Serial electrophysiologic studies after single chamber atrial pacemaker implantation in patients with symptomatic sinus node dysfunction

After single chamber atrial pacemaker implantation, serial electrophysiologicstudies were performed noninvasively at intervals of 3 monthsover a total period of 3 years in 24 patients with symptomaticsinus node dysfunction. All patients underwent invasive electrophysiologicstudies before pacemaker implantation and demonstrated intactanterograde AV conduction. Patients were divided into 2 groupsgroup I did not require antiarrhythmic drugs during follow-upwhereas group 2 received antiarrhythmic drugs. In group 1(11 patients) the atrial paced heart rate producingAV Wenckebach phenomenon (AVWHR) remained stable during a meanfollow-up of 22±10 months, with a variability not exceeding10 beats min^–1 with respect to the initial AVWHR obtainedduring preoperative electrophysiologic study. In group 2 (13patients) with a mean follow-up of 15±8 months a meandecrease of AVWHR of 19.2±17.5 beats min^–1 waspresent between AVWHR before and 3 months after initiation oforal antiarrhythmic drugs (P<0.01) During chronic (>3months) antiarrhythmic drug therapy the variability of the AVWHRnever exceeded 10 beats min^–1 with respect to the AVWHRobtained 3 months after the initiation of oral drug therapy. Deterioration of anterograde AV conduction during long-termfollow-up of patients with symptomatic sinus node dysfunctionand intact anterograde AV conduction at the time of pacemakerimplantation is a consequence of orally taken antiarrhythmicdrugs, rather than a consequence of degeneration of the AV conductingsystem.     

CCRL2 promotes antitumor T-cell immunity via amplifying TLR4-mediated immunostimulatory macrophage activation

Macrophages are the key regulator of T-cell responses depending on their activation state. C-C motif chemokine receptor-like 2 (CCRL2), a nonsignaling atypical receptor originally cloned from LPS-activated macrophages, has recently been shown to regulate immune responses under several inflammatory conditions. However, whether CCRL2 influences macrophage function and regulates tumor immunity remains unknown. Here, we found that tumoral CCRL2 expression is a predictive indicator of robust antitumor T-cell responses in human cancers. CCRL2 is selectively expressed in tumor-associated macrophages (TAM) with immunostimulatory phenotype in humans and mice. Conditioned media from tumor cells could induce CCRL2 expression in macrophages primarily via TLR4, which is negated by immunosuppressive factors. Ccrl2^−/− mice exhibit accelerated melanoma growth and impaired antitumor immunity characterized by significant reductions in immunostimulatory macrophages and T-cell responses in tumor. Depletion of CD8⁺ T cells or macrophages eliminates the difference in tumor growth between WT and Ccrl2^−/− mice. Moreover, CCRL2 deficiency impairs immunogenic activation of macrophages, resulting in attenuated antitumor T-cell responses and aggravated tumor growth in a coinjection tumor model. Mechanically, CCRL2 interacts with TLR4 on the cell surface to retain membrane TLR4 expression and further enhance its downstream Myd88-NF-κB inflammatory signaling in macrophages. Similarly, Tlr4^−/− mice exhibit reduced CCRL2 expression in TAM and accelerated melanoma growth. Collectively, our study reveals a functional role of CCRL2 in activating immunostimulatory macrophages, thereby potentiating antitumor T-cell response and tumor rejection, and suggests CCLR2 as a potential biomarker candidate and therapeutic target for cancer immunotherapy.

