Dysplastic Syndrome Research Articles

Mid-aortic dysplastic syndrome as a rare cause of hypertension in young

Introduction: Mid-aortic syndrome (MAS), coarctation of abdominal aorta is a rare disease with only 200 reported cases. It is characterized by constriction of distal thoracic and/or abdominal aorta and its branches, therefore is also known as abdominal aortic coarctation. The MAS is characterized radiologically by severe narrowing of abdominal aorta and its branches and most of these patients usually die due to progressive severe hypertension before the age of 35-40 if left untreated. Case Report: A 13-year-old boy was admitted with persistent headache and vomiting for one month and repeated generalized tonic clonic seizures for two days. His past history was unremarkable. The highlight of the clinical examination blood pressure was 240/150 mmHg in both the upper limbs, and all peripheral pulses were palpable. Blood pressure was similar in upper and lower limbs and a systolic bruit heard over the epigastrium. Ultrasonography showed a localized narrowing of a suprarenal segment of the abdominal aorta with an abrupt focal dilatation of the abdominal aorta approx 1.7cm below origin of superior mesenteric artery. Magnetic resonance angiography of the aorta and its branches showed a distinct fusiform dilatation of abdominal aorta just below the origin of the superior mesenteric artery. Focal narrowing of abdominal aorta was noted just proximal to the dilatation. Conclusion: We diagnosed a case of mid-aortic coarctation with post stenotic dilatation associated with left renal artery stenosis leading to secondary hypertension in a teenage boy presenting with reversible posterior leukoencephalopathy and seizures. The boy was referred for vascular surgery but the patient refused any operative procedure.

Revascularization of midaortic dysplastic syndrome

Revascularization of midaortic dysplastic syndrome

Takayasu arteritis with mid aortic dysplastic syndrome presenting as dilated cardiomyopathy

Takayasu arteritis (TA) is a chronic inflammatory and obliterative disease of large vessels particularly the aorta and its major branches. Takayasu arteritis can have various presentations, depending on site and extent of disease. We describe a case of TA with mid aortic dysplastic syndrome, which presented as dilated cardiomyopathy.

Editorial Coarctation of the aorta

Editorial Coarctation of the aorta

The Sequential Combination Paradigm in Epigenetic Therapy

Copyright: © 2012 Fandy TE. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Epigenetic therapy is a novel therapeutic approach that targets DNA methylation, histone modifications or microRNAs (miRNAs). Drugs targeting DNA methylation (azacitidine and decitabine) and histone acetylation (vorinostat) are currently FDA-approved for the treatment of Myelo Dysplastic Syndromes (MDS) and cutaneous T-Cell Lymphoma (CTCL), respectively. Drugs targeting miRNAs and other histone modifications are currently in preclinical and clinical trials. A central hypothesis in epigenetic therapy is the combination of epigenetic modifiers in a specific sequential order to achieve optimal expression of epigenetically silenced tumor suppressor genes. This paradigm was established based on the observation that inhibitors of class I & II Histone Deacetylase (HDAC) enzymes cannot re-express genes silenced by promoter hypermethylation [1]. The use of a DNA Methyl Transferase (DNMT) inhibitor followed by an HDAC inhibitor is required for the re-expression of genes silenced by promoter hypermethylation. Consequently, the sequential or overlapping combination of DNA hypomethylating agents and HDAC inhibitors has been utilized in several clinical trials based on this hypothesis [2,3].

Letters to Editor Hypertension without renovascular stenosis: a rare case of abdominal aorta coarctation treated with percutaneous transluminal angioplasty

Letters to Editor Hypertension without renovascular stenosis: a rare case of abdominal aorta coarctation treated with percutaneous transluminal angioplasty

Spontaneous patella fracture presenting as osteomyelitis in focal dermal hypoplasia

We report the first case of the assessment and treatment of a spontaneous patellar fracture in a patient with Goltz syndrome—a rare dermal hypoplasia. This case illustrates the non-straightforward presentation of a spontaneous patellar fracture in seemingly osteoporotic bone stock further complicated by the inability to rule out osteomyelitis. In this confusing presentation, a high index of suspicion for patella fracture should be maintained for patients with knee pain and osteoporosis on x-ray with a dysplastic syndrome.

