RESUMO
The history of the treatment of vestibular schwannoma (VS) clearly shows a shift from microsurgery towards radiotherapy as "standard therapy". The microsurgical approach obviously yields excellent tumour control, but is hampered by a high morbidity rate, especially at the level of cranial nerves. The literature reports a normal facial nerve function in only 60% of patients surgically treated for VS with a maximum diameter of 25 mm. Hearing preservation is only around 15% for tumours > 15 mm and around 50% for tumours less than 15 mm. Progress in techniques and computer sciences in the field of radiotherapy provides the opportunity to reach high levels of tumour control (92 - 98%), keeping cranial nerve morbidity on a very low level (< 2%). Hearing capacity and serviceable hearing can be maintained in about 70% of cases. Based on these results, one can assume that radiation therapy should be used upfront for those benign tumours.
Assuntos
Neuroma Acústico/cirurgia , Radiocirurgia , Fracionamento da Dose de Radiação , HumanosRESUMO
BACKGROUND: Our discovery in 2003 of the first mutations of PCSK9 gene causing autosomal dominant hypercholesterolaemia (ADH) shed light on an unknown factor that strongly influences the level of circulating low density lipoprotein cholesterol (LDL-C). PCSK9 gain of function mutations cause hypercholesterolaemia by a reduction of LDL receptor levels, while PCSK9 loss of function variants are associated with a reduction of LDL-C values and a decreased risk of coronary heart disease. METHODS AND RESULTS: We report an insertion of two leucines (p.L21tri also designated p.L15_L16ins2L) in the leucine stretch of the signal peptide of PCSK9 that is found in two of 25 families with familial combined hyperlipidaemia (FCHL). This mutant is associated with high total cholesterol and LDL-C values in these families and is found also in a patient with familial hypercholesterolaemia and her father. CONCLUSION: PCSK9 variants might contribute to FCHL phenotype and are to be taken into consideration in the study of this complex and multigenic disease with other genes implicated in dyslipidaemia.
Assuntos
Variação Genética , Hiperlipidemia Familiar Combinada/genética , Serina Endopeptidases/genética , Adulto , Sequência de Bases , Feminino , Humanos , Leucina/genética , Leucina/metabolismo , Dados de Sequência Molecular , Mutação , Fenótipo , Pró-Proteína Convertase 9 , Pró-Proteína Convertases , Receptores de LDL/genéticaRESUMO
Congenital hyperinsulinism, or persistent hyperinsulinemic hypoglycemia of infancy (PHHI), is a glucose metabolism disorder characterized by unregulated secretion of insulin and profound hypoglycemia. From a morphological standpoint, there are two types of histopathological lesions, a focal adenomatous hyperplasia of islet cells of the pancreas in approximately 30% of operated sporadic cases, and a diffuse form. In sporadic focal forms, specific losses of maternal alleles (LOH) of the imprinted chromosomal region 11p15, restricted to the hyperplastic area of the pancreas, were observed. Similar mechanisms are observed in embryonal tumors and in the Beckwith-Wiedemann syndrome (BWS), also associated with neonatal but transient hyperinsulinism. However, this region also contains the sulfonylurea receptor (SUR1) gene and the inward rectifying potassium channel subunit (KIR6.2) gene, involved in recessive familial forms of PHHI, but not known to be imprinted. Although the parental bias in loss of maternal alleles did not argue in favor of their direct involvement, the LOH may also unmask a recessive mutation leading to persistent hyperinsulinism. We now report somatic reduction to hemizygosity or homozygosity of a paternal SUR1 constitutional heterozygous mutation in four patients with a focal form of PHHI. Thus, this somatic event which leads both to beta cell proliferation and to hyperinsulinism can be considered as the somatic equivalent, restricted to a microscopic focal lesion, of constitutional uniparental disomy associated with unmasking of a heterozygous parental mutation leading to a somatic recessive disorder.
