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Purpose: Thoracic aortic dissection (TAD) is a life-threatening cardiovascular disease that often results in sudden cardiac death (SCD). However, the genetic characteristics of individuals with TAD confirmed at autopsy have been rarely studied. Our objective was to determine the prevalence of pathogenic variants in TAD-associated genes in a cohort of sporadic deaths resulting from spontaneous rupture of TAD and identify relevant genotype-phenotype relationships in Han Chinese population., Methods: We included sixty-one consecutive sporadic decedents whose primary cause of death was spontaneous rupture of TAD, and performed a whole exome sequencing based strategy comprising 26 known TAD-associated genes., Results: We identified 7 pathogenic or likely pathogenic (P/LP) variants in 7 cases (11.48 %) and 22 variants of uncertain significance (VUS) in 22 cases (36.07 %). The FBN1 gene was found to be the major disease-causing gene. Notably, TAD decedents with P/LP variant exhibited significantly earlier mortality. Moreover, we reported for the first time that TAD decedents with P/LP variant had a shorter diagnosis and treatment time., Conclusion: Our study investigated the genetic characteristics of TAD individuals confirmed until autopsy in Han Chinese population. The findings enhanced the understanding of the genetic underpinnings of TAD and have significant implications for clinical management and forensic investigations., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cranial cruciate ligament disease and rupture (CCLD/R) is one of the most common orthopaedic conditions in dogs, eventually leading to osteoarthritis of the stifle joint. Certain dog breeds such as the Staffordshire bull terrier have an increased risk of developing CCLD/R. Previous studies into CCLD/R have found that glycosaminoglycan levels were elevated in cranial cruciate ligament (CCL) tissue from high-risk breeds when compared to the CCL from a low-risk breed to CCLD/R. Our objective was to determine specific proteoglycans/glycosaminoglycans in the CCL and to see whether their content was altered in dog breeds with differing predispositions to CCLD/R. Disease-free CCLs from Staffordshire bull terriers (moderate/high-risk to CCLD/R) and Greyhounds (low-risk to CCLD/R) were collected and key proteoglycan/glycosaminoglycans were determined by semi-quantitative Western blotting, quantitative biochemistry, quantitative reverse transcription polymerase chain reaction, and immunohistochemistry. Gene expression of fibromodulin (P = 0.03), aggrecan (P = 0.0003), and chondroitin-6-sulphate stubs (P = 0.01) were significantly increased, and for fibromodulin this correlated with an increase in protein content in Staffordshire bull terriers compared to Greyhound CCLs (P = 0.02). Decorin (P = 0.03) and ADAMTS-4 (P = 0.04) gene expression were significantly increased in Greyhounds compared to Staffordshire bull terrier CCLs. The increase of specific proteoglycans and glycosaminoglycans within the Staffordshire bull terrier CCLs may indicate a response to higher compressive loads, potentially altering their risk to traumatic injury. The higher decorin content in the Greyhound CCLs is essential for maintaining collagen fibril strength, while the increase of ADAMTS-4 indicates a higher rate of turnover helping to regulate normal CCL homeostasis in Greyhounds., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Cranial cruciate ligament disease (CCLD) is the most common cause of pelvic limb lameness in dogs but its precise aetiopathogenesis is uncertain. Fibrillin microfibrils (FM) are complex macro-molecular assemblies found in many tissues including ligaments, where they are thought to play an important mechanical role. We hypothesised that FM ultrastructural variation correlates with the differing predisposition of canine breeds to CCLD. Non-diseased cranial and caudal cruciate ligaments (CCLs and CaCLs) were obtained from Greyhound (GH) and Staffordshire Bull Terrier (SBT) cadavers. Fibrillin microfibrils were extracted from the ligaments by bacterial collagenase digestion, purified by size-exclusion chromatography and subsequently visualized by atomic force microscopy (AFM). With AFM, FMs have a characteristic beads-on-a-string appearance. For each FM, periodicity (bead-bead distance) and length (number of beads/FM) was measured. Fibrillin microfibril length was found to be similar for GH and SBT, with non-significant inter-breed and inter-ligament differences. Fibrillin microfibril periodicity varied when comparing GH and SBT for CCL (GH 60.2 ± 1.4 nm; SBT 56.2 ± 0.8 nm) and CaCL (GH 55.5 ± 1.6 nm; SBT 61.2 ± 1.2 nm). A significant difference was found in the periodicity distribution when comparing CCL for both breeds (P < 0.00001), further, intra-breed differences in CCL vs CaCL were statistically significant within both breeds (P < 0.00001). The breed at low risk of CCLD exhibited a periodicity profile which may be suggestive of a repair and remodelling within the CCL., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Emery Dreifuss muscular dystrophy (EDMD) is an inherited myopathy characterized by early contractures, slow progressive muscle weakness and cardiac involvement. To date at least seven genes have been associated to EDMD with different inheritance patterns, being emerin gene responsible for the X-linked form of the disease. We report a 40-year-old man who was referred for severe gait difficulty. At age 6 years the patient presented with a waddling gate, lumbar lordosis and heel contractures. Both electrophysiology and muscle biopsy were consistent with a neurogenic disorder and he received a diagnosis of spinal muscular atrophy type 3. At the age of 30 the patient developed heart involvement with junctional escape rhythm and, eight years later, had a spontaneous chordae tendinae rupture. A new clinical examination showed severe muscular weakness and atrophy in scapulohumeroperoneal pattern with significant involvement of the lower facial and intrinsic hand muscles and on a second muscle biopsy emerin was absent by immunohistochemistry and by immunoblot analysis. Sequence analysis of EMD gene revealed the presence of a novel mutation represented by an out-of-frame deletion spanning from the beginning of exon 1 to the half of intron 2 (p.Asp6Glyfs*27). Our study expands the clinical and molecular spectrum of X-linked EDMD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Intracranial aneurysm (IA) is a critical acquired cerebrovascular disease that may cause subarachnoid hemorrhage, and nuclear factor-κB (NF-κB)-mediated inflammation is involved in the pathogenesis of IA. Adenomatous polyposis coli ( Apc ) gene is a tumor suppressor gene associated with both familial and sporadic cancer. Herein, the purpose of our study is to validate effect of Apc gene on IA formation and rupture by regulating the NF-κB signaling pathway mediated inflammatory response. Methods: We collected IA specimens (from incarceration of IA) and normal cerebral arteries (from surgery of traumatic brain injury) to examine expression of Apc and the NF-κB signaling pathway related factors (NF-κB p65 and IκBα). ELISA was used to determine levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β (IL-1β), and IL-6. IA model was established in rats, and Apc-siRNA was treated to verify effect of Apc on IA formation and rupture. Next, regulation of Apc on the NF-κB signaling pathway was investigated. Results: Reduced expression of Apc and IκBα, and increased expression of NF-κB p65 were found in IA tissues. MCP-1, TNF-α, IL-1β, and IL-6 exhibited higher levels in unruptured and ruptured IA, which suggested facilitated inflammatory responses. In addition, the IA rats injected with Apc-siRNA showed further enhanced activation of NF-κB signaling pathway, and up-regulated levels of MCP-1, TNF-α, IL-1β, IL-6, MMP-2, and MMP-9 as well as extent of p65 phosphorylation in IA. Conclusion: Above all, Apc has the potential role to attenuate IA formation and rupture by inhibiting inflammatory response through repressing the activation of the NF-κB signaling pathway., (© 2019 The Author(s).)

Pathogenic variants in the lysyl-hydroxylase-1 gene (PLOD1) are responsible for the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS). The disease is classically responsible for severe hypotonia at birth, progressive kyphoscoliosis, generalised joint hypermobility and scleral fragility. Arterial fragility is an important feature of the disease, but its characterisation remains limited. We report the clinical history of a 41-year-old woman who presented repeated arterial accidents, which occurred in previously normal medium size arteries within a limited time span of 2 years. Molecular investigations revealed compound heterozygosity for two PLOD1 gene deletions of exons 11-12 and 14-15. Arterial fragility is an important characteristic of kyphoscoliotic EDS. It manifests as spontaneous arterial rupture, dissections and dissecting aneurysms which may occur even during early childhood. This fragility is particularly likely to manifest during surgical intervention. Early medical management and surveillance may be indicated, but its modalities remain to be defined., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Tumour rupture is a strong predictor of poor outcome in gastrointestinal stromal tumours (GISTs) of the stomach and small intestine. The objective was to determine whether tumour genotype was associated with risk of rupture., Methods: Rupture was classified according to the definition proposed by the Oslo Sarcoma Group. Since January 2000, data were registered retrospectively for all patients at Oslo University Hospital undergoing surgery for localized GIST of the stomach or small intestine. Tumour genotype was analysed by Sanger sequencing., Results: Two hundred and nine patients with mutation data available were identified. Tumour rupture occurred in 37 patients. Among the 155 patients with KIT exon 11 mutations, an increased risk of rupture was observed with a deletion or insertion-deletion (25 of 86, 29 per cent) compared with substitutions (5 of 50, 10 per cent) or duplications/insertions (2 of 19, 11 per cent) (P = 0·014). Notably, rupture occurred in 17 of 46 tumours (37 per cent) with deletions involving codons 557 and 558 (del557/558) versus 15 of 109 (13·8 per cent) with other exon 11 mutations (P = 0·002). This association was confined to gastric tumours: 12 of 34 (35 per cent) with del557/558 ruptured versus six of 77 (8 per cent) with other exon 11 mutations (P = 0·001). In multivariable logistic regression analysis, del557/558 and tumour size were associated with an increased likelihood of tumour rupture, but mitotic count was not., Conclusion: Gastric GISTs with KIT exon 11 deletions involving codons 557 and 558 are at increased risk of tumour rupture. This high-risk feature can be identified in the diagnostic evaluation and should be included in the assessment when neoadjuvant imatinib treatment is considered., (© 2018 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Background: Mitral chordae tendineae rupture (MCTR) is a progressive disorder which leads to severe mitral regurgitation. Despite its importance, the precise pathogenetic mechanism of MCTR remains unclear. The study aim was to investigate the expression profile of circulating microRNAs (miRNAs) as being potentially involved in the development of MCTR., Methods: Twenty-one patients with 'primary' MCTR, and 30 age- and gender-matched controls, were enrolled in the study. Comparisons were made between the expression levels of circulating miRNAs in MCTR patients and controls. Four target gene databases were used to predict target genes and pathways of differentially expressed miRNAs., Results: Compared to controls, the expression of 22 miRNAs (hsa-miR-106b-5p, hsa-miR-126-3p, hsa-miR-150-5p, hsa-miR-17-5p, hsa-miR-195-5p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-20a-5p, hsa-miR-21-5p, hsa-miR-222-3p, hsa-miR-223-3p, hsa-miR-23a-3p, hsa-miR-25-3p, hsa-miR-92a-3p, hsa-miR-93-5p, hsa-miR-26b-5p, hsa-miR-30e-5p, hsa-miR-373-3p, hsa-miR-15b-5p, hsa-miR-16-5p, hsa-miR-191-5p, hsa-miR-26a-5p) were significantly down-regulated in the MCTR group. Bioinformatic analysis indicated that the following potential miRNA targets and pathways are commonly related to the development of MCTR: MMPs, TIMP-2,TGFBR2, VEGFA, PIK3R2, NRAS, PPP3CA, PPP3R1, PTGS 2 were predicted as putative targets of 13 of these miRNAs., Conclusions: The present study is the first to describe altered miRNA expression in patients with MCTR. Bioinformatic analysis has revealed that target genes involved in MCTR development were regulated by miRNAs.

History and clinical findings | A 57-year-old woman with a history of emphysematous COPD GOLD D and homozygotic alpha-1-antitrypsin deficiency presented with aggravated dyspnoea, presyncope and left thoracic chest pain. 12 years previously Stanford type B dissection had been conservatively treated. Examinations | Chest radiograph revealed extended infiltrates of the left lower lobe. Seen together with elevated inflammatory values and the patient´s hemodynamic instability it pointed at a pneumonia-driven septic shock. In view of a progressive respiratory insufficiency and an acute drop in haemoglobin computed tomography was performed. It showed rupture of an aneurysmatic left lower pulmonary artery with consecutive intraparenchymal bleeding. Treatment and course | Because of persistent bleeding and respiratory failure requiring invasive ventilation, thoracotomy was performed. Left lower pulmonary artery was sutured and left lower lobe resected. After initial postoperative stabilization bronchopleural fistula demanded re-thoracotomy and parenchymal lesions of left upper lobe were sutured. In consequence of progressive sepsis and manifest multiorgan failure patient died 15 days after initial surgical bleeding control. Conclusion | Though homozygotic alpha-1-antitrypsin deficiency is primarily associated with lung and liver disease, extrapulmonary and extrahepatic manifestation may occur. In view of consistent case reports and plausible pathogenetic mechanisms, vascular complications comprising arterial aneurysms and dissection due to compromised vascular integrity in alpha-1-antitrypsin deficient individuals is conceivable, but lacks scientific proof., (© Georg Thieme Verlag KG Stuttgart · New York.)

