Successful treatment of congenital acute myeloid leukemia (AML-M6) in a premature infant.

Congenital acute myeloid leukemia (AML), and especially AML-M6 is a rare disease with a poor prognosis. Moreover, reports of treatment outcome of congenital AML-M6 in premature infants are not available. We report the first treated case of congenital AML-M6 in a premature girl, who received a full AML protocol. She presented with blueberry-muffin spots, anemia, high white blood cell count, and serious cardiopulmonary distress. Peripheral blood smears showed AML-M6 blasts. After treatment with a sequential low-dose cytarabine after birth and full-dose AML treatment according to the MRC-12 protocol at the age of 2 months, she now is in continuous complete remission for 4 years.

Variability in AC amplifier distortions: estimation and correction.

AC amplifiers can introduce significant distortions into the low frequency and DC components of recorded electrophysiological data such as event-related potentials (ERPs). Methods for correcting such distortions (i.e., estimating the waveform of the original data) after the data have been amplified and recorded rely on an accurate estimate of the amplifier's time constant (TC). We show that the filter characteristics of AC amplifiers in at least some commercially available ERP recording instruments may vary considerably across individual channels, even when each houses an identical AC amplifier circuit. Clearly, distortion correction methods must take this variability into account. We propose an empirical means of estimating the correct TC value. This approach yields more accurate correction than those based on TCs calculated analytically.

Subtelomeric rearrangements: results from a study of selected and unselected probands with idiopathic mental retardation and control individuals by using high-resolution G-banding and FISH.

The cause of mental retardation, present in approximately 3% of the population, is unexplained in the majority of cases. Recent reports have suggested that cryptic telomeric rearrangements resulting in segmental aneuploidy and gene-dosage imbalance might represent a significant cause of idiopathic mental retardation (IMR). Two groups of patients with unexplained developmental delay (unselected and selected) and a group of control individuals have been investigated to determine the frequency of submicroscopic telomeric rearrangements associated with IMR and the frequency within the normal population. In contrast to current thinking, our data have shown that true cryptic telomeric rearrangements are not a significant cause of IMR. No fully cryptic abnormalities were detected in our IMR groups, although a semi-cryptic unbalanced telomeric translocation was identified in one selected patient by high-resolution G-band analysis. This abnormality was confirmed and characterised by fluorescence in situ hybridisation (FISH) with telomere-specific probes. A further 13 cytogenetically detected subtle terminal rearrangements were characterised by using multi-telomere FISH. Seven of these had previously been reported as normal, three of which were shown to be interstitial deletions. These cases illustrate the importance of high-resolution analysis to exclude subtle but cytogenetically visible abnormalities prior to subtelomere FISH screening when determining the frequency of cryptic telomeric rearrangements. Unexpectedly, two cryptic telomeric abnormalities were detected among our control individuals, suggesting that submicroscopic telomeric abnormalities may be a not uncommon finding in the general population. Hence, our data have important implications when defining the significance of cryptic telomeric rearrangements detected during screening programmes.

Multipaint FISH: a rapid and reliable way to define cryptic and complex abnormalities.

We present the use of a multipaint fluorescence in situ hybridisation (FISH) approach for the detection and interpretation of chromosome abnormalities that could not be resolved by conventional cytogenetics alone. In case 1, a de novo add(Xp) was shown to be an unbalanced X;12 translocation; in case 2, a complex rearrangement involving a deletion of 5p was shown to include a previously undetected cryptic 5;6 translocation. In addition, in case 3, this technique defined additional complexities and nine breakpoints in an acquired rearrangement of chromosomes 2, 9, 11, 16 and 22 in a patient with myelodysplasia. The technique allows the simultaneous identification of up to 24 chromosomes on a single slide using FISH with directly labelled whole chromosome paints. This simple and rapid method does not require image enhancement, produces results within 48 h and, therefore, offers an alternative to other recent developments, such as combinatorial multifluor FISH, spectral karyotyping or comparative genomic hybridisation.

A de novo complex chromosomal rearrangement with nine breakpoints characterized by FISH in a boy with mild mental retardation, developmental delay, short stature and microcephaly.

