Biochemical and clinical response after umbilical cord blood transplant in a boy with early childhood-onset beta-mannosidosis.

BACKGROUND: Deficiency in the enzyme ß-mannosidase was described over three decades ago. Although rare in occurrence, the presentation of childhood-onset ß-mannosidase deficiency consists of hypotonia in the newborn period followed by global development delay, behavior problems, and intellectual disability. No effective pharmacologic treatments have been available. METHODS: We report 2-year outcomes following the first umbilical cord blood transplant in a 4-year-old boy with early childhood-onset disease. RESULTS: We show restoration of leukocyte ß-mannosidase activity which remained normal at 2 years posttransplant, and a simultaneous increase in plasma ß-mannosidase activity and dramatic decrease in urine-free oligosaccharides were also observed. MRI of the brain remained stable. Neurocognitive evaluation revealed test point gains, although the magnitude of improvement was less than expected for age, causing lower IQ scores that represent a wider developmental gap between the patient and unaffected peers. CONCLUSION: Our findings suggest that hematopoietic cell transplant can correct the biochemical defect in ß-mannosidosis, although preservation of the neurocognitive trajectory may be a challenge.

Gene Signatures of 1,25-Dihydroxyvitamin D3 Exposure in Normal and Transformed Mammary Cells.

To elucidate potential mediators of vitamin D receptor (VDR) action in breast cancer, we profiled the genomic effects of its ligand 1,25-dihydroxyvitamin D3 (1,25D) in cells derived from normal mammary tissue and breast cancer. In non-transformed hTERT-HME cells, 483 1,25D responsive entities in 42 pathways were identified, whereas in MCF7 breast cancer cells, 249 1,25D responsive entities in 31 pathways were identified. Only 21 annotated genes were commonly altered by 1,25D in both MCF7 and hTERT-HME cells. Gene set enrichment analysis highlighted eight pathways (including senescence/autophagy, TGFß signaling, endochondral ossification, and adipogenesis) commonly altered by 1,25D in hTERT-HME and MCF7 cells. Regulation of a subset of immune (CD14, IL1RL1, MALL, CAMP, SEMA6D, TREM1, CSF1, IL33, TLR4) and metabolic (ITGB3, SLC1A1, G6PD, GLUL, HIF1A, KDR, BIRC3) genes by 1,25D was confirmed in hTERT-HME cells and similar changes were observed in another comparable non-transformed mammary cell line (HME cells). The effects of 1,25D on these genes were retained in HME cells expressing SV40 large T antigen but were selectively abrogated in HME cells expressing SV40 + RAS and in MCF7 cells. Integration of the datasets from hTERT-HME and MCF7 cells with publically available RNA-SEQ data from 1,25D treated SKBR3 breast cancer cells enabled identification of an 11-gene signature representative of 1,25D exposure in all three breast-derived cell lines. Four of these 11 genes (CYP24A1, CLMN, EFTUD1, and SERPINB1) were also identified as 1,25D responsive in human breast tumor explants, suggesting that this gene signature may prove useful as a biomarker of vitamin D exposure in breast tissue.

The impact of vitamin D in breast cancer: genomics, pathways, metabolism.

Nuclear receptors exert profound effects on mammary gland physiology and have complex roles in the etiology of breast cancer. In addition to receptors for classic steroid hormones such as estrogen and progesterone, the nuclear vitamin D receptor (VDR) interacts with its ligand 1α,25(OH)2D3 to modulate the normal mammary epithelial cell genome and subsequent phenotype. Observational studies suggest that vitamin D deficiency is common in breast cancer patients and that low vitamin D status enhances the risk for disease development or progression. Genomic profiling has characterized many 1α,25(OH)2D3 responsive targets in normal mammary cells and in breast cancers, providing insight into the molecular actions of 1α,25(OH)2D3 and the VDR in regulation of cell cycle, apoptosis, and differentiation. New areas of emphasis include regulation of tumor metabolism and innate immune responses. However, the role of VDR in individual cell types (i.e., epithelial, adipose, fibroblast, endothelial, immune) of normal and tumor tissues remains to be clarified. Furthermore, the mechanisms by which VDR integrates signaling between diverse cell types and controls soluble signals and paracrine pathways in the tissue/tumor microenvironment remain to be defined. Model systems of carcinogenesis have provided evidence that both VDR expression and 1α,25(OH)2D3 actions change with transformation but clinical data regarding vitamin D responsiveness of established tumors is limited and inconclusive. Because breast cancer is heterogeneous, analysis of VDR actions in specific molecular subtypes of the disease may help to clarify the conflicting data. The expanded use of genomic, proteomic and metabolomic approaches on a diverse array of in vitro and in vivo model systems is clearly warranted to comprehensively understand the network of vitamin D regulated pathways in the context of breast cancer.

Adult informal caregivers reporting financial burden in Hawaii, Kansas, and Washington: Results from the 2007 Behavioral Risk Factor Surveillance System.

