Seven novel and four recurrent point mutations in the factor VIII (F8C) gene

Haemophilia A is a X‐linked bleeding disorder, caused by deficiency in the activity of coagulation factor VIII due to mutations in the corresponding gene. The most common defect in patients is an inversion of the factor VIII gene that accounts for nearly 45% of individuals with severe hemophilia A. Point mutations and small deletions/insertions are responsible for the majority of cases with moderate to mild clinical course and for half of the severe hemophilia A occurrences. The majority of these mutations are “private”, because of the high mutation rate for this particular gene. We report on eleven pathological changes in the factor VIII sequence detected in male patients with haemophilia A or in female obligate carriers. Seven of these mutations are novel [E204N, E265X, M320T, F436C, S535C, N2129M and R2307P] and four have been previously identified [V162M, R527W, R1966X, and R2159C]. Genotype‐phenotype correlations and computer prediction analysis on the effect of missense mutations on the secondary structure of the factor VIII protein are performed and the relationships evaluated. © 2001 Wiley‐Liss, Inc.     

Seven novel and four recurrent point mutations in the factor VIII (F8C) gene

Haemophilia A is a X‐linked bleeding disorder, caused by deficiency in the activity of coagulation factor VIII due to mutations in the corresponding gene. The most common defect in patients is an inversion of the factor VIII gene that accounts for nearly 45% of individuals with severe hemophilia A. Point mutations and small deletions/insertions are responsible for the majority of cases with moderate to mild clinical course and for half of the severe hemophilia A occurrences. The majority of these mutations are “private”, because of the high mutation rate for this particular gene. We report on eleven pathological changes in the factor VIII sequence detected in male patients with haemophilia A or in female obligate carriers. Seven of these mutations are novel [E204N, E265X, M320T, F436C, S535C, N2129M and R2307P] and four have been previously identified [V162M, R527W, R1966X, and R2159C]. Genotype‐phenotype correlations and computer prediction analysis on the effect of missense mutations on the secondary structure of the factor VIII protein are performed and the relationships evaluated. © 2001 Wiley‐Liss, Inc.     

Rapid diagnosis of anaerobic infections by gas-liquid chromatography.

It was postulated that the short chain fatty acids (SCFA) produced by anaerobic bacteria might serve as microbial markers in purulent material. Eighteen pus specimens from various sources were analysed by gas-liquid chromatography (GLC), and the SCFA detected were compared with the microorganisms isolated by conventional methods. It was found that the detection of propionic, isobutyric, butyric, or isovaleric acids by direct GLC of pus specimens is strong evidence for anaerobic infection but not specific for Bacteroides fragilis. It was also shown that the presence of succinic acid in pus specimens does not necessarily indicate infection by anaerobes. It can be concluded that direct GLC of purulent material provides a rapid and reliable presumptive method for the differentiation between anaerobic and aerobic infections.     

Growing skull fractures of childhood. A particular form of posttraumatic encephalopathy

Summary The authors describe the findings in 12 cases of growing skull fracture of childhood as revealed by clinical and paraclinical investigations. Based on these findings the authors regard this pathological entity as a separate form of posttraumatic encephalopathy.

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Zusammenfassung Die Autoren beschreiben die klinischen und paraklinischen Befunde bei 12 Fällen von wachsender Schädelfraktur des Kindesalters. Auf Grund dieser Befunde betrachten die Autoren dieses Krankheitsbild als eine besondere Form der posttraumatischen Enzephalopathie.

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Resumen Los autores describen los hallazgos obtenidos en 12 casos de fractura de craneo en niños con el hueso craneal en crecimiento, como revelan sus estudios clínicos y paraclínieos. Estos hallazgos permiten al autor considerar esta entidad patológica como una forma particular de la encefalopatía postraumética.

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Résumé Les auteurs exposent leurs constatations dans douze cas de fracture progressive du crâne chez l'enfant, ceci à la lumière d'investigations cliniques et para-cliniques. Il leur est ainsi possible de considérer cette entité pathologique comme une forme particulière d'encéphalopathie post-traumatique.

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Riassunto Gli AA. descrivono i risultati di indagini cliniche e paracliniche di 12 casi si accrescimento delle fratture craniche infantili. Essi sono d'avviso che detta entità patologica debba essere considerata corne una forma particolare di encefalopatia posttraumatica.

