Long-term clinical and economic outcomes in previously untreated paediatric patients with severe haemophilia A: A nationwide real-world study with 700 person-years.

AIM: For previously untreated patients (PUPs) with severe haemophilia A in Finland for the past 2 decades, the standard practice has been to start early primary prophylaxis. We evaluated the long-term clinical outcomes and costs of treatment with high-dose prophylaxis in PUPs from birth to adolescence, including immune tolerance induction (ITI). METHODS: From the medical records of all PUPs born between June 1994 and May 2013 in Finland, we retrospectively extracted data on clinical outcomes and healthcare use. Using linear mixed models, we analysed longitudinal clinical outcome data. To analyse skewed cost data, including zero costs, we applied hurdle regression. RESULTS: All 62 patients received early regular prophylaxis; totally, they have had treatment for nearly 700 patient-years. The median age of starting home treatment was 1.1 years. The mean (SD) annual treatment costs (€ per kg) were 4391€ (3852). For ages 1-3, ITI comprised over half of the costs; in other groups, prophylactic FVIII treatment dominated. With these high costs, however, clinical outcomes were desirable; median (IQR) ABR was low at 0.19 (0.07-0.46) and so was AJBR at 0.06 (0-0.24). Thirteen (21%) patients developed a clinically significant inhibitor, 10 (16%) with a high titre. All ITIs were successful. The mean costs for ITI were 383 448€ (259 085). The expected ITI payback period was 1.81 (95% CI 0.62-12.12) years. CONCLUSIONS: Early high-dose prophylaxis leads to excellent long-term clinical outcomes, and early childhood ITI therapy seems to turn cost-neutral generally already in 2 years.

Inhibitor development in previously untreated patients with severe haemophilia A: a nationwide multicentre study in Finland.

INTRODUCTION: Currently the most serious treatment complication of haemophilia is the inhibitor development (ID), i.e. neutralizing antibody development. AIM: This nationwide multicentre study in Finland evaluated the incidence and risk factors of ID in previously untreated patients (PUPs) with severe haemophilia A (FVIII:C < 0.01 IU mL(-1) ). METHODS: We enrolled all PUPs (N = 62) born between June 1994 and May 2013 with at least 75 exposure days (EDs) to screen ID during follow-up extending to September 2013. RESULTS: Thirteen ID (21% of 62) occurred; 10 (16% of 62) with high titre. Fifty-one patients (82%) were on primary prophylaxis (regular prophylaxis before the age of 2 and before the first joint bleed) from the median age of 11.4 months, 90% via a central venous access device. The initial product was rFVIII in 63% and pd-FVIII in 37%, moreover in 24% pd-FVIII was switched to rFVIII concentrate during the 75 EDs. Non-transient inhibitors developed in 9/51 (17.6%; 13.7% high titre) children with primary and in 4/11 (36.4%; 27.3% high titre) patients with secondary prophylaxis (P = 0.24). Overall, 74% had a high-risk genotype similarly distributed among the prophylaxis groups. The history of a major bleed enhanced ID (aHR, 4.0; 95% CI, 1.2-13.7), whereas FVIII treatment intensity or source and early implantation of ports did not increase ID risk. CONCLUSION: The cumulative incidence of ID was low notwithstanding prevalent high-risk mutations. Despite patient-related risk factors, our management involving early intensive primary prophylaxis via ports helps to prevent bleeds and lower the incidence of inhibitors.

Diffuse gastrointestinal bleeding and BK polyomavirus replication in a pediatric allogeneic haematopoietic stem cell transplant patient.

Patients undergoing haematopoietic stem cell transplantation (HSCT) are at high risk of severe gastrointestinal bleeding caused by infections, graft versus host disease, and disturbances in haemostasis. BK polyomavirus (BKPyV) is known to cause hemorrhagic cystitis, but there is also evidence of BKV shedding in stool and its association with gastrointestinal disease. We report putative association of BKPyV replication with high plasma viral loads in a pediatric HSCT patient developing hemorrhagic cystitis and severe gastrointestinal bleeding necessitating intensive care. The observation was based on chart review and analysis of BKPyV DNA loads in plasma and urine as well as retrospective BKPyV-specific IgM and IgG measurements in weekly samples until three months post-transplant. The gastrointestinal bleeding was observed after a >100-fold increase in the plasma BKPyV loads and the start of hemorrhagic cystitis. The BKPyV-specific antibody response indicated past infection prior to transplantation, but increasing IgG titers were seen following BKPyV replication. The gastrointestinal biopsies were taken at a late stage of the episode and were no longer informative of BK polyomavirus involvement. In conclusion, gastrointestinal complications with bleeding are a significant problem after allogeneic HSCT to which viral infections including BKPyV may contribute.

