Pace-Termination and Pacing for Prevention of Atrial Tachyarrhythmias: Results from a Multicenter Study with an Implantable Device for Atrial Therapy

INTRODUCTION: Patients with bradycardia requiring permanent pacing frequently suffer from additional atrial tachyarrhythmias (ATs). This study evaluated the safety and efficacy of atrial antitachycardia pacing (ATP) and the performance of pacing for AT prevention implemented into a new pacemaker. METHODS AND RESULTS: In patients with conventional indications for permanent pacing, an investigational DDDRP pacemaker (Medtronic AT500, model 7253) was implanted. The primary study objectives were to determine the safety of overall device functioning and its efficacy in terminating spontaneous AT. A secondary endpoint was to determine the reliability of AT detection. Pacemaker memory functions were used to analyze the impact of dedicated pacing algorithms on AT prevention. In 33 European and Canadian centers, 325 patients were enrolled (mean follow-up 2.3+/-1.3 months). Complication-free survival at 3 months was 88%. In 2,145 episodes stored with atrial electrograms, AT detection was confirmed in 97%. The algorithm for continuous overdrive pacing increased the percentage of atrial pacing to 97%. After ATP activation, 16,683 of 52,468 AT episodes were treated (120 patients). Of these, 8,903 episodes (53%) were terminated successfully by ATP. No proarrhythmic effect of preventive pacing or atrial ATP was observed. Preventive pacing algorithms increased the median percentage of atrial pacing from 62% to 97%. However, the number of AT/AF (atrial fibrillation) episodes (4.1 vs 4.1 per patient per day) and the time in AT/AF (13.7% vs 12.8%) was not significantly different before and after activation of preventive pacing. CONCLUSION: DDDRP pacing with a new system for AT therapy was safe and associated with successful pace-termination of AT in 53% of episodes. Preventive pacing and atrial ATP algorithms represent two new functions that can be implemented safely into pacemaker systems for nonpharmacologic treatment of ATs in patients requiring pacemaker therapy.     

大肠癌免疫组化表达与临床病理的关系

目的:探讨大肠癌CEA、P53、nm23、Ki-67、MRP免疫组化表达特点和相互关系,及其与临床病理的关系．方法:回顾性分析2003-01／2006-07我院收治的73例大肠癌患者的临床病理及随访资料,并对其石蜡标本采用免疫组化SP染色法检测CEA、P53、nm23、Ki-67、MRP,分析其免疫组化特点及其与临床病理之间的关系．结果:CEA、P53、nm23、Ki-67、MRP在大肠癌中的阳性表达率依次为82．2％、68．5％、75.3％、84．9％和64．4％．CEA、MRP与大肠癌患者的各因素无统计学差异．P53、Ki-67和nm23与肿瘤的Dukes分期和淋巴结转移有关, P53、Ki-67在Dukes C、D期的阳性表达率(依次为82．8％和100％1明显高于Dukes A、B期者(59．1％和75．0％)(P<0．05),而nm23在Dukes C、D期的阳性表达率(58．6％)明显低于Dukes A、B期者(86．4％)(P<0．05)．CEA与nm23的表达呈明显的负相关(r=-0．296,P=0．011),而P53和Ki-67表达之间呈现明显的正相关(r= 0．308,P=0．008),其他各指标间的表达无相关性．nm23、P53和Ki-67与预后因素关系明显,nm23在生存期≥3 a患者的阳性表达率(92．9%)高于生存期<3 a者(71．2％)(P<0．05),而P53和Ki-67在生存期≥3 a患者的阳性表达率(依次为42．9％和64.3％)明显低于生存期<3 a者(74．6％和89．8％)(P<0．05)．结论:P53、Ki-67和nm23的表达与大肠癌的侵袭转移和预后密切相关．CEA可能是大肠癌的侵袭转移的促进因素．MRP所引起的耐药机制是一个相对独立的机制．CEA、P53、nm23、Ki-67可作为判断大肠癌恶性程度、侵袭转移以及预后的指标．     

The specific power of parentage exclusion in a child's blood relatives

BACKGROUND: The impersonation of parent and child by two other blood relatives is an important problem in parentage analysis involving potential immigrants. STUDY DESIGN AND METHODS: A statistic (AR) is proposed, based on the specific power of exclusion of paternity, which describes the ability of a child's test results to demonstrate evidence of nonparentage under the hypothesis that an ostensible parent is actually an older sibling. A case illustrates the value of A(R): a woman and her two alleged children were typed at 3 variable number of tandem repeat (VNTR) loci after 18 short tandem repeat (STR) loci initially showed strong evidence of the woman's maternity of one child and her exclusion from parentage of the second. AR and 1 - AR were calculated from the STR types of the first child. RESULTS: The woman was excluded from maternity of both children with the additional VNTR tests. Given the 18 STR test findings of the first child, the probability was 12 percent that there would be no inconsistencies with parentage in a sibling pretending to be a parent. CONCLUSION: The value 1 - AR, siblings not excluded from parentage, explains how a seemingly large number of examined loci can fail to reveal even one genetic inconsistency if two siblings have posed as parent and child. Approximately 25 STR loci appear necessary to achieve 95 percent confidence of detecting at least one genetic inconsistency indicative of nonparentage.     