Cranial Cruciate Ligament rupture (CCLR) is one of the most common forms of lameness in dogs and is analogous to rupture of the anterior cruciate ligament in humans, for which it can serve as a model. As there is a strong breed-related predisposition to CCLR in dogs, a study was undertaken to consider putative genetic components in susceptible dog breeds. A candidate gene, single nucleotide polymorphism (SNP) genotyping approach using MALDI-TOF mass spectrometry (Sequenom Ltd) was designed to investigate several CCLR-susceptible dog breeds and identify CCLR-associated genes/gene regions that may confer susceptibility or resistance. A meta-analysis was performed using the breed case/control candidate gene data to identify SNP associations that were common to the whole cohort of susceptible dogs. We identified SNPs in key genes involved in ligament strength, stability and extracellular matrix formation (COL5A1, COL5A2, COL1A1, COL3A1, COL11A1, COL24A1, FBN1, LOX, LTBP2) which were significantly associated with CCLR susceptibility across the dog breeds used in this study. These SNPs could have an involvement in CCLR due to a detrimental effect on ligament structure and strength. This is the first published candidate gene study that has revealed significant genetic associations with canine CCLR.

Background: Genetic risk factors for intracranial aneurysms may influence the size of aneurysms., Objective: To assess the association between genetic risk factors and the size of aneurysms at the time of rupture., Methods: Genotypes of 7 independent single-nucleotide polymorphisms (SNPs) of the 6 genetic risk loci identified in genome-wide association studies of patients with intracranial aneurysms were obtained from 700 Dutch patients with an aneurysmal subarachnoid hemorrhage (1997-2007) previously genotyped in the genome-wide association studies; 255 additional Dutch patients with an aneurysmal subarachnoid hemorrhage (2007-2011) were genotyped for these SNPs. Aneurysms were measured on computerized tomography angiography or digital subtraction angiography. The mean aneurysm size (with standard error) was compared between patients with and without a genetic risk factor by the use of linear regression. The association between SNPs and size was assessed for single SNPs and for the combined effect of SNPs by using a weighted genetic risk score., Results: Single SNPs showed no association with aneurysm size, nor did the genetic risk score., Conclusion: The 6 genetic risk loci have no major influence on the size of aneurysms at the time of rupture. Because these risk loci explain no more than 5% of the genetic risk, other genetic factors for intracranial aneurysms may influence aneurysm size and thereby proneness to rupture.

Many people carry cerebral aneurysms but are generally unaware of their presence until they rupture, resulting in high morbidity or mortality. The pathogenesis and aetiology of aneurysms are largely unknown; however, a greater understanding, by analysing the genetic, molecular and haemodynamic risk factors involved in the initiation, enlargement, and rupture of aneurysms, could lead to effective prevention, early diagnosis and more effective treatment. The risk of aneurysm is increased by a family history of aneurysms, and amongst certain populations, namely in Japan and Finland. Several other risk factors are documented, including hypertension, smoking, alcohol consumption, and female sex. Studies indicate a higher occurrence of cerebral aneurysms in females compared to males. Oestrogen protects several components within the artery wall, and inhibits some of the inflammatory molecules that could cause aneurysms. At menopause, the oestrogen level decreases and the incidence of aneurysm increases. Haemodynamic stresses have been shown to be involved in the formation, growth and rupture of aneurysms. This is often associated with hypertension, which also increases the risk of aneurysm rupture. When an unruptured aneurysm is detected the decision to treat can be complicated, since only 1-2% of aneurysms eventually rupture. Haemodynamic simulation software offers an effective tool for the consideration of treatment options for patients who carry unruptured aneurysms. The assessment must consider the risks of interventional treatments versus non-interventional management options, such as controlling blood pressure., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objectives: Lysozyme amyloidosis (ALys) is a form of hereditary systemic non-neuropathic amyloidosis, which is inherited in an autosomal dominant fashion. Lysozyme, which is the amyloidogenic precursor protein in ALys, is a ubiquitous bacteriolytic enzyme synthesized by hepatocytes, polymorphs and macrophages. The aim of this study is to describe the phenotype and outcome of patients with ALys including the role of solid organ transplantation., Design: Retrospective evaluation of patients with ALys., Setting: UK National Amyloidosis Centre., Patients: All 16 patients with ALys followed at the centre., Results: A family history of amyloidosis was present in every affected individual. Although the phenotype was broadly similar amongst those from the same kindred, there were marked phenotypic differences between kindreds who possessed the same amyloidogenic mutation. Symptomatic gastrointestinal (GI) amyloid was prevalent, and macroscopically visible amyloidotic lesions were present in nine of 10 patients who underwent GI endoscopy. All symptomatic ALys individuals had hepatic amyloid. Four patients received orthotopic liver transplants (OLT), three for spontaneous hepatic rupture and one case, who had extensive hepatic amyloid and a strong family history of hepatic rupture, pre-emptively. All of the liver grafts were functioning at censor 1.7, 5.8, 9.0 and 11.0 years after OLT. Five patients had progressive amyloidotic renal dysfunction culminating in end-stage renal failure, three of whom underwent renal transplantation (RTx). There was no evidence of renal allograft dysfunction at censor 6.6, 1.8 and 0.8 years after RTx., Conclusions: Lysozyme amyloidosis is a disease of the GI tract, liver and kidneys, which has a slow natural history. There was a clear family history in all cases within this cohort, demonstrating a high clinical penetrance in the presence of an amyloidogenic lysozyme mutation. There is currently no amyloid-specific therapy for the condition which is managed symptomatically. OLT and RTx appear to be successful treatments for patients with liver rupture or end-stage renal disease, respectively, with excellent outcomes in terms of medium-term graft function and patient survival., (© 2011 The Association for the Publication of the Journal of Internal Medicine.)

