Cellular trafficking of nicotinic acetylcholine receptors

Nicotinic acetylcholine receptors （nAChRs） play critical roles throughout the body. Precise regulation of the cellular loca- tion and availability of nAChRs on neurons and target cells is critical to their proper function. Dynamic, post-translational regulation of nAChRs, particularly control of their movements among the different compartments of cells, is an important aspect of that regulation. A combination of new information and new techniques has the study of nAChR trafficking poised for new breakthroughs.     

A programme for developing nurses'' skills and nursing practice

In this paper we describe a programme for developing nursing care for patients with myocardial infarction (MI) and report some results of a study in which applicability and effectiveness of this programme were evaluated. To investigate how the programme influenced nursing practice, nurses' readiness (knowledge, skills, motivation, accountability) to provide care for MI patients was followed for 2 years. Data for the evaluation were collected by questionnaires from three categories of nurses, by analysing nursing documents before and 1 and 2 years after the programme started, and by keeping a continuous diary. This programme made an impact on many variables that measure changes in nursing practice and nurses' readiness to provide care. The implications of this programme for nursing practice, research, education and administration are discussed.     

Family history of myocardial infarction is an independent risk factor for venous thromboembolism: the Tromsø study

Summary. Background: Recent studies indicate that arterial cardiovascular diseases and venous thromboembolism (VTE) share common risk factors. A family history of myocardial infarction (MI) is a strong and independent risk factor for future MI. Objectives: The purpose of the present study was to determine the impact of cardiovascular risk factors, including family history of MI, on the incidence of VTE in a prospective, population‐based study. Patients and methods: Traditional cardiovascular risk factors and family history of MI were registered in 21 330 subjects, aged 25–96 years, enrolled in the Tromsø study in 1994–95. First‐lifetime VTE events during follow‐up were registered up to 1 September 2007. Results: There were 327 VTE events (1.40 per 1000 person‐years), 138 (42%) unprovoked, during a mean of 10.9 years of follow‐up. In age‐ and gender‐adjusted analysis, age [hazard ratio (HR) per decade, 1.97; 95% confidence interval (CI), 1.82–2.12], gender (men vs. women; HR, 1.25; 95% CI, 1.01–1.55), body mass index (BMI; HR per 3 kg m^?2, 1.21; 95% CI, 1.13–1.31), and family history of MI (HR, 1.31; 95% CI, 1.04–1.65) were significantly associated with VTE. Family history of MI remained a significant risk factor for total VTE (HR, 1.27; 95% CI, 1.01–1.60) and unprovoked VTE (HR, 1.46; 95% CI, 1.03–2.07) in multivariable analysis. Blood pressure, total cholesterol, HDL‐cholesterol, triglycerides, and smoking were not independently associated with total VTE. Conclusions: Family history of MI is a risk factor for both MI and VTE, and provides further evidence of a link between venous and arterial thrombosis.     

Erythrocyte membrane proteins reactive with IgG (warm-reacting) anti- red blood cell autoantibodies: II. Antibodies coprecipitating band 3 and glycophorin A

In our initial immunochemical study of the red blood cell (RBC) membrane proteins targeted in 20 cases of warm-antibody autoimmune hemolytic anemia (AHA), RBC eluates of 6 patients mediated immunoprecipitation (IP) of both band 3 and glycophorin A (GPA). This dual IP pattern had previously been observed with murine monoclonal antibodies (MoAbs) against the high frequency blood group antigen, Wrb (Wright), suggesting that the Wrb epitope may depend on a band 3-GPA interaction. Earlier, anti-Wrb had been identified serologically as a prominent non-Rh specificity of AHA autoantibodies. In the present study, 6 autoantibody eluates immunoprecipitating band 3 and GPA from common Wr(b+) RBCs were retested, in parallel with murine anti-Wrb MoAbs, against very rare Wr(a+b-)En(a+)RBCs. One patient's autoantibodies were unreactive with the Wr(b-) RBCs by either IP or indirect antiglobulin test (IAT) and were judged to have "pure" anti- Wrb specificity. Two other patients' autoantibodies displayed both IP and serologic evidence for anti-Wrb as a major component in combination with one or more additional specificities. However, among 3 other patients whose autoantibodies coprecipitated band 3 and GPA, there was no reduction in IP or IAT reactivity with Wr(b-) RBCs in 2 and only slight reduction in the third. We conclude (1) that human anti-Wrb autoantibodies, like their murine monoclonal counterparts, coprecipitate band 3 and GPA from human RBCs; but (2) that not all antibodies with this IP behavior have anti-Wrb serologic specificity, as defined by this donor's Wr(b-) RBCs. The possibility of an additional (non-Wrb) RBC epitope dependent on a band 3-GPA interaction is raised.     