BACKGROUND: Given the unpaid nature of the work, informal caregiving can create a financial burden for caregivers. Little has been done to identify specific predictors of experiencing financial burden. This study investigated demographic and health factors comparing caregivers who reported having or not having financial burden. METHODS: Data are derived from adult caregivers (N = 3,317) as part of the 2007 Behavioral Risk Factor Surveillance System in Hawaii, Kansas, and Washington. The adjusted odds ratios for reporting a financial burden were estimated for demographic and other risk factors. RESULTS: Caregivers who reported a financial burden were younger, had lower incomes, were more likely to be current smokers, have had a stroke, and rate their health as fair or poor compared to caregivers who did not report a financial burden. Caregivers who were younger (ages 18-34), resided with care recipients, spent 20-39 hours per week providing care, and reported having a disability were at a statistically significantly higher odds of reporting a financial burden. CONCLUSIONS/IMPLICATIONS: Given the current economic difficulties faced by many Americans, further insights into the perceived financial burdens experienced by informal caregivers as well as linkages to policy and programs designed to support caregivers are critical for public health professionals to address the expanding needs in states and communities.

Demonstrating the importance and feasibility of including sexual orientation in public health surveys: health disparities in the Pacific Northwest.

OBJECTIVES: We identified health disparities for a statewide population of lesbian, gay, and bisexual (LGB) men and women compared with their heterosexual counterparts. METHODS: We used data from the 2003-2006 Washington State Behavioral Risk Factor Surveillance System to examine associations between sexual orientation and chronic health conditions, health risk behaviors, access to care, and preventive services. RESULTS: Lesbian and bisexual women were more likely than were heterosexual women to have poor physical and mental health, asthma, and diabetes (bisexuals only), to be overweight, to smoke, and to drink excess alcohol. They were also less likely to have access to care and to use preventive services. Gay and bisexual men were more likely than were heterosexual men to have poor mental health, poor health-limited activities, and to smoke. Bisexuals of both genders had the greatest number and magnitude of disparities compared with heterosexuals. CONCLUSIONS: Important health disparities exist for LGB adults. Sexual orientation can be effectively included as a standard demographic variable in public health surveillance systems to provide data that support planning interventions and progress toward improving LGB health.

Exhaustive Enumeration of Kinetic Model Topologies for the Analysis of Time-Resolved RNA Folding.

Unlike protein folding, the process by which a large RNA molecule adopts a functionally active conformation remains poorly understood. Chemical mapping techniques, such as Hydroxyl Radical (·OH) footprinting report on local structural changes in an RNA as it folds with single nucleotide resolution. The analysis and interpretation of this kinetic data requires the identification and subsequent optimization of a kinetic model and its parameters. We detail our approach to this problem, specifically focusing on a novel strategy to overcome a factorial explosion in the number of possible models that need to be tested to identify the best fitting model. Previously, smaller systems (less than three intermediates) were computationally tractable using a distributed computing approach. However, for larger systems with three or more intermediates, the problem became computationally intractable. With our new enumeration strategy, we are able to significantly reduce the number of models that need to be tested using non-linear least squares optimization, allowing us to study systems with up to five intermediates. Furthermore, two intermediate systems can now be analyzed on a desktop computer, which eliminates the need for a distributed computing solution for most medium-sized data sets. Our new approach also allows us to study potential degeneracy in kinetic model selection, elucidating the limits of the method when working with large systems. This work establishes clear criteria for determining if experimental ·OH data is sufficient to determine the underlying kinetic model, or if other experimental modalities are required to resolve any degeneracy.

Rapid quantification and analysis of kinetic •OH radical footprinting data using SAFA.

The use of highly reactive chemical species to probe the structure and dynamics of nucleic acids is greatly simplified by software that enables rapid quantification of the gel images that result from these experiments. Semiautomated footprinting analysis (SAFA) allows a user to quickly and reproducibly quantify a chemical footprinting gel image through a series of steps that rectify, assign, and integrate the relative band intensities. The output of this procedure is raw band intensities that report on the relative reactivity of each nucleotide with the chemical probe. We describe here how to obtain these raw band intensities using SAFA and the subsequent normalization and analysis procedures required to process these data. In particular, we focus on analyzing time-resolved hydroxyl radical ((•)OH) data, which we use to monitor the kinetics of folding of a large RNA (the L-21 T. thermophila group I intron). Exposing the RNA to bursts of (•)OH radicals at specific time points during the folding process monitors the time progress of the reaction. Specifically, we identify protected (nucleotides that become inaccessible to the (•)OH radical probe when folded) and invariant (nucleotides with constant accessibility to the (•)OH probe) residues that we use for monitoring and normalization of the data. With this analysis, we obtain time-progress curves from which we determine kinetic rates of folding. We also report on a data visualization tool implemented in SAFA that allows users to map data onto a secondary structure diagram.

General population norms about child abuse and neglect and associations with childhood experiences.