Assuntos
Transportadores de Cassetes de Ligação de ATP , Deleção Cromossômica , Cromossomos Humanos Par 11 , Impressão Genômica , Hiperinsulinismo/genética , Ilhotas Pancreáticas/patologia , Pâncreas/patologia , Pancreatopatias/genética , Mutação Puntual , Canais de Potássio Corretores do Fluxo de Internalização , Canais de Potássio/genética , Receptores de Droga/genética , Substituição de Aminoácidos , Mapeamento Cromossômico , Éxons , Feminino , Heterozigoto , Homozigoto , Humanos , Hiperinsulinismo/patologia , Hiperinsulinismo/cirurgia , Hiperplasia , Lactente , Recém-Nascido , Masculino , Pancreatopatias/patologia , Pancreatopatias/cirurgia , Linhagem , Reação em Cadeia da Polimerase , Canais de Potássio/química , Receptores de Droga/química , Receptores de SulfonilureiasRESUMO
Familial hypercholesterolemia and familial ligand-defective apolipoprotein B-100 (FDB) are dominantly inherited disorders leading to impaired low-density lipoprotein receptor (LDLR) and apolipoprotein B-100 (APOB) interaction, plasma LDL elevation, and hypercholesterolemia. We previously identified the first French FDB-R3531C proband, a woman with very high total cholesterol, in a group of type IIa hypercholesterolemic families. We report here the investigation of her family at large that revealed the total absence of cosegregation with hypercholesterolemia. Six of the 10 subjects heterozygous for the R3531C mutation had plasma cholesterol lower than the 97.5th percentile for their age and gender, and mean cholesterol levels were not significantly different between affected and unaffected persons. Furthermore, 2 family members with similar high LDL-cholesterol levels were not carriers of the R3531C substitution, suggesting the implication of another mutation. Segregation analysis of the LDLR gene revealed statistically significant genetic linkage with hypercholesterolemia, and analysis of the proband LDLR gene led to the identification of the 664 proline to leucine defective mutation and its detection in all 6 hypercholesterolemic-related members of this family. Therefore, our results show that the family presents with familial hypercholesterolemia and give evidence that the R3531C substitution in the APOB gene is not an allelic variant leading to FDB. Furthermore, thorough analysis of our data suggests that the APOB-R3531C mutation enhances the hypercholesterolemic effect of the LDLR-P664L defect, suggesting that it is a susceptibility mutation.
Assuntos
Apolipoproteínas B/genética , Hiperlipoproteinemia Tipo II/genética , Mutação , Receptores de LDL/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , LDL-Colesterol/sangue , Feminino , Haplótipos , Heterozigoto , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Leucina , Escore Lod , Masculino , Pessoa de Meia-Idade , Núcleo Familiar , Linhagem , Polimorfismo de Fragmento de Restrição , Prolina , Receptores de LDL/químicaRESUMO
Autosomal dominant type IIa hypercholesterolaemia (ADH) is characterised by an elevation of total plasma cholesterol associated with increased LDL particles. Numerous different molecular defects have been identified in the LDL receptor (LDLR) and few specific mutations in the apolipoprotein B (APOB) gene resulting in familial hypercholesterolaemia and familial defective apoB-100 respectively. To estimate the respective contribution of LDLR, APOB and other gene defects in this disease, we studied 33 well characterised French families diagnosed over at least three generations with ADH through the candidate gene approach. An estimation of the proportions performed with the HOMOG3R program showed that an LDLR gene defect was involved in approximately 50% of the families (P = 0.001). On the other hand, the estimated contribution of an APOB gene defect was only 15%. This low estimation of ADH due to an APOB gene defect is further strengthened by the existence of only two probands carrying the APOB (R3500Q) mutation in the sample. More importantly and surprisingly, 35% of the families in the sample were estimated to be linked to neither LDLR nor APOB genes. These data were confirmed by the exclusion of both genes through direct haplotyping in three families. Our results demonstrate that the relative contributions of LDLR and APOB gene defects to the disease are very different. Furthermore, our results also show that genetic heterogeneity is, generally, underestimated in ADH, and that at least three major groups of defects are involved. At this point, the contribution of the recently mapped FH3 gene to ADH cannot be assessed nor its importance in the group of 'non LDLR/non APOB' families.
