PubMed Health⌕ Search

Biomedical subjects

J A Veltman

Publications and source records attributed to J A Veltman.

18 recordsLinked to original sources
PubMed2006

Novel candidate tumour suppressor gene loci on chromosomes 11q23-24 and 22q13 involved in human insulinoma tumourigenesis.

Insulinomas represent the predominant syndromic subtype of endocrine pancreatic tumours. Previous molecular studies have shown that gain of chromosome 9q rather than MEN1 gene mutation is an important early event in tumour development and that chromosomal instability is associated with metastatic disease. In order to identify new gene loci and to define further the critical genetic events in insulinoma tumourigenesis, 27 insulinomas were investigated by array-based comparative genomic hybridization (array CGH) on 3.7 k genomic BAC arrays (resolution < or =1 Mb). Fluorescence in situ hybridization was used to validate alterations in a subset of tumours. Array CGH most frequently detected loss of chromosomes 11q and 22q and gains of chromosome 9q. The chromosomal regions of interest (CRI) included 11q24.1 (56%), 22q13.1 (67%), 22q13.31 (56%), and 9q32 (63%). Evaluation of the simultaneous occurrence of these aberrations in the individual tumours revealed that gain of 9q32 and loss of 22q13.1 are early genetic events in insulinomas, occurring independently of the other alterations. In tumours with increased genomic complexity, these alterations were often detected simultaneously, occurring in the same tumour cells. Losses of 11q24.1 and 22q13.31 were also associated with these more advanced tumour cases. The CRIs identified most likely harbour crucial candidate genes important in insulinoma tumourigenesis.

Chromosomal Instability↗
PubMed2006

Molecular parameters associated with insulinoma progression: chromosomal instability versus p53 and CK19 status.

Insulinomas represent the predominant syndromic subtype of endocrine pancreatic tumors (EPTs). Their metastatic potential cannot be predicted reliably using histopathological criteria. In the past few years, several attempts have been made to identify prognostic markers, among them TP53 mutations and immunostaining of p53 and recently cytokeratin 19 (CK19). In a previous study using conventional comparative genomic hybridization (CGH) we have shown that chromosomal instability (CIN) is associated with metastatic disease in insulinomas. It was our aim to evaluate these potential parameters in a single study. For the determination of CIN, we applied CGH to microarrays because it allows a high-resolution detection of DNA copy number changes in comparison with conventional CGH as well as the analysis of chromosomal regions close to the centromeres and telomeres, and at 1pter-->p32, 16p, 19 and 22. These regions are usually excluded from conventional CGH analysis, because they may show DNA gains in negative control hybridizations. Array CGH analysis of 30 insulinomas (15 tumors of benign, eight tumors of uncertain and seven tumors of malignant behavior) revealed that >or=20 chromosomal alterations and >or=6 telomeric losses were the best predictors of malignant progression. A subset of 22 insulinomas was further investigated for TP53 exon 5-8 gene mutations, and p53 and CK19 expression. Only one malignant tumor was shown to harbor an arginine 273 serine mutation and immunopositivity for p53. CK19 immunopositivity was detected in three malignant tumors and one tumor with uncertain behavior. In conclusion, our results indicate that CIN as well as telomeric loss are very powerful indicators for malignant progression in sporadic insulinomas. Our data do not support a critical role for p53 and CK19 as molecular parameters for this purpose.

Chromosomal Instability↗
PubMed2005

Chromosomal copy number changes in patients with non-syndromic X linked mental retardation detected by array CGH.

Several studies have shown that array based comparative genomic hybridisation (CGH) is a powerful tool for the detection of copy number changes in the genome of individuals with a congenital disorder. In this study, 40 patients with non-specific X linked mental retardation were analysed with full coverage, X chromosomal, bacterial artificial chromosome arrays. Copy number changes were validated by multiplex ligation dependent probe amplification as a fast method to detect duplications and deletions in patient and control DNA. This approach has the capacity to detect copy number changes as small as 100 kb. We identified three causative duplications: one family with a 7 Mb duplication in Xp22.2 and two families with a 500 kb duplication in Xq28 encompassing the MECP2 gene. In addition, we detected four regions with copy number changes that were frequently identified in our group of patients and therefore most likely represent genomic polymorphisms. These results confirm the power of array CGH as a diagnostic tool, but also emphasise the necessity to perform proper validation experiments by an independent technique.

Chromosome Aberrations↗
PubMed2005

CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene.

