Use of coping strategies in multiple sclerosis: Association with demographic and disease-related characteristics✰.

BACKGROUND: Coping positively and negatively influences psychosocial and other outcomes in multiple sclerosis (MS), but there is conflicting evidence about the use of different coping strategies and their associations with demographic and disease characteristics. Our aims were to examine which coping strategies are used by a large sample of people with MS, then to identify any associations between demographic and disease related factors with use of individual coping strategies. METHODS: Participants in the Trajectories of Outcomes in Neurological Conditions (TONiC) study completed the Coping Orientations to Problems Experienced (COPE60) questionnaire. Relationships between demographic and clinical characteristics and coping strategies were examined by multiple ordinal logistic regression to assess the effect of each potential predictor after adjustment for other possible covariates. RESULTS: From 722 patients, the most commonly used strategy was Acceptance, followed by Active Coping, Planning and Positive Reinterpretation and Growth. All but two strategies showed significant associations with demographic and clinical characteristics. The most marked effects were found for Restraint, with people in employment 2.1 times as likely to utilise this strategy compared to those unemployed, and Seeking of Emotional Social Support and Focus on and Venting of Emotions, which were utilised twice as much by women compared to men. Behavioural and Mental Disengagement were highly associated with greater disability and not being in employment. CONCLUSION: Clinicians should be aware of several disease and demographic characteristics that are associated with use of potentially maladaptive coping strategies.

Homeless shelter context and tuberculosis illness experiences during a large outbreak in Atlanta, Georgia.

Setting: Persons experiencing homelessness (PEH) represent a population at high risk for tuberculosis (TB). While quantitative studies have characterized some important features of this key group, less has been captured directly from PEH about how they experience TB illness itself and the prevention and control measures implemented in response to an outbreak. This qualitative study aimed to explore PEH's TB disease experiences in the context of a large TB outbreak involving homeless shelters in Atlanta, Georgia, USA. Design: This was a qualitative cross-sectional study involving in-depth interviews with 10 PEH with active TB disease. Key themes were identified through coded data analysis. Results: The central theme to emerge was that stressful social environments of homeless shelters shape illness experiences and health care seeking behaviors, and limit the influence of shelter-based prevention and control measures implemented in response to a TB outbreak. Despite availability, shelter-based latent tuberculous infection (LTBI) testing and education services were minimally engaged. Furthermore, hardships inherent to homelessness were interrelated with disease normalization and symptom minimization. Conclusions: Homeless shelter-related stress may have important implications for the prevention and control of TB outbreaks in this setting. This stress may hinder case finding; a model of supplemental TB education and testing for LTBI at proximal community venues is necessary.

Contexte: Les personnes sans domicile fixe (SDF) représentent une population à haut risque de tuberculose (TB). Si les études quantitatives ont caractérisé certains traits importants de ce groupe clé, moins d'informations ont été obtenues directement des SDF sur la façon dont ces personnes expérimentent la TB maladie elle-même et les mesures de prévention et de lutte mises en œuvre en réponse à l'épidémie. Cette étude qualitative visait à explorer l'expérience des SDF en matière de TB maladie dans le contexte d'une vaste flambée épidémique impliquant des centres d'hébergement de SDF à Atlanta, Georgie.Schéma : Une étude qualitative transversale impliquant des entretiens approfondis avec dix SDF atteints de TB active. Les thèmes clés ont été identifiés grâce à une analyse des données codées.Résultats : Le thème central qui a émergé est que l'environnement social stressant des centres d'hébergement façonne les expériences de la maladie et les comportements de recherche de soins et limite l'influence des mesures de prévention et de lutte basées dans ces centres et mises en œuvre en réponse à une flambée de TB. En dépit de leur disponibilité dans les centres d'hébergement, le dépistage de l'infection tuberculeuse latent (ITL) et les services d'éducation ont été très peu engagés. Plus encore, les difficultés inhérentes à l'absence de domicile fixe ont été indissociables de la normalisation de la maladie et de la minimisation des symptômes.Conclusions: Le stress lié à l'hébergement dans un refuge pour SDF peut avoir des implications majeures dans la prévention et la lutte contre les flambées de TB dans ce contexte. Ce stress peut entraver la découverte des cas et soutenir un modèle d'éducation supplémentaire à la TB et une recherche de l'ITL dans les lieux communautaires proches.