Assuntos
Apolipoproteínas B/genética , Hiperlipoproteinemia Tipo II/genética , Receptores de LDL/genética , LDL-Colesterol/análise , Mapeamento Cromossômico , Cromossomos Humanos Par 1 , Feminino , Heterogeneidade Genética , Ligação Genética , Haplótipos , Humanos , Escore Lod , Masculino , Computação Matemática , Repetições de Microssatélites , Linhagem , Análise de Sequência de DNA , Triglicerídeos/análiseRESUMO
Surgery, after hematology, is the biggest consumer of homologous platelet concentrates. Platelet transfusion is indicated to prevent or control bleeding associated with deficiencies in platelet number or function. In surgery, general patterns (in function of pre-surgery platelet count) can be adopted in most of the indications for platelets. In emergency situations, and in some particular cases (related to the patient, the type of operation, etc.), the transfusion procedure depends on the team's experience, the results of the available clinical and biological tests, and the drugs. Strict monitoring is required during the transfusion procedure. The efficacy of the transfusion must be controlled 1 h and 24 hours after the transfusion, and a number of factors must be assessed, namely the immunological impact of the transfusion (on red blood cells, leukocytes and platelets) and the occurrence of infectious diseases transmitted via transfusion. In addition, for a possible future transfusion, a strategy must be proposed.
Assuntos
Perda Sanguínea Cirúrgica/prevenção & controle , Transfusão de Plaquetas/normas , Árvores de Decisões , Humanos , Monitorização Fisiológica , Transfusão de Plaquetas/efeitos adversosRESUMO
The authors report the case of a primary myocardiopathy of the young adult, related in fact to a rare muscular congenital disease: centro-nuclear myopathy. The case is different from the classic picture in that it is revealed late, by its cardiac manifestations which dominate the clinical picture and lead to an irreducible cardiac insufficiency requiring a heart transplant. Only a muscular biopsy with histological and histo chemical study permits to make the diagnosis, while the lesions of the myocardium are non-specific.
Assuntos
Cardiomiopatia Dilatada/etiologia , Doenças Musculares/congênito , Adulto , Cardiomiopatia Dilatada/patologia , Humanos , Masculino , Doenças Musculares/patologia , Miocárdio/patologiaRESUMO
BACKGROUND: Myotonic dystrophy type 1 may be associated with low circulating dehydroepiandrosterone (DHEA) levels. This study was aimed at investigating the efficacy and safety of DHEA in myotonic dystrophy type 1 patients. METHODS: This was a prospective, multicenter, randomized, double-blind, placebo-controlled trial conducted from February 2005 to January 2006 at 10 university-affiliated neuromuscular disease centers in France. Seventy-five ambulatory adults with myotonic dystrophy type 1 received an oral replacement dose (100 mg/d) or a pharmacologic dose (400 mg/d) of DHEA, or placebo. The primary endpoint was the relative change in the manual muscle testing (MMT) score from baseline to week 12. Secondary outcome measures included changes from baseline to week 12 in quantitative muscle testing and timed functional testing, respiratory and cardiac function, and quality of life. This study was registered with ClinicalTrials.gov identifier NCT00167609. RESULTS: The median (1st, 3rd quartile) relative changes in MMT score from baseline to week 12 after randomization were 3.1 (-0.9, 6.7), 1.9 (-2.7, 3.5), and 2.2 (0, 7.9), in the DHEA 100 mg, DHEA 400 mg, and placebo groups, respectively. There were no differences between placebo and combined DHEA groups (p = 0.34), placebo and DHEA 100 mg (p = 0.86), or placebo and DHEA 400 mg (p = 0.15). There were also no evidence for a difference between groups for the changes from baseline to week 12 in any secondary outcome. CONCLUSIONS: There is no evidence that a 12-week treatment with replacement or pharmacologic doses of dehydroepiandrosterone improves muscle strength in ambulatory myotonic dystrophy type 1 patients.
Assuntos
Desidroepiandrosterona/uso terapêutico , Distrofia Miotônica/tratamento farmacológico , Adulto , Desidroepiandrosterona/efeitos adversos , Método Duplo-Cego , Determinação de Ponto Final , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiopatologia , Distrofia Miotônica/fisiopatologia , Distrofia Miotônica/psicologia , Estudos Prospectivos , Qualidade de VidaRESUMO
In Besançon, we carried out 40 plateletphereses with the latest model of the Fresenius cell separator AS 104 to check this new system against the new generation of cell separators, according to the following criteria: less than 2x10 6 leukocytes (before filtration) and more than 5x10 11 platelets. The results show that platelet concentrates contained 5.04+/-0.88x10 11 platelets in a total volume of 435+/-113 mL. The mean platelet recovery was 40.95+/-4.86% (from 31.7 to 51.6). The leukocyte content was 2.28+/-5.48x10 6 and the red blood cell contamination was 3.48+/-2.38x10 8. The quality of the platelets was very satisfactory. There was no problem with donor biocompatibility or procedure safety, few adverse donor reactions (0.6%) and good therapeutic efficiency of platelet concentrates.
