Particle size distribution of workplace aerosols in manganese alloy smelters applying a personal sampling strategy.

Air samples were collected by personal sampling with five stage Sioutas cascade impactors and respirable cyclones in parallel among tappers and crane operators in two manganese (Mn) alloy smelters in Norway to investigate PM fractions. The mass concentrations of PM collected by using the impactors and the respirable cyclones were critically evaluated by comparing the results of the parallel measurements. The geometric mean (GM) mass concentrations of the respirable fraction and the <10 µm PM fraction were 0.18 and 0.39 mg m(-3), respectively. Particle size distributions were determined using the impactor data in the range from 0 to 10 µm and by stationary measurements by using a scanning mobility particle sizer in the range from 10 to 487 nm. On average 50% of the particulate mass in the Mn alloy smelters was in the range from 2.5 to 10 µm, while the rest was distributed between the lower stages of the impactors. On average 15% of the particulate mass was found in the <0.25 µm PM fraction. The comparisons of the different PM fraction mass concentrations related to different work tasks or different workplaces, showed in many cases statistically significant differences, however, the particle size distribution of PM in the fraction <10 µm d(ae) was independent of the plant, furnace or work task.

Balanced complex chromosomal rearrangements (BCCR) with at least three chromosomes and three or more breakpoints: report of three new cases.

Balanced complex chromosomal rearrangements (BCCR) encompass a heterogeneous group of rare chromosomal aberrations. In this paper, we report three cases of BCCRs. In two the probands were referred for either genetic counseling or prenatal management. One case was ascertained after chromosome analysis performed because of psychiatric manifestations; this was an isolated finding. We also outline the molecular cytogenetic techniques, which were essential in confirming and precisely delineating the BCCRs identified in these patients. In addition the various aspects of genetic counseling for this type of chromosomal rearrangement, highlighting the details particular to each individual case are discussed. We discuss the classification for this type of chromosomal mutation.

De novo complex chromosomal rearrangements (CCR) involving chromosome 1, 5, and 6 resulting in microdeletion for 6q14 in a female carrier with psychotic disorder.

A 23-year-old obese woman with a psychotic disorder was found to have a de novo apparently balanced complex chromosomal rearrangement involving chromosomes 1, 5, and 6. Molecular cytogenetic analyses using high-resolution comparative genomic hybridization (HR-CGH) showed a microdeletion at 6q14 in a der(6). Application of HR-CGH facilitated detection of micro-rearrangement of all de novo apparently balanced complex chromosomal rearrangements (CCR) and supported the localization of the breakpoint. According to our knowledge, no constitutional interstitial microdeletion of chromosome 6q14 has been found associated with a schizoid-type phenotype.

Abdominal wall defects in Denmark, 1970-89.

In the last two to three decades, increasing rates of gastroschisis but not of omphalocele have been reported from different parts of the world. The present study represents a register containing 469 children born with abdominal wall defects based on data retrieved from 20 birth cohorts (1970-89) in three nationwide registries. A tentative estimate of the completeness as regards identification of liveborn and stillborn infants is a minimum of 95% and 90% respectively. All cases were reclassified to 166 cases of gastroschisis, 258 of omphalocele and 16 of gross abdominal wall defect. The average point prevalence at birth of gastroschisis was 1.33 per 10 000 live and stillbirths. During the first decade, an increase in prevalence occurred culminating in 1976, followed by a decrease reaching its initial value in 1983 and then a new increase. Overall, no significant linear trend could be demonstrated for the entire period. The average point prevalence at birth for omphalocele was 2.07 and for gross abdominal wall defect 0.12 per 10 000 live and stillbirths with no significant change in the period. The geographical distribution of gastroschisis and omphalocele showed no difference per county.

Aortic surgery in patients with marfan syndrome: long-term survival, morbidity and function.

