Tuberous sclerosis complex and Wolff-Parkinson-White syndrome

This report highlights the association between tuberous sclerosis and Wolff-Parkinson-White syndrome. Ten patients with concurrent diagnoses of Wolff-Parkinson-White syndrome and tuberous sclerosis were identified. Wolff-Parkinson-White syndrome presented early in life, nine cases being diagnosed in the first year. Eight of the 10 cases were male. In eight cases, the syndrome was associated with supraventricular tachycardias, and in nine with cardiac rhabdomyomata. One child died from cardiac failure secondary to obstruction of the left ventricular outflow tract by a rhabdomyoma. Five of nine survivors showed resolution of Wolff-Parkinson-White syndrome on follow up. The accessory pathway was localised in nine patients from surface electrocardiograms: six children had left sided pathways and three had right sided pathways.     

Blood-brain barrier and blood volume imaging of cerebral glioma using functional CT: A pictorial review

Five cases of cerebral glioma are presented here that illustrate the benefit of functional CT imaging of blood-brain barrier permeability and cerebral blood volume. Functional CT uses Patlak analysis of a single location dynamic sequence to extract physiological information that is useful clinically in the assessment of cerebral gliomas. Functional CT offers distinct advantages over other functional modalities including clearer delineation of tumour, tumour grading, measurement of tumour activity and monitoring response to therapy.     

A new heparin fragment decreases liver ischemia-reperfusion injury

<正>To the Editor:Ischemia-reperfusion injury following surgery and transplantation can lead to irreversible multiorgan failure.Intracellular calcium overload is associated to cellular death during ischemiareperfusion.A recently discovered heparin fragment (HF),trisulfated disaccharide (TD),that acts on sodium-calcium exchanger(NCX) decreasing intracellular Ca²⁺,showed effectiveness on protecting hepatocytes from ischemia-reperfusion injury [1],     

Human erythrocyte protein 4.2 deficiency associated with hemolytic anemia and a homozygous 40glutamic acid-->lysine substitution in the cytoplasmic domain of band 3 (band 3Montefiore)

Red blood cell (RBC) protein 4.2 deficiency is often associated with a moderate nonimmune hemolytic anemia, splenomegaly, and osmotically fragile RBCs resembling, but not identical to, hereditary spherocytosis (HS). In the Japanese type of protein 4.2 deficiency (protein 4.2Nippon), the anemia is associated with a point mutation in the protein 4.2 cDNA. In this report, we describe a patient with moderate and apparently episodic nonimmune hemolytic anemia with splenomegaly, spherocytosis, osmotically fragile RBCs, reduced whole cell deformability, and abnormally dense cells. Sodium dodecyl sulfate- polyacrylamide gel electrophoresis analysis of the proposita's RBC membrane proteins showed an 88% deficiency of protein 4.2 and a 30% deficiency of glyceraldehyde-3-phosphate dehydrogenase (band 6). Structural and molecular analyses of the proposita's protein 4.2 were normal. In contrast, limited tryptic digestion of the proposita's band 3 showed a homozygous abnormality in the cytoplasmic domain. Analysis of the pedigree disclosed six members who were heterozygotes for the band 3 structural abnormality and one member who was a normal homozygote. Direct sequence analysis of the abnormal band 3 tryptic peptide suggested that the structural abnormality resided at or near residue 40. Sequence analysis of the proposita's band 3 cDNA showed a 232G-->A mutation resulting in a 40glutamic acid-->lysine substitution (band 3Montefiore). Allele-specific oligonucleotide hybridization was used to probe for the mutation in the pedigree, showing that the proposita was homozygous, and the pedigree members who were heterozygous for the band 3 structural abnormality were also heterozygous for the band 3Montefiore mutation. The band 3Montefiore mutation was absent in 26 chromosomes from race-matched controls and in one pedigree member who did not express the band 3 structural abnormality. In coincidence with splenectomy, the proposita's anemia was largely corrected along with the disappearance of most spherocytes and considerable improvements of RBC osmotic fragility, whole cell deformability, and cell density. We conclude that this hereditary hemolytic anemia is associated with the homozygous state for band 3Montefiore (40glutamic acid-->lysine) and a decreased RBC membrane content of protein 4.2. We speculate that band 3 structural abnormalities can result in defective interactions with protein 4.2 and band 6, and in particular, that the region of band 3 containing 40glutamic acid is involved directly or indirectly in interactions with these proteins.     

A truncating PET100 variant causing fatal infantile lactic acidosis and isolated cytochrome c oxidase deficiency

Isolated mitochondrial complex IV (cytochrome c oxidase) deficiency is an important cause of mitochondrial disease in children and adults. It is genetically heterogeneous, given that both mtDNA-encoded and nuclear-encoded gene products contribute to structural components and assembly factors. Pathogenic variants within these proteins are associated with clinical variability ranging from isolated organ involvement to multisystem disease presentations. Defects in more than 10 complex IV assembly factors have been described including a recent Lebanese founder mutation in PET100 in patients presenting with Leigh syndrome. We report the clinical and molecular investigation of a patient with a fatal, neonatal-onset isolated complex IV deficiency associated with multiorgan involvement born to consanguineous, first-cousin British Asian parents. Exome sequencing revealed a homozygous truncating variant (c.142C>T, p.(Gln48*)) in the PET100 gene that results in a complete loss of enzyme activity and assembly of the holocomplex. Our report confirms PET100 mutation as an important cause of isolated complex IV deficiency outside of the Lebanese population, extending the phenotypic spectrum associated with abnormalities within this gene.     