Modern aspects in radiodiagnosis of dysplastic gonarthrosis (a review of literature)

Osteoarthrosis (OA) takes the first place among all diseases of joints and is one of the most common forms of human diseases. Particular attention in OA structure is attracted by a lesion of the knee joint. Dysplastic deformities of the knee joint are risk factors for OA development. These are characterized by polymorphous soft-tissue and bone dystrophic changes and clinical signs. The dysplastic process affects all elements of the knee joint and includes underdevelopment of soft-tissue components of the joint (the capsular-ligamentous apparatus, menisci), dysplastic changes in the femoropatellar and tibiofemoral joints.It is very difficult to diagnose dysplastic syndromes of the knee joint with their complex genesis, different cause-and-effect relations at each stage of the disease development, multiple factors and polymorphous clinical nature. Despite a wide spectrum of diagnostic methods, today the priority in diagnosing OA belongs to traditional radiography, because the latter is sufficiently informative, available, simple for carrying studies and economical.

ACE-536, a Modified Type II Activin Receptor Increases Red Blood Cells In Vivo by Promoting Maturation of Late Stage Erythroblasts

AbstractAbstract 4236Anemia is one of the most common blood disorders in several diseases including cancer, heart failure, chronic kidney disease (CKD) and Myeloid Dysplastic Syndromes (MDS) associated with a negative outcome. Administration of recombinant Erythropoietin (EPO) represents the most common treatment for anemia. However, a significant number of people remain hypo or non-responsive to EPO treatment, and in some cases its use has been linked to tumor growth, cardiovascular disease and poorer survival. The members of TGFβ super family of ligands (Activins, GDFs and BMPs) and receptors (Type I and II) regulate more than 500 target genes transcriptionally by Smad phosphorylation and are involved in many cellular functions including cell growth, adhesion, migration, differentiation and apoptosis in a concentration and context dependent manner. Members of the TGFβ family have also demonstrated a role in erythropoiesis. ACE-536, a non-ESA agent is a soluble human Fc fusion chimera of a modified Activin Type IIb receptor with a mutation in its extracellular domain. Surface Plasmon Analysis (Biacore) analysis and cell based reporter assays revealed that this mutation disrupted its binding to Activin A but not to GDF11 or GDF8. ACE-536 acts as a decoy receptor for TGFβ signaling and demonstrated potent increase in red blood cells in all the tested animals (mice, rats and monkeys). Subcutaneous administration of ACE-536 (10mg/kg) to C57BL/6 mice resulted in a significant increase in hematocrit, hemoglobin and red blood cells (RBC) over the TBS treated vehicle group after 4 days. These observations were seen even in the presence of an EPO neutralizing antibody; suggesting that EPO is not directing the initial RBC response to ACE-536 treatment. There were no increase in BFU-E or CFU-E colony formation from bone marrow and spleen after 48hrs treatment with ACE-536 over TBS treated group demonstrating that it does not have effect on erythroid progenitor population. Differentiation profiling of bone marrow and splenic erythroblasts by flow cytometric analysis revealed that ACE-536 promotes maturation of developing erythroblasts. ACE-536 treatment for 72 hours resulted in a decrease in basophilic erythroblasts and an increase in late stage poly, ortho chromatophilic erythroblasts in bone marrow and spleen compared to the TBS treated mice. Treatment of Sprague-Dawley rats with a murine analogue of ACE-536 (RAP-536; 10mg/kg) increased the reticulocyte formation in peripheral blood over vehicle treated group. ACE-536 (10mg/kg) treatment combined with recombinant human EPO (1800 units/kg) for 72 hours increased RBC, hematocrit and hemoglobin by approximately 23% over TBS treated vehicle group and 12% over EPO treatment alone. Consistent with its role in proliferation, EPO increased splenic basophilic erythroblast formation. However, ACE-536 treatment combined with EPO significantly promoted maturation of late stage erythroblasts; demonstrating a novel mechanism during erythroid differentiation. To gain further insights into its mechanism of action, C57BL/6 mice were administered with or without RAP-536 (10mg/ml twice a week) pre treated for a week with neutralizing anti-Activin A (10mg/kg) or ActRIIa (10mg/ml) or ActRIIb (10mg/ml) (does not bind ACE-536) antibodies. Anti-ActRIIa but not anti-Activin A or anti- ActRIIb antibody pre-treatment inhibited the RBC increase by RAP-536 suggesting that ActRIIa or its ligands are necessary for transducing the signal. To summarize, ACE-536 treatment results in a rapid increase in red blood cells by a novel mechanism promoting maturation of late stage erythroblasts. The efficacy of ACE-536 molecule was tested in several acute and chronic anemia animal models including blood loss anemia, chemotherapy induced anemia, chronic kidney disease (5/6 Nephrectomy) and Myeloid Dysplastic Syndrome (MDS) and found that ACE-536 treatment prevents or decreases anemia in all these models. Furthermore, unlike EPO, ACE-536 did not promote tumor progression (in Lewis Lung Carcinoma model) thus offering strong promise as alternate treatments for anemia. Disclosures:Suragani:Acceleron Pharma: Employment. Cadena:Acceleron Pharma: Employment. Mitchell:Acceleron Pharma: Employment. Sako:Acceleron Pharma: Employment. Davies:Acceleron Pharma: Employment. Tomkinson:Acceleron Pharma: Employment. Devine:Acceleron Pharma: Employment. Ucran:Acceleron Pharma: Employment. Grinberg:Acceleron Pharma: Employment. Underwood:Acceleron Pharma: Employment. Pearsall:Acceleron Pharma: Employment. Seehra:Acceleron Pharma: Employment. Kumar:Acceleron Pharma: Employment.

