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Notes: Abstract PURPOSE: We have investigated the use of anorectal manometry to distinguish encopretic-constipated children (n=88) from sibling controls (n=16) and nonsibling controls (n=11). METHODS: Study variables included manometrically determined resting and maximum voluntary anal sphincter pressure, depth and speed of rectoanal inhibitory reflex, minimum rectal volume sensation, critical distending volume for fecal urgency, rectal and anal pressure responses during attempted defecation, and ability to defecate a water-filled balloon. RESULTS: Change in anal sphincter pressure during attempted defecation (P=0.03), gradient between rectal and sphincter pressure during attempted defecation (P=0.02), critical distending volume for fecal urgency (P=0.02), and ability to defecate a water-filled balloon (P=0.05) distinguished encopretic-constipated from control children. The change in rectal pressure associated with the rectoanal inhibitory reflex just escaped significance at P=0.07. CONCLUSIONS: Anal sphincter spasm and megacolon are pathophysiologic abnormalities associated with pediatric constipation-encopresis.

Notes: Abstract Pneumatoceles are an infrequent manifestation of blunt chest trauma in children. They are important to present immediately after trauma and can be mistaken for more serious surgical conditions, such as diaphragmatic rupture. In this case report, we present one such case in which we present one such case in which posttraumatic pneumatoceles were mistaken for diaphragmatic injury with bowel herniation.

Notes: Abstract The objective of this study was to investigate the value of ultrasound to establish alternative diagnoses in pediatric patients with clinical suspicion of acute appendicitis. A total of 206 consecutive patients with right lower abdominal pain were evaluated by ultrasound. For each case, the sonographic findings documented on the report at the time of examination were compared with the final diagnosis. Our results demonstrated that ultrasound was 94% accurate in the diagnosis of acute appendicitis. Among all 42 of the 108 truenegative cases of appendicitis, there was a variety of sonographic findings other than appendiceal abnormality, comprising intestinal and/or mesenteric, gallbladder, and ovarian abnormalities. Sonographic findings were well correlated with clinical and/or surgical diagnoses. Only 3 of these 42 cases were treated by surgical intervention. Ultrasound of pediatric right lower abdominal pain is a reliable diagnostic tool not only for appendicitis but for alternative diagnoses mimicking appendicitis.

Notes: Zusammenfassung Hintergrund: Chronischer Tinnitus tritt bei Kindern und Jugendlichen mit einem normalen Ton- und Sprachhörvermögen nur selten auf. Die nosologische Einordnung dieser Störung ist auch anhand der Kriterien des ICD-10 schwierig. Aktuelle epidemiologische Daten sowie allgemein anerkannte diagnostische und therapeutische Konzepte fehlen. In der Erwachsenenmedizin haben psychosomatische Aspekte des chronisch-komplexen Tinnitus einen hohen Stellenwert. Gegenstand dieser Arbeit ist die Frage, ob dies auf Kinder und Jugendliche übertragen werden kann. Es soll ein rationelles diagnostisches Vorgehen im Hinblick auf die in dieser Altersgruppe naturgemäß schwierige Indikationsstellung für eine invasive Therapie diskutiert werden. Die Ergebnisse nach parenteraler Lidocain-Gabe als organbezogener medikamentöser Therapie werden vorgestellt. Patienten und Methode: Im Zeitraum vom Januar 1992 bis zum Dezember 1995 wurden insgesamt 31 Kinder und Jugendliche im Alter zwischen 6 und 17 Jahren ambulant und stationär wegen eines chronischen Tinnitus aurium bei normalem Ton- und Sprachhörvermögen behandelt. Der Tinnitus war in 2/3 der Fälle beidseitig lokalisiert. Bei 24 Kindern konnte anhand der systematischen Anamnese und Befundung eine in der Folge des Tinnitus aufgetretene psychische Störung ausgeschlossen werden. In diesen Fällen wurde als alleinige therapeutische Maßnahme ein Tinnitus-Counselling durchgeführt. In 7 Fällen, bei 3 Mädchen und 4 Jungen im Alter von 10–17 Jahren, lag eine Dekompensation der Beschwerden vor: Bei ihnen waren die diagnostischen Kriterien einer depressiven Episode nach ICD-10 erfüllt. In diesen Fällen erfolgte unter stationären Bedingungen für 10 Tage eine auf das organische Symptom bezogene Behandlung mit Lidocain-haltigen Infusionen in einer dem Körpergewicht angepaßten Dosierung. Die Patientendaten wurden retrospektiv-katamnestisch anhand der Krankengeschichten ausgewertet. Ergebnisse: Bei normalem Ton- und Sprachhörvermögen konnten die transitorisch evozierten otoakustischen Emissionen im gesamten Krankheitsverlauf nur unregelmäßig nachgewiesen werden. Die Ableitung der auditorisch evozierten Hirnstammpotentiale ergab keine auffälligen Befunde. Die Tinnitusbestimmung und die audiometrische Prüfung der Tinnitusverdeckung gelang nur bei den älteren Jugendlichen. In allen Fällen ohne eine Dekompensation schwanden die Tinnitusbeschwerden. Im Nachbeobachtungszeitraum von 12–44 Monaten konnte bei den mit Lidocain behandelten Patienten in 4 Fällen eine komplette Remission verzeichnet werden, in 3 Fällen eine Verminderung der Beschwerden und der Klagsamkeit bei adäquater Krankheitsbewältigung. Bei einer Patientin der Lidocain-Gruppe war wegen einer komplexeren Somatisierungsstörung die Einleitung einer Phsychotherapie erforderlich. Unerwünschte Wirkungen des Lidocains wurden nicht beobachtet. Schlußfolgerungen: Bei normalem Ton- und Sprachhörvermögen und fehlenden weiteren körperlichen Auffälligkeiten kann sich beim chronischen Tinnitus im Kindes- und Jugendalter die Organdiagnostik auf ein Basisprogramm beschränken. Die Primärdiagnostik sollte also ein Ton- und Sprachaudiogramm umfassen und nur bei einer unsicheren Hörschwelle auch die Ableitung der autitorisch evozierten Hirnstammpotentiale. Die Messung der otoakustischen Emissionen sowie die Tinnitusbestimmung und Maskierungsuntersuchungen haben nach den hier erhobenen Befunden in dieser Altersgruppe keine diagnostische oder prognostische Bedeutung. Bei fehlenden weiteren Symptomen sind weitergehende diagnostische Maßnahmen (Bildgebung, Serologie) nicht erforderlich. Die Einordnung des chronischen Tinnitus aurium als eine psychosomatische Störung bewährt sich auch im Kindes- und Jugendalter. Die diagnostischen Kriterien des ICD-10 psychischer Störungen sind eine wertvolle Strukturierungshilfe im Hinblick sowohl auf die nosologische Zuordnung wie auch insbesondere im Hinblick auf die Entscheidung zu einer invasiven Therapie, sofern nämlich die diagnostischen Kriterien einer depressiven Episode erfüllt sind. In diesen Fällen sollte eine Lidocain-Infusionsbehandlung versucht werden. In allen anderen Fällen ist ein Tinnitus-Counselling ausreichende Therapie.

Notes: Abstract  The various aspects of supportive care in children suffering from cancer, diagnosed at the Children's Hospital Aglaia Kyriakou, in Athens, are presented from the diagnosis to each step of therapy, and afterwards. It is stressed that cultural, religious and social parameters are crucial in defining the way to approach the family as a whole.

Notes: Tränenwegsoperationen an der Universitäts-Augenklinik Münster von 296 Kindern aus den Jahren von 1987 – 1992 wurden untersucht. Patienten und Methode: Alter der Patienten, Ätiologie und die Operationsmethoden wurden retrospektiv ausgewertet. Um die Operationsergebnisse und die subjektive Zufriedenheit zu erfassen, wurden an die Eltern der Patienten Fragebögen verschickt. Ergebnisse: 181 Fragebögen (Ergebnisse von 210 Operationen, davon 24 Voroperationen) wurden zurückgeschickt. 124 Kinder waren bis zu 3 Jahre alt. 197 Stenosen wurden kongenital, 7 traumatisch, 4 entzündlich und 2 iatrogen bedingt. 184 Tränenwegsspülungen mit Intubationen (I) der Tränenwege, 7 Canaliculusrekonstruktionen und 19 Dakryozystorhinostomien (DCR) wurden durchgeführt. Praktisch beschwerdefrei waren 87,5% der Patienten mit Tränenwegsintubation, 85,7% nach Canaliculusrekonstruktion und 78,9% nach DCR. 5 Patienten mußten wegen anhaltender starker Beschwerden ein zweites Mal operiert werden.

Notes: Between 1972 and 1994 21 children up to 14 years old sustained complex pelvic trauma treated at the Trauma Department of the Hannover Medical School. Sixteen of the 17 survivors were followed at an average of 8.9 years. In 8 patients operative treatment of the disrupted pelvic ring (external or internal fixation) was performed; in 8 patients the treatment was conservative. At follow-up 9 patients (56%) were pain-free; 4 reported slight, 2 moderate and one patient severe pain (at rest). There were no neurological deficits. Four patients had disturbed micturia, and 1 had bowel incontinence. Radiological evaluation showed anatomic reconstruction of the pelvic ring in 9 cases (56%). Residual maximum displacement of 12 mm was detected in 2 patients. In 3 cases osteoarthritis or ancylosis of the SI joint was present. In 3 cases a clinically not disturbing heterotopic ossification was found. Another 2 cases had ossifications of the pubic symphyses. A post-traumatic acetabular dysplasia was detected in 2 cases; a hypoplasia of the hemipelvis was seen in 3 patients. In a retrospective analysis of the primary radiographs, 13 pelvic lesions were not detected during the primary clinical course (sacral fracures, lesions of the triradiate cartilage). Despite this finding the pelvic outcome was rated good and excellent in 10 patients (63%), moderate in 1 patient (hypoplasia of the hemipelvis, and poor in 5 patients (31%) with severe pain or urogenital disturbancies. The maximum ratings in social reintegration was given to 9 patients, a medium rating to 7 patients. All patients were socially integrated.

Notes: Zusammenfassung Fragestellung: Das Ziel der Studie war die Validierung einer kindgerechten Modifikation des bei Erwachsenen angewandten 13C-Harnstoff-Atemtests zur Diagnose einer Helicobacter-pylori-Infektion. Methode: Bei 30 asymptomatischen Kindern wurden die Ergebnisse des Atemtests mit dem eines Helicobacter-pylori-ELISA-Tests verglichen. Bei 10 symptomatischen Kindern konnte das Atemtestergebnis mit einem histologischen Befund der Magenschleimhaut verglichen werden. Mittels Ultraschall wurde bei 7 Probanden untersucht, ob gekühlter Orangensaft als Testmahlzeit geeignet ist. Ergebnisse: Gegenüber dem serologischen bzw. histologischen Untersuchungsergebnis als Referenzmethode wies der für Kinder ermittelte Grenzwert ( δ -Wert = 5 ‰) eine Sensitivität bzw. Spezifität von 70 bzw. 95 % und 100 bzw. 100 % auf. Kalter Orangensaft war in der Lage, die Magenentleerung signifikant für die Dauer des Atemtests zu hemmen und erfüllt damit die Kriterien einer Testmahlzeit. 30 min nach 13C-Harnstoff-Einnahme war der optimale Zeitpunkt für den 2. Probesammelzeitpunkt. Schlußfolgerung: Auch in seiner kindgerechten Modifikation ist der 13C-Harnstoff-Atemtest zur Diagnose einer Infektion mit Helicobacter pylori geeignet.

Notes: During the war period 1991–1992 in Croatia, ten wounded children (16 years of age or younger) with war injuries to the brain were admitted to the Division of Neurosurgery, Osijek Clinical Hospital. Six of them had been wounded by shrapnel and four by pistol or rifle bullets. All but one were managed surgically (i.e. by craniotomy). The outcome was: as follows three children had a good recovery, four retained a moderate neurological deficit, and three died (injured by shrapnel). Five of the wounded (four injured by shrapnels and one by bullets) had associated injuries (fractures of the leg bones, eye lesion, amputation of the right leg) which influenced morbidity, and in one case mortality. Children wounded with shrapnel had brain edema on admission to hospital. Our experience indicates that the thermal effect from heated shrapnel, as well as velocity, mass, size and shape of the shrapnel, could be an additional factor for the development of severe brain edema.