BACKGROUND: CHARGE syndrome is a non-random clustering of congenital anomalies including coloboma, heart defects, choanal atresia, retarded growth and development, genital hypoplasia, ear anomalies, and deafness. A consistent feature in CHARGE syndrome is semicircular canal hypoplasia resulting in vestibular areflexia. Other commonly associated congenital anomalies are facial nerve palsy, cleft lip/palate, and tracheo-oesophageal fistula. Specific behavioural problems, including autistic-like behaviour, have been described. The CHD7 gene on chromosome 8q12.1 was recently discovered as a major gene involved in the aetiology of this syndrome. METHODS: The coding regions of CHD7 were screened for mutations in 107 index patients with clinical features suggestive of CHARGE syndrome. Clinical data of the mutation positive patients were sampled to study the phenotypic spectrum of mutations in the CHD7 gene. RESULTS: Mutations were identified in 69 patients. Here we describe the clinical features of 47 of these patients, including two sib pairs. Most mutations were unique and were scattered throughout the gene. All patients but one fulfilled the current diagnostic criteria for CHARGE syndrome. No genotype-phenotype correlations were apparent in this cohort, which is best demonstrated by the differences in clinical presentation in sib pairs with identical mutations. Somatic mosaicism was detected in the unaffected mother of a sib pair, supporting the existence of germline mosaicism. CONCLUSIONS: CHD7 mutations account for the majority of the cases with CHARGE syndrome, with a broad clinical variability and without an obvious genotype-phenotype correlation. In one case evidence for germline mosaicism was provided.

Abnormalities, Multiple↗
PubMed2003

Human mitochondrial complex I deficiency: investigating transcriptional responses by microarray.

NADH:ubiquinone oxidoreductase (complex I) deficiency is one of the most frequently encountered defects of the mitochondrial energy generating system. A deficiency of this enzyme complex leads to a wide variety in clinical disease expression. The cell biological consequences of such mutations, however, are poorly understood. We investigated transcriptional responses in fibroblast cell lines harboring mutations in the five different nuclear DNA encoded subunits using a mitochondria-targeting microarray. Expression profiles of cell lines cultured under conditions that favor glycolytic metabolism were compared to profiles when cultured under conditions favoring oxidative metabolism. Approximately 60 genes displayed differential expression under these conditions in either all mutated cell lines or selected cell lines only. A marked induction of metallothioneins as well as ATP1G1 transcripts was detected in all patient cell lines. Transcriptional responses such as the induction of heat shock protein transcripts, decreased PDK1,BNIP3 and mitochondrial genome encoding gene transcripts occurred in selected patient cell lines. The observed transcript profile points to a common, putative defensive, response relating to oxidative stress. Although further investigations of other human OXPHOS system diseases is warranted, these results clearly underline that functional genomics holds for the study of inherited metabolic disease.

Adult↗
PubMed2001

Specific steps in aneuploidization correlate with loss of heterozygosity of 9p21, 17p13 and 18q21 in the progression of pre-malignant laryngeal lesions.

Laryngeal squamous-cell carcinoma is often preceded by pre-malignant lesions. In this study, pre-malignant as well as malignant laryngeal lesions were analyzed using p53 immunohistochemistry and in situ hybridization for chromosomes 1, 7, 9, 17 and 18. Microsatellite analysis was performed on laser-microdissected tissue fragments with the aim of studying loss of heterozygosity (LOH) of 9p21, 17p13 and 18q21. Sequential biopsies were analyzed from a few cases to study genetic progression in more detail. The following genetic progression patterns were observed: (i) histologically normal mucosa and hyperplastic lesions without malignant progression were typically disomic for all chromosomes tested and showed no or only basal cell layer positivity for p53 and no allelic loss; (ii) hyperplastic lesions preceding dysplastic/invasive growth frequently showed trisomy for chromosome 7 and LOH of 9p21 and 17p13, and small foci within these lesions sometimes showed tetraploidization and p53 positivity; (iii) dysplastic lesions were characterized by a tetraploid chromosome content, LOH of 9p21 and 17p13 and p53 positivity; (iv) carcinoma in situ lesions and invasive laryngeal carcinomas showed a more unbalanced chromosome pattern and an additional 18q21 LOH. These results show that different steps in aneuploidization correlate with LOH of 9p21, 17p13 and 18q21 in early laryngeal carcinogenesis. These genomic changes could be of potential use in the diagnosis and prognosis of pre-malignant laryngeal lesions.