     

Cerebral abscesses in children

Summary The authors analyze 81 cases of cerebral abscess in children admitted to the Clinic of Neurosurgery Bucharest, from 1936 to 1964; these cases represent 15 per cent of the total number of 542 cerebral abscesses treated in the clinic.A progressive increase was found in the incidence of cerebral abscesses during the last 10 years; an increase was also observed with the increase in age-group.Of the 81 cases 49 occurred in boys.In accordance with their origin there were: 56% contiguous cerebral abscesses (46% otogenic, 6% rhinogenic, 4% other causes); 17% were associated with the congenital cyanotic disease; 15% were post-traumatic abscesses and 12% of undetermined origin.The location was supratentorial in 56 cases, infratentorial in 23 cases and supra- and infratentorial in 2 cases. There were 17 frontal locations, 17 temporal locations, 4 parietal, 2 occipital; in 10 cases two lobes were involved, in 4 cases three lobes and in 1 case one of the cerebral hemispheres. There were 23 cerebellar abscesses and in 2 cases the abscess was supra- and infratentorial.The clinical picture was dominated by the syndrome of raised intracranial pressure (80 per cent of the cases); the evolution of almost half of the cases was afebrile.Among the clinical features of cerebral abscesses in children particular stress is laid on cerebral abscess in infants and on abscesses accompanying a congenital cyanotic cardiopathy.The difficulties of differential diagnosis with focal encephalities, cortical thrombophlebitis, otogenic hydrocephalus, cerebral tumour, etc. are discussed.The treatment of cerebral abscesses in children is considered by the authors as a neurosurgical emergency. They recommend total ablation of the abscess as the best method of treatment, because of the favourable, immediate and late results (the formation of a supple cicatrix) it offers. The surgical treatment was associated with antibiotics, antioedematous medication, corticotherapy and anticonvulsants.Of the 75 children operated on 42 recovered and 12 showed improvement. There was no lethal case in the 25 cerebral abscesses operated on during the last 5 years.

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Zusammenfassung Die Autoren geben eine Analyse von 81 Fällen kindlicher Hirnabszesse, die zwischen 1936 und 1964 in der Neurochirurgischen Klinik Bukarest beobachtet wurden. In dieser Zeit wurden insgesamt 542 Hirnabszesse behandelt. Die kindlichen machen davon 15% aus. Die Häufigkeit hat in den letzten Jahren zugenommen. Die Hirnabszesse sind bei älteren Kindern häufiger. Sie kommen bei Knaben häufiger vor als bei Mädchen.56% waren fortgeleitet entstanden (46% otogen, 6% rhinogen, 4% andere Ursachen). 17% traten im Verlauf angeborener Herzmißbildungen mit Zyanose auf. 15% entstanden posttraumatisch. Bei 12% war die Ursache nicht zu klären.56 Fälle lagen supratentoriell, 24% infratentoriell und 2 sowohl supra- als auch infratentoriell. 17 waren frontal, 17 temporal, 4 parietal und 2 okzipital lokalisiert. Bei 10 Fällen waren zwei Hirnlappen, bei 4 Fällen drei und bei 2 Fällen eine ganze Hirnhemisphäre befallen. Bei 23 Fällen fand sich der Abszeß im Kleinhirn.Das klinische Bild wurde von den Zeichen intrakranieller Drucksteigerung (80%) beherrscht. Beinahe 50% der Fälle verliefen afebril.Auf die Besonderheiten des Hirnabszesses bei Säuglingen und bei angeborenen Herzmißbildungen im Rahmen des Morbus Coerulius wurde eingegangen. Die Schwierigkeiten der Diagnose und der differentialdiagnostischen Abgrenzung von Herdenzephalitiden, kortikaler Thrombophlebitis, otogenem Hydrozephalus, Hirntumoren usw. wurden besprochen. Der diagnostische Wert von EEG, Angiographie und Kontrastdarstellung des Abszesses wurde betont.Als Behandlung der Wahl gilt die Totalexstirpation, weil sie die besten Früh- und Spätergebnisse gewährleistet und die resultierende Hirnnarbe weniger derb ist. Zusätzlich wurden Antibiotika, Osmotherapeutika, Kortikoide und Antiepileptika gegeben.Von 75 operierten Kindern genasen 42. Bei 12 weiteren wurde eine Besserung erzielt. In den letzten 5 Jahren wurde bei 25 operierten Kindern kein Todesfall mehr verzeichnet.

