Multi-site, multi-country randomized clinical trial of an acute traumatic brain injury caregiver transition assistance program in Latin America.

BACKGROUND: Individuals with traumatic brain injury (TBI) in Latin America experience high levels of disability and extremely poor functional outcomes, and their informal caregivers play a key role in their rehabilitation and care. OBJECTIVE: To improve TBI rehabilitation through stronger informal caregiving, this study developed and evaluated an evidence-based and culturally appropriate Transition Assistance Program (TAP) for informal caregivers of individuals with TBI in Latin America, specifically targeting the time period before and after the transition from hospital to home. METHODS: A sample of 89 people with a new TBI and their primary informal caregiver (n = 178) was recruited from two hospitals in Mexico City, Mexico, and in Cali, Colombia. Caregivers were randomly assigned to either the TAP group or to a control group receiving the standard care provided by the hospital. Caregivers completed measures of depression and burden, and individuals with TBI completed measures of depression and self-perceived burden on caregivers before hospital discharge and at 2- and 4-month follow ups. RESULTS: Caregivers in the TAP group reported significantly lower burden than those in the control group and marginally lower depression. Individuals with TBI whose caregivers had been in the TAP group reported significantly lower depression than those whose caregivers had been in the control group, and a non-significant but lower self-perceived burden on their caregivers. CONCLUSION: The results suggest that the TAP has strong potential to benefit both TBI caregivers and individuals with TBI during the transition from acute TBI hospitalization to home in Latin America, generally showing small-or medium-sized effects on key outcomes.

Suicidal ideation after acute traumatic brain injury: A longitudinal actor-partner interdependence model of patients and caregivers in Latin America.

PURPOSE/OBJECTIVE: Traumatic brain injury (TBI) is associated with depression, anxiety, and even suicidality in individuals with TBI and in caregivers. Moreover, emotional functioning in individuals with TBI is linked with caregiver functioning. However, no known studies to date have examined linkages in suicidal ideation in individuals with TBI and family caregivers. This is especially important in Latin America, where TBI rates are high, and where cultural norms influence family caregiving. This study examined associations among self-reported suicidal ideation in individuals with TBI and their primary caregivers over time in Mexico and Colombia. Research Method/Design: A total of 109 individuals and their primary caregivers completed measures during hospitalization for TBI and at 2- and 4-months posthospitalization. The primary outcome was Item 9 from the Spanish version of the Patient Health Questionnaire-9, assessing for thoughts of death or suicide in the previous 2 weeks. RESULTS: Patients and caregivers reported high levels of suicidal ideation (18.3%-22.4% and 12.4%-15.7%, respectively) at each time point, and suicidal ideation at one time point strongly predicted ideation at the next. When patients endorsed suicidal ideation in the hospital, their caregivers tended to endorse suicidal ideation 2 months later. Although unaccounted for variables could be driving these relationships, they may also provide possible evidence of causal preponderance between patient and caregiver suicidal ideation post-TBI. CONCLUSIONS/IMPLICATIONS: Clinicians and rehabilitation specialists can use these findings to inform suicide risk assessment by expanding these practices to caregivers of patients who endorsed suicidal ideation. Interventions after TBI should incorporate caregivers given this study showed significant interdependence of suicidality between patients and caregivers. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

A Multi-Site Study of Traumatic Brain Injury in Mexico and Colombia: Longitudinal Mediational and Cross-Lagged Models of Family Dynamics, Coping, and Health-Related Quality of Life.

Latin America has high rates of traumatic brain injury (TBI), yet reduced mental and physical health outcomes due to limited rehabilitation services. To understand the psychosocial adjustment process in TBI patients in Latin America, the incorporation of cultural values including family-based variables is imperative. The current study examined relations among healthy family dynamics, coping, and mental and physical health related quality of life (HRQL) among a sample of TBI patients across three sites and two countries over the first 4 months post-injury. A sample of 109 acute TBI patients from Mexico and Colombia were recruited, and a series of longitudinal mediation and cross-lag panel analyses were run. Mental and physical HRQL were positively associated with each other, as well as healthy family dynamics and coping. Coping partially mediated the effects of healthy family dynamics on both mental and physical HRQL. Family dynamics showed the strongest cross-lag relationships with coping going from 2 months to 4 months. Similarly, coping showed the strongest cross-lag relationships with both mental and physical HRQL going from baseline to 2 months. Results provide empirical support for the importance of a rehabilitation workforce that has been trained in and can effectively implement family-based interventions for individuals with TBI in Latin America.

