Reduced-intensity allogeneic stem cell transplantation in children and young adults with ultrahigh-risk pediatric sarcomas

Some subsets of pediatric sarcoma patients have very poor survival rates. We sought to determine the feasibility and efficacy of allogeneic hematopoietic stem cell transplantation (alloHSCT) in pediatric sarcoma populations with <25% predicted overall survival (OS). Patients with ultrahigh-risk Ewing's sarcoma family of tumors (ESFT), alveolar rhabdomyosarcoma, or desmoplastic small round cell tumors received EPOCH-fludarabine induction, a cyclophosphamide/fludarabine/melphalan preparative regimen, and HLA matched related peripheral blood stem cells. Thirty patients enrolled; 7 did not undergo alloHSCT because of progressive disease with diminishing performance status during induction. All 23 alloHSCT recipients experienced rapid full-donor engraftment, with no peritransplantation mortality. Five of 23 alloHSCT recipients (22%) remain alive (OS of 30% by Kaplan-Meier analysis at 3 years), including 3 of 7 (42%) transplanted without overt disease (median survival 14.5 versus 29.0 months from alloHSCT for patients transplanted with versus without overt disease, respectively). Among the 28 patients who progressed on the study, the median survival from date of progression was 1.9 months for the 7 who did not receive a transplant compared with 11.4 months for the 21 transplanted (P = .0003). We found prolonged survival after posttransplantation progression with several patients exhibiting indolent tumor growth. We also saw several patients with enhanced antitumor effects from posttransplantation chemotherapy (objective response to pretransplantation EPOCH-F was 24% versus 67% to posttransplantation EOCH); however, this was associated with increased toxicity. This largest reported series of alloHSCT in sarcomas demonstrates that alloHSCT is safe in this population, and that patients undergoing alloHSCT without overt disease show higher survival rates than reported using standard therapies. Enhanced chemo- and radiosensitivity of tumors and normal tissues was observed posttransplantation.     

Recovery from ischemia in the middle-aged brain: a nonhuman primate model

Studies of recovery from stroke mainly utilize rodent models and focus primarily on young subjects despite the increased prevalence of stroke with age and the fact that recovery of function is more limited in the aged brain. In the present study, a nonhuman primate model of cortical ischemia was developed to allow the comparison of impairments in young and middle-aged monkeys. Animals were pretrained on a fine motor task of the hand and digits and then underwent a surgical procedure to map and lesion the hand-digit representation in the dominant motor cortex. Animals were retested until performance returned to preoperative levels. To assess the recovery of grasp patterns, performance was videotaped and rated using a scale adapted from human occupational therapy. Results demonstrated that the impaired hand recovers to baseline in young animals in 65-80 days and in middle-aged animals in 130-150 days. However, analysis of grasp patterns revealed that neither group recover preoperative finger thumb grasp patterns, rather they develop compensatory movements.     

Larvicidal efficacy of the Citrus limetta peel extracts against Indian strains of Anopheles stephensi Liston and Aedes aegypti L.

The extracts from the peels of Citrus limetta were prepared using hexane and petroleum ether as the solvents. The larvicidal potential of each extract was assessed against dengue fever vector, Aedes aegypti, and malarial vector, Anopheles stephensi, by evaluating the toxicity effects on early fourth instars. Both the extracts were found effective against both the species. The bioassay with hexane extracts resulted in LC(50) values of 132.45 and 96.15 ppm against A. stephensi and A. aegypti, respectively; while the petroleum ether extracts from the C. limetta peels showed LC(50) values of 244.59 and 145.50 ppm, respectively. It revealed that the hexane extracts possessed 1.9-fold more larvicidal potential against A. stephensi and 1.5-fold more efficacy against A. aegypti as compared to the extracts obtained using petroleum ether as solvent. The data further revealed that the extracts were 1.4-1.7 times more effective against A. aegypti as compared to A. stephensi. The qualitative phytochemical study of the extracts showed the presence of terpenoids and flavonoids as the common phytochemical constituents in the extracts suggesting their possible role in the toxicity. Other constituents tested were not detected except alkaloids which were found to be present only in the petroleum ether extract. Further studies are needed to isolate and identify the active principles involved, their mode of action, formulated preparations for enhancing potency and stability, toxicity, and effects on non-target organisms and the environment. This could help in formulating efficient strategies for mosquito control.     