Background: Spontaneous intracerebral hemorrhage (ICH) represents about 15% of all strokes and is associated with high mortality rates. Our aim was to identify the gene expression changes and biological pathways altered in the brain following ICH., Methodology/principal Findings: Twelve brain samples were obtained from four deceased patients who suffered an ICH including perihematomal tissue (PH) and the corresponding contralateral white (CW) and grey (CG) matter. Affymetrix GeneChip platform for analysis of over 47,000 transcripts was conducted. Microarray Analysis Suite 5.0 was used to process array images and the Ingenuity Pathway Analysis System was used to analyze biological mechanisms and functions of the genes. We identified 468 genes in the PH areas displaying a different expression pattern with a fold change between -3.74 and +5.16 when compared to the contralateral areas (291 overexpressed and 177 underexpressed). The top genes which appeared most significantly overexpressed in the PH areas codify for cytokines, chemokines, coagulation factors, cell growth and proliferation factors while the underexpressed codify for proteins involved in cell cycle or neurotrophins. Validation and replication studies at gene and protein level in brain samples confirmed microarray results., Conclusions: The genomic responses identified in this study provide valuable information about potential biomarkers and target molecules altered in the perihematomal regions.

Background: In patients with myocardial infarction, high serum levels of interleukin-6 cytokines predict a poor outcome. The common receptor of interleukin-6 cytokines, glycoprotein-130 (gp130), signals via janus kinase/signal transducer and activator of transcription (STAT), cytoplasmic protein tyrosine phosphatase/extracellular signal-regulated kinase, and phosphoinositide-3-kinase/Akt pathways, and the regulation of these pathways depends at least in part on the gp130 tyrosine-757 residue. By analyzing cardiomyocyte-specific gp130(Y757F) mutant mice, we investigated the effect of disturbed gp130 signaling after myocardial infarction., Methods and Results: The cardiomyocyte-restricted alpha-myosin heavy chain-Cre-recombinase-loxP system was used to generate mice with gp130(Y757F) mutant cardiomyocytes (alphaMHC-Cre(tg/-);gp130(fl/Y757F) [Y(757)F]); all other cells carried at least 1 functional gp130 gene, ensuring normal gp130 signaling. Y(757)F mice displayed normal cardiac function and morphology at 3 months of age comparable to their nonmutant littermates. In response to myocardial infarction, Y(757)F mice displayed higher mortality associated with increased left ventricular rupture rate, sustained cardiac inflammation, and heart failure. These adverse effects were associated with prolonged and enhanced STAT3 activation and increased expression of interleukin-6 and of the complement-activating mannose-binding lectin C. Pharmacological inhibition of the complement system by cobra venom factor attenuated inflammation, prevented left ventricular rupture, and improved cardiac function in Y(757)F mice. Stronger effects were observed with a genetic reduction of STAT3 (STAT3(flox/+)) restricted to cardiomyocytes in Y(757)F mice, which prevented extensive upregulation of interleukin-6, complement activation, and sustained inflammation and lowered left ventricular rupture rate, heart failure, and mortality in subacute myocardial infarction., Conclusions: Impaired downregulation of gp130-mediated STAT3 activation in subacute infarction promotes cardiac inflammation, adverse remodeling, and heart failure, suggesting a potential causative role of high interleukin-6 serum levels after myocardial infarction.