Relationship Satisfaction and Depression After Traumatic Brain Injury: An Actor-Partner Interdependence Model of Patients and Caregivers in Mexico and Colombia.

OBJECTIVE: Traumatic brain injury represents a major public health concern, particularly in low- and middle-income countries like in Latin America. Family members are often caregivers for individuals with traumatic brain injury, which can result in significant stress. Research is needed to examine depression and quality of the caregiving relationship in these dyads. This study examined relationship quality and depression longitudinally after traumatic brain injury within the caregiving relationship. DESIGN: Dyads (N = 109) composed of individuals with traumatic brain injury and their caregivers were recruited from three hospitals in Mexico and Colombia. They self-reported depression and relationship satisfaction during hospitalization and at 2 and 4 mos after hospitalization. RESULTS: A 2-lag Actor Partner Interdependence Model demonstrated that patients and caregivers reporting high relationship satisfaction at baseline experienced lower depression 2 mos later, which then predicted higher caregiver relationship satisfaction at 4 mos. Moreover, patients with high relationship satisfaction at baseline had caregivers with lower depression at 2 mos, which was then associated with patients' higher satisfaction at 4 mos. CONCLUSIONS: Within individuals with traumatic brain injury and caregivers, depression and relationship satisfaction seem to be inversely related. Furthermore, patients' and caregivers' depression and relationship satisfaction impact each other over time, demonstrating interdependence within the caregiving relationship.

Predictors of longitudinal depression trajectories after traumatic brain injury in Latin America: A multi-site study.

BACKGROUND: Latin America has exceptionally high rates of traumatic brain injury (TBI), but very little research has been conducted on longitudinal TBI outcomes in this global region. OBJECTIVE: This study examined whether cognitive dysfunction and social disadaptation in individuals with TBI in Latin America at hospital discharge predict longitudinal trajectories of depression at baseline, 2 months, and 4 months. METHODS: A sample of 109 people with a new TBI was recruited from three hospitals: Mexico City, Mexico, Cali, Colombia and Neiva, Colombia. Participants completed measures of cognitive dysfunction and social disadaptation before hospital discharge and measures of depression at baseline, 2 months, and 4 months. RESULTS: Results suggested that depression scores were found to decrease over time in a quadratic (or U-shaped) fashion, and more significant cognitive dysfunction at hospital discharge was associated with higher longitudinal depression trajectories. Social disadaptation did not exert a unique effect on depression trajectories after controlling for cognitive dysfunction. Depression trajectories changed differentially over time as a function of baseline cognitive dysfunction, such that for those with high cognitive impairment, depression scores started high and then dropped to a moderated range and plateaued, but for individuals with low cognitive dysfunction, depression scores started lower and decreased linearly but moderately. CONCLUSIONS: The results suggest a strong need for neuropsychological assessments and evidence-based cognitive rehabilitation strategies to be implemented immediately after TBI in Latin America, which could exert salubrious effects on depression trajectories over time.

Health-related quality of life and depression in a sample of Latin American adults with rheumatoid arthritis.

OBJECTIVE: To compare the health related quality of life (HRQoL) and depression of individuals with rheumatoid arthritis (RA) to healthy controls in Colombia, as well as to examine the connections between these two variables in individuals with RA. METHOD: One hundred and three individuals with RA were recruited from ambulatory centers in Colombia. Seventy-three control participants were recruited from the local community. Both groups differed with respect to age, gender and marital status (P < 0.001), while education and socio-economic levels were similar. HRQoL was assessed using the Short Form-36 (SF-36) and depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9). RESULTS: A multivariate analysis of covariance found that RA patients reported substantially higher depressive symptoms and lower HRQoL than healthy controls (P < 0.01 and P < 0.05, respectively). The effect sizes of the differences between patients and controls in HRQoL and depressive symptoms were all large. All SF-36 HRQoL variables were significantly correlated with depressive symptoms in patients and controls (P < 0.05). Social functioning and vitality were uniquely associated with depressive symptoms in the RA group (P < 0.01 and P < 0.05, respectively), whereas education and social functioning were uniquely associated with depressive symptoms in controls (P < 0.05 and P < 0.005, respectively). CONCLUSIONS: Research indicates that individuals with RA have deteriorated HRQoL, and this study extends these findings to a Colombian sample and highlights the importance of the independent relationship between depressive symptoms and vitality in this group of Colombians with RA.