BACKGROUND AND AIM OF THE STUDY: The natural history of patients with Marfan syndrome is depressing, but surgical intervention on the aorta can improve the prognosis. Study results were analyzed with reference to long-term survival, morbidity and function. METHODS: Seventy-four Marfan patients (51 males, 23 females; mean age 41+/-14 years), underwent first-time aortic surgery between 1977 and 1998. Follow up information regarding mortality, morbidity and functional status was obtained from patient records and by questionnaire. The mean follow up was 5 years (range: 0-19 years). Forty-seven patients (64%) had a dissection, 27 (36%) an aneurysm, and 45 (61%) patients underwent emergency operations (<4 h from arrival at hospital). In 72 patients (97%) the disease affected the ascending aorta, and implantation of a composite graft was the most frequent operation. RESULTS: Overall 30-day mortality was 12% (3% in elective cases, 18% in emergency cases, p <0.05). Emergency operations and surgery extended to the aortic arch were risk factors for early mortality. Overall actuarial survival was 63.4+/-8% at 10 years. Age was the only risk factor for late mortality. Seventeen patients were reoperated on due to pathologies of the remaining aorta (n = 12), pseudoaneurysms (n = 4) and aortic valve endocarditis (n = 1). A total of five patients had endocarditis; one patient with a homograft required surgery, and medical treatment was successful in the other four patients. Five patients had neurological thromboembolic episodes without permanent damage, and six had minor bleeding complications. Freedom from early and late mortality, reoperation on the aorta and major cardiovascular events (endocarditis episodes, thromboembolic/hemorrhagic strokes and other major bleeding/embolic episodes) was 33.3 +/- 8.1% at 10 years. At follow up, 98% of patients were in NYHA functional class I or II, and 80% were working. CONCLUSION: Elective aortic surgery in Marfan patients can be performed with good results. Close follow up of patients undergoing surgery is important. The long-term functional status of surviving patients is satisfactory.

Disease associated balanced chromosome rearrangements: a resource for large scale genotype-phenotype delineation in man.

Disease associated balanced chromosomal rearrangements (DBCRs), which truncate, delete, or otherwise inactivate specific genes, have been instrumental for positional cloning of many disease genes. A network of cytogenetic laboratories, Mendelian Cytogenetics Network (MCN), has been established to facilitate the identification and mapping of DBCRs. To get an estimate of the potential of this approach, we surveyed all cytogenetic archives in Denmark and southern Sweden, with a population of approximately 6.6 million. The nine laboratories have performed 71 739 postnatal cytogenetic tests. Excluding Robertsonian translocations and chromosome 9 inversions, we identified 216 DBCRs ( approximately 0.3%), including a minimum estimate of 114 de novo reciprocal translocations (0.16%) and eight de novo inversions (0.01%). Altogether, this is six times more frequent than in the general population, suggesting a causal relationship with the traits involved in most of these cases. Of the identified cases, only 25 (12%) have been published, including 12 cases with known syndromes and 13 cases with unspecified mental retardation/congenital malformations. The remaining DBCRs were associated with a plethora of traits including mental retardation, dysmorphic features, major congenital malformations, autism, and male and female infertility. Several of the unpublished DBCRs defined candidate breakpoints for nail-patella, Prader-Willi, and Schmidt syndromes, ataxia, and ulna aplasia. The implication of the survey is apparent when compared with MCN; altogether, the 292 participating laboratories have performed >2.5 million postnatal analyses, with an estimated approximately 7500 DBCRs stored in their archives, of which more than half might be causative mutations. In addition, an estimated 450-500 novel cases should be detected each year. Our data illustrate that DBCRs and MCN are resources for large scale establishment of phenotype-genotype relationships in man.

High resolution comparative genomic hybridisation analysis reveals imbalances in dyschromosomal patients with normal or apparently balanced conventional karyotypes.

A sensitive technique is needed for screening whole genome imbalances in dyschromosomal patients when G-banding shows normal karyotypes or apparently balanced translocations. In this study we performed highly sensitive comparative genomic hybridisation analysis on a number of such cases and revealed chromosomal imbalances in all.

Early outcome and graft patency in mammary artery grafting of left anterior descending artery with sternotomy or anterior minithoracotomy.

BACKGROUND: The main objective of this study was to retrospectively compare early outcome and graft patency in patients who underwent coronary artery bypass grafting with the internal thoracic artery to the left anterior descending artery via an anterior minithoracotomy or median sternotomy and without the use of extracorporeal circulation. METHODS: One hundred thirty consecutive patients were studied. Median sternotomy was performed in 77 patients and anterior minithoracotomy in 53 patients. RESULTS: There were no differences in early clinical data or persistent postoperative pain between the groups. Early graft patency was 88% in the thoracotomy group and 96% in the sternotomy group (p = 0.3). Five of 7 patients who presented with a significant stenosis at the first coronary angiography had a normal angiogram at the reangiography. None of the patients with nonsignificant stenosis at the early coronary angiography had any clinical signs of ischemia or chest pain. CONCLUSIONS: In our experience, anterior minithoracotomy and median sternotomy are different and distinguishable regarding early outcome and early graft patency. Most of the stenoses visualized at the early coronary angiography had vanished at a later coronary angiography, which makes the interpretation of the angiogram hazardous as a tool for the decision for redo procedure in the early postoperative period.