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Resumen Los autores presentan el análisis de 81 casos de absceso cerebral en niños, casos que se investigaron en la Clínica de Neurocirurgía de Bucarest entre los años 1936 y 1964 y que representan un 15% del total de los 542 abscesos cerebrales registrados en la clínica.Se comprueba un crecimiento progresivo de la frecuencia de los abscesos cerebrales en los últimos 10 años; se observa tambien que la frecuencia crece paralelamente al aumento de la edad de los niños.Predominan los abscesos cerebrales entre los varones (49 casos).Según su origen se encontraron: 56% abscesos cerebrales subyacentes (46% otógenos, 6% rinógenos, 4% debidos a otras causas); 17% abscesos asociados a la enfermedad cianógena congénita; 15% abscesos post-traumáticos y 12% abscesos de origen indeterminado.Desde el punto de vista de su localización, hubo 56 casos supratentoriales, 23 casos infratentoriales y 2 casos supra e infratentoriales. Con localización frontal hubo 17 casos, temporal 17 casos, parietal 4 casos y occipital 2 casos; en 10 casos, el absceso afectó 2 lóbulos, en 4 casos 3 lóbulos y en 2 casos un hemisferio cerebral. 23 abscesos fueron cerebelosos y 2 situados encima y debajo del tentorio.El síndrome de hipertensión intracraneana predominó en el cuadro clínico (80% de los casos); y casi la mitad de los casos evolucionaron sin fiebre.Entre las peculiaridades clínicas del absceso cerebral infantil se ponen de relieve los abscesos cerebrales entre los niños de pecho y los que se asocian a una cardiopatia cianógena congénita.Se discuten las dificultades que encuentra el diagnóstico del absceso infantil en comparación con la encefalitis en el foco, la tromboflebitis cortical, la hidrocefalia otógena, el tumor cerebral, etcétera.Los exámenes paraclínicos subrayan el valor de la electroencefalografia, de la arteriografia cerebral y de la abscesografia.El tratamiento de los abscesos infantiles impone, según los autores, la urgencia neuroquirúrgica; basados en su experiencia, ellos recomiendan como método exclusivo de tratamiento la ablación total del absceso, por dar este método los resultados más favorables tanto inmediatos como ulteriores (permitiendo la formación de una cicatriz cerebral más blanda. El tratamiento quirúrgico se asoció a una medicación antibiótica, antiedematosa, a la corticoterapia y al empleo de anticonvulsivos.De los 74 niños operados sanaron 42 y mejoraron 12. En los últimos 5 años, entre los 25 abscesos cerebrales infantiles operados, no se registró ningún caso de fallecimiento.

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Résumé Les auteurs présentent l'analyse clinique de 81 cas d'abcès cérébraux chez l'enfant, opérés dans la Clinique Neurochirurgicale de Bucarest (Roumanie), depuis 1936 jusqu'à 1964. Ces cas représentent 15% du nombre total de 542 abcès cérébraux hospitalisés dans cette période.On a pu constater, surtout dans les deux dernières années, une fréquence plus grande aussi bien qu'un accroissement du nombre des cas par rapport aux groupes d'âge des enfants.Le nombre de cas chez les garçons (49) l'a emporté sur ceux de l'autre sexe. La répartition des cas d'après leur origine fut la suivante: abcès de voisinage: 56% (dont 46% otogènes, 6% rhinogènes et 4% d'origine différente); abcès associes à une maladie cyanogène congénitale: 17%; abcès posttraumatiques: 15%; abcès d'origine indéterminée: 12%.La répartition des cas d'après la localisation: 56 cas furent des abcès supratentoriels, 23 cas soustentoriels et 2 cas mixtes. Parmi les 56 cas à localisation supratentorielle 17 étaient dans le lobe frontal; 17 dans le lobe temporal, 4 dans le lobe pariétal et 2 dans le lobe occipital; dans 10 cas l'abcès s'étendait à deux lobes, dans 4 cas à trois lobes et dans 2 cas l'abcès envahissait tout un hemisphère cérébral.Un syndrome d'hypertension intracranienne dominait l'aspect clinique dans 80% des cas et environ la moitié des cas eurent une évolution afébrile.Les auteurs insistent sur les particularités cliniques des abcès cérébraux chez le nourrisson et sur ceux accompagnant une cardiopathie cyanogène congénitale.On discute les difficultés diagnostiques de l'abcès cérébral chez les enfants surtout avec l'encéphalite en foyer, avec la trombophlébite corticale, l'hydrocéphalie otogène et les tumeurs cérébrales.Parmi les investigations paracliniques, on souligne la valeur de l'electroencéphalogramme, de l'angiographie cérébrale et de l'abcessographie.Les auteurs insistent sur le caractère d'urgence neurochirurgicale et, de par leur expérience, sont d'avis que le seul traitement qui puisse assurer les meilleurs résultats aussi bien immédiats que tardifs (cicatrice cérébrale plus souple) est l'ablation totale de l'abcès.Une médication antibiotique et antioedémateuse aussi bien qu'une corticotherapie et, des anticonvulsivants ont été constamment associées au traitement chirurgical.Du nombre de 75 enfants opérés, 42 ont été complètement guéris et 12 ameliorés. Dans les derniers 5 ans, il n'y eut aucun decès parmi les 25 enfants opérés pour abcès cérébral.