Aneuploidy↗
PubMed2001

Mapping of resection margins of oral cancer for p53 overexpression and chromosome instability to detect residual (pre)malignant cells.

Oral squamous cell cancers (OSCCs) have a high local recurrence rate, partly due to problems in the recognition of minimal residual disease. The use of molecular markers is shown to increase the sensitivity of detection of residual malignant cells in tumour margins of OSCC. p53 immunohistochemistry was combined with in situ hybridization for chromosomes 1 and 7 to determine the presence of genetically unstable cells in resection specimens of OSCC containing invasive cancer. An increased frequency of genetically aberrant cells was observed, as detected by p53 overexpression and/or aneusomy, with histological progression of normal mucosa via hyperplasia to dysplasia. Of clinical importance was the finding that 11 of 20 resection margins, all of which were initially diagnosed as being tumour-free, were found to contain genetically aberrant (pre)malignant cells. In these areas, closer histological examination of the genetically aberrant compartment within these margins often also revealed small dysplastic areas that were missed in the initial diagnosis, showing that this genetic approach can assist in diagnosis.

Biomarkers, Tumor↗
PubMed2000

Chromosome instability as an indicator of malignant progression in laryngeal mucosa.

PURPOSE: Routine histologic examination cannot predict whether premalignant laryngeal lesions will progress toward invasive growth. The acquisition of changes in chromosome constitution has been suggested to be essential for driving tumor progression by enhancing mutagenic mechanisms. The aim of the present study was to determine whether chromosomal changes occur in the subsequent stages of early laryngeal carcinogenesis and, if so, whether these changes can be of prognostic value. MATERIALS AND METHODS: Numerical aberrations for chromosomes 1 and 7 were detected in tissue sections from archival material using an improved in situ hybridization protocol. In total, eight benign laryngeal lesions, 37 premalignant laryngeal lesions, and 16 specimens containing histologically normal epithelia adjacent to laryngeal squamous cell carcinomas were studied. Both the histologic and the cytogenetic classifications were correlated with progression to laryngeal cancer. RESULTS: No evidence for chromosome alterations was obtained in the control group, nor in histologically normal epithelia adjacent to laryngeal squamous cell carcinomas, nor in all but one hyperplastic lesion (n = 11). In contrast, 14 of 15 dysplastic lesions and nine of 11 carcinomas-in-situ contained numerical chromosomal aberrations. Tetrasomy was present in the majority of the dysplastic lesions. An unstable chromosome content (indicated by the presence of chromosome imbalances and/or polyploidization) in the premalignant lesion strongly predicted its malignant progression. CONCLUSION: Our results show that laryngeal tumor development involves chromosome tetraploidization. The further change from a stable to an unstable chromosome constitution is of importance for malignant progression.

Carcinoma in Situ↗
PubMed1998

Double-target fluorescence in situ hybridization distinguishes multiple genetically aberrant clones in head and neck squamous cell carcinoma.

Genomic heterogeneity has been observed in several solid tumor types. To investigate this phenomenon in head and neck squamous cell carcinoma (HNSCC), we analyzed macroscopically distinct tissue samples of 12 resected tumors by a combination of fluorescence in situ hybridization (FISH) and DNA flow cytometry. Using a panel of centromeric DNA probes, numerical chromosomal aberrations were detected in 10 tumors, 9 of which showed a single DNA aneuploid peak. Imbalances in chromosomal copy numbers resulted in unique patterns of chromosomal aberrations for each tumor case. Two types of tumors could be distinguished, i.e., tumors (n = 5) containing a single aneusomic clone and tumors (n = 5) with multiple aneusomic clones. The center of this latter group of tumors was shown to be genetically more heterogeneous than the tumor margin. In conclusion, this study showed that 1) the pattern of chromosomal aberrations varies greatly between different HNSCC, 2) a major clone with a specific pattern of chromosomal aberrations has spread throughout most HNSCC, and 3) a subgroup of HNSCCs contains additional clones with a different pattern of chromosomal aberrations. Based on these results, HNSCC can be divided into a genetically more homogeneous and a genetically more heterogeneous group.

Adult↗
PubMed1998

Physiological workload reactions to increasing levels of task difficulty.

