Correlation between ultrasound and autopsy findings after 2nd trimester terminations of pregnancy.

OBJECTIVE: To compare ultrasound (US) and fetal autopsy findings in 2(nd) trimester termination of pregnancy because of structural fetal anomalies. METHODS: A total of 112 terminations of pregnancy (TOP) between 1999-2003 were reviewed retrospectively. The cases originated from a secondary and a tertiary Fetal Medicine unit in the south Stockholm area, using a common specialized perinatal pathology service. Karyotype was not known at the time of US examination. The findings were compared and classified into four groups according to the degree of agreement between US and autopsy. RESULTS: In 45% of cases there was total agreement between US and autopsy. In 40%, autopsy confirmed all US findings but provided additional information of clinical importance. Partial or total lack of agreement was noted in 11% and 4% of the cases, respectively. Areas of discrepancy involved mainly CNS- and cardiovascular abnormalities and, to a lesser extent, renal anomalies, abdominal wall defects and hydrops/hygroma. Regarding CNS abnormalities the overall rate of agreement was 62%; it was highest in acrania/anencephaly (92%) and lowest in hydrocephaly (39%). CONCLUSION: We find an overall high degree of agreement between US and autopsy findings. Autopsy often provided additional information of clinical value and it should always follow US examination and TOP. Fixation of CNS is crucial for optimal results. Specific limitations of autopsy, i.e., detection of CNS abnormalities, may be reduced by complementary imaging techniques, such as MRI. The ability of US to detect cardiac anomalies is enhanced with the close contact to specialized fetal cardiology.

Comparison of ultrasound and autopsy findings in pregnancies terminated due to fetal anomalies.

OBJECTIVE: To compare antenatal diagnoses with autopsy findings in pregnancies terminated after ultrasound detection of fetal anomalies. A second aim was to study the quality of antenatal fetal diagnosis over time. DESIGN: Retrospective, multicenter study over two consecutive six-year periods in Uppsala and Stockholm. SETTING: Cases were identified through fetal autopsy reports. SUBJECTS: Three hundred and twenty-eight fetuses from pregnancies terminated between 1992 and 2003 because of ultrasonographically diagnosed anomalies. MAIN OUTCOME MEASURES: The findings at the last ultrasound examination were compared with the autopsy reports. RESULTS: In 299 cases (91.2%) ultrasound findings either exactly matched or were essentially similar to the autopsy findings. In 23 cases (7%) ultrasound findings were not confirmed at autopsy, but the postnatal findings were at least as severe as the antenatal ones. In six cases (1.8%) termination was performed for an anomaly which proved to be less severe than was predicted by ultrasound. The number of such cases was the same in both six-year periods, while the total number of cases increased from 113 in the first to 215 in the second period. Fetal examination provided further diagnostic information in 47% of the cases. In 10% a syndrome was disclosed. CONCLUSION: Termination of pregnancy was not always based on a correct antenatal diagnosis. All fetuses but one from terminated pregnancies had evident anomalies. In six cases (1.8%) the decision to terminate was based on suboptimal prognostic and diagnostic information. Fetal autopsy by an experienced perinatal pathologist is essential to provide a definitive diagnosis.

Identification of the antigenic epitopes in staphylococcal enterotoxins A and E and design of a superantigen for human cancer therapy.

Monoclonal antibodies have a potential for cancer therapy that may be further improved by linking them to effector molecules such as superantigens. Tumor targeting of a superantigen leads to a powerful T cell attack against the tumour tissue. Encouraging results have been observed preclinically and in patients using the superantigen staphylococcal enterotoxin A, SEA. To further improve the concept, we have reduced the reactivity to antibodies against superantigens, which is found in all individuals. Using epitope mapping, antibody binding sites in SEA and SEE were found around their MHC class II binding sites. These epitopes were removed genetically and a large number of synthetic superantigens were produced in an iterative engineering procedure. Properties such as decreased binding to anti-SEA as well as higher selectivity to induce killing of tumour cells compared to MHC class II expressing cells, were sequentially improved. The lysine residues 79, 81, 83 and 84 are all part of major antigenic epitopes, Gln204, Lys74, Asp75 and Asn78 are important for optimal killing of tumour cells while Asp45 affects binding to MHC class II. The production properties were optimised by further engineering and a novel synthetic superantigen, SEA/E-120, was designed. It is recognised by approximately 15% of human anti-SEA antibodies and have more potent tumour cell killing properties than SEA. SEA/E-120 is likely to have a low toxicity due to its reduced capacity to mediate killing of MHC class II expressing cells. It is produced as a Fab fusion protein at approximately 35 mg/l in Escherichia coli.

Identification of phosphorylation sites within the SH3 domains of Tec family tyrosine kinases.

Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the SH3 domain via a transphosphorylation mechanism, which for Bruton's tyrosine kinase (Btk) affects tyrosine 223. We found that TFKs phosphorylate preferentially their own SH3 domains, but differentially phosphorylate other member family SH3 domains, whereas non-related SH3 domains are not phosphorylated. We demonstrate that SH3 domains are good and reliable substrates. We observe that transphosphorylation is selective not only for SH3 domains, but also for dual SH3SH2 domains. However, the dual domain is phosphorylated more effectively. The major phosphorylation sites were identified as conserved tyrosines, for Itk Y180 and for Bmx Y215, both sites being homologous to the Y223 site in Btk. There is, however, one exception because the Tec-SH3 domain is phosphorylated at a non-homologous site, nevertheless a conserved tyrosine, Y206. Consistent with these findings, the 3D structures for SH3 domains point out that these phosphorylated tyrosines are located on the ligand-binding surface. Because a number of Tec family kinases are coexpressed in cells, it is possible that they could regulate the activity of each other through transphosphorylation.