The morphological diagnosis of congenital dyserythropoietic anemia: results of a quantitative analysis of peripheral blood and bone marrow cells

The congenital dyserythropoietic anemias comprise a group of very rare hereditary disorders characterized by ineffective erythropoiesis and by distinct morphological abnormalities of the erythroblasts in the bone marrow. The classification proposed in 1968[1][1] is still used today.[2][2], [3][3]

Abdominal aorta coarctation: The first three case reports in our literature

Congenital coarctation of the thoracic aorta at the ligamentum arteriosum or the aortic arch is well recognized. But a much less common variety (0.5-2.0%) of aortic coarctation is located in the distal thoracic aorta or abdominal aorta or both and is often called "middle aortic syndrome" or "mid-aortic dysplastic syndrome". This represents serious pathological condition and indicates multidisciplinary therapy approach. From 1996 to 2007, at the Vascular Surgery Clinic of the Institute for Cardiovascular Diseases "Dedinje", Belgrade, three patients were treated due to abdominal aorta coarctation, two females aged 55 and 50 and a 4-year-old child. The patients were treated surgically (by-pass with a prosthetic graft and patch angioplasty) and endovascular- percutaneous transluminal angioplasty (PTA) with and without a stent. The follow-up period was 3-70 months. In the 50-year-old patient, angiography showed severe narrowing of the suprarenal segment of the abdominal aorta. Thoraco-abdominal bypass with a 16 mm dacronic tubular graft was performed. In the 4-year-old patient angiography also showed a suprarenal aorta narrowing. In the first act patch angioplasty was performed and after PTA of the visceral arteries was done on several occasions. In the 55-year-old patient, after diagnostic angiography, infrarenal aorta coarctation was registered. PTA was performed with stent placement. All patients were asymptomatic on control check-ups. Abdominal coarctation is a pathological disease which is seldom found in vascular surgery. Angiography is of major importance for setting the diagnosis and for the control of the results of surgical and nonsurgical treatment. The combination of surgical and endovascular treatment in our patients showed very good results in the studied period.

