Lymphocyte reconstitution following autologous stem cell transplantation for progressive MS

BACKGROUND: Autologous stem cell transplantation (ASCT) for progressive multiple sclerosis (MS) may reset the immune repertoire. OBJECTIVE: The objective of this paper is to analyse lymphocyte recovery in patients with progressive MS treated with ASCT. METHODS: Patients with progressive MS not responding to conventional treatment underwent ASCT following conditioning with high-dose cyclophosphamide and antithymocyte globulin. Lymphocyte subset analysis was performed before ASCT and for two years following ASCT. Neurological function was assessed by the EDSS before ASCT and for three years post-ASCT. RESULTS: CD4+ T-cells fell significantly post-transplant and did not return to baseline levels. Recent thymic emigrants and naïve T-cells fell sharply post-transplant but returned to baseline by nine months and twelve months, respectively. T-regulatory cells declined post-transplant and did not return to baseline levels. Th1 and Th2 cells did not change significantly while Th17 cells fell post-transplant but recovered to baseline by six months. Neurological function remained stable in the majority of patients. Progression-free survival was 69% at three years. CONCLUSION: This study demonstrates major changes in the composition of lymphocyte subsets following ASCT for progressive MS. In particular, ablation and subsequent recovery of thymic output is consistent with the concept that ASCT can reset the immune repertoire in MS patients

Characteristics and prevalence of hardcore smokers attending UK general practitioners

BACKGROUND: Smoking remains a public health problem and although unsolicited GPs' advice against smoking causes between one and three percent of smokers to stop, a significant proportion of smokers are particularly resistant to the notion of stopping smoking. These resistant smokers have been called "hardcore smokers" and although 16% of smokers in the community are hardcore, little is known about hardcore smokers presenting to primary care physicians. Consequently, this study reports the characteristics and prevalence of hardcore smokers attending UK GPs. METHODS: A cross-sectional survey using data from two different research projects was conducted. Data for this analysis had been collected from surgery consultation sessions with 73 GPs in Leicestershire, England, (42 GPs from one project). Research assistants distributed pre-consultation questionnaires to 4147 adults attending GPs' surgery sessions. Questionnaires identified regular smokers, the proportion of hardcore smokers and their characteristics. Non-hardcore and hardcore smokers' ages, gender and nicotine addiction levels were compared. RESULTS: 1170 regular smokers attended surgery sessions and, 16.1% (95% CI, 14.1 to 18.4) were hardcore smokers. Hardcore smokers had higher levels of nicotine addiction than others (p = 0.000), measured by the Heaviness of Smoking Index and were more likely to be male [50.5% hardcore versus 35.3% non-hardcore, (OR = 1.88, 95% CI = 1.4 to 2.6)] but no age differences were observed between groups. CONCLUSION: A significant minority of the smokers who present in general practice are resistant to the notion of smoking cessation and these smokers are more heavily nicotine addicted than others. Although clinical guidelines suggest that GPs should regularly advise all smokers against smoking, it is probable that hardcore smokers do not respond positively to this and help to make up the 97%–99% of smokers who do not quit after being advised to stop smoking by GPs. General practitioners need to find approaches for raising the issue of smoking during consultations in ways that do not reinforce the negative opinions of hardcore smokers concerning smoking cessation

U.S./Russian lab-to-lab materials protection, control and accounting program efforts at the Institute of Inorganic Materials. Revision 1

The All-Russian Scientific Research Institute of Inorganic Materials (VNIINM) performs research in nuclear power reactor fuel, spent fuel reprocessing and waste management, materials science of fissionable and reactor structural materials, metallurgy, superconducting materials, and analytical sciences. VNIINM supports the Ministry of Atomic Energy of the Russian Federation (MINATOM) in technologies for fabrication and processing of nuclear fuel. As a participant in the US/Russian Lab-to-Lab nuclear materials protection, control and accounting (MPC and A) program, VNIINM is providing support for measurements of nuclear materials in bulk forms by developing specifications, test and evaluation, certification, and implementation of measurement methods for such materials. In 1996, VNIINM will be working with Brookhaven staff in developing and documenting material control and accounting requirements for nuclear materials in bulk form, Livermore and Los Alamos staff in testing and evaluating gamma-ray spectrometry methods for bulk materials, Los Alamos staff in test and evaluation of neutron-coincidence counting techniques, Oak Ridge staff in accounting of bulk materials with process instrumentation, and Pacific Northwest staff on automating VNIINM`s coulometric titration system. In addition, VNIINM will develop a computerized accounting system for nuclear material within VNIINM and their storage facility. The paper will describe the status of this work and anticipated progress in 1996

