Continuous flow synthesis of peptides using a polyacrylamide gel resin (Expansin™)

The continuous flow syntheses of endothelin 1, proendothelin 2. ATP binding site of the CDC2 kinase 3, and fragment 18-30 of an actin 4, have been performed by using a polyacrylamide gel resin Expansin? (about 0.6 mmol NH₂/g) with the glycolamidic ester handle as labile anchorage. In addition, we report here a method of air oxidation which reduces the formation of side-products related to the formation of intermolecular disulfide bridges.     

Human Calcitonin Delivery in Rats by Iontophoresis

Abstract— In-vitro iontophoresis (0·33 mA cm⁻²) of calcitonin (50 μg mL⁻¹, pH 4) was performed with the hairless rat skin model. Direct current was as potent as pulse current (2·5 kHz on/off 1/1) iontophoresis in promoting transdermal permeation of calcitonin. Increase in duration of current application from 20 min to 1 h did not increase calcitonin flux. Results suggest that calcitonin can be blocked in the skin pores through which it travels or can accumulate in the skin and be progressively released from the depot. Invivo experiments showed that transdermal iontophoretic administration of calcitonin induced a hypocalcaemic effect in rats.     

Clinical Interest of a Sensor Driven Algorithm Limiting Ventricular Pacing Rate During Supraventricular Tachycardia in Dual Chamber Pacing

A sensor driven algorithm limiting ventricular pacing rate during supraventricular tachycardia (SVT) is included in a dual chamber rate modulated pacemaker sensitive to acceleration forces (Relay, 294-03, Intermedics Inc.). According to the intensity of concomitant exercise, the ventricular pacing rate is limited either to the programmed maximum pacing rate (MPR) or to an interim lower limit, called "conditional ventricular tracking limit" (CVTL). The MPR prevails over the CVTL when the sensor calculated pacing rate exceeds the minimal rate by more than 20 beats/mm. The purpose of the study is to determine the clinical safety and efficacy of this algorithm in patients with intermittent SVT. Method: a Relay was implanted in four patients with a bradycardia/tachycardia syndrome and in four patients with complete atrioventricular block (CAVB). All had episodes of paroxysmal atrial tachycardia. The units were programmed in DDDR: rate responsive parameters were adjusted by simulating the rate response during three levels of exercise to let the MPR override the CVTL only during strenuous exercise. Holter monitors and exercise testings were performed at 3-month follow-up. Results: in seven patients, Holter recordings showed Supraventricular arrhythmias at rest with a ventricular pacing rate limited to the CVTL. Appropriate rate increases during exercise testings were also demonstrated. Three devices had to be reprogrammed in DDIR tone patient suffering from nearly permanent atrial flutter and two patients not tolerating the CVTL pacing rate at rest). Conclusion: the CVTL algorithm is effective in protecting against high ventricular pacing rates during Supraventricular arrhythmias. It allows the selection of the DDDR mode even with a high MPR in patients with intermittent SVT.     

Effects of medium- and long-chain triglycerides on sleep and thermoregulatory processes in neonates

Sleep processes and body temperature regulation of neonates are never taken into account in the evaluation of nutrients, although these functions are implicated in the regulation of energy metabolism and are influenced by the nutritional state and its metabolic consequences. Medium-chain triglycerides (MCT) are currently used in paediatric units during the first weeks of because they are considered to be a rapid source of energy, easy to assimilate for growing premature infants, whose digestive function is immature. However, no study has described the thermic effect of these nutrients on body temperature regulation and sleep. The present study aimed at analysing the influence of three feeding formulas with different content of MCT on sleep processes and on thermoregulation of neonates fed until desired intake was reached. Whatever the thermal conditions (thermal equilibrium or cool environment), the MCT-fed groups had higher body temperatures and than groups fed without MCT, for whom total sleep time was reduced at thermal equilibrium. In this group, the large amount of quiet sleep seems to favour a strategy of conserving energy . Higher energy expenditure in MCT-fed groups is not harmful to growth rate since nutritional efficiency is even better reflected by a larger body mass gain. The thermic effect of MCT contributes to lessening the vulnerability of neonates exposed to low incubator temperatures.     