Quality of T-cells after stimulation with leukemia-derived dendritic cells (DC) from patients with acute myeloid leukemia (AML) or myeloid dysplastic syndrome (MDS) is predictive for their leukemia cytotoxic potential

Myeloid leukemic cells can differentiate into leukemia-derived dendritic cells (DC leu), presenting known/unknown leukemic-antigens. Induced anti-leukemic T-cell-responses are variable. To further elicit DC/DC leu-induced T-cell-response-patterns we performed (functional)flow-cytometry/fluorolysis-assays before/after mixed lymphocyte cultures (MLC) of matched (allogeneic) donor-T-cells ( n = 6), T-cells prepared at relapse after stem cell transplantation ( n = 4) or (autologous) patients’-T-cells ( n = 7) with blast-containing-mononuclear-cells (‘MNC’) or DC leu-containing DC (‘DC’). Compared to ‘MNC’ ‘DC’ were better mediators of anti-leukaemic T-cell-activity, although not in every case effective. We could define cut-off proportions of mature DC, DC leu, proliferating, CD4 +, CD8 + and non-naive T-cells after ‘MNC’- or ‘DC’-stimulation, that were predictive for an anti-leukemic-activity of stimulated T-cells as well as a response to immunotherapy. Interestingly especially ratios >1 of CD4:CD8 or CD45RO:CD45RA T-cells were predictive for anti-leukemic function after DC-stimulation. In summary the composition and quality of DC and T-cells after a MLC-stimulating-phase is predictive for a successful ex-vivo and in-vivo anti-leukemic response, especially with respect to proportions of proliferating, CD4 + and CD45RO + T-cells. Successful cytotoxicity and the development of a T-cell-memory after ‘DC’-stimulation could be predictive for the clinical course of the disease and may pave the way to develop adoptive immunotherapy, especially for patients at relapse after SCT.

Algorithms of diagnostics of widespread dysplastic syndromes and phenotypes. Theoretical approaches and practical application of classifi cation

The heritable connective tissue disorders with common general phenotypical and clinical features should be called dysplasia of the connective tissue. Classification of the basic dysplastical syndromes and phenotypes is offered. Article considers the algorithm of diagnostics of the basic syndromes and phenotypes and the practical questions arising at attempt of their classification.

Coarctation of the Abdominal Aorta

A 14-year old male with no previous medical history presented with headache, left third cranial nerve palsy, and generalized tonic-clonic seizures. Magnetic resonance imaging of the brain revealed subarachnoid hemorrhage secondary to an aneurysm of the left posterior communicating artery. The patient underwent successful transcatheter coil occlusion of the aneurysm, and his neurological symptoms improved (Figure 1). Figure 1. A, Cerebral angiogram demonstrating a large ruptured aneurysm (arrow) of the posterior communicating artery. B, Angiogram after endovascular coil embolization showing exclusion of the aneurysm. During admission, he remained hypertensive, with an arterial blood pressure of 170/96 mm Hg in the upper limbs despite medical treatment with atenolol, amlodipine, and enalapril. On physical examination, an abdominal systolic bruit was heard, and weak femoral pulses were noted. Blood pressure in the right and left arms was similar, but there was a significant differential …

Phosphorylation and Stabilization of TAp63γ by IκB Kinase-β

Post-translational modification of the p53 family members is key to their regulation. Here we report the phosphorylation of TAp63gamma, but not DeltaNp63gamma, by IkappaB kinase beta (IKKbeta). Activation of IKKbeta by gamma radiation or tumor necrosis factor-alpha led to increased TAp63gamma protein levels in cells. IKKbeta, but not its kinase-defective mutant IKKbeta-K44A, led to this observed stabilization of TAp63gamma. This stabilization of TAp63gamma in response to gamma radiation was significantly decreased in the absence of IKKbeta. Phosphorylation of TAp63gamma blocks ubiquitylation and possible degradation of this protein. We postulate that phosphorylation of TAp63gamma by IKKbeta stabilizes the TAp63gamma protein by blocking ubiquitylation-dependent degradation of this protein.

