E. Bakker

Image and Video Retrieval

We have witnessed a decade of exploding research interest in multimedia content analysis. The goal of content analysis has been to derive automatic methods for high-level description and annotation. In this paper we will summarize the main research topics in this area and state some assumptions that we have been using all along. We will also postulate the main future trends including usage of long term memory, context, dynamic processing, evolvable generalized detectors and user aspects.

PRENATAL-DIAGNOSIS AND CARRIER DETECTION OF DUCHENNE MUSCULAR-DYSTROPHY WITH CLOSELY LINKED RFLPS

By the use of a series of closely linked DNA probes detecting restriction fragment length polymorphisms (RFLPs) distributed over the short arm of the X chromosome, a double crossover was detected in a Duchenne muscular dystrophy carrier and an affected male fetus was diagnosed at 12 weeks of gestation, with a probable accuracy of more than 99.0%. A new mutation was identified in another family with the same degree of reliability; three females in this family were thus deemed not to be DMD carriers. The eleven RFLP-markers presently available on the short arm of the X chromosome are useful in the diagnosis of DMD since they bridge the Duchenne locus at genetic distances varying between 3 and 20 cmo. Moreover, recombination within the set of markers provides an independent way of regionally mapping these probes relative to each other along the short arm of the X chromosome.

Isolation of probes detecting restriction fragment length polymorphisms from X chromosome-specific libraries: potential use for diagnosis of Duchenne muscular dystrophy

SummaryWe have isolated 23 human X chromosome-specific DNA fragments from λ libraries, prepared from flow-sorted X chromosomes. To increase diagnostic potential for X-linked genetic disorders, including Duchenne muscular dystrophy (DMD), the fragments were tested for restriction fragment length polymorphisms (RFLPs) with six restriction enzymes. All fragments were regionally mapped to segments of the X chromosome with a panel of somatic cell hybrids and with human cell lines carrying unbalanced chromosomal abnormalities. Two of the isolated probes detected a high frequency RFLP. One, 754, maps between Xp11.3 and Xp21 and detects a PstI polymorphism with an allele frequency of 0.38. The other, 782, maps between Xp22.2 and Xp22.3 and reveals an EcoRI polymorphism with an allele frequency of 0.40. According to a pilot linkage study of families at risk for Duchenne muscular dystrophy, 754 gives a maximum Lod score of 7.6 at a recombination fraction of 0.03. Probe 782 lies telomeric to DMD with a maximum Lod score of 2.2 at a recombination fraction of 0.17. Using our X-chromosomal probes and a set of autosomal probes, isolated and examined in an identical way, we found a significantly lower RFLP frequency for the X chromosome as compared to the autosomes.

Germinal mosaicism increases the recurrence risk for 'new' Duchenne muscular dystrophy mutations.

In 288 Dutch and Belgian Duchenne and Becker muscular dystrophy families, the parental origin of 41 new deletion or duplication mutations was determined. Twenty seven of the new mutations occurred in the maternal X chromosome and nine in the grandmaternal and five in the grandpaternal X chromosome. The grandparental data are compatible with equal mutation rates for DMD in male and female X chromosomes. New mutations were defined by their presence in one or more progeny and absence in the lymphocytes of the mother or the grandparents. In one family a fraction of the maternal lymphocytes was found to carry the mutation, suggesting somatic mosaicism. In six cases out of 41, the mutation was transmitted more than once by a parent in whom the mutation was absent in lymphocytes, suggesting gonadal mosaicism as the explanation for the multiple transmission. Using our data for the recurrence of the mutations among the total of at risk haplotypes transmitted, we arrive at a recurrence risk of 14% for the at risk haplotype. The observation of this high risk of germinal mosaicism is crucially important for all physicians counselling females in DMD families. Recently, germinal mosaicism has been observed also in a number of other X linked and autosomal disorders. The implications and appropriate diagnostic precautions are discussed.

Cerebral microbleeds in CADASIL

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary arteriopathy leading to recurrent cerebral infarcts and dementia. Intracerebral hemorrhage (ICH) has been described sporadically in patients with CADASIL, suggesting that the affected arteries in CADASIL are not bleed-prone. However, the presence of cerebral microbleeds, which often remain undetected on conventional MRI, has not been determined in CADASIL. Objective: To determine whether cerebral vessels in patients with CADASIL are prone to microbleeding. Methods: T2*-weighted gradient echo MRI, which is highly sensitive for visualizing microbleeds, was performed in patients with CADASIL and their family members (n = 63). Known risk factors for ICH were determined for all individuals. On an exploratory basis, the presence of cerebral microbleeds was correlated with demographic variables, vascular risk factors, disease progression, ischemic MR lesions, and genotype. Results: Cerebral microbleeds were present in 31% of symptomatic CADASIL mutation carriers, predominantly in the thalamus. Vascular risk factors such as hypertension did not account for the microbleeds in these patients. Factors associated with microbleeds were age (p = 0.008), Rankin disability score (p = 0.017), antiplatelet use (p = 0.025), number of lacunae on MRI (p = 0.009), and the Arg153Cys Notch3 mutation (p = 0.017). After correction for age, only the Arg153Cys mutation remained significantly associated with the presence of microbleeds. Conclusion: Patients with CADASIL have an age-related increased risk of intracerebral microbleeds. This implies that they may have an increased risk for ICH, which should be taken into account in CADASIL diagnosis and patient management.

Mutations in the EXT1 and EXT2 Genes in Hereditary Multiple Exostoses

Hereditary multiple exostoses (EXT; MIM 133700) is an autosomal dominant bone disorder characterized by the presence of multiple benign cartilage-capped tumors (exostoses). Besides suffering complications caused by the pressure of these exostoses on the surrounding tissues, EXT patients are at an increased risk for malignant chondrosarcoma, which may develop from an exostosis. EXT is genetically heterogeneous, and three loci have been identified so far: EXT1, on chromosome 8q23-q24; EXT2, on 11p11-p12; and EXT3, on the short arm of chromosome 19. The EXT1 and EXT2 genes were cloned recently, and they were shown to be homologous. We have now analyzed the EXT1 and EXT2 genes, in 26 EXT families originating from nine countries, to identify the underlying disease-causing mutation. Of the 26 families, 10 families had an EXT1 mutation, and 10 had an EXT2 mutation. Twelve of these mutations have never been described before. In addition, we have reviewed all EXT1 and EXT2 mutations reported so far, to determine the nature, frequency, and distribution of mutations that cause EXT. From this analysis, we conclude that mutations in either the EXT1 or the EXT2 gene are responsible for the majority of EXT cases. Most of the mutations in EXT1 and EXT2 cause premature termination of the EXT proteins, whereas missense mutations are rare. The development is thus mainly due to loss of function of the EXT genes, consistent with the hypothesis that the EXT genes have a tumor- suppressor function.

Cardiac involvement in carriers of Duchenne and Becker muscular dystrophy

A cross-sectional study in a cohort of DNA proven carriers of Duchenne (DMD) and Becker (BMD) muscular dystrophy was undertaken with the following objectives: (1) to estimate the frequency of electrocardiographic (ECG) and echocardiographic abnormalities; (2) to establish the proportion of carriers with dilated cardiomyopathy and (3) to assess possible associations between dilated cardiomyopathy and genotype. One hundred and twenty nine DMD and BMD carriers, aged 18-60 years, were traced through the files of the central register kept at the department of Human Genetics in Leiden. Investigations included full medical history, physical examination, ECG and two-dimensional and M-mode echocardiographic examination. Forty-seven percent had ECG changes. Thirty-six percent (DMD 41%, BMD 27%) had at least one abnormality as is usually found in the male patients. Echocardiographic examination was abnormal in 36% (DMD 38%, BMD 34%). Dilated cardiomyopathy was found in seven DMD carriers (8%), and in none of BMD carriers. In addition, 18% had left ventricle dilatation (DMD 19%, BMD 16%). Only 38% had a completely normal investigation of the heart. We found no association between genotype and cardiac manifestations. Our study underlines that cardiac involvement is part of the dystrophinopathies. Carriers should be told about the increased risk of this complication when asking genetic advice. It also implicates that a complete cardiological evaluation should be performed at least once in all carriers. If left ventricle dilatation or dilated cardiomyopathy is present a yearly follow up is needed, in order to start timely therapy.

A physical map of 4 million bp around the Duchenne muscular dystrophy gene on the human X-chromosome

Employing pulsed field gradient electrophoresis, we constructed a 4.5 million bp (Mb) Sfil restriction map of the human X-chromosomal region p21, harboring genes for Duchenne (DMD) and Becker Muscular Dystrophy. In a DMD patient with additional chronic granulomatosis and retinitis pigmentosa, the proximal 3.5 Mb is deleted. Another DMD patient, with additional glycerol kinase deficiency and adrenal hypoplasia, lacks at least 3.3 Mb in the middle region, including marker C7 but not B24, placing C7 closer to DMD. Another DMD patient has a partial pERT-87 deletion of minimally 140 kb. Truncated Sfil fragments in a female X:21 translocation patient place the junction probe XJ1.1 115 kb from the distal end of the normal fragment. Probe pERT-84 maps to the same fragment, within 750 kb of XJ1.1.

Population-based incidence and prevalence of facioscapulohumeral dystrophy

Objective: To determine the incidence and prevalence of facioscapulohumeral muscular dystrophy (FSHD) in the Netherlands. Methods: Using 3-source capture-recapture methodology, we estimated the total yearly number of newly found symptomatic individuals with FSHD, including those not registered in any of the 3 sources. To this end, symptomatic individuals with FSHD were available from 3 large population-based registries in the Netherlands if diagnosed within a 10-year period (January 1, 2001 to December 31, 2010). Multiplication of the incidence and disease duration delivered the prevalence estimate. Results: On average, 52 people are newly diagnosed with FSHD every year. This results in an incidence rate of 0.3/100,000 person-years in the Netherlands. The prevalence rate was 12/100,000, equivalent to 2,000 affected individuals. Conclusions: We present population-based incidence and prevalence estimates regarding symptomatic individuals with FSHD, including an estimation of the number of symptomatic individuals not present in any of the 3 used registries. This study shows that the total number of symptomatic persons with FSHD in the population may well be underestimated and a considerable number of affected individuals remain undiagnosed. This suggests that FSHD is one of the most prevalent neuromuscular disorders.

The state of the art in image and video retrieval

Image and video retrieval continues to be one of the most exciting and fastest-growing research areas in the field of multimedia technology. What are the main challenges in image and video retrieval? Despite the sustained efforts in the last years, we think that the paramount challenge remains bridging the semantic gap. By this we mean that low level features are easily measured and computed, but the starting point of the retrieval process is typically the high level query from a human. Translating or converting the question posed by a human to the low level features seen by the computer illustrates the problem in bridging the semantic gap. However, the semantic gap is not merely translating high level features to low level features. The essence of a semantic query is understanding the meaning behind the query. This can involve understanding both the intellectual and emotional sides of the human, not merely the distilled logical portion of the query but also the personal preferences and emotional subtons of the query and the preferential form of the results.