Arachidonic acid metabolism plays a key role in atherothrombotic events affecting the coronary or cerebrovascular territory, as reflected by experimental studies based on biochemical measurements of eicosanoid biosynthesis and the results of inhibitor trials in these settings. Two cyclooxygenase (COX)-isozymes exist, COX-1 and COX-2, that differ in terms of regulatory mechanisms of expression, tissue distribution, substrate specificity, and susceptibility to inhibition by drugs. Whereas the role of COX-1 expressed in platelets in acute coronary syndromes and ischemic stroke is definitely established through several large clinical studies with aspirin, the role of COX-2 activity in these settings is still unclear, because this enzyme was characterized only recently (1991) and its inhibitors (coxibs) only became available in 1998. In this review, we discuss the different expression profile of COX-2-related enzymes in the cells actively involved in atherothrombosis, the role of these enzymes as cause of plaque "instability", and the clinical consequences of their inhibition. Recent studies suggest that variable expression of transmembrane and downstream receptors, as well as genetic mutations represent important determinants of the functional consequences of COX-2 expression and inhibition in different clinical settings.

A 62-year-old woman was admitted to hospital because of nausea. A grade 5/6 continuous murmur was audible near the left sternal border at the second intercostal space. Chest X-ray showed cardiomegaly and bilateral pleural effusion. She was diagnosed as heart failure and a diuretic was prescribed. After remission of the heart failure, echocardiography showed shunt flow from the right coronary cusp to the right ventricle. Aortography revealed that an aneurysm of the right coronary sinus of Valsalva had ruptured into the right ventricle. Coronary angiography revealed a single coronary artery. Chest computed tomography revealed persistent left superior vena cava. Surgical repair was carried out and the patient made an uneventful recovery. In addition to these cardiovascular abnormalities, she had Wildervanck syndrome (Klippel-Feil syndrome, Duane syndrome and sensorineural hearing disturbance), blepharoptosis and short stature. This rare combination has not been reported previously.

Mutations in the COL1A1 and COL1A2 genes, encoding the proalpha1 and 2 chains of type I collagen, cause osteogenesis imperfecta (OI) or Ehlers-Danlos syndrome (EDS) arthrochalasis type. Although the majority of missense mutations in the collagen type I triple helix affect glycine residues in the Gly-Xaa-Yaa repeat, few nonglycine substitutions have been reported. Two arginine-to-cysteine substitutions in the alpha1(I)-collagen chain are associated with classic EDS [R134C (p.R312C)] or autosomal dominant Caffey disease with mild EDS features [R836C (p.R1014C)]. Here we show alpha1(I) R-to-C substitutions in three unrelated patients who developed iliac or femoral dissection in early adulthood. In addition, manifestations of classic EDS in Patient 1 [c.1053C>T; R134C (p.R312C); X-position] or osteopenia in Patients 2 [c.1839C>T; R396C (p.R574C); Y-position] and 3 [c.3396C>T; R915C (p.R1093C); Y-position] are seen. Dermal fibroblasts from the patients produced disulfide-bonded alpha1(I)-dimers in approximately 20% of type I collagen, which were efficiently secreted into the medium in case of the R396C and R915C substitution. Theoretical stability calculations of the collagen type I heterotrimer and thermal denaturation curves of monomeric mutant alpha1(I)-collagen chains showed minor destabilization of the collagen helix. However, dimers were shown to be highly unstable. The R134C and R396C caused delayed procollagen processing by N-proteinase. Ultrastructural findings showed collagen fibrils with variable diameter and irregular interfibrillar spaces, suggesting disturbed collagen fibrillogenesis. Our findings demonstrate that R-to-C substitutions in the alpha1(I) chain may result in a phenotype with propensity to arterial rupture in early adulthood. This broadens the phenotypic range of nonglycine substitutions in collagen type I and has important implications for genetic counseling and follow-up of patients carrying this type of mutation., (Copyright 2007 Wiley-Liss, Inc.)