Notes: Zusammenfassung Die erfolgreiche Rehabilitation hörgestörter Kinder hängt wesentlich von der Qualität der Hörgeräteversorgung mit einer gezielten Vorauswahl des Hörgeräts ab. Daher wurden insgesamt 253 Hörgeräteüberprüfungen bei 39 schwerhörigen Kindern mit 71 HdO- Gerät-versorgten Schallempfindungsschwerhörigkeiten aller Schwerhörigkeitsgrade ausgewertet. Wir untersuchten, wie viele Hörgerätetypen angepaßt worden sind, sowie welche Fehler in welcher Häufigkeit bei der Hörgeräteüberprüfung festgestellt wurden. Gleichzeitig wurde die Effektivität und Regelmäßigkeit der in der Göttinger Klinik durchgeführten Hörgerätekontrollen ausgewertet. Eine Reduktion der zunächst 33 – meist anderenorts verordneten – Hörgerätetypen auf 23 fand statt, nachdem die entsprechenden Geräte die Erfordernisse für Art und Grad der jeweiligen Schwerhörigkeit nicht zufriedenstellend erfüllten bzw. die Akzeptanz schlecht war. Eine weitere Reduzierung dieser nicht erforderlichen, unüberschaubaren Anzahl an nicht bestmöglich ausgewählten Hörgeräten war wegen der bereits erfolgten Endverordnungen nicht mehr durchführbar. Bei 60% aller Überprüfungen konnten insgesamt 222 Mängel nachgewiesen werden: Am häufigsten war mit 59% die dynamische Hörgerätanpassung [Verstärkung (37%), Verzerrung (18%) und Dynamik (4%)], seltener mit jeweils 16% die Hörgerätfunktion und die Otoplastik [Form (9%), Material (4%) und Schlauch (3%)] und am seltensten mit 9% die Potentiometerabdeckung betroffen, die etwa zu gleichen Anteilen beim Tragen verlorengegangen war bzw. primär nicht angebracht wurde. Die qualitative Hörgerätkontrolle erfolgte nicht nur in 76% der Fälle regelmäßig, sondern war in 73% auch erfreulich effektiv. Unsere Ergebnisse weisen auf die Wichtigkeit der pädaudiologischen Qualitätssicherung kindlicher Hörgerätversorgungen hin.

Notes: Zusammenfassung Fragestellung: Ist die Bestimmung der kreatininbezogenen Ausscheidung von Deoxypyridinolin (DPD/Cr) und Pyridinolin (PYD/Cr) bei Kindern mit Störungen des Kalziumphosphatstoffwechsels sinnvoll? Patienten/Methoden: DPD/Cr und PYD/Cr wurden mittels 2er kompetitiver Enzymimmunoassays im Morgenurin bei 102 gesunden Kindern und 50 Patienten mit Knochenstoffwechselerkrankungen (Vitamin-D-Mangel-Rachitis; Phosphatdiabetes; Pseudohypoparathyreoidismus) zusammen mit der kreatininbezogenen Hydroxyprolinausscheidung untersucht. Ergebnisse: Bei Gesunden korrelierten PYD/Cr und DPD/Cr (r=0,59; p≤0,001), PYD/Cr und kretatininbezogene Hydroxyprolinausscheidung (r=0,72; p≤0,001) sowie DPD/Cr und kreatininbezogene Hydroxyprolinausscheidung (r=0,42; p≤0,001). PYD/Cr und DPD/Cr waren altersabhängig mit hohen Werten bei Säuglingen und Kleinkindern, die bis zur Pubertät abfielen. Bei allen 3 Krankheitsbildern waren PYD/Cr und DPD/Cr mit der kreatininbezogenen Hydroxyprolinausscheidung korreliert (Vitamin-D-Mangel-Rachtitis: r=0,54, p≤0,05 bzw. r=0,72 p≤0,01; Phosphatdiabetes: r=0,36, p≤0.05 bzw. r=0,60, p≤0,001; Pseudohypoparathyreoidismus: r=0,67, p≤0,01 bzw. r=0,84, p≤0,001). Bei einigen Patienten mit Vitamin-D-Mangel-Rachitis, Phosphatdiabetes und Pseudohypoparathyreoidismus konnten z.T. erheblich erhöhte Werte für PYD/Cr (Vitamin-D-Mangel-Rachitis: n=6, Phosphatdiabetes: n=14, Pseudohypoparathyreoidismus: n=4), DPD/Cr (Vitamin-D-Mangel-Rachitis: n=7, Phosphatdiabetes: n=14, Pseudohypoparathyreoidismus: n=4) und die kreatininbezogene Hydroxyprolinausscheidung (Vitamin-D-Mangel-Rachitis: n=8, Phosphatdiabetes: n=17, Pseudohypoparathyreoidismus: n=5) gefunden werden. Schlußfolgerung: Bei Kindern kann der Knochenumsatz durch die Bestimmung von PYD/Cr, DPD/Cr und der kreatininbezogenen Hydroxyprolinausscheidung bestimmt werden. Die alleinige Messung von DPD/Cr ist jedoch sehr viel einfacher, spezifischer und sensitiver als die Bestimmung der kreatininbezogenen Hydroxyprolinausscheidung und könnte in Zukunft ein wertvolles diagnostisches Werkzeug für Kinder mit Kalziumphosphatstoffwechselstörungen werden.

Notes: Zusammenfassung Fragestellung: Mittels ambulanter 24-h-Blutdruckmessung soll bei jungen Patienten mit Diabetes mellitus frühzeitig eine arterielle Hypertonie erkannt werden. Methode: Es wurden bei 48 Kindern und Jugendlichen mit Diabetes mellitus (24 Mädchen, 24 Knaben) im Alter von 9–18 Jahren ambulante 24-h-Blutdruckmessungen durchgeführt. Langzeitmessungen wurden ebenso bei einer Kontrollgruppe von 48 gesunden Kindern und Jugendlichen durchgeführt, die nach Geschlecht, Alter, Größe und Gewicht den Patienten mit Diabetes mellitus zugeordnet wurden (Matched-pairs-Technik). Ergebnisse: Keines der Kinder und Jugendlichen mit Diabetes mellitus hatte eine arterielle Hypertonie. Überraschenderweise lagen jedoch sowohl der systolische als auch der diastolische Blutdruck um 4 bzw. 6 mm Hg über den Werten der gesunden Kontrollgruppe (Methode der gleitenden Mittelwerte). Mittels konventioneller Auswertung (Bildung des arithmetischen Mittels) wurden diese Ergebnisse bestätigt (p 〈 0,001, t-Test für unverbundene Stichproben). Bezüglich der Stoffwechseleinstellung fanden wir bei Kindern und Jugendlichen mit HbA1c-Werten 〉 7 % (Median) um 5 mm Hg höhere diastolische Blutdruckwerte. Im Gegensatz zur Literatur zeigte sich in dieser Studie, daß bereits Kinder und Jugendliche mit Diabetes mellitus trotz Normotonie höhere Blutdruckwerte im Vergleich zur gesunden Kontrollgruppe haben. Schlußfolgerungen: Langzeitmessungen müssen in multizentrischen, longitudinal angelegten Studien durchgeführt werden, um Aufschlüsse über pathogenetisch bedeutsame Zusammenhänge bei der Entwicklung einer arteriellen Hypertonie bei Kindern und Jugendlichen mit Diabetes mellitus zu erhalten.

Notes: Zusammenfassung Die Heparin-induzierte Thrombozytopenie (HIT) Typ II ist ein lebensbedrohliches Krankheitsbild, bei der es unter Heparintherapie zu venösen Thrombosen und arteriellen Gefäßverschlüssen kommen kann. Bei Kindern wurde eine HIT Typ II sehr selten beschrieben. Wir berichten über einen 12jährigen Patienten, der aus völliger Gesundheit an einer tiefen Bein- und Beckenvenenthrombose ungeklärter Genese erkrankte. Er entwickelte im Rahmen einer thrombolytischen Therapie mit Streptokinase und Urokinase sowie einer begleitenden Behandlung mit unfraktioniertem Heparin eine Thrombozytopenie, multiple Embolien der linken A. femoralis und eine Thrombose der V. cava inferior. HIT-Antikörper wurden durch ELISA gegen Plättchenfaktor-4-(PF4)-Heparin-Komplexe und den Heparin-induced-platelet-activation-(HIPA)-Assay nachgewiesen. Nach sofortiger Beendigung der Heparinzufuhr wurde die Antikoagulation zunächst kurzzeitig mit einem Heparinoid und dann mit rekombinantem Hirudin fortgeführt. Danach kam es zu einer weitgehenden Besserung der Symptomatik, allerdings ließ sich eine Vorfußamputation nach Chopart nicht vermeiden. Unser Fallbericht zeigt, daß eine HIT Typ II nicht auf das Erwachsenenalter beschränkt ist. Auch bei pädiatrischen Patienten sollte bei jeder Heparinapplikation eine regelmäßige Kontrolle der Thrombozytenzahl erfolgen und bei entsprechendem Verdacht geeignete Maßnahmen eingeleitet werden.

Notes: Zusammenfassung In der retrospektiven Studie untersuchten wir 27 Kinder mit akuter Immunthrombozytopenie (ITP), die bei Diagnosestellung Blutungszeichen und Thrombozytenwerte von 〈 20 000/μl aufwiesen. Die Behandlung erfolgte mit i. v. gegebenen Immunglobulinen (IVIG) in einer Dosis von 0,4 g/kgKG. 24 h nach einer Einzeldosis IVIG hatten 19 von 27 Kindern (70 %) Thrombozytenwerte von 〉 20 000/μl erreicht. Bei 12 der 19 Kinder wurde daraufhin die Behandlung beendet und bei 7 Kindern über 2–4 Tage fortgeführt. Der Thrombozytenverlauf der 12 Kinder mit nur einer Einzeldosis IVIG unterschied sich nicht von dem der 7 Kinder, die länger behandelt wurden. Patienten, deren Thrombozyten nach der ersten IVIG-Gabe nicht innerhalb von 24 h über 20 000/μl anstiegen, zeigten trotz weiterer Therapie einen protrahierteren Krankheitsverlauf. Eine Einzeldosistherapie mit 0,4 g/kgKG IVIG erscheint uns ausreichend für die meisten Kinder mit akuter ITP, Blutungszeichen und niedrigen Thrombozytenwerten.

Notes: Abstract  A case of a mobile, calcified, intrapelvic mass representing an autoamputated ovary in an asymptomatic girl is presented. There was no previous history of acute abdominal pain indicating possible torsion of the adnexa. The diagnosis should be suspected when radiological investigations show a freely mobile, calcified intraperitoneal mass incidentally in young females with absent adnexa. The diagnostic and therapeutic role of laparoscopy in this case is emphasised.

Notes: Abstract Two children with fungal urinary tract infections (UTI) were treated with fluconazole. One had bilateral megaureters, an almost non-functioning right kidney, and a moderately functioning left kidney because of severe vesicoureteric reflux. He underwent a ureteric reimplantation procedure but developed a fungal UTI postoperatively. The other child had bilateral refluxing megaureters, one of which appeared to open ectopically into the urethra. He acquired a fungal infection during intensive and prolonged antibiotic therapy for a bacterial UTI and septicaemia in the neonatal period. Both fungal infections were cured successfully. We recommend fluconazole as a safe and effective antifungal agent that may be used as a drug of choice for this difficult problem.

Notes: Abstract Our initial experience over the last 3 years with laparoscopic and thoracoscopic surgery in children and adolescents is reported. Between September 1992 and August 1995, a total of 215 laparoscopic and thoracoscopic procedures were performed: 32 appendectomies for acute appendicitis, 10 cholecystectomies for symptomatic gallstones, 11 procedures for adnexal pathology, 6 laparoscopies in children with nonpalpable testes, 3 diagnostic laparoscopies, and 153 thoracoscopic sympathectomies in children suffering from primary palmar hyperhidrosis. The post-operative course was uneventful in all cases. In 2 children with acute appendicitis we converted to the open technique due to technical difficulties. We are encouraged by the results of our initial experience. There is no doubt that laparoscopic cholecystectomy, laparoscopic surgery of adnexal pathology, and thoracoscopic sympathectomy, because of their numerous benefits - shorter operative time, hospitalization, and convalescence as well as less postoperative pain and improved cosmetic results - are replacing the open techniques. We are not convinced as yet of the advantages of laparoscopic appendectomy in children; we are presently performing both laparoscopic and conventional techniques and studying the various parameters in order to reach a more definite conclusion. Various other endoscopic surgical procedures will be carefully considered in the near future.

Notes: Abstract  Twenty patients aged 5 months – 4 years (mean 14 months) with Hirschsprung’s disease were operated upon. In all cases a pull-through resection and stapled circular coloanal anastomosis was performed, in 11 with a single-stapling technique and in 9 with double-stapling. Isopaque rectography 4 – 10 days postoperatively showed an intact anastomosis in all 20 patients, i. e., there were no clinical or subclinical leaks. On palpation 4 – 6 weeks postoperatively, there were signs of stenosis in 4 patients. However, no. 9 – 11 Hegar dilators passed easily and there was no residual stenosis at follow-up 3 months after surgery. The technique can be recommended in children over 6 months of age.

Notes: Abstract The authors evaluated the relationship between drug intake and upper gastrointestinal (GI) bleeding. The endoscopic files of the previous 2 years were reviewed and the incidence and age and sex distribution recorded. GI bleeding is indication for a high percentage of lower endoscopies and a low percentage of upper endoscopies. On the other hand, although rarer upper GI bleeding is more severe and frequently related to drug ingestion. About 50% of cases showed gastric erosions secondary to drug intake. A relation between gastric bleeding and paracetamol is considered, as is the possibility of preventing secondary severe bleeding by pharmacologic gastric protection in children with risk factors such as chronic use of other drugs or portal hypertension.

Notes: Abstract Twenty-one consecutive laparoscopic cholecystectomies (LC) were compared with 29 consecutive open cholecystectomies (OC). Sickle-cell disease (SCD) was the most common reason for cholecystectomy in both groups. The average length of operative time for LC was significantly longer than that of OC (P=0.0149). In 1 patient there was conversion from LC to OC due to severe adhesions. Common bile duct (CBD) stones were diagnosed in 8 (27.6%) of the OC group; in 4 of them the diagnosis was made preoperatively by ultrasound, in 4 by intraoperative cholangiogram. All 8 patients required CBD exploration, and 2 had additional transduodenal sphincteroplasties. In the LC group 5 patients (23.8%) had CBD stones. All had (ERCP) endoscopic retrograde cholangiopancreatography sphincterotomy, and stone extraction followed by LC. ERCP is a necessary adjunct to treatment if LC is to be contemplated. Six patients in the OC group developed complications, while only 4 patients in the LC group developed minor complications. The length of hospitalization after LC was significantly shorter than after OC (P=0.0150). LC is the procedure of choice in the management of cholelithiasis in children, especially those with SCD.