Assuntos
Separação Celular/instrumentação , Plaquetoferese/instrumentação , Separação Celular/métodos , Segurança de Equipamentos , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Plaquetoferese/métodosRESUMO
Congenital hyperinsulinism (CHI), previously named persistent hyperinsulinemic hypoglycemia of infancy, is characterized by profound hypoglycemia because of excessive insulin secretion. CHI presents as two different morphological forms: a diffuse form with functional abnormality of islets throughout the pancreas and a focal form with focal islet cell adenomatous hyperplasia, which can be cured by partial pancreatectomy. Recently, we have shown that focal adenomatous hyperplasia involves the specific loss of the maternal 11p15 region and a constitutional mutation of a paternally inherited allele of the gene encoding the regulating subunit of the K(+)(ATP) channel, the sulfonylurea receptor (ABCC8 or SUR1). In the present study on a large series of 31 patients, describing both morphological features and molecular data, we report that 61% of cases (19 out of 31) carried a paternally inherited mutation not only in the ABCC8 gene as previously described but also in the second gene encoding the K(+)(ATP) channel, the inward rectifying potassium channel (KCNJ11 or KIR6.2), in 15 cases and 4 cases, respectively. Moreover our results are consistent with the presence of a duplicated paternal 11p15 allele probably because of mitotic recombination or reduplication of the paternal chromosome after somatic loss of the maternal chromosome. In agreement with the loss of the maternal chromosome, the level of expression of a maternally expressed tumor suppressor gene, H19, was greatly reduced compared to the level of expression of the paternally expressed growth promoter gene, IGF2. The expression of IGF2 was on average only moderately increased. Thus, focal forms of CHI can be considered to be a recessive somatic disease, associating an imbalance in the expression of imprinted genes in the 11p15.5 region to a somatic reduction to homozygosity of an ABCC8- or KCNJ11-recessive mutation. The former is responsible for the abnormal growth rate, as in embryonic tumors, whereas the latter leads to unregulated secretion of insulin.
Assuntos
Transportadores de Cassetes de Ligação de ATP , Adenoma de Células das Ilhotas Pancreáticas/genética , Cromossomos Humanos Par 11 , Impressão Genômica , Hiperinsulinismo/genética , Neoplasias Pancreáticas/genética , Canais de Potássio Corretores do Fluxo de Internalização , Canais de Potássio/genética , Receptores de Droga/genética , Adenoma de Células das Ilhotas Pancreáticas/congênito , Adenoma de Células das Ilhotas Pancreáticas/metabolismo , Dosagem de Genes , Humanos , Hiperinsulinismo/congênito , Hiperplasia , Fator de Crescimento Insulin-Like II/biossíntese , Fator de Crescimento Insulin-Like II/genética , Perda de Heterozigosidade , Mutação , Neoplasias Pancreáticas/congênito , Neoplasias Pancreáticas/metabolismo , RNA Longo não Codificante , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , RNA não Traduzido/biossíntese , RNA não Traduzido/genética , Receptores de SulfonilureiasRESUMO
Autosomal dominant hypercholesterolemia (ADH), one of the most frequent hereditary disorders, is characterized by an isolated elevation of LDL particles that leads to premature mortality from cardiovascular complications. It is generally assumed that mutations in the LDLR and APOB genes account for ADH. We identified one large French pedigree (HC2) and 12 additional white families with ADH in which we excluded linkage to the LDLR and APOB, implicating a new locus we named "FH3." A LOD score of 3.13 at a recombination fraction of 0 was obtained at markers D1S2892 and D1S2722. We localized the FH3 locus to a 9-cM interval at 1p34.1-p32. We tested four regional markers in another set of 12 ADH families. Positive LOD scores were obtained in three pedigrees, whereas linkage was excluded in the others. Heterogeneity tests indicated linkage to FH3 in approximately 27% of these non-LDLR/non-APOB ADH families and implied a fourth locus. Radiation hybrid mapping located four candidate genes at 1p34.1-p32, outside the critical region, showing no identity with FH3. Our results show that ADH is genetically more heterogeneous than conventionally accepted.