ACE inhibition reduces activity of the plasminogen/plasmin and MMP systems in the brain of spontaneous hypertensive stroke-prone rats

The spontaneously hypertensive stroke-prone rat (SHR-SP) is an experimental model of malignant hypertension which lead to secondary alterations of the extracellular matrix. Our aim was to determine ACE-inhibitor related changes of proteases involved in the reconstruction of the extracellular matrix in the brain. Twelve SHR-SP rats were randomized into two groups. Each group was treated with either an antihypertensive dose of ramipril or placebo for 6 months. Brain tissue plasminogen activator (t-PA) and urokinase (u-PA) were quantified by using casein-dependent plasminogen zymography, matrix metalloproteinase (MMP)-2 and MMP-9, by MMP-zymography, and tissue inhibitor of MMP (TIMP)-1 and -2, by reverse zymography. The amounts of u-PA, t-PA, and MMPs were significantly reduced in animals treated with ACE inhibitor. Plasminogen zymography showed a 39% reduction of u-PA in the basal ganglia (p < 0.0001); t-PA expression was reduced by 26% in the cortex and by 33% in the basal ganglia (p < 0.0001). MMP-2 expression was reduced by 15% in the cortex (p < 0.05) and by 10% in the basal ganglia (p < 0.05); MMP-9 expression significantly decreased by 37% in the cortex and by 25% in the basal ganglia (p < 0.0001 each). No differences were observed in the amount of TIMP-1 or TIMP-2. These findings provide new insights into the biochemical mechanisms underlying extracellular matrix proliferation and its modulation by ACE inhibitors. Therapeutic alterations that influence the proteolytic systems might prove important in the prevention of extracellular matrix accumulation and secondary microvascular vessel wall changes.     

Fibrodysplasia ossificans progressiva: Still turning into wood after 300 years?

Fibrodysplasia ossificans progressiva (FOP), a rare autosomal dominant disorder, is characterized by symmetrical congenital skeletal abnormalities and progressive heterotopic ossification of the connective tissues. At present, more than 300 years after the first report by Patin in 1648 in which he described the woman who turned to wood, its pathogenesis remains largely unknown and its therapy is limited to symptom-modifying trials. However, significant progress has been recently made and new data on the molecular organization and regulation of normal and disordered bone induction are likely to lead to a more specific therapy. FOP is believed to be a genetic disorder characterized by a disturbed expression of the endochondral osteogenesis programme, and the remarkable clues from the fly reported by Kaplan et al. [8] in 1990 suggest a gain-of-function mutation in the genetic regulation of bone morphogenetic proteins.     

Tumor necrosis factor-{alpha} up-regulates Bcl-2 expression and decreases calcium-dependent apoptosis in human B cell lines

Group I and Epstein–Barr virus-negative Burkitt's lymphomacell lines and the B104 lymphoma cell line which expresses aphenotype of immature B cells undergo apoptosis after cross-linkingof their surface Ig receptors or after exposure to a calciumionophore. We show here that tumor necrosis factor (TNF)- protectsthese B cell lines against Ca²⁺-dependent apoptosis. Protectionwas associated with up-regulatlon of bcl-2 mRNA and proteinexpression. The increase of Bcl-2 expression induced by TNF-was inhibited by chelerythrine, a specific inhibitor of proteinkinase C (PKC), suggesting that Bcl-2 expression was dependenton PKC activation. Furthermore, we show that phorbol estersand cyclosporin A (CsA), which prevent Ca²⁺-dependent apoptosis,up-regulated Bcl-2 expression. The effect of CsA on Bcl-2 expressionis controlled by calcineurin since we have shown that FK506but not rapamycin had the same effect on Bcl-2 expression, whereasokadaic acid, an inhibitor of phosphatases 1, 2A and 2C, wasineffective. These data provide direct evidence that TNF- preventsCa²⁺-dependent apoptosis by a Bcl-2-dependent mechanism mediatedby PKC.     