Notes: Abstract Twenty-one consecutive laparoscopic cholecystectomies (LC) were compared with 29 consecutive open cholecystectomies (OC). Sickle-cell disease (SCD) was the most common reason for cholecystectomy in both groups. The average length of operative time for LC was significantly longer than that of OC (P = 0.0149). In 1 patient there was conversion from LC to OC due to severe adhesions. Common bile duct (CBD) stones were diagnosed in 8 (27.6%) of the OC group; in 4 of them the diagnosis was made preoperatively by ultrasound, in 4 by intraoperative cholangiogram. All 8 patients required CBD exploration, and 2 had additional transduodenal sphincteroplasties. In the LC group 5 patients (23.8%) had CBD stones. All had (FRCP) endoscopic retrograde cholangiopancreatography sphincterotomy, and stone extraction followed by LC. FRCP is a necessary adjunct to treatment if LC is to be contemplated. Six patients in the OC group developed complications, while only 4 patients in the LC group developed minor complications. The length of hospitalization after LC was significantly shorter than after OC (P = 0.0150). LC is the procedure of choice in the management of cholelithiasis in children, especially those with SCD.

Notes: Abstract The hospital records of patients who underwent splenectomy during the last 2 years were reviewed to compare the advantages of the laparoscopic approach with traditional open splenectomy (OS). Between March 1994 and March 1996, 16 children underwent splenectomy, in 8 using an open approach and 8 by a laparoscopic procedure. Of the patients who underwent laparoscopic splenectomy (LS), 2 had a concomitant cholecystectomy. Ages ranged between 4 and 11 years (mean 6.4 years); there were 9 girls and 7 boys. The indications for splenectomy were: hereditary spherocytosis (7 cases); idiopathic thrombocytopenic purpura (4); sickle-cell disease (3); and β-thalassemia (2). The average operating time for OS was 100 min (range, 50–155), for LS 170 min (range 125–240). The hospital stay for patients who had OS ranged from 3 to 9 days (mean 4.7), for those who had LS from 2 to 5 days (mean 3). One OS patient developed a wound infection. In 3 of the LS patients, the spleen was removed via a 7-cm Pfannenstiel minilaparotomy in the suprapubic region; in 5 cases the spleen was captured into an extraction bag, crushed, and removed through the umbilical orifice. The authors believe that LS must be performed only when it is possible to use the extraction bag to remove the spleen from the umbilical orifice (spleens weighing less than 700 g) and when a concomitant procedure such as cholecystectomy is indicated; in other cases OS is preferable.

Notes: Abstract A case of a mobile, calcified, intrapelvic mass representing an autoamputated ovary in an asymptomatic girl is presented. There was no previous history of acute abdominal pain indicating possible torsion of the adnexa. The diagnosis should be suspected when radiological investigations show a freely mobile, calcified intraperitoneal mass incidentally in young females with absent adnexa. The diagnostic and therapeutic role of laparoscopy in this case is emphasised.

Notes: Abstract Two children with fungal urinary tract infections (UTI) were treated with fluconazole. One had bilateral megaureters, an almost non-functioning right kidney, and a moderately functioning left kidney because of severe vesicoureteric reflux. He underwent a ureteric reimplantation procedure but developed a fungal UTI postoperatively. The other child had bilateral refluxing megaureters, one of which appeared to open ectopically into the urethra. He acquired a fungal infection during intensive and prolonged antibiotic therapy for a bacterial UTI and septicaemia in the neonatal period. Both fungal infections were cured successfully. We recommend fluconazole as a safe and effective antifungal agent that may be used as a drug of choice for this difficult problem.

Notes: Abstract The hospital records of patients who underwent splenectomy during the last 2 years were reviewed to compare the advantages of the laparoscopic approach with traditional open splenectomy (OS). Between March 1994 and March 1996, 16 children underwent splenectomy, in 8 using an open approach and 8 by a laparoscopic procedure. Of the patients who underwent laparoscopic splenectomy (LS), 2 had a concomitant cholecystectomy. Ages ranged between 4 and 11 years (mean 6.4 years); there were 9 girls and 7 boys. The indications for splenectomy were: hereditary spherocytosis (7 cases); idiopathic thrombocytopenic purpura (4); sickle-cell disease (3); and β-thalassemia (2). The average operating time for OS was 100 min (range, 50–155), for LS 170 min (range 125–240). The hospital stay for patients who had OS ranged from 3 to 9 days (mean 4.7), for those who had LS from 2 to 5 days (mean 3). One OS patient developed a wound infection. In 3 of the LS patients, the spleen was removed via a 7-cm Pfannenstiel minilaparotomy in the suprapubic region; in 5 cases the spleen was captured into an extraction bag, crushed, and removed through the umbilical orifice. The authors believe that LS must be performed only when it is possible to use the extraction bag to remove the spleen from the umbilical orifice (spleens weighing less than 700 g) and when a concomitant procedure such as cholecystectomy is indicated; in other cases OS is preferable.

Notes: Abstract Our initial experience over the last 3 years with laparoscopic and thoracoscopic surgery in children and adolescents is reported. Between September 1992 and August 1995, a total of 215 laparoscopic and thoracoscopic procedures were performed: 32 appendectomies for acute appendicitis, 10 cholecystectomies for symptomatic gallstones, 11 procedures for adnexal pathology, 6 laparoscopies in children with nonpalpable testes, 3 diagnostic laparoscopies, and 153 thoracoscopic sympathectomies in children suffering from primary palmar hyperhidrosis. The post-operative course was uneventful in all cases. In 2 children with acute appendicitis we converted to the open technique due to technical difficulties. We are encouraged by the results of our initial experience. There is no doubt that laparoscopic cholecystectomy, laparoscopic surgery of adnexal pathology, and thoracoscopic sympathectomy, because of their numerous benefits – shorter operative time, hospitalization, and convalescence as well as less postoperative pain and improved cosmetic results – are replacing the open techniques. We are not convinced as yet of the advantages of laparoscopic appendectomy in children; we are presently performing both laparoscopic and conventional techniques and studying the various parameters in order to reach a more definite conclusion. Various other endoscopic surgical procedures will be carefully considered in the near future.

Notes: Abstract The prevalence of cholelithiasis was studied prospectively by abdominal ultrasound (US) examination in 305 children with sickle cell disease aged 1–18 years (mean 10.45). Gallstones were present in 60 children (19.7%); an additional 50 had biliary sludge only (16.4%). On follow-up of 35 of the 50 children with sludge, 23 (65.7%) had developed gallstones and 5 had already had a cholecystectomy. Five continued to have sludge on follow-up while 7 were reported to have no sludge. Children with US evidence of sludge should be followed up regularly by US, and those who develop gallstones should undergo elective cholecystectomy. For those with biliary sludge only, we recommend elective cholecystectomy if there are hepatobiliary symptoms.

Notes: Abstract Over a period of 6 months, 48 children who underwent conventional appendectomy (CA) were compared to 34 children who had laparoscopic appendectomy (LA) for acute and recurrent subacute appendicitis. Their ages ranged from 4 to 12 years (mean 8). LA took significantly longer, 76 min, versus 50 min for CA. Less than 2 days' hospitalization was required in 95% of LA cases and 45% of CA cases. Time to return to normal activity averaged 7 days for LA and 12 days for CA (P 〈 0.001). Wound complications were fewer and the cosmetic appearance was most satisfactory in LA patients. LA is a safe operation that has the advantage of being exploratory, with shorter hospitalization time, early ambulation, and superior cosmetic results.

Notes: Abstract Two experiments were conducted to investigate developmental changes in children's use of rime-level units of sound-to-spelling correspondence when spelling nonwords under varying task demands. In Experiment 1, nonwords were presented in isolation. Older children spelled more of the nonwords by analogy than younger children. Experiment 2 adopted versions of the clue word technique employed by Goswami (1988a) and found that significantly more analogous, rime-based responses were given to the same stimuli in both younger and older children. However, fewer analogous responses were given when the salience of the clue word was reduced by presentation of multiple target nonwords. The results suggest that while children in the early stages of development possess the ability to use rime-based units in spelling, they do not always make spontaneous use of this analogy strategy. However, when the potential to use rime-based units is highlighted by task demands, as is the case in Experiment 2 when a clue word is provided, even young children make considerable use of analogy in spelling.

Notes: Abstract A hemopoietin with the ability to accelerate both platelet and granulocyte recovery after intensive chemotherapy would have great clinical utility. The recombinant fusion protein composed of human granulocyte-macrophage colony-stimulating factor and interleukin-3 (PIXY321), showed some promise in early adult trials. However, studies for pediatric patients are limited, and there are no systematic data on the pharmacokinetics of PIXY321 given over prolonged periods at current dosage levels. Purpose: To determine the safety, clinical effects and plasma concentrations of increasing doses of PIXY321 in children treated with myelosuppressive chemotherapy. Methods: A total of 39 children with relapsed or high-risk solid tumors were enrolled in this phase I/II study. PIXY321 was administered once or twice daily by subcutaneous injection in total doses of 500 to 1000 μg/m2 per day for 14 days after each course of chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). Pharmacokinetic studies were performed on day 1 of the first course in 33 patients and repeated on day 14 in 13 patients (once-daily schedule only). Results: Although mild local skin reactions and fever were frequent, no dose-limiting toxicity was identified at the maximum dose studied (1000 μg/m2 per day). There were no statistically significant differences in chemotherapy-induced hematologic toxicity with increasing doses of PIXY321 or with twice-daily vs once-daily dosing. On day 1, the median PIXY321 clearance was 657 ml/min per m2 (range 77–1804 ml/min per m2) and the median half-life was 3.7 h (range 2.1–20.8 h). On day 14, clearance increased in all patients studied (median increase 63%), with a corresponding decrease in the median 12-h concentration (from 1.2 to 0.25 ng/ml). Maximum concentrations were 〈1 ng/ml in 81% of patients, and only two patients had maximum plasma concentrations equivalent to those required for consistent activity in vitro. Conclusions: The recombinant fusion protein PIXY321 proved safe in children treated with myelosuppressive ICE chemotherapy but had no demonstrable clinical benefits. The pharmacokinetic studies suggest that the observed lack of hematologic benefit may be explained by low plasma concentrations resulting from increased clearance with prolonged administration. Moreover, the significant increase in PIXY321 systemic clearance in the absence of increased circulating myeloid cells suggests that the upregulation of either extravascular compartment hematopoietic progenitor cells or nonhematopoietic cells may play an important role in controlling circulating concentrations of this unique cytokine. These findings highlight the importance of a thorough assessment of the systemic disposition of cytokines when determining the dose and schedule necessary to achieve clinical activity in patients.

Notes: Abstract To assess the efficacy of a serotonin re-uptake inhibitor, sertraline hydrochloride, in preventing recurrent neurocardiogenic syncope, we studied 15 patients (10 female; mean age 12.9 ± 2 years) with positive head-upright tilt test and resistant to standard pharmacotherapy, atenolol or disopyramide. The patients were given 50 mg oral sertraline hydrochloride daily for 6 weeks. Intolerance to the drug was seen in 3 patients and 2 had syncopal episodes during the therapy. A head-upright tilt table test was then repeated in 10 patients. Six were tilt negative and asymptomatic over a mean follow up period of 7 ± 3 months while four remained tilt positive: two experienced marked hypotension and bradycardia, characterized as mixed type syncope, and two had cardiac asystole, lasting 〉10 s, during tilting, thereby exhibiting a cardio-inhibitory response. Conclusion Sertraline hydrochloride may be useful in preventing recurrent neurocardiogenic syncope resistant to standard pharmacotherapy but careful clinical studies are essential before such a treatment strategy can be recommended since serious asystole could develop.

Notes: Abstract Serum total cholesterol (TC), high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C) and very low-density lipoprotein cholesterol, triglyceride, apolipoproteins A1 and B levels were studied in 57 healthy children and in 39 children with epilepsy who had been receiving carbamazepine (CBZ) (23 children) for 1.58 ± 1.10 years or valproic acid (VPA) (16 children) for 1.34 ± 1.11 years. In patients receiving CBZ, mean TC level, mean LDL-C level, mean TC/HDL-C ratio and mean LDL-C/HDL-C ratio were significantly higher than controls. None of the mean levels of serum lipids evaluated in patients receiving VPA was significantly different from the corresponding control group mean. Changes in serum lipids correlated with neither duration of therapy or plasma antiepileptic levels nor age or gender. Conclusion Our results suggested that CBZ, a hepatic-enzyme-inducing drug, affects serum lipid status. Long-term prospective studies are necessary to determine whether chronic CBZ therapy is a risk factor for atherosclerotic disorders.