BACKGROUND: A variety of definitions of child abuse and neglect exist. However, little is known about norms in the general population as to what constitutes child abuse and neglect or how perceived norms may be related to personal experiences. METHODS: We conducted a random-digit-dialed telephone survey of 504 Washington State adults. Respondents were asked whether they believed each of 34 behaviors, identified in focus groups as possibly physically, sexually or emotionally abusive or neglectful, constituted abuse or neglect. Then, they were asked whether they had experienced 33 of the behaviors. RESULTS: Five of the six behaviors with the highest levels of consensus were for sexual abuse, whereas only one emotionally abusive behavior had a high level of consensus (95% agreement). Consensus that spanking constituted abuse increased with severity. Those respondents who reported experiencing a particular behavior were significantly less likely to believe the behavior abusive for 11 of the 33 behaviors and more likely to believe the behavior abusive for two of the behaviors. Where comparisons were possible, there was a high level of consensus that behaviors identified as abusive in Child Protective Service operational definitions constituted abuse. CONCLUSIONS: Self-reported childhood experiences were associated with perceived norms about child abuse. A better understanding of community norms about child abuse and neglect may be helpful in communicating with the public or allow for better targeting of educational messages through the media, parenting education classes, and so forth.

Community responses and perceived barriers to responding to child maltreatment.

Although child maltreatment has important effects on physical and psychological health, even serious cases often go unreported. Little is known about actions that individuals take when they know of an abused child, factors influencing whether they take action, or general population beliefs about how best to prevent maltreatment. A random-digit-dialed telephone survey of 504 Washington State civilian, English-speaking adults living in households with telephones was conducted in 2002. Respondents were asked whether they had ever known an abused child and if so, how they responded and any barriers they experienced to responding. Regardless of whether they had known an abused child, they were asked how they would respond in a hypothetical situation and hypothetical barriers. They were also asked what they believed to be effective in preventing maltreatment. Half (49% +/- 5%) of the respondents indicated that they had known a child they believed to be abused and of these, four-fifths (84% +/- 5%) indicated that they took some action, most frequently reporting the abuse to Child Protective Services, talking to the parents about the abuse or how to parent, or calling the police or other law enforcement. The most frequently reported barriers were fear of retaliation by the abusive parent, being afraid of making the child's situation worse, and not wanting to intrude on family privacy. About nine-tenths of respondents believed that mental health services and drug and alcohol treatment, support services such as food banks and crisis nurseries, and parenting education classes were effective in preventing abuse. These results provide evidence that most people are willing to intervene to help an abused child. However, barriers to intervening (particularly fear of retaliation) exist and may account for some of the failures to report abuse.

Childhood family violence history and women's risk for intimate partner violence and poor health.

BACKGROUND: There is growing evidence for associations between generations in family violence and between family violence in both childhood and adulthood and women's health. Most studies focus on a subset of family violence (child abuse, witnessing intimate partner violence [IPV] as a child, and/or adult IPV), and few examine possible differences associated with the nature of abusive experiences, such as physical versus sexual abuse. METHODS: A population-based telephone survey, the 1999 and 2001 Washington State Behavioral Risk Factor Surveillance System, asked a representative sample of 3527 English-speaking, non-institutionalized adult women whether they had been physically or sexually assaulted or witnessed interparental violence in childhood, and whether they had experienced physical assault or emotional abuse from an intimate partner in the past year. The survey also asked about current general health and mental distress in the past month. RESULTS: The risks associated with childhood family violence experiences varied depending on the nature of those experiences. Women reporting childhood physical abuse or witnessing interparental violence were at a four- to six-fold increase in risk of physical IPV, and women reporting any of the experiences measured were at three- to four-fold increase in risk of partner emotional abuse. In contrast, women reporting childhood sexual abuse only were not at increased risk of physical IPV. Women reporting childhood physical abuse were at increased risk of poor physical health, and women reporting any type of childhood family violence were at increased risk of frequent mental distress. Approximately one third of women reporting poor general health and half of women reporting frequent mental distress also reported at least one of the childhood experiences measured. CONCLUSIONS: These findings underscore the role of childhood experiences of abuse and of witnessing family violence in women's current risk for IPV, poor physical health, and frequent mental distress.

Behavioral risk factors and use of preventive services among veterans in Washington State.

BACKGROUND: Little is known about the special preventive health needs of U.S. veterans and the 3.6 million users of VA health care. METHODS: The Washington State version of the 1999 Behavioral Risk Factor Survey included three new questions about veteran status and use of VA health care. Data on this population-based sample of 3,608 adults were used to compare sociodemographic, health, and behavioral characteristics between veterans and nonveterans and between VA users and nonusers. RESULTS: Veterans were nearly 13 years older than nonveterans. VA users were socioeconomically worse off and had poorer health status than nonusers. Current smoking among males was more common among veterans than among nonveterans (24% vs 18%). This difference persisted after controlling for age, race, education, and income and held across all age groups. Use of several screening tests varied little in relation to veteran or VA user status. CONCLUSIONS: The BRFSS has become a rich source of data on veteran health. Veterans and VA users have distinct sociodemographic profiles that must be considered when comparing health-related characteristics. Cigarette smoking is especially prevalent among veterans--an excess unexplained by sociodemographic differences.