Primary tumor cells of myeloma patients induce interleukin-6 secretion in long-term bone marrow cultures

Long-term bone marrow cultures (LTBMC) from patients with multiple myeloma (MM) and normal donors were analyzed for immunophenotype and cytokine production. Both LTBMC adherent cells from myeloma and normal donor origin expressed CD10, CD13, the adhesion molecules CD44, CD54, vascular cell adhesion molecule 1, very late antigen 2 (VLA-2), and VLA- 5, and were positive for extracellular matrix components fibronectin, laminin, and collagen types 3 and 4. LTBMC from myeloma patients and normal donors spontaneously secreted interleukin-6 (IL-6). However, levels of IL-6 correlated with the stage of disease; highest levels of IL-6 were found in LTBMC from patients with active myeloma. To identify the origin of IL-6 production, LTBMC from MM patients and normal donors were cocultured with BM-derived myeloma cells and cells from myeloma cell lines. IL-6 was induced by plasma cell lines that adhered to LTBMC such as ARH-77 and RPMI-8226, but not by nonadhering cell lines U266 and FRAVEL. Myeloma cells strongly stimulated IL-6 secretion in cocultures with LTBMC adherent cells from normal donors and myeloma patients. When direct cellular contact between LTBMC and plasma cells was prevented by tissue-culture inserts, no IL-6 production was induced. This implies that intimate cell-cell contact is a prerequisite for IL-6 induction. Binding of purified myeloma cells to LTBMC adherent cells was partly inhibited by monoclonal antibodies against adhesion molecules VLA-4, CD44, and lymphocyte function-associated antigen 1 (LFA-1) present on the plasma cell. Antibodies against VLA-4, CD29, and LFA-1 also inhibited the induced IL-6 secretion in plasma cell-LTBMC cocultures. In situ hybridization studies performed before and after coculture with plasma cells indicated that LTBMC adherent cells produce the IL-6. These results suggest that the high levels of IL-6 found in LTBMC of MM patients with active disease are a reflection of their previous contact with tumor cells in vivo. These results provide a new perspective on tumor growth in MM and emphasize the importance of plasma cell-LTBMC interaction in the pathophysiology of MM.     

Dynamic changes of GAD65 autoantibody epitope specificities in individuals at risk of developing type 1 diabetes

Aims/hypothesis Progression to type 1 diabetes is associated with intramolecular epitope spreading to disease-specific antibody epitopes located in the middle region of glutamic acid decarboxylase 65 (GAD65).Methods The relationship between intramolecular epitope spreading of autoantibodies specific to GAD65 in relation to the risk of developing type 1 diabetes was tested in 22 high-risk individuals and 38 low-risk individuals. We determined the conformational epitopes in this longitudinal study by means of competition experiments using recombinant Fab of four GAD65-specific monoclonal antibodies.Results Sera from high-risk children in the preclinical stage recognise a specific combination of GAD65 antibody epitopes located in the middle and the C-terminus of GAD65. High risk of progressing to disease is associated with the emergence of antibodies specific for conformational epitopes at the N-terminus and the middle region. Binding to already established antibody epitopes located in the middle and at the N-terminus increases and shows a significant relation (p=0.005) with HLA, which confers risk of developing diabetes.Conclusions/interpretation In type 1 diabetes, GAD65 antibodies are initially generated against the middle and C-terminal regions of GAD65. In genetically predisposed subjects the autoimmune response may then undergo intramolecular epitope spreading towards epitopes on the N-terminus and further epitopes located in the middle. These findings clearly demonstrate that the GAD65 autoantibody response in the preclinical stage of type 1 diabetes is dynamic and related to the HLA genotypes that confer risk of diabetes. GAD65-specific Fab should prove useful in predicting progression from islet autoimmunity to clinical onset of type 1 diabetes.     

Changes in epicardial coronary arterial diameter following intracoronary papaverine in man

The effect of intracoronary papaverine administration on epicardial coronary arterial diameter was examined in 18 male patients. Coronary-artery cineangiograms were acquired with a power injector before intervention, 20 sec after intracoronary saline (control), and 20 sec after administration of papaverine into either the left (12 mg) or right (8 mg) coronary artery. Absolute coronary arterial diameter of a normal-appearing segment was quantified using a previously validated, fully automated digital edge detection program with an ADAC digital radiographic unit. Baseline coronary arterial diameter of 3.1 +/- 0.8 mm did not significantly change after saline administration (3.1 +/- 0.9 mm) but did significantly increase (p less than .001) to 3.4 +/- 0.9 mm after papaverine administration. No significant percent change in diameter occurred in either the left anterior descending (-.5 +/- 1.7%), left circumflex (-.2 +/- 1.1%), or right (-3.0 +/- 3.8%) coronary arteries with saline, but significant (p less than .001) increases occurred with papaverine (7.2 +/- 4.1%, 7.0 +/- 4.5%, 6.8 +/- 2.7%, respectively). The response of 7 coronary arteries examined immediately proximal to a significant lesion was not significantly different from the response of the remaining 11 coronary arteries. In conclusion, intracoronary papaverine causes a significant increase in coronary arterial diameter. This has clinical implications for assessing coronary flow reserve with devices that defect flow velocity.