Marco de referencia: Las personas que carecen de vivienda constituyen una población con alto riesgo de contraer la tuberculosis (TB). Los estudios cuantitativos han caracterizado algunos aspectos importantes de este grupo poblacional, pero poco se ha captado directamente de su forma de vivenciar la enfermedad tuberculosa y las medidas de prevención y de control que se instauran en respuesta a un brote epidémico. El presente estudio cualitativo tuvo por objeto analizar las vivencias de la enfermedad tuberculosa por parte de las personas que carecen de vivienda, en el contexto de un amplio brote epidémico de TB que ocurrió en los albergues para personas sin techo en Atlanta, Georgia.Método: Fue este un estudio cualitativo transversal, que comportó entrevistas exhaustivas a 10 personas sin vivienda, con enfermedad tuberculosa activa. Se reconocieron los principales temas mediante un análisis temático con datos codificados.Resultados: El principal tema que surgió en el análisis fue que los entornos sociales estresantes de los albergues determinan las experiencias de la enfermedad y el comportamiento de búsqueda de atención y limitan la repercusión de las medidas de prevención y control que se aplican en los albergues en respuesta a un brote epidémico de TB. Pese a su disponibilidad, las pruebas diagnósticas de la infección tuberculosa latente y los servicios educativos prestados en los albergues se utilizaban poco. Además, las adversidades inherentes a la falta de vivienda se correlacionaron con una normalización de la enfermedad y la minimización de los síntomas.Conclusión: El estrés generado en los albergues destinados a las personas sin vivienda puede tener repercusiones importantes en la prevención y el control de los brotes de TB en estos entornos. Este estrés puede obstaculizar la búsqueda de casos y su demostración respalda la aplicación de un modelo de educación complementaria en materia de TB y de pruebas diagnósticas de la infección latente en los centros comunitarios próximos.

Tackling the unknowns of short-course rifapentine-based treatment for active tuberculosis: a decision analysis.

BACKGROUND: Shorter treatment regimens for tuberculosis (TB) are deemed vital for advancing TB control. Murine studies have suggested potential new regimens; however, Phase II human studies of these drug combinations have not shown clear improvement in 2-month culture conversion over current therapy. Nevertheless, drugs such as rifapentine (RPT) may have additional sterilizing effects after 2 months that are difficult to measure in current Phase II studies. OBJECTIVES: To model potential bactericidal effects of RPT in a Phase III trial of a 4-month anti-tuberculosis regimen. METHODS: We developed a Markov model of anti-tuberculosis treatment to compare two regimens for treating TB: a 6-month standard (rifampin-based) treatment and a 4-month regimen using high-dose RPT. The primary outcome was the number of relapses. RESULTS: In the base-case scenario, standard therapy resulted in fewer relapses; improvement in 2-month culture conversion rates in the RPT arm did not change this result. However, while RPT has better sterilizing ability during months 3 and 4 (as observed in the mouse model), the 4-month regimen results in fewer relapses. CONCLUSIONS: Higher 2-month culture conversion rates are neither sufficient nor necessary for making a theoretical 4-month anti-tuberculosis treatment regimen advantageous.

Medium matters: modeling the impact of solid medium performance on tuberculosis trial sample size requirements.

