Analysis of the autism chromosome 2 linkage region: GAD1 and other candidate genes

Autism has a strong and complex genetic component, involving several genes. Genomic screens, including our own, have shown suggestive evidence for linkage over a 20-30 cM region on chromosome 2q31-q33. Two subsequent reports showed that the linkage evidence increased in the subset of families with phrase speech delay (PSD), defined as onset of phrase speech later than 3 years of age. To further investigate the linkage in the presumptive candidate region, microsatellite markers in a 2 cM grid covering the interval from 164 to 203 cM were analyzed in 110 multiplex (2 or more sampled autism patients) families. A maximum heterogeneity LOD (HLOD) score of 1.54 was detected at D2S1776 (173 cM) in the overall dataset (dominant model), increasing to 1.71 in the PSD subset. While not conclusive, these data continue to provide suggestive evidence for linkage, particularly considering replication by multiple independent groups. Positive LOD scores extended over the entire region, continuing to define a broad candidate interval. Association studies were performed on several functional candidates mapping within the region. These included GAD1, encoding GAD67, whose levels are reduced in autopsy brain material from autistic subjects, and STK17B, ABI2, CTLA4, CD28, NEUROD1, PDE1A, HOXD1 and DLX2. We found no evidence for significant allelic association between autism and any of these candidates, suggesting that they do not play a major role in the genetics of autism or that substantial allelic heterogeneity at any one of these loci dilutes potential disease-allele association.     

Postweaning exposure to aflatoxin results in impaired child growth: a longitudinal study in Benin, West Africa

Aflatoxins are dietary contaminants that are hepatocarcinogenic and immunotoxic and cause growth retardation in animals, but there is little evidence concerning the latter two parameters in exposed human populations. Aflatoxin exposure of West African children is known to be high, so we conducted a longitudinal study over an 8-month period in Benin to assess the effects of exposure on growth. Two hundred children 16-37 months of age were recruited from four villages, two with high and two with low aflatoxin exposure (50 children per village). Serum aflatoxin-albumin (AF-alb) adducts, anthropometric parameters, information on food consumption, and various demographic data were measured at recruitment (February) and at two subsequent time points (June and October). Plasma levels of vitamin A and zinc were also measured. AF-alb adducts increased markedly between February and October in three of the four villages, with the largest increases in the villages with higher exposures. Children who were fully weaned at recruitment had higher AF-alb than did those still partially breast-fed (p < 0.0001); the major weaning food was a maize-based porridge. There was no association between AF-alb and micronutrient levels, suggesting that aflatoxin exposure was not accompanied by a general nutritional deficiency. There was, however, a strong negative correlation (p < 0.0001) between AF-alb and height increase over the 8-month follow-up after adjustment for age, sex, height at recruitment, socioeconomic status, village, and weaning status; the highest quartile of AF-alb was associated with a mean 1.7 cm reduction in growth over 8 months compared with the lowest quartile. This study emphasizes the association between aflatoxin and stunting, although the underlying mechanisms remain unclear. Aflatoxin exposure during the weaning period may be critical in terms of adverse health effects in West African children, and intervention measures to reduce exposure merit investigation.     

Anaplastic large cell lymphoma: a clinicopathologic analysis

The clinicopathologic features of anaplastic large cell lymphoma (ALCL) are reviewed. ALCL is a heterogeneous group of tumours, and histologic examination alone is not adequate in providing useful prognostic information. However, using a combination of clinical, phenotypic, and genotypic features, several distinct clinicopathologic entities have been identified. A subset of ALCL as presently defined is characterized by a balanced translocation, t(2;5)(p23;q35), resulting in a novel fusion protein (NPM-ALK) that can be readily detected by immunohistochemical methods using antibodies against the ALK protein. Detection of ALK protein, along with other methods for demonstrating the t(2;5), has assisted in identifying a distinct biologic entity within the heterogeneous group of ALCL with significant prognostic implications. It is important to separate these from cases of ALK-negative ALCL, which have a poorer prognosis, and cases of primary cutaneous ALCL, which have an excellent prognosis.     