Relevance of platelet serotonin and plasma tryptophan concentration in normal pregnant women and newborns to early child psychiatry

Dysfunctions of the serotonergic system are implicated in psychiatric disorders, and there is evidence that a familial element may be significant in childhood autism. The concentrations of platelet 5-HT and free and total plasma tryptophan were determined in healthy pregnant women at each month of pregnancy and, at delivery, in both maternal and umbilical cord blood. A significant rise in the level of platelet 5-HT occured during month 3 and 4 followed by a retum to normal from month 5 until the delivery. The level of total plasma tryptophan remained equal to that in normal healthy non pregnant women until the 6th month. By month 7, it had decreased significantly and remained low until the month 9. At delivery the level fell significantly by –41%. The concentration of free tryptophan varied widely from one month to another but there was a trend towards a progressive increase from month 1 to 9, and at delivery the level returned to basal values. The concentration of 5-HT in the umbilical cord blood was about half that of the maternal blood. Inversely the concentrations of both free and total plasma tryptophan in the umbilical cord blood were nearly twice that of the maternal blood.

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Zusammenfassung Dysfunktionen des serotoninergen Systems werden bei verschiedenen psychiatrischen Störungen angenommen, wobei es Hinweise für eine familiäre Komponente im Rahmen des kindlichen Autismus gibt. Die Konzentrationen der 5-Hydroxyindolessigsäure in Blutplättchen und des Tryptophans (freie und Gesamtplasmakonzentrationen) wurden in gesunden schwangeren Frauen sowohl im mütterlichen Blut als auch im Nabelschnurblut in jedem Schwangerschaftsmonat und bei der Geburt bestimmt. Ein signifikanter Anstieg der Konzentration der 5-Hydroxyindolessigsäure in Blutplättchen ereignete sich zwischen Mens III und IV, und von Mens V ab an bis zur Geburt normalisierte sich die Konzentration. Der Gesamtplasmaspiegel von Tryptophan glich dem in gesunden nicht-schwangeren Frauen bis zu Mens VI, in Mens VII war er signifikant abgefallen und blieb bis zur Mens IX niedrig. Zum Geburtstermin fiel der Spiegel signifikant um 41%. Die Konzentration des freien Tryptophans zeigte von Monat zu Monat deutliche Schwankungen, wobei es einen Trend in Richtung eines kontinuierlichen Anstiegs von Mens I–IX gab. Zum Termin fiel der Spiegel auf die basalen Werte ab. Die Konzentration der 5-Hydroxyindolessigsäure im Nabelschnurblut betrug ca. die Hälfte derer im maternalen Blut. Umgekehrt waren die Konzentrationen sowohl des freien als auch Gesamtplasmatryptophans im Nabelschnurblut ca. doppelt so hoch wie im maternalen Blut.

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Résumé Le système sérotonergique semble impliqué dans les psychoses infantiles précoces, et, dans la mesure où une prévalence familiale existe pour ces affections, il nous a paru intéressant de déterminer un profil normal de la sérotonine (5-HT) plaquettaire et du tryptophane au cours de la gestation. Ceci dans le but de puvoir interpréter des résultats trouvés pendant la grossesse de femmes déjà mères d'un enfant psychotique. Nous avons déterminé les concentrations en 5-HT plaquettaire et en tryptophane plasmatique total et libre chez des femmes enceintes témoins à chaque mois de grossesse et, à l'accouchement, dans le sang maternel et dans le sang du cordon. La concentration en 5-HT plaquettaire augmente significativement aux 3ème et 4ème mois puis revient à la normale à partir du 5ème mois jusqu'à l'accouchement. Le tryptophane total est normal jusqu'au 6ème mois, il diminue significativement au 7ème mois et reste bas jusqu'au 9ème mois. A l'accouchement, il s'effondre (–41%). Le tryptophane libre varie beaucoup d'un mois à l'autre, il augmente progressivement du début à la fin de la grossesse, à l'accouchement par contre, il est normal. Dans le sang du cordon, la concentration en 5-HT est environ la moitié de celle du sang maternel, le tryptophane total et le tryptophane libre environ deux fois plus élevés.