Regulation of synaptojanin 1 by cyclin-dependent kinase 5 at synapses

Synaptojanin 1 is a polyphosphoinositide phosphatase concentrated in presynaptic nerve terminals, where it dephosphorylates a pool of phosphatidylinositol 4,5-bisphosphate implicated in synaptic vesicle recycling. Like other proteins with a role in endocytosis, synaptojanin 1 undergoes constitutive phosphorylation in resting synapses and stimulation-dependent dephosphorylation by calcineurin. Here, we show that cyclin-dependent kinase 5 (Cdk5) phosphorylates synaptojanin 1 and regulates its function both in vitro and in intact synaptosomes. Cdk5 phosphorylation inhibited the inositol 5-phosphatase activity of synaptojanin 1, whereas dephosphorylation by calcineurin stimulated such activity. The activity of synaptojanin 1 was also stimulated by its interaction with endophilin 1, its major binding partner at the synapse. Notably, Cdk5 phosphorylated serine 1144, which is adjacent to the endophilin binding site. Mutation of serine 1144 to aspartic acid to mimic phosphorylation by Cdk5 inhibited the interaction of synaptojanin 1 with endophilin 1. These results suggest that Cdk5 and calcineurin may have an antagonistic role in the regulation of synaptojanin 1 recruitment and activity, and therefore in the regulation of phosphatidylinositol 4,5-bisphosphate turnover at synapses.     

Photoaging of the skin from phenotype to mechanisms

The skin is increasingly exposed to ambient UV-irradiation thus increasing its risk for photooxidative damage with longterm detrimental effects like photoaging, which is characterized by wrinkles, loss of skin tone, and resilience. Photoaged skin displays prominent alterations in the cellular component and the extracellular matrix of the connective tissue with an accumulation of disorganized elastin and its microfibrillar component fibrillin in the deep dermis and a severe loss of interstitial collagens, the major structural proteins of the dermal connective tissue. The unifying pathogenic agents for these changes are UV-generated reactive oxygen species (ROS) that deplete and damage non-enzymatic and enzymatic antioxidant defense systems of the skin. As well as causing permanent genetic changes, ROS activate cytoplasmic signal transduction pathways in resident fibroblasts that are related to growth, differentiation, senescence, and connective tissue degradation. This review focuses on the role of UV-induced ROS in the photodamage of the skin resulting in biochemical and clinical characteristics of photoaging. In addition, the relationship of photoaging to intrinsic aging of the skin will be discussed. A decrease in the overall ROS load by efficient sunscreens or other protective agents may represent promising strategies to prevent or at least minimize ROS induced photoaging.     

Inhibition of day-12 spleen colony-forming units by a monoclonal antibody to the murine macrophage/monocyte colony-stimulating factor receptor

Primitive hematopoietic stem cells differentiate into committed progenitors that are thought to selectively express hematopoietic growth factor receptor(s), thereby acquiring hematopoietic growth factor responsiveness. To assess whether hematopoietic stem cells express hematopoietic growth factor receptors, the progenitor activity of bone marrow (BM) fractions, isolated by expression of receptors for macrophage/monocyte colony-stimulating factor (M-CSF), were examined. Recovery of day-12 spleen colony-forming units (CFU-S) is diminished in both M-CSF receptor-positive (M-CSFR+) and M-CSFR- fractions, indicating antibody inhibition of day-12 CFU-S. Incubation of BM cells with antibody without fractionation inhibits 50% to 60% of day-12 CFU- S. This inhibition is specific (control antibodies have no effect) and reversible by removal of bound antibody at low pH. Incubating BM cells with control or antireceptor antibody does not affect day-8 CFU-S, which are predominantly erythroid. Treating sublethally irradiated mice with antibody inhibits endogenous day-12 CFU-S. These results indicate that some early progenitors express M-CSFRs, and blocking M-CSFRs inhibits the ability of these progenitors to form colonies, possibly because of inactivation caused by prolonged receptor blockade.     

Studies on the dynamics of transmission of onchocerciasis in a Sudan-savanna area of North Cameroon V. What is a tolerable level of Annual Transmission Potential?

