Segmental pulmonary vein antrum isolation using the "large-size" lasso catheter in patients with atrial fibrillation.

BACKGROUND: The limited efficacy and complications of segmental ostial pulmonary vein isolation (PVI) for treating atrial fibrillation (AF) have been discussed so, in the present study the feasibility and efficiency of performing segmental pulmonary vein (PV) antrum isolation to treat AF were assessed. METHODS AND RESULTS: A total of 187 patients with drug-refractory AF (paroxysmal 120, persistent 67) underwent segmental PVI guided by circumferential 20-electrode catheters (Lasso). Radiofrequency (RF) current was delivered either at the ostium using a regular Lasso (15-20 mm in diameter, 70 patients: Group 1) or at the antrum using a larger Lasso (25-30 mm in diameter, 117 patients: Group 2). A significantly wider region had to be ablated, with a longer RF application time, to isolate all 4 PVs in Group 2 patients than in Group 1 patients. Although the rate of recurrence of AF after the initial session was equal in both groups, a significantly greater number of patients were free from AF after a mean of 1.4 procedures in Group 2 than in Group 1 (93% vs 76% for paroxysmal AF, 78% vs 48% for persistent AF). CONCLUSIONS: Segmental antral PVI using large-sized Lasso catheters was found to be more effective and safer than ostial PVI for the treatment of AF.     

Differential effects of troglitazone and D-chiroinositol on glucosamine-induced insulin resistance in vivo in rats

Troglitazone and D-chiroinositol have been shown to exert antidiabetic effects by either potentiating or mimicking insulin action. We studied whether pretreatment with these compounds can prevent the deleterious effects of glucosamine on insulin action that may play an important role in hyperglycemia-induced insulin resistance. Normal Wistar rats were pretreated with troglitazone (100 mg/kg/d), D-chiroinositol (100 mg/kg/d), or placebo (saline) for 7 days. Glucosamine (50 micromol/kg/min) was then infused for 210 minutes, and a euglycemic glucose clamp was performed during the last 120 minutes. Pretreatment with troglitazone or D-chiroinositol had no effect on fasting plasma glucose or insulin or basal hepatic glucose output (HGO). Under the euglycemic-hyperinsulinemic (956+/-93 pmol/L) clamp condition, HGO in glucosamine-infused placebo-treated rats was not suppressed, but instead was increased over the basal level, indicative of hepatic insulin resistance. In contrast, HGO failed to increase during glucosamine infusion in rats pretreated with troglitazone but was not normally suppressed. This may indicate a partial improvement in the hepatic insulin resistance. D-Chiroinositol pretreatment had no effect on the glucosamine-induced increase in HGO. The glucose disposal rate (GDR) was 25% lower in rats infused with glucosamine versus saline-infused rats (25.5+/-2.5 v 34.1+/-2.0 mg/kg/min), indicative of peripheral insulin resistance. Pretreatment with D-chiroinositol (34.5+/-2.3 mg/kg/min) prevented the glucosamine-induced decrease in the GDR, indicating an improvement in peripheral insulin resistance. Troglitazone (25.2+/-3.3 mg/kg/min) was without effect. In conclusion, (1) in normal control rats, glucosamine infusion induced hepatic and peripheral insulin resistance; (2) D-chiroinositol, but not troglitazone, pretreatment prevented glucosamine-induced peripheral insulin resistance; and (3) troglitazone, but not D-chiroinositol, partially blocked the glucosamine-induced hepatic insulin resistance. D-Chiroinositol may provide a novel pharmacological approach to hexosamine-induced peripheral insulin resistance.     

Accumulation of cholera toxin and GM1 ganglioside in the early endosome of Niemann–Pick C1-deficient cells

