Association between the HOXA1 A218G polymorphism and increased head circumference in patients with autism.

BACKGROUND: The HOXA1 gene plays a major role in brainstem and cranial morphogenesis. The G allele of the HOXA1 A218G polymorphism has been previously found associated with autism. METHODS: We performed case-control and family-based association analyses, contrasting 127 autistic patients with 174 ethnically matched controls, and assessing for allelic transmission disequilibrium in 189 complete trios. RESULTS: A, and not G, alleles were associated with autism using both case-control (chi(2) = 8.96 and 5.71, 1 df, p <.005 and <.025 for genotypes and alleles, respectively), and family-based (transmission/disequilibrium test chi(2) = 8.80, 1 df, p <.005) association analyses. The head circumference of 31 patients carrying one or two copies of the G allele displayed significantly larger median values (95.0th vs. 82.5th percentile, p <.05) and dramatically reduced interindividual variability (p <.0001), compared with 166 patients carrying the A/A genotype. CONCLUSIONS: The HOXA1 A218G polymorphism explains approximately 5% of the variance in the head circumference of autistic patients and represents to our knowledge the first known gene variant providing sizable contributions to cranial morphology. The disease specificity of this finding is currently being investigated. Nonreplications in genetic linkage/association studies could partly stem from the dyshomogeneous distribution of an endophenotype morphologically defined by cranial circumference.     

Relationship between maternal- and fetal-specific IgE

AIM: A positive correlation between maternal and cord-blood IgE levels is well documented for total IgEs, but not for specific IgEs. The difficulty in detecting specific cord-blood IgEs is due to their low concentrations, which hinder their dosage by low-sensitivity methods. The study aimed to correlate maternal and foetal specific IgEs against individual cow's milk proteins, detected by highly sensitive and specific techniques. METHODS: Cow's milk specific IgE detection was performed by chemiluminescence on 52 specimens of maternal and cord blood after cow's milk protein separation by 1D and 2D gel electrophoresis. Cow's milk protein (CMP) antigens were identified by mass spectrometry techniques. RESULTS: Specific IgEs for CMPs were found in 25/52 (48.1%) of maternal sera and in 19/52 (37%) of cord-blood sera. In order of decreasing frequency, the proteins found were BSA, IgG heavy chain, caseins and, in a single case, b-lactoglobulin. Positive cord-blood sera in all cases corresponded to a positive maternal result, and maternal and foetal immunoreactivity patterns were closely correlated. Moreover, in no case was there a positive cord-blood response with a negative maternal response. CONCLUSION: The study demonstrates a close relationship between maternal and cord-blood specific IgE patterns. The phenomenon observed could provide a model to elucidate the general production method of foetal IgEs, which might only be produced in the presence of both the corresponding maternal IgE and the related allergen.     

Functioning human insulinomas

Sixty-seven insulinomas were investigated by immunohistochemistry using site-directed antibodies against insulin, proinsulin, chromogranin A, HISL-19, and four proteins directly or indirectly involved in the proteolytic processing of proinsulin: the prohormone convertases PC2 and PC3, carboxypeptidase H (CPH) and 7B2. Results were expressed in a six-grade score according to the frequency of immunoreactive tumour cells. Insulin was expressed by all tumours, appearing in either a diffuse or a polarized pattern and being detected in more than 30% of tumour cells in all cases but three. Proinsulin was also expressed in all tumours, with more than 50% of tumour cells immunoreactive in all cases but 5. It was consistently localized in the Golgi apparatus. In about half the cases, moreover, it also showed diffuse cytoplasmic staining, usually with a very sparse distribution. Trabecular and solid insulinomas did not present specific, homogeneous patterns of insulin immunostaining. However, insulin immunoreactivity was much more abundant in trabecular than in solid neoplasms, being present in virtually all tumour cells (score 6) in 50% and 8% of cases, respectively. Virtually all insulinomas expressed PC2, PC3, CPH and 7B2, usually in 30–100% of tumour cells, with a frequency significantly related to that of insulin. However, detection of PC2 and 7B2 was slightly less frequent than that of PC3 and CPH. In consecutive sections these proteins were found to be mostly co-localized with insulin and chromogranin A but not with proinsulin. They were heavily expressed in all 10 tumours with more than 10% of cells showing cytoplasmic proinsulin immunoreactivity, indicating that the leakage of proinsulin from the Golgi compartment is not associated with faulty expression of converting enzymes and possibly reflects a saturated processing capacity. HISL-19 immunoreactivity was found in both Golgi apparatus and insulin stores, indicating that the relevant antigen is different from all other proteins investigated. These results do not support a defect in expression or localization of proinsulin-processing enzymes in most insulinomas.     