The central role of T cells, particularly cytotoxic CD8⁺ T cells (CTL), in anti-tumor immunity has been highlighted by the clinical success of cancer immunotherapies. Melanoma is known as an immunogenic tumor with abundant tumor-infiltrating T cells and is susceptible to immune checkpoint blockades (1). However, many types of cancer are not responsive to immunotherapy, and even for melanoma, less than 40% of patients could benefit from these therapies, possibly due to insufficient activation of tumor-specific CTL or their failure to infiltrate tumors (2).Macrophages constitute the largest fraction of tumor-infiltrating immune cells and act as an important regulator during cancer progression (3–6). The abundance of tumor-associated macrophages (TAM) is generally associated with impaired anti-tumor T-cell immunity and poor clinical outcome and response to treatment in solid tumors (7–10). However, in some cases, macrophages can be associated with a good prognosis; for example, high frequencies of HLA-DR⁺ macrophages within tumors have been associated with good outcomes (11–13). It has become clear that TAM consist of a continuum of phenotypes, ranging from an immunostimulatory M1-like phenotype to an immunosuppressive M2-like phenotype (14, 15). M1-like macrophages predominate at sites of early oncogenesis, mediating anti-tumor effects including direct killing and activation of anti-tumor T-cell immunity (5, 7, 16–18). Over tumor progression, macrophages can be shifted toward M2-like phenotype by responding to cues within the tumor microenvironment (TME) (19–21). M2-like macrophages predominate in established tumors, mediating protumor effects including the induction of immunosuppression, promotion of angiogenesis, and tumor cell biology (5, 7). Thus, targeting macrophages has become an attracting strategy to complement the existing cancer immunotherapy. Instead of depletion of all macrophages which contain both anti- and protumor subsets, induction of immunostimulatory phenotype or reprograming TAM from protumor into anti-tumor phenotype could be more efficient to control tumor progression primarily by enhancing anti-tumor T-cell responses (7). Thus, identification of the key factors that regulate the activation state of macrophages, particularly those enforcing anti-tumor M1-like phenotype, could facilitate the development of new therapeutic targets to improve the efficacy of anti-cancer immunotherapy.C-C motif chemokine receptor-like 2 (CCRL2) was originally cloned from LPS-stimulated macrophages and first named as a LPS inducible C-C chemokine receptor related gene (l-CCR) (22). CCRL2 is absent in resting immune cells and induced in activated myeloid cells, but not T cells, under certain pathological conditions (23–27). CCRL2 was later identified as a nonsignaling atypical receptor to enrich and present its ligand chemerin to the functional receptor, CMKLR1 (24). Further studies demonstrated that CCRL2 expressed in endothelial cells promotes CMKLR1-dependent dendritic cell (DC) and natural killer (NK) cell transmigration (28, 29). In addition, CCRL2 expression in activated neutrophils regulates CXCR2-dependent neutrophil chemotaxis toward CXCL8 (25). Surprisingly, the role of CCRL2 in macrophages remains unknown. Preclinical mouse studies demonstrated that CCRL2 is involved in several inflammatory diseases (25, 27, 30). However, the involvement of CCRL2 in tumors has been reported until very recently. CCRL2 expression in nonhematopoietic cells inhibits lung tumors by facilitating NK cell migration (29), while CCRL2 expression in human breast cancer tissues positively correlates to tumor-infiltrating immune cells (31).Here, we demonstrate that CCLR2 expression is not only a predictive indicator of robust anti-tumor immunity in human cancers but also plays a functional role in the activation of immunostimulatory macrophages via interacting with surface TLR4 and amplifying its downstream inflammatory signaling, finally leading to optimal anti-tumor T-cell responses.     

Effect of metergoline,a powerful and long-acting antiserotoninergic agent,on insulin secretion in normal subjects and in patients with chemical diabetes

Summary The effect of metergoline on insulin secretion has been evaluated in normal subjects and in patients with chemical diabetes. The repeated administration of metergoline, 2 mg at four-hour intervals to give a total of 24 mg, has enhanced insulin secretion in response to i. v. glucose in normal subjects but not in chemical diabetics. No changes in blood glucose pattern were observed. Under similar conditions, metergoline administration caused a slight but significant decrease in arginine-induced insulin release, both in normal subjects and in chemical diabetics. These results support the concept of a serotoninergic control of insulin secretion and suggest that serotonin exerts different effects on insulin release according to the different stimuli.     

Effectiveness of intravenous propafenone for conversion of recent-onset atrial fibrillation: A placebo-controlled study

To evaluate the efficacy of propafenone in converting recent-onset atrial fibrillation (AF) lasting <7 days, 182 patients were treated intravenously with propafenone (Group 1, n = 98) and with placebo 0.9% saline solution (Group 2, n = 84) in a double blind study. The treatment was continued until sinus rhythm (SR) was restored, but for no more than 24 h. Eighty-nine patients treated with propafenone (90.8%) and 27 patients treated with placebo (32.1%) responded to the treatment and SR was restored (p < 0.0005). The mean time for SR restoration was 2.51± 2.77 h in Group 1, and 17.15± 7.8 h in Group 2 (p < 0.0005). In both groups the patients in whom SR was not restored (nonresponders) had larger left atrial size and longer duration of AF than responders at the onset of the arrhythmia. Nonresponders in Group 1 showed a decrease in mean ventricular rate (MVR) from 143± 16 to 101± 18 (p < 0.0005), while in the nonresponders in Group 2 no reduction of MVR was observed. Two patients whose SR was restored with propafenone had sinus standstill lasting 3.4 and 3.8 s, respectively. Propafenone used intravenously is an effective, quick, and safe drug for treating AF. Moreover, it significantly reduces MVR in nonresponders.     

