High-density lipoprotein subclasses and esterification rate of cholesterol in children: effect of gender and age

Since the development of coronary heart disease (CAD) is affected by a specific pattern of plasma high density lipoprotein (HDL) effects it may be useful to know whether this occurs already in childhood. In this study we evaluated particle size distribution of HDL by gradient gel electrophoresis and the determination of cholesterol esterification rate (FER_HDL) in plasma depleted of apo B lipoproteins in 221 children (108 boys and 113 girls) aged 4 months to 20 years. Total plasma- (TC), low-density lipoprotein- (LDL-C) and HDL- (HDL-C) cholesterol, HDL unesterified cholesterol (HDL-UC) and plasma triglycerides (TG) were also measured. There were no significant gender and age differences with respect to the plasma TC, LDL-TC and TG but concentration of HDL-TC increased with age. Post-pubertal girls had significantly higher relative concentrations of HDL_2b compared to boys (30.4% vs 17.2%), while HDL_3b,c was lower in post-pubertal girls (8.7% vs. 16.5 %). FER_HDL correlated inversely with HDL_2b and positively with HDL_3b,c particles and was significantly higher in boys of the post-pubertal group compared to girls (16.9%/h vs 12.5%/h). While in girls there was a positive correlation between age and HDL-C, HDL-UC and the relative concentration of HDL_2b no significant correlation were observed in boys. In girls the increase in TC showed a significant correlation with a simultaneous increase in HDL-C, HDL-UC and HDL_2b. In boys TC correlated significantly with changes in TG only. When HDL_2b and HDL_3b,c cholesterol levels are calculated from HDL-C concentration and per cent distribution the differences between males and females are further emphasized. These data indicate that HDL particle size distribution is age- and gender-dependent.     

Hypoglycémie hyperinsulinémique persistante du nouveau-né et du nourrisson

Persistent hyperinsulinemic hypoglycaemia of infancy (PHHI) is the most frequent cause of hypoglycaemia in infancy. Clinical presentation is heterogeneous, with variable onset of hypoglycaemia and response to diazoxide, and presence of sporadic or familial forms. Underlying histopathological lesions can be focal or diffuse. Focal lesions are characterised by focal hyperplasia of pancreatic islet-like cells, whereas diffuse lesions implicate the whole pancreas. The distinction between the two forms is important because surgical treatment and genetic counselling are radically different. Focal lesions correspond to somatic defects which are totally cured by limited pancreatic resection, whereas diffuse lesions require a subtotal pancreatectomy exposing to high risk of diabetes mellitus. Diffuse lesions are due to functional abnormalities involving several genes and different transmission forms. Recessively inherited PHHI have been attributed to homozygote mutations for the beta-cell sulfonylurea receptor (SUR1) or the inward-rectifying potassium-channel (Kir6.2) genes. Dominantly inherited PHHI can implicate the glucokinase gene, particularly when PHHI is associated with diabetes, the glutamate dehydrogenase gene when hyperammonaemia is associated, or another locus.     

Interpreting the improved outcome of patients with central nervous system metastases managed in clinical trials compared with standard hospital practice*

The aims were to determine the median survival and prognostic factors of patients with central nervous system (CNS) metastases managed with whole‐brain radiation therapy (WBRT), and to explore selection criteria in recently published clinical trials using aggressive interventions in CNS metastases. A retrospective audit was performed on patients managed with WBRT for CNS metastases. Potential prognostic factors were recorded and analysed for their association with survival duration. The proportion of patients with these factors was also compared with those of patients managed under three recently reported studies investigating aggressive interventions, such as radiosurgery and chemotherapy for CNS metastases. Seventy‐three patients were treated with WBRT for cerebral metastases over a 12‐month period. The median survival of the population was 3.4 months (95% confidence interval: 2.7–4.1), with 6‐ and 12‐month survival rates of 30 and 18%, respectively. Significant prognostic factors for prolonged median survival were Eastern Cooperative Oncology Group status 0–2 (P = 0.015), Medical Research Council neurological functional status 0–1 (P = 0.006), and Recursive Partitioning Analysis Class 2 versus Class 3 (P = 0.020). On multivariate analysis, younger patient age (P = 0.02) and better performance status (P < 0.01) were associated with improved outcome. When comparing these characteristics with selected published studies, our study cohort demonstrated a higher proportion of patients with poor performance status, a greater number of metastases per patient and a higher incidence of extracranial disease. This reflects the selected nature of patients in these published studies. Central nervous system metastases confer a poor prognosis and, for the majority of patients, aggressive interventions are unlikely to improve survival. The use of potentially toxic and expensive treatments should be reserved for those few in whom these studies have shown a potential benefit.     