Family dynamics and psychosocial functioning in children with SCI/D from Colombia, South America.

OBJECTIVE: The purpose of this study was to examine the connections between family dynamics and the psychosocial functioning of children with spinal cord injuries and disorders (SCI/D). DESIGN: Cross-sectional. SETTING: Participants were recruited from communities in Neiva, Colombia. PARTICIPANTS: Thirty children with SCI/D and their primary caregiver participated. Children were between 8 and 17 years of age, and had sustained their injury at least six months prior to data collection. INTERVENTIONS: NA. OUTCOME MEASURES: Participating children completed measures assessing their own psychosocial functioning (Children's Depression Inventory, Revised Children's Manifest Anxiety Scale-2, Pediatric Quality of Life Inventory), and their primary caregiver completed measures of family dynamics (Family Adaptability and Cohesion Evaluation Scale- Fourth Edition, Family Communication Scale, Family Assessment Device- General Functioning, Family Satisfaction Scale, Relationship-Focused Coping Scale). RESULTS: A correlation matrix showed a number of significant bivariate correlations between child and family variables, and three multiple regressions showed that family satisfaction, empathy, and flexibility significantly explained 27% of the variance in child worry; family satisfaction and communication explained 18% of the variance in child social anxiety; and family cohesion and communication explained 23% of the variance in child emotional functioning. CONCLUSIONS: These findings highlight the importance of rehabilitation professionals considering the association between family dynamics and the psychosocial functioning of children with SCI/D when working with this population.

Pilot Study of a Newly Developed Intervention for Families Facing Serious Injury.

Background: There is a need to develop interventions that address the entire family after spinal cord injury (SCI), especially in Latin America, where rehabilitation resources are limited and little is known about family adjustment to SCI. Objective: To evaluate the short-term (post-intervention) and longer term (6-month) effectiveness of the newly developed, 8-session manualized family intervention for individuals with SCI and their family members compared to a control group. Methods: In this clinical demonstration project, longitudinal self-report data were collected from 8 individuals with SCI and their family members in Colombia, South America. The 8 families were randomly assigned to either the SCI intervention group or the waitlist control group. The intervention group included 10 individuals from 4 different families, with a mean age of 41.40 years (SD = 14.18). The control group was composed of 13 individuals from 4 different families with a mean age of 44.38 years (SD = 14.76). All participants completed Spanish versions of instruments that assessed depression (Patient Health Questionnaire-9), anxiety (Generalized Anxiety Disorder-7), burden (Zarit Burden Interview), and perceived problem-solving skills (Problem-Solving Inventory). Results: Results provide preliminary evidence that symptoms of depression, anxiety, and burden as well as problem-solving appraisals improved significantly for individuals who participated in the intervention, whereas no change in symptoms was observed among those in the waitlist control group. Conclusions: Findings suggest that this newly developed intervention for families facing SCI can be beneficial; however, this pilot study represents only the first step in the examination of the efficacy and effectiveness of this intervention.

