First Experimental Characterization of Microwave Emission from Cosmic Ray Air Showers.

We report the first direct measurement of the overall characteristics of microwave radio emission from extensive air showers. Using a trigger provided by the KASCADE-Grande air shower array, the signals of the microwave antennas of the Cosmic-Ray Observation via Microwave Emission experiment have been read out and searched for signatures of radio emission by high-energy air showers in the GHz frequency range. Microwave signals have been detected for more than 30 showers with energies above 3×10^{16} eV. The observations presented in this Letter are consistent with a mainly forward-directed and polarized emission process in the GHz frequency range. The measurements show that microwave radiation offers a new means of studying air showers at E≥10^{17} eV.

The significance of lower jaw position in relation to postural stability. Comparison of a premanufactured occlusal splint with the Dental Power Splint.

AIM: The purpose of this study was to investigate the effects on postural stability of two different lower jaw positions held in place by splints with eyes open and eyes closed. METHODS: The postural stability in 21 healthy adult volunteers was investigated using two different sets of occlusal conditions with the lower jaw being at rest either with the eyes opened or closed. Two occlusal splints (standard splint and DPS splint) were used in order to maintain this lower jaw position. The balance behaviour was recorded using a balance platform. RESULTS: In a comparison of the habitual occlusion with the two occlusal splints, the balance posturographic values with the eyes opened fell between 7-9% and those for weight distribution with the eyes closed between 22-26% (with greater improvement being achieved with DPS) with the result that the variability in the range of fluctuations was reduced. The level of positioning accuracy deteriorated with the wearing of a splint between 13% with the DPS splint and 30% with the standard splint. Gender-specific differences of minor importance in relation to the positioning accuracy were recorded, with there being significant differences in the female participants (P≤0.00). CONCLUSION: An occlusal change in the stomatognathic system impacts on postural stability. Balance deficits seem to correlate with deteriorated body sway, which, according to the results, can be improved by a myocentric bite position using a DPS splint. This is more the case with the eyes closed than with the eyes opened.

Persistent low thymic activity and non-cardiac mortality in children with chromosome 22q11.2 microdeletion and partial DiGeorge syndrome.

A subgroup of patients with 22q11.2 microdeletion and partial DiGeorge syndrome (pDGS) appears to be susceptible to non-cardiac mortality (NCM) despite sufficient overall CD4(+) T cells. To detect these patients, 20 newborns with 22q11.2 microdeletion and congenital heart disease were followed prospectively for 6 years. Besides detailed clinical assessment, longitudinal monitoring of naive CD4(+) and cytotoxic CD3(+)CD8(+) T cells (CTL) was performed. To monitor thymic activity, we analysed naive platelet endothelial cell adhesion molecule-1 (CD31(+)) expressing CD45RA(+)RO(-)CD4(+) cells containing high numbers of T cell receptor excision circle (T(REC))-bearing lymphocytes and compared them with normal values of healthy children (n = 75). Comparing two age periods, low overall CD4(+) and naive CD4(+) T cell numbers were observed in 65%/75%, respectively, of patients in period A (< 1 year) declining to 22%/50%, respectively, of patients in period B (> 1/< 7 years). The percentage of patients with low CTLs (< P10) remained robust until school age (period A: 60%; period B: 50%). Low numbers of CTLs were associated with abnormally low naive CD45RA(+)RO(-)CD4(+) T cells. A high-risk (HR) group (n = 11) and a standard-risk (SR) (n = 9) group were identified. HR patients were characterized by low numbers of both naive CD4(+) and CTLs and were prone to lethal infectious and lymphoproliferative complications (NCM: four of 11; cardiac mortality: one of 11) while SR patients were not (NCM: none of nine; cardiac mortality: two of nine). Naive CD31(+)CD45RA(+)RO(-)CD4(+), naive CD45RA(+)RO(-)CD4(+) T cells as well as T(RECs)/10(6) mononuclear cells were abnormally low in HR and normal in SR patients. Longitudinal monitoring of naive CD4(+) and cytotoxic T cells may help to discriminate pDGS patients at increased risk for NCM.

Duplications in addition to terminal deletions are present in a proportion of ring chromosomes: clues to the mechanisms of formation.

