Family screening in patients with isolated bicuspid aortic valve : Restriction to those with aortic dilatation is not justified.

AIM: To determine the prevalence of undiagnosed bicuspid aortic valve (BAV) and isolated aortic dilatation in first-degree relatives (FDRs) of patients with isolated BAV and to explore the recurrence risk of BAV in different subgroups of probands with BAV. Recent American College of Cardiology (ACC)/American Heart Association (AHA) Guidelines recommend family screening in patients with associated aortopathy only. METHODS: During follow-up visits, patients with isolated BAV received a printed invitation for their FDRs advising cardiac screening. RESULTS: From 2012-2019, 257 FDRs of 118 adult BAV patients were screened, among whom 63 (53%) index patients had undergone aortic valve surgery (AVS), including concomitant aortic replacement in 25 (21%). Of the non-operated index patients, 31 (26%) had aortic dilatation (> 40 mm). Mean age of the FDRs was 48 years (range 4-83) and 42% were male. The FDR group comprised 20 parents, 103 siblings and 134 offspring. Among these FDRs, 12 (4.7%) had a previously undiagnosed BAV and 23 (8.9%) had an isolated aortic dilatation. FDRs of the probands with previous AVS (n = 147) had a risk ratio for BAV of 2.25 (95% confidence interval (CI) 0.62-8.10). FDRs of the probands with BAV and repaired or unrepaired aortic dilatation (n = 127) had a risk ratio for BAV of 0.51 (95% CI 0.16-1.66). CONCLUSION: Screening FDRs of patients with isolated BAV resulted in a reasonable yield of 14% new cases of BAV or isolated aortic dilatation. A trend towards an increased risk of BAV in FDRs was observed in the probands with previous AVS, whereas this risk seemed to be diminished in the probands with associated aortic dilatation. This latter finding does not support the restrictive ACC/AHA recommendation.

Recurrent and founder mutations in the Netherlands-Phospholamban p.Arg14del mutation causes arrhythmogenic cardiomyopathy.

BACKGROUND: Recently, we showed that the c.40_42delAGA (p.Arg14del) mutation in the phospholamban (PLN) gene can be identified in 10-15 % of Dutch patients with dilated cardiomyopathy or arrhythmogenic cardiomyopathy. The arrhythmogenic burden of the p.Arg14del mutation was illustrated by the high rate of appropriate ICD discharges and a positive family history for sudden cardiac death. METHODS: Our goal was to evaluate the geographical distribution and the origin of this specific mutation in the Netherlands and to get an estimation of the prevalence in a Dutch population cohort. Therefore, we investigated the postal codes of the places of residence of PLN p.Arg14del mutation carriers and places of birth of their ancestors. In addition, a large population-based cohort (PREVEND) was screened for the presence of this mutation. RESULTS: By April 2012, we had identified 101 probands carrying the PLN p.Arg14del mutation. A total of 358 family members were also found to carry this mutation, resulting in a total of 459 mutation carriers. The majority of mutation carriers live in the northern part of the Netherlands and analysing their grandparents' places of birth indicated that the mutation likely originated in the eastern part of the province of Friesland. In the PREVEND cohort we identified six heterozygous PLN p.Arg14del mutation carriers out of 8,267 subjects (0.07 %). CONCLUSION: The p.Arg14del mutation in the PLN gene is the most frequently identified mutation in Dutch cardiomyopathy patients. The mutation that arose 575-825 years ago is likely to have originated from the eastern part of the province of Friesland and is highly prevalent in the general population in the northern part of the Netherlands.

Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis.

Heterozygous fumarate hydratase (FH) germline mutations cause hereditary leiomyomatosis and renal cell cancer (HLRCC), an autosomal dominant syndrome characterized by multiple cutaneous piloleiomyomas, uterine leiomyomas and papillary type 2 renal cancer. The main objective of our study was to evaluate clinical and genetic data from families suspected of HLRCC on a nationwide level. All families referred for FH mutation analysis in the Netherlands were assessed. We performed FH sequence analysis and multiplex ligation-dependent probe amplification. Families with similar FH mutations were examined for haplotype sharing. In 14 out of 33 families, we identified 11 different pathogenic FH germline mutations, including 4 novel mutations and 1 whole-gene deletion. Clinical data were available for 35 FH mutation carriers. Cutaneous leiomyomas were present in all FH mutation carriers older than 40 years of age. Eleven out of 21 female FH mutation carriers underwent surgical treatment for symptomatic uterine leiomyomas at an average of 35 years. Two FH mutation carriers had papillary type 2 renal cancer and Wilms' tumour, respectively. We evaluated the relevance of our findings for clinical practice and have proposed clinical diagnostic criteria, indications for FH mutation analysis and recommendations for management.