Video capsule endoscopy for previous overt obscure gastrointestinal bleeding in patients using anti‐thrombotic drugs

Background and Aim: Little is known about the causes of overt obscure gastrointestinal bleeding (OGIB) in patients using anti‐thrombotic therapy. We aimed to describe video capsule endoscopy (VCE) findings and to identify factors associated with positive findings in these patients. Methods: We carried out a retrospective study of 56 patients who underwent VCE for evaluation of previous overt OGIB during anti‐thrombotic therapy. VCE studies were re‐evaluated by a gastroenterologist blinded to clinical details. Clinical data included in the multivariate analysis were sex, age, indication for and type of anti‐thrombotic therapy, hemodynamic instability on admission, type of blood loss, hemoglobin on admission, use of a proton pump inhibitor, NSAID use, time between bleeding episodes and VCE, and whether or not anti‐thrombotic therapy was resumed before the VCE study. Results: A probable cause for gastrointestinal bleeding was identified in 28 (50%) of the 56 studies. Angiodysplasia was found in 19 patients. Twenty‐two studies showed a possible cause in the small bowel. Multivariate logistic regression analysis showed that reinstitution of anti‐thrombotic therapy before VCE was carried out was the only independent predictor of positive VCE findings (OR: 8.61, 95% CI: 1.20–60.42, P = 0.032). Conclusions: Small intestinal angiodysplasia was the most common cause for overt OGIB. Reinstitution of withdrawn anti‐thrombotic drugs before the VCE examination was carried out was associated with positive VCE findings in multivariate analysis.     

大花紫玉盘中新多氧取代环己烯类的结构鉴定

从番荔枝科紫玉盘属植物大花紫玉盘( Uvaria grandiflora Roxb.)根茎中分得4种新的多氧取代环己烯及已知化合物zeylenol,应用波谱分析、X-射线衍射、园二色谱和 Mosher 酯制备等手段确定了全部新化合物的结构及其绝对构型,分别命名为大花紫玉盘醇A(1),B(2),E(3)和F(4)。     

Human erythrocyte protein 4.2 deficiency associated with hemolytic anemia and a homozygous 40glutamic acid-->lysine substitution in the cytoplasmic domain of band 3 (band 3Montefiore)

Red blood cell (RBC) protein 4.2 deficiency is often associated with a moderate nonimmune hemolytic anemia, splenomegaly, and osmotically fragile RBCs resembling, but not identical to, hereditary spherocytosis (HS). In the Japanese type of protein 4.2 deficiency (protein 4.2Nippon), the anemia is associated with a point mutation in the protein 4.2 cDNA. In this report, we describe a patient with moderate and apparently episodic nonimmune hemolytic anemia with splenomegaly, spherocytosis, osmotically fragile RBCs, reduced whole cell deformability, and abnormally dense cells. Sodium dodecyl sulfate- polyacrylamide gel electrophoresis analysis of the proposita's RBC membrane proteins showed an 88% deficiency of protein 4.2 and a 30% deficiency of glyceraldehyde-3-phosphate dehydrogenase (band 6). Structural and molecular analyses of the proposita's protein 4.2 were normal. In contrast, limited tryptic digestion of the proposita's band 3 showed a homozygous abnormality in the cytoplasmic domain. Analysis of the pedigree disclosed six members who were heterozygotes for the band 3 structural abnormality and one member who was a normal homozygote. Direct sequence analysis of the abnormal band 3 tryptic peptide suggested that the structural abnormality resided at or near residue 40. Sequence analysis of the proposita's band 3 cDNA showed a 232G-->A mutation resulting in a 40glutamic acid-->lysine substitution (band 3Montefiore). Allele-specific oligonucleotide hybridization was used to probe for the mutation in the pedigree, showing that the proposita was homozygous, and the pedigree members who were heterozygous for the band 3 structural abnormality were also heterozygous for the band 3Montefiore mutation. The band 3Montefiore mutation was absent in 26 chromosomes from race-matched controls and in one pedigree member who did not express the band 3 structural abnormality. In coincidence with splenectomy, the proposita's anemia was largely corrected along with the disappearance of most spherocytes and considerable improvements of RBC osmotic fragility, whole cell deformability, and cell density. We conclude that this hereditary hemolytic anemia is associated with the homozygous state for band 3Montefiore (40glutamic acid-->lysine) and a decreased RBC membrane content of protein 4.2. We speculate that band 3 structural abnormalities can result in defective interactions with protein 4.2 and band 6, and in particular, that the region of band 3 containing 40glutamic acid is involved directly or indirectly in interactions with these proteins.     

