Development and construction of a neutron beam line for accelerator-based boron neutron capture synovectomy

A potential application of the 10B(n, alpha)7Li nuclear reaction for the treatment of rheumatoid arthritis, termed Boron Neutron Capture Synovectomy (BNCS), is under investigation. In an arthritic joint, the synovial lining becomes inflamed and is a source of great pain and discomfort for the afflicted patient. The goal of BNCS is to ablate the synovium, thereby eliminating the symptoms of the arthritis. A BNCS treatment would consist of an intra-articular injection of boron followed by neutron irradiation of the joint. Monte Carlo radiation transport calculations have been used to develop an accelerator-based epithermal neutron beam line for BNCS treatments. The model includes a moderator/reflector assembly, neutron producing target, target cooling system, and arthritic joint phantom. Single and parallel opposed beam irradiations have been modeled for the human knee, human finger, and rabbit knee joints. Additional reflectors, placed to the side and back of the joint, have been added to the model and have been shown to improve treatment times and skin doses by about a factor of 2. Several neutron-producing charged particle reactions have been examined for BNCS, including the 9Be(p,n) reaction at proton energies of 4 and 3.7 MeV, the 9Be(d,n) reaction at deuteron energies of 1.5 and 2.6 MeV, and the 7Li(p,n) reaction at a proton energy of 2.5 MeV. For an accelerator beam current of 1 mA and synovial boron uptake of 1000 ppm, the time to deliver a therapy dose of 10,000 RBEcGy ranges from 3 to 48 min, depending on the treated joint and the neutron producing charged particle reaction. The whole-body effective dose that a human would incur during a knee treatment has been estimated to be 3.6 rem or 0.75 rem, for 1000 ppm or 19,000 ppm synovial boron uptake, respectively, although the shielding configuration has not yet been optimized. The Monte Carlo design process culminated in the construction, installation, and testing of a dedicated BNCS beam line on the high-current tandem electrostatic accelerator at the Laboratory for Accelerator Beam Applications at the Massachusetts Institute of Technology.     

Increased CD8+ T Cell Apoptosis in Scleroderma Is Associated with Low Levels of NF-κB

Our objectives were (1) to compare lymphocyte subpopulation apoptosis rates in SSc patients versus healthy controls and (2) to compare Bcl-2 and NF-kappa B expression in cultured CD8 lymphocytes of SSc patients versus controls. Peripheral blood samples were obtained from 27 SSc patients meeting the American College of Rheumatology criteria for SSc and 28 healthy individuals. Mononuclear cells were isolated by Ficoll-Hypaque density gradient separation and cultured for 48 hr. For determination of apoptosis within specific cell populations, samples were labeled with PE-conjugated monoclonal antibody to CD8, CD4, and a FITC-conjugated monoclonal antibody to Annexin V. Flow cytometry was carried out with a FACS operating with Cellquest software. CD8+ lymphocytes were positively selected with magnetic microbeads conjugated to antihuman CD8. CD8 T cells were separated, then incubated with activation for 48 hr, and NF-kappa B and Bcl-2 analysis was carried out using Western immunoblotting. The CD4:CD8 ratio was increased in SSc compared to controls (2.6 +/- 1.13 vs.1.87 +/- 0.76; P = 0.018). The spontaneous apoptosis rate of SSc CD8 lymphocytes was increased compared to that of controls of (21.9 +/- 13.7 vs. 13.3 +/- 9.9; P = 0.019). No difference was found in the rate of CD4 apoptosis of SSc patients versus controls (9.8 +/- 5.2 vs. 7.18 +/- 4.89%; P = ns). The expression of NF-kappa B in SSc CD8 lymphocytes was decreased compared with that of CD8 lymphocytes from healthy controls (144 +/- 13 vs. 188 +/- 11; P = 0.018). Whereas expression of Bcl-2 was similar in activated CD8+ T cells of SSc patients and healthy controls, CD8+ T cell apoptosis rate was found to be in reverse correlation with expression of NF-kappa B in these cells ( r = - 0.53, P = 0.029). The increased CD4:CD8 ratio in SSC may result from increased CD8+ T cell apoptosis. Increased SSc CD8 T cell apoptosis is associated with low levels of NF-kappa B.     