Sintomas depressivos e de ansiedade e apoio social estão associados de modo independente à qualidade de vida específica da doença em pacientes colombianos com artrite reumatoide / Depressive and anxiety symptoms and social support are independently associated with disease-specific quality of life in Colombian patients with rheumatoid arthritis

RESUMOObjetivo:Analisar a relação entre a qualidade de vida (QV) específica da doença e fatores sociodemográficos, clínicos e psicossociais em pacientes colombianos com artrite reumatoide (AR).Métodos:Recrutaram-se 103 pacientes com AR em centros ambulatoriais de Neiva, na Colômbia. Eles responderam ao Disease Activity Scale 28 (DAS-28), QOL-RA, Escala de Autoavaliação da Depressão de Zung, Inventário de Ansiedade Traço-Estado (Idate), Interpersonal Support Evaluation List-12 (Isel-12) e Symptom Checklist-90 Revised (SCL-90R).Resultados:Escores mais baixos de QOL-RA estiveram associados a uma pior condição socioeconômica (CSE; r = 0,26, p < 0,01), maior probabilidade de usar opioides (t = -2,51, p < 0,05), maior probabilidade de doença pulmonar comórbida (t = -2,22, p < 0,05) e pontuações inferiores nas subescalas do ISEL-12 (r's = 0,41-0,31, p's < 0,001). Uma menor pontuação no QOL-RA esteve associada a escores mais elevados no DAS-28 (r = -0,28, p < 0,01), Escala Analógica Visual (EVA; r = -0,35, p < 0,001), Escala de Autoavaliação da Depressão de Zung (r = -0,72, p < 0,001), Idate-Estado (r = -0,66, p < 0,001), Idate-Traço (r = -0,70, p < 0,001), SCL-90R Índice de Gravidade Global (r = -0,50, p < 0,001), SCL-90R Total de Sintomas Positivos (r = -0,57, p < 0,001) e todas as subescalas do SCL-90R (r's = -0,54 a -0,21, p's < 0,01). Um modelo de regressão linear múltipla indicou que a CSE (B = 2,77, p < 0,05), a Escala de Autoavaliação da Depressão de Zung (B = -0,53, p < 0,001), o Idate-Estado (B = -0,26, p < 0,05) e o Isel-12 Pertencimento (B = 1,15, p < 0,01) estavam independentemente associados à pontuação no QOL-RA, mesmo quando controlados por associações significativas.Conclusões:Mais sintomas depressivos e de ansiedade estiveram independentemente associados a uma menor QV específica da doença, enquanto a percepção aumentada de ter pessoas com quem fazer atividades (pertencimento, apoio social) e CSE mais elevados estiveram independentemente associados a uma maior QV específica da doença. Os fatores psicossociais impactam na QV na AR acima e além da atividade da doença. É necessária pesquisa adicional acerca dos benefícios da avaliação psicossocial do paciente com AR e da prestação de cuidados abrangentes para melhorar a QV.

ABSTRACTObjective:To examine the relationship between disease-specific quality of life (QOL) and socio-demographic, medical, and psychosocial factors in Colombian patients with Rheumatoid Arthritis (RA).Methods:One hundred and three RA patients recruited from ambulatory centers in Neiva, Colombia were administered the Disease Activity Scale 28 (DAS-28), QOL-RA, Zung Self-Rating Depression Scale, State-Trait Anxiety Inventory (STAI), Interpersonal Support Evaluation List-12 (ISEL-12), and Symptom Checklist-90 Revised (SCL-90R).Results:Lower QOL-RA was associated with lower socio-economic status (r = 0.26, p < 0.01), higher likelihood of using opioids (t = -2.51, p< 0.05), higher likelihood of comorbid pulmonary disease (t = -2.22, p < 0.05), and lower ISEL-12 sub-scales (r's = 0.41-0.31, p's < 0.001). Lower QOL-RA was associated with higher DAS-28 (r = -0.28, p < 0.01), Visual Analog Scale (VAS; r = -0.35, p < 0.001), Zung Depression (r = -0.72, p < 0.001), STAI-State (r = -0.66, p < 0.001), STAI-Trait (r = -0.70, p < 0.001), SCL-90R Global Severity Index (r = -0.50, p < 0.001), SCL-90R Positive Symptom Total (r = -0.57, p < 0.001), and all SCL-90R sub-scales (r's = -0.54 to -0.21, p's < 0.01). A multivariate linear regression model indicated that SES (B = 2.77, p < 0.05), Zung Depression (B = -0.53, p < 0.001), STAI-State (B = -0.26, p < 0.05), and ISEL-12 Belonging (B = 1.15, p< 0.01) were independently associated with QOL-RA, controlling for significant associations.Conclusions:More depressive and anxiety symptoms were independently associated with lower disease-specific QOL, while higher perceptions of having people to do activities with (belonging social support) and higher SES were independently associated with higher disease-specific quality of life. Psychosocial factors impact QOL in RA above and beyond disease activity. Additional research into the benefits of psychosocial assessment of RA patients and provision of comprehensive care to improve QOL is warranted.