Longitudinal health study of US 1991 Gulf War veterans: changes in health status at 10-year follow-up

The authors assessed changes in the health status of US 1991 Gulf War-era veterans from a 1995 baseline survey to a 2005 follow-up survey, using repeated measurement data from 5,469 deployed Gulf War veterans and 3,353 nondeployed Gulf War-era veterans who participated in both surveys. Prevalence differences in health status between the 2 surveys were estimated for adverse health indices and chronic diseases for each veteran group. Persistence risk ratios and incidence risk ratios were calculated after adjustment for demographic and military service characteristics through Mantel-Haenszel stratified analysis. At 10-year follow-up, deployed veterans were more likely to report persistent poor health, as measured by the health indices (functional impairment, limitation of activities, repeated clinic visits, recurrent hospitalizations, perception of health as fair or poor, chronic fatigue syndrome-like illness, and posttraumatic stress disorder), than nondeployed veterans. Additionally, deployed veterans were more likely to experience new onset of adverse health (as measured by the indices) and certain chronic diseases than were nondeployed veterans. During the 10-year period from 1995 to 2005, the health of deployed veterans worsened in comparison with nondeployed veterans because of a higher rate of new onset of various health outcomes and greater persistence of previously reported adverse health on the indices.     

Trends in hospitalizations with antibiotic-resistant infections: U.S., 1997-2006

Objectives

Antibiotic resistance is a significant global problem, but the trends in prevalence and impact of antibiotic resistance in hospitalizations in the United States are unclear. We evaluated the trends in hospitalizations associated with antibiotic-resistant infections in U.S. hospitals from 1997 to 2006.

Methods

We analyzed the National Hospital Discharge Survey (NHDS) during 1997–2006 (unweighted n=3.3 million hospitalizations; weighted n=370.3 million hospitalizations) and examined trends in prevalence of hospitalizations with antibiotic-resistant infections, length of stay, and discharge status.

Results

The number of infection-related hospitalizations with antibiotic resistance increased 359% during the 10-year period, from 37,005 in 1997 to 169,985 in 2006. The steepest rise was seen among individuals <18 years of age. The mean age of individuals with infection-related hospitalizations that had antibiotic-resistant infections decreased substantially, from 65.7 years (standard error [SE] = 2.01) in 1997 to 44.2 years (SE=1.47) in 2006. As the proportion of patients with antibiotic-resistant infections who did not have insurance increased, the length of stay for those hospitalizations had a corresponding decrease (r=0.91, p<0.01).

Conclusions

Antibiotic-resistant infections are becoming increasingly commonplace in hospitalizations in the U.S., with a steady upward trend between 1997 and 2006. Antibiotic-resistant infections are increasingly being seen in younger patients and those without health insurance.Despite the clear benefits of antibiotic therapy for a variety of infectious diseases, the widespread use of these agents has facilitated the emergence of a variety of antibiotic-resistant pathogens.¹ Because of the significant impact antibiotic resistance has on morbidity and mortality, it is considered a threat to U.S. public health and national security by the Institute of Medicine and the Infectious Diseases Society of America.^2,3Since the 1990s in the United States, the prevalence of antibiotic resistance has increased for a variety of pathogens. Increased resistance has been found for Neisseria gonorrhoeae, Salmonella ser Typhi, Escherichia coli, and Mycobacterium tuberculosis.^4–7 In particular, the emergence of vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) has raised serious questions about the ability to treat some of these new resistant pathogens.^8,9 At first, many of these resistant organisms were confined to hospitalized populations; however, in recent years the emergence of community-associated infections with these resistant organisms has become more common.^10,11 Community-associated MRSA is particularly important because it is not simply an extension of hospital-associated MRSA into the community, but rather a different strain.The purpose of this study was to describe the trends in hospitalizations and deaths associated with antibiotic-resistant infections in U.S. hospitals from 1997 to 2006.     

Map: study sites in the special issue on structural vulnerability: Latino migrants in the United States

The map and index presented here accurately represent the places the authors involved in the special theme on structural vulnerability in Latino migrants in the United States (in Medical Anthropology, Volume 30, Numbers 4 and 5) have worked and undertaken research as pertains to the articles they wrote.     

Genetic correction and analysis of induced pluripotent stem cells from a patient with gyrate atrophy

Gene-corrected patient-specific induced pluripotent stem (iPS) cells offer a unique approach to gene therapy. Here, we begin to assess whether the mutational load acquired during gene correction of iPS cells is compatible with use in the treatment of genetic causes of retinal degenerative disease. We isolated iPS cells free of transgene sequences from a patient with gyrate atrophy caused by a point mutation in the gene encoding ornithine-δ-aminotransferase (OAT) and used homologous recombination to correct the genetic defect. Cytogenetic analysis, array comparative genomic hybridization (aCGH), and exome sequencing were performed to assess the genomic integrity of an iPS cell line after three sequential clonal events: initial reprogramming, gene targeting, and subsequent removal of a selection cassette. No abnormalities were detected after standard G-band metaphase analysis. However, aCGH and exome sequencing identified two deletions, one amplification, and nine mutations in protein coding regions in the initial iPS cell clone. Except for the targeted correction of the single nucleotide in the OAT locus and a single synonymous base-pair change, no additional mutations or copy number variation were identified in iPS cells after the two subsequent clonal events. These findings confirm that iPS cells themselves may carry a significant mutational load at initial isolation, but that the clonal events and prolonged cultured required for correction of a genetic defect can be accomplished without a substantial increase in mutational burden.