The sensitivity of physiological measures to mental workload was investigated in a flight simulator. Twelve pilots had to fly through a tunnel with varying levels of difficulty. Additionally, they had to perform a memory task with four levels of difficulty. The easiest memory task was combined with the easiest tunnel task and the most difficult memory task with the most difficult tunnel task. Between the tunnel tasks, subjects had to fly a pursuit task in which a target jet had to be followed. Rest periods before and after the experiment were used as a baseline for the physiological measures. Mental workload was measured with heart period, continuous blood pressure, respiration and eye blinks. Several respiratory parameters, heart rate variability, blood pressure variability and the gain between systolic blood pressure and heart period (modulus) were scored. All measures showed differences between rest and flight, and between the pursuit and the tunnel task. Only heart period was sensitive to difficulty levels in the tunnel task. Heart rate variability increased when respiratory activity around 0.10 Hz increased, which occurred often. The modulus was hardly influenced by respiration and therefore appears to be a better measure than heart rate variability. Among the respiratory parameters, the duration of a respiratory cycle was the most sensitive to changes in workload. The time in between two successive eye blinks (blink interval) increased and the blink duration decreased as more visual information had to be processed. Increasing the difficulty of the memory task led to a decrement in blink interval, probably caused by subvocal activity during rehearsal of target letters. The data show that physiological measures are sensitive to mental effort, whereas rating scales are sensitive to both mental effort and task difficulty.

Adult↗
PubMed1997

Detection of chromosomal aberrations in cytologic brush specimens from head and neck squamous cell carcinoma.

BACKGROUND: Detection of genetic changes in the mucosa of the upper aerodigestive tract may provide a target for the screening of cytologic specimens to identify premalignant transformation in this region. In this pilot study, the feasibility of the fluorescence in situ hybridization (FISH) technique to detect genetically aberrant cells in brush specimens was evaluated. METHODS: Brush specimens taken from the tumors of 20 patients with head and neck squamous cell carcinoma (HNSCC) and from the normal mucosa of 8 control patients were analyzed by FISH using DNA probes for the chromosomes 1 and 7. The FISH results were compared with DNA flow cytometry and FISH results of the solid tumor specimens. RESULTS: The results of this study showed that 15 of the 20 tumor brush specimens contained numeric chromosomal aberrations in at least 5% of the cells collected. Chromosomal aberrations were detected in all brush specimens taken from tumors that were DNA aneuploid and showed aneusomy. The presence of these aberrations correlated well with the classification "suspicious for malignancy," which was based on Papanicolaou stained slides of the same specimens. In the control group the percentage of chromosomally aberrant cells did not exceed 2%; in addition, no suspiciously malignant cells were observed in this group. CONCLUSIONS: This study reveals that the FISH technique can be applied diagnostically to brush specimens of HNSCC. The presence of chromosomal aberrations in > 5% of the cells in these specimens can be considered as a marker for malignancy.

Adult↗
PubMed1996

Physiological indices of workload in a simulated flight task.

The sensitivity of physiological measures to evaluate workload was investigated in a simulated flight task. Heart rate, blood pressure (from beat to beat), respiration and eye blinks were recorded in 14 subjects while they performed a complex task in a flight simulator. Workload was manipulated by introducing an additional task and by varying the task difficulty of segments of the flight scenarios. Heart rate and blood pressure were both affected by the different levels of task difficulty. Heart-rate variability was found to be confounded by respiration. Slow respiratory activity contributed considerably to heart rate variability, especially after periods of high workload (for example, after landing). The gain between blood-pressure and heart-rate variability (modulus) was sensitive to mental effort and was not influences by respiration. Eye blinks, in particular the duration, were specifically affected by the visual demands of the task and not by the workload in general. When subjects had to process visual information, the number and duration of blinks decreased.

Adult↗
PubMed1996

Cardiovascular and respiratory responses during a complex decision-making task under prolonged isolation.