The many faces of aggressive aortic pathology: Loeys-Dietz syndrome.

BACKGROUND: Loeys-Dietz syndrome (LDS) is a newly recognised disorder of connective tissue which shares overlapping features with Marfan syndrome (MFS) and the vascular type of Ehlers-Danlos syndrome, including aortic root dilatation and skin abnormalities. It is clinically classified into types 1 and 2. LDS type 1 can be recognised by craniofacial characteristics, e.g. hypertelorism, bifid uvula or cleft palate, whereas these are absent in LDS type 2. It is important to recognise LDS because its vascular pathology is aggressive. We describe nine LDS patients from four families, relate their features to published cases, and discuss important aspects of the diagnosis and management of LDS in order to make clinicians aware of this new syndrome. RESULTS: Characteristics found in the majority of these LDS patients were aortic root dilatation, cleft palate and/or a bifid/abnormal uvula. CONCLUSION: Because aortic dissection and rupture in LDS tend to occur at a young age or at aortic root diameters not considered at risk in MFS, and because the vascular pathology can be seen throughout the entire arterial tree, patients should be carefully followed up and aggressive surgical treatment is mandatory. Clinicians must therefore be aware of LDS as a cause of aggressive aortic pathology and that its distinguishing features can sometimes be easily recognised. (Neth Heart J 2008;16:299-304.).

The use of generic failure frequencies in QRA: the quality and use of failure frequencies and how to bring them up-to-date.

Quantitative Risk Assessment (QRA) is a method which is often used in the chemical industry and, in some countries, also in land-use planning. In QRA calculations the frequency of an accident scenario is most often assessed by a generic failure frequency approach. The credibility and validity of the failure frequencies used in the Netherlands for land-use planning is evaluated by means of an historical review. Furthermore, the possibility is presented how these generic data can be revised and updated.

Germline mutations of EXO1 gene in patients with hereditary nonpolyposis colorectal cancer (HNPCC) and atypical HNPCC forms.

BACKGROUND & AIMS: Germline mutations in one of four mismatch repair genes have been found in the majority of families with hereditary nonpolyposis colorectal cancer (HNPCC), but only in a small part of families with atypical HNPCC. The recently cloned EXO1 gene might be involved in the pathogenesis of HNPCC because the EXO1 protein strongly interacts with the MSH2 protein. To determine its role in HNPCC, EXO1 was scanned for germline mutations. METHODS: All 14 exons of EXO1 were scanned for mutations in index patients from 33 families with HNPCC fulfilling the Amsterdam criteria and in 225 index patients suspected of HNPCC. RESULTS: Germline variants of EXO1 were detected in 14 patients, including one splice-site mutation in a family with HNPCC and 13 missense mutations in patients with atypical HNPCC. These variants did not occur in more than 200 control individuals. From 13 of these 14 patients, tumors were available for analysis of microsatellite instability and loss of heterozygosity. Six of the tumors showed microsatellite instability. Heterozygosity analysis showed one case without EXO1 allelic loss and 12 tumors with loss of the mutant allele and retention of the normal one. CONCLUSIONS: The results indicate a possible association of germline EXO1 variants with HNPCC and atypical HNPCC.

Standard methods for land-use planning to determine the effects on societal risk.

In the Netherlands, the individual risk and the societal risk are used in efforts to reduce the number of people exposed to the effects of an accident. In principle, the societal risk for each new land-use plan should be recalculated. Since this is proving increasingly cumbersome for planning agencies, several methods have been developed for SEVESO establishments and establishments for which in the Netherlands a generic zoning policy is used to determine the effects of new land-use plans on the societal risk. The methods give the uniform population density from a certain distance around the establishment at which the indicative limit for the societal risk is not exceeded. Correction factors are determined for non-uniform population distributions around the establishment, non-continuous residence times and deviating societal risk limits. Using these methods allows decision-making without the necessity of repeating quantified risk analyses for each alternative proposal.

