Allogeneic Stem Cell Transplantation from HLA-Mismatched Donors for Pediatric Patients with Acute Lymphoblastic Leukemia Treated According to the 2003 BFM and 2007 International BFM Studies: Impact of Disease Risk on Outcomes

Allogeneic hematopoietic stem cell transplantation (HSCT) is beneficial for pediatric patients with relapsed or (very) high-risk acute lymphoblastic leukemia (ALL) in remission. A total of 1115 consecutive patients were included in the ALL SCT 2003 BFM study and the ALL SCT 2007 I-BFM study and were stratified according to relapse risk (standard versus high versus very high risk of relapse) and donor type (matched sibling versus matched donor versus mismatched donor). A total of 148 patients (60% boys; median age, 8.7 years; B cell precursor ALL, 75%) were transplanted from mismatched donors, which was defined as either less than 9/10 HLA-compatible donors or less than 5/6 unrelated cord blood after myeloablative conditioning regimen (total body irradiation based, 67%) for high relapse risk (HRR; n?=?42) or very HRR (VHRR) disease (n?=?106). The stem cell source was either bone marrow (n?=?31), unmanipulated peripheral stem cells (n?=?28), T cell ex vivo depleted peripheral stem cells (n?=?59), or cord blood (n?=?25). The median follow-up was 5.1 years. The 4-year rates of overall survival (OS) and event-free survival were 56%?±?4% and 52%?±?4%, respectively, for the entire cohort. Patients transplanted from mismatched donors for HRR disease obtained remarkable 4-year OS and event-free survival values of 82%?±?6% and 80%?±?6%, respectively, whereas VHRR patients obtained values of 45%?±?5% and 42%?±?5% (P?<?.001), respectively. The cumulative incidence of relapse was 29%?±?4% and that of nonrelapse mortality 19%?±?3%. The cumulative incidence of limited and extensive chronic graft-versus-host disease was 13%?±?3% and 15%?±?4%, respectively, among the 120 patients living beyond day 100. Multivariate analysis showed that OS was lower for transplanted VHRR patients (P?=?.002; hazard ratio [HR], 3.62; 95% confidence interval [CI], 1.60 to 8.20) and for patients beyond second complete remission (CR2) versus first complete remission (P?<?.001; HR, 3.68; 95% CI, 1.79 to 7.56); relapse occurred more frequently in patients with VHRR disease (P?=?.026; HR, 3.30; 95% CI, 1.16 to 9.60) and for those beyond CR2 (P?=?.005; HR, 4.16; 95% CI, 1.52 to 10.59). Nonrelapse mortality was not significantly higher for cytomegalovirus-positive recipients receiving cytomegalovirus-negative grafts (P?=?.12; HR, 1.96; 95% CI, .84 to 4.58). HSCT with a mismatched donor is feasible in pediatric ALL patients but leads to inferior results compared with HSCT with better matched donors, at least for patients transplanted for VHRR disease. The results are strongly affected by disease status. The main cause of treatment failure is still relapse, highlighting the urgent need for interventional strategies after HSCT for patients with residual leukemia before and/or after transplantation     

Environmental enrichment extends ocular dominance plasticity into adulthood and protects from stroke-induced impairments of plasticity

Ocular dominance (OD) plasticity in mouse primary visual cortex (V1) declines during postnatal development and is absent beyond postnatal day 110 if mice are raised in standard cages (SCs). An enriched environment (EE) promotes OD plasticity in adult rats. Here, we explored cellular mechanisms of EE in mouse V1 and the therapeutic potential of EE to prevent impairments of plasticity after a cortical stroke. Using in vivo optical imaging, we observed that monocular deprivation in adult EE mice (i) caused a very strong OD plasticity previously only observed in 4-wk-old animals, (ii) restored already lost OD plasticity in adult SC-raised mice, and (iii) preserved OD plasticity after a stroke in the primary somatosensory cortex. Using patch-clamp electrophysiology in vitro, we also show that (iv) local inhibition was significantly reduced in V1 slices of adult EE mice and (v) the GABA/AMPA ratio was like that in 4-wk-old SC-raised animals. These observations were corroborated by in vivo analyses showing that diazepam treatment significantly reduced the OD shift of EE mice after monocular deprivation. Taken together, EE extended the sensitive phase for OD plasticity into late adulthood, rejuvenated V1 after 4 mo of SC-rearing, and protected adult mice from stroke-induced impairments of cortical plasticity. The EE effect was mediated most likely by preserving low juvenile levels of inhibition into adulthood, which potentially promoted adaptive changes in cortical circuits.Ocular dominance (OD) plasticity induced by monocular deprivation (MD) is one of the best studied models of experience-dependent plasticity in the mammalian cortex (1, 2). OD plasticity in primary visual cortex (V1) of C57BL/6J mice is maximal at 4 wk of age, declines after 2–3 mo, and is absent beyond postnatal day 110 (PD110) if animals are raised in standard cages (SCs) (3–6). In 4-wk-old mice, 4 d of MD are sufficient to induce an OD shift to the open eye; therefore, neurons in the binocular V1, which are usually dominated by the contralateral eye in rodents (3, 7), become activated more equally by both eyes (5, 8). This juvenile OD shift is predominantly mediated by a decrease in the visual cortical responses to the deprived eye (1, 9–11), whereas significant OD shifts in older animals up to PD110 need 7 d of MD and are mediated primarily by increased open-eye responses in V1. Raising animals in an enriched environment (EE) gives them the opportunity of enhanced physical, social, and cognitive stimulation and influences brain physiology and behavior in many ways (12, 13). It has been shown previously that EE enhances visual system development in rats (14) and mice (15–17), increases levels of the brain-derived neurotrophic factor and serotonin (18), reduces both extracellular GABA levels (18, 19) and the density of ECM perineuronal nets (PNNs) (19), and promotes OD plasticity in adult and aging rats (18–21). Here, we explored cellular mechanisms of EE in V1 of mice and the therapeutic potential of EE to prevent impairments of plasticity after a cortical stroke. Furthermore, we studied whether EE would prolong the sensitive phase for OD plasticity into adulthood and also restore this form of plasticity in mice that were raised in SC until PD110 (i.e., in animals that were already beyond their sensitive phase for OD plasticity). Despite pharmacological detection of in vivo GABA levels, suggesting that EE reduces intracortical inhibition, direct electrophysiological evidence is still missing. We therefore recorded GABA, AMPA, and NMDA currents in slices from EE- and SC-raised mice and also tested the efficacy of diazepam injections to abolish OD plasticity of EE mice in vivo. Finally, we studied whether raising mice in EE would protect them from lesion-induced impairments of OD plasticity. Our results show that raising mice in EE preserved OD plasticity into late adulthood rejuvenated the brain after 3 mo of SC-rearing, and protected adult mice from stroke-induced impairments of cortical plasticity. Our electrophysiological measurements and diazepam treatment indicate that the plasticity-promoting effect of EE was primarily mediated by reduced intracortical inhibition compared with SC-raised mice. These results suggest EE as a preventive intervention to enhance and preserve plasticity in adulthood and after a cortical lesion.     