Depressive and anxiety symptoms and social support are independently associated with disease-specific quality of life in Colombian patients with rheumatoid arthritis.

OBJECTIVE: To examine the relationship between disease-specific Quality of Life (QOL) and socio-demographic, medical, and psychosocial factors in Colombian patients with Rheumatoid Arthritis (RA). METHODS: One hundred and three RA patients recruited from ambulatory centers in Neiva, Colombia were administered the Disease Activity Scale 28 (DAS-28), QOL-RA, Zung Self-Rating Depression Scale, State-Trait Anxiety Inventory (STAI), Interpersonal Support Evaluation List-12 (ISEL-12), and Symptom Checklist-90 Revised (SCL-90R). RESULTS: Lower QOL-RA was associated with lower socio-economic status (SES; r=0.26, p<0.01), higher likelihood of using opioids (t=-2.51, p<0.05), higher likelihood of comorbid pulmonary disease (t=-2.22, p<0.05), and lower ISEL-12 sub-scales (r's=0.41-0.31, p's<0.001). Lower QOL-RA was associated with higher DAS-28 (r=-0.28, p<0.01), Visual Analog Scale (VAS; r=-0.35, p<0.001), Zung Depression (r=-0.72, p <0.001), STAI-State (r=-0.66, p<0.001), STAI-Trait (r=-0.70, p<0.001), SCL-90R Global Severity Index (r=-0.50, p<0.001), SCL-90R Positive Symptom Total (r=-0.57, p<0.001), and all SCL-90R sub-scales (r's=-0.54--0.21, p's<0.01). A multivariate linear regression model indicated that SES (B=2.77, p<0.05), Zung Depression (B=-0.53, p<0.001), STAI-State (B=-0.26, p<0.05), and ISEL-12 Belonging (B=1.15, p<0.01) were independently associated with QOL-RA, controlling for significant associations. CONCLUSIONS: More depressive and anxiety symptoms were independently associated with lower disease-specific QOL, while higher perceptions of having people to do activities with (belonging social support) and higher SES were independently associated with higher disease-specific QOL. Psychosocial factors impact QOL in RA above and beyond disease activity. Additional research into the benefits of psychosocial assessment of RA patients and provision of comprehensive care to improve QOL is warranted.

Ancient transposable elements transformed the uterine regulatory landscape and transcriptome during the evolution of mammalian pregnancy.

A major challenge in biology is determining how evolutionarily novel characters originate; however, mechanistic explanations for the origin of new characters are almost completely unknown. The evolution of pregnancy is an excellent system in which to study the origin of novelties because mammals preserve stages in the transition from egg laying to live birth. To determine the molecular bases of this transition, we characterized the pregnant/gravid uterine transcriptome from tetrapods to trace the evolutionary history of uterine gene expression. We show that thousands of genes evolved endometrial expression during the origins of mammalian pregnancy, including genes that mediate maternal-fetal communication and immunotolerance. Furthermore, thousands of cis-regulatory elements that mediate decidualization and cell-type identity in decidualized stromal cells are derived from ancient mammalian transposable elements (TEs). Our results indicate that one of the defining mammalian novelties evolved from DNA sequences derived from ancient mammalian TEs co-opted into hormone-responsive regulatory elements distributed throughout the genome.

Psychological Functioning in Youth With Spina Bifida Living in Colombia, South America.

OBJECTIVE: No studies have examined psychological functioning among youth with spina bifida (SB) living in a developing country where access to mental health resources is often scarce. This study compared self-reported psychological functioning between youth with SB living in Colombia, South America, and a demographically matched comparison group of healthy Colombian children. METHODS: 22 children with SB and 22 comparison children completed assessments of depression and anxiety. Most (68.81%) participants were male, and the sample had a mean age of 13.25 years (SD = 2.65 years). RESULTS: Results revealed that children with SB reported greater total symptoms of depression (p < .05), but fewer worry-related symptoms of anxiety (p < .05). In addition, mean total scores for both depression and anxiety were in the nonclinical range for youth with SB. CONCLUSIONS: These findings highlight the need for targeted mental health (i.e., depression) services for poor children with SB living in Colombia.