Notes: Abstract Objective: To assess the efficacy of gastric intramucosal pH for the evaluation of tissue perfusion and prediction of hemodynamic complications in critically ill children. Design: Open prospective study without controls

Notes: Abstract Objective: To validate clinically cardiac output (CO) measurements using femoral artery thermodilution in ventilated children and infants by comparison with CO estimated from the Fick equation via a metabolic monitor. Design: Prospective, comparison study. Setting: Paediatric intensive care unit of a university hospital. Patients: 24 ventilated infants and children, aged 0.3 to 175 months (median age 19 months). Interventions: Oxygen consumption measurements were made and averaged over a 5-min period, at the end of which arterial and mixed venous blood samples were taken and oxygen saturations measured by co-oximetry, with CO being calculated using the Fick equation. Over this 5-min period, five sets of femoral arterial thermodilution (FATD) measurements were made and averaged. One comparison of CO values was made per patient. Results: Mean Fick CO was 2.55 l/min (range 0.24 to 8.71 l/min) and mean FATD CO was 2.51 l/min (range 0.28–7.96 l/min). The mean bias was 0.03 l/min (95 % confidence interval –0.07 to 0.14 l/min), with limits of agreement of –0.45 to 0.52 l/min. When indexed to body surface area, the mean Fick cardiac index became 3.51 l/min per m2 (1.52–6.98 l/min per m2) and mean FATD 3.49 l/min per m2 (1.74–6.84 l/min per m2). The mean bias was 0.02 l/min per m2 (95 % confidence interval –0.11 to 0.15 l/min per m2) with limits of agreement of –0.57 to 0.61 l/min per m2. The mean FATD coefficient of variation was 5.8 % (SEM 0.5 %). Conclusions: FATD compares favourably with Fick derived CO estimates in infants and children and may represent an advance in haemodynamic monitoring of critically ill children.

Notes: Abstract Objective: To determine the combinations of nitric oxide (NO), oxygen (O2), minute ventilation (MV) and total gas flow (TGF) which generate toxic concentrations of nitrogen dioxide (NO2) during mechanical ventil

Notes: Abstract The study included 162 second-grade children (85 boys and 77 girls) aged 8–9 years, attending two schools in an area with a fertilizer production plant, and 59 second-graders of the same age (32 boys and 27 girls) from a small neighbouring town located 20 km west of the plant, without any particular source of pollution. During the period from December 1990 to May 1991 the incidence of acute respiratory diseases was surveyed in children and their family members, and forced expiratory volumes were measured in selected second-graders in December 1990 and April 1991. In the area with the fertilizer plant as well as in the compared area ammonia, hydrogen fluoride, nitrogen dioxide, total suspended particulate matter and smoke were measured daily in ambient air and inside the school buildings. The mean concentrations of pollutants during the study period were below the recommended limits, with only a few exceptions, but daily fluctuations, particularly of ammonia and hydrogen fluoride in the area around the plant happened to exceed these values. The observed differences in the levels of air pollution correlated to some extent with the health parameters followed up during the study period. The incidence of acute respiratory diseases corresponded to the registered differences in the exposure to measured pollutants. Forced expiratory volume values in the compared groups of children did not consistently reflect the differences in exposure levels.

Notes: Abstract. The appearances of knee injuries on MR imaging are less well documented in children than adults. Some patterns of injury are shared by both groups of patients, e. g. meniscal damage. The frequency of specific injuries may differ, e. g. anterior cruciate ligament (ACL) tear. Congenital abnormality, coexistent pathology and previous treatment of the knee appear to be associated with meniscal problems. Discoid menisci are seen most frequently in children and have unique features on MR scans. Cruciate ligament tears are difficult to diagnose in the smallest children. The ACL may not be identified due to its small size. Normal bone marrow signal may be confused with marrow infiltration or bone microfracture. Radiographically occult fractures around the knee appear to be strongly associated with ligamentous injury as in adult patients. Osteochondral fractures, osteochondral lesions and articular cartilage damage are revealed on MR scans, but their long-term effects are uncertain. It is possible to diagnose a range of knee injuries on MR scans in children. The biggest diagnostic challenge is in pre-school children.

Notes: Summary. A double-blind, parallel-group trial was performed in 96 children in order to evaluate and compare the safety and efficacy of iopentol (Imagopaque®, Nycomed Imaging AS, Oslo, Norway) with those of routinely used contrast media. Ten children below 1 year of age received iopentol and eight received iohexol (Omnipaque®, Nycomed Imaging AS, Oslo, Norway) (both 300 mg I/ml) in a random manner. Seventy-eight children (39 in each group), between one and 10 years of age, received iopentol 300 or diatrizoate (UrografinØ, Schering AG, Berlin, Germany) 292 mg I/ml for urography. No adverse events were observed among the children below 1 year of age. In the group between one and 10 years there was a statistically and clinically significant difference (p = 0.007) in the incidence of adverse events between the iopentol (2.6 %) and diatrizoate (25.6 %) groups. All adverse events were of mild or moderate intensity. No serious reactions were encountered. The overall quality of visualization was judged to be diagnostic for all patients. This study supports the use of non-ionic contrast media in pediatric patients and confirms that iopentol is a safe and effective contrast medium well suited for children from 0–10 years of age.

Notes: Abstract We present a 4-year-old child who suffered bilateral third nerve palsies secondary to bilateral giant saccular cavernous carotid artery aneurysms. Endovascular treatment was performed by means of direct endosaccular aneurysm occlusion on the right side and parent vessel occlusion on the left, using mechanically detachable coils. No complication occurred during or after the procedure. The bilateral third nerve palsies resolved over 3 months. Follow-up angiography at 1 year is presented.

Notes: Zusammenfassung Das idiopathische Bauchschmerzsyndrom (IBS) gehört zu den verbreitetsten Schmerzerkrankungen im Kindesalter. Etwa jedes 5. bis 10. Kind leidet unter wiederkehrenden Bauchschmerzattacken. In fast 50% der Fälle persistieren die Beschwerden über Jahre bis ins Erwachsenenalter. Obwohl das IBS damit zu den häufigsten Anlässen für Arztkonsultationen in der pädiatrischen Praxis zählt, wird die Thematik in der empirischen Forschung bisher stark vernachlässigt. Die Erkenntnisse zur Pathophysiologie der rezidivierenden Abdominalbeschwerden im Kindesalter sind trotz zunehmenden Forschungsinteresses noch rudimentär, die Resultate vielfach noch inkonsistent. Aktuelle Erklärungs- und Therapiemodelle verstehen das IBS als komplexe und multifaktoriell verursachte Störung (biopsychosoziales Paradigma). Das Auftreten der Symptomatik scheint v.a. mit psychopathologischen und psychosozialen Belastungen (Ängste, Depressionen, Alltagsstreß, Lebensereignisse) sowie familiären und Umweltfaktoren (psychopathologische Probleme der Eltern, soziales Modell- bzw. Verstärkerverhalten) in Zusammenhang zu stehen. Die auffällig ausgeprägte Komorbidität des Bauchschmerzsyndroms mit anderen Schmerzbeschwerden deutet auf eine zugrundeliegende (psychopathologische) Somatisierungstendenz bei den betroffenen Kindern hin. Die ungünstige Langzeitprognose unterstreicht die Notwendigkeit frühzeitiger und zielgerichteter Intervention. Voraussetzung für eine effektive psychologische Therapie ist eine z.T. relativ aufwendige organmedizinische Ausschlußdiagnose. Die verhaltensmedizinische Behandlung, die auf der Grundlage einer gründlichen Familienanamnese und Symptomanalyse durchgeführt wird, greift dabei auf die in der psychologischen Schmerztherapie bewährten Verfahren zurück und umfaßt prophylaktische Maßnahmen, Interventionen zum Symptommanagement und Veränderung von krankheitsrelevanten Umweltbedingungen. In den letzten Jahren werden verstärkt komplexere und multidimensionale Schmerzbehandlungsprogramme für Kinder entwickelt, die trotz vielversprechender erster Resultate für den spezifischen Anwendungsbereich des kindlichen Bauchschmerzes aber noch nicht ausreichend evaluiert sind.

Notes: Abstract. The safety profile of ProHance in special populations was evaluated by analyzing data extracted from the database of phase I-III studies which included data on 2,656 ProHance injections of which 119 in pediatric patients, 814 in elderly patients and 30 in patients with varying degrees of renal impairment (moderate, severe or end stage requiring hemodialysis). ProHance was administered at doses ranging from 0.1 mmol/kg to 0.3 mmol/kg and was found to be safe in all patient populations irrespective of age and of pre-existing renal impairment. There appeared to be no correlation between incidence of adverse events and dose level in these special populations and the higher dose level of 0.3 mmol/kg could be safely administered also to patients with end stage renal disease requiring hemodialysis, from whom the contrast medium was rapidly and efficiently dialysed.

Notes: Abstract We compared the postprandial blood glucose (BG)-levels following preprandial regular insulin or lispro insulin before and after eating in adolescents with diabetes. Lispro is a rapidly absorbed insulin analogue. Lispro insulin injected immediately before breakfast reduced the postprandial BG-rise significantly compared to the 20 min preprandially administered regular insulin (P〈0.01). Postprandial lispro injection resulted in similar BG values as the standard treatment with regular insulin 20 min preprandially. Conclusion Lispro insulin injected immediately before the meal leads to lower postprandial BG levels and seems to be an option for teenagers who use multiple preprandial insulin injections. Postprandial lispro administration could be a benefit in certain situations since it resulted in similar BG values to preprandial regular insulin.

Notes: Abstract Children with underlying medical conditions have to be given careful attention at the time of planned immunization in order to define the individual benefit/risk ratio of a given vaccination. Analysis of available data demonstrates that vaccine administration is indeed both safe and efficient in most children. Immunization of very premature infants may require specific vaccine strategies consisting either of short-term deferral of immunization or the addition of an extra vaccine dose. With the exception of influenza immunization of children with egg allergy, immunization is safe and efficient in atopic or asthmatic children. A family or personal history of seizure without evidence of encephalopathy is no longer considered a limitation to pertussis immunization. Children with mild intercurrent infection can be immunized without further delay. Repeated pneumococcal immunization should be offered to children at high risk of pneumococcal disease after the age of 2 years. Optimal protection of immunodeficient children could include immunization of family members. Conclusion This article attempts to review existing data upon which immunization practices have been recommended by expert societies. It outlines some areas that need additional studies before specific recommendations can be made and it proposes attitudes that could be considered in the meantime.

Notes: Abstract We report on our experience with routine abdominal ultrasonography in 120 children (aged 3–15 years) with recurrent abdominal pain, in order to determine the diagnostic value of this investigation. Eight children (7%) revealed sonographic abnormalities: gallbladder stone (n = 2), splenomegaly (n = 1) and urogenital abnormalities (n = 5). The recurrent abdominal pain could be explained by these findings in only two (may be three) cases. Conclusion The diagnostic value of abdominal ultra‐sonography in unselected children with recurrent abdominal pain is low. However, the direct visualization of the abdominal structures as being normal may be helpful to the parents and the child in their understanding and acceptance of the benign nature of recurrent abdominal pain.

Notes: Abstract The clinical course of 48 children with chronic hepatitis C (33 boys, 15 girls; mean age: 12.2 years) was monitored for more than 3 years to clarify its natural course. All patients were positive for the second-generation antibody to hepatitis C virus (anti-HCV) and for serum hepatitis C virus (HCV) RNA. All but one patient had a history of blood transfusion. Serum levels of alanine aminotransferase (ALT) had been abnormal for more than 1.5 years. Spontaneous remission defined as a biochemical remission lasting more than 1 year in association with the disappearance of serum HCV RNA, occurred in 4 (8.3%), however, in 25%, HCV RNA was still detectable in the liver even after its disappearance from serum. In this patient, the level of antibody to HCV core antigen (anti-HCV core) did not decrease significantly and serum HCV RNA eventually reappeared. The serum titre of HCV RNA in the 4 children with spontaneous remission was lower than in the remaining 44 children. Spontaneous remission may occur in children with chronic hepatitis C in whom the serum titre of HCV RNA is low and serum level of anti-HCV core decreases significantly. Assessment of the intrahepatic HCV RNA is necessary to confirm complete remission. Conclusion A low serum titre of HCV RNA and a significant decrease in the serum titre of anti-HCV core were associated with spontaneous remission in children with chronic hepatitis C. Intrahepatic HCV RNA assessment is necessary to confirm complete remission.

Notes: Abstract. A series of 14 vein of Galen vascular malformations diagnosed in the pediatric populations and treated at the Hospital for Sick Children-Necker, Paris, between 1988 and 1994 is presented. Five of the patients were diagnosed in the neonatal period, of whom 4 presented with life-threatening, intractable cardiac decompensation and high-flow arteriovenous fistulae. Embolization was performed on vital indications in 4 patients during the first week after birth. One embolization failed with fatal outcome. Of the 3 who were embolized, 2 succumbed within 1 week and 1 survived with marked improvement of cardiac symptoms. The older children presented with hydrocephalus and neurologic symptoms. The 10 patients older than 1 year were embolized. These procedures were successful in 90 %, with hemodynamic stabilization and improvement of clinical symptoms. In this group the mortality rate was 10 %. The total mortality rate was 29 %. Hydrocephalus was secondary to a compression of the Sylvian aqueduct in 44 % of cases. Five patients had ventricular drainage before embolization followed by a staged elective embolization. Transarterial embolizations were performed in 11 patients, whereas 2 patients were embolized via the transvenous route.

Notes: Abstract We studied 18 patients who had undergone surgery for herniated lumbar discs between the ages of 11 and 17 years. The inclusion criteria for girls was an age of 15 years or below and for boys 17 or below at surgery. The mean follow-up time was 10 years and the clinical outcome was good. Age at surgery and length of the follow-up had no effect on the result. The radiological disc height at follow-up did not correlate with the follow-up time or age of the patient at operation. MRI scans at follow-up from ten patients operated at less than 15 years of age revealed multilevel disc degeneration but favourable clinical results.