Management of extensive lesions of the aortic arch: review of 42 consecutive cases.

This retrospective study reviews the long-term results in aortic arch surgery. Forty-two consecutive patients (44-74 years) were operated on between 1980 and 1995. Nineteen patients had acute dissections of the aortic arch, 11 had chronic dissections and 12 had aneurysms. Twenty patients were given emergency surgery and 22 were operated on electively. Reconstruction of the aortic arch alone (31%) or with other aortic segments (69%) was performed during antegrade cerebral perfusion (81%) or circulatory arrest (17%). Sixteen patients died during the first 30 days (38%). Early mortality rates were 60% in emergencies and 18% in elective cases. Early mortality in the group with aneurysms was 33% and 40% in patients in the dissection group. Long-term follow-up to July 1998 is now complete. Twelve patients (28%) died during the follow-up period; 4 of these deaths were due to a rupture of the descending aorta. Three patients (11.5%) underwent late reoperations on the remaining aorta, without operative mortality. We recommend careful follow-up of patients with aortic arch disease and, when indicated, surgery to avoid the rupture of the remaining aorta.

Off-pump bypass surgery--experience of 250 cases.

From April 1996 to October 1998, 250 patients with a mean age of 63 years (31-86 years) underwent coronary artery bypass grafting using the off-pump technique. The prime reason for using this technique was the need to minimize the surgical trauma by avoiding extracorporeal circulation. Fifty-seven percent of the patients had 1-vessel disease, 39% had 2-vessel disease and 4% 3-vessel disease. Sternotomy was performed in 196 patients and an anterior mini-thoracotomy in 54 patients. The mean number of coronary anastomoses was 1.5. Perioperative mortality was 0.4%. The first consecutive 87 patients underwent an early postoperative coronary angiography (days 1-5) revealing a graft patency of 96.5%. Five out of the 7 patients with occluded grafts subsequently underwent another intervention (surgical revascularization in 4 patients and percutaneous transluminal coronary angioplasty in one); 1.2% developed transmural myocardial infarction and 2.8% were reoperated upon for bleeding. The mean time of ventilatory support was 2.5+/-0.5 h. The mean ICU time for all patients was 12 h (0-10 days). The mean in-hospital time was 7 days (2-30 days). Coronary artery bypass surgery without the use of extracorporeal circulation is a safe procedure that can be performed with limited need for intensive care resources. However, long-term results remain to be investigated.

Difficulties in the interpretation of coronary angiogram early after coronary artery bypass surgery on the beating heart.

OBJECTIVE: The major objective of this study was to evaluate the findings in early postoperative coronary angiography in patients who underwent coronary revascularization on the beating heart without cardiopulmonary bypass. METHODS: Eighty-four consecutive patients receiving 113 grafts were studied. A coronary angiography was performed 0 to 5 days postoperatively. All the grafts were reviewed and classified in the following way: grade A (unimpaired run-off); grade B1 (<50 stenosis); grade B2 (>50% stenosis); grade O (occlusion). A second coronary angiography was performed in patients with a stenosis grade B2, 4 to 30 months postoperatively. An exercise test was performed by patients with B1 stenosis. RESULTS: Overall graft patency was 96% in the 113 grafts. None of the 14 patients with B1 stenosis in the early coronary angiography had any clinical signs of ischemia. Eight of the 12 patients who exhibited B2 stenosis either at the anastomotic site, in the graft or in the distal coronary artery at the first coronary angiography had a normal angiogram at the re-angiography. CONCLUSION: A majority of stenoses visualized at the early coronary angiography could not be seen at a later coronary angiography, which makes the interpretation of the angiogram unreliable as a tool for the decision as to redo-procedure in the early postoperative period.

Systematic characterisation of disease associated balanced chromosome rearrangements by FISH: cytogenetically and genetically anchored YACs identify microdeletions and candidate regions for mental retardation genes.