We investigated intracellular trafficking of GM1 ganglioside in Niemann-Pick C1 (NPC1)-deficient Chinese hamster ovary cells [NPC1(-) cells] by using cholera toxin (CT) as a probe. Both the holotoxin and the B subunit (CTB) accumulated in GM1-enriched intracellular vesicles of NPC1(-) cells. CTB-labeled vesicles contained the early endosome marker Rab5 but not lysosome-associated membrane protein 2 and were not labeled with either Texas red-transferrin or Lysotracker, indicating that they represent early endosomes. Similarly, CT accumulated in intracellular vesicles of human NPC fibroblasts that contained both Rab5 and early endosomal antigen 1. CTB accumulation in NPC1(-) cells was abolished by expression of wild-type NPC1 but not by mutant proteins with a mutation either in the NPC domain or the sterol-sensing domain. A part of these mutant NPC1 proteins expressed in NPC1(-) cells was localized on CTB-labeled vesicles. U18666A treatment of "knock in" cells [NPC1(-) cells that stably expressed wild-type NPC1] caused CTB accumulation similar to that in NPC1(-) cells, and a part of wild-type NPC1was localized on CTB-labeled vesicles in drug-treated cells. Finally, CT tracer experiments in NPC1(-) cells revealed retarded excretion of internalized toxin into the culture medium and an increase in the intracellular release of A subunits. In accordance with the latter result, CT was more effective in stimulating cAMP formation in NPC1(-) than in wild-type cells. These results suggest that transport of CT/GM1 complexes from the early endosome to the plasma membrane depends on the function of NPC1, whereas transport to the Golgi apparatus/endoplasmic reticulum does not.     

Phenotyping of malignant hematopoietic cells

Summary 1255 cases of leukemia-lymphoma were tested between 1972 and 1984 by multiple marker analysis. Routine leukemia phenotyping was performed using standard morphological and cytochemical techniques in combination with clinical and histo-pathological information; the main emphasis was put on immunological surface marker analysis using erythrocyte rosette assays, TdT and a large panel of poly- and monoclonal antibody tests. The 1255 cases were divided into these major types and subtypes: 349 cases of ALL and related immature T- and Burkitt-lymphomas (cALL, pre B-ALL, B-ALL and Burkitt-lymphomas, T-ALL and immature, mostly leukemic T-lymphomas, Null-ALL), 454 cases of mature T- and B-cell malignancies (T-CLL, mycosis fungoides, Sezary-syndrome, T-lymphomas, B-CLL, hairy cell leukemia, multiple myeloma, B-lymphomas), 263 cases of acute myeloid leukemias (AML, AMMoL/AMoL), 182 cases of chronic myeloid leukemias (CML in chronic phase, CMoL, CML in blast crisis), 6 cases of erythroleukemia and 1 case of megakaryoblastic leukemia. A simplified classification scheme which has been used in our laboratories is presented. Phenotyping is of diagnostic, prognostic and therapeutic relevance, most evidently for patients with ALL. Routine leukemia phenotyping should be performed with highly standardized techniques and reagents and by combining information from several fields in the multiple marker analysis. New areas of leukemia research might become very useful for the routine procedure of phenotyping.Abbreviations ALL acute lymphoblastic leukemia - AML acute myeloblastic leukemia - AMMoL acute myelomonoblastic leukemia - AMoL acute monoblastic leukemia - cALL common ALL - CLL chronic lymphocytic leukemia - CML chronic myelocytic leukemia - CML-BC CML in blastic crisis - CMoL chronic monocytic leukemia     

Galpha(12/13) mediates alpha(1)-adrenergic receptor-induced cardiac hypertrophy

In neonatal cardiomyocytes, activation of the G(q)-coupled alpha(1)-adrenergic receptor (alpha(1)AR) induces hypertrophy by activating mitogen-activated protein kinases, including c-Jun NH(2)-terminal kinase (JNK). Here, we show that JNK activation is essential for alpha(1)AR-induced hypertrophy, in that alpha(1)AR-induced hypertrophic responses, such as reorganization of the actin cytoskeleton and increased protein synthesis, could be blocked by expressing the JNK-binding domain of JNK-interacting protein-1, a specific inhibitor of JNK. We also identified the classes and subunits of G proteins that mediate alpha(1)AR-induced JNK activation and hypertrophic responses by generating several recombinant adenoviruses that express polypeptides capable of inhibiting the function of specific G-protein subunits. alpha(1)AR-induced JNK activation was inhibited by the expression of carboxyl terminal regions of Galpha(q), Galpha(12), and Galpha(13). JNK activation was also inhibited by the Galpha(q/11)- or Galpha(12/13)-specific regulator of G-protein signaling (RGS) domains and by C3 toxin but was not affected by treatment with pertussis toxin or by expression of the carboxyl terminal region of G protein-coupled receptor kinase 2, a polypeptide that sequesters Gbetagamma. alpha(1)AR-induced hypertrophic responses were inhibited by Galpha(q/11)- and Galpha(12/13)-specific RGS domains, C3 toxin, and the carboxyl terminal region of G protein-coupled receptor kinase 2 but not by pertussis toxin. Activation of Rho was inhibited by carboxyl terminal regions of Galpha(12) and Galpha(13) but not by Galpha(q). Our findings suggest that alpha(1)AR-induced hypertrophic responses are mediated in part by a Galpha(12/13)-Rho-JNK pathway, in part by a G(q/11)-JNK pathway that is Rho independent, and in part by a Gbetagamma pathway that is JNK independent.     