A de novo complex chromosome rearrangement (CCR) involving chromosomes 1, 6, 7, 15 and Y was detected in a boy with mental retardation, short stature, and microcephaly. Fluorescence in situ hybridisation (FISH) with whole chromosome painting libraries, band-specific cosmids and telomeric probes was essential for the characterisation of the rearrangement. The CCR was shown to be the result of at least nine chromosomal breaks and involved the alternating insertion of two segments of the short arm of chromosome 1 and two segments of the long arm of chromosome 6 into a novel derived chromosome 7. A non-reciprocal translocation between the distal short arm of the same chromosome 7 and the distal long arm of the Y chromosome was also found, together with a paracentric inversion of the long arm of chromosome 15. The only detectable imbalance was a deletion of the heterochromatic Yq telomeric region. FISH investigations in this case have revealed an additional complexity in this CCR, which has implications for reproductive risk assessment and genetic counselling.

An electrophysiological analysis of modality-specific aspects of word repetition.

Priming effects to words are reduced when modality changes from study to test. This change was examined here using behavioral and electrophysiological measures of priming. During the study, half of the words were presented visually and half auditorally; during a subsequent lexical decision test, all words were presented visually. Lexical decisions were faster for within- than cross-modality repetitions. In contrast, modality influenced recognition only for low-frequency words. During lexical decision, event-related brain potentials were more positive to studied than unstudied words (200-500 ms). A larger and shorter duration effect was observed for within- than cross-modality repetitions (300-400 ms). This later effect is viewed as an electrophysiological index of modality-specific processing associated with priming. Results suggest that multiple events--both modality-specific and modality-nonspecific--underlie perceptual priming phenomena.

Amplification of a pseudogene cassette underlies euchromatic variation of 16p at the cytogenetic level.

Euchromatic imbalances at the cytogenetic level are usually associated with phenotypic consequences. Among the exceptions are euchromatic variants of chromosomes 8, 9, 15 and 16, which have each been reported in multiple unrelated families. In this paper, we present a new family and an unrelated individual who have euchromatic variants of 16p. Enhanced hybridisation to the extra material was found by using fluorescence in situ hybridisation with cosmids for both the 16p11.2-specific non-functional immunoglobin heavy chain segments and the pseudogenetic 16p11.2 creatine transporter region. Computerised measurement of the fluorescent signals was consistent with amplification of a pseudogene cassette comprising both these paralogous domains, which were originally transposed from 14q32.3 and Xq28, respectively. Amplification of pseudogenetic sequences is consistent with the normal phenotype in 36/46 carriers from the 18 families reported to date. Inconsistent phenotypic anomalies in the remaining 10 carriers probably reflect bias of ascertainment. These results are analogous to the amplification of the 15q11.2-specific pseudogene cassette in euchromatic variants of chromosome 15. They also suggest that the majority of established euchromatic variants are associated with variation in the copy number of sequences that have been dispersed between pericentromeric and telomeric loci over recent evolutionary time. We propose that constitutional cytogenetic amplification of this kind is part of a more widespread continuum of genomic flux affecting regions in which heterochromatin and euchromatin interpose. Euchromatic sequences that vary in a heterochromatic manner might usefully be termed "hemichromatic".

Duplication of 7p12.1-p13, including GRB10 and IGFBP1, in a mother and daughter with features of Silver-Russell syndrome.

Silver-Russell syndrome (SRS) has been associated with maternal uniparental disomy (UPD) of chromosome 7 in approximately 10% of cases, suggesting that at least one imprinted gene on chromosome 7 is involved in the pathogenesis of the disease. We report a proximal 7p interstitial inverted duplication in a mother and daughter both of whom have features of SRS, including marked short stature, low birth weight, facial asymmetry and 5th finger clinodactyly. Fluorescence in situ hybridisation (FISH) with YAC probes enabled delineation of the duplicated region to 7p12.1-p13. This region of proximal chromosome 7 is known to be homologous to an imprinted region in the mouse chromosome 11 and contains the growth-related genes GRB10 (growth factor receptor-bound protein 10), EGFR (epidermal growth factor receptor) and IGFBP1 (insulin-like growth factor binding protein 1), all of which have been suggested as candidate genes for SRS. Molecular analysis showed that the duplication in both mother and daughter spanned a distance of approximately 10 cM and included GRB10 and IGFBP1 but not EGFR. The de novo duplication in the proband's mother was shown to be of paternal origin. In order to test the hypothesis that sub-microscopic duplications of 7p, whether maternal or paternal in origin, are responsible for at least some cases of SRS, we screened a further eight patients referred to our laboratory for SRS. None were found to have duplications of either GRB10 or IGFBP1. The hypothesis that sub-microscopic duplications including GRB10 and IGFBP1 is a cause of SRS remains a possibility and warrants further investigation. Importantly, in contrast to current thinking, our results suggest that imprinted genes may not underlie the SRS phenotype, and we propose an alternative hypothesis to explain the occurrence of maternal UPD 7 seen in some cases of SRS.