Involuntary human hand movements due to FM radio waves in a moving van.

Finland TRACT Involuntary movements of hands in a moving van on a public road were studied to clarify the possible role of frequency modulated radio waves on driving. The signals were measured in a direct 2 km test segment of an international road during repeated drives to both directions. Test subjects (n=4) had an ability to sense radio frequency field intensity variations of the environment. They were sitting in a minivan with arm movement detectors in their hands. A potentiometer was used to register the hand movements to a computer which simultaneously collected data on the amplitude of the RF signal of the local FM tower 30 km distance at a frequency of about 100 MHz. Involuntary hand movements of the test subjects correlated with electromagnetic field, i.e. FM radio wave intensity measured. They reacted also on the place of a geomagnetic anomaly crossing the road, which was found on the basis of these recordings and confirmed by the public geological maps of the area.In conclusion, RF irradiation seems to affect the human hand reflexes of sensitive persons in a moving van along a normal public road which may have significance in traffic safety.

Resistance exercise-induced hormonal response under the influence of delayed onset muscle soreness in men and boys.

It was hypothesized that exercise-induced muscle damage (EIMD)-related alterations in hormonal responses could be observed if a second exercise bout is performed soon after an identical unaccustomed bout leading to delayed onset muscle soreness (DOMS). Eight men (31 ± 7 years) and eight boys (14 ± 0 years) performed two exercise bouts (E1 and E2, with 48 h rest in between) consisting of three sets of bilateral knee extensions until exhaustion with 40% load. No differences between the groups or bouts were observed in the number of repetitions performed and maximal isometric force decline, or between groups in serum creatine kinase activity and DOMS. Decreased peak epinephrine (EPI) (-38%), growth hormone (GH) (-45%) and cortisol (COR) (-31%) concentrations were found in E2 in men (P<0.05). In men, the peak GH concentration was also lower in E2 and COR was higher in both bouts than in boys. No changes in norepinephrine and testosterone responses were found in either group. The results suggest that in men, the responses of EPI, GH and COR are attenuated when the second bout is performed under the influence of DOMS. In boys, the lack of this attenuation may not be explained by less severe EIMD.

Effects of long-term whole-body cold exposures on plasma concentrations of ACTH, beta-endorphin, cortisol, catecholamines and cytokines in healthy females.

OBJECTIVE: Cold therapy is used to relieve pain and inflammatory symptoms. The present study was designed to determine the influence of long-term regular exposure to acute cold temperature. Two types of exposure were studied: winter swimming in ice-cold water and whole-body cryotherapy. The outcome was investigated on humoral factors that may account for pain alleviation related to the exposures. MATERIAL AND METHODS: During the course of 12 weeks, 3 times a week, a group of healthy females (n = 10) was exposed to winter swimming (water 0-2 degrees C) for 20 s and another group (n = 10) to whole-body cryotherapy (air -110 degrees C) for 2 min in a special chamber. Blood specimens were drawn in weeks 1, 2, 4, 8 and 12, on a day when no cold exposure occurred (control specimens) and on a day of cold exposures (cold specimens) before the exposures (0 min), and thereafter at 5 and 35 min. RESULTS: Plasma ACTH and cortisol in weeks 4-12 on time-points 35 min were significantly lower than in week 1, probably due to habituation, suggesting that neither winter swimming nor whole-body cryotherapy stimulated the pituitary-adrenal cortex axis. Plasma epinephrine was unchanged during both experiments, but norepinephrine showed significant 2-fold to 3-fold increases each time for 12 weeks after both cold exposures. Plasma IL-1-beta, IL-6 or TNF alpha did not show any changes after cold exposure. CONCLUSIONS: The main finding was the sustained cold-induced stimulation of norepinephrine, which was remarkably similar between exposures. The frequent increase in norepinephrine might have a role in pain alleviation in whole-body cryotherapy and winter swimming.

