suppression was primarily dependent upon the pacing rate. A nonlinear regression model was applied to predict the number of heals required for return of the escape rhythm toward prepacing control values. The predicted maximum mean number of beats was 15.4 ± 5.9 and independent of the rate and duration of pacing, although, the initial temporary instability of the escape rhythm was directly related to the degree of overdrive.     

Stridor in the neonate and infant. Implications for the paediatric anaesthetist. Prospective description of 155 patients with congenital and acquired stridor in early infancy

One hundred-and-fifty-five neonates and infants up to the sixth month of postnatal age were investigated to reveal the cause of clinically relevant stridor. In 100 patients congenital stridor was found, in 55 children the stridor was considered to be acquired. A curled, soft epiglottis, almost synonymously used with the diagnosis of congenital stridor, was found in 7% only, indicating different methods of investigation and different selection of patients compared to previous years. In acquired stridor the majority of infants showed laryngeal and tracheal trauma, mostly due to the use of too large tracheal tubes.     

Solution structure of the cytoplasmic domain of the human immunodeficiency virus type 1 encoded virus protein U (Vpu)

The HIV-1-specific Vpu protein is an 81 amino acid class I integral membrane phosphoprotein that induces degradation of the virus receptor CD4 in the endoplasmic reticulum and enhances the release of virus particles from infected cells. Vpu is of amphipathic nature and consists of a hydrophobic N-terminal membrane anchor proximal to a polar C-terminal cytoplasmic domain. In our recent work, focussed on the structural analysis of the cytoplasmic tail, we established an α-helix-flexible-α-helix-turn model. Now we present the experimental solution structure of the Vpu cytoplasmic domain which has been elucidated in aqueous 50% trifluoroethanol solution by 2D ¹H NMR spectroscopy, and restrained molecular dynamics and energy minimization calculations. Under these conditions the peptide, Vpu^32-81, is predominantly monomeric and adopts a well defined helix-interconnection-helix-turn conformation, in which the four regions are bounded by residues 37-51, 52-56, 57-72 and 73-78. The presence of the cis isomer of Pro-75 manifests itself as a doubling of cross peaks of neighbouring residues in the 2D spectra. A related variant peptide, Vpum^32-81, in which the Vpu-phosphoacceptor sites Ser⁵² and Ser⁵⁶ were exchanged for Asn, adopts a very similar structure and, taken together, provides evidence that the second helix and the turn form a comparatively rigid region. Both helices are amphipathic in character, but show different charge distributions. In general the cytoplasmic region is N-terminally positively charged, passes through a region of alternating charges in helix 1 and then becomes negatively charged. The flexibility of the interconnection permits orientational freedom of the two helices. The motif found here is the first experimentally refined solution structure of the cytoplasmic domain of Vpu, and it is conceivable that these α-helices are important for a previously defined physical interaction with an α-helical Vpu-responsive element located within the cytoplasmic tail of CD4. © Munksgaard 1996.     

Activity-Controlled Circadian Base Rate

The current pacing rates are clustered around a fixed base rate since pacemaker patients are usually sedentary, resting, or sleeping most of the time. This fixed base rate is either too low for daytime hemodynamic support or too high for nighttime rest and recovery. Multiple Holter studies involving normal individuals have suggested that the resting base rate fluctuates during the course of the day. The circadian base rate (CBR) algorithm was designed to provide patients with a circadian change in paced resting rate and a normal rate distribution. The CBR algorithm, using a sophisticated accelerometer sensor, was developed and tested using the downloaded activity data from patients implanted with Trilogy DR+ pacemakers. Twenty-five patients (19 men, 6 women, age 72 ± 9 years) were studied. Trilogy DR+ is able to record the detailed sensor and system behavior data for a week. During outpatient visits, the pacemaker was interrogated and the data accumulated in the pacemaker memory were downloaded. The CBR algorithm was applied to the activity variance histogram to calculate the base rate and to construct its histogram. The base rates in the CBR histogram are generally below 100 ppm with a distribution that mimics the natural sinus rate distribution of normal subjects. The CBR algorithm provides the highest daytime rates for hemodynamic support and the lowest nighttime rates for cardiac recovery, with a smoothly changing base rate modeling the normal circadian variation in heart rate.