BACKGROUND AND METHODS: Ring chromosomes are often associated with abnormal phenotypes because of loss of genomic material at one or both ends. In some cases no deletion has been detected and the abnormal phenotype has been attributed to mitotic ring instability. We investigated 33 different ring chromosomes in patients with phenotypic abnormalities by array based comparative genomic hybridisation (CGH) and fluorescence in situ hybridisation (FISH). RESULTS: In seven cases we found not only the expected terminal deletion but also a contiguous duplication. FISH analysis in some of these cases demonstrated that the duplication was inverted. Thus these ring chromosomes derived through a classical inv dup del rearrangement consisting of a deletion and an inverted duplication. DISCUSSION: Inv dup del rearrangements have been reported for several chromosomes, but hardly ever in ring chromosomes. Our findings highlight a new mechanism for the formation of some ring chromosomes and show that inv dup del rearrangements may be stabilised not only through telomere healing and telomere capture but also through circularisation. This type of mechanism must be kept in mind when evaluating possible genotype-phenotype correlations in ring chromosomes since in these cases: (1) the deletion may be larger or smaller than first estimated based on the size of the ring, with a different impact on the phenotype; and (2) the associated duplication will in general cause further phenotypic anomalies and might confuse the genotype-phenotype correlation. Moreover, these findings explain some phenotypic peculiarities which previously were attributed to a wide phenotypic variation or hidden mosaicism related to the instability of the ring.

Cryptic deletions are a common finding in "balanced" reciprocal and complex chromosome rearrangements: a study of 59 patients.

Using array comparative genome hybridisation (CGH) 41 de novo reciprocal translocations and 18 de novo complex chromosome rearrangements (CCRs) were screened. All cases had been interpreted as "balanced" by conventional cytogenetics. In all, 27 cases of reciprocal translocations were detected in patients with an abnormal phenotype, and after array CGH analysis, 11 were found to be unbalanced. Thus 40% (11 of 27) of patients with a "chromosomal phenotype" and an apparently balanced translocation were in fact unbalanced, and 18% (5 of 27) of the reciprocal translocations were instead complex rearrangements with >3 breakpoints. Fourteen fetuses with de novo, apparently balanced translocations, all but two with normal ultrasound findings, were also analysed and all were found to be normal using array CGH. Thirteen CCRs were detected in patients with abnormal phenotypes, two in women who had experienced repeated spontaneous abortions and three in fetuses. Sixteen patients were found to have unbalanced mutations, with up to 4 deletions. These results suggest that genome-wide array CGH may be advisable in all carriers of "balanced" CCRs. The parental origin of the deletions was investigated in 5 reciprocal translocations and 11 CCRs; all were found to be paternal. Using customized platforms in seven cases of CCRs, the deletion breakpoints were narrowed down to regions of a few hundred base pairs in length. No susceptibility motifs were associated with the imbalances. These results show that the phenotypic abnormalities of apparently balanced de novo CCRs are mainly due to cryptic deletions and that spermatogenesis is more prone to generate multiple chaotic chromosome imbalances and reciprocal translocations than oogenesis.

Cognitive control over memory - individual differences in memory performance for emotional and neutral material.

It is widely accepted that people differ in memory performance. The ability to control one's memory depends on multiple factors, including the emotional properties of the memorized material. While it was widely demonstrated that emotion can facilitate memory, it is unclear how emotion modifies our ability to suppress memory. One of the reasons for the lack of consensus among researchers is that individual differences in memory performance were largely neglected in previous studies. We used the directed forgetting paradigm in an fMRI study, in which subjects viewed neutral and emotional words, which they were instructed to remember or to forget. Subsequently, subjects' memory of these words was tested. Finally, they assessed the words on scales of valence, arousal, sadness and fear. We found that memory performance depended on instruction as reflected in the engagement of the lateral prefrontal cortex (lateral PFC), irrespective of emotional properties of words. While the lateral PFC engagement did not differ between neutral and emotional conditions, it correlated with behavioural performance when emotional - as opposed to neutral - words were presented. A deeper understanding of the underlying brain mechanisms is likely to require a study of individual differences in cognitive abilities to suppress memory.

European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations (ECARUCA); an online database for rare chromosome abnormalities.

During recent years a considerable improvement in diagnostic techniques has enabled cytogeneticists to find more and smaller chromosomal aberrations. However, accurate clinical knowledge about rare chromosome disorders is frequently lacking, mostly due to a significant decline in publishable cases. On the other hand, there is an increasing demand from parents and physicians for reliable information. In order to improve the quality and the quantity of data available, we designed a new database named the European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations (ECARUCA) at http://www.ecaruca.net. This Internet-database contains cytogenetic and clinical data of patients with rare chromosome abnormalities, including microscopically visible aberrations, as well as microdeletions and -duplications. Cases with certain breakpoints collected in the Zurich Cytogenetic Database were transferred to ECARUCA. The advantages of ECARUCA compared to existing sources are that ECARUCA is interactive, dynamic and has long-term possibilities to store cytogenetic, molecular and clinical data. Professionals can login to submit new cases and perform searches in the database through the Internet. Currently the database contains 1500 unique chromosomal aberrations from almost 4000 patients. A frequent submission of new data ensures the up-to-date quality of the collection. Individual parent accounts allow parents to inform the ECARUCA team about the follow-up of their child. The ECARUCA database provides health care workers with accurate information on clinical aspects of rare chromosome disorders. Additionally, detailed correlations between chromosome aberrations and their phenotypes are of invaluable help in localising genes for mental retardation and congenital anomalies.

Unbalanced 18q/21q translocation in a patient previously reported as monosomy 21.

We describe a patient in whom full monosomy 21 was initially assumed from routine GTG-banded karyotyping. Re-examination with chromosome painting demonstrated an unbalanced translocation between the long arms of chromosomes 18 and 21. Fluorescence in situ hybridisation (FISH) and microsatellite marker analysis revealed partial monosomy of chromosome 21 (pter-q21) and 18(q22-qter). The patient, 18 years old at the second examination, revealed multiple dysmorphic features, genital hypoplasia, dilated cerebral ventricles, muscular hypotonia and severe mental retardation. In not one out of all patients investigated postnatally in whom an initial examination had revealed monosomy 21, this could be confirmed by FISH; in all of them, re-examination detected an unbalanced rearrangement leading to only partial monosomy 21 plus partial monosomy of another chromosome to which the distal 21q segment was attached. Thus, it is still highly likely that full monosomy 21 is incompatible with intra-uterine survival.

Non-random asynchronous replication at 22q11.2 favours unequal meiotic crossovers leading to the human 22q11.2 deletion.

BACKGROUND: Analyses of the replication timing at 22q11.2 were prompted by our finding of a statistically significant bias in the origin of the regions flanking the deletion site in patients with 22q11.2 deletions, the proximal region being in the majority of cases of grandmaternal origin. We hypothesised that asynchronous replication may be involved in the formation of the 22q11.2 deletion, the most frequently occurring interstitial deletion in humans, by favouring the mispairing of low-copy repeats. METHODS: Replication timing during S phase at 22q11.2 was investigated by fluorescent in situ hybridisation on interphase nuclei. We report on the detection of non-random asynchronous replication at the human chromosome region 22q11.2, an autosomal locus believed not to contain imprinted genes. RESULTS: Asynchronous replication at 22q11.2 was observed without exception in all 20 tested individuals; these comprised individuals with structurally normal chromosomes 22 (10 cases), individuals with translocations involving the locus 22q11.2 (eight cases), and patients with a 22q11.2 deletion (two cases). The non-random nature of the asynchronous replication was observed in all individuals for whom the chromosomes 22 were distinguishable. The earlier replicating allele was found to be of paternal origin in all cases where the parental origin of the translocation or deletion was known.

Aqueous humor pilocarpine and timolol levels after instillation of the single drug or in combination.

Aqueous humor levels of pilocarpine and timolol in rabbits after administration of either 2% pilocarpine or 0.5% timolol in single-drug solutions were compared with the concentrations found after instillation of a fixed combination of 0.5% timolol and 2% pilocarpine drops. Time intervals considered were 15 min, 30 min, 1 hr, 4 hr, and 8 hr after application. Drug concentrations were analyzed in individual aqueous samples by high-performance liquid chromatography. No statistically significant differences in either pilocarpine or timolol concentrations in aqueous humor were found at any time tested between the single-drug preparations and the combination.

Distal deletion, del(2)(q33.3q33.3), in a patient with severe growth deficiency and minor anomalies.

We report on an 18-month-old boy with a 2q33.3 deletion. The clinical findings observed in the propositus included minor anomalies of face and distal limbs, intrauterine and postnatal growth retardation, microcephaly and, so far, moderate developmental delay. Conventional GTG banded chromosome analysis indicated a small deletion in distal 2q. Subsequent analysis by fluorescent in situ hybridization (FISH) using different probes allowed us to narrow down the deletion to most or all of segment 2q33.3. This case shows the importance of the application of different YAC probes for a precise determination of breakpoints in small interstitial deletions.

Short stature, myopia, severe developmental delay, and peculiar facial appearance in two brothers: a new syndrome?

We report on 2 brothers with short stature, microcephaly, myopia, retarded osseous maturation, severe developmental delay, and minor anomalies including temporal narrowing, periorbital fullness, full cheeks in infancy, and protruding lower lip. Both brothers and their parents had normal chromosomes. Fluorescence in situ hybridization with probes from all (sub-)telomeric chromosomal regions excluded a structural rearrangement involving telomeric segments. Because the pattern of congenital abnormalities is not like that of any well-known multiple congenital anomaly/mental retardation syndrome, we suggest a previously undescribed syndrome of autosomal recessive or X-linked inheritance.

Terminal deletion, del(1)(p36.3), detected through screening for terminal deletions in patients with unclassified malformation syndromes.

We report on a 4 year-old girl with a 1p36.3-pter deletion. Clinical findings included minor anomalies of face and distal limbs, patent ductus arteriosus, the Ebstein heart anomaly, and brain atrophy with seizures. Conventional GTG-banded chromosome analysis revealed a normal (46,XX) result. Subsequent analysis by fluorescent in situ hybridization (FISH) using distal probes demonstrated a deletion of 1p36.6-pter. Molecular investigations with microsatellite markers showed hemizygosity at three loci at 1p36.3 with loss of the paternal allele. The deletion of 1p36.3 is difficult to identify by banding alone; indeed, our patient represents the third reported case with a del(1)(p36.3) that was detected only after more detailed analysis. In all three cases the deletion was detected through screening of patients with multiple congenital anomalies/mental retardation syndromes suggestive of autosomal chromosome aberrations for subtelomeric submicroscopic deletions by means of FISH or microsatellite marker analysis. On the basis of these observations we highly recommend that FISH with a subtelomeric 1p probe be routinely performed in patients with similar facial phenotype, severe mental retardation and seizures, and a heart malformation, particularly the Ebstein anomaly.

Epilepsy and trisomy 19q--different seizure patterns in a brother and a sister.

In symptomatic epilepsies due to chromosomal aberrations, epileptogenesis may be either the direct consequence of deletion or duplication of a gene causing seizures or may have a more complex etiology caused by the disturbance of the interaction of several genes and environmental factors. We report on a brother and a sister with trisomy 19q13.3-->qter who present different epileptologic features and discuss epileptogenesis in this syndrome with respect to genes known to be located on the distal part of chromosome 19q. Both patients share mental retardation and several dysmorphic features. The boy was hypoxic at birth and showed an extremely delayed psychomotor development. The girl, however, had no significant neonatal problems, and her psychomotor development was better. Although the male had an abnormal EEG in childhood, his first partial seizures occurred only as late as at age 31 years. He subsequently became seizure-free with carbamazepine (CBZ). In contrast, the girl already suffered from absence-like seizures during childhood and became seizure-free under ethosuccimide (ESM). A photoparoxysmal response, however, is still visible in her EEG. The difference between the epileptologic features in these siblings points to epileptogenic mechanisms placed far downstream on the way from genotype to phenotype. The photoparoxysmal response--otherwise a facultative finding in genetically determined epilepsies--in the EEG of the sister, however, points to a closer relationship between the duplicated genes and epileptogenesis. The fact that genes encoding potassium channels are located on 19q13.3-q13.4 may also support the latter assumption.

Effect of nasolacrimal occlusion on timolol concentrations in the aqueous humor of the human eye.

We studied the effect of manual nasolacrimal occlusion on the concentration of timolol in the aqueous humor of eyes of patients undergoing cataract extraction. Aqueous humor samples were obtained at various times after timolol maleate instillation from patients with or without 5 min of nasolacrimal occlusion; aliquots were assayed by HPLC. In patients receiving occlusion treatment, average timolol concentrations were statistically greater than those in control patients both between 15 and 90 min after instillation and also at 180 min. Pharmacokinetic analysis indicated that occlusion increased the concentration of timolol in the aqueous humor 1.7 times. In both groups, timolol concentrations were highest approximately 1 h after instillation. The decline in aqueous humor timolol concentrations occurred at similar rates in both groups.

Clastogenic effect of cisplatin on Wistar rat bone marrow cells.

The clastogenic effect of the drug cis-diamminedichloroplatinum II (cisplatin, CDDP) was investigated in Wistar rat bone marrow cells. Male rats, 3 per treatment time, aged 4 months and weighing 250-350 g were injected intraperitoneally with 6.0 mg/kg CDDP solution, and the control group received isotonic saline. The animals were sacrificed 6, 12, 18, 24 and 48 h after the injection. The chromosome preparation was obtained from bone marrow cells. Chromatid and chromosome aberrations were investigated in 300 metaphases per animal. A significant increase in number of chromosome aberrations was observed from 6 to 24 h, the majority being of the break and gap type. After 48 h a progressive reduction was observed, without differences from the negative control. These data confirm the mutagenic effect of CDDP in rats demonstrated for mice bone marrow by micronuclei assay, for murine ovary cells and mice spermatocytes.

Two sibs with duplication of 4q31-->qter due to 3:1 meiotic disjunction and mild phenotype.

Two sibs with duplication of 4q31-->qter due to 3:1 meiotic disjunction and mild phenotype: Clinical and cytogenetic findings in two sibs with partial duplication of 4q31.3-->qter and 21q11.2-->pter are reported. These patients are rare cases of reoccurrence of those partial trisomies due to 3:1 segregation of a maternal balanced translocation. A review of the literature reporting cases of trisomy of the 4q31-->qter segment is also made; previously reported cases mostly in addition have deletions of other chromosomes resulting from adjacent segregation of balanced translocation. The findings of our study confirm the high risk for offspring with unbalanced rearrangements in women with reciprocal translocation involving acrocentric and short chromosome segments. The study also points out that duplication of 4q31-->qter may go along with only mild phenotypic findings if there is no significant additional aneuploidy of the other chromosome involved in the rearrangement.

De novo unbalanced t(11q;21q) leading to a partial monosomy 21pter-q22.2 and 11q24-qter in a patient initially diagnosed as monosomy 21.

We describe a patient in whom full monosomy 21 was initially assumed from routine GTG banded karyotyping. Re-examination with chromosome painting demonstrated an unbalanced translocation between the long arms of chromosomes 11 and 21. Fluorescence in situ hybridization (FISH) and microsatellite marker analysis revealed partial monosomy of chromosome 21 (pter-q22.2) and 11 (q24-qter). The patient was prematurely born in the 31st week of gestation and expired 3 days after delivery. She showed multiple minor anomalies, a complex cardio-vascular malformation, intestinal malrotation and cerebellar hypoplasia.

De novo complex chromosome rearrangement: a study of two patients.

Complex chromosome rearrangements (CCR) involving multiple breaks in two or more chromosomes are rare. We describe a girl with development delay and overgrowth who presents a nine-break apparently balanced de novo rearrangement involving chromosomes 1, 2, 3, 4 and 12, and a boy with developmental delay and seizures with a complex three-chromosome apparently balanced de novo rearrangement involving chromosomes 2, 7 and 13. The relationship between clinical abnormalities and apparently balanced rearrangements is discussed.

Marfan's syndrome and surgical repair of ascending aortic aneurysms.

Marfan's syndrome is an inherited, degenerative connective tissue disorder that affects many body systems (eg, skeletal, ocular, cardiovascular, cutaneous, pulmonary, abdominal, neurologic). The cause of Marfan's syndrome is unknown, but recent genetic studies have linked this disorder to chromosome 15q15-q21.3. The characteristics associated with Marfan's syndrome require a multidisciplinary approach to patient care. This article discusses one serious complication of Marfan's syndrome-aortic root dilatation- and composite graft repairs of ascending aortic aneurysms. Physicians and nurses must be more aware of Marfan's syndrome so that life-threatening medical conditions can be evaluated and followed by health care providers.