Quantifying infection risks in incompatible living donor kidney transplant recipients

Desensitization has enabled incompatible living donor kidney transplantation (ILDKT) across HLA/ABO barriers, but added immunomodulation might put patients at increased risk of infections. We studied 475 recipients from our center from 2010 to 2015, categorized by desensitization intensity: none/compatible (n = 260), low (0-4 plasmaphereses, n = 47), moderate (5-9, n = 74), and high (≥10, n = 94). The 1-year cumulative incidence of infection was 50.1%, 49.8%, 66.0%, and 73.5% for recipients who received none, low, moderate, and high-intensity desensitization (P < .001). The most common infections were UTI (33.5% of ILDKT vs. 21.5% compatible), opportunistic (21.9% vs. 10.8%), and bloodstream (19.1% vs. 5.4%) (P < .001). In weighted models, a trend toward increased risk was seen in low (wIRR = _0.771.40_2.56,P = .3) and moderately (wIRR = _0.881.35_2.06,P = .2) desensitized recipients, with a statistically significant 2.22-fold (wIRR = _1.332.22_3.72,P = .002) increased risk in highly desensitized recipients. Recipients with ≥4 infections were at higher risk of prolonged hospitalization (wIRR = _2.623.57_4.88, P < .001) and death-censored graft loss (wHR = _1.154.01_13.95,P = .03). Post–KT infections are more common in desensitized ILDKT recipients. A subset of highly desensitized patients is at ultra-high risk for infections. Strategies should be designed to protect patients from the morbidity of recurrent infections, and to extend the survival benefit of ILDKT across the spectrum of recipients.     

Receptor-mediated toxicity of pahutoxin, a marine trunkfish surfactant.

Pahutoxin (PHN, choline chloride ester of 3-acetoxypalmitic acid) is a natural fish-killing (ichthyotoxic) agent derived from the defensive secretions of trunkfish. In spite of its obvious structural resemblance to synthetic cationic long-chain quaternary ammonium detergents, we show that PHN's action does not rely on its surfactant properties and is in fact, receptor-mediated. The above conclusion is supported by the following data: 1. Ichthyotoxicity is not related to its detergency or surfactivity, as indicated by the fact that the lethal concentration is about 1.5 orders of magnitude below its critical micelle concentration value (69 microM) and its liposomal/seawater partition coefficient is low (62-85); 2. The trunkfish is tolerant to its own pahutoxin; 3. Ichthyotoxicity occurs only upon application to the surrounding water, suggesting the existence of externally located receptors; 4. The receptor hypothesis was supported by the aid of equilibrium saturation binding assays revealing the presence of specific binding sites to PHN on the fish gill membranes; 5. The PHN tolerant trunkfish was shown to be devoid of PHN-binding sites. Some chemo-ecological, and environmental implications are discussed.     

The phenotypic plasticity of myeloma plasma cells as expressed by dedifferentiation into an immature, resilient, and apoptosis-resistant phenotype.

PURPOSE: We previously showed the ability of osteoclasts to support myeloma plasma cell survival and proliferation in vivo and ex vivo. The aim of the current study was to investigate osteoclast-induced phenotypic changes associated with long-term survival of myeloma cells in coculture. EXPERIMENTAL DESIGN: CD138-selected myeloma plasma cells from 16 patients were cocultured with human osteoclasts for up to 20 weeks. RESULTS: Precultured cells were typically CD45(low/intermediate) CD38(high) CD138(high), CD19(-)CD34(-). After >6 weeks, the phenotype of cocultured myeloma cells consistently shifted to cells expressing CD45(intermediate/high) CD19(low) CD34(low). Expression of CD38 and CD138 were reduced to subpopulations with CD38(intermediate) and CD138(low) levels. Morphologically, cocultured plasma cells became plasmablastic. Blocking interleukin-6 activity did not affect the immature phenotype of myeloma cells. The effect of dexamethasone on myeloma cells cultured alone or in cocultures at baseline and after 6 weeks of coculture was determined. When baseline myeloma cells were cultured alone, dexamethasone significantly increased the percentage of apoptotic cells over the spontaneous rate. Conversely, myeloma cells recovered from cocultures had high survival rates and were resistant to dexamethasone-induced apoptosis. Long-term coculture of normal CD34-expressing hematopoietic stem cells (HSC) resulted in loss of CD34 expression, suggesting a common mechanism for osteoclast-induced myeloma and HSC plasticity. CONCLUSIONS: This study indicates that myeloma cells have plasticity expressed by their ability to reprogram, dedifferentiate, and acquire autonomous survival properties.     

Doppler‐guided haemorrhoidal artery ligation in patients with Crohn’s disease

Aim: The outcome of Doppler‐guided haemorrhoidal artery ligation (DGHAL) was assessed in patients with Crohn’s disease (CD) suffering from grade III haemorrhoids. Method: A retrospective study was carried out of patients with CD and symptomatic Grade III haemorrhoids treated by DGHAL. Perioperative and follow‐up data were retrieved from our database of patients undergoing DGHAL. Results: The study included seven men and six women. The mean age was 34 years old. All had CD without anorectal involvement. The median duration of haemorrhoidal symptoms was 6.3 years. There was no mortality, new incontinence, faecal impaction, urinary retention, abscess formation or persistent pain following the procedure. Mean pain score based on a visual analogue scale (VAS) decreased from 2.4 at 24 h postoperatively to 1.6 on the seventh postoperative day. All patients had completely recovered by the third postoperative day. At 18 months, three (77%) of the patients were asymptomatic and three had recurrent symptoms. Conclusion: Doppler‐guided haemorrhoidal artery ligation is safe and effective in treating Grade III haemorrhoids in patients with CD without rectal involvement.     

Influence of conduction disturbances on clinical outcome in patients with acute myocardial infarction receiving thrombolysis (results from the ARGAMI-2 study)

Right bundle branch block and complete atrioventricular (AV) block are conduction disorders (CDs) that have been observed in 14% of patients admitted with ST-elevation acute myocardial infarction. CDs carry a poor prognosis, with a threefold increase in the mortality rate, mainly due to cardiogenic shock and recurrent fatal myocardial infarction at 1-year follow-up. According to multivariable analysis, CD was the second strongest predictor of death, after high Killip class. Compared with patients without CD, the 1-year outcome of patients with CD was identically worse, irrespective of whether CD appeared during admission, disappeared, or remained constant. Similar adverse outcomes were seen in patients with complete AV block and right bundle branch block.     

Current perspectives in therapeutic myocardial angiogenesis

The complex mechanisms mediating the development of new blood vessels are now beginning to be unraveled. In conjunction with major biotechnology advances, this has facilitated the initiation of translational research related to a novel treatment strategy for patients with myocardial or leg ischemia due to obstructive arterial disease--therapeutic angiogenesis. At present, at least 17 clinical trials of myocardial angiogenesis have been presented involving over 900 patients. Uncertainty exists as to the optimal delivery route and angiogenic agent, and this uncertainty is reflected in the diverse methodology of the trials published thus far. The majority of patients received an angiogenic protein via the intracoronary route. Other delivery techniques--such as direct intramyocardial injection via transepicardial or transendocardial routes--and other angiogenic agents, including master genes, have also been studied. Most recently, interest has grown in the potential angiogenesis effects of cell therapy--such as autologous bone marrow cells or cultured stem cells--and there are now several groups initiating Phase I/II trials in this area. This review summarizes the current evidence pertaining to the safety, feasibility, and efficacy of various angiogenic techniques aimed at enhancing myocardial blood flow and alleviating angina.