Expression of estrogen receptors in the coronary arteries of young and premenopausal women in relation to central obesity.

OBJECTIVE: To examine the relationship of coronary estrogen receptor (ER) expression with atherosclerotic lesions and central fat accumulation in premenopausal women. SUBJECTS: A total of 52 female forensic autopsy cases aged between 18 and 49 y. METHODS: Height, body weight and waist and hip circumferences were measured and body mass index (BMI) and waist-to-hip ratio (WHR) were calculated. Intima thickness or maximal thickness of the plaque were measured from samples taken from the left anterior descending artery (LAD). Macrophage infiltration and smooth muscle cells were localized by immunostaining. ER was detected immunohistochemically and by Western blot analysis, and the ER immunopositive area in the intima was measured. RESULTS: ER immunoreactivity was observed in the intima in 60% of the samples, and it was most intense in the advanced plaques near the lipid core next to the maximal intensity of macrophage staining. The ER immunopositive area had a significant positive correlation with LAD intima thickness, which in turn was significantly correlated with waist circumference and WHR when adjusted for age and BMI. CONCLUSIONS: Premenopausal women with the central type of fat accumulation have advanced coronary plaques in which ER expression is localized near the lipid-rich and macrophage-rich zone. The higher expression of ER in the arterial plaques may represent a compensatory mechanism against atherosclerosis.

A comparison of propofol infusion and propofol/isoflurane anaesthesia in dexmedetomidine premedicated dogs.

The effects of propofol infusion were compared with propofol/isoflurane anaesthesia in six beagles premedicated with 10 microg/kg intramuscular (i.m.) dexmedetomidine. The suitability of a cold pressor test (CPT) as a stress stimulus in dogs was also studied. Each dog received isoflurane (end tidal 1.0%, induction with propofol) with and without CPT; propofol (200 microg/kg/min, induction with propofol) with and without CPT; premedication alone with and without CPT in a randomized block study in six separate sessions. Heart rate and arterial blood pressures and gases were monitored. Plasma catecholamine, beta-endorphin and cortisol concentrations were measured. Recovery profile was observed. Blood pressures stayed within normal reference range but the dogs were bradycardic (mean heart rate < 70 bpm). PaCO2 concentration during anaesthesia was higher in the propofol group (mean > 57 mmHg) when compared with isoflurane (mean < 52 mmHg). Recovery times were longer with propofol than when compared with the other treatments. The mean extubation times were 8 +/- 3.4 and 23 +/- 6.3 min after propofol/isoflurane and propofol anaesthesia, respectively. The endocrine stress response was similar in all treatments except for lower adrenaline level after propofol infusion at the end of the recovery period. Cold pressor test produced variable responses and was not a reliable stress stimulus in the present study. Propofol/isoflurane anaesthesia was considered more useful than propofol infusion because of milder degree of respiratory depression and faster recovery.

Exercise-induced changes in atrial peptides in relation to neuroendocrine responses and fluid balance in the horse.

Previous data show that, in horses, plasma atrial natriuretic peptides (ANP and NT-ANP) remain elevated for a long time after exercise. To study whether exercise-induced changes in hormonal and fluid balance explain this, we measured plasma concentrations of COOH- and NH2-terminal atrial natriuretic peptides (ANP(99-129) and NT-ANP(1-98) together with arginine vasopressin (AVP), adrenocorticotrophin (ACTH), beta-endorphin, cortisol, catecholamines, and indicators of fluid balance in six Finnhorses after a graded submaximal exercise test on a treadmill. After exercise, AVP and catecholamines diminished rapidly; atrial peptides, ACTH, beta-endorphin, and cortisol remained elevated longer. ANP reached its peak value at 5 min and NT-ANP at 30 min post-exercise. At 60 min, ANP was still significantly increased and NT-ANP even above its level at the end of exercise. The different temporal patterns of ANP and NT-ANP are most probably explained by differences in their plasma half-lives. The post-exercise increase in NT-ANP indicates that the release of atrial peptides is stimulated during recovery after exercise. The rapid decrease in AVP and catecholamines suggests that these hormones do not explain the long-lasting increase in atrial peptides. Cortisol remained elevated longer and it may have contributed to some extent. After exercise, the packed cell volume (PCV) decreased more slowly than plasma total protein and electrolytes, which refers to a slow post-exercise return in blood volume. Taken together, the present results show that the long-lasting post-exercise increase in plasma atrial peptides in horses is most probably explained by elevated central blood volume and that the role of vasoactive hormones is small.