PROTEUS, a technical and management model for aquatic risk assessment of industrial spills.

The assessment of risks to the aquatic environment related to industrial installations is a priority in environmental pollution control in the Netherlands. Major accidents to the surface water such as the Sandoz incident, but also the high number of smaller accidents that occur every year has invoked the need for an effective method to assess these risks. Two different models have been used in this field in the Netherlands over several years. These two software applications, VERIS and RISAM were developed from two different perspectives: VERIS from the perspective of supplying major accidents related information in the safety report, RISAM form the perspective of controlling risks for both smaller and larger facilities that may pollute surface waters through accidents. Both systems comprised particular strong points: VERIS considers safety management aspects in the assessment, RISAM considers differences in surface water vulnerability and involves quantitative probabilities in the assessment. It was decided to integrate both methods and maintain these strong points in the resulting method. This paper describes the new integrated risk assessment method that now has been developed in a concerted effort between the Ministry of Transport, Public Works and Water Management, the Ministry of Housing, Spatial Planning and Environment, and the National Institute for Public Health and Environment. It also describes the essential elements of the computer program PROTEUS that is based on the new method and that makes the assessment of aquatic risks for industrial activities an easy task, partly due to the automatic generation of the assessment report.

Cerebellar ataxia, dementia, pyramidal signs, cortical cataract of the posterior pole and a raised IgG index in a patient with a sporadic form of olivopontocerebellar atrophy.

Middle-aged patients who initially present with a progressive cerebellar ataxia, in the absence of a known familial pattern are often referred to under the descriptive diagnosis of 'idiopathic' late onset cerebellar ataxia. If these patients in time develop additional pyramidal or extrapyramidal features then they should be labeled as olivopontocerebellar atrophy (sOPCA). This case report describes a patient with OPCA with cerebellar ataxia as the presenting and most prominent feature in combination with dementia, pyramidal signs, cortical cataract of the posterior pole and a raised IgG index in cerebrospinal fluid. To the best of our knowledge this combination of signs and symptoms have not been described before.

A comparison of functional bladder damage after intravesical photodynamic therapy with three different photosensitizers.

The influence of type of photosensitizer, drug and light dose, and time interval between photosensitizer and illumination on the extent of photodynamic therapy (PDT)-induced bladder damage and recovery was investigated using a mouse model. The three photosensitizers studied were Photofrin, meso-tetrahydroxyphenylchlorin (m-THPC) and bacteriochlorin a (BCA). Functional bladder damage was quantitatively assessed from increases in urination frequency index (FI) at 1-35 weeks after illumination and histological damage was qualitatively assessed at 1 day, 1, 2 and 12 weeks. Photofrin-mediated PDT caused an acute increase in FI at 1 week, with recovery within 2-8 weeks after light doses of 2.7-8.2 J/cm2. After higher light doses there was only partial recovery. Previous results indicated that the acute response and rate of recovery was the same whether Photofrin was given at 1 day or up to 7 days before illumination. The m-THPC-mediated PDT at drug doses of > or = 0.3 mg/kg also resulted in a marked acute response with good recovery, even after 10.8 J/cm2. Lower drug doses in combination with 5.4 J/cm2 did not result in acute or late damage. There was no significant difference in acute response when m-THPC was given 1, 3 or 7 days before illumination, although recovery was faster for the longer illumination intervals (3 or 7 days). Illumination at 1 h after 20 mg/kg BCA induced an acute response within 2 days after illumination, with recovery within 4-8 weeks. Lower drug doses did not result in damage. The most prominent histological changes during the acute period with all three photosensitizers were submucosal edema and vessel dilation, with epithelial denudation (depending on drug/light dose). We conclude that BCA and m-THPC are both potent new photosensitizers. They can induce a moderate to severe acute bladder response with complete healing over a period of a few weeks. The photosensitizer m-THPC is very effective with low doses of photosensitizer and light, whereas relatively high doses of BCA and light are required to obtain equivalent functional bladder damage in our mouse model.

The influence of intravesical photodynamic therapy on subsequent bladder irradiation tolerance.