     

Technetium-99m-MRP20, a potential brain perfusion agent: in vivo biodistribution and SPECT studies in non-primate animals

MRP20 (N-(2(1H pyrolylmethyl]N'-(4-pentene-3-one-2] ethane-1,2-diamine) complexes with technetium-99m, yielding a neutral, lipophilic species. This compound has been characterized as [TcO(MRP20)]. Biologic investigation of [99mTc][TcO(MRP20)] in female rats showed 2.35% ID in the brain 30 min p.i. with no significant wash-out over 3 hr. A single-photon emission computed tomography (SPECT) study in a dog demonstrated rapid tracer uptake in the brain, reaching a maximum within 1 min, with 2.24% i.d. 15 min p.i., decreasing to 1.7% after 4 hr. The complex undergoes hydrolysis in vitro forming a cationic species. This is possibly the trapping mechanism in the brain in vivo. The main excretory route of [99mTc][TcO(MRP20)] is via the hepatobiliary tract. There is evidence of some "in vivo" cell labeling and soft-tissue uptake.     

Reliability of the Dominic-R: A Young Child Mental Health Questionnaire Combining Visual and Auditory Stimuli

Reliability of the Dominic-R, a. questionnaire combining visual and auditory stimuli, was tested in 340 community children aged 6 to 11 years. Test-retest reliability of symptoms of, and of symptom scores of, DSM-III-R disorders including simple phobias, separation anxiety disorder, overanxious disorder, depression/dysthymia, attention deficit/ hyperactivity disorder, oppositional defiant disorder, and conduct disorder was assessed. Most symptoms yielded kappas greater than .40, and ICCs ranged from .74 to .81. In conclusion, reliability of the Dominic-R compares favourably with that of other child assessment questionnaires.     

Diagnosis of ectopic pregnancy after in vitro fertilization and embryo transfer

Objective: The combination of transvaginal sonography and serum hCG measurement is reliable in the diagnosis of ectopic pregnancy (EP) in spontaneous pregnancies. In patients who became pregnant through IVF-ET, transfer of multiple embryos after IVF could be responsible for the different performance of these tests. We evaluated the discriminative capacity of transvaginal sonography in combination with hCG measurement in the diagnosis of EP after IVF-ET.

Design: Prospective cohort study.

Setting and Patient(s): Consecutive patients, pregnant through IVF-ET, who presented with clinically suspected EP.

Intervention(s): Transvaginal sonography, serum hCG measurement at 6, 9, and 15 days after ET and after a negative transvaginal sonography.

Main Outcome Measure(s): Ectopic pregnancy confirmed at laparoscopy.

Result(s): Between September 1993 and May 1996, 86 women were included in the study, of whom 24 had an EP. Transvaginal sonography identified 46 intrauterine pregnancies and 5 EPs, but serum hCG could not diagnose EPs in patients in whom transvaginal sonography did not show a gestational sac. Serum hCG measurement 9 days after ET could identify pregnancy failure with 100% specificity at a cut-off value of 18 IU/L, but it could not identify patients with EP with enough certainty to justify immediate treatment.

Conclusion(s): We recommend single serum hCG measurement 9 days after ET to discriminate between viable and nonviable pregnancies. Transvaginal sonography can be postponed until 5 weeks after ET, except for patients with abdominal pain and/or vaginal bleeding, or patients with a serum hCG level of <18 IU/L.     

Coexistence of an adrenocortical carcinoma with an abdominal ganglioneuroma in a child

We report a 3-year, 5-month-old boy with an adrenocortical carcinoma. These tumours are rare and highly malignant in childhood. In most cases they are functional, secreting adrenocortical hormones. In this case there was a misleading coexistence with a second abdominal neoplasm, which was a ganglioneuroma; this is a rare benign tumour arising from the sympathetic nervous system. The imaging investigations and their findings are discussed and correlated with pathology. Received: 15 January 1997 Accepted: 15 October 1997     

How we approach: Severe congenital neutropenia and myelofibrosis due to mutations in VPS45

Mutations in the VPS45 gene lead to a severe primary immune deficiency characterized by severe congenital neutropenia and primary myelofibrosis, leading to overwhelming infection and early death. This condition is exceedingly rare with only 16 patients previously reported, including four with successful hematopoietic stem cell transplantation. We review the pathophysiology underlying this condition and detail our approach to treatment, particularly vis‐à‐vis bone marrow transplantation and the challenges of transplanting into a diseased bone marrow niche. We provide an update on the progress of our three previously reported patients, and two additional patients transplanted at our center.