Factor analysis of the Spanish Multidimensional Attitudes Scale Toward Persons with Disabilities.

PURPOSE/OBJECTIVE: To study the psychometric properties of a Spanish version of the Multidimensional Attitudes Scale toward Persons with Disabilities (MAS) and examine its factor structure using confirmatory and exploratory factor analyses on data from a Colombian collegiate sample. RESEARCH METHOD/DESIGN: Five hundred students from Sur Colombia University in Neiva, Colombia, completed the Multidimensional Attitudes toward People with Disability scale. Forty-eight percent were male, and the average age for the entire sample was 21.25 years (SD = 3.50). Ninety-eight percent were undergraduates, 23% of whom were business majors and 33% of whom were education majors. RESULTS: An exploratory factor analysis (EFA) of data from half of participants suggested the retention of 4 factors and the deletion of 4 items. A confirmatory factor analysis (CFA) on the data from the second half of participants using the 30 retained items and 4-factor structure suggested that the 4-factor model fit adequately with the remaining 30 items. High internal consistency was found for the overall scale (α = .77, .78) and for the 4 resulting subscales: Affect (α = .88, .87), Cognition (α = .92, .90), Behavior (α = .88, .88), and Calm (α = .90, .89). CONCLUSIONS/IMPLICATIONS: This study modified the MAS to assess attitudes toward persons with disabilities in Colombia. The adequate reliability and fit of the factor structure of the Spanish MAS suggests that it holds promise to help researchers investigate attitudes toward persons with disabilities in Latin America, an important topic to the global disability community.

Evidence for independent evolution of functional progesterone withdrawal in primates and guinea pigs.

BACKGROUND AND OBJECTIVES: Cervix remodeling (CRM) is a critical process in preparation for parturition. Early cervix shortening is a powerful clinical predictor of preterm birth, and thus understanding how CRM is regulated is important for the prevention of prematurity. Humans and other primates differ from most other mammals by the maintenance of high levels of systemic progesterone concentrations. Humans have been hypothesized to perform functional progesterone withdrawal (FPW). Guinea pigs are similar to humans in maintaining high-progesterone concentrations through parturition, thus making them a prime model for studying CRM. Here, we analyze the phylogenetic history of FPW and document gene expression in the guinea pig uterine cervix. METHODOLOGY: Data on progesterone withdrawal were collected from the literature, and character evolution was analyzed. Uterine cervix samples were collected from non-pregnant, mid-pregnant and late pregnant guinea pigs. RNA was extracted and sequenced. Relative transcript levels were estimated and compared among sample groups. RESULTS: The phylogenetic analysis shows that FPW evolved independently in primates and guinea pigs. The transcriptome data confirms that guinea pigs down-regulate progesterone receptor toward parturition, in contrast to humans. Some of the similarities between human and guinea pig are: down-regulation of estrogen receptor, up-regulation of VCAN and IGFBP4 as well as likely involvement of prostaglandins. CONCLUSIONS AND IMPLICATIONS: (i) FPW in guinea pigs evolved independently from that in primates. (ii) A small set of conserved gene regulatory changes has been detected.

Factors influencing acceptance of disability in individuals with spinal cord injury in Neiva, Colombia, South America.