Notes: Abstract Cysticercosis is the most frequent parasitic disease of the central nervous system in the world and is endemic in such developing countries as Mexico. There is insufficient information about neurocysticercosis in children. The purpose of this study was to collect information on the main social factors associated with neurocysticercosis, the clinical picture, diagnosis and treatment, and the final outcome in 122 Mexican children. The ages of the patients ranged from 14 months to 17 years, with a mean of 8 years; 51 male (41.8%) and 71 female (51.8%) patients were seen; half of these patients (61) lived in well-urbanized areas; the parents of 77 families (57.3%) had only an elementary school grade average, and 46 (37.7%) lived in close proximity to animals. The most common features were seizures, intracranial hypertension and learning disabilities. The diagnosis of neurocysticercosis was supported by computed tomography or magnetic resonance imaging studies and cerebrospinal fluid analysis. The treatment was varied, with anticonvulsives, steroids, and albendazole, and only 8 patients underwent ventriculo-peritoneal shunts for hydrocephalus. The follow-up ranged from 6 months to 5 years; 90 patients became asymptomatic; 6 developed refractory epilepsy; 14, learning disabilities; and 10, a chronic type of the disease with repeated episodes of intracranial hypertension; 2 died because of chronic arachnoiditis.

Notes: Abstract Discitis in children commonly presents with fever, back pain, irritability, and an inability to walk. An elevated ESR and characteristic changes on plain X-rays or bone scan are sufficient for diagnosis, but MRI is more sensitive and more specific, and it shows pathologic changes earlier. Intravenous antibiotics are administered when cultures of the disc space are positive, but in more than half of the cases, no organism can be grown. Symptoms are alleviated with bedrest or external orthoses, but neither the duration nor the kind of symptomatic treatment influences outcome.

Notes: Abstract Between July 1987 and June 1994 we operated upon 30 consecutive children suffering from endophytic intra-axial tumors located in the pons and/or medulla oblongata. The 25 children operated on between July 1987 and October 1993 whose postoperative course could be assessed for a minimum of 2 years after operation were included in this study. Operability of a brain stem tumor was shown to be independent of its size. A gross tumor resection between 80% and 100% could be performed in half these cases, and subtotal or partial resection in the other half. The radicality of resection was not influenced by tumor histopathology, but was dependent on intraoperative findings relating to its consistency, infiltration, and visibility. On follow up, 15 of the 25 children were found to have died within the period of 2 years. Two children died in the immediate postoperative period (at 2 days and 2 weeks after surgery), of acute brain stem swelling and an unsuspected bleeding disorder, respectively. The other 13 of these 15 children died of tumor progression between 1 and 19 months after operation, with a median survival time of 9 months. In the group of the surviving 10 children the histopathology was grade I astrocystoma in 6 cases, angioma in 2 cases, and grade II oligodendroglioma and grade II ependymoma in 1 case each. Postoperatively, most of the children showed some increase in their preoperative deficits, but recovered after 2–3 months. After 2 years, 10 of the 25 children who were followed up are alive and 9 of them attend regular school or kindergarten.

Notes: Abstract Results of the treatment of 27 children with craniopharyngioma are reported. A subfrontal pterional approach was used in 55.6% of cases, a transsphenoidal and a transcallosal or transcortical approach in 25.9% and 18.5% of cases, respectively. Radical removal was the goal of surgery and was achieved in 70.8% of cases treated as primary surgery. The operative mortality was 3.7% and was due to hypothalamic failure. Most (81.4%) patients were followed up, for a mean of 7 years. Patients were evaluated according to a functional evaluation scale and outcome categories proposed by us. The scale takes account of tumor (recurrences and their eventual evolution); visual functions; endocrine functions (mainly hypothalamic), attainment of endocrine balance and drug regimen; headache; and psychosocial function. Recurrences were observed in 17.6% of patients treated with radical surgery and in 42.8% of those treated with limited surgery plus radiotherapy. A progressive amelioration of visual, endocrine and neuropsychosocial functions from the intervention to follow-up was observed in the majority of patients. Complete tumor excision was associated in 85% of cases with a low score on the functional scale, reflecting a high functional performance. Adequate substitution therapy maintained endocrine balance in 81% of patients. Since the intervention a progressive decrease in the number and dosages of medications has been observed. The majority of patients were again able to lead a normal social life. Small stature, obesity, headache, and emotional and sexual disturbances were frequent cause of long-term disability even despite adequate drug regimens. The functional evaluation scale we propose is a simple and effective tool that can be easily used during routine evaluation of patients with craniopharyngioma.

Notes: Abstract Few cases of fracture of the odontoid process in children have been reported in the literature. A case with an associated severe traumatic brain injury and a suspected clinical high cervical spinal cord injury is reported here. This case is of interest because of the surgical treatment selected. A direct surgical approach was used for anterior screwing, with an excellent result. In some precisely defined circumstances, therefore, this treatment can be indicated.

Notes: Abstract It is difficult to predict the onset of clinical symptoms due to Chiari II malformation. Brainstem auditory evoked potentials (BAEPs) may be useful to select potential candidates for surgery. We studied 158 BAEPs in 134 asymptomatic children with meningomyelocele (MMC) during the first year of life. Both wave latencies (WLs) and interpeak latencies (IPLs) in asymptomatic children with MMC gradually became shorter during the first year of life. In particular, the shortening of III–V IPLs was observed in the asymptomatic children with MMC from 2 or 3 weeks to 4–6 months of age. This may be a characteristic parameter of the development of the intrinsic brainstem function in patients with MMC. Comparison of these data on BAEPs in asymptomatic children with MMC with the published data on BAEPs in normal neonates and infants showed that the maturation of brainstem function was delayed in the asymptomatic children with MMC during the first year of life. These data on asymptomatic neonates and infants with MMC could potentially be a good reference for selecting the modalities of treatment in patients with MMC associated with symptomatic Chiari II malformation.

Notes: Abstract  Objective. To determine in a prospective study the normal MRI morphology of the sacroiliac joints (SIJs) in relation to age and sex during adolescence. Design and patients. A total of 98 children (63 boys, mean age 12.7±2.8 years; 35 girls, mean age 13.7±2.3 years), ranging in age from 8 to 17 years, with juvenile chronic arthritis (JCA) but without signs of sacroiliitis fulfilled the study prerequisites (no back pain and no pathologic changes of the SIJs on physical examination before MRI in a 1.5-year follow-up). An additional eight HLA-B27-negative boys and eight HLA-B27-negative girls without arthritis served as controls. The MRI protocol comprised a T1-weighted SE sequence, an opposed-phase T2*-weighted GE sequence, and a dynamic contrast-enhanced study in single-section technique. Results. Noncontrast MRI permitted differentiation of “open” from ossified segmental and lateral apophyses of the sacral wings, with a significant difference in age (P 〈0.05) between children with open and ossified apophyses. Ossification of the apophyses of the sacral wings was seen significantly earlier (P 〈0.05) in girls than in boys. Girls also had a significantly higher incidence of transitional lumbosacral vertebrae, pelvic asymmetries, and accessory joints. In the contrast-enhanced opposed-phase MRI study, normal cartilage of the SIJs showed no contrast enhancement whereas the joint capsule showed a moderate enhancement. Conclusion. There are significant age- and sex-related differences in the normal MRI morphology of juvenile SIJs. Our findings might serve as a standard of comparison for the evaluation of pathologic changes – in particular for the early identification of juvenile sacroiliitis.

Notes: Abstract  Objective. To describe the imaging findings of vascularized fibular grafts (VFG) in large bone reconstruction in children and teenagers. Design and patients. Fifteen patients aged from 4 to 19 years underwent VFG for bone reconstruction for primary tumors involving bone in 13 cases and for chronic osteomyelitis in 2 cases. Lesions were located in the femur (6 cases), the tibia (6 cases), the humerus, the distal fibula and the ilium. Radiographic follow-up was performed in all patients, radionuclide studies in 12 patients and MRI in 8. Results. Plain films showed a lamellated periosteal reaction on the VFG within 3 weeks following the procedure in all cases. Fusion of VFG and host bone occurred during the first 3 months. Radionuclide uptake of the VFG was seen in all cases but one. MRI showed cortical thickening and conservation of the high signal intensity of fatty marrow on T1-weighted sequences, and periosteal enhancement on dynamic post-contrast studies in all but one of the patients. Conclusion. Radionuclide studies and MRI show the periosteal enhancement and assess the viability of the VFG satisfactorily. However, we feel that plain films may be sufficient to ascertain this viability.

Notes: Abstract  Objective. To assess the correlation between a pediatric patient’s proximal femur and lumbar spine bone mineral density (BMD) Z-scores, and the side-to-side difference between proximal femurs. Design. Three hundred and thirty-nine patients aged 2.2–17.0 years with an assortment of underlying conditions underwent dual-energy X-ray absorptiometry (DXA) measures of BMD in both proximal femurs and the lumbar spine. Results. Z-scores in the proximal femur and lumbar spine correlated highly (r=0.73, P=0.0001), but for individual patients the difference was often significant, and increased as BMD deviated further from normal. For patients with proximal femur Z-scores of 1 to –1 the mean difference between proximal femur and lumbar spine Z-scores was 0.5; with proximal femur Z-scores of less than –3 the mean difference was increased to 1.7. In conditions which symmetrically involve the lower extremities, the right and left proximal femur Z-scores differed on average by only 0.2. Conclusion. BMD measurements for pediatric patients are most easily interpreted by clinicians if converted to Z-scores, yet these are usually available only for the lumbar spine. Age-normalized BMD assessment at more than one site is necessary to provide a more reliable, complete assessment of bone mineral status in pediatric patients.

Notes: Abstract Thalamic tumors (TT) merit individual analysis and must not be confused with tumors that, while involving the entire thalamus have a different origin. We analyzed 26 patients who fulfilled our criteria of having ``strictly'' TT. We examined incidence, clinical features, histology, response to treatment (mainly surgery), recurrence rate, mortality and prognosis. We considered that histology and surgical treatment were the most important items related to prognosis. Low-grade tumors (LGT) had a good prognosis, while anaplastic tumors (AT) had a discouraging one; nevertheless both must be operated on. We believe that total removal of LGT is curative and total removal of AT, even if it is not curative, can extend survival by some months. Radiotherapy and chemotherapy seemed to be of little value in our series of TT.

Notes: Abstract Malignant rhabdoid tumor (MRT) is a recently described variety of childhood renal neoplasm. MRT arising primarily in the central nervous system (CNS) is still a rather unfamiliar pathological entity and is frequently misdiagnosed as medulloblastoma or primitive neuroectodermal tumor (PNET). We describe a 7-month-old boy who harbored a CNS-MRT that originated within the IV ventricle and invaded the brain stem and the cerebellar hemispheres. After an initial documented good response to chemotherapy the tumor recurred locally 9 months after operation. We discuss clinical and histopathological features distinguishing between PNET/medulloblastoma and MRTs. Current literature on MRT of the CNS is briefly reviewed.

Notes: Abstract There have been relatively wide variations in the results of studies examining the outcomes of severe brain injury in children. Among the reasons for these variations in outcome, prehospital care can be considered as one of the factors. In Korea, major hospitals use an aggressive and sophisticated management policy very similar to that practiced in the West. However, effective prehospital management, such as emergency care at the scene of injury and during transport by paramedics, have not yet been established. In order to evaluate the influence of prehospital care on the outcome in severely brain-injured children, we report the outcome recorded in 73 pediatric patients treated in our hospital following severe brain injury and compare these results with those reported from centers in the western community, where well-trained paramedic care and an excellent transfer system are in operation. The overall mortality rate in our patients was 23%; 41% had a good recovery, 22% moderate disability, and 12% severe disability, and 1% remained in a vegetative state. In conclusion, we would like to suggest that prehospital care does not remarkably influence mortality rates in severely brain-injured children.

Notes: Abstract. This study addresses the question of whether the normal range for distribution of local cerebral blood flow (lCBF) in adults can be transferred to the 4- to 15-year-old age group. Twenty-three children (age: 4–15 years; mean 11±3 years, group I) and 10 adults (age: 27–56 years; mean 45±10 years, group II) without evidence of cerebrovascular disease or other brain diseases underwent technetium-99m ethyl cysteinate dimer single-photon emission tomography. Counts in cortical and subcortical regions of interest (ROIs) were related to those in cerebellar ROIs (= 100%). Relative cortical activity in group I exceeded that in group II, particularly in left parietal (107.6%±9.8% vs 84.1%±12.4%), left frontal (97.7%±6.7% vs 79.4%±8.9%) and left temporal areas (99.7%±7.4% vs 84.9%±10.1%) and in the cingulate cortex (112.1%±9.1% vs 95.9%±10.1%, P〈0.05). Cerebral activity uptake per injected dose was inversely correlated with age in 19 children of group I (r = –0.77, P〈0.001). In group I, there was also an inverse correlation between age and the relative local count density in the parietal (r = –0.42 to –0.57), frontal (r = –0.48), temporal (r = –0.42 to –0.58) and occipital cortex (r = –0.44). In these cortical regions relative counts differed when subgroups of children aged 4–10 and 11–15 years were analysed. It is concluded that there are systematic differences between 4- to 15-year-old children and adults with regard to normal lCBF. Diagnostic use of perfusion agents has to consider age-adjusted normal flow maps; normal ranges should be determined separately for the age groups 4–10 and 11–15 years.