Effect of regular winter swimming on the activity of the sympathoadrenal system before and after a single cold water immersion.

This study deals with the adaptation of the sympathoadrenal responses to an acute cold water immersion in ordinary winter swimmers. Hormonal responses were determined at the beginning of the winter swimming period in the autumn and after regular swimming for one and three months. Water temperature in the river was 10 degrees C at the beginning and 4 degrees C after one and three months. The mean duration of the test immersion was 36 s. Plasma catecholamine levels determined before the test immersion decreased with the winter swimming period for one month (NA, p < 0.001, A, p < 0.01). The test immersion significantly increased noradrenaline levels (p < 0.001). Plasma adrenaline and serum cortisol levels were increased or decreased by the immersion. After 1 month's swimming the test immersion to 4 degrees C increased noradrenaline to a similar level than the immersion to 10 degrees C at the beginning. Regularly practiced winter swimming for three months led to diminished catecholamine levels measured immediately after the test immersion (p < 0.01). The results suggest that cold adaptation induced by winter swimming attenuates the catecholamine responses to cold water. Adrenaline responses are also affected by its level prior to the immersion.

Factors derived from adrenals are required for activation of cardiac gene expression in angiotensin II-induced hypertension.

The mechanisms mediating the activation of cardiac gene expression during pressure overload are not fully understood. We examined whether angiotensin II-induced activation of ventricular gene expression is related to blood pressure and ventricular mass or requires other factors by infusing angiotensin II in sham-operated and adrenalectomized rats. In sham-operated rats, angiotensin II (33 microg/kg x h, sc) produced a significant increase in mean arterial pressure (measured by telemetry) within 3 h. Mean arterial pressure (up to 45 h) and the increase in left ventricular hypertrophy in adrenalectomized rats during angiotensin II infusion were similar to those in sham-operated rats. Angiotensin II produced 3.6-fold (P < 0.01) and 20.4-fold (P < 0.001) increases in ventricular atrial natriuretic peptide mRNA levels at 12 and 72 h, respectively. Angiotensin II infusion for 12 h also significantly increased the ventricular mRNA levels of B-type natriuretic peptide (5.2-fold) and adrenomedullin (1.4-fold). Adrenalectomy either abolished (atrial natriuretic peptide and adrenomedullin) or blunted (B-type natriuretic peptide) the early activation of ventricular gene expression by angiotensin II. The baseline synthesis of atrial natriuretic peptide, B-type natriuretic peptide, and adrenomedullin in the ventricle remained unchanged in adrenalectomized rats. In conclusion, our results indicate that factors derived from the adrenals are required for angiotensin II-induced early activation of cardiac gene expression.

Blood pressure and endocrine responses of healthy subjects in cold pressor test after acutely increased dietary sodium intake.

The objective of the study was to compare blood pressure and endocrine responses in a cold pressure test in young healthy subjects who had shown increased blood pressure during an acutely increased sodium intake. Subjects (n = 53) added 121 mmol sodium into their normal diet for one week. If the mean arterial pressure had increased by a minimum of 5 mmHg compared to the control measure, they were selected for the experiments. The selected subjects (n = 8) were given 121 mmol supplemental sodium d-1 for 14 days after which they immersed the right hand into a cold (+10 degrees C) water bath for 5 min. The blood pressure increased (P < 0.05) during the test and was independent of the sodium intake. The plasma noradrenaline increased from 2.41 +/- 0.38 nmol l-1 to 2.82 +/- 0.42 nmol l-1 (P < 0.05) with normal diet and from 1.85 +/- 0.29 nmol l-1 to 2.40 +/- 0.37 nmol l-1 (P < 0.05) with high sodium diet. The starting concentrations and the endpoint concentrations were statistically similar. The plasma levels of natriuretic peptides (NT-proANP, ANP and BNP) did not change during the test, and the concentrations were independent of the sodium diet. To conclude, acutely increased sodium intake does not change blood pressure or hormonal responses in a cold pressor test in young healthy subjects.