Synthesis of Thiazolotriazine Derivatives and Their Antinociceptive Effects in Mice

A series of 2-(4-arylpiperazin-1-yl-methyl)-4-methyl-1-oxo-5,6,8,8a-tetrahydro-thiazolo[3,4-d] [1,2,4]triazines was prepared and tested for antinociceptive activity. The compounds were prepared by the Mannich reaction from the corresponding 2-unsubstituted thiazolotriazines. When administered intraperitoneally most were found to have potent analgesic activity in the mouse during tests of phenylbenzoquinone-induced abdominal constriction; ED50 values (doses resulting in half the maximum effect) ranged from 10 to 87 mg kg^?1. Derivatives with a 3-chloro- or 4-fluorophenylpiperazinylmethyl side-chain in the 2-position of the bicyclic system were, when administered intraperitoneally at doses greater than 25 mg kg^?1, also effective in the hot-plate test without associated sedative effects. The compounds have a large therapeutic index; intraperitoneal LD50 values (doses which result in the death of half the animals) were > 700 mg kg^?1. Naloxone attenuated the analgesic activity of the 3-chloro derivative, suggesting the participation of μ-receptors in the antinociceptive effects of this drug. In addition, a non-opioid mechanism, probably related to enhancement of the release of 5-hydroxytryptamine and noradrenaline, or inhibition of the neuronal re-uptake of these compounds, has been evinced to explain the analgesic properties of the 3-chloro or 4-fluoro derivatives. These results provide evidence for the involvement of noradrenergic and 5-hydroxytryptaminergic pathways in the analgesic activity of 3 and 4. Because of their potential effectiveness, the 3-chloro- or 4-fluorophenylpiperazinylmethyl derivatives might be suitable for treatment of a wide variety of painful conditions and could be attractive reserve agents for patients dissatisfied with opioids.     

Body Composition in 995 Acutely ill or Chronically ill Patients at Hospital Admission: A controlled population Study

Objective To determine if fat-free mass and fat mass in acutely ill and chronically ill patients differed from healthy controls at hospital admission and if prevalence of malnutrition differed by body mass index (BMI) or fat-free mass percentile.Subjects/Setting 995 consecutive patients 15 to 100 years of age admitted to the hospital were measured in the hospital admission center and compared with 995 healthy age- and height-matched subjectsDesign Cross-sectional study. Fat-free mass, fat mass, and percentage fat mass were determined by 50 kHz bioelectrical impedance analysis. Prevalence of malnutrition was determined by BMI <20 kg/m² or fat-free mass in the 10th percentile.Statistical Analysis Analysis of variance was used to examine differences between acutely ill and chronically ill patients and controls and between age groups.Results Fat-free mass was significantly lower in patients than controls (P<.05), and the difference with age in fat-free mass in patients was greater than the age-related difference in the controls. A higher percentage fat mass was found in spite of lower BMI in chronically ill patients older than 55 years. Among participants, 25% of acutely ill and 37.3% of chronically ill patients fell below fat-free mass in the 10th percentile, compared with 15.6% of acutely ill and 18.9% of chronically ill patients falling below BMI ≤20 kg/m².Applications/Conclusion Weight and BMI do not evaluate body compartments and therefore do not reveal if weight changes result in loss of fat-free mass or gain in fat mass. In spite of minimal differences in BMI between patients and controls, we found that fat-free mass was lower and fat mass was higher in acutely ill and chronically ill patients than controls. The objective measurement of body composition, as part of a comprehensive nutritional assessment, helps to identify subjects who have low fat-free mass or high fat mass. J Am Diet Assoc. 2002;102:944-948,953-955.     

SPECIAL ARTICLE ESBRA 1997 AWARD LECTURE: RELATIONSHIP BETWEEN EXCESSIVE ALCOHOL DRINKING AND VIRAL INFECTIONS

Several epidemiological studies suggest that chronic alcoholicsare at risk of viral infections. Clinical and basic researchhas demonstrated that alcohol not only worsens the natural historyof chronic viral hepatitis, but also seems to interact withthe viral replication cycle leading to an unusual serum virologicalprofile and/or modification in the serum concentration of viralparticles. Infections with hepatitis B and C viruses are a majorrisk for the development of hepatocellular carcinoma in excessivedrinkers who should be protected against these viruses.     