Notes: Abstract This study examined the relationships between thigh muscle volume (TMV) and aerobic and anaerobic performance in children. A total of 32 children, 16 boys and 16 girls, aged 9.9 (0.3) years completed a treadmill running test to exhaustion for the determination of peak oxygen uptake (peak V˙O2) and a Wingate Anaerobic Test (WAnT) for the determination of peak power (PP) and mean power (MP). The volume of the right thigh muscle was determined using magnetic resonance imaging. TMV was not significantly different in boys and girls [2.39 (0.29) l vs 2.18 (0.38) l, P 〉 0.05]. Peak V˙O2 and MP were significantly higher in boys than girls (P 〈 0.01) whether expressed in absolute, mass-related or allometrically scaled terms. Absolute PP was not significantly different in boys and girls but mass-related and allometrically scaled values were higher in boys (P 〈 0.01). TMV was correlated with absolute peak V˙O2, PP and MP in both sexes (r = 0.52–0.89, P 〈 0.01). In boys, mass-related PP was correlated with TMV (r =0.53, P 〈 0.01), and in girls mass-related peak V˙O2 was correlated with TMV (r = −0.61, P 〈 0.01). However, in neither sex were allometrically scaled peak V˙O2, PP or MP correlated with TMV (P 〉 0.05). There were no significant differences between boys and girls in terms of peak V˙O2, PP or MP when expressed in a ratio to TMV or allometrically scaled TMV. In conclusion, this study has demonstrated that, when body size is appropriately accounted for using allometric scaling, TMV is unrelated to indices of aerobic and anaerobic power in 10-year-old children. Furthermore, there appear to be no qualitative differences in the muscle function of boys and girls in respect of aerobic and anaerobic function.

Notes: Abstract Examination of the evaluation sample and the outcome data from the Fort Bragg Demonstration Project suggests that the children served were mildly disturbed, were atypical of those served in most public mental health clinics, spent less than optimal time in the new services developed, and were judged as making considerable progress with minimal treatment regardless of age or level of judged psychopathology. The use of normative outcome measures in a pre-post design was considered a major reason for failure to find any significant differences between differently treated children.

Notes: Abstract In a prospective study of 560 children treated for burns as in-patients over a period of four-and-a-half years in specialized hospitals responsible for the majority of burn cases in Kuwait, 388 patients (69%) had sustained scalds. The mean age of these 388 children, between 0 to 12 years, was 3.02 ± 2.08, and male to female ratio 1.5 to 1. They were categorized into three age groups, first, up to 1 year comprised 17.5% cases, who were solely dependent on parents or childminder; second, 2 to 5 years of age, who were inquisitive, independent, pre-school children, and constituted the majority of cases (73%), and third 6 to 12 years who were 9.5% school children. The pre-school children (2--5 yrs) thus formed a highly vulnerable group in the country. Accidents (99.4%) occurred at home and the kitchen being the commonest place. The hot water from pan and pots in the kitchen was the most common etiologic factor in 229 cases (59%), followed by tea/coffee 20.7%, soup 9.0%, hot oil 6.7%, and milk 4.6% patients. The most common circumstance was the child upsetting the pan of hot fluid in the kitchen. The mean total body surface areas of second and third degree burns were 14.21 ± 9.66 (range 1 to 60%). The average length of stay in the hospital was 16.90 ± 15.74 days, varying from one to 109 days. Thirty-nine children were ill prior to burn, and the commonest disease was respiratory tract infection. Three patients (0.8%) with 3rd degree burns were treated with primary excision and grafting, and 137 (35.3%) needed secondary skin grafting for residual burn wounds. Four patients (1%) died, one due to burn shock, two due to septicemia and one due to multiorgan failure. There is need for general awareness through public education, which may lead to the prevention of significant number of such accidents.

Notes: Abstract The effect of milk on dental caries was studied on a sample of 6-to-11-year-old Italian schoolchildren. The daily amount of milk consumed and the frequency of consumption of sucrose-containing foods were obtained by a 24-hour dietary diary. In the subsequent oral examination, the level of visible plaque and the number of decayed, extracted and filled teeth (both primary and permanent) of the children were recorded. 439 children (217 boys) who did not use fluoride prophylaxis and with poor oral hygiene were selected from among 890 children. They were divided into three groups according to the frequency of sucrose consumption. The data were statistically analysed using multiple logistic regression. The children consumed a daily average of 209 ± 133 ml of milk and there were no differences among the three groups in this respect. As expected, the dental health of the children with low sucrose frequency was significantly better than that of the children with high sucrose frequency. The regression on the whole sample showed a weak, significant, negative association between milk consumption and caries (p 〈 0.05). In the group of high sucrose-consuming children a negative, highly significant association was found (p 〈 0.001), while in the two groups of low and moderate sucrose-consuming children no association was found. These data suggest that, in the present sample of children who did not use fluoride and with poor oral hygiene, milk has a caries preventive effect only on those subjects with a high daily sucrose-consuming frequency.

Notes: Abstract To estimate the incidence of Haemophilus influenzae type b (Hib) invasive disease in Italian infants we performed a prospective study in a cohort of newborns enrolled for a randomized trial on safety and efficacy of three pertussis vaccines and followed for onset of serious disease or pertussis. The overall cumulative incidence observed in 15,601 children was 51.3/100,000 for all invasive Hib infections and 38.4/100,000 for Hib meningitis, over 27 months of observation. The incidence density of all invasive Hib diseases was 28.7/100,000 person-years, while meningitis occurred with an incidence of 21.5/100,000 person-years. Among the eight cases detected, six were meningitis, one sepsis, and one cellulitis. The child with sepsis died. The incidence and epidemiology of invasive Hib disease in Italy are comparable to those reported from other European countries. Cost-benefit analyses are needed for planning Italian vaccination policy.

Notes: Abstract Elective mutism (EM) is not regarded as a separate diagnostic category in the ICD-9, but is included under the heading “313: Disturbance of emotions specific to childhood and adolescence.” In the ICD-10 EM is acknowledged as a separate diagnosis defined as “a marked, emotionally determined lack of speech in certain situations in a child with a normal or near normal speech/language ability.” The diagnosis excludes pervasive developmental disorder and specific developmental disorders of speech and language. Two patients referred for EM to a child and adolescent psychiatry outpatient clinic, showed specific developmental delays and assessment indicated slight mental retardation in one of them. The question arose regarding how extensively EM is reported in the literature as associated with developmental disorder/delay. A search was carried out in four data-bases where most references were listed under the keyword “mutism”. This paper presents the two case studies, and the results of the literature inventory. It concludes that EM may be associated with developmental disorder/delay and suggests that this could be a predisposing factor for an emotionally determined lack of speech in certain situations.

Notes: Summary The authors describe a 12-year old girl with a painful syndrome at the distal side of the left leg, resulting in limping, incapacity and severe muscle atrophy. Full investigation — no inflammatory laboratory signs, diffuse osteoporosis at the left leg, decreased bone mineral content at the same place, marked hypofixation on bone and vascular scintigraphy — suggested pseudodystrophy (5), which is often induced by psychological factors. Successful treatment was obtained by physiotherapy, hydrotherapy, slight doses of NSAID and psychological assistance. With regard to recent literature, the authors believe that reflex sympathetic dystrophy (RSD) in children is often over-diagnosed, since there are no recognised criteria for diagnosiing RSD. Besides the clinical picture, changes on radiography (focal osteoporosis) and on scintigraphy (disturbed vascular scintigraphy with increased pooling in the initial phase and hyperfixation on bone scintigraphy) are necessary. When these are not available, pseudodystrophy is a more correct diagnosis.

Notes: Abstract Objective: Children with chronic health conditions face special issues in their interactions with managed care. These children often require additional and more varied services than do other children. Managed care plans increasingly include these children, especially with the growth of Medicaid managed care. This article examines the special issues facing children with chronic conditions and develops strategies for monitoring their care in managed care settings. Methods: The project staff conducted an extensive review of the research and policy literature related to managed care and the special needs of families with children with chronic conditions. The project also reviewed current and proposed plans of federal, state, and private groups for monitoring and, working with parents and other outside groups, identified key issues to consider in developing monitoring plans. Results: The relative rarity of many childhood conditions and the complex interactions among child, family, and community over time make assessment of their care difficult. We describe these child and family characteristics, outline essential features and domains for monitoring systems, and describe population-based and plan-based monitoring systems to assess managed care for these children and their families. Conclusions: Monitoring for children with chronic conditions in managed care arrangements will require public health agencies and health providers to define populations systematically, assess across a variety of conditions, and monitor several domains central to the health of these families.

Notes: Two new enantioselective syntheses of the naphthopyranquinone antibiotic frenolicin B (1), of its enantiomer 2, and of its diastereoisomers 3 and 4 were accomplished using two different routes from optically active β-Hydroxy esters (R)- and (S)-11 and 18. β-Hydroxy esters (R)- and (S)-11 were prepared stereoselectively from optically active sulfenylacetates (S)- and (R)-10, respectively (Scheme 2, Method A). Alternatively, compound 18 was obtained in excellent yield by enantioselective hydrogenation of the corresponding β-keto ester 17, using a chiral ruthenium-complex catalyst (Scheme 3, Method B). Subsequently, compounds (S)-11 and 18 were transformed into frenolicin B (1). In analogy, Stereoisomers 2-4 were prepared from (S)- and (R)-11 in good yields.

Notes: The 2′-deoxyisoguanosine phosphonates 3a and 4a and the phosphoramidites 3b and 4b were prepared as building blocks for solid-phase oligonucleotide synthesis. The diphenylcarbamoyl (dpc) residue was introduced as 2-oxo protecting group which stabilizes the N-glycosylic bond against hydrolysis and prevents the molecule from side reactions. The dpc-protected building blocks 4a, b were employed in solid-phase synthesis and were found to be much more efficient than the unprotected compounds 3a, b. Oligonucleotides with alternating (11) or consecutive isoguanine residues (13-15) were synthesized. They form duplexes with parallel chain orientation. The aggregate d(T4-iG4-T4) (15) containing four consecutive 2′-deoxyisoguanosine is shown to be a tetramer similar to that of d(T4-G4-T4).

Notes: Khusimone (1), one of the main odor-donating compounds of vetiver oil is subject of the following study on structure/odor relationship. The omittance of the ethano bridge of the tricyclic khusimone leads to a bicyclic system. The stereoselective approach to this degraded structure is described, and the olfactory properties are studied. The key step of the synthesis of the hydrindane nucleus is based on a highly diastereoselective conjugate addition to a chiral oxo-cyclopentene-2-carboxylate.

Notes: The (2-dansylethoxy)carbonyl (= {2-{[5-(dimethylamino)naphthalen-l-yl]sulfonyl}ethoxy}carbonyl; dnseoc) group was employed for protection of the amino functions of the aglycone residues. The lactam function of 2′-deoxyguanosine was on the one hand unprotected and on the other hand alkylated at O6 of the aglycone with the 2-(4-nitrophenyl)ethyl (npe) and 2-(phenylsulfonyl)ethyl (pse) group, respectively. The syntheses of monomeric building blocks, both phosphoramidites and nucleoside- functionalized supports, are described for the three common 2′-deoxynucleosides (2′-deoxycytidine, 2′-deoxyadenosine, 2′-deoxyguanosine). As kinetic studies with the tritylated nucleosides showed, the dnseoc group is more labile towards DBU cleavage than the corresponding 2-(4-nitrophenyl)ethyl-(npe) and [2-(4-nitrophenyl)ethoxy]carbonyl(npeoc)-protected analogues (see Table 2). These results were confirmed by the very fast deprotection rate of the dnseoc groups at some oligonucleotides.

Notes: The absolute configuration of 3-methylpyrrolidine alkaloids isolated from the poison gland of ants Leptothoracini was determined as (3R). The enantiomeric separation by chiral gas chromatography and unambiguous structural assignment of the target compounds are described.

Notes: The synthesis of π-substituted heptalenecarboxylates or -dicarboxylates, starting with the easily available dimethyl 9-isopropyl-1, 6-dimethylheptalene-4, 5-dicarboxylate (2b), are described. Treatment of 2b with t-BuOK and C2Cl6 at -78° leads to the chemoselective introduction of a Cl substituent in Me-C(1) (see 5b in Scheme 1). Formation of the corresponding triphenylphosphonium salt 7b via the iodide 6b (Scheme 2) allowed a Wittig reaction with cinnamaldehyde in the two-phase system CH2Cl2/2N NaOH. Transformation of the 4, 5-dicar-boxylate of 2b into the corresponding pseudo-ester 10b allowed the selective reduction of the carbonyl function at C(4) with DIBAH to yield the corresponding 4-carbaldehyde 11b (Scheme 3). Wittig reaction of 11b with (benzyl) triphenylphosphonium bromide led to the introduction of the 4-phenylbuta-1, 3-dienyl substituent at C(4). The combination of both Wittig reactions led to the synthesis of the 1, 4-bis(4-phenylbuta-1, 3-dienyl)-substituted heptalene-5-carboxylate (all-E)-17b (Scheme 5). In a similar manner, by applying a Horner-Wadsworth-Emmons reaction, followed by the Wittig reaction, the donor-acceptor substituted heptalene-5-carboxylate (E;E)-22b was synthesized (Scheme7). Most of these new heptalenes are in solution, at room temperature, in thermal equilibrium with their double-bond shifted (DBS) isomers. In the case of (all-E)-17b and (E;E)-22b, irradiation of the thermal equilibrium mixture with light of λ -(439 ± 10) nm led to a strong preponderance ( 〉 90%) of the DBS isomers 17a and (E;E)-22a, respectively (Schemes 6 and 7). Heating of the photo-mixtures at 40° re-established quickly the thermal equilibrium mixtures. Heptalenes-carboxylates (all-E)-17a and (E;E)-22a which represent the off-state of a 1,4-conjugative switch (CS) system show typical heptalene UV/VIS spectra with a bathochromically shifted heptalene band III and comparably weak heptalene bands II and I which appear only as shoulders (Figs. 4 and 5). In contrast, the DBS isomers (all-E)-17b and (all-E)-22b, equivalent to the on-state of a 1,4-CS system, exhibit extremely intense heptalene bands I and, possibly, II which appear as a broad absorption band at 440 and 445 nm, respectively, thus indicating that the CSs (all-E)-17a⇌(all-E)-17b and (E;E)-22a⇌(E;E)-22b are perfectly working.

