Immune tolerance induction with mycophenolate-mofetil in two children with haemophilia B and inhibitor

Summary.  Immune tolerance induction (ITI) in haemophilia B patients with inhibitor should be carefully considered because of the relatively poor (25%) overall success rate and the high risk of complications. ITI in combination with an immunosuppressive treatment was started in two children with haemophilia B with factor IX (FIX) inhibitor. To avoid anaphylactic reactions and inhibitor boost, the FIX replacement therapy was stopped and patients received a treatment with recombinant activated factor VII (rFVIIa). After disappearance of FIX inhibitor, a combination of mycophenolate-mofetil (MMF), dexamethasone (DEXA) and intravenous immunoglobulin (IVIG) and a high dose FIX replacement therapy was started. Immune tolerance could be induced in patient 2, whereas eradication of FIX inhibitor was incomplete in patient 1. Both patients benefited from the immune suppressive treatment and FIX replacement therapy was tolerated without any allergic complications. Neither development of a nephrotic syndrome nor a severe bleeding episode was observed. Strategies to induce tolerance in haemophilia B patients with inhibitors need to be explored in a systematic way. Given the low frequency of disease and even lower incidence of inhibitors, prospective randomized studies may not be possible. International registry-based retrospective and prospective data collection could play the key role in the study of the outcome variables in ITI for haemophilia B.     

Parent–child communication and adolescent self-esteem in separated, intercountry adoptive and intact non-adoptive families

The purpose of the present study was to verify whether there are some differences in parent–child communication and in adolescent self-esteem among adoptive, separated and intact non-adoptive families and to investigate the extent to which parent–child communication is related to adolescent self-esteem in the three types of families. The study sample was composed of 450 adolescents aged between 11 and 17 years (160 from intact non-adoptive families, 140 from separated or divorced families and 150 from intercountry adoptive families). Subjects completed the Parent–Adolescent Communication Scale by Barnes and Olson, the Rosenberg Self-esteem Scale and some socio-demographic items. The results show that adolescents from separated families have more difficulties in their relationships with both the mother and the father than their peers, and that adoptive children perceive a more positive communication with their parents than biological children. Moreover, adoptees showed lower self-esteem than the other two groups of adolescents. Lastly, it emerged that male and female adolescents' self-esteem is related to positive communication with both parents in intact non-adoptive families, while no link was significant for male and female children of divorced parents or for adoptees.     

Synthesis and biological activities of some cholecystokinin analogues substituted in position 29 by a β-alanine

Syntheses of analogues of the C-terminal heptapeptide of cholecystokinin are described. These analogues were obtained by replacing glycine 29 by a β-alanine. The C-terminal phenylalanine amide was in some cases substituted by 2-phenylethyl alcohol and/or residues of the C-terminal tetrapeptide by their d -enantiomers. These compounds were tested for their action on stimulation of amylase release from rat pancreatic acini and for their ability to inhibit binding of labeled CCK to rat pancreatic acini and guinea pig brain membranes. Some of these derivatives behaved as CCK receptor antagonists.     

Antiarrhythmic Effects of VVI Pacing at Physiologic Rates: A Crossover Controlled Evaluation

Ventricular pacing can prevent bradycardia-dependent ventricular ectopic activity (VEA) and is helpful in some cases of drug-refractory venfricuiar tachycardia (VT). This study is a prospective evaluation of VVI pacing for the control of VEA not related to underlying bradycardia, drug side-effects, or prolonged QT interval syndromes. Twenty-nine patients undergoing serial electrophysioiogic-pharmacoiogic testing for VT control were studied. Eighteen of these patients (12 men; meon age = 60.1) both completed ihe protocol and had sufficient VEA for analysis. Coronary disease was present in 13 patients, cardiomyopathy in two patients, and one patient each had myocarditis, mitral valve prolapse, and no structural heart disease. Ambulatory (Holter) monitor recordings during VVI pacing were compared with control recordings made in the absence of pacing, VVI pacing rates were 10–15 bpm above the mean daily heart rate (mean = 92 bpm; range = 63–110). Hours from paced recordings were paired with hours from control (prior to analysis) according to time of day to reduce the effects of spontaneous variability in VEA frequency. Overall, VVI pacing reduced ventricular premature complexes (VPGs) 26% from 331 to 245/hour (p < 0.001). During pacing, couplets (pairs, successive VPGs) were reduced from 6.95 to 1.03/hour (p < 0.000001) and VT (≥3 successive VPCs) from 0.89 to 0.045 episodes/hour (p < 0.003). Of 13 patients with couplets, 11 had ≥50% reduction and five had ≥90% reduction. Baseline VT was eliminated in four out of nine patients during pacing. Pacing did not increase VEA significantly in any patient. In this group of patients, reduction of VEA by VVI pacing was significant and was comparable to pharmacologic interventions. Higher forms of VEA fcouplets and VT) appeared to respond better than single VPCs. Further studies may define patients with VEA who can benefit from pacing     

Concentrations of calmodulin in sperm in relation to their motility in fertile euspermic and infertile asthenozoospermic men

The relationship between calmodulin and sperm motility was assessed in euspermic and asthenozoospermic men using radioimmunoassay and time-lapse photography, respectively. There was a significant decrease in the % sperm motility, mean sperm velocity, motility index and % of progressively motile sperm in the asthenozoospermic group when compared with euspermic men. The former also exhibited a higher % of sperm with erratic or circular motility. Calmodulin concentration in sperm from the asthenozoospermic men was 4.8 +/- 1.4 micrograms/mg protein compared with 12.6 +/- 2.3 in euspermic men (P less than 0.0005). The differences observed in sperm motility characteristics between the two groups may, thus, be due to the observed differences in the concentration of calmodulin.     