Are the blood pressure and endocrine responses of healthy subjects exposed to cold stress altered by an acutely increased sodium intake?

In the study reported here, we examined blood pressure and endocrine responses in cold conditions during salt load in young healthy subjects who had previously shown increased resting blood pressure during acutely increased sodium intake. Subjects (n = 53) added 121 mmol sodium into their normal diet for 1 week. If their mean arterial pressure had increased by a minimum of 5 mmHg compared to the previous measure they were selected for subsequent experiments. The subjects (n = 8) were given 121 mmol supplemental sodium.day-1 for 14 days. They were then put into a wind tunnel for 15 min (temperature--15 degrees C, wind speed 3.5.ms-1). Their blood pressure increased (P < 0.05) during the cold exposure, independent of the sodium intake. Their mean (SEM) plasma noradrenaline increased from 3.58 (0.62) nmol.l-1 to 5.61 (0.79) nmol.l-1 (P < 0.05) when the subjects were given a normal diet, and from 2.45 (0.57) nmol.l-1 to 5.06 (0.56) nmol.l-1 (P < 0.05) when the subjects were given an elevated sodium diet. The starting concentrations and the endpoint concentrations were statistically similar. The plasma levels of the N-terminal fragment of pro-atrial natriuretic peptide decreased during the whole-body cold exposure: with the sodium load the change was from 256.6 (25.5) nmol.l-1 to 208.0 (25.3) nmol.l-1, and with the normal diet, from 205.8 (16.4) nmol.l-1 to 175.1 (16.1) nmol.l-1. The haematocrit and red blood cell count increased (P < 0.05) with normal and elevated sodium diet in cold conditions, but haemoglobin increased (P < 0.05) only with high salt in cold conditions. To conclude, acutely increased sodium intake does not change the blood pressure response or hormonal responses to exposure to acute cold stress in healthy subjects.

Ketamine for procedural pain relief in newborn infants.

AIM: To assess the suitability of ketamine for relief of pain caused by tracheal suction during ventilator treatment in newborn infants. STUDY DESIGN: In a randomised, double blind, cross over trial, 16 newborn infants received placebo or 0.5, 1, or 2 mg/kg ketamine as two minute infusions in random order five minutes before four separate endotracheal suctions, with intervals of at least 12 hours. RESULTS: Mean (SD) plasma ketamine concentration increased linearly with the dose (103 (49), 189 (75), and 379 (97) ng/ml after 0.5, 1, and 2 mg/kg respectively). Heart rate decreased significantly only after 2 mg/kg ketamine (-7 (10) beats/min, p = 0.029 v placebo). The increases in heart rate, arterial blood pressure, and pain score in response to tracheal suction during the placebo phase (11 (23) beats/min, p = 0.065; 6 (7) mm Hg, p = 0.004; 3.5 (interquartile range (IQR) 2.75-5) points, p = 0.001) were not attenuated by 0.5 or 2 mg/kg ketamine. However, 1 mg/kg ketamine attenuated the increase in pain score (1 (IQR 0.75-4.25) points, p = 0.043 v placebo), but not in heart rate (7 (23) beats/min) or blood pressure (7 (9) mm Hg). CONCLUSION: None of the doses of ketamine attenuated the changes in heart rate or blood pressure caused by suction, and only with a dose of 1 mg/kg was the suction induced pain moderately reduced. Thus infusion of ketamine at the doses used appears to be an ineffective method of relieving the pain caused by endotracheal suction.

Effects of echovirus 1 infection on cellular gene expression.

To obtain a view of the influence of enterovirus infection on host cell gene expression, multiple cellular mRNA levels were first investigated during echovirus 1 (EV1) infection in HOS palpha2AW cells using cDNA array analysis. Visible cytopathic effect and partial shut-off of host cell protein synthesis were observed 6-10 h after the EV1 infection. Simultaneously, approximately 2% of the investigated genes, among them immediate-early response genes and genes involved in apoptotic pathways and cell growth regulation, were activated over twofold and less than 0.5% of genes were downregulated. For comparison, the cellular effects of coxsackievirus B4 and poliovirus 1 infections were studied in HeLa-Ohio cells by cDNA arrays. Gene activation patterns detected in the host cells during the infection by the three enteroviruses were only partially similar.