Memory changes with normal aging: behavioral and electrophysiological measures.

We examined performance in young and elderly on an implicit (lexical decision) and an explicit (recognition) memory test. The difference in lexical decision times between old and new words was equivalent in the two groups, although the elderly were slower. In both groups, recognition accuracy (lower in the elderly) was higher following semantic than nonsemantic encoding, whereas lexical decision times were unaffected. Divergent brain potentials for old and new words during lexical decisions constituted a repetition effect, which reflected greater positivity (200-800 ms) for old words, particularly over the left hemisphere; this effect was smaller and later in the elderly. An electrophysiological marker of enhanced recollection for words from the semantic encoding task took the form of a left-sided positivity (500-800 ms). The effect was smaller in the elderly than the young, providing an additional index of their impaired recognition processes.

Duplication of 8p23.1: a cytogenetic anomaly with no established clinical significance.

We present seven families with a cytogenetic duplication of the short arm of chromosome 8 at band 8p23.1. The duplication has been transmitted from parents to offspring in four of the seven families. In three families, the source of the extra material and its euchromatic origin were established using FISH with a YAC which was mapped to 8p23.1 and a whole chromosome paint for chromosome 8. FISH signals from this YAC were significantly larger on the duplicated chromosome compared with the normal chromosome in all six family members tested. Comparative genomic hybridisation (CGH) on a representative subject was consistent with these results. The families were ascertained for a variety of mostly incidental reasons including prenatal diagnosis for advanced maternal age. The transmission of this duplication by multiple phenotypically normal family members with no history of reproductive loss suggests the existence of a novel class of 8p23.1 duplications, which can be regarded as euchromatic variants or duplications with no phenotypic effect.

Isolated sacral agenesis in a fetus monosomic for 7q36.1-->qter.

A fetus with severe sacral agenesis and intrauterine growth retardation, ascertained at prenatal diagnosis, was found to be carrying an unbalanced form of a paternal balanced reciprocal translocation (7;19)(q36.1;q13.43), resulting in functional monosomy for 7q36.1-->qter. Necropsy confirmed that the fetus had isolated sacral agenesis type II. A critical region for autosomal dominant sacral agenesis has recently been mapped to the 7q36 region. This case provides further evidence for a sacral agenesis locus in this region and may help to refine the critical region further.

Williams-Beuren syndrome: phenotypic variability and deletions of chromosomes 7, 11, and 22 in a series of 52 patients.

Fluorescence in situ hybridisation (FISH) and conventional chromosome analysis were performed on a series of 52 patients with classical Williams-Beuren syndrome (WBS), suspected WBS, or supravalvular aortic stenosis (SVAS). In the classical WBS group, 22/23 (96%) had a submicroscopic deletion of the elastin locus on chromosome 7, but the remaining patient had a unique interstitial deletion of chromosome 11 (del(11)(q13.5q14.2)). In the suspected WBS group 2/22 (9%) patients had elastin deletions but a third patient had a complex karyotype including a ring chromosome 22 with a deletion of the long arm (r(22)(p11-->q13)). In the SVAS group, 1/7 (14%) had an elastin gene deletion, despite having normal development and minimal signs of WBS. Overall, some patients with submicroscopic elastin deletions have fewer features of Williams-Beuren syndrome than those with other cytogenetic abnormalities. These results, therefore, emphasise the importance of a combined conventional and molecular cytogenetic approach to diagnosis and suggest that the degree to which submicroscopic deletions of chromosome 7 extend beyond the elastin locus may explain some of the phenotypic variability found in Williams-Beuren syndrome.

Oxygen consumption and noise-induced TTS in humans.

Young adult men (N:16) were used to examine the effects of increased oxygen availability upon noise-induced TTS. In 2 sessions a day apart, Ss inhaled either medical grade air or 100% oxygen during monaural exposure in their better ear to 10 min of narrow-band noise centered a 3 kc/s at 100 db SPL. Oxygen consumption was recorded with a respirometer during oxygen breathing. Conditions were counterbalanced among Ss. TTS2 min at 4 kc/s was significantly less with oxygen inhalation, confirming a previous study; however, no relationship was found between amount of oxygen consumed and the amount of TTS during pure oxygen inhalation.