Direct carrier testing of haemophilia B by SSCP

Summary. Haemophilia B is due to multiple molecular defects in the factor IX gene. Most of them are single base substitutions, and can now be identified by direct sequencing of the coding sequence of the factor IX gene, preceded or not by a screening strategy. In some instances the mutation alters an enzyme recognition site and this allows rapid and accurate carrier testing and prenatal diagnosis in the affected pedigree. This was not the case for the previously described nt 31119 (G– > A) mutation that we found in an extended haemophilia B pedigree, during the search for mutations in the factor IX gene in patients from Southern France. We first detected this mutation by single stranded conformation polymorphism (SSCP) and then identified it by DNA sequencing. Carriership could be easily determined in the females of the pedigree by analysis of the SSCP patterns. Our results indicate that the SSCP analysis of amplified genomic DNA fragments can be successfully used as a diagnosis approach for direct carrier testing and prenatal diagnosis.     

Clinical Utility of Rapid Clonidine-naltrcxone Detoxification for Opioid Abusers

Clonidine hydrochloride (an alpha-2 adrenergic agonist) and naltrexone hydrochloride (an opioid antagonist), given in combination, provide a safe and effective treatment of abrupt opioid withdrawal over 4 or 5 days in an outpatient/day setting. Following a naloxone challenge test to verify and quantify opioid dependence, 14 of 17 (82%) heroin users successfully withdrew from opioids and attained maintenance levels of naltrexone. Eight of 9 (89%) successfully completed the 4-day study in which naltrexone therapy was begun on day I. Three to 5 days of clonidine hydrochloride treatment with a peak mean dose of 0.6 mg/day on day 2 for the patients in the S-day study, and 0.5 mg on days 1 and 2 for patients in the 4-day study, attenuated the withdrawal inducing effects of naltrexone. Both groups received naltrexone in single morning doses which were rapidly increased from 12.5 mg on the first day of naltrexone therapy to SO mg on the third day. Clonidine significantly decreased blood pressure in both groups without producing clinical problems. This study has improved the availability of the clonidine-naltrexone combination by developing a single dose per day naltrexone regimen with naltrexone doses generally available to any opioid treatment facility.     

Characterization of variable immunodominant antigens of Cowdria ruminantium by ELISA and immunoblots

Cross-immunization experiments have revealed a significant antigenic diversity of the isolate of Cowdria ruminantium which needs to be characterized for the development of vaccines. We identified polymorphic immunodominant antigens by ELISA and immunoblot. Using serum from a goat immune to the Gardel stock of Cowdria (isolated in Guadeloupe) adsorbed on antigen of the Senegal stock of this pathogen, distinct serogroups were revealed by ELISA among six isolates from different geographical origins. Furthermore, a goat serum directed against the Senegal stock and adsorbed on Gardel antigens was shown to be specific for the Senegal stock, thus confirming the existence of serotypes in Cowdria . The Major Antigenic Protein 1 (MAP1) of Cowdria was shown to have variable antigenic determinants. Also in a group of variable proteins ranging from 23 to 29 kDa, one antigen of 26–27 kDa had a determinant specific for the Gardel isolate. These polymorphic antigens may be relevant components of Cowdria ruminantium for a vaccine as the sera revealing these antigens originated from a goat surviving a lethal challenge. However, the presence of T-cell epitopes and the ability of these antigens to confer protection to ruminants remain to be investigated. The production of a rabbit antiserum against this group of polypeptides will be of great use for their purification and for the screening of expression libraries .     

Biopharmaceutics: Changes in Gastric Mucosal Permeability Induced by Haemorrhagic Shock in the Anaesthetized Rat: Modulation by Acid

Gastric mucosal damage induced by haemorrhagic shock in the anaesthetized rat has been evaluated by studying changes in capillary-to-lumen clearance of fluorescein isothiocyanate (FITC)-labelled dextran. Haemorrhagic shock (20 min ischaemia + 20 min reperfusion) induced a significant increase in blood-to-lumen permeability to FITC-dextran of different molecular weight (10 000, 40 000 and 70 000) without modifying the macroscopic integrity of the gastric mucosa. The increase in vascular permeability was dependent on the time of administration of the tracer and was correlated with an elevation of the protein content of the gastric lumen. Intravenous administration of the secretagogue pentagastrin (20 or 50 μg kg^?1 h^?1) did not significantly modify the vascular permeability to dextran in control animals or in animals subjected to haemorrhagic shock. When the intraluminal pH was reduced by intragastric administration of acidic saline solution, only pH 1, which itself induced the appearance of macroscopic mucosal lesions, significantly increased vascular permeability to dextran, both in control animals and in animals subjected to haemorrhagic shock. These findings suggest that stress induced by haemorrhagic shock increases vascular gastric permeability to dextran, by an acid-independent mechanism, without affecting the macroscopic integrity of the gastric mucosa.