Objective: Lysosomal proteinases have been implicated in a number of pathologies associated with extracellular matrix breakdown. Therefore, we investigated the possibility that the lysosomal proteinase cathepsin S may be involved in atherosclerotic plaque destabilization., Methods and Results: Atherosclerotic plaques in the brachiocephalic arteries of fat-fed apolipoprotein E/cathepsin S double knockout mice had 73% fewer acute plaque ruptures (P=0.026) and were 46% smaller (P=0.025) than those in age-, strain-, and sex-matched apolipoprotein E single knockout controls. When the incidence of acute plaque rupture was normalized for plaque size, the reduction in the double knockouts was 72% (P=0.039). The number of buried fibrous layers, indicative of an unstable plaque phenotype, was reduced by 67% in the double knockouts (P=0.008). The cysteine proteinase inhibitor, egg white cystatin, was biotinylated and used as an active-site-directed probe for cathepsins. Biotinylated cystatin selectively detected cathepsin S in extracts of human carotid atherosclerotic plaque. Active cathepsin S was detectable in extracts of human atherosclerotic plaque but not in nondiseased carotid arteries. Active cathepsins were especially prominent in macrophages in the shoulder regions of plaques, areas considered to be vulnerable to rupture. Cathepsin S protein colocalized with regions of elastin degradation in human coronary plaques., Conclusions: These data provide direct evidence that an endogenous proteinase, cathepsin S, plays an important role in atherosclerotic plaque destabilization and rupture.

Purpose of Review: Rupture of an atherosclerotic plaque is the predominant underlying event in the pathogenesis of acute coronary syndromes and stroke. While ruptured plaques are morphologically well described, the precise molecular mechanisms involved in plaque rupture are still incompletely understood. Over the last few years, techniques like microarray, suppression subtractive hybridization and differential display enabled us to study complex gene expression profiles that occur during the process of atherogenesis. In this review we focus on recent large-scale gene expression profiles performed on whole mount vascular specimens., Recent Findings: The gene expression profiles on whole mount vascular tissue confirmed that at least three mechanisms are involved in plaque rupture: (1) a disturbed balance in extracellular matrix turnover, (2) disturbed regulation of cell turnover and (3) processes involved in lipid metabolism. Animal models exhibiting features of plaque rupture reflect the involvement of these three mechanisms. The most dramatic mouse phenotypes were observed after interventions in at least two of these mechanisms., Summary: The observation of plaque rupture in recent mice models is indicative of the multifactorial process of plaque rupture. This multifactorial character of plaque rupture suggests that interventions may be most effective when they influence more than one mechanisms at a time.

Atherosclerosis and plaque rupture represent complex "traits" of unknown cause that involve multiple genes and their variants. Novel genomic technologies provide us with the tools that will allow for the identification of groupings of genes that determine either susceptibility or resistance relative to the development of atherosclerosis and its thromboembolic complications. This information may, in turn, lead to a clearer understanding of the cause and risk for atherosclerosis. Diagnostic tools, as well as preventive and therapeutic strategies, will be derived from such heightened understanding of the disease process. With this chapter, we have presented the current state of knowledge of atherosclerosis genomics., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

We treated a patient who had previously undergone a hepatic resection for ruptured hepatocellular carcinoma (HCC) but developed a solitary peritoneal recurrence at the site of the incision 8 years and 9 months later. Since no other recurrence was evident, we resected the tumour. The primary tumour was 2.5 cm in size and histological examination revealed HCC without any histological risk factors for intrahepatic recurrence. The peritoneal tumour consisted of less differentiated cancer cells than those found in the primary tumour. The positive rates of Ki-67 were 10% in the primary tumour and 23.3% in the peritoneal recurrence. The DNA indexes in both tumours were considered to be identical. The comparison between the primary and peritoneal tumours suggested that the histological differentiation and proliferation activity can change after recurrence, in spite of consistent DNA ploidy contents. Clinically, a patient who undergoes a hepatic resection for ruptured HCC can survive for a long time, such as 10 years, if they have good liver function and small HCC without any histological risk factors for intrahepatic recurrence. However, since late recurrence is possible, a follow up for as long as 10 years is recommended.