Heterogeneous pattern of chromosomal breakpoints involving the MYC locus in multiple myeloma

Chromosomal rearrangements of the MYC locus, which often involve the IG loci, are recurrent events in multiple myeloma (MM) and plasma cell leukemia (PCL). We used dual-color fluorescence in situ hybridization (FISH) to characterize the breakpoint locations of chromosomal translocations/rearrangements involving the MYC locus at 8q24 found in a panel of 14 MM cell lines and 70 primary tumors (66 MM and 4 PCL). MYC locus alterations were observed in 21 cases: MYC/IG (mainly IGH@) fusions in 11 cell lines and three patients (2 MM and 1 PCL), and extra signals and/or abnormal MYC localizations in seven patients (5 MM and 2 PCL). Fourteen of these cases were investigated by FISH analyses by use of a panel of BAC clones covering about 6 Mb encompassing the MYC locus. The breakpoints were localized in a region 100-250 kb centromeric to MYC in four cases, a region 500-800 kb telomeric to the gene in four cases, and regions > or = 2 Mb centromeric or telomeric to MYC in five cases. Two different breakpoints were detected in the KMS-18 cell line, whereas the insertion of a MYC allele was found in a complex t(16;22) chromosomal translocation in the RPMI8226 cell line. Our data document a relatively high dispersion of 8q24 breakpoints in MM.     

Infant Manipulative Actions upon Customary and Uncustomary Objects in Independent and Joint Activity

Eight 12 month-olds acting on objects were observed in two sessions: 1) the objects were home objects; 2) they were brought by the observer as new exemplars of previous toys. Infants were observed manipulating objects independently and with their mothers. Type and cognitive level of infant's actions were coded. Conventional actions were more frequent in joint than independent activity. In independent activity, conventional actions were more frequent with customary objects. High cognitive level was more frequent with customary objects. Acting with an adult is the major influential factor in promoting conventional usage of an object. However, acting on customary objects influences both conventional usage and organization of the actions. Notion of joint activity as a social practice rather than interactional event can be useful in accounting for this influence.     

Prognostic value of galactose elimination capacity,aminopyrine breath test,and ICG clearance in patients with cirrhosis

Seventy-eight patients with cirrhosis were prospectively followed for up to 20 months, on the average. At entry into the study, galactose elimination capacity, aminopyrine breath test, and ICG clearance were measured. At the end of the study, 27 patients had died. Univariate analysis using the Kaplan-Meier method showed that both quantitative liver function tests (galactose elimination capacity:P<0.025; aminopyrine breath test:P<0.001; ICG clearance:P<0.005) and common clinical and biochemical data (encephalopathy:P<0.001; ascites:P<0.001; serum bilirubin:P<0.005; serum albumin:P<0.001; prothrombin index:P<0.05) were significant predictors of survival. To investigate whether quantitative liver function tests could contribute to a better definition of the prognosis, once Pugh score had already been taken into account, a multiple regression analysis according to the Cox model was performed. Pugh score and galactose elimination capacity resulted in the only independent prognostic covariates. From them a prognostic index was calculated, and the model was validated in an additional sample of 70 patients investigated according to the same protocol. The contribution GEC gave to the assessment of overall prognosis over that obtained using the Pugh score was slight, as estimated by the statistical parameters of the Cox's model, but was significant as assessed by a ROC curve analysis (P=0.05). These data show that all quantitative liver function tests were predictors of survival in cirrhosis, and that the galactose elimination capacity added some new prognostic information to those already available using the Child-Turcotte-Pugh classification.This study was supported in part by a grant from the Italian Ministry of Education (National Project Liver Cirrhosis). Part of this study was presented at the 22nd Meeting of the European Society for Clinical Investigation, Graz, Austria, April 20–23, 1988.