Self-administered psychophysiological assessment during a mission is not only feasible, but yields reliable data that can be related to mission demands in a meaningful way. The unique methodology that has been employed during the EXEMSI campaign, may be of great promise for the development of techniques that provide daily monitoring of physiological cost of mission demands. This approach can thus be used for obtaining a better understanding of problems that can arise with regard to the functioning of individual crew members. The response profiles of the individual crew members showed remarkable quantitative and qualitative differences during isolation. Due to the limitations of this study, these differences could by no means all be explained in terms of mission demands, operator workload or other relevant parameters. However, the findings do seem to permit some tentative conclusions. In subjects B and D the cardiovascular response profiles suggested that cumulative stress effects emerged, in particular during the second part of the mission. It is important to note that both subjects carried specific responsibilities for the success of the mission, and that there was evidence for a conflict between them. Concerning the question which physiological measures are most appropriate for in-mission psychophysiological assessment, these results can appear to imply that cardiovascular measures yield more valid information about the effects of mission demands that respiratory measures. However, it should be noted that important aspects of respiratory activity, namely, respiratory volume measures and ventilation, could not be reliably determined in this study. Therefore, definitive conclusions concerning the choice of measures wait until the validity of the measures has been more extensively evaluated. Although the methodology that was developed for this study appears to be promising, it is obvious that its value can only be properly assessed when the physiological findings are correlated with behavioral, performance and subjective data. An extensive analysis of the covariation of the daily variations in physiological response, performance measures, and subjective assessments of workload and mood, is currently in progress in collaboration with Hockey and Sauer. Finally, if the usefulness and validity of this type of in-mission self-administered psychophysiological assessment are confirmed in ongoing and future studies (e.g., the 1994 HUBES mission), protocols will have to be worked out for practical implementation during actual spaceflights. In this regard, it has been advocated that psychophysiological monitoring techniques should include feedback and support policies, make crew members aware of potential risks for breakdown, and enable them to take appropriate measures when necessary. Initially, this can perhaps best be realized by procedures which include a data-link between the spacecraft and ground mission control. On the basis of ground-based analysis and evaluation of the data, psychologists at mission control may decide to provide information to the crew concerning potential individual or intragroup overload or stress problems, and to implement specific supportive measures. The effectiveness of the supportive activities should be closely monitored by mission control. Future work should also be aimed at developing expert-systems, which will enable the crew to maintain an appropriate degree of inflight biobehavioral self-regulation by providing a range of support techniques, like biofeedback, coping techniques against individual and group stressors, work/rest and sleep/wake schedules, and emergency procedures.

Adult↗
PubMed1996

Application of a three-dimensional auditory display in a flight task.

The effectiveness of a three-dimensional (3D) auditory display in conveying directional information was investigated in a flight simulation experiment. While flying a simulated fighter aircraft, participants followed a target aircraft that suddenly disappeared and reemerged at an unknown position. The task was to locate and trail the target as quickly as possible. In all conditions the participants viewed a computer-generated outside image, on which they could spot the target only when it was at short range, and a three-dimensional (3D) tactical display indicating the target position at all distances within a limited field of view. Additional displays were a bird's-eye-view radar display, which also indicated whether the target was above or below the own plane, and a 3D auditory display, which generated a warning sound from the relative direction of the target. The auditory display used individualized head-related transfer functions to create a virtual sound source and a head-tracking device to decouple the position of the source from head movements. Results show that the radar and auditory displays caused about the same significant reduction in search time in comparison with the tactical display only. A further reduction was found when the two additional displays were presented simultaneously.

Adult↗
PubMed1993

Indices of mental workload in a complex task environment.

The aim of the present experiment is to evaluate heart rate variability (HRV) and cortisol as indices of mental workload in a complex environment. Heart rate was continuously recorded during flight scenarios that differed in difficulty. The HRV nicely reflected the changes in difficulty. The results support the idea that HRV is a sensitive index for mental workload when tasks are highly demanding and subjects are motivated to exert additional effort whenever the task becomes more demanding. Cortisol was only slightly increased on the experimental day compared to the training day. On the experimental day, post-task levels did not differ from pre-task levels. The level of cortisol in saliva was, however, related to overall task performance. Subjects who had a high level of cortisol had a low level of performance.

Adult↗
PubMedDate not supplied

Cognitive task load in a naval ship control centre: from identification to prediction.

Deployment of information and communication technology will lead to further automation of control centre tasks and an increasing amount of information to be processed. A method for establishing adequate levels of cognitive task load for the operators in such complex environments has been developed. It is based on a model distinguishing three load factors: time occupied, task-set switching, and level of information processing. Application of the method resulted in eight scenarios for eight extremes of task load (i.e. low and high values for each load factor). These scenarios were performed by 13 teams in a high-fidelity control centre simulator of the Royal Netherlands Navy. The results show that the method provides good prediction of the task load that will actually appear in the simulator. The model allowed identification of under- and overload situations showing negative effects on operator performance corresponding to controlled experiments in a less realistic task environment. Tools proposed to keep the operator at an optimum task load are (adaptive) task allocation and interface support.

Cognition↗