SETTING: Two-month solid medium culture conversion is a commonly used, if suboptimal, endpoint for phase 2 anti-tuberculosis treatment trials. OBJECTIVE AND DESIGN: To model the effect of the performance characteristics (sensitivity and contamination rate) of solid medium on required sample size for a two-arm clinical trial with 85% true (gold standard) culture conversion in the control and 95% in the experimental arm. RESULTS: Increasing sensitivity and decreasing contamination reduced the sample size from 239 subjects/arm (60% sensitivity, 30% contamination) to 138 subjects/arm (95% sensitivity, 1% contamination). CONCLUSION: Optimizing solid medium has significant potential to reduce sample size and increase the efficiency of tuberculosis clinical trials.

Cost-effectiveness of a 12-dose regimen for treating latent tuberculous infection in the United States.

SETTING: A large randomized controlled trial recently showed that for treating latent tuberculous infection (LTBI) in persons at high risk of progression to tuberculosis (TB) disease, a 12-dose regimen of weekly rifapentine plus isoniazid (3HP) administered as directly observed treatment (DOT) can be as effective as 9 months of daily self-administered isoniazid (9H). OBJECTIVES: To assess the cost-effectiveness of 3HP compared to 9H. DESIGN: A computational model was designed to simulate individuals with LTBI treated with 9H or 3HP. Costs and health outcomes were estimated to determine the incremental costs per active TB case prevented and per quality-adjusted life year (QALY) gained by 3HP compared to 9H. RESULTS: Over a 20-year period, treatment of LTBI with 3HP rather than 9H resulted in 5.2 fewer cases of TB and 25 fewer lost QALYs per 1000 individuals treated. From the health system and societal perspectives, 3HP would cost respectively US$21,525 and $4294 more per TB case prevented, and respectively $4565 and $911 more per QALY gained. CONCLUSIONS: 3HP may be a cost-effective alternative to 9H, particularly if the cost of rifapentine decreases, the effectiveness of 3HP can be maintained without DOT, and 3HP treatment is limited to those with a high risk of progression to TB disease.

Public health costs for tuberculosis suspects in Wake County, North Carolina, United States.

SETTING: As the incidence of tuberculosis (TB) declines in high-income countries, resources to control TB are also declining. A portion of these resources are utilized for the evaluation and treatment of persons initially suspected of, but who do not actually have, TB (TB suspects). OBJECTIVE: To describe the cost of TB suspects to public health departments, and determine whether part of this cost can be averted using improved diagnostic tools. DESIGN: We evaluated resource utilization for all TB suspects as well as a random sample of TB cases managed at the Wake County public health clinic during 2008-2010. The proportion of total health department costs attributable to TB suspects was estimated. A sensitivity analysis assessed the potential impact of a rapid, accurate diagnostic test to avert suspect-associated costs. RESULTS: Of 135 patients evaluated for TB, 36 (27%) were suspects, accounting for 14% (US5,885) of the total estimated costs for managing all patients. A perfect diagnostic test with a 3-day turnaround would have averted US27,975 (53%) of the costs attributable to suspects. CONCLUSION: A substantial proportion of public health resources is utilized to manage persons whose final diagnosis is not TB. Efficient implementation of novel rapid tests could avert substantial public health costs.

Did the 'Great Recession' produce a depression in tuberculosis incidence?

In 2009, the United States experienced a record drop in its tuberculosis (TB) case rate, coinciding with a major economic downturn. To investigate this relationship, we modeled short-term changes in gross domestic product, unemployment, and immigration as predictors of TB incidence. We also correlated each state's 2009-2010 change in unemployment with its 2008-2009 change in TB incidence. Although economic factors did not explain the decline, the 2009-2010 change in unemployment negatively correlated with incidence. We hypothesize that factors related to increased unemployment, such as diagnostic delay, may have played a role in the sudden drop in TB case rates.

Biochemical and genetic defects in the DNA-dependent protein kinase in murine scid lymphocytes.

