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1.
Clin Exp Immunol ; 176(3): 394-400, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24611904

ABSTRACT

X-linked inhibitor of apoptosis (XIAP) deficiency, caused by mutations in BIRC4, is an immunodeficiency associated with immune dysregulation and a highly variable clinical presentation. Current diagnostic screening tests such as flow cytometry for XIAP expression or lymphocyte apoptosis assays have significant limitations. Based on recent evidence that XIAP is essential for nucleotide-binding and oligomerization domains (NOD)1/2 signalling, we evaluated the use of a simple flow cytometric assay assessing tumour necrosis factor (TNF) production of monocytes in response to NOD2 stimulation by muramyl dipeptides (L18-MDP) for the functional diagnosis of XIAP deficiency. We investigated 12 patients with XIAP deficiency, six female carriers and relevant disease controls. Irrespective of the diverse clinical phenotype, the extent of residual protein expression or the nature of the mutation, the TNF response was severely reduced in all patients. On average, L18-MDP induced TNF production in 25% of monocytes from healthy donors or female carriers, while fewer than 6% of monocytes responded in affected patients. Notably, the assay clearly discriminated affected patients from disease controls with other immunodeficiencies accompanied by lymphoproliferation, hypogammaglobulinaemia or inflammatory bowel disease. Functional testing of the NOD2 signalling pathway is an easy, fast and reliable assay in the diagnostic evaluation of patients with suspected XIAP deficiency.


Subject(s)
Immunologic Deficiency Syndromes/diagnosis , Immunologic Deficiency Syndromes/genetics , X-Linked Inhibitor of Apoptosis Protein/deficiency , Acetylmuramyl-Alanyl-Isoglutamine/analogs & derivatives , Acetylmuramyl-Alanyl-Isoglutamine/pharmacology , Adolescent , Adult , Aged , Case-Control Studies , Child , Child, Preschool , Female , Flow Cytometry , Humans , Immunophenotyping , Infant , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Male , Middle Aged , Mutation , Nod2 Signaling Adaptor Protein/metabolism , Phenotype , T-Lymphocytes/metabolism , Tumor Necrosis Factors/metabolism , X-Linked Inhibitor of Apoptosis Protein/genetics , Young Adult
2.
Klin Padiatr ; 225(6): 343-6, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24166087

ABSTRACT

X-linked lymphoproliferative syndromes (XLP) are rare primary immunodeficiencies. Mutations within the XIAP/BIRC4 gene characterize XLP type 2 and cause XIAP deficiency. We present the case of a 5-year-old boy with a novel mutation of the XIAP/BIRC4 gene and describe the immunological phenotype for the first time. We characterized the distinct immunological phenotype and evaluated the family history accordingly.


Subject(s)
DNA Mutational Analysis , Genetic Diseases, X-Linked/genetics , Lymphohistiocytosis, Hemophagocytic/genetics , Lymphoproliferative Disorders/genetics , Phenotype , X-Linked Inhibitor of Apoptosis Protein/genetics , Cell Death/genetics , Cell Death/immunology , Child, Preschool , Epstein-Barr Virus Infections/diagnosis , Epstein-Barr Virus Infections/genetics , Epstein-Barr Virus Infections/immunology , Gene Expression/genetics , Genetic Carrier Screening , Genetic Diseases, X-Linked/diagnosis , Genetic Diseases, X-Linked/immunology , Humans , Killer Cells, Natural/immunology , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/immunology , Lymphoproliferative Disorders/diagnosis , Lymphoproliferative Disorders/immunology , Male , Pedigree , Perforin/genetics , Prognosis , T-Lymphocytes, Cytotoxic/immunology
3.
J Hum Hypertens ; 22(1): 32-7, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17625588

ABSTRACT

Approximate entropy (ApEn) of blood pressure (BP) can be easily measured based on software analysing 24-h ambulatory BP monitoring (ABPM), but the clinical value of this measure is unknown. In a prospective study we investigated whether ApEn of BP predicts, in addition to average and variability of BP, the risk of hypertensive crisis. In 57 patients with known hypertension we measured ApEn, average and variability of systolic and diastolic BP based on 24-h ABPM. Eight of these fifty-seven patients developed hypertensive crisis during follow-up (mean follow-up duration 726 days). In bivariate regression analysis, ApEn of systolic BP (P<0.01), average of systolic BP (P=0.02) and average of diastolic BP (P=0.03) were significant predictors of hypertensive crisis. The incidence rate ratio of hypertensive crisis was 14.0 (95% confidence interval (CI) 1.8, 631.5; P<0.01) for high ApEn of systolic BP as compared to low values. In multivariable regression analysis, ApEn of systolic (P=0.01) and average of diastolic BP (P<0.01) were independent predictors of hypertensive crisis. A combination of these two measures had a positive predictive value of 75%, and a negative predictive value of 91%, respectively. ApEn, combined with other measures of 24-h ABPM, is a potentially powerful predictor of hypertensive crisis. If confirmed in independent samples, these findings have major clinical implications since measures predicting the risk of hypertensive crisis define patients requiring intensive follow-up and intensified therapy.


Subject(s)
Blood Pressure Monitoring, Ambulatory , Hypertension, Malignant/diagnosis , Adult , Aged , Blood Pressure Monitoring, Ambulatory/methods , Blood Pressure Monitoring, Ambulatory/statistics & numerical data , Diagnosis, Computer-Assisted , Female , Humans , Longitudinal Studies , Male , Middle Aged , Nonlinear Dynamics , Predictive Value of Tests , Prospective Studies
4.
Thorac Cardiovasc Surg ; 55(1): 19-23, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17285469

ABSTRACT

BACKGROUND: There are few families with the diagnosis of ascending aortic aneurysm and acute type-A aortic dissection inherited as an autosomal-dominant disorder in the absence of a known genetic syndrome. METHODS: We investigated a family with 26 members in whom ascending aortic aneurysms and acute type-A aortic dissections occurred over three generations. Examinations were performed to identify family members at specific risk. RESULTS: Six members presented with acute type-A aortic dissections and three relatives had ascending aortic aneurysms. Clinical examinations showed no characteristics of a known genetic syndrome. Molecular genetic analysis revealed no mutations known to cause a form of autosomal-dominant inherited aortic disease. CONCLUSION: Adequate diagnostic measures are mandatory in families with ascending aortic aneurysms or type-A aortic dissections to identify or exclude family members at risk for aortic diseases. Even in the absence of identifiable mutations causing isolated aortic aneurysms or aortic dissections, we recommend standardised examinations of all first-degree relatives of affected families. An indication for prophylactic aortic root replacement should be considered for patients at risk.


Subject(s)
Aortic Aneurysm, Thoracic/congenital , Aortic Dissection/congenital , DNA/genetics , Microfilament Proteins/genetics , Mutation , Adolescent , Adult , Aortic Dissection/diagnosis , Aortic Dissection/genetics , Aortic Aneurysm, Thoracic/diagnosis , Aortic Aneurysm, Thoracic/genetics , Calcium-Binding Proteins , Diagnosis, Differential , Echocardiography , Female , Fibrillins , Follow-Up Studies , Genetic Predisposition to Disease , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Pedigree , Polymerase Chain Reaction , Prognosis , Retrospective Studies , Tomography, X-Ray Computed
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