TEL gene is involved in myelodysplastic syndromes with either the typical t(5;12)(q33;p13) translocation or its variant t(10;12)(q24;p13)

A t(5;12)(q33;p13) translocation is a recurrent chromosome abnormality in a subgroup of myeloid malignancies with features of both myeloproliferative disorders and myelodysplastic syndromes (MDSs). The molecular consequence of a t(5;12) is a fusion between the platelet- derived growth factor receptor-B gene on chromosome 5 and a novel ETS- like gene, TEL, on chromosome 12. We report on three patients with a t(5;12)(q33;p13) diagnosed as chronic myelomonocytic leukemia, and one case of a t(10;12)(q24;p13) in a progressive MDS, with eosinophilia and monocytosis. Involvement of the TEL gene in these chromosome translocations was investigated by fluorescence in situ hybridization (FISH) with cosmid probes containing selectively the 5' end or 3' end of TEL. Hybridization of these cosmids to the der(5)/der(10) or a der(12), respectively, demonstrated a rearrangement of TEL in both translocations, showing that the t(10;12) is a variant translocation of the t(5;12). Cloning of the fusion cDNA of one case of t(5;12) showed that the breakpoint occurred at the RNA level at exactly the same position as reported by Golub et al (Cell 77:307, 1994). In addition, the TEL gene on chromosome 12 could be localized between two probes previously mapped to 12p13, namely PRB1 and D12S178, leading to a better definition of the position of TEL in this chromosome region. Moreover, in the case involving chromosome 10, the breakpoint occurred between cKTN206 and cKTN312/LYT-10 at 10q24. Clinicohematological data in these studies as well as the restriction mapping of chromosomal breakpoints strongly suggest that (1) common features in MDSs involving the TEL gene are monocytosis and eosinophilia, (2) chromosomes other than no. 5 may be involved and at least a t(10;12)(q24;p13) variant chromosome translocation does exist in these MDSs, and (3) both standard and variant 12p/TEL translocations may be identified by FISH with appropriate probes.     

Multifocal and microscopic chromophobe renal cell carcinomatous lesions associated with ‘capsulomas’ without FCLN gene abnormality

Chromophobe renal cell carcinoma (RCC) accounts for approximately 5% of renal epithelial neoplasms. Multiple and/or bilateral chromophobe RCCs in an individual are generally rare but frequently occur in patients with Birt–Hogg–Dubé syndrome (BHDS) and in patients with tuberous sclerosis complex (TSC). The responsible genes in both BHDS and TSC act as tumor suppressors. Therefore, it seems that some genetic backgrounds are required for the generation and progression of multiple chromophobe RCCs. Here, we report a case of multiple and bilateral chromophobe RCCs along with several small‐sized capsular angiomyolipomas known as ‘capsulomas’ in a 39‐year‐old woman who had neither a particular medical history nor specific gene mutation. There has been no report of sporadic multiple chromophobe RCCs and ‘capsulomas’ developing in a patient without genetic features, having potential for novel genetic variation.     