Effects of marathon running on running economy and kinematics.

The present study was designed to investigate interactions between running economy and mechanics before, during, and after an individually run marathon. Seven experienced triathletes performed a 5-min submaximal running test on a treadmill at an individual constant marathon speed. Heart rate was monitored and the expired respiratory gas was analyzed. Blood samples were drawn to analyze serum creatine kinase activity (S-CK), skeletal troponin I (sTnI), and blood lactate (B-La). A video analysis was performed (200 frames x s(-1)) to investigate running mechanics. A kinematic arm was used to determine the external work of each subject. The results of the present study demonstrate that after the marathon, a standardized 5-min submaximal running test resulted in an increase in oxygen consumption, ventilation, and heart rate (P < 0.05), with a simultaneous decrease in the oxygen difference (%) between inspired and expired air, and respiratory exchange ratio (P < 0.05). B-La did not change during the marathon, while sTnI and S-CK values increased (P < 0.05), peaking 2 h and 2 days after the marathon, respectively. With regard to the running kinematics, a minor increase in stride frequency and a similar decrease in stride length were observed (P < 0.01). These results demonstrate clearly that weakened running economy cannot be explained by changes in running mechanics. Therefore, it is suggested that the increased physiological loading is due to several mechanisms: increased utilization of fat as an energy substrate, increased demands of body temperature regulation, and possible muscle damage.

Plasma catecholamine responses and neural adaptation during short-term resistance training.

Low exercise-induced plasma adrenaline (A) responses have been reported in resistance-trained individuals. In the study reported here, we investigated the interaction between strength gain and neural adaptation of the muscles, and the plasma A response in eight healthy men during a short-term resistance-training period. The subjects performed 5 resistance exercises (E1-E5), consisting of 6 sets of 12 bilateral leg extensions performed at a 50% load, and with 2 days rest in between. Average electromyographic (EMG) signal amplitude was recorded before and after the exercises, from the knee extensor muscles in isometric maximal voluntary contraction (MVC) as well as during the exercises (aEMGmax and aEMGexerc, respectively). Total oxygen consumed during the exercises (VO2tot) was also measured. All of the exercises were exhaustive and caused significant decreases in MVC (34-36%, P < 0.001). As expected, the concentric one-repetition maximum (1-RM), MVC and aEMGmax were all higher before the last exercise (E5) than before the first exercise (E1; 7, 9 and 19%, respectively, P < 0.05). In addition, in E5 the aEMGexerc:load and VO2tot:load ratios were lower than in E1 (-5 and -14%, P < 0.05), indicating enhanced efficiency of the muscle contractions, However, the post-exercise plasma noradrenaline (NA) and A were not different in these two exercises [mean (SD) 10.2 (3.8) nmol x l(-1) vs 11.3 (6.0) nmol x l(-1), ns, and 1.2 (1.0) nmol x l(-1) vs 1.9 (1.1) nmol x l(-1), ns, respectively]. However, although NA increased similarly in every exercise (P < 0.01), the increase in A reached the level of statistical significance only in E1 (P < 0.05). The post-exercise A was also already lower in E2 [0.7 (0.7) nmol x l(-1), P < 0.05) than in E1, despite the higher post-exercise blood lactate concentration than in the other exercises [9.4 (1.1) mmol x l(-1), P < 0.05]. Thus, the results suggest that the observed attenuation in the A response can not be explained by reduced exercise-induced strain due to the strength gain and neural adaptation of the muscles. Correlation analysis actually revealed that those individuals who had the highest strength gain during the training period even tended to have an increased post-exercise A concentration in the last exercise as compared to first one (r = 0.76, P < 0.05).

Catecholamines in pericardial fluid of normotensive, spontaneously hypertensive and reserpine-treated rats.