The aim of this project was to measure the irradiation tolerance of normal (non tumour bearing) mouse bladder after previous intravesical photodynamic therapy (PDT). Illumination with a range of light doses at 24 h after Photofrin was used as the initial PDT treatment and irradiation with a range of X-ray doses was given at 12 or 24 weeks after the initial therapy. Functional bladder damage was assessed from changes in micturition frequency (tested regularly for a follow-up period of 53 weeks after irradiation) and from cystometry measurements of the bladder at 53-56 weeks. PDT alone caused a marked increase in micturition frequency, with (partial) recovery by the time of irradiation. Irradiation alone caused a modest, transient acute response within 5 weeks and a progressive, permanent late response starting from about 25 weeks depending on X-ray dose. A reduced bladder capacity was also evident at 53-56 weeks after 20 Gy X-rays and after PDT alone. Irradiation after previous intravesical PDT caused an acute reaction similar to X-rays alone, but there was a much earlier expression of late functional bladder damage. The final level of damage prior to sacrifice at 53-56 weeks, was not significantly greater than after X-rays alone. These results suggest that irradiation after previous whole bladder PDT, for refractory bladder tumours, may lead to an increased risk of persistent increases in micturition frequency and reduced bladder capacity, beginning at very early times after irradiation.

Carrier detection of Batten disease (juvenile neuronal ceroid-lipofuscinosis).

Batten disease, or the juvenile form of neuronal ceroid lipofuscinosis, is an autosomal recessive neurodegenerative disorder manifesting with progressive blindness, seizures, and dementia, leading to an early death. The CLN3 locus which is involved in Batten disease had been localized to chromosome 16p11.2. Linkage disequilibrium has been observed between CLN3 and polymorphic microsatellite markers D16S288, D16S299, and D16S298, making carrier detection and prenatal diagnosis by haplotype analysis possible. For the purpose of carrier detection, haplotypes from Dutch Batten patients and their families were constructed. Most patients share the same D16S298 allele, suggesting the presence of a founder effect in the Dutch population. In a large inbred Dutch family, in which Batten disease occurs with high frequency, haplotype analysis has been carried out with high accuracy for carrier detection.

Radiation tolerance of normal mouse bladders after intravesical chemotherapy.

The aim of this study was to compare functional damage in normal mouse bladder after various initial intravesical therapies and to investigate tolerance to subsequent irradiation. Six consecutive weekly intravesical instillations of Mitomycin C (MMC) or doxorubicin (DOX) were used as the initial therapy. Irradiation with single doses of 10-25 Gy (X-rays) was given at 4 or 12 weeks after intravesical treatment. Functional bladder damage was assessed from changes in the micturition frequency, expressed as frequency index (FI, number of urination events/ml urine in a 24-h test period) and from cystometry measurements of bladder volume at 52-56 weeks. Irradiation alone caused a temporary acute response (increased FI) within the first 4 weeks and a progressive late response starting from 15 to 37 weeks, depending on the radiation dose. A reduced bladder capacity was also evident at 52-56 weeks after 25 Gy. Intravesical MMC or DOX caused a 3-fold increase in FI during intravesical therapy with recovery to control levels within 2-3 weeks after cessation of treatment. Irradiation 4 weeks after MMC, or 4 or 12 weeks after DOX resulted in acute responses very similar to irradiation alone. There was no difference in time of onset or extent of late bladder damage when irradiation was given after DOX, compared with irradiation alone as assessed from repeated measurements of FI or cystometry at 52-56 weeks. In contrast, irradiation 12 weeks after MMC led to a decrease in acute radiation response compared with X-rays alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Bladder damage in mice after single and repeated intravesical instillations of mitomycin C or doxorubicin.

Functional and histological damage after intravesical administration of mitomycin C or doxorubicin were studied in mouse bladders. Dosing schedules were based on those commonly used in the clinic, and bladder function was assessed from changes in urination frequency. Repeated weekly instillations of 1 mg./ml. mitomycin C induced a transient three-fold increase in Frequency Index (FI) with recovery to control levels within 3 weeks. Weekly instillations of 6 mg./ml. doxorubicin also resulted in a three-fold increase in FI, but lower doses produced only minimal changes. There was, again, full recovery within 3 weeks. Our experiments indicate that repeated intravesical instillations of mitomycin C or doxorubicin are well tolerated, with rapid recovery from functional damage within a few weeks of cessation of therapy. There was significantly less damage after repeated instillations of clinically relevant doses of doxorubicin than mitomycin C.