Clinical features and outcome of T-cell acute lymphoblastic leukemia in childhood with respect to alterations at the TAL1 locus: a Pediatric Oncology Group study

Alteration of the TAL1 locus is the most common nonrandom genetic defect in childhood T-cell acute lymphoblastic leukemia (T-ALL). To determine if rearrangements of the TAL1 proto-oncogene confer a distinct leukemic phenotype, we studied leukemic peripheral blood or bone marrow samples from 182 children with newly diagnosed T-ALL enrolled on Pediatric Oncology Group treatment protocols. Forty-eight (26%) of the samples had a local rearrangement of the TAL1 locus. Demographic and clinical features were compared for patient subgroups with and without TAL1 rearrangements. The only clinical correlates that were significantly associated with TAL1 gene rearrangements were higher white blood cell count (P = .017) and higher hemoglobin (P = .007) at diagnosis. Immunophenotypically, samples with altered TAL1 were more likely to be CD2+ (P = .001) and lack CD10 (cALLa) expression (P = .007) than those without the rearrangement. There was a trend toward improved event-free survival (EFS) in patients with TAL1 rearrangements (4-year EFS was 44% +/- 7% for patients without the rearrangements v 59% +/- 11% for those with rearrangements), but the difference was not significant (P = .34). The role of TAL1 in leukemogenesis has yet to be clearly defined, and the prognostic significance of TAL1 gene rearrangements in T-ALL deserves further study.     

Minor histocompatibility antigens HA-1-, -2-, and -4-, and HY-specific cytotoxic T-cell clones inhibit human hematopoietic progenitor cell growth by a mechanism that is dependent on direct cell-cell contact

HLA-identical bone marrow transplantation (BMT) may be complicated by graft-versus-host disease or graft rejection. Both complications are thought to be initiated by recognition of minor histocompatibility (mH) antigens by HLA-restricted mH-antigen-specific T lymphocytes. Using HLA- A2-restricted mH antigens HA-1-, -2-, and -4-, and HY-specific cytotoxic T lymphocyte (CTL) clones, we studied the recognition by these CTL clones of interleukin-2 (IL-2)-stimulated T cells (IL-2 blasts), BM mononuclear cells (BMMNCs), and hematopoietic progenitor cells (HPCs). We showed that, when IL-2 blasts from the BM donors who were investigated were recognized by the HA-1-, -2-, and -4-, and HY- specific CTL clones, their BMMNCs and HPCs were recognized as well by these CTL clones, resulting in antigen-specific growth inhibition of erythrocyte burst-forming units (BFU-E), colony-forming units- granulocyte (CFU-G), and CFU-macrophage (CFU-M). the HA-2-specific CTL clone, however, inhibited BFU-E and CFU-G growth from four donors to a lesser extent than from two other donors. We further investigated whether inhibitory cytokines released into the culture medium by the antigen-specific stimulated CTLs or by stimulated BMMNCs were responsible for suppression of HPC growth or whether this effect was caused by direct cell-cell contact between CTLs and HPCs. HPC growth inhibition was only observed after preincubation of BMMNCs and CTLs together for 4 hours before plating the cells in semisolid HPC culture medium. When no cell-cell contact was permitted before plating, neither antigen-stimulated CTL nor antigen-nonstimulated CTLs provoked HPC growth inhibition. Culturing BMMNCs in the presence of supernatants harvested after incubation of BMMNCs and CTL clones together for 4 or 72 hours did also not result in HPC growth inhibition. Both suppression of HPC growth and lysis of IL-2 blasts and BMMNCs in the 51Cr-release assay appeared to be dependent on direct cell-cell contact between target cells and CTLs and were not caused by the release of inhibitory cytokines into the culture medium by antigen-specific stimulated CTLs or by stimulated BMMNCs. Our results show that mH-antigen-specific CTLs can inhibit HPC growth by a direct cytolytic effect and may therefore be responsible for BM graft rejection after HLA-identical BMT.