PURPOSE: The aim of the present study was to determine the level of acceptance of disability as measured by the Acceptance of Disability Scale (ADS) within a sample of individuals with spinal cord injury (SCI) from Neiva, Colombia and to examine the influence of sociodemographic variables, injury characteristics, and level of depression on ADS score. METHODS: The ADS was administered to 40 adults with SCI from Nieva, Colombia who were recruited from an organization that connects individuals with disabilities to resources. Most (92.5%) participants were men, with a mean age of 34.75 years and approximately 12 years since injury. Fifty-five percent of subjects were diagnosed with paraplegia and the remainder with tetraplegia. Descriptive, linear model and multiple regression analyses were used to describe the relationship between the independent and dependent variables. RESULTS: The mean total ADS score of this sample was 171.5, indicating overall low disability acceptance. After controlling for level of depression and time since injury, gender was significantly related to ADS score such that women reported higher acceptance of disability. After controlling for gender and time since injury, level of depression was significantly related to ADS score. CONCLUSION: Acceptance of disability is a serious problem in this group of SCI survivors in Neiva, Colombia, especially among women and individuals with higher levels of depression. Because acceptance of disability is likely a problem for many individuals living with disability in the developing world, future researchers should investigate what interventions (e.g. counseling, pharmacological intervention, social service programs) can be implemented to improve acceptance of disability in this population.

The relationship between tumor MSLN methylation and serum mesothelin (SMRP) in mesothelioma.

Malignant pleural mesothelioma (MPM) remains a cancer of poor prognosis. It is hoped that implementation of effective screening biomarkers will lead to earlier diagnoses and improved outcomes. Serum-measured soluble mesothelin-related peptide (SMRP) has been demonstrated to have excellent specificity for MPM, but poor sensitivity precludes its use as a screening biomarker. Using a case series of MPM patients from the International Mesothelioma Program at the Brigham and Women's hospital, we sought to determine whether epigenetic change at the MSLN gene in patient tumors is responsible for the poor sensitivity of SMRP. We identified three potential target regions for CpG methylation silencing in the MSLN promoter, one of which was amenable to bisulfite pyrosequencing and located 214 bp upstream of the transcription start site. MSLN promoter methylation was significantly higher in normal pleura than tumor tissue (P < 6.0x10-9). Next, we compared cases according to serum SMRP status and observed that MSLN methylation was significantly higher among tumors from patients testing negative for SMRP (< 1.5nM) versus those that were SMRP positive (P < 0.03). These results demonstrate that MSLN is normally methylated in the pleura, and that methylation is lost in most tumors. However, in a subset of tumors methylation is retained, and this mechanism explains the poor sensitivity of the SMRP assay. These results may lead to additional biomarker targets that will resolve the poor sensitivity of the SMRP assay and allow implementation of screening among exposed populations.

Family needs and psychosocial functioning of caregivers of individuals with spinal cord injury from Colombia, South America.

OBJECTIVE: 1) To determine the most frequent needs in a group of family caregivers of individuals with spinal cord injury in Neiva Colombia; 2) to describe caregivers' psychosocial functioning; and 3) to examine the relationship between caregiver needs and caregiver psychosocial functioning. DESIGN: Cross-sectional. PARTICIPANTS/METHODS: 37 caregivers completed a caregiver needs questionnaire composed of 27 questions (1-5 scale) and 9 sub-scales (emotional, information, economic, community, and household support, respite, physical health, sleep, and psychological health). The Patient Health Questionnaire (PHQ-9) was used to measure caregiver depression, the Zarit Burden Interview (ZBI) measured stress, the Interpersonal Support Evaluation List Short Version (ISEL-12) measured social support, and the Satisfaction With Life Scale (SWLS) was used to assess satisfaction with life. RESULTS: Information, economic, emotional, community support, and respite needs were most frequently reported among this group of Colombian caregivers. Forty-three percent of the family caregivers reported some level of depression, 68% reported being overwhelmed by their caretaking responsibilities, and 43% reported dissatisfaction with their lives. Information, emotional, economic, physical, sleep, and psychological needs were positively correlated with depression and burden. Those with more household, physical, sleep, economic, and psychological needs had less satisfaction with life and social support. Caregivers with more community and respite needs had less social support, while those with more emotional needs had less satisfaction with life. Caregivers with more respite needs had more burden and those with more household needs had more depression. CONCLUSION: Approximately half of the sample reports some level of burden, depression, or being dissatisfied with life. Psychosocial functioning was related to various family needs. Further longitudinal research is needed to determine whether caregivers with more needs report worse psychosocial functioning or if those with worse psychosocial functioning report more needs.

Implications of LINE1 methylation for bladder cancer risk in women.