In Vitro Evaluation of a Sensor Sensitive to Acceleration Forces Included in a New Rate Modulated Pacemaker

The characteristics of the sensor and rate adaptive algorithm included in a new dual chamber rate responsive pacemaker (Relay 294–03, Intermedics, Inc.) were studied by submitting the device to calibrated to-and-fro movements of specific frequencies and peak accelerations by means of a mechanical arm connected to a speed adapter. Atrial pacing rate was continuously recorded on a Holter monitor. The influences of the frequency, the magnitude, and the axis of the acceleration forces as well as the reproducibility of the rate response were evaluated. Results: (1) the sensor was sensitive to frequencies ranging from 0.5 to 7 Hz with a peak sensitivity at 3 Hz; (2) the pacing rate was not affected during movements at frequencies > 6 Hz, commonly presented as nonactivity related signals fear, bus transportation, drilling); (3) the pacing rate increased as a function of the acceleration magnitude up to 0.5 G (0.3 G for 3 Hz), then remained constant. This level of acceleration usually corresponds to high degrees of activity; (4) rate response was maximum when acceleration was directed in the anteroposterior direction; (5) reproducibility of the rate response was excellent (R²: 0.999; slope of the regression line: 0.999). Conclusion: Relay 294-03 is a low frequency signal sensing rate modulated pacemaker using an accelerometer sensitive to motion, mainly in the anteroposterior direction.     

Usefulness and Adequacy of Sensor Data Storage and Retrieval for Rate Response Simulation

The usefulness of sensor data storage for rate response simulation was evaluated using a new dual chamber rate modulated pacemaker sensitive to acceleration forces (Relay 294–03 [lntermedics Inc.]). The pacemaker can store the sensor output during routine exercise and those values can be used to simulate rate profiles for other rate response settings. The predictive value of this feature was evaluated in three studies (mechanical, external pacemaker, and implanted pacemaker). In the first study, the pacemaker was submitted to three runs of eight different mechanical calibrated to-and-fro movements. In the second study, nine external pacemakers were strapped on healthy volunteers who performed three jogging tests. Finally, the predictive value of the simulation was studied in five implanted patients during three successive walking tests. In each study, the pacemaker was submitted three times to the same activity. The responsiveness was successively set to 5, 1, and 10, and the pacemaker outputs were continuously recorded on a Holter monitor. At the end of the first run, rate profile simulations for slopes 1 and 10 were performed; slope 5 rate response was simulated after the second run. A regression analysis was used to establish the correlation between predicted and achieved pacing rates for each study. The coefficients of correlation between predicted and measured pacing rates for the mechanical, external, and clinical studies were 0.999, 0.985, and 0.823, respectively. The corresponding slopes of regression lines were 1.005, 0.971, and 0.935. Calculated rate profile has a high predictive value and could be used to optimize rate responsive settings without serial exercise testings.     

Neurohormonal Profile Before and After β-Blockade in Patients with Neurocardiogenic Syncope

Our objective was to evaluate the effects of beta-blockers on the neurohormonal profile, particularly vasopressin (VP) release, in vasovagal syncope and to gain further insight on the pathophysiology of this syndrome. Patients (< or =75 years) with no cardiovascular, neurological disorders, or contraindications to the use of isoproterenol or beta-blockers and being explored for unexplained syncope were included. An 80 degrees HUT was performed under identical conditions. After a 25-min period of passive tilt, isoproterenol was infused at a rate of 1-5 microg/mn if required. Two groups matched for age and sex were considered: a HUT-positive and a HUT-negative group. The HUT-positive group was then given beta-blockers, subsequently reassessed, and divided into two subgroups: alpha beta-blocker nonresponder group and a beta-blocker responder group. Blood samples for assays of norepinephrine (NE), epinephrine (E), and VP were taken at baseline and the end of the procedure. In all, 44 subjects entered the study, 22 in each group. The HUT-positive group exhibited an obvious lesser increase in plasma NE and a clear-cut rise in plasma E and VP compared to the HUT-negative group (P < 0.05). Even though no patient in the HUT-positive group reported recurrent symptoms under treatment, the second HUT could distinguish two subgroups: a beta-blocker nonresponder group (n = 12) whose HUT remained positive and a beta-blocker responder group (n = 10) whose HUT was normalized. The time course of plasma E and VP during the second HUT was similar to that for the HUT-positive and HUT-negative groups. In conclusion, the efficacy of beta-blockers is associated not only with a reduction of the sympathoadrenal stimulation seen in vasovagal syncope but also with a lower release of VP suggesting that low-pressure baroreceptors might be involved in VP release.