The fragile X syndrome: no evidence for any recent mutations.

Fragile X (fra(X)) syndrome, the most common form of familial mental retardation, is caused by heritable unstable DNA composed of CGG repeats. As reproductive fitness of fra(X) patients is severely compromised, a high mutation rate has been proposed to explain the high prevalence. However, we have been unable to show any new mutation for 84 probands referred to us to date. We show here the same fra(X) gene in five fra(X) probands with common ancestors married in 1747. The lack of new fra(X) mutations implies that there must be many more fra(X) gene carriers in the population than previously realised. As it is now possible to detect asymptomatic fra(X) gene carriers by DNA analysis, extended family studies for any new proband are recommended. A family illustrating the importance of fra(X) carriership determination is reported.

Trisomy 16 confined to the placenta.

Two cases with trisomy 16 confined to the placenta are presented. Prenatal diagnosis was indicated because of fetal growth retardation. In case 1, a phenotypically normal but small-for-date boy was born. In case 2, the fetus turned out to be triploid on cordocentesis. In both instances the trisomy 16 was recovered from the placenta. Recovery indicates that the abnormality was present in the placenta during the time of fetal growth retardation, which supports an aetiological relationship. Strict appliance of the current models cannot readily explain the observed discrepancies. In case 2, a chimeric placenta as a result of a vanishing twin is assumed. Cases of placental trisomy 16 published after 1988 are reviewed. It is concluded that confined placental trisomy 16 can cause intrauterine growth retardation if present in both the direct preparation and the villus culture. The chances of finding a chromosomally abnormal fetus (mosaic trisomy 16, triploidy) after diagnosis of trisomy 16 in chorionic villi are low but warrant further investigations.

Genotoxicity of benzo[a]pyrene, 2-nitrofluorene and airborne particulates in the DNA-repair host-mediated assay.

The genotoxic activity of benzo[a]pyrene (BAP), 2-nitrofluorene (NF) and airborne particulate matter was evaluated in the DNA-repair host-mediated assay after intraperitoneal or intratracheal administration. Dimethylnitrosamine (DMNA), used as a positive control, showed a genotoxic effect after both intraperitoneal and intratracheal administration, the strongest effect being found in liver, followed by lungs and kidneys, whereas a weak effect was observed in the spleen. In general no difference in genotoxicity was found between the 2 administration routes used. For BAP, although clearly positive in vitro, a moderate dose-dependent effect was found only in the liver after intraperitoneal administration. NF, which was positive in vitro both with and without a metabolizing system, produced no genotoxic effect in any of the organs tested after intraperitoneal administration. Extracts of airborne particulate matter which were genotoxic in vitro failed to cause a genotoxic effect in vivo by either route of administration. Possible explanations for the differences between the data obtained in vitro and in vivo are discussed.

Bone disease after orthotopic liver transplantation.

After orthotopic liver transplantation (OLT), not infrequently a deterioration of bone disease leading to compression fractures of vertebrae is seen. In a consecutive series of 36 adult OLT patients, we studied, clinically and radiologically, the incidence and degree of bone disease before and after OLT; we also studied whether clinical, radiological and laboratory findings were related to the event of postoperative vertebral collapse. Before OLT, radiological signs of mostly slight osteoporosis were seen in a minority of patients. After OLT, 38% of patients developed vertebral collapse, mainly in the second trimester. Collapse occurred in both previously normal and abnormal vertebrae. Of the preoperative parameters sex, age, menopause, intake of prednisolone, duration and diagnosis of liver disease, duration and degree of cholestasis, bone radiology and urinary calcium, only a low urinary calcium was related to postoperative collapse. Of the postoperative parameters duration of cholestasis, urinary calcium, duration of hospital stay, prednisolone dose and outcome in terms of life and death, none was related to collapse. We conclude that vertebral collapse after OLT occurs frequently and is not easily predicted. Early prevention of bone disease in patients with chronic liver disease before OLT and a low steroid-containing immunosuppressive regimen after OLT are advocated.