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.     

The expression of CEA, CA 19-9 and HMFG antigens in ovarian clear-cell and endometrioid carcinomas.

The tumour antigen expression of ovarian and endometrial endometrioid carcinomas, ovarian clear-cell carcinomas as well as endometrial and cervical clear-cell carcinomas were immunohistochemically compared. Of special interest were potential differences between the endometrioid and clear-cell carcinomas of the ovary. The expression of CEA and CA 19-9 tumour antigens in all these tumour types was heterogeneous, with 10-20% of the cases being positive for CEA and 40-75% being positive for CA 19-9. In contrast, HMFG IIIC 12, a monoclonal antibody originally directed against human milk fat globule (HMFG) membrane antigens, invariably detected a corresponding antigen on every case of these tumour types. Another HMFG antibody, SM IF 3, on the other hand, detected antigenic material on all clear-cell tumour types, but only rarely on endometrioid tumours of the ovary or endometrium. While HMFG IIIC 12 detects an antigen present on all ovarian, endometrial and mammary carcinomas, antibody SM IF 3 thus appears to be more restricted in its staining patterns. Our results with both of these antibodies indicate that ovarian clear-cell carcinomas and ovarian endometrioid carcinomas have antigenic differences, which provides further evidence that they belong to different tumour entities.     

Invasive pneumococcal infections in Denmark from 1995 to 1999: epidemiology, serotypes, and resistance

Danish nationwide surveillance data on invasive pneumococcal disease from the 5-year period from 1995 to 1999, including 5,452 isolates, are presented and described. Annual overall incidence rates, serotype distribution, and antimicrobial susceptibility patterns of the isolates were monitored. Major changes in the total annual incidence rate from 27/100,000 in 1996 to 17/100,000 in 1999 and a significant change in the proportion of invasive isolates belonging to types 1 and 12F were observed. The serotype coverage rate by the 23-valent polysaccharide vaccine among the elderly was 92.9%, and the serotype coverage rate by the 7-, 9-, and 11-valent pneumococcal conjugate vaccines among children less than 2 years old were 71.7, 75.2, and 81.4%, respectively. Invasive isolates with reduced susceptibility to penicillin or erythromycin increased from 1995 to 1999, with a high proportion of the penicillin-nonsusceptible invasive isolates originating from people 60 years old or older (57.0%). These observations underline the importance of adequate surveillance systems of invasive pneumococcal disease to introduce and maintain national vaccine strategies and adequate antibiotic policy.     

Usefulness of high-resolution comparative genomic hybridization (CGH) for detecting and characterizing constitutional chromosome abnormalities

Comparative genomic hybridization (CGH) is a technique for detection of chromosomal imbalances in a genomic DNA sample. We here report the application of the recently developed method of high-resolution CGH on DNA samples from 66 children having various degrees of delayed psychomotor development with or without clear dysmorphic features and congenital malformations. In 5 of 50 patients with apparently normal karyotypes, a deletion or duplication was revealed by CGH. Only one of these cases had a subtelomeric rearrangement. In one of seven cases with a de novo apparently balanced translocation, deletions were found. In all nine cases where the origin of a marker chromosome or additional chromosomal material was difficult to determine, CGH gave a precise identification. The following findings were from cases having a deletion or duplication as the sole chromosomal imbalance; dup(2)(p16p21), del(4)(q21q21), del(6)(q14q15), del(6)(p12p12), dup(6)(q24qter), and dup(15)(q11q13). One case had dup(9)(p11pter) combined with a very small subtelomeric deletion on 6q. In our hands, CGH is highly useful not only for identifying known chromosomal imbalances, but also for finding elusive deletions or duplications in the large group of children with developmental delay with or without congenital abnormalities. In such cases, the diagnostic yield of CGH appears to be higher than what has been reported from subtelomeric FISH screening.     

Comparison of the effects of recombinant interleukin 6 and recombinant interleukin 1 on nonspecific resistance to infection

Interleukin 1 (IL 1) is a potent enhancer of nonspecific resistance to infection in mice. Since IL 1 also induces interleukin 6 (IL 6), we tested the hypothesis that IL 6 mediates the effect of IL 1 on nonspecific resistance. In a lethal Pseudomonas aeruginosa infection in granulocytopenic mice, in which 80 ng of recombinant human IL 1 alpha protects against death, IL 6 appeared to be much less effective. Dosages of 8 ng, 80 ng and 320 ng IL 6 did not differ from the control, whereas 800 ng had a marginal protective effect (0.05 less than p less than 0.1). IL 1 and IL 6 did not potentiate each other in animals treated with suboptimal dosages of both cytokines. Numbers of bacteria cultured from the blood, thigh muscle, liver, spleen, and kidney were similar in animals treated with 800 ng IL 6 and in control animals, arguing against activation of microbicidal mechanisms. The serum concentration profile of IL 6 after an i.p. injection of 80 ng IL 1 was similar to that after 80 ng IL 6 i.p. Only minute amounts of IL 1 were detected in serum after an i.p. injection of IL 6. Taken these data together, it appears that increased resistance to infection induced by IL 1 is not mediated by IL 6.     

Proliferative activity and steroid receptors determined by immunohistochemistry in adjacent frozen sections of 102 breast carcinomas

Adjacent frozen sections of 102 consecutive female breast carcinomas were examined for the expression of the Ki-67 antibody-reactive proliferation-associated nuclear antigen and of estrogen and progesterone receptors with the use of monoclonal antibodies and peroxidase histochemistry. The results of steroid receptor stainings were semiquantitatively assessed (histoscore) on the basis of nuclear staining intensity and the percentage of positively stained carcinoma cell nuclei. Carcinomas negative for either receptor had significantly higher percentages of Ki-67-positive cells. The highest percentages of Ki-67-positive cells were observed in carcinomas negative for both estrogen and progesterone receptors. There was a highly significant decrease in receptor histoscores with increasing proliferative cell fractions as determined by Ki-67 positivity. No significant (progesterone receptor) or poor negative correlation (estrogen receptor) was observed when proliferative cell fractions were related to receptor concentrations from conventional steroid-binding assays. Immunoperoxidase staining for the Ki-67 antibody-defined proliferation antigen and steroid receptors in tissue sections provides a simple means to gain information of therapeutic and prognostic importance.     

Application of molecular and cytogenetic techniques to the detection of a de novo unbalanced t(11q;21q) in a patient previously diagnosed as having monosomy 21

Hertz B, Brandt CA, Petersen MB, Pedersen S, König U, Strømkjær H, Jensen PKA. Application of molecular and cytogenetic techniques to the detection of a de novo unbalanced t(11q;21q) in a patient previously diagnosed as having monosomy 21.
Clin Genet 1993: 44: 89–94. © Munksgaard, 1993
The occurrence of complete autosomal monosomy in man is extremely rare and generally considered to be incompatible with life. Since the introduction of banding techniques in human cytogenetics, several cases of presumptive monosomy for chromosome 21 have nevertheless been reported. However, it has been suggested that most, if not all, of these cases may represent unbalanced translocations or other structural aberrations resulting in only partial monosomy 21. Here we describe a patient in whom full monosomy 21 was initially diagnosed by routine karyotyping. Re-examination with a combination of high resolution banding technique, chromosome painting and DNA polymorphism analysis demonstrated the presence of an unbalanced translocation between the long arms of chromosome 11 and 21, respectively. Consequently, the case was re-classified as a partial monosomy for the proximal long arm of chromosome 21.