Vascular complications in steroid treated patients undergoing transfemoral aortic valve implantation

• Steroids if taken chronically or periprocedurally contribute to delayed wound healing and decreased vascular patency
• Access site complications after diagnostic interventional procedures carry significant morbidity, increased cost, and prolonged hospital stay
• TAVI offers high risk surgical candidates with severe aortic stenosis a significant survival advantage

     

Physicians’ preferences for active-controlled versus placebo-controlled trials of new antihypertensive drugs

OBJECTIVE: To evaluate physicians' preferences for referring patients to, and using information from, active-controlled trials (ACTs) versus placebo-controlled trials (PCTs) of new antihypertensive drugs. DESIGN AND SETTING: Nationwide mailed survey, with telephone contact of nonresponders to assess nonresponse bias. PARTICIPANTS: One thousand two hundred primary care physicians randomly selected from the American Medical Association's Master File. Of 1,154 physicians eligible to respond, 651 (56.4%) returned completed questionnaires. MEASUREMENTS AND MAIN RESULTS: We measured physicians' stated willingness to encourage hypertensive patients to enroll in ACTs and PCTs of new antihypertensive drugs, their views of the relative merits of ACTs versus PCTs, their stated willingness to prescribe new drugs tested in ACTs or PCTs, and their views regarding the overall justifiability of the 2 designs. Physicians were significantly more likely to indicate they would encourage their patients to enroll in ACTs than in PCTs (P <.0001). Physicians thought ACTs provided more valuable information for their practices, were more likely to lead to a public health benefit, offered enrolled patients greater opportunity for personal benefit, and were less likely to expose enrolled patients to unnecessary risks (all P <.0001). Physicians were more likely to prescribe new drugs that had been compared in ACTs (P <.0001), and viewed ACTs as a more justifiable method for testing new antihypertensive drugs (P <.0001). There was no evidence of nonresponse bias for these main results. CONCLUSIONS: Although PCTs remain the standard method for testing new antihypertensive drugs, physicians strongly prefer ACTs. Using ACTs to test new antihypertensive drugs may enhance the efficiency of patient recruitment and more strongly influence physicians' prescribing practices.     

青蒿琥酯分别与诺氟沙星、甲硝唑伍用的体内、外抗恶性疟作用

目的　了解青蒿琥酯分别与诺氟沙星、甲硝唑伍用的体内、外抗疟作用。　方法　采用青蒿琥酯与诺氟沙星 (A组 )或甲硝唑 (B组 )联用 3d疗法治疗无并发症的恶性疟。体外测定采用 Rieckmann体外微量法测定恶性疟原虫对 3种药物单一用药及青蒿琥酯分别与诺氟沙星或甲硝唑联用的敏感性。　结果　体内观察法共收治 70例病人 ,其中 A组 5 5例 ,B组 15例。平均退热时间分别为 (2 6 .5± 16 .5 ) h(8h～ 93h)、(19.2± 11.0 ) h(4h～ 4 1h) ;平均原虫无性体转阴时间分别为 (37.4± 15 .3) h(13h～ 93h)和 (42 .8± 14 .7) h(2 5 h～ 72 h) ;2 8d复燃率分别为 4 7.4 %和 75 .0 %。体外微量法测得青蒿琥酯与诺氟沙星伍用的 ID50 分别为单用组的 5 .9%和 0 .3% ;青蒿琥酯与甲硝唑伍用的 ID50 分别为单用组的38.8%和 5 .6 %。　结论　青蒿琥酯分别与诺氟沙星、甲硝唑伍用在体外对抗青蒿琥酯恶性疟原虫有明显增效作用 ,但在临床治疗中未能提高治愈率     

Risk factors for hospitalized gastrointestinal bleeding among older persons. Cardiovascular Health Study Investigators

OBJECTIVES: We sought to estimate the incidence of hospitalization for upper and lower gastrointestinal bleeding among older persons and to identify independent risk factors. DESIGN: Prospective cohort study. SETTING: The Cardiovascular Health Study (CHS). PARTICIPANTS: 5,888 noninstitutionalized men and women age 65 years or older in four U.S. communities enrolled in the CHS. MEASUREMENTS: Gastrointestinal bleeding events during the period 1989 through 1998 were identified using hospital discharge diagnosis codes and confirmed by medical records review. Risk-factor information was collected in a standardized fashion at study baseline and annually during follow-up. RESULTS: Among CHS participants (mean baseline age 73.3 years, 42% male), the incidence of hospitalized gastrointestinal bleeding was 6.8/1,000 person-years. In multivariate analyses, advanced age, male sex, unmarried status, cardiovascular disease, difficulty with daily activities, use of multiple medications, and use of oral anticoagulants were independent risk factors. Compared with nonsmokers, subjects who smoked more than half a pack per day had a multivariate-adjusted hazard ratio (HR) of 2.14 (95% confidence interval [CI] = 1.22-3.75) for upper gastrointestinal bleeding and a multivariate-adjusted HR of 0.21 (95% CI = 0.03-1.54) for lower gastrointestinal bleeding. Aspirin users did not have an elevated risk of upper gastrointestinal bleeding (HR = 0.76, 95% CI = 0.52-1.11), and users of other nonsteroidal anti-inflammatory drugs had a HR of 1.54 (95 % CI = 0.99-2.36). Low ankle-arm systolic blood pressure index was associated with higher risk of gastrointestinal bleeding among subjects with clinical cardiovascular disease but not among those without clinical cardiovascular disease. CONCLUSION: This study identifies risk factors for gastrointestinal bleeding, such as disability, that may be amenable to modification. The findings will help clinicians to identify older persons who are at high risk for gastrointestinal bleeding.