Catheter-based pulmonary vein isolation fails to prevent transient atrial arrhythmogenic changes related to acute obstructive respiratory events in a porcine model.

AIMS: Pulmonary vein isolation (PVI) is the corner stone of modern rhythm control strategies in patients with atrial fibrillation (AF). Sleep-disordered breathing (SDB) is prevalent in more than 50% of patients undergoing AF ablation, and studies have indicated a greater recurrence rate after PVI in patients with SDB. Herein, we study the effect of catheter-based PVI on AF in a pig model for SDB. METHODS AND RESULTS: In 11 sedated spontaneously breathing pigs, obstructive apnoeas were simulated by 75 s of intermittent negative upper airway pressure (INAP) applied by a negative pressure device connected to the endotracheal tube. Intermittent negative upper airway pressures were performed before and after PVI. AF-inducibility and atrial effective refractory periods (aERPs) were determined before and during INAP by programmed atrial stimulation. Pulmonary vein isolation prolonged the aERP by 48 ± 27 ms in the right atrium (RA) (P < 0.0001) and by 40 ± 34 ms in the left atrium (LA) (P = 0.0004). Following PVI, AF-inducibility dropped from 28 ± 26% to 0% (P = 0.0009). Intermittent negative upper airway pressure was associated with a transient aERP-shortening (ΔaERP) in both atria, which was not prevented by PVI (INAP indued ΔaERP after PVI in the RA: -57 ± 34 ms, P = 0.0002; in the LA: -42 ± 24 ms, P < 0.0001). Intermittent negative upper airway pressure was associated with a transient increase in AF-inducibility (from 28 ± 26% to 69 ± 21%; P = 0.0008), which was not attenuated by PVI [INAP-associated AF-inducibility after PVI: 58 ± 33% (P = 0.5)]. CONCLUSION: Transient atrial arrhythmogenic changes related to acute obstructive respiratory events are not prevented by electrical isolation of the pulmonary veins, which partially explains the increased AF recurrence in patients with SDB after PVI procedures.

Late-appearing Philadelphia chromosome in childhood acute myeloid leukemia.

A 3-year-old female was diagnosed with acute myeloid leukemia (AML-M2). The disease was refractory to various chemotherapeutic agents. Cytogenetic analysis revealed a clone with trisomy 8 at diagnosis that was replaced by a clone containing a t(11;15) and del(20q) by the end of the second induction. A new clone, characterized by a Philadelphia chromosome, with the minor BCR/ABL p190 transcript, emerged 14 months after diagnosis and remained to the end of disease course. The late occurrence of the Philadelphia chromosome in AML has been documented rarely in adults.

Requirement of VPS33B, a member of the Sec1/Munc18 protein family, in megakaryocyte and platelet alpha-granule biogenesis.

Bleeding problems are associated with defects in platelet alpha-granules, yet little is known about how these granules are formed and released. Mutations affecting VPS33B, a novel Sec1/Munc18 protein, have recently been linked to arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome. We have characterized platelets from patients with ARC syndrome and observed reduced aggregation with arachidonate and adenosine diphosphate (ADP). Structural abnormalities seen in ARC platelets included increased platelet size, a pale appearance in blood films, elevated numbers of delta-granules, and completely absent alpha-granules. Soluble and membrane-bound alpha-granule proteins were significantly decreased or undetectable in ARC platelets, suggesting that both the releasable protein pools and membrane components of alpha-granules were absent. The role of VPS33B in platelet granule biogenesis was evaluated by immunofluorescence microscopy in normal human megakaryocytes. VPS33B colocalized appreciably with markers of alpha-granules, moderately with late endosomes/lysosomes, minimally with delta-granules/lysosomes, and not with cis-Golgi complexes. VPS33B protein expression determined by immunoblotting confirmed the presence of VPS33B in control fibroblasts but not in ARC fibroblasts, and in normal megakaryocytes but not in platelets. We conclude that like other Sec1/Munc18 proteins, VPS33B is involved in intracellular vesicle trafficking, being essential for the development of platelet alpha-granules but not for granule secretion.

A der(19)t(12;19)(q12;p13.3) in a case of pediatric acute leukemia with unusual immunophenotype.