PURPOSE: Epigenetic alterations including changes to cellular DNA methylation levels contribute to carcinogenesis and may serve as powerful biomarkers of the disease. This investigation sought to determine whether hypomethylation at the long interspersed nuclear elements (LINE1), reflective of the level of global DNA methylation, in peripheral blood-derived DNA is associated with increased risk of bladder cancer. EXPERIMENTAL DESIGN: LINE1 methylation was measured from blood-derived DNA obtained from participants of a population-based incident case-control study of bladder cancer in New Hampshire. Bisulfite-modified DNA was pyrosequenced to determine LINE1 methylation status; a total of 285 cases and 465 controls were evaluated for methylation. RESULTS: Being in the lowest LINE1 methylation decile was associated with a 1.8-fold increased risk of bladder cancer [95% confidence interval (95% CI), 1.12-2.90] in models controlling for gender, age, and smoking, and the association was stronger in women than in men (odds ratio, 2.48; 95% CI, 1.19-5.17 in women; and odds ratio, 1.47; 95% CI, 0.79-2.74 in men). Among controls, women were more likely to have lower LINE1 methylation than men (P = 0.04), and levels of arsenic in the 90th percentile were associated with reduced LINE1 methylation (P = 0.04). CONCLUSIONS: LINE1 hypomethylation may be an important biomarker of bladder cancer risk, especially among women.

A let-7 microRNA-binding site polymorphism in the KRAS 3' UTR is associated with reduced survival in oral cancers.

MicroRNA (miRNA)-binding site polymorphisms that could contribute to disease risk and prognosis are rapidly being identified and investigated as this genetic variation may have a potentially profound impact on human health. A recently described variant allele in the KRAS 3' untranslated region that arises in the let-7 miRNA complementary site (KRAS-LCS6) and leads to increased KRAS expression in lung cancer was examined for its association with the occurrence of head and neck squamous cell carcinoma (HNSCC). We examined the prevalence of the KRAS-LCS6 variant allele in a population-based case-control study of HNSCC to determine if this KRAS-LCS6 genotype was associated with disease occurrence and patient survival. Although the KRAS-LCS6 variant genotype was not associated with the overall risk of HNSCC, cases with the KRAS-LCS6 variant genotype had significantly reduced survival [hazard ratio (HR), 1.6; 95% confidence interval (CI), 1.0-2.5] in models controlled for confounders of survival. This risk was greatest in cases of oral cavity carcinoma (HR, 2.7; 95% CI, 1.4-5.3). These data demonstrate that cases with the KRAS-LCS6 variant have significantly reduced survival time and suggest that this variant may alter the phenotype or therapeutic response of this disease.

Mdm2 promotes genetic instability and transformation independent of p53.

Mdm2, a regulator of the tumor suppressor p53, is frequently overexpressed in human malignancies. Mdm2 also has unresolved, p53-independent functions that contribute to tumorigenesis. Here, we show that increased Mdm2 expression induced chromosome/chromatid breaks and delayed DNA double-strand break repair in cells lacking p53 but not in cells with a mutant form of Nbs1, a component of the Mre11/Rad50/Nbs1 DNA repair complex. A 31-amino-acid region of Mdm2 was necessary for binding to Nbs1. Mutation of conserved amino acids in the Nbs1 binding domain of Mdm2 inhibited Mdm2-Nbs1 association and prevented Mdm2 from delaying phosphorylation of H2AX and ATM-S/TQ sites, repair of DNA breaks, and resolution of DNA damage foci. Similarly, the mutation of eight amino acids in the Mdm2 binding domain of Nbs1 inhibited Mdm2-Nbs1 interaction and blocked the ability of Mdm2 to delay DNA break repair. Both Nbs1 and ATM, but not the ubiquitin ligase activity of Mdm2, were necessary to inhibit DNA break repair. Only Mdm2 with an intact Nbs1 binding domain was able to increase the frequency of chromosome/chromatid breaks and the transformation efficiency of cells lacking p53. Therefore, the interaction of Mdm2 with Nbs1 inhibited DNA break repair, leading to chromosome instability and subsequent transformation that was independent of p53.