P15Ink4b: Dual function in myelopoiesis and inactivation in myeloid disease

p15Ink4b (p15) is a cyclin- dependent kinase inhibitor (CDKI) that is known for arresting the cell cycle in early G1 phase by inhibiting the activation of cyclin dependent kinases 4 and 6. Loss of p15 expression has been associated with several cancer types but its silencing is frequent in acute myeloid leukemia (AML) and myeloid dysplastic syndrome (MDS). Several mechanisms have been identified that are responsible for silencing the gene encoding p15 in myeloid disease, including gene hypermethylation, transcription factor deregulation and direct inhibition by translocation products. The effect of p15 loss during disease may be attributed to the dual role of this protein as a mediator of cell cycle arrest in late stage myeloid progenitors and as a regulator of differentiation in early common myeloid progenitors (CMP). Here we outline the mechanisms by which p15 is silenced and the functions of this CDKI in myelopoiesis as well as discuss the implications of these findings to myeloid disease.

Cor triventriculare with pericardial aplasia and mitral valve prolapse: a novel congenital dysplastic syndrome?

A 37-year-old man was admitted to our hospital because of an apical abnormality, which was incidentally detected for the first time 10 years ago by echocardiography. The patient reported on normal physical activity and denied clinical signs of heart failure. His ECG showed antero-septal ST-segment alterations. For further assessment, magnetic resonance imaging was performed on a 1.5 T whole body scanner (Intera CV, Philips Medical Systems, Best, The Netherlands). The four-chamber view displays an …

Histone modifying and chromatin remodelling enzymes in cancer and dysplastic syndromes

Inactivation of tumour suppressor genes is central to the development of cancer. Although this inactivation was once considered to be secondary to intragenic mutations, it is now clear that silencing of these genes often occurs by epigenetic means. Hypermethylation of CpG islands associated with the tumour suppressor genes was the first manifestation of this phenomenon to be described. It is apparent, however, that this is one of a host of chromatin modifications which characterize gene silencing. Although we know little about what determines which loci are affected, our understanding of the nature of the epigenetic marks and how they are established has blossomed. There is no compelling evidence that cancer ever develops by purely epigenetic means, but it is apparent that perturbations in the apparatus which establish the epigenome may contribute to the development of cancer. This review will focus on the role of two classes of chromatin remodelling enzymes, those that alter histones by the addition or removal of acetyl and methyl groups and those of the SWI/SNF family of proteins that change the topology of the nucleosome and its DNA strand via the hydrolysis of ATP, and we shall examine the consequence of mutations in, or mis-expression of, these factors. In some cases, mutations in these factors appear to play a direct role in cancer development. However, their general role as important intermediaries involved in regulating gene expression makes them attractive therapeutic targets. In exciting developments, it has been shown that inhibition of these factors leads to the reversal of tumour suppressor gene silencing and the inhibition of cancer cell growth.