Notes: Configurational and Conformational Isomeric Antiaromatic [28]Tetraoxaporphyrinoids(4.2.4.2) and Aromatic [26]Tetraoxaporphyrin(4.2.4.2) Dications. A New Type of Molecular Dynamics in Macrocyclic SystemsThe [28]tetraoxaporphyrinoids(4.2.4.2) 6 are synthesized by cyclizing Wittig reaction of (E, E)-5, 5′-(buta-1, 3-diene-1, 4-diyl)bis[furan-2-carbaldehyde] (8) with (E, E)-{(buta-1, 3-diene-diyl)bis[(furan-5, 2-diyl)methylene]}bis-[triphenylphosphonium] dibromide (9) and 3, 3′-{[(E)-ethene-1, 2-diyl]bis(furan-5, 2-diyl)}bis[(E)-prop-2-enal] (22) with (E)-{(ethene-1, 2-diyl)bis[(furan-5.2- diy)methylene]}bis[triphenylphosphonium] dibromide (23). An alternative path to get 6 is the McMurry condensation of 8. Four different configurational isomers of 6 could be isolated and characterized by 1H-NMR spectroscopy. The (Z, EE, Z, EE)-isomer 6a is the first macrocyclic system where the inner and outer protons of the (E, E)-dienediyl bridges exchange by rotation around the adjacent single bonds. In the (Z, EE, E, EE)-isomer 6b, the (E)-ethenediyl bridge is rotationally active, while in the (E, ZE, E, EZ)-isomer 6c and in the (E, EZ, E, EZ)-isomer 6e, the rotation of both (E)-ethenediyl bridges is observed. When in the dynamic systems the rotation of the active (E)-double bonds at temperatures T 〈 -90° is frozen, all configurational isomers of 6 appear to be antiaromatic and paratropic. The oxidation of the [28]tetraoxaporphyrinoids 6c and 6e with DDQ yields the aromatic, diatropic [26]tetraoxaporphyrin(4.2.4.2) dications 21e/21e′ both with (E, EZ, E, EZ)-configuration but different fixed conformations. (Z, EE, Z, EE)-Isomer 6a is oxidized to give the (Z, EE, Z, EE)-dication 21a, while the oxidation of 6b yields a mixture of 21a and 21e/21e′. The standard formation enthalpies of the obtained and expected [28]tetraoxaporphyrinoids 6 and [26]tetraoxaporphyrin dications 21 have been calculated with the AM1 method, showing good accordance with the experimental results.

Notes: The synthesis of substituted cyclododeca-1,6-diallenes.( = cyclododeca-1,2,6,7-tetraenes) from cyclododeca-5,11-diyne-1,4-diols is described (Schemes 1 and 3). The ca. 1:1 mixtures of the stereoisomers of the cyclododeca-1,6-diallenes were formed in high yields from the ca. 1:1 diastereoisomer mixtures of the 1,4-disubstituted cyclododeca-5,11-diynes by reactions with Me2CuLi or t-BuMgCl/CuII. In mechanistically relevant experiments with the pure diastereoisomers of 1,4-dimethylcyclododeca-5,11-diyne-1,4-diol, it is demonstrated that the configuration is conserved in these reactions. The first synthesis of a 1-substituted cyclododeca-2,8-diyne bearing only one propargylic leaving group gives access to a mixed 12-membered allen-yne (Scheme 5).

Notes: This study was designed to unravel lipophilicity changes associated with the oxidation state of the S-atom in model compounds, drugs, and metabolites, special attention being given both to intermolecular and intramolecular effects. The methods used were experimental (potentiometry, CPC, and shake-flask techniques to measure lipophilicity, 13C-NMR spectroscopy to investigate tautomeric equilibria) and computational (quenched molecular dynamics and molecular lipophilicity potential). Simple, monofunctional model compounds were used to assess intermolecular forces, as revealed by the Δlog Poct-alk and Δlog Poct-chf parameters. Drugs and their metabolites proved to be good probes to study intramolecular effects in both neutral and anionic forms, as revealed by the difference between calculated and experimental log Poct values (the diff(log Pexp-calc) parameter). Sulindac and its metabolites showed a normal partitioning behavior, whereas the lipophilicity of sulfmpyrazone and its metabolites' was markedly affected by tautomeric and conformational equilibria.

Notes: The synthesis of (E)-hex-3-ene-l, 5-diynes and 3-methylidenepenta-1, 4-diynes with pendant methano[60]-fullerene moieties as precursors to C60-substituted poly(triacetylenes) (PTAs, Fig. 1) and expanded radialenes (Fig. 2) is described. The Bingel reaction of diethyl (E)-2, 3-dialkynylbut-2-ene-1, 4-diyl bis(2-bromopropane-dioates) 5 and 6 with two C60 molecules (Scheme 2) afforded the monomeric, silyl-protected PTA precursors 9 and 10 which, however, could not be effectively desilylated (Scheme 4). Also formed during the synthesis of 9 and 10, as well as during the reaction of C60 with thedesilylated analogue 16 (Scheme 5), were the macrocyclic products 11, 12, and 17, respectively, resulting from double Bingel addition to one C-sphere. Rigorous analysis revealed that this novel macrocyclization reaction proceeds with complete regio- and diastereoselectivity. The second approach to a suitable PTA monomer attempted N, N′-dicyclohexylcarbodiimide(DCC)-mediated esterification of (E)-2, 3-diethynylbut-2-ene-l, 4-diol (18, Scheme 6) with mono-esterified methanofullerene-dicarboxylic acid 23; however, this synthesis yielded only the corresponding decarboxylated methanofullerene-carboxylic ester 27 (Scheme 7). To prevent decarboxylation, a spacer was inserted between the reacting carboxylic-acid moiety and the methane C-atom in carboxymethyl ethyl 1, 2-methano[60]fullerene-61, 61-dicarboxylate (28, Scheme 8), and DCC-mediated esterification with diol 18 afforded PTA monomer 32 in good yield. The formation of a suitable monomeric precursor 38 to C60-substituted expanded radialenes was achieved in 5 steps starting from dihydroxyacetone (Schemes 9 and 10), with the final step consisting of the DCC-mediated esterification of 28 with 2-[1-ethynyl(prop-2-ynylidene)]propane-1, 3-diol (33). The first mixed C60-C70 fullerene derivative 49, consisting of two methano[60]fullerenes attached to a methano[70]fullerene, was also prepared and fully characterized (Scheme 13). The Cs-symmetrical hybrid compound was obtained by DCC-mediated esterification of bis[2-(2-hydroxy-ethoxy)ethyl] 1, 2-methano[70]fullerene-71, 71-dicarboxylate (46) with an excess of the C60-carboxylic acid 28. The presence of two different fullerenes in the same molecule was reflected by its UV/VIS spectrum, which displayed the characteristic absorption bands of both the C70 and C60 mono-adducts, but at the same time indicated no electronic interaction between the different fullerene moieties. Cyclic voltammetry showed two reversible reduction steps for 49, and comparison with the corresponding C70 and C60 mono-adducts 46 and 30 indicated that the three fullerenes in the composite fullerene compound behave as independent redox centers.

Notes: By the tether-directed remote functionalization method, a series of bis- to hexakis-adducts of C60, i.e., 1-7 (Fig. 1), had previously been prepared with high regioselectivity. An efficient method for the removal of the tether-reactive-group conjugate was now developed and its utility demonstrated in the regioselective synthesis of bis- to tetrakis(methano)fullerenes ( = di- to tetracyclopropafullerenes-C60-Ih) 9-11 starting from 4, 5, and 7, respectively (Schemes 2, 4, and 5). This versatile protocol consists of a 1O2 ene reaction with the two cyclohexene rings in the starting materials, reduction of the formed mixture of isomeric allylic hydroperoxides to the corresponding alcohols, acid-promoted elimination of H2O to cyclohexa-1,3-dienes, Diels-Alder addition of dimethyl acetylenedicarboxylate, retro-Diels-Alder addition, and, ultimately, transesterification. In the series 9-11, all methano moieties are attached along an equatorial belt of the fullerene. Starting from C2v-symmetrical tetrakis-adduct 15, transesterification with dodecan-1-ol or octan-1-ol yielded the octaesters 16 and 17, respectively, as noncrystalline fullerene derivatives (Scheme 3). The X-ray crystal structure of a CHCl3 solvate of 11 (Fig. 3) showed that the residual conjugated π-chromophore of the C-sphere is reduced to two tetrabenzopyracylene substructures connected by four biphenyl-type bonds (Fig. 5). In the eight six-membered rings surrounding the two pyracylene (= cyclopent[fg]acenaphthylene) moieties, 6-6 and 6-5 bond-length alteration (0.05 Å) was reduced by ca. 0.01 Å as compared to the free C60 skeleton (0.06 Å) (Fig. 4). The crystal packing (Fig. 6) revealed short contacts between Cl-atoms of the solvent molecule and sp2- and sp3-C-atoms of the C-sphere, as well as short contacts between Cl-atoms and O-atoms of the EtOOC groups attached to the methano moieties of 11. The physical properties and chemical reactivity of compounds 1-11 were comprehensively investigated as a function of degree and pattern of addition and the nature of the addends. Methods applied to this study were UV/VIS (Figs. 7-11), IR, and NMR spectroscopy (Table 2), cyclic (CV) and steady-state (SSV) voltammetry (Table 1), calculations of the energies of the lowest uunoccupied mmolecular orbitals (LUMOs) and electron affinities (Figs. 12 and 13), and evaluation of chemical reactivity in competition experiments. It was found that the properties of the fullerene derivatives were not only affected by the degree and pattern of addition but also, in a remarkable way, by the nature of the addends (methano vs. but-2-ene-1, 4-diyl) anellated to the C-sphere. Attachment of multiple thano moieties along an equatorial belt as in the series 8-11 induces only a small perturbation of the original fullerene π-chromophore. In general, with increasing attenuation of the conjugated fullerene π-chromophore, the optical (HOMO-LUMO) gap in the UV/VIS spectrum is shifted to higher energy, the number of reversible one-electron reductions decreases, and the first reduction potential becomes increasingly negative, the computed LUMO energy increases and the electron affinity decreases, and the reactivity of the fullerene towards nucleophiles and carbenes and as dienophile in cycloadditions decreases.

Notes: Crystal and solution structures of the enantiomerically pure and the racemic pairs of (η3-allyl) {2-[2′-(diphenylphosphino)phenyl]-4,5-dihydro-4-phenyloxazole}palladium(II) hexafluorophosphates (1, and rac-1, resp.) and tetraphenylborates (2, and rac-2, resp.) as well as (η3-allyl){2-[2′-(diphenylphosphino)phenyl]-4,5-dihydro-4-isopropyloxazole}palladium(II) tetraphenylborate (3) were characterized by X-ray crystallography and 1H-NMR spectroscopy. In the solid state, rac-1 and rac-2 proved to be disordered with both diastereoisomeric complexes in the crystal. The complexes 2 and 3 exist only in the ‘exo’ form. The X-ray structures show that the [PdII(η3-allyl)] moiety may adopt different configurations between a nearly symmetrical three-electron PdII(π3-allyl) system and an asymmetrical allyl group with a η1- and a η2-bonding to the metal center. The [PdII(η3-allyl)] system of rac-1 and of ‘endo’ rac-2 is closer to the former, and that of 2, ‘exo’-rac-2, and 3 closer to the later geometry. The 1H-NMR spectra of the hexafluorophosphates 1 and rac-1 show two sets of signals of the allylic protons in an ‘exo’/‘endo’ ratio of 2:3. The tetraphenylborates 2, rac-2, and 3 give only one set of broad signals of the allylic protons.

Notes: ‘Acetyleno-oligosaccharides’ in which two terminal ethynyl substituents enclose an angle (significantly) below 180° are building blocks for the preparation of cyclodextrin analogues. This is illustrated by the preparation of a cyclotrimer and a cyclotetramer; the C3-symmetrical cyclotrimer 18 (Scheme 1) was synthesized in 13 steps (7.7%) and the C4-symmetrical cyclotetramer 51 (Scheme 3) in 14 steps (4.3%) from the known dialkyne 21. The solubilities of 18 and 51 in H2O were determined by gravimetry; a saturated solution is 130 mM in the trimer 18 and 12.8 mM in the tetramer 51. The dependence of the optical rotation of 18 and 51 in H2O on the concentration, and the concentration dependence of the 1H-NMR chemical shift of the signals of the 1CH groups of 51 (D2O) suggest that there is no significant self-association of 18 and 51.