The scid gene product has been identified as the 460-kDa catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs p460), a member of the phosphatidylinositol 3-kinase family. DNA-PK activity is undetectable in scid cells, but the molecular basis for this defect has not been identified. Here we report that expression of p460 in scid lymphocyte precursors is detectable but is reduced at least 10-fold relative to that in wild-type lymphocytes. In addition, we show that the scid mutation disturbs p460 nuclear association, presumably affecting its role in DNA repair pathways. To examine the molecular basis for our observations, we used a degenerate PCR strategy to clone the C-terminal p460 kinase domain from wild-type and scid thymocytes. Northern (RNA) analysis with these probes revealed normal steady-state p460 mRNA levels in scid cells, suggesting that the reduced abundance of p460 protein is due to a posttranscriptional defect. Sequence comparisons identified a single-base-pair alteration in the scid C-terminal p460 kinase domain, resulting in a premature stop codon. This mutation is predicted to truncate p460 by approximately 8 kDa, but it preserves the conserved motifs required for kinase activity in members of the phosphoinositidyl 3-kinase family. Despite a computed molecular weight alteration of less than 2%, we were able to visualize this difference by Western blot (immunoblot) analysis of wild-type and scid p460. These data demonstrate that the scid DNA-PKes mutation is not a null allele and suggest a molecular rationale for the well-described leakiness of the scid phenotype.

CNTF or (-)-deprenyl in immature rats: survival of axotomized facial motoneurons and weight loss.

The application of ciliary neurotrophic factor (CNTF) to the cut ends of transected facial nerves in newborn rats has been reported to reduce the death of facial motoneurons (FMns) axotomized by the transection. Systemically delivered CNTF has been found to cause cachexia in adult mice. We compared the influence of dosage of CNTF and (-)-deprenyl on FMn death, weight loss, and animal survival in rat pups that underwent facial nerve transection at the 14th postnatal day (P14). CNTF was administered by osmotic mini-pumps connected to tubing ending either intrathecally or extrathecally near the craniocervical junction. CNTF caused weight loss and animal death that was similar to the cachexia reported in mice if administered in amounts of 1.1 microgram/day or greater. At the same doses, intrathecal CNTF was more effective than extrathecal CNTF in inducing the cachexia. (-)-Deprenyl did not alter animal survival or weight gain, even at high doses (10 mg/kg every 2 days). Intrathecal CNTF and intraperitoneal (-)-deprenyl, but not extrathecal CNTF, significantly increased the survival of the axotomized FMns. (-)-Deprenyl administered twice daily at 0.01 mg/kg was considerably more effective than CNTF in increasing FMn survival due to the limitation on CNTF dosage caused by the animal death.

(-)-Deprenyl reduces PC12 cell apoptosis by inducing new protein synthesis.

(-)-Deprenyl, a monoamine oxidase (MAO)-B inhibitor, has been shown to increase neuronal survival and to alter protein synthesis and gene expression in astrocytic or PC12 cells independently of MAO-B inhibition. We used serum and nerve growth factor withdrawal to induce apoptotic death in PC12 cells to determine whether (-)-deprenyl increases neuronal survival by reducing apoptosis. (-)-Deprenyl reduced both cell death and internucleosomal DNA degradation in a concentration-dependent manner and was effective at concentrations too low to inhibit MAO (< 10(-9) M). (+)-Deprenyl did not increase PC12 cell survival, and, with the exception of pargyline, other MAO-A and MAO-B inhibitors did not alter apoptotic death. Transcriptional and translational inhibition showed that the reduction in apoptosis required the induction of new protein synthesis by (-)-deprenyl. Increased survival was induced if transcription was maintained for 4 h and translation for 6 h after (-)-deprenyl addition. The findings suggest that transcriptional induction may underlie the other MAO-independent actions of (-)-deprenyl.

(-)-Deprenyl alters the time course of death of axotomized facial motoneurons and the hypertrophy of neighboring astrocytes in immature rats.

(-)-Deprenyl previously was shown to increase the survival of rat facial motoneurons (FMns) after a loss of muