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The results of the recent European collaborative prenatal study suggested a segregation distortion of balanced pericentric inversions from carrier fathers but not carrier mothers (Boue & Gallano 1984). In an attempt to confirm these unexpected results, we examined 216 pedigrees with balanced pericentric inversions collected from three centers and from the literature. We were unable to detect any significant deviation from the expected 1:1 segregation of balanced pericentric inversions to normal karyotypes among the offspring of either carrier parent. To clarify the discrepancy between the studies, we reanalyzed the data from the prenatal study using all karyotyped individuals and, assuming conventional ascertainment rules, found a normal segregation pattern. We conclude that balanced pericentric inversions segregate normally in both males and females and that some retrospectively selected pedigrees were included as prospective in the prenatal study and this misclassification caused the apparent segregation distortion from carrier fathers.

The presence of maternal cells in fetal samples constitutes a serious potential source for prenatal misdiagnosis. Here we present our approach for detecting maternal cell contamination (MCC) at prenatal diagnosis for eight monogenic disorders (autosomal recessive: beta-thalassaemia, sickle-cell anaemia, cystic fibrosis, prelingual deafness; autosomal dominant: achondroplasia, Huntington disease, myotonic dystrophy, neurofibromatosis type I; X-linked: spinobulbar muscular atrophy). Our aim was to apply a simple and low-cost approach, which would easily and accurately provide information on the fetal tissue MCC status. MCC testing was applied to cases of recessive inheritance where the primary mutation screening of the fetus revealed the presence of the maternal mutation, to cases concerning dominant inheritance and to cases of multiple gestation. The potential presence of maternal cells was determined by the amplification of the 3'-HVR/APO B, D1S80, THO1 and VNTRI of vWf polymorphic loci, which have previously demonstrated high heterozygosity in Caucasians. Among 135 prenatal diagnoses, 44 finally needed to be tested for MCC (32.6%). MCC was detected in four cases, where DNA was isolated directly from chorionic villi samples (CVS), and in one case with DNA isolated directly from amniotic fluid (AF). In almost 90% of cases a simple test of one polymorphic locus provided sufficient information about MCC. The choice of the appropriate locus is therefore essential, while the simultaneous screening of both parents provides the means for distinguishing non-informative sites about MCC.

Eight substances (histamine, compound 48/80, kallikrein, trypsin, papain, substance P, serotonin and platelet activating factor) were injected intradermally (volume 50 microl) into the rostral back (neck) of rats in order to establish an animal model for peripherally elicited pruritus. While serotonin induced excessive scratching at the site of injection, the other substances were weak or inactive. The dose-response relationship of serotonin was sigmoid, EC50=2.1 mg/ml (95% confidence interval: 1.0 to 4.3 mg/ml). Injections of serotonin 1 mg/ml into the caudal back elicited no scratching at all, i.e. neither at the site of injection nor elsewhere, so the experiment indicated no systemic effect of serotonin 1 mg/ml intradermally. Scratching was probably elicited histamine-independently, since histamine itself did not elicit scratching. The intra- and inter-observer variations were 3-4%. We conclude that serotonin is a reproducible local pruritogen eliciting scratching in the rat. The model may be useful in research and development of topical antipruritics of the nonhistaminic type as well as for various other purposes in pruritus research.

The present study involved a laboratory scale experiment where the impact of post-harvest storage on the quality of sour cherries (Prunus cerasus L.) cv Stevnsbaer was investigated. Cherries were stored for 7 days at temperatures of 2 °C, 10 °C, 20 °C, and 30 °C, and at 20 °C in combination with a 20% CO2 atmosphere. Cherry quality was assessed by analysis of soluble solids, titrateable acids, anthocyanins and aroma compounds. The content of soluble solids of cherries decreased at storage temperatures above 10 °C. The anthocyanin content of cherries decreased during storage at all temperatures. A decrease, followed by an increase, in titrateable acid was observed for all temperatures except 2 °C. Aroma components were also affected by storage time and temperature. The level of benzaldehyde decreased during storage at higher temperatures, while those of eugenol and vanillin increased at all temperatures. The levels of "off" odour compounds, like acetic acid and fermentation alcohols, increased at higher temperatures during storage. The CO2-enriched atmosphere (20% CO2) did not affect the different quality factors significantly.

We studied the results for 168 available hips from a series of 324 consecutive primary total hip arthroplasties that had been performed with insertion of a Harris-Galante-I acetabular component without cement. The acetabulum had been reamed in a so-called line-to-line manner, and the cup had been fixed with one to four screws. A femoral component with a modular alumina-ceramic head had been inserted with cement in all hips. The median duration of follow-up was 112 months (range, 101 to 131 months). Of the original 324 hips, 109 could not be included in the clinical and radiographic follow-up because the patients had died and thirty could not be included because the patients were not available for examination. Seventeen hips had had a revision of the acetabular cup: five, because of infection; five, because of dislocation; three, because of aseptic loosening; and four, because of technical failure. This left 168 hips for clinical and radiographic follow-up; of these, fifteen had had a revision of the femoral component only. Of the remaining 153 hips, which had not had a revision, 147 (96 percent) were considered by the patient to have a satisfactory, good, or excellent result. One hip was found to have a loose cup on radiographic evaluation and was therefore considered to have failed, but the clinical function was good. We concluded that, with an overall rate of aseptic loosening of 1 percent (four of 324) after an intermediate (ten-year) duration of follow-up, use of this cup has good results.

Objective To evaluate hereditary and acquired hemostatic abnormalities associated with recurrent spontaneous early (first-trimester) abortions.Method A group of 56 Greek women with two or more unexplained primary spontaneous abortions, and a reference group of 148 women without a history of recurrent abortions, were screened for hypercoagulability. A randomly selected population of first-trimester pregnant women was also chosen for factor V Leiden genetic screening.Results A total of 21% of the women with recurrent abortions, compared with 12% of the reference group, showed increased activated protein C resistance. Fourteen per cent had positive lupus anticoagulant, compared with 11.5% of the reference group. For the rest of the parameters, there was no difference between the two groups. Of 22 women studied for factor V Leiden, one was homozygous and one was heterozygous. Results were compared using Fisher' exact test and two-tailed Student' t tests.Conclusions Increased activated protein C resistance app...

13q-syndrome is a rare chromosomal disorder caused by partial deletion of the long arm of chromosome 13 with variable phenotypic presentation. Further sonographic features involve fetal growth restriction, bradycardia, encephalocele, facial dysmorphism and upper extremity deformity. We report a case of 13q-syndrome presenting as increased nuchal translucency diagnosed by chromosome studies and confirmed by array comparative genomic hybridization (CGH) analysis in the first trimester of pregnancy. Pregnancy was terminated at 14 weeks' gestation. The parents did not give consent for a postmortem examination. Furthermore we performed a systematic review of the international literature on previous cases of 13q-syndrome diagnosed prenatally. Our case emphasizes the importance of a detailed 11-14 week ultrasound assessment in diagnosing fetal chromosomal aberrations in combination with the modern aspects of array CGH, thus providing more precise and rapid prenatal diagnosis.

Most work dealing with the impact of species-rich herbage on milk fatty acid content has hitherto been carried out in alpine areas or semi-natural grasslands. The main objective of the present study was to examine the effect of herbs sown and intensively managed in a lowland sward on the concentration of n−3 and n−6 fatty acids and vitamins in cows' milk compared to clover grass and total mixed ration (TMR) feeding. Twelve cows were housed in tie-stall and randomly allocated to three diets fed ad libitum for 14 days: HERBS (mixture of fresh herbs); CLOVER (mixture of fresh white clover and ryegrass); or TMR (total mixed ration based on silage and concentrate). n−3 fatty acid (FA) content was similar between the three diets, while n−6 FA content was highest in the TMR diet. A twofold increase in n−3 FA concentration in milk was observed when feeding HERBS compared to CLOVER and TMR (0.8, 0.4 and 0.3 g/kg milk, respectively). n−6 FA concentration increased as well when feeding HERBS (1.4, 0.9 and 1.0 g/kg milk for HERBS, CLOVER and TMR, respectively). Transfer efficiency from feed to milk was doubled for n−3 FA when feeding HERBS and for transfer efficiency of n−6 FA from feed to milk an increase of 28% was observed for HERBS compared to CLOVER. Retinol content was highest in HERBS milk, while there was no difference in α-tocopherol and s-carotene milk content between the three diets. The results thus support previous findings on the effect of herbs on the milk fatty acid profile, but it will require further research to understand the effect of herbs on n−3 and n−6 FA concentration in milk. In conclusion, milk content of polyunsaturated fatty acids (PUFA), like n−3 and n−6 FA, was significantly increased when herbs constituted the major part of the herbage, despite lower or similar dietary content of n−3 and n−6 FA in herbs compared to clover grass- and TMR diets.

Non-syndromic deafness is a paradigm of genetic heterogeneity with 85 loci and 39 nuclear disease genes reported so far. Autosomal-recessive genes are responsible for about 80% of the cases of hereditary non-syndromic deafness of pre-lingual onset with 23 different genes identified to date. In the present article, we review these 23 genes, their function, and their contribution to genetic deafness in different populations. The wide range of functions of these DFNB genes reflects the heterogeneity of the genes involved in hearing and hearing loss. Several of these genes are involved in both recessive and dominant deafness, or in both non-syndromic and syndromic deafness. Mutations in the GJB2 gene encoding connexin 26 are responsible for as much as 50% of pre-lingual, recessive deafness. By contrast, mutations in most of the other DFNB genes have so far been detected in only a small number of families, and their contribution to deafness on a population scale might therefore be limited. Identification of all genes involved in hereditary hearing loss will help in our understanding of the basic mechanisms underlying normal hearing, in early diagnosis and therapy.

Displaced femoral neck fractures are known to be associated with high rates of mortality. The purpose of the present study is to investigate pre- and postoperative factors which influence this mortality in a series of 1186 consecutive Danish patients presenting to one hospital's orthopaedic department with Garden type 3-4 fractures. Subsequent mortality data was obtained from the state population register (224 were still alive). The stepwise Cox proportional hazards model was used for multivariate analysis in order to obtain the predictors of postoperative mortality. The median survival of male subjects fell from 5.2 years in an age-matched control population to 1.6 years in the patients. In women survival time fell from 6.6 to 2.8 years. Almost all excess mortality occurred during the first 3 months following hemiarthroplasty. In order of significance, key factors negatively influencing mortality at 3 months were: cardiac complications, dementia, male sex, age, waiting time before operation, stroke and dislocation of the prosthesis and perioperative fracture. Of these, waiting time for surgery and dislocation of the prosthesis could be modified. A number of other studies have confirmed the importance of optimising these factors.

The GLC1C locus for primary open-angle glaucoma (POAG) is inherited as an autosomal dominant trait. This region on chromosome 3 is 11 cM long. DNA samples from members of a Greek and an American GLC1C family were obtained to determine whether additional typing of microsatellite markers in family members might narrow the region. GLC1C family members were evaluated clinically for POAG on the basis of open angles, intraocular pressures, cupping of discs, and visual fields. DNA samples from the Greek and Oregon GLC1C families were used to further refine the GLC1C region using microsatellite markers. A total of 22 affected members were identified in the two families. Common alleles for D3S3637 and D3S3612 were present in the disease haplotype from both families, suggesting that they may have a common founder. A newly diagnosed patient in the American family had a recombination in the distal portion of the GLC1C haplotype. This recombination narrows the GLC1C region from 11 to 4 cM.

The present study describes the audiological profile of genetic hearing loss resulting from GJB2 mutations in northern Greece, as this represents the most frequent single cause of childhood sensorineural hearing loss. The 35delG mutation in homozygosity was detected in 27 of 107 patients (25.2%). The audiological profile is that of a profound or severe sensorineural hearing loss, with a sloping or flat configuration of the audiogram, mostly symmetrical, non-progressive and affecting more the higher frequencies. This profile underlines the importance of early identification and genetic family counseling leading to the future possibility of prevention of deafness. Eur Arch Otorhinolaryngol

Mutations in the gene encoding the gap-junction protein connexin 26 (GJB2) on chromosome 13q11 have been shown as a major contributor to prelingual, sensorineural, nonsyndromic deafness. One specific mutation, 35delG, has accounted for the majority of the mutations detected in the GJB2 gene in Caucasian populations and is one of the most frequent disease mutations identified so far with highest carrier frequency of 3,5% in the Greek population. In a collaboration with the major referral centers for childhood deafness in Greece, patients were examined by an extensive questionnaire to exclude syndromic forms and environmental causes of deafness and by allele-specific PCR for the detection of the 35delG mutation. The 35delG mutation was found in 32.1% of the alleles in 173 unrelated cases of prelingual deafness: 50 homozygotes and 11 heterozygotes. Individuals heterozygous for the 35delG mutation were further analyzed by direct genomic sequencing of the coding region of the GJB2 gene, which revealed R184P and 486insT mutations in single alleles. We conclude that the 35delG GJB2 mutation is responsible for one third of prelingual, sensorineural deafness in Greece, which is higher than the usually quoted 20% for Caucasian populations.

Non-syndromic deafness is a paradigm of genetic heterogeneity. More than 70 loci have been mapped, and 25 of the nuclear genes responsible for non-syndromic deafness have been identified. Autosomal-dominant genes are responsible for about 20% of the cases of hereditary non-syndromic deafness, with 16 different genes identified to date. In the present article we review these 16 genes, their function and their contribution to deafness in different populations. The complexity is underlined by the fact that several of the genes are involved in both dominant and recessive non-syndromic deafness or in both non-syndromic and syndromic deafness. Mutations in eight of the genes have so far been detected in only single dominant deafness families, and their contribution to deafness on a population base might therefore be limited, or is currently unknown. Identification of all genes involved in hereditary hearing loss will help in the understanding of the basic mechanisms underlying normal hearing, will facilitate early diagnosis and intervention and might offer opportunities for rational therapy.

OBJECTIVES—To investigate a reported cluster of Down's syndrome in offspring of former pupils of a girls' school in Ireland, to establish the prevalence of Down's syndrome among live births in the area around the school, and to review the literature on the possible causes of reported clusters of Down's syndrome. METHODS—Questionnaire survey of obstetric and personal histories of women who had attended the girls' school at Dundalk, County Louth, Republic of Ireland, at some time during 1956-7, and also of women who had attended another, nearby, girls' school during the same period. Comparison of observed numbers of cases of Down's syndrome identified by these surveys with maternal age adjusted expected numbers for the reported live births. Laboratory tests were conducted to verify and characterise the cases of Down's syndrome constituting the cluster. Retrospective collection and collation of data on Down's syndrome occurring among live births, and the compilation of maternal age specific incidences, in County Louth and in Newry and Mourne District in neighbouring Northern Ireland, during 1961-80. These rates were compared with reference rates and rates for other areas of Ireland. RESULTS—Six children with Down's syndrome were confirmed among 387 reported live births to women who had been pupils at the girls' school in Dundalk during 1956-7, compared with 0.69 expected (nominal p

We report a case of Angelman syndrome (AS) with paternal uniparental disomy (pUPD) of chromosome 15. This 6-year-old girl with overgrowth had frequent, but only provoked laughter, was mildly ataxic with limb hypertonia, and had no intelligible speech. She had deep-set eyes, protruding tongue, and prominent chin. The karyotype was normal. DNA analysis with microsatellites from chromosome 15 showed no inheritance of maternal alleles both within and outside the AS critical region. Proximal markers showed reduction to homozygosity of paternal alleles, intermediate markers showed nonreduction, and distal markers reduction, thus suggesting a meiosis II nondisjunction event in the father with two crossovers. This is, to our knowledge, the first reported case of AS due to meiosis II nondisjunction. We present detailed physical measurements in this patient, adding to the clinical description of the milder phenotype in AS due to pUPD.

The pathogenesis of venous thrombosis involves the interaction of genetic and environmental factors. In order to estimate the frequency of the factor V Leiden, the prothrombin G20210A, and the MTHFR C677T mutations in the Greek population, we analyzed 160 healthy Greek blood donors by PCR amplification and detected allele frequencies of 2.5%, 2.2%, and 35.3%, respectively. The allele frequencies were compared with reported frequencies of other populations of southern Europe. The identification of these common genetic risk factors for thrombosis should enable easy DNA diagnosis and carrier detection in a high proportion of cases and will contribute to a better understanding of the interaction of genetic and environmental risk factors.

In homozygous beta-thalassemia, the organ damage is mainly attributed to excessive iron deposition through the formation of oxygen free radicals. Despite appropriate transfusion and chelation therapy and low ferritin levels, patients still develop organ failure, heart failure being the main cause of death. This study was designed to determine whether the decreased antioxidant activity of the apolipoprotein E (APOE) 4 allele could represent a genetic risk factor for the development of left ventricular failure (LVF) in beta-thalassemia homozygotes. A total of 251 Greek beta-thalassemia homozygotes were studied. Patients were divided in three groups: group A (n = 151) with no cardiac impairment, group C (n = 47) with LVF, and 53 patients with LV dilatation and normal LV systolic function constituted the group B. DNA was obtained from all patients, and the polymerase chain reaction was used to analyze the polymorphism at the APOE locus. The APOE allele frequencies were compared with those of a Greek control sample of 216 healthy blood donors. Patients with no cardiac impairment had an APOE 4 allele frequency (7.9%) not different from population controls (6.5%, P.05), while patients with LVF had a significantly higher frequency of APOE 4 (12.8%) than the controls (P.05, odds ratio = 2.11, 95% confidence interval 1.03 to 4.32). The APOE 4 allele may represent an important genetic risk factor for the development of organ damage in homozygous beta-thalassemia.

This is a retrospective clinical evaluation of 1028 primary hip arthroplasties performed with the non-cemented Harris-Galante I acetabulaer cup. Hospital records regarding all hips operated from July 1985 through March 1992 were evaluated after a median of 48 (12-93) months. Furthermore, questionnaires were sent out to all patients still alive in order to establish the actual function of the hips. At time of evaluation, 43 of the 1028 primary acetabular cups (4.2%) had been or were due to be revised. (20 because of one or more episodes of dislocation or displacement of the cup, 10 due to deep infection, eight following aseptic loosening of the cup, two because of implant failure and three due to other reasons). Four hundred and twenty-six hips were without pain, 274 had only mild or slight pain, whereas 84 experienced moderate or worse pain. We conclude, that the results after non-cemented hemispheric acetabular arthroplasties in this study are satisfying with a low rate of aseptic loosening.

This study evaluates 376 total hip arthroplasties performed between 1978 and 1983 using 276 Müller long-stem and 100 Müller curved-stem prostheses. Demographic and clinical data were obtained from patient records. All patients still alive who did not undergo revision arthroplasty were sent a detailed questionnaire. Results indicated that long-term survival of the femoral component of the arthroplasty was significantly better when the Müller long-stem was used. Furthermore, there was no difference in the clinical out-come between patients who underwent revision and those who did not. To eliminate demographic differences between the two groups, 77 patients from each group were paired. There was no difference in clinical results of the hips between the paired groups, and long-term survival of the Müller long-stem was still significantly better using Kaplan-Meier analysis.

Mutations at FRAXA and FRAXE loci are due to expansions of a CGG trinucleotide repeat and are characterized by mental retardation. Here we report a pilot screening survey by means of cytogenetic and molecular methods of 433 unrelated retarded individuals and their parents of Hellenic origin coming from various parts of Greece and Cyprus. The purpose of the study was to estimate the frequency of FRAXA mutation in individuals with nonspecific mental retardation without family history and phenotypic stigmata in the Hellenic population. Five FRAXA-positive children (1.15%) were identified, of whom four were found to carry a full mutation and one a premutation. Furthermore we present preliminary data on a screening of FRAXE mutation frequency. We screened 257 male patients with nonspecific mental retardation, finding none positive for FRAXE mutation.

Partial trisomy 17q22-qter is a rare but well-recognized clinical entity. We present a case of partial trisomy for the long arm of chromosome 17, which was detected in a female infant with severe psychomotor and somatic retardation, Stargardt disease, short limbs, and numerous minor anomalies. Differential chromosomal staining demonstrated an excess of genetic material on the long arm of the late replicating X chromosome. FISH and DNA polymorphism analysis showed that the extra material belonged to the distal part of the long arm of chromosome 17 and that there was a partial monosomy of the distal part of the long arm of the derivative X chromosome. The breakpoint regions of this translocation were identified by molecular analysis using polymorphic microsatellite markers on human chromosomes 17 and X. The origin of the abnormal X chromosome was found to be paternal, whereas the origin of the duplicated part of chromosome 17 was maternal. The unbalanced translocation between the paternal X and the maternal chromosome 17 is, therefore, suggested to be due to a postzygotic error.

In this report, we present MIC, bactericidal activity, postantibiotic effect (PAE), and in vivo infectivity data for postantibiotic-phase pneumococci. We compared and evaluated penicillin G and six macrolides, erythromycin, azithromycin, clarithromycin, dirithromycin, roxithromycin, and spiramycin, against 10 strains of pneumococci with various levels of susceptibility to penicillin. All of the agents, except azithromycin, exhibited a bactericidal effect (a > or = 3 log10 decrease in the number of CFU per milliliter) after 4 h of exposure to a concentration equal to 10 times the MIC, displaying the following hierarchy: spiramycin = penicillin G = erythromycin = dirithromycin = clarithromycin = roxithromycin > azithromycin. The bactericidal rate of penicillin G was significantly lower for resistant strains (MIC, > or = 2 microg/ml), while bactericidal rates of macrolides were unaffected by penicillin susceptibility. A PAE was induced in all of the strains by all of the antibiotics after exposure for 1 h to a concentration equivalent to 10 times the MIC. The mean duration of PAEs varied between 2.3 and 3.9 h, showing the following hierarchy: spiramycin = dirithromycin = clarithromycin = erythromycin = roxithromycin > azithromycin > penicillin G. Virulence studies were performed with immunocompetent mice by intraperitoneal inoculation of virulent, penicillin-susceptible serotype 3 pneumococci which had been pre-exposed to penicillin G or a macrolide for 1 h. A significant decrease in the virulence of postantibiotic-phase pneumococci was induced only by erythromycin, azithromycin, dirithromycin, and spiramycin, displaying 5.9-, 7.1-, 4.2-, and 3.6-fold increases in the 50% lethal dose (LD50) compared to a control suspension, respectively. No significant correlation could be demonstrated between the LD50 and the MIC, bactericidal activity, or PAE duration. These results suggest that antimicrobial interaction with host defenses in terms of virulence might be a significant parameter that could influence the drug or drug regimen of choice.

A collection of 99 clinical isolates of Streptococcus pneumoniae, chosen due to their different susceptibilities to penicillin, were investigated with respect to their susceptibility to the macrolides azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, spiramycin, and to clindamycin and tetracycline by the agar dilution method. We found complete cross resistance among the macrolides. The pneumococci were either susceptible, MICor = 0.5 micrograms/ml, or resistant, MICor = 16 micrograms/ml, to the tested macrolides, giving a bimodal distribution. In addition, complete cross resistance was observed between clindamycin and macrolides. Pneumococci resistant to macrolides were also resistant to tetracycline, and 26% of the macrolide-susceptible strains were tetracycline resistant.

Characteristics are hypotonia, problems with feeding and thriving in the neonate and infant, later hyperphagia and severe obesity. Other findings are dysmorphic traits, hypogonadism, short stature, developmental delay, mental retardation and behavioural problems. Diabetes mellitus (NIDDM) is frequent in adults. Treatment is symptomatic. Prognosis is determined by obesity. PWS occurs almost always sporadically and is found in all ethnic groups and in both sexes. The epidemiology of PWS in Denmark is unknown. In 95% of cases with PWS cytogenetic and molecular genetic investigations show either deletion of the paternal chromosome 15q11q13 or uniparental maternal disomy of chromosome 15. Since 1992 150 bloodsamples of patients suspected for PWS have been investigated by cytogenetic and molecular genetic techniques at the John F. Kennedy Institute, DK-2600 Glostrup; deletion of the paternal chromosome 15 was found in 15 and uniparental maternal disomy of chromosome 15 in eight cases.

Foetal blood sampling was performed at 35 weeks of gestation due to abnormal foetal ultrasound findings. There was apparent monosomy 21 (45,XX,-21) in all mitoses analyzed. The infant died at 37 weeks during delivery. Examination disclosed facial anomalies, clubfeet, hypoplasia of the left urogenital tract, agenesis of corpus callosum, ventricular dilatation, and heterotopias. Reevaluation of the karyotype showed an unbalanced translocation t(1;21) (q44;q22.11) which resulted from a maternal balanced translocation. These findings were confirmed by fluorescence in situ hybridization and molecular studies with chromosome 21 specific markers. The latter showed a proximal deletion of the maternally derived chromosome 21 including all loci from centromere down to the D21S210 locus. This case illustrates the need for complementary cytogenetic and molecular investigations in cases of apparent monosomy 21.

We studied the mechanism of ring chromosome 21 (r(21)) formation in 13 patients (11 unique r(21)s), consisting of 7 from five families with familial r(21) and 6 with de novo r(21). The copy number of chromosome 21 sequences in the rings of these patients was determined by quantitative dosage analyses for 13 loci on 21q. Nine of 11 r(21)s, including the 5 familial r(21)s, showed no evidence for duplication of 21q sequences but did show molecular evidence of partial deletion of 21q. These data were consistent with the breakage and reunion of short- and long-arm regions to form the r(21), resulting in deletion of varying amounts of 21q22.1 to 21qter. The data from one individual who had a Down syndrome phenotype were consistent with asymmetric breakage and reunion of 21q sequences from an intermediate isochromosome or Robertsonian translocation chromosome as reported by Wong et al. Another patient, who also exhibited Down syndrome, showed evidence of a third mechanism of ring formation. The likely initial event was breakage and reunion of the short and long arms, resulting in a small r(21), followed by a sister-chromatid exchange resulting in a double-sized and symmetrically dicentric r(21). The phenotype of patients correlated well with the extent of deletion or duplication of chromosome 21 sequences. These data demonstrate three mechanisms of r(21) formation and show that the phenotype of r(21) patients varies with the extent of chromosome 21 monosomy or trisomy.

Abstract #6072 Background: Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) is a naturally occuring proteinase inhibitor, which inhibits most matrix metalloproteinases. It has previously been reported that high levels of tumor TIMP-1 is associated with lack of clinical benefit from anthracycline based chemotherapy in metastatic breast cancer and preliminary data suggest that this is also true for adjuvant treatment. Plasma TIMP-1 has also been shown to predict response to endocrine therapy in patients with metastatic breast cancer. No data regarding TIMP-1 response to neo-adjuvant treatment exists. Material and Methods: NICE (1839IL/0712) is a randomized phase II trial, assigning 144 patients per protocol with primary operable estrogen receptor negative breast cancer and tumor ≥ 2 cm to either four cycles of EC (epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2) plus placebo or EC plus gefitinib 250 mg daily. The primary endpoint was pCR (no invasive residual) at surgery and secondary endpoints were complete (CR) and overall objective (OR) tumor response rates (CR+PR) assessed by palpation, mammography and ultrasonography (the last prevailed in case of disagreements). Plasma TIMP-1 levels were measured (blinded and in duplicates) before and after preoperative EC using a validated enzyme-linked immunosorbent assay. Results: 'pCR was attained by 8/71 patients in the EC + gefitinib group and 8/73 patients in the EC + placebo group, and OR by 50 patients in each treatment group. The addition of gefitinib to pre-operative EC was not associated with any significant benefit, thereby justifying pooling of the 2 groups of patients. TIMP-1 ranged from 55.1 to 519 ng/ml, median 126.8 ng/ml at baseline. Patients who obtained pCR had numeric higher plasma TIMP-1 values than non-responders (155.2ng/ml against 139.9 ng/ml, p=0.35). Dichotomizing patients by the plasma TIMP-1 median showed, that patients with elevated TIMP-1 had a numeric increased likelihood of obtaining pCR and OR: Patients with plasma TIMP-1 above the median had a numeric higher pCR rate (6.6% against 4.4%; odds ratio 1.60, p=0.39), and OR (51.0% against 49.0%; odds ratio 1.20, p=0.61). A small decline in TIMP-1 was observed after four cycles of EC (median difference 4.5, 25% and 75% quartile of -28.6 and 27.9, p=0.85) and the change was nearly the same in responders as in non-responders. Conclusion: This study could not demonstrate a predictive role of pre-treatment plasma TIMP-1 in neo-adjuvant chemotherapy for primary breast cancer. A change in plasma levels of TIMP-1 during 4 cycles of EC was not associated with response to the treatment. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6072.

Samples of genomic DNA from three unrelated American black infants having both biochemical and clinical features of classical infantile Tay-Sachs disease were sequenced following PCR amplification. A G----T transversion was observed in the AG acceptor splice site preceding exon 5 of the beta-hexosaminidase alpha-subunit gene in the first black family. This transversion changed the acceptor splice site from the consensus sequence, AG, to AT, thereby interfering with splicing at this intron 4/exon 5 junction. The proband was homozygous for this mutation; his mother and a brother are heterozygous. The same mutation was found in a second, apparently unrelated, black GM2-gangliosidosis patient. The second patient was a compound heterozygote, as only one allele carried this mutation. The mother and a brother in this second family are carriers for this mutation, while the father and a noncarrier sister are normal for this region of the gene. The third proband did not have this mutation; nor did the mother of a fourth black proband. Eight other independently ascertained non-black, non-Jewish, GM2-gangliosidosis families did not have this mutation. The observation of the same novel mutation in two unrelated black GM2-gangliosidosis patients indicates that the American black population has segregating within it at least one GM2-gangliosidosis mutation which may be specific to this population and not a result of migration.

During recent years, skateboards have become increasingly popular in Denmark. According to trade reports, skateboards for a two-figure million Danish crowns are sold annually and the number of users is estimated to be 300,000. During the summer period from 1.5 1988 to 31.10 1988, 71 skateboard injuries were registered in the Casualty Department, Gentofte Hospital. The average age of the patients was 14 years and a 90% predominance of boys was observed. 31% of the injured persons had fractures. The mechanism of injury appears to be an averting movement when the balance is suddenly lost and more than 50% of the injuries and more than 80% of the fractures were localised to the upper limbs. More than 8% of the injured patients required hospitalisation. Only 15.2% of the patients registered here had used any form of protective equipment. Possible prophylaxis includes protective equipment and restricted rinks for skateboard enthusiasts.

The origin of nondisjunction in trisomy 21 has so far been studied using cytogenetic heteromorphisms and DNA polymorphisms using Southern blot analysis. Short sequence repeats have recently been described as an abundant class of DNA polymorphisms in the human genome, which can be typed using the polymerase chain reaction (PCR) amplification. We describe the usage of such markers on chromosome 21 in the study of parental origin of the additional chromosome 21 in 87 cases of Down syndrome. The polymorphisms studied were (a) two (GT)n repeats and a poly(A) tract of an Alu sequence within the HMG14 gene and (b) a (GT)n repeat of locus D21S156. The parental origin was determined in 68 cases by studying the segregation of polymorphic alleles in the nuclear families (either by scoring three different alleles in the proband or by dosage comparison of two different alleles in the proband). Our results demonstrate the usefulness of highly informative PCR markers for the study of nondisjunction in Down syndrome.

Down syndrome is rarely due to a de novo duplication of chromosome 21 [dup(21q)]. To investigate the origin of the dup(21q) and the nature of this chromosome, we used DNA polymorphisms in 10 families with Down syndrome due to de novo dup(21q). The origin of the extra chromosome 21q was maternal in six cases and paternal in four cases. Furthermore, the majority (eight of 10) of dup(21q) chromosomes were isochromosomes i(21q) (four were paternal in origin, and four were maternal in origin); however, in two of 10 families the dup(21q) chromosome appeared to be the result of a Robertsonian translocation t(21q;21q) (maternal in origin in both cases).

Karyotype 47,XY,+22 was found in a newborn infant with primitive and low-set ears, bilateral preauricular pit, broad nasal bridge, antimongoloid palpebral fissures, macroglossia, enlarged sublingual glands, cleft palate, micrognathia, clinodactyly of the fifth fingers, hypoplastic finger nails, hypoplastic genitalia, short lower limbs, bilateral sandal gap and deep plantar furrows. The child developed signs of congenital heart disease and died at the age of 10 weeks. Non-disjunction studies showed maternal origin (meiosis I) of the extrachromosome.

High resolution chromosome analysis showed the karyotype 46,XX,del(1)(p22.1 p31.2) in a 30 year old woman with psychomotor retardation and various malformations. Determination of the enzyme phosphoglucomutase 1 (PGM1) showed that she was a heterozygote. Three other cases of interstitial deletion 1p have been reported previously, and one of these cases had several features in common with our case, suggesting a distinct syndrome.

A 4-year-old child with a ring 20 chromosome mosaicism, low grade developmental delay, and seizures is described.