Disease associated balanced chromosome rearrangements (DBCRs) have been instrumental in the isolation of many disease genes. To facilitate the molecular cytogenetic characterisation of DBCRs, we have generated a set of >1200 non-chimeric, cytogenetically and genetically anchored CEPH YACs, on average one per 3 cM, spaced over the entire human genome. By fluorescence in situ hybridisation (FISH), we have performed a systematic search for YACs spanning translocation breakpoints. Patients with DBCRs and either syndromic or non-syndromic mental retardation (MR) were ascertained through the Mendelian Cytogenetics Network (MCN), a collaborative effort of, at present, 270 cytogenetic laboratories throughout the world. In this pilot study, we have characterised 10 different MR associated chromosome regions delineating candidate regions for MR. Five of these regions are narrowed to breakpoint spanning YACs, three of which are located on chromosomes 13q21, 13q22, and 13q32, respectively, one on chromosome 4p14, and one on 6q25. In two out of six DBCRs, we found cytogenetically cryptic deletions of 3-5 Mb on one or both translocation chromosomes. Thus, cryptic deletions may be an important cause of disease in seemingly balanced chromosome rearrangements that are associated with a disease phenotype. Our region specific FISH probes, which are available to MCN members, can be a powerful tool in clinical cytogenetics and positional cloning.

Molecular cytogenetic detection of 9q34 breakpoints associated with nail patella syndrome.

The nail patella syndrome (NPS1) is an autosomal dominant disorder characterised by dysplasia of the finger nails and skeletal abnormalities. NPS1 has been mapped to 9q34, to a 1 cM interval between D9S315 and the adenylate kinase gene (AK1). We have mapped the breakpoints within the candidate NPS1 region in two unrelated patients with balanced translocations. One patient [46,XY,t(1;9)(q32.1;q34)] was detected during a systematic survey of old cytogenetic files in Denmark and southern Sweden. The other patient [46,XY,t(9;17)(q34.1;q25)] was reported previously. D9S315 and AK1 were used to isolate YACs, from which endclones were used to isolate PACs. Two overlapping PAC clones span the 9q34 breakpoints in both patients, suggesting that NPS1 is caused by haploinsufficiency due to truncation or otherwise inactivation of a gene at or in the vicinity of the breakpoints.

Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene.

The recessive autosomal disorder known as ICF syndrome (for immunodeficiency, centromere instability and facial anomalies; Mendelian Inheritance in Man number 242860) is characterized by variable reductions in serum immunoglobulin levels which cause most ICF patients to succumb to infectious diseases before adulthood. Mild facial anomalies include hypertelorism, low-set ears, epicanthal folds and macroglossia. The cytogenetic abnormalities in lymphocytes are exuberant: juxtacentromeric heterochromatin is greatly elongated and thread-like in metaphase chromosomes, which is associated with the formation of complex multiradiate chromosomes. The same juxtacentromeric regions are subject to persistent interphase self-associations and are extruded into nuclear blebs or micronuclei. Abnormalities are largely confined to tracts of classical satellites 2 and 3 at juxtacentromeric regions of chromosomes 1, 9 and 16. Classical satellite DNA is normally heavily methylated at cytosine residues, but in ICF syndrome it is almost completely unmethylated in all tissues. ICF syndrome is the only genetic disorder known to involve constitutive abnormalities of genomic methylation patterns. Here we show that five unrelated ICF patients have mutations in both alleles of the gene that encodes DNA methyltransferase 3B (refs 5, 6). Cytosine methylation is essential for the organization and stabilization of a specific type of heterochromatin, and this methylation appears to be carried out by an enzyme specialized for the purpose.

Origin of nondisjunction in trisomy 8 and trisomy 8 mosaicism.

Causes of chromosomal nondisjunction is one of the remaining unanswered questions in human genetics. In order to increase our understanding of the mechanisms underlying nondisjunction we have performed a molecular study on trisomy 8 and trisomy 8 mosaicism. We report the results on analyses of 26 probands (and parents) using 19 microsatellite DNA markers mapping along the length of chromosome 8. The 26 cases represented 20 live births, four spontaneous abortions, and two prenatal diagnoses (CVS). The results of the nondisjunction studies show that 20 cases (13 maternal, 7 paternal) were probably due to mitotic (postzygotic) duplication as reduction to homozygosity of all informative markers was observed and as no third allele was ever detected. Only two cases from spontaneous abortions were due to maternal meiotic nondisjunction. In four cases we were not able to detect the extra chromosome due to a low level of mosaicism. These results are in contrast to the common autosomal trisomies (including mosaics), where the majority of cases are due to errors in maternal meiosis.