Rituximab for congenital haemophiliacs with inhibitors: a Canadian experience

When a high titre inhibitor develops in a patient with haemophilia, attempts are made to eradicate it through immune tolerance induction therapy (ITI) involving the frequent and regular administration of factor, usually for months to years. ITI is successful in only two thirds of patients prompting investigators to explore alternate regimens to use in haemophiliacs failing conventional ITI. Rituximab is an anti-CD20 monoclonal antibody, which has shown promise in the treatment of B-cell-mediated disorders. We developed a protocol for the use of rituximab in haemophilia A (HA) patients failing conventional ITI or in those haemophiliacs where the likelihood of success of conventional ITI is poor. Patients receive 375 mg m(-2) of intravenous rituximab weekly for 4 weeks followed by monthly (up to 5 months) until inhibitor disappearance and establishment of normal FVIII pharmacokinetics (recovery and half-life). Patients are concurrently placed on recombinant FVIII (100 U kg(-1) day(-1)). We have placed five haemophiliacs (four children with severe HA, and one adult with mild HA) on this protocol. In three patients (two with severe HA and one with mild HA) inhibitors disappeared although in neither severe haemophiliac did FVIII pharmacokinetics completely normalize. The fourth patient had a significant drop in inhibitor titres although not a complete disappearance of the inhibitor. All four of these patients ceased bleeding following rituximab. The fifth patient had no response to rituximab. This non-responding patient was not placed on concurrent FVIII. Our five cases suggest that rituximab may hold promise in the eradication of inhibitors. Prospective randomized studies are required to determine the value of this agent in inhibitor management.     

Myocardial oxygen consumption in left ventricular hypertrophy and its relation to left ventricular mechanics

Alterations in left ventricular (LV) mechanics have significant effects on myocardial oxygen consumption (MV?O₂₂) as a result of changing LV pressure and dimensions. However, the effects of load alteration on MV?O₂₂ in the setting of LV hypertrophy and LV dysfunction have not been well characterized. Therefore, we examined changes in LV mechanics and MV?O₂₂ in 32 patients with varying degrees of LV hypertrophy and LV dysfunction before and after pharmacologic alteration of load. With phenylephrine or nitroglycerin-induced load alteration, changes in peak systolic meridional stress, mean systolic stress and the area of a stress-dimension loop all correlated modestly with changes in MV?O₂₂ (r = 0.66, 0.62, 0.63, respectively). However, changes in the time integral of LV ejection stress, or shortening load, were significantly correlated with changes in MV?O₂₂ (r = 0.88, p < 0.001). In particular, load reduction results in a beneficial effect on MV?O₂₂. In addition, for a given change in LV systolic pressure, changes in shortening load (38 + 3.7%) were significantly greater than changes in tension-time index (13 ± 1.4%), thus providing a sensitive marker of alteration of mechanical load.We conclude that physiologic alterations in mechanical load in normal persons as well as patients with LV hypertrophy are reflected in significant changes in the time integral of LV ejection stress. These changes in shortening load, mediated by changing LV pressure and dimension, are significantly related to changes in MV?O₂₂.     

Phase II trial of 2-chlorodeoxyadenosine for the treatment of cutaneous T-cell lymphoma [see comments]

We investigated the efficacy of 2-chlorodeoxyadenosine (2-CdA) therapy in patients with mycosis fungoides (MF) and the Sezary syndrome (SS). Between February 1991 and November 1993, 21 patients with relapsed or refractory MF/SS were treated with 2-CdA. 2-CdA was administered by continuous intravenous infusion at a dose of 0.1 mg/kg/d for 7 days initially (13 patients), but was subsequently reduced to 5 days (nine patients) due to hematologic toxicity. All patients had failed to respond to at least one prior treatment for MF/SS (median number of total prior therapies, five; median number of systemic prior therapies, three) and had an Eastern Cooperative Oncology Group performance status of two or better. Cycles were administered at 28-day intervals. Assessable patients received at least 5 days of 2-CdA. Fourteen patients received more than one cycle of 2-CdA. An overall response rate of 28% was achieved. Three patients (14%) had a complete response with a median duration of 4.5 months (range, 2.5 to 16). Three (14%) had a partial response with a median duration of 2 months (range, 2 to 4). Fifteen patients (72%) had no response. The most significant toxicities encountered were bone marrow suppression (62% of patients) and infectious complications (62% of patients). Thirty-eight percent of patients experienced no toxicity from 2-CdA. 2-CdA has activity as a single agent in patients with previously treated relapsed MF/SS. Studies in less heavily pretreated individuals with 2-CdA alone or in combination will be undertaken.     

Image‐guided video assisted thoracoscopic surgery (iVATS) ‐ phase I‐II clinical trial

Purpose

To facilitate localization and resection of small lung nodules, we developed a prospective clinical trial ( ClinicalTrials.gov number NCT01847209) for a novel surgical approach which combines placement of fiducials using intra‐operative C‐arm computed tomography (CT) guidance with standard thoracoscopic resection technique using image‐guided video‐assisted thoracoscopic surgery (iVATS).

Methods

Pretrial training was performed in a porcine model using C‐arm CT and needle guidance software. Methodology and workflow for iVATS was developed, and a multi‐modality team was trained. A prospective phase I‐II clinical trial was initiated with the goal of recruiting eligible patients with small peripheral pulmonary nodules. Intra‐operative C‐arm CT scan was utilized for guidance of percutaneous marking with two T‐bars (Kimberly‐Clark, Roswell, GA) followed by VATS resection of the tumor.