The prevalence and intensity of infection with Onchocerca volvulus were assessed in population surveys in nine villages, situated at different distances from Simulium damnosum s.l. breeding sites. The prevalence varied from 48 to 89%, the arithmetic mean densities of microfilariae per skin snip were between 16 and 109, and severe ocular lesions were found in from 1 to 22% of patients. Annual Transmission Potentials (ATP) were measured for up to three years in the near vicinity of nine villages at several fly-catching sites. Weighted means of the ATP over the three years, and of the sojourn times of the human population, were calculated at three of the villages, where the prevalence of onchocerciasis was 51, 61 and 89%. An average ATP of 100 larvae or less in the head, thorax and abdomen of the flies was associated with an onchocerciasis prevalence of 50 to 60%, a mean microfilarial density below 40 microfilariae per skin-snip, less than 5% of ocular lesions, and no onchocercal blindness. This value might therefore be considered to be an indication of the level to which the transmission must be reduced in the savanna in order to prevent the occurrence of severe ocular lesions or blindness. It is lower than the present level accepted by the Onchocerciasis Control Programme in the Volta River Basin.     

The contribution of activated factor XIII to fibrinolytic resistance in experimental pulmonary embolism

BACKGROUND: The resistance of thrombi to fibrinolysis induced by plasminogen activators remains a major impediment to the successful treatment of thrombotic diseases. This study examines the contribution of activated factor XIII (factor XIIIa) to fibrinolytic resistance in experimental pulmonary embolism. METHODS AND RESULTS: The fibrinolytic effects of specific inhibitors of factor XIIIa-mediated fibrin-fibrin cross-linking and alpha2-antiplasmin-fibrin cross-linking were measured in anesthetized ferrets with pulmonary emboli. Five experimental groups were treated with heparin (100 U/kg) and/or tissue plasminogen activator (TPA, 1 mg/kg) and the percent (mean+/-SD) lysis of emboli was determined: (1) control, normal factor XIIIa activity (14.1+/-4. 8% lysis); (2) inhibited factor XIIIa activity (42.7+/-7.4%); (3) normal factor XIIIa activity+TPA (32.3+/-7.7%); (4) inhibited factor XIIIa activity+TPA (76.0+/-11.9%); and (5) inhibited alpha2-antiplasmin-fibrin cross-linking+TPA (54.7+/-3.9%). Inhibition of factor XIIIa activity increased endogenous lysis markedly (group 1 versus 2; P<0.0001), to a level comparable to that achieved with TPA (group 2 versus 3; P<0.05). Among groups receiving TPA, selective inhibition of factor XIII-mediated alpha2-antiplasmin-fibrin cross-linking enhanced lysis (group 3 versus 5; P<0.0005). Complete inhibition of factor XIIIa also amplified lysis (group 3 versus 4; P<0.0001) and had greater effects than inhibition of alpha2-antiplasmin cross-linking alone (group 4 versus 5; P<0.0005). No significant fibrinogen degradation occurred in any group. CONCLUSIONS: Factor XIIIa-mediated fibrin-fibrin and alpha2-antiplasmin-fibrin cross-linking both caused experimental pulmonary emboli to resist endogenous and TPA-induced fibrinolysis. This suggests that factor XIIIa may play a critical role in regulating fibrinolysis in human thrombosis.     

Coagulant stability and sterility of thawed S/D-treated plasma

BACKGROUND: Units of frozen S/D-treated plasma (SDP) must be transfused within 24 hours after thawing. To avoid waste, an attempt was made to determine how long SDP could be therapeutically effective after thawing and storing it at 20 degrees C. STUDY DESIGN AND METHODS: The microbiologic safety and the activity of labile coagulation factors were evaluated in units stored at 20 degrees C of thawed SDP units and FFP within 24 hours of collection (FFP24). Five SDP and FFP24 samples of each ABO blood group were cultured and assayed for coagulation factors daily over 5 days. Assays included FV, FVII, FVIIa, FVIII, F IX, FXI, protein S, antiplasmin, fibrinogen, prothrombin times (PTs), and activated partial thromboplastin times (aPTTs). RESULTS: None of the 80 bacterial cultures demonstrated growth under either aerobic or anaerobic conditions. FV, FVIII, F IX, FXI, fibrinogen, and the aPTT appeared to be stable in both thawed FFP24 and SDP. The PT increased slightly in thawed FFP24 and insignificantly in SDP. FVII decreased slightly in FFP24 but remained in the normal range, and FVIIa was low and constant. FVII was increased in SDP and FVIIa was markedly increased. Protein S decreased from initial normal values in FFP24 to very low values. Protein S was very low immediately after thawing in the SDP and continued to decline. Antiplasmin was normal and stable in thawed FFP24 but was low in SDP and remained constant after thawing. CONCLUSION: Sterile SDP that is stored at 20 degrees C provides sufficient coagulant activity of labile FV and FVIII to transfuse it for up to 5 days after thaw. Caution is warranted by decreases in Protein S and antiplasmin, clinical evidence of coagulopathy in some recipients of SDP, and a recent manufacturer's warning.