Ischemic heart disease in nuclear workers first employed at the Mayak PA in 1948-1972

Following an earlier study of incidence and mortality of ischemic heart disease (IHD) published in 2010, a second analysis has been conducted based on an extended cohort and five additional years of follow-up. The cohort includes 18,763 workers, of whom 25% were females, first employed at the Mayak PA in 1948-1972 and followed up to the end of 2005. Some of these workers were exposed to external gamma rays only, and others were exposed to a mixture of external gamma-rays and internal alpha-particle radiation. A total of 6,134 cases and 2,629 deaths from IHD were identified in the study cohort. A statistically significant increasing trend was found with total external gamma-ray dose in IHD incidence (ERR/Gy 0.099; 95% CI: 0.045-0.153) after adjusting for non-radiation factors. This value reduced slightly when adjusting for internal liver dose. There was no statistically significant increase trend for internal liver dose in IHD incidence. These findings were consistent with an earlier study. New findings in IHD incidence revealed a statistically significant decrease in IHD incidence among workers exposed to external gamma-rays doses of 0.2-0.5 Gy in relation to the external doses below 0.2 Gy. This decreased risk is heavily influenced by female workers. This finding has never been reported in other studies, and the results should be treated with caution. The findings for IHD mortality are similar to those results in the earlier analysis; there was no statistically significant trend with external gamma-ray dose or for internal liver dose after adjustment for external dose. The risk estimates obtained from these analyses of IHD incidence and mortality in relation to external gamma-rays in the cohort of Mayak workers are generally compatible with those from other large occupational radiation worker studies and the Japanese atomic bomb survivors.     

Apoptosis of peripheral blood lymphocytes and mutations in the gene of the T-cell receptor in survivors of chronic radiation exposure

This research has been conducted to study the activity of apoptosis of peripheral blood lymphocytes (PBLs) and the frequency of CD3-/CD4+ PBLs in people who have suffered chronic low-intensity radiation exposure. An increase in the frequency of apoptotic cells (TUNEL) is demonstrated in the group of exposed individuals relative to the control group. The frequency of mutations in the gene of the T-cell receptor in the exposed individuals is also elevated. Analyses of the mean values of apoptosis and CD3-CD4+ PBLs in different dose subgroups have found an increase in the proportion of cells with mutant T-cell receptors against the background of a decrease in the frequency of apoptotic cells in the range of low and medium radiation doses.     

Occupational radiation doses to operators performing fluoroscopically-guided procedures

In the past 30 y, the numbers and types of fluoroscopically-guided (FG) procedures have increased dramatically. The objective of the present study is to provide estimated radiation doses to physician specialists, other than cardiologists, who perform FG procedures. The authors searched Medline to identify English-language journal articles reporting radiation exposures to these physicians. They then identified several primarily therapeutic FG procedures that met specific criteria: well-defined procedures for which there were at least five published reports of estimated radiation doses to the operator, procedures performed frequently in current medical practice, and inclusion of physicians from multiple medical specialties. These procedures were percutaneous nephrolithotomy (PCNL), vertebroplasty, orthopedic extremity nailing for treatment of fractures, biliary tract procedures, transjugular intrahepatic portosystemic shunt creation (TIPS), head/neck endovascular therapeutic procedures, and endoscopic retrograde cholangiopancreatography (ERCP). Radiation doses and other associated data were abstracted, and effective dose to operators was estimated. Operators received estimated doses per patient procedure equivalent to doses received by interventional cardiologists. The estimated effective dose per case ranged from 1.7-56 μSv for PCNL, 0.1-101 μSv for vertebroplasty, 2.5-88 μSv for orthopedic extremity nailing, 2.0-46 μSv for biliary tract procedures, 2.5-74 μSv for TIPS, 1.8-53 μSv for head/neck endovascular therapeutic procedures, and 0.2-49 μSv for ERCP. Overall, mean operator radiation dose per case measured over personal protective devices at different anatomic sites on the head and body ranged from 19-800 (median = 113) μSv at eye level, 6-1,180 (median = 75) μSv at the neck, and 2-1,600 (median = 302) μSv at the trunk. Operators' hands often received greater doses than the eyes, neck, or trunk. Large variations in operator doses suggest that optimizing procedure protocols and proper use of protective devices and shields might reduce occupational radiation dose substantially.