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Riassunto Gli AA. fanno l'analisi clinica di 81 casi di ascessi cerebrali nei bambini, osservati nella Clinica Neurochirurgica di Bucarest, dal 1936 al 1964, e scelti tra 542 casi di ascessi osservati nello stesso periodo.Si nota un accrescimento notevole della casistica negli ultimi 10 anni e con l'età del malato; il sesso maschile è stato molto più frequentemente colpito (49 casi).Dal punto di vista dell'eziologia sono stati riscontrati: 56% di ascessi per contiguità, tra cui: 46% ascessi otitici, 6% ascessi rinogeni e 4% da altre cause; 17% associati a cardiopatie cianogene congenite, 15% ascessi post-traumatici e 12% ascessi d'origine sconosciuta.La sede degli ascessi è stata molto variabile: 56 ascessi erano sopratentoriali, 23 ascessi sottotentoriali e 2 sopra- e sottotentoriali insieme. Tra gli ascessi sopratentoriali sono stati osservati: 17 casi in sede frontale, 17 in sede temporale, 4 in sede parietale e 2 in sede occipitale. In 20 altri casi risultavano lesi 2 lobi cerebrali, in quattro 3 lobi ed in un caso un emisfero intero.In quadro clinico era dominato dclla sindrome di ipertensione endocranica (80% dei casi); il 50% dei malati era apirettico.Tra le forme cliniche dell'ascesso cerebrale nei bambini, si mettono in rilievo quello del neonato e quello associato alla cardiopatia cianogena congenita.Vengono indicate inoltre brevemente le difficoltà di una diagnosi differenziale tra encefalite a focolaio, tromboflebite corticale, l'idrocefalia otitica ed i tumori cerebrali. Tra le indagini paracliniche si sottolinea l'importanza dell'elettroencefalografia, dell'angiografia cerebrale e dell'ascessografia con aria.La terapia degli ascessi cerebrali nei bambini costituiscono, secondo gli AA., una necessità neurochirurgica urgente e, come tale, il metodo chirurgico di elezione è l'asportazione totale dell'ascesso, visto che i risultati, tanto immediati quanto a distanza, sono migliori dopo l'operazione: per es. si ha una gliosi cerebrale meno retrattile e quindi una minore frequenza dell'epilessia.Alla cura chirurgica si è associato la terapia antibiotica, la medicazione dell'edema cerebrale, i cortisonici ed i farmaci anticonvulsivi.Tra i 75 casi operati si notano: 42 guarigioni e 12 miglioramenti clinici. Negli ultimi 5 anni non si deplora nessun caso mortale nei 25 ascessi cerebrali operati.

     

Focal epileptic seizures ipsilateral to the tumour

Summary The authors report on six cases of cerebral tumours: three astrocytomas (two temporal and one frontal), two meningiomas (one parietal and one frontal), and a metastasis with a temporal location causing sensory-motor epileptic seizures ipsilateral to the lesion. The discussion includes comments on the pathogenesis of these manifestations viewed in the light of experimental and electrophysiological data, and on the hypotheses of the mirror focus, irritation of the supplementary motor and secondary somato-sensory areas, compression of the opposite hemisphere, and possible absence of decussation of the sensory-motor pathways. The false localization suggested by this type of paroxysmal seizures and their rare clinical occurrence is emphasized.     

Spectrum of molecular defects and mutation detection rate in patients with mild and moderate hemophilia A

The amount of residual F8 (FVIII:C) determines the clinical severity of hemophilia A. Recently, we showed that the mutation detection rate in severely affected male patients (FVIII:C<1% of normal) is virtually 100% when testing for the common intron 22-/intron 1- inversions and big deletions, followed by genomic sequencing of the F8 gene. Here we report on the spectrum of mutations and their distribution throughout the F8 gene sequence in 135 patients with moderate (n=23) or mild (n=112) hemophilia A. In contrast to the severe form of the disorder, analysis on the genomic level failed to detect the molecular defect in approximately 4% of the moderately and in approximately 12% of the mildly affected patients. A total of 36 of the mutations identified in this study are novel. The vast majority of the detected changes were missense. The newly detected amino acid substitutions were scored for potential distant or local conformational changes and influence on molecular stability for every single F8 domain with available structures, using homology modeling. Two molecular changes in the promoter region of the factor VIII gene (c.-112G>A and -219C>T), affecting the core segment (minimal promoter) were detected in two patients with mild hemophilia A. To our knowledge this is the first report on promoter mutations in the F8 gene.     

Investigations on the presence of papova virus in certain forms of human cancer. Note 2. Brain tumors

Two serially transmissible tumors (metastatic lymphosarcomas) were induced in the hamster by inoculation of human brain tumor material--tissue homogenate from a malignized fibroma or DNA extracted from a meningioma. SV40 V antigen was made evident by indirect immunofluorescence in 4 out of 18 human tumors, while SV40 T antigen could only be demonstrated in the tumors experimentally induced in hamsters. Antibodies to SV40 T antigen were detected in 12 out of 60 patients with different tumors, in 1 out of 40 blood donors and in 7 out of 18 hamsters carrying experimentally induced tumors.