Evaluation of immunomodulatory treatment based on conventional and lineage-specific chimerism analysis in patients with myeloid malignancies after myeloablative allogeneic hematopoietic cell transplantation

Both conventional chimerism analysis (CCA) and lineage-specific chimerism analysis (LCA) have potential pitfalls as diagnostic means for the detection of minimal residual disease after allogeneic hematopoietic cell transplantation (aHCT). Therefore, the present study examines the results of both methods in order to determine how predictive consecutive evaluations were, with respect to the risk that the patient would relapse during post-transplant follow-up and with respect to responsiveness to immunomodulatory treatment. A total of 168 individuals with acute myeloid leukemia (AML) (n = 137) and myelo dysplastic syndrome (n = 31) were investigated with CCA and LCA at mean intervals of 24 days (range: 11-116). The median follow-up after myeloablative aHCT was 22 months (range: 4-49). Of 168 patients, 65 experienced a clinical relapse after aHCT. CCA and LCA were comparatively sensitive and specific for relapse at the intervals of chimerism testing employed in this study. Of 32 patients, 10 who were offered donor lymphocyte infusions (DLI) treatment for increasing (n = 29) or stable (n = 3) mixed chimerism (MC) achieved at least transitory CC. The observation that all patients with increasing MC relapsed despite DLI treatment (54%) or withdrawal of immune suppression (24%) indicates that novel strategies to deal with rapidly evolving relapse in AML patients, such as shortening of chimerism monitoring intervals, need to be evaluated.

Images in vascular medicine

A 41-year-old woman presented complaining of discomfort in the gluteal region while walking. She initially developed claudicationwhile walking up hills, which progressed over 4 months to discomfort after walking only 200 feet (61m). Past medical history included diet-controlled hypertension and remote history of cigarette smoking. On physical examination, blood pressure was 120=80 in the left arm and 130=80 in the right arm. The femoral, posterior tibial and dorsalis pedis pulses were not appreciated bilaterally. There were no bruits present and no evidence of livedo reticularis on the skin. Laboratory studies included total cholesterol of 208, triglycerides 83, low density lipoprotein 130 and high density lipoprotein of 59mg=dl. Testing for thrombophilia was negative. A lower extremity vascular laboratory study revealed a right ankle–brachial index (ABI) of 0.55 and a left ABI of 0.51 with segmental pressures and pulse volume recordings consistent with bilateral aorto-iliac occlusive disease. The complete blood count and chemistry tests were within normal limits. An echocardiogram and carotid ultrasound were normal and an electron beam computed tomography scan had a calcium score of 9. An abdominal X-ray angiogram (Panel A) revealed total occlusion of the distal abdominal aorta occurring at a level just distal to the origin of the inferior mesenteric artery. There is reconstitution of the iliac vessels via collaterals derived from the inferior mesenteric artery. The common iliac arteries were uniformly small in caliber but without any localized areas of stenosis. The femoral, popliteal and trifurcation vessels were patent. The posterior tibial arteries were patent and in continuity down to the level of the ankles bilaterally. The patient was offered vascular surgery which she declined, opting for a rigorous exercise program. She maintained an exercise program, a low-cholesterol diet and medications which included a statin and an anti-platelet agent (clopidogrel). Four years after initial presentation the ABI increased to 0.7 bilaterally. The patient can currently walk approximately 1 mile (1.6km) on  at ground without any lower extremity discomfort and notes bilateral calf discomfort only when walking up hills. The patient describedhas distal abdominal aortic occlusionwith narrowing of the common iliac arteries. The narrow iliac arteries suggest that the patient may have had an asymptomatic narrowing of the distal abdominal aorta before complete occlusion occurred. There are many different terms in the medical literature used to describe congenital narrow distal aorta. The more commonly used terms are mid-aortic dysplasia, mid-aortic (dysplastic) syndrome, atrophy of the aorta, atresia of the terminal aorta, atypical coarctation, and hypoplasia of the abdominal aorta. The patient’s history and radiographic images suggest a coarctation of the distal abdominal aorta. Coarctation of the aorta is deŽ ned as luminal narrowing of the aorta that produces hemodynamically signiŽ cant obstruction to blood  ow. Coarctation at the attachment of the ductus arteriosus accounts for approximately 98% of the aortic coarctations. Abdominal aorta coarctation is exceedingly rare and found in fewer than 2% of all cases. Additionally, further classifying the coarctation as Panel A