5 research outputs found
Validation and application of intravascular ultrasound in endovascular treatment of abdominal aortic aneurysm
An abdominal aortic aneurysm (AAA) is a localized and permanent
dilatation of the aorta that presents a clear danger for the patient because of
the risk of rupture. The chance of rupture increases with the size of the
aneurysm. Mortality after rupture is high: 60-70% of patients with a
ruptured AAA will not reach the hospital alive. Furthermore, surgical
treatment of ruptured AAA carries an additional mortality of 45-55%.
Because of the poor prognosis of ruptured AAA, prophylactic exclusion of
AAA is performed for AAA larger than 5.0 to 5.5 cm in diameter. The
standard way of treating AAA is by elective open surgery. In this procedure,
the diseased aortic segment is opened after proximal and distal cleaning of
the vessel and the contents of the aneurysm are removed. A synthetic
prosthesis is placed inside the aneurysm. The proximal and distal ends of
the prosthesis are anastomosed via continuous sutures to the normal aorta
and/or iliac arteries, after which the aneurysm wall is closed around the
prosthesis. Elective surgery itself carries a mortality of 5_7% ,patients
aged over 70 years, patients with congestive heart failure, cardiac ischemia,
preexistent dysrythmia, renal impairment or pulmonary impairment are
known to have an increased mortality
Intravascular ultrasound evidence for coarctation causing symptomatic renal artery stenosis
BACKGROUND: A recent study of human cadaveric renal arteries revealed that
renal artery narrowing could be due not only to atherosclerotic plaque
compensated for by adaptive remodeling, but also to hitherto undescribed
focal narrowing of an otherwise normal renal arterial wall (ie,
coarctation). The present study investigated whether vessel coarctation
could be identified in patients with symptomatic renal artery stenosis
(RAS). METHODS AND RESULTS: Consecutive symptomatic patients with
angiographically proven atherosclerotic RAS who were referred for stent
placement were studied by 30-MHz intravascular ultrasound before
intervention (n=18) or after predilatation (n=18). Analysis included
assessment of the media-bounded area and plaque area (PLA) at the most
stenotic site and at a distal reference site (most distal cross-section in
the main renal artery with normal appearance). Coarctation was considered
present whenever the target/reference media-bounded area was </=85%.
Before intervention, coarctation was observed in 9 of 18 patients and
adaptive remodeling in 9 of 18 patients. Coarctation lesions had a
significantly smaller PLA than adaptive remodeled lesions (P=0.001).
Similarly, despite predilatation, coarctation was seen in 8 of 18 patients
who had significantly smaller PLAs (P=0. 008) when compared with those
patients who had adaptive remodeled lesions. No differences in severity of
RAS or angiographic or clinical parameters were observed. CONCLUSIONS:
Low-plaque coarctation may cause a considerable proportion of symptomatic
RAS, which is angiographically and clinically indistinguishable from
plaque-rich RAS
The clinical spectrum of limb girdle muscular dystrophy. A survey in the Netherlands
A cross-sectional study was performed in the Netherlands to define the clinical characteristics of the various subtypes within the broad and heterogeneous entity of limb girdle muscular dystrophy (LGMD). An attempt was made to include all known cases of LGMD in the Netherlands. Out of the reported 200 patients, 105 who fulfilled strictly defined criteria were included. Forty-nine patients, mostly suffering from dystrophinopathies and facioscapulohumeral muscular dystrophy, appeared to be misdiagnosed. Thirty-four cases were sporadic, 42 patients came from autosomal recessive and 29 from autosomal dominant families. The estimated prevalence of LGMD in the Netherlands was at least 8.1 x 10-6. The clinical features of the autosomal recessive and sporadic cases were indistinguishable from those of the autosomal dominant patients, although half hypertrophy was seen more frequently, and the course of the disease was more severe in autosomal recessive and sporadic cases. The pectoralis, iliopsoas and gluteal muscles, hip adductors and hamstrings were the most affected muscles. Distal muscle involvement occurred late in the course of the disease. Facial weakness was a rare phenomenon. The severity of the clinical picture was correlated with a deteriorating lung function. All autosomal dominantly inherited cases showed a mild course, although in two families life-expectancy was reduced because of concomitant cardiac involvement
Heterogeneous clinical phenotypes and cerebral malformations reflected by rotatin cellular dynamics
Recessive mutations in RTTN, encoding the protein rotatin, were originally identified as cause of polymicrogyria, a cortical malformation. With time, a wide variety of other brain malformations has been ascribed to RTTN mutations, including primary microcephaly. Rotatin is a centrosomal protein possibly involved in centriolar elongation and ciliogenesis. However, the function of rotatin in brain development is largely unknown and the molecular disease mechanism underlying cortical malformations has not yet been elucidated. We performed both clinical and cell biological studies, aimed at clarifying rotatin function and pathogenesis. Review of the 23 published and five unpublished clinical cases and genomic mutations, including the effect of novel deep intronic pathogenic mutations on RTTN transcripts, allowed us to extrapolate the core phenotype, consisting of intellectual disability, short stature, microcephaly, lissencephaly, periventricular heterotopia, polymicrogyria and other malformations. We show that the severity of the phenotype is related to residual function of the protein, not only the level of mRNA expression. Skin fibroblasts from eight affected individuals were studied by high resolution immunomicroscopy and flow cytometry, in parallel with in vitro expression of RTTN in HEK293T cells. We demonstrate that rotatin regulates different phases of the cell cycle and is mislocalized in affected individuals. Mutant cells showed consistent and severe mitotic failure with centrosome amplification and multipolar spindle formation, leading to aneuploidy and apoptosis, which could relate to depletion of neuronal progenitors often observed in microcephaly. We confirmed the role of rotatin in functional and structural maintenance of primary cilia and determined that the protein localized not only to the basal body, but also to the axoneme, proving the functional interconnectivity between ciliogenesis and cell cycle progression. Proteomics analysis of both native and exogenous rotatin uncovered that rotatin interacts with the neuronal (non-muscle) myosin heavy chain subunits, motors of nucleokinesis during neuronal migration, and in human induced pluripotent stem cell-derived bipolar mature neurons rotatin localizes at the centrosome in the leading edge. This illustrates the role of rotatin in neuronal migration. These different functions of rotatin explain why RTTN mutations can lead to heterogeneous cerebral malformations, both related to proliferation and migration defects.Genetics of disease, diagnosis and treatmen
Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction
Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein–protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families