Notes: The chiral biyclic bis-lactams of structures 3 and 4 were synthesized from the key intermediate 2′b, the N,N′-bis(4-methoxybenzyl) derivative of 2 (X = MeO) (Scheme 6). The synthesis of this intermediate involved two key steps: (1) a double condensation of glyoxylic acid/anisamide (= oxoacetic acid/4-methoxybenzamide) adduct 11c with veratrole (1,2-dimethoxybenzene; 10) allowed the introduction of two glycine units at the 4,5-positions of the veratrole ring to give 18c (Schemes 3 and 4); (2) in order to circumvent the hydrolysis of 4-methoxybenzoyl protective groups which proved to be unfeasible, these groups were transformed into 4-methoxybenzyl groups through a sequence involving thiocarbonylation followed by reduction (Scheme 5). Thereafter, the double intramolecular cyclization of the resulting diamino diester 22c proceeded easily to afford 2′b. This intermediate may be transformed via the tetrol 2′g or the diol 2′h into the N-protected derivatives of 2 (X = OR) and of 3 (X = OCOR). Cleavage of the 4-alkuxybenzyl groups was achieved by ceric ammonium nitrate. However, when the aromatic ring bore ether functions (N-protected 2), this normal reaction was accompanied by the oxidative ring cleavage to give the diene-diester structure 4 (Schemes 5 and 6).

Notes: The kinetics of the Cu2+ complexation by macrocycles 1 (4-[(l,4,8,11-tetraazacyclotetradec-1-yl)methyl]-benzoic acid) and 2 (N-propyl-4-[(1,4,8,11-tetraazacyclotetradec-1-yl)methyl]-benzamide) as well as by macrocycle 1 conjugated to bovine serum albumin (bsa) and to ribonuclease A (rnase) were studied by stopped flow techniques. For 1 and 2, the kinetics were followed in the mM range monitoring the d-d* absorption band of the Cu2+ complex. From the pH dependence of kobs, the rate law is v = [Cu2+] (kLH[LH] + kLH2[LH2]), where kLH and kLK2 are the bimolecular rate constants for Cu2+ with the diprotonated (LH2) and monoprotonated (LH1) form of the ligand, respectively. The values are kLH2 = 1.7(1) M-1s-1 and kLH = 2.3(1) 105 M-1s-1 for 1, and kLH2, = 0.28(9) M-1s-1 and kLH = 2.0(1) 105 M-1s-1 for 2. The kinetics of the Cu2+ incorporation into 1,2 and 1 conjugated to bsa and rnase, i.e., 3 and 4, respectively, were also followed using nitroso-R salt as a metal indicator in the μM range, i.e., under conditions typical for the ‘post-labeling’ technique to give radiolabeled monoclonal antibodies. In these cases, the reaction takes place between the 1:1 complex of Cu2+ with nitroso-R-salt and the macrocycle. At pH 6.5, the rates are very similar to each other indicating that the complexation properties of the macrocycle attached to a protein are not very different from those of the free ligand under comparable conditions.

Notes: The synthesis of a variety of hydroxylactams from ω-phthalimidoalkanoates using a triplet-sensitized photodecarboxylation reaction initiated by intramolecular photo electron transfer is described. Ring sizes available by this method span from 4 (benzazepine-1,5-dione 7) to 26 (cyclodipeptide 26e). Ground-state template formation is proposed as the explanation for the high efficiency of this reaction and for the decrease in reactivity in the presence of organic bases instead of metal carbonates. The crucial step in this macrocyclization reaction seems to be the protonation of the intermediary ketyl radials (Scheme 4). Spacer groups investigated were alkyl chains (C3-C11: 5c-h, 11a, 12), ether (16, 18), ester (20, 22), and amide (26a-f) linkages. Within the detection limits, no dimeric (= decarboxylative coupling) products were observed, indicating the high preference for intra-vs. intermolecular photoelectron transfer. The C,C radical combination step proceeds with low stereoselectivity (cf, products 11 and 12) in contrast to comparable singlet reactions. Except for the lactones 22, all products were stable under the photolysis conditions. Prolonged irradiation of 22 led to the formation of the spiro compounds 23, probably via an intermediary acyliminium betaine (Scheme 8). One serious limitation of the decarboxylative macrocyclization is its incompatibility with the glycine spacer (as in 27a and 27b), probably the consequence of a strong intramolecular H-bond (Scheme 10).

Notes: A novel tricyclic dipeptide template, formally derived by coupling (2S,4S)-4-aminoproline (Pro(NH2)) and (S)-2-(carboxymethyl)proline (Pro(CH2COOH)) as a diketopiperazine, has been synthesized in a form suitable for solid-phase peptide synthesis using Fmoc chemistry. This template was incorporated into the cyclic molecule cyclo(-Ala1-Asn2-Pro3-Asn4-Ala5-Ala6-Temp-) (Temp = template), whose conformation in H2O was studied by NMR methods. Average solution structures derived by restrained simulated annealing point to a highly populated βI-turn within the Asn-Pro-Asn-Ala motif and also indicate which conformations are likely to be preferred by the template.

Notes: The syntheses of both diastereoisomers of 5′-ethyl-substituted thymidine dimers, the (5′R)- and (5′S)-configurated 33a and 33b respectively, in which the natural phosphodiester linkage is replaced by an amide group (C(3′)-CH2CONH-CH(5′)(Et)), arc described. Their fully protected derivatives 35a and 35b, respectively, are suitable for incorporation into antisense oligonucleotides. Unexpectedly, an attempted PdII-catalysed aza-Claisen rearrangement of trichloroacetimidate 7 provided the diastereoisomerically pure cyclopropane derivative 17, whose structure was confirmed by X-ray analysis.

Notes: New Pathways to Precursors of PentalenePentalene dimers 2 and 3 are easily available in moderate yields by CuCl2-induced oxidative coupling of dilithium-pentalenediide (5) (Scheme 1). On the other hand, NBS bromination of 1,5-dihydropentalene (4) or of 1,2-dihydropentalene (8) gives unstable 1-bromo-1,2-dihydropentalene (9), while subsequent in-situ elimination with Et3N exclusively gives syn-cis-pentalene dimer 2 in moderate yields (Scheme 3). NMR-Spectroscopic evidence for compounds 2, 3, and 9 is presented, and mechanistic alternatives for the formation of pentalene dimers 2 and 3 are discussed.

Notes: Four new iridoid glucosides 1-4, named blumeosides A-D, were isolated from the methanolic stem-bark extract of Fagraea blumei G. DON. (Loganiaceae). They were accompanied by the benzyl-alcohol derivative di-O-methylcrenatin (5) and the flavone C-glucoside swertisin (6). The structures of 1-4 were established by spectroscopic methods, including FAB-MS, and 1H- and 13C-NMR, and by alkaline hydrolysis. Blumeosides A (1) and C (3) are 10-O-(2,5-dihydroxytercphthalo) adoxosidic acid and 10-O-(2-hydroxyterephthalo)adoxosidic acid, respectively. In blumeosides B (4) and D (2), both carboxylic groups of the terephthalic-acid moiety are esterified by adoxosidic-acid units, Blumeosides A-D (1-4) inhibited bleaching of crocin induced by alkoxyl radicals. Blumeosides A (1) and D (2) also demonstrated scavenging properties towards the 2,2-diphenyl-1-picryl-hvdrazvl (CDPPH) radical in TLC autographic and spectrophotometric assays.

Notes: The kinetic model of column chromatography is revisited to explicitly show that this approach yields, when neglecting axial dispersion, a rather simple analytical expression depending only on two dimensionless parameters, namely a dimensionless kinetic retention parameter and a dimensionless time parameter. An expression for the time corresponding to the maximum of the peak is also proposed.

Notes: The αv/β3 integrin is implicated in human tumor metastasis and angiogenesis. It has been shown that structures of the sequence cyclo(-Arg1-Gly2-Asp3-D-Phe4-Xaa5-) (I) and cyclo(-Arg1-Gly2-Asp3-Phe4-D-Xaa5-) (II) bind with high affinity and the latter with high selectivity to this receptor. The residues Xaa and D-Xaa accept a broad variety of amino acids. Here, we report on the synthesis, activities, and conformational analysis of cyclic Arg-Gly-Asp (RGD) peptides containing liophilic amino acids Xaa or D-Xaa in position 5. For I, these were (2S)-2-aminohexadecanoic acid (Ahd) and N′-hexadecylglycine (Hd-Gly) and in II, D-Ahd and Hd-Gly, and, for control purposes, Ahd were incorporated (Fig. 1). The enantiomerically pure a-amino acids were obtained by non-enantioselective synthesis and subsequent enzymatic separation of isomers using acylase I (Scheme). Hd-Gly was prepared in a modified procedure according to Stewart from ethyl bromoacetate and hexadecylamine (Scheme). The synthesis and physicochemical properties of the corresponding (9H-fluoren-9-ylmethoxy)carbonyl (Fmoc) derivatives, compatible with solid-phase peptide synthesis, are described. Structure elucidation by NMR reveals that the lipid modification has no significant impact on the template structures when incorporated into them. For peptides I with Xaa = Ahd or Hd-Gly (1 or 2), a βII′/γ-turn-like arrangement with D-Phe in i+1 position of the β-turn is found. Peptides II with D-Xaa = D-Ahd or Hd-Gly (3 or 4) exhibit a βII′/γ-turn conformation with Gly in i+1 position of the β-turn, whereas II with Ahd instead of D-Xaa, i.e., lacking a D-amino acid in position 4 or 5 (5). adopts no defined conformation. However, in assays of receptor specificity employing human αvv/β3 integrin, the compounds exhibit IC50 values ranging from nanomolar to less than millimolar. These results indicate that although the arrangement of the pharmacophoric groups is preserved in the target compounds, the biological activity is highly dependent on spatial requirements of the lipid anchor in the receptor binding pocket. Obviously, only certain positions do not affect the binding.

Notes: The conformational analysis of naturally occurring cytostatic cyclic heptapeptides axinastatin 2, 3, and 4 was carried out by two-dimensional NMR spectroscopy in combination with distance-geometry (DG) and molecular-dynamics (MD) calculations in explicit solvents. The synthesized secondary metabolites were examined in (D6)DMSO. Axinastatin 2 was also investigated in CD3OH. In all structures, Pro2 is in the i + 1 position of a βI turn and Pro6 occupies the i + 2 position of a βVIa turn about the cis amide bond between residue 5 and Pro6. In all peptides, a bifurcated H-bond occurs between residue 4 CO and the amide protons of residue 1 and 7. For axinastatin 2 and 3, an Asn Ig turn was found about Asn1 and Pro2. We compared these structures with conformations of cyclic heptapeptides obtained by X-ray and NMR studies. A β-bulge motif with two β turns and one bifurcated H-bond is found as the dominating backbone conformation of cyclic all-L-heptapeptides. Axinastatin 2, 3, and 4 can be characterized by six trans and one cis amide bond resulting in a β/βVI(a)-turn motif, a conformation found for many cyclic heptapeptides. Detailed biological tests of the synthetic compounds in different human cancer cell lines indicates these axinastatins to be inactive or of low activity.

Notes: In the presence of activating agents, the N-acylglycine 8 reacts with electrophilic alkynes via the münchnone9 to the pyrrolopyridines (= indolizines) 10, 18, and 19 (Scheme 1 ), Depending on the nature of the activating agent and the reaction temperature, the formation of the pyrroles was accompanied by partial epimerization to the manna-configurated epimers 16 and 17. The gluco-configurated pyrrolopyridine 10 was deprotected to 12. Silylation of 12, followed by reduction and desilylation, gave the hexol 15. Cycloaddition of 9 to 4-toluenesulfonyl cyanide yielded 53% of the imidazole 23, while cycloaddition to phenyl cyanate gave the phenoxyimidazole 28 in low yields only (Scheme 2). As expected, the deprotected pyrroles 12, 15, 20, and 21 are weak inhibitors of retaining β-glucosidases, while the deprotected imidazole 24 derived from 23 proved a good inhibitor of sweet-almond β-glucosidases and a powerful inhibitor of Caldocellum saccharolyticum β-glucosidase.

Notes: Tetrahydrobenzo[a]pyrrolizidines (= octahydro-1H-pyrrolo[2,1-a]isoindoles) and tetrahydrobenzo[a]indo-lizidines, (= decahydropyrido[2,1-a]isoindoles) were prepared stereoselectively in four steps through an amineinduced ring-opening of 3-bromo-2,5-dimethylthiophene 1,1-dioxide (1) with L-prolinol (9), piperidine-2-methanol (10), and piperidine-2-ethanol (11), yielding the dienes (2S)-1-[(2E,4Z)-4-bromohexa-2,4-dienyl]pyrrolidine-2-methanol (12), 1-[(2E,4Z)-4-bromohexa-2,4-dienyl]piperidine-2-methanol (13), and 1-[(2E,4Z)-4-bromo-hexa-2,4-dienyl]piperidine-2-ethanol (14; Scheme2), which, after conversion into their α,β-unsaturated esters, cyclized in a TiCl4-catalyzed intramolecular Diets-Alder reaction (Scheme3). A discussion on the mechanism of the ring opening reaction including semiempirical and ab initio calculations is also presented.

Notes: The X-ray crystal-structure analyses of two N-enoyl-toluenesultam derivatives 1 are reported. The structural differences with their bornanesultam analogues 2 as well as stereochemical aspects with respect to their [4 + 2] and [3 + 2] cycloadditions are discussed.