Disseminated gonococcal infection in a Japanese man with complement 7 deficiency with compound heterozygous variants: A case report

Rationale:Complement deficiency are known to be predisposed to disseminated gonococcal infection (DGI). We herein present a case of DGI involving a Japanese man who latently had a complement 7 deficiency with compound heterozygous variants.Patient concerns:A previously healthy 51-year-old Japanese man complained of sudden-onset high fever. Physical examination revealed various skin lesions including red papules on his trunk and extremities, an impetigo-like pustule on left forearm, and tendinitis of his right forefinger.Diagnosis:Blood culture testing detected gram-negative cocci, which was confirmed to be Neisseria gonorrhoeae based on mass spectrometry and a pathogen-specific PCR test.Interventions:Screening tests for underlying immunocompromised factors uncovered that complement activities (CH50) was undetectable. With a suspicion of a congenital complement deficiency, genetic analysis revealed rare single nucleotide variants in complement 7 (C7), including c.281-1G>T and a novel variant c.1454C>T (p.A485V). CH50 was normally recovered by adding purified human C7 to the patient''s serum, supporting that the patient has C7 deficiency with compound heterozygous variants.Outcomes:Under a diagnosis of DGI, the patient underwent an antibiotic treatment with cefotaxime for a week and was discharged without any sequela.Lessons:DGI is a rare sexually-transmitted infection that potentially induces systemic complications. Complement immunity usually defeats N. gonorrhoeae and prevents the organism from causing DGI. This case highlighted the importance of suspecting a complement deficiency when a person develops DGI.     

Repeated piezoelectric lithotripsy for gallstones with and without ursodeoxycholic acid dissolution: A multicenter study

The use of bile acid dissolution therapy in extracorporeal shockwave lithotripsy of gallstones, remains controversial. Our study examined whether chemolitholysis after sufficient disintegration enhanced stone clearance within 6 months of the first lithotripsy. A total of 143 patients who developed one to three radiolucent stones measuring⪯30 mm in diameter were randomly separated into two treatment groups: 47% were given lithotripsy alone, and 53% lithotripsy plus ursodeoxycholic acid (UDCA). Repeated piezoelectric lithotripsy was given, with no limit on the total number of treatment sessions, to pulverize or disintegrate stones into fragments<3 mm. Stones were disintegrated in 97% of all patients, and the fragments were ⪯2 mm in 50% of these patients. According to an intention-to-treat analysis, 52% in the lithotripsy alone group and 58% in the UDCA group were free of stones 6 months after the first lithotripsy (P=0.61). Of the patients with fragments⪯2 mm, 71% in the former and 86% in the latter group were free of stones 6 months after the first lithotripsy, with no significant difference between the groups. Biliary pain occurred in 25% of all patients, including 3 with acute cholecystitis. We concluded that the sufficient disintegration of gallstones achieved with repeated lithotripsy enhanced the early clearance of fragments, regardless of whether chemolitholysis was employed.     

Acute myeloid leukemia with t(8;21)(q22;q22) manifesting as granulocytic sarcomas in the rhinopharynx and external acoustic meatus at relapse after high-dose cytarabine: case report and review of the literature

We report a 31-year-old female with t(8;21)(q22;q22) acute myeloid leukemia (AML), M2 in the FAB classification. Complete remission was achieved with daunorubicin and cytarabine induction therapy followed by three courses of high-dose cytarabine consolidation. Only 3 months later, the patient relapsed with granulocytic sarcomas (GSs) in her rhinopharynx, external acoustic meatus, and bone marrow. She received focal radiation for the GSs and successfully underwent reinduction chemotherapy. Subsequently, she received a matched related donor peripheral blood stem cell transplantation followed by high-dose chemotherapy and is now in a second remission. We summarized 79 reported cases of t(8;21) AML with GS and reviewed the literature to identify differences in the characteristics of t(8;21) AML with GS between adults and children. To our knowledge, this is the first report of pharyngeal GS in t(8;21) AML, and focal irradiation plus more intensive postinduction therapy during first remission, such as allogeneic-SCT, may be effective in adult t(8;21) AML patients with GS.