We describe a case of acute leukemia in a child with an unusual immunophenotype and a novel cytogenetic abnormality. The leukemia blasts expressed myeloid, natural killer and B-lineage associated antigens. Cytogenetics showed the presence of a novel unbalanced chromosomal translocation, der(19)t(12;19)(q12;p13.3). The patient achieved and maintained remission with myeloid-directed chemotherapy. The differential diagnosis of the immunophenotype and the potential fusion genes are discussed.

Leptomeningeal precursor B-cell lymphoblastic lymphoma in a child with minimal bone marrow involvement.

The authors report an unusual presentation of a leptomeningeal lymphoblastic lymphoma in a 6-year-old boy with headache and papilledema as the only initial manifestations. The diagnosis was confirmed by the presence of precursor B-cell lymphoblasts in the cerebrospinal fluid, with no cerebral mass and with only 9% phenotypically identical blasts in the bone marrow. This patient was treated on a high-risk ALL protocol with intensive systemic/intrathecal chemotherapy plus cranial irradiation, and he remained in complete remission 6 months after his initial diagnosis.

Interphase cytogenetic analysis of clonality in peripheral blood cells from a patient with Down syndrome and acute megakaryoblastic leukemia.

A combination of fluorescence-activated cell sorting and interphase fluorescence in situ hybridization (FISH) techniques was used to detect a clonal chromosomal marker in blasts, granulocytes, and T and B lymphocytes of the peripheral blood from a patient with Down syndrome and acute megakaryoblastic leukemia (AMKL) associated with trisomy 8 as a karyotypic abnormality. Immunophenotypic studies with flow cytometry showed two populations of leukemic blasts distinguished by their expression of the CD34 antigen. Interphase FISH studies revealed clonal trisomy 8 FISH signals in almost all blast cells, regardless of CD34 expression, as well as in a small subpopulation of granulocytes. Normal chromosome 8 signal patterns were detected in T and B cells and in a great majority of granulocytes. The present study provides evidence for the clonal involvement of leukemic blasts in AMKL of Down syndrome, indicating that a trisomy 8 abnormality may be a primary event in leukemogenesis. The transformation occurs in progenitor cells with limited myeloid differentiation and without involvement of lymphoid lineage cells.

Purine nucleoside phosphorylase deficiency associated with a dysplastic marrow morphology.

Purine nucleoside phosphorylase (PNP) deficiency is an autosomal recessive metabolic disorder characterized by severe combined immunodeficiency and by complex neurologic symptomatology including ataxia, developmental delay, and spasticity. Herein we report severe marrow dysplasia in a patient with PNP deficiency. Drug-related marrow dysfunction was unlikely, and marrow virological studies were negative. A preleukemic myelodysplastic syndrome was also unlikely due to normal marrow CD34+ cells, colony growth in clonogenic assay of marrow mononuclear cells, apoptosis rate, and Fas expression on marrow nucleated cells, as well as morphologic improvement of the marrow dysplasia after normal red blood cell transfusion. The patient's marrow stroma showed hypersensitivity to irradiation and undetectable PNP enzyme activity similar to peripheral lymphocytes. This is the first report of PNP deficiency associated with increased lymphocyte and marrow stromal sensitivity to irradiation. We conclude that marrows from patients with PNP deficiency might have hypersensitivity to irradiation and can develop dysplastic morphology, caused either directly or indirectly by the inherited enzymatic defect.

T-cell blast crisis of chronic myelogenous leukemia manifesting as a large mediastinal tumor.

We report an unusual case of T-cell blast crisis of chronic myelogenous leukemia (CML) with a clinical presentation more typical of de novo T-cell lymphoblastic lymphoma. The patient was a 32-year-old man who presented with acute superior vena cava syndrome 19 months after an initial diagnosis of CML and 5 months after allogeneic bone marrow transplantation. The tumor was composed of primitive lymphoid cells expressing CD2, CD3, CD4, CD5, CD7, CD8, and CD10. Although the clinical features were more typical of acute lymphoblastic leukemia/lymphoma, fluorescence in situ hybridization analysis showed the bcr-abl fusion gene within blastic tumor cells. This finding confirmed that the mass represented a blastic transformation of CML. We use the unusual features of the current case and the previous reports to suggest that the development of T-cell blast crisis of CML is dependent on the presence of both marrow and extramedullary disease and a mechanism to evade apoptosis.