Results

Twenty‐five patients were enrolled; 23 underwent iVATS, one withdrew, and one lesion resolved. Size of lesions were: 0.6–1.8 cm, mean = 1.3 ± 0.38 cm.. All 23 patients underwent complete resection of their lesions. CT imaging of the resected specimens confirmed the removal of the T‐bars and the nodule. Average and total procedure radiation dose was in the acceptable low range (median = 1501 μGy*m², range 665–16,326). There were no deaths, and all patients were discharged from the hospital (median length of stay = 4 days, range 2–12). Three patients had postoperative complications: one prolonged air‐leak, one pneumonia, and one ileus.

Conclusions

A successful and safe step‐wise process has been established for iVATS, combining intra‐operative C‐arm CT scanning and thoracoscopic surgery in a hybrid operating room. J. Surg. Oncol. 2015 111:18–25. © 2015 The Authors. Journal of Surgical Oncology Published by Wiley Periodicals, Inc.     

Mechanism for cotolerance in nonlethally conditioned mixed chimeras: negative selection of the Vbeta T-cell receptor repertoire by both host and donor bone marrow-derived cells

Bone marrow (BM) chimeras prepared by complete recipient ablation (A-- >B) exhibit donor-specific tolerance, yet survival is often limited by graft-versus-host disease (GVHD). Negative selection of potentially donor-reactive T cells, as assessed by relative T-cell receptor (TCR)- Vbeta expression, is dependent on donor BM-derived deleting ligands. Mixed chimerism and tolerance for both donor and host antigens can be achieved using partial recipient myeloablation with 500 cGy total-body irradiation (TBI) before transplantation followed by cyclophosphamide (CyP) on day +2. To examine the influence of residual host elements on negative selection, the peripheral TCR-Vbeta repertoire was analyzed in partially ablated C57BL/10SnJ (B10) recipients reconstituted with BM from major histocompatibility complex (MHC)-disparate B10.BR/SgSnJ or MHC, Hh-1 and Mls-disparate BALB/cByJ donors, which delete Vbeta5+ and 11+ or Vbeta3+, 5+, and 11+ TCR subsets, respectively. As in myeloblated recipients, donor-reactive subfamilies were deleted in B10.BR-->B10 and BALB/c-->B10 chimeras, suggesting that donor I-E and minor lymphocyte-stimulating (Mls) antigens contribute to the deleting ligands in the nonmyeloablated host. In striking contrast to completely ablated B10-->B10.BR chimeras, partially ablated recipients showed intramedullary I-E expression in the thymus and deleted host-reactive Vbeta5+ and Vbeta11+ subfamilies. These data demonstrate that efficient clonal deletion occurs after partial myeloablation and that both donor and host ligands contribute to TCR repertoire selection.     

X-sizer for thrombectomy in acute myocardial infarction improves ST-segment resolution: results of the X-sizer in AMI for negligible embolization and optimal ST resolution (X AMINE ST) trial

OBJECTIVES: We sought to compare, in a prospective randomized multicenter study, the effect of adjunctive thrombectomy using X-Sizer (eV3, White Bear Lake, Minnesota) before percutaneous coronary intervention (PCI) versus conventional PCI in patients with acute myocardial infarction (AMI) for <12 h and Thrombolysis In Myocardial Infarction (TIMI) flow grade 0 to 1. The primary end point was the magnitude of ST-segment resolution after PCI. BACKGROUND: Despite a high rate of TIMI flow grade 3 achieved by PCI in patients with AMI, myocardial reperfusion remains relatively low. Distal embolization of thrombotic materials may play a major role in this setting. METHODS: We conducted a prospective, randomized, multicenter study in patients with AMI <12 h and initial TIMI flow grade 0 to 1 who were treated with primary PCI. The magnitude of ST-segment resolution 1 h after PCI was the primary end point. RESULTS: A total of 201 patients were included. Treatment groups were comparable by age (61 +/- 13 years), diabetes (22%), previous MI (8%), anterior MI (52%), onset-to-angiogram (258 +/- 173 min), and glycoprotein IIb/IIIa inhibitor use (59%). The magnitude of ST-segment resolution was greater in the X-Sizer group compared with the conventional group (7.5 vs. 4.9 mm, respectively; p = 0.033) as ST-segment resolution >50% (68% vs. 53%; p = 0.037). The occurrence of distal embolization was reduced (2% vs. 10%; p = 0.033) and TIMI flow grade 3 was obtained in 96% vs. 89%, respectively (p = 0.105). Myocardial blush grade 3 was similar (30% vs. 31%; p = NS). Six-month clinical outcome was comparable (death, 6% vs. 4% and major adverse cardiac and cerebral events, 13% vs. 13%, respectively). By multivariate analysis, independent predictors of ST-segment resolution >50% were: younger age, non-anterior MI, use of the X-Sizer, and a short time interval from symptom onset. CONCLUSIONS: Reducing thrombus burden with X-Sizer before stenting leads to better myocardial reperfusion, as illustrated by a reduced risk of distal embolization and better ST-segment resolution.