In this study our aims were to investigate the presence and source of catecholamines in pericardial fluid of normotensive, reserpine-treated and spontaneously hypertensive rats. We found that noradrenaline is the only detectable catecholamine present in rat pericardial fluid. The effect of reserpine 6, 12, and 214 h after pre-treatment with 5 mg kg(-1) (8.2 micromol kg(-1)) i.p. shows that the concentration of noradrenaline in pericardial fluid reflects the amount of noradrenaline released within the heart rather than the amount of noradrenaline in plasma. Using spontaneously hypertensive rats (SHR) as a model for primary hypertension we could show that the level of pericardial noradrenaline is approximately threefold in the pericardial fluid of the SHRs when compared to respective values of age-matched normotensive Wistar-Kyoto rats (WKY), suggesting that there was an increased noradrenaline overflow in the hearts of the SHRs. In conclusion, determination of the noradrenaline concentration in the pericardial fluid might provide a new method for estimating the release of noradrenaline in the heart.

Advantages of fentanyl over morphine in analgesia for ventilated newborn infants after birth: A randomized trial.

OBJECTIVE: To compare the efficacy and adverse effects of fentanyl or morphine analgesia during the first 2 days of life in newborn infants who underwent mechanical ventilation. STUDY DESIGN: In a randomized double-blind trial, 163 infants were allocated to receive a continuous infusion of fentanyl (10.5 microg/kg over a 1-hour period followed by 1.5 microg/kg/hr) or morphine (140 microg/kg over a 1-hour period followed by 20 microg/kg/hr) for at least 24 hours. The severity of pain was assessed with physiological parameters, a behavioral pain scale, and stress hormone concentrations before and 2 and 24 hours after the start of treatment. RESULTS: The analgesic effect was similar in both groups, as judged by the pain scale. Plasma adrenaline and noradrenaline concentrations decreased significantly from 0 to 24 hours in both groups. Median adrenaline decrease was 0.5 nmol/L (interquartile range [IQR] 1.1;0.0) in the fentanyl and 0.7 nmol/L (IQR 1.3;0.1) in the morphine group, noradrenaline 2.1 nmol/L (IQR 9.0;0.2), and 3.0 nmol/L (IQR 7. 5;0.3), respectively. beta-endorphin decreased significantly only in the fentanyl group ( 14 pmol/L (IQR 28; 7), P <.05). Decreased gastrointestinal motility was less frequent in the fentanyl group (23% vs 47%, P <.01). CONCLUSIONS: With at least as effective analgesia as with morphine, fentanyl had fewer side effects. Fentanyl may be superior to morphine for short-term postnatal analgesia in newborn infants.

A peptide inhibiting the collagen binding function of integrin alpha2I domain.

Integrin alpha2 subunit forms in the complex with the beta1 subunit a cell surface receptor binding extracellular matrix molecules, such as collagens and laminin-1. It is a receptor for echovirus-1, as well. Ligands are recognized by the special "inserted" domain (I domain) in the integrin alpha2 subunit. Venom from a pit viper, Bothrops jararaca, has been shown to inhibit the interaction of platelet alpha2beta1 integrin with collagen because of the action of a disintegrin/metalloproteinase named jararhagin. The finding that crude B. jararaca venom could prevent the binding of human recombinant ralpha2I domain to type I collagen led us to study jararhagin further. Synthetic peptides representing hydrophilic and charged sequences of jararhagin, including the RSECD sequence replacing the well known RGD motif in the disintegrin-like domain, were synthesized. Although the disintegrin-like domain derived peptides failed to inhibit ralpha2I domain binding to collagen, a basic peptide from the metalloproteinase domain proved to be functional. In an in vitro assay, the cyclic peptide, CTRKKHDNAQC, was shown to bind strongly to human recombinant alpha2I domain and to prevent its binding to type I and IV collagens and to laminin-1. Mutational analysis indicated that a sequence of three amino acids, arginine-lysine-lysine (RKK), is essential for ralpha2I domain binding, whereas the mutation of the other amino acids in the peptide had little if any effect on its binding function. Importantly, the peptide was functional only in the cyclic conformation and its affinity was strictly dependent on the size of the cysteine-constrained loop. Furthermore, the peptide could not bind to alpha2I domain in the absence of Mg2+, suggesting that the conformation of the I domain was critical, as well. Cells could attach to the peptide only if they expressed alpha2beta1 integrin, and the attachment was inhibited by anti-integrin antibodies.