Thoracic radiation therapy before autologous bone marrow transplantation in relapsed or refractory Hodgkin's disease. PMH Lymphoma Group, and the Toronto Autologous BMT Group

The aim of this study was to assess the relationship between radiation therapy (RT) and treatment-related mortality in patients receiving high-dose chemotherapy (HDCT) and autologous bone marrow transplantation (ABMT) for recurrent/refractory Hodgkin's disease (HD). Between December 1986 and December 1992, 59 patients previously treated at the Princess Margaret Hospital underwent HDCT (etoposide 60 mg/kg, melphalan 160 mg/m2) and ABMT, performed for refractory (13 patients) or relapsed (46 patients) HD. RT was incorporated in the salvage treatment with the intent to achieve complete control of disease prior to ABMT. RT was given before ABMT in 33 patients, and after ABMT in 4 patients. Treatment-related (TR) mortality was defined as any death occurring within 100 days of ABMT. Autopsies were performed for all patients with TR deaths. With a median follow-up of 4.6 years (range 1.2-7.4 years), the actuarial overall survival was 41% +/- 14% at 5 years. We observed 37 deaths, and 10 of these were TR deaths. Among the 24 patients who received thoracic RT before ABMT, there were 8 TR deaths, 3 of these solely attributable to radiation pneumonitis. The remaining 5 TR deaths all had respiratory failure with complicating sepsis as a major medical problem. The interval from RT to ABMT was shorter for 8 patients dying of TR death (mean 37 days; range 0-103 days), than for the 16 survivors (mean 105 days; range 0-263 days) (P = 0.026). Among 9 patients with ABMT within 50 days of thoracic RT, 6 had TR death. In contrast, among the 35 patients without thoracic RT (26 no RT, 9 non-thoracic RT), there were only 2 TR deaths. The 4 patients treated with mantle RT post-ABMT had no serious pulmonary complications. The use of thoracic RT before HDCT and ABMT was associated with a high post-transplant mortality rate. It was most evident in patients who received thoracic RT within 50 days prior to ABMT, or when the target volume included large volume of lung. We recommend that the use of post-transplant RT be investigated to decrease TR mortality.     

Hypophosphatasia

Radiographic analysis of 24 cases of hypophosphatasia (H) from 9 Paediatric Centres was performed. 3 cases were of neonatal (lethal), 18 cases of infantile (severe) and 3 cases of late (benign) type. Some of the patients were in reality borderline cases between these groups.In the authors' material all the patients showed radiographic signs of the disease. These were divided into diagnostic, characteristic and suggestive features.All of the patients had in common generalised (usually irregular) osteoporosis, generalised (usually irregular) metaphyseal changes, craniostenosis (13 of 18 infantile cases) or widened cranial sutures and often bowing of the long bones.Besides the well know radiographic features of hypophosphatasia some less well known, rare or new ones such as, 1. spurs of the long bones (Bowdler sign), 2. distal femoral central metaphyseal defects and epiphyseal defects, 3. S-like deformities of the tibiae, 4. abnormal shape of the distal phalanges of the fingers, 5. multiple rib fractures and slender bones, 6. wedging of the lower thoracic and upper lumbar vertebrae, 7. partial premature fusion of the epiphyses, 8. nephrocalcinosis, 9. loss of lamina dura around the teeth, 10. variation in radiographic appearances of a pair of siblings with lethal form, and, 11. rapid changes in roentgen appearances, are discussed. In two of our patients (siblings) phosphoethanolamine was undetectable in the urine.The authors doubt if a normal skeletal survey may be present at any stage in any of the three major types of hypophosphatasia.Presented at the 13th Meeting of the European Society of Paediatric Radiology, Stockholm, Sweden, May 19–22, 1976, and at the 27th Annual General and Scientific Meeting of the Royal Australian College of Radiologists, Jakarta, Indonesia, October 10–15, 1976     

Bone tumor mimics: avoiding misdiagnosis

Whether discovered incidentally or as part of a focused diagnostic evaluation, the finding of a benign osseous lesion that has radiologic features resembling a bone tumor is not uncommon. Some of the more common benign and nonneoplastic entities that can sometimes be confused with tumors are the following: cortical desmoid, Brodie abscess, synovial herniation pit, pseudocyst, enostosis, intraosseous ganglion cyst, fibrous dysplasia, stress fracture, avulsion fracture (healing stage), bone infarct, myositis ossificans, brown tumor, and subchondral cyst. Accurate diagnosis and management of these lesions require a basic understanding of their epidemiology, clinical presentations, anatomic distributions, imaging features, differential considerations, and therapeutic options. This in-depth review of 13 potential bone tumor mimics will assist the radiologist in correctly identifying these benign lesions and in avoiding misdiagnosis and related morbidity. This review will also aid the radiologist in making appropriate recommendations to the referring physician for management or further imaging.     

高三尖杉酯碱酰胺的结构测定

三尖杉树皮粗提取物中的一个新生物碱—高三尖杉酯碱酰胺(homoharringtonamide)的结构,经质谱—质谱分析,初步建议为16。类似的酰胺类生物碱,例如三尖杉碱酰胺(cephalotaxamide,6)、11-羟基三尖杉碱酰胺(11-hydroxycephalotaxamide,9)、三尖杉酯碱酰胺(harfingtonamide,14)或异三尖杉酯碱酰胺(isoharringtonamide,15)也可能存在,后三者(9,14,15)尚未见报道。