Multisite spectroscopic seismic study of the beta Cep star V2052 Oph: inhibition of mixing by its magnetic field

We used extensive ground-based multisite and archival spectroscopy to derive observational constraints for a seismic modelling of the magnetic beta Cep star V2052 Ophiuchi. The line-profile variability is dominated by a radial mode (f_1=7.14846 d^{-1}) and by rotational modulation (P_rot=3.638833 d). Two non-radial low-amplitude modes (f_2=7.75603 d^{-1} and f_3=6.82308 d^{-1}) are also detected. The four periodicities that we found are the same as the ones discovered from a companion multisite photometric campaign (Handler et al. 2012) and known in the literature. Using the photometric constraints on the degrees l of the pulsation modes, we show that both f_2 and f_3 are prograde modes with (l,m)=(4,2) or (4,3). These results allowed us to deduce ranges for the mass (M \in [8.2,9.6] M_o) and central hydrogen abundance (X_c \in [0.25,0.32]) of V2052 Oph, to identify the radial orders n_1=1, n_2=-3 and n_3=-2, and to derive an equatorial rotation velocity v_eq \in [71,75] km s^{-1}. The model parameters are in full agreement with the effective temperature and surface gravity deduced from spectroscopy. Only models with no or mild core overshooting (alpha_ov \in [0,0.15] local pressure scale heights) can account for the observed properties. Such a low overshooting is opposite to our previous modelling results for the non-magnetic beta Cep star theta Oph having very similar parameters, except for a slower surface rotation rate. We discuss whether this result can be explained by the presence of a magnetic field in V2052 Oph that inhibits mixing in its interior.Comment: 12 pages, 6 figures and 5 tables; accepted for publication in MNRAS on 2012 August 1

Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis

PURPOSE: Oral melphalan and dexamethasone (MDex) were considered a standard of care in light-chain (AL) amyloidosis. In the past decade, bortezomib has been increasingly used in combination with alkylating agents and dexamethasone. We prospectively compared the efficacy and safety of MDex and MDex with the addition of bortezomib (BMDex). METHODS: This was a phase III, multicenter, randomized, open-label trial. Patients were stratified according to cardiac stage. Patients with advanced cardiac stage (stage IIIb) amyloidosis were not eligible. The primary end point was hematologic response rate at 3 months. This trial is registered with ClinicalTrials.gov identifier NCT01277016. RESULTS: A total of 109 patients, 53 in the BMDex and 56 in the MDex group, received ≥ 1 dose of therapy (from January 2011 to February 2016). Hematologic response rate at 3 months was higher in the BMDex arm (79% v 52%; P = .002). Higher rates of very good partial or complete response rates (64% v 39%; hazard ratio [HR], 2.47; 95% CI, 1.30 to 4.71) and improved overall survival, with a 2-fold decrease in mortality rate (HR, 0.50; 95% CI, 0.27 to 0.90), were observed in the BMDex arm. Grade 3 and 4 adverse events (the most common being cytopenia, peripheral neuropathy, and heart failure) were more common in the BMDex arm, occurring in 20% versus 10% of cycles performed. CONCLUSION: BMDex improved hematologic response rate and overall survival. To our knowledge, this is the first time a controlled study has demonstrated a survival advantage in AL amyloidosis. BMDex should be considered a new standard of care for AL amyloidosis

Comorbidity as a prognostic variable in multiple myeloma: comparative evaluation of common comorbidity scores and use of a novel MM–comorbidity score

Comorbidities have been demonstrated to affect progression-free survival (PFS) and overall survival (OS), although their impact in multiple myeloma (MM) patients is as yet unsettled. We (1) assessed various comorbidities, (2) compared established comorbidity indices (CIs; Charlson comorbidity index (CCI), hematopoietic cell transplantation-specific comorbidity index (HCT-CI)), Kaplan Feinstein (KF) and Satariano index (SI) and (3) developed a MM-CI (Freiburger comorbidity index, FCI) in 127 MM patients. Univariate analysis determined moderate or severe pulmonary disease (hazard ratio (HR): 3.5, P<0.0001), renal impairment (via estimated glomerular filtration rate (eGFR); HR: 3.4, P=0.0018), decreased Karnofsky Performance Status (KPS, HR: 2.7, P=0.0004) and age (HR: 2, P=0.0114) as most important variables for diminished OS. Through multivariate analysis, the eGFR ⩽30 ml/min/1.73m2, impaired lung function and KPS ⩽70% were significant for decreased OS, with HRs of 2.9, 2.8 and 2.2, respectively. Combination of these risk factors within the FCI identified significantly different median OS rates of 118, 53 and 25 months with 0, 1 and 2 or 3 risk factors, respectively, (P<0.005). In light of our study, comorbidities are critical prognostic determinants for diminished PFS and OS. Moreover, comorbidity scores are important treatment decision tools and will be valuable to implement into future analyses and clinical trials in MM

Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production

Despite recent therapeutic advancements, multiple myeloma (MM) remains incurable and new therapies are needed, especially for the treatment of elderly and relapsed/refractory patients. We have screened a panel of 100 off-patent licensed oral drugs for anti-myeloma activity and identified niclosamide, an anti-helminthic. Niclosamide, at clinically achievable non-toxic concentrations, killed MM cell lines and primary MM cells as efficiently as or better than standard chemotherapy and existing anti-myeloma drugs individually or in combinations, with little impact on normal donor cells. Cell death was associated with markers of both apoptosis and autophagy. Importantly, niclosamide rapidly reduced free light chain (FLC) production by MM cell lines and primary MM. FLCs are a major cause of renal impairment in MM patients and light chain amyloid and FLC reduction is associated with reversal of tissue damage. Our data indicate that niclosamides anti-MM activity was mediated through the mitochondria with rapid loss of mitochondrial membrane potential, uncoupling of oxidative phosphorylation and production of mitochondrial superoxide. Niclosamide also modulated the nuclear factor-κB and STAT3 pathways in MM cells. In conclusion, our data indicate that MM cells can be selectively targeted using niclosamide while also reducing FLC secretion. Importantly, niclosamide is widely used at these concentrations with minimal toxicity

Prevalence and factors associated with difficulty and intention to quit smoking in Switzerland

ABSTRACT: BACKGROUND: Recent data indicate a slight decrease in the prevalence of smoking in Switzerland, but little is known regarding the intention and difficulty to quit smoking among current smokers. Hence, we aimed to quantify the difficulty and intention to quit smoking among current smokers in Switzerland. METHODS: Cross-sectional study including 607 female and 658 male smokers. Difficulty, intention and motivation to quit smoking were assessed by questionnaire. RESULTS: 90% of women and 85% of men reported being "very difficult" or "difficult" to quit smoking. Almost three quarters of smokers (73% of women and 71% of men) intended to quit; however, less than 20% of them were in the preparation stage and 40% were in the precontemplation stage. On multivariate analysis, difficulty to quit was lower among men (Odds ratio and 95% [confidence interval]: 0.51 [0.35-0.74]) and increased with nicotine dependence and number of previous quitting attempts (OR=3.14 [1.75-5.63] for 6+ attempts compared to none). Intention to quit decreased with increasing age (OR=0.48 [0.30-0.75] for [greater than or equal to]65 years compared to &lt;45 years) and increased with nicotine dependence, the number of previous quitting attempts (OR=4.35 [2.76-6.83] for 6+ attempts compared to none) and among non-cigarette smokers (OR=0.51 [0.28-0.92]). Motivation to quit was inversely associated with nicotine dependence and positively associated with the number of previous quitting attempts and personal history of lung disease. CONCLUSION: Over two thirds of Swiss smokers want to quit. However, only a small fraction wishes to do so in the short term. Nicotine dependence, previous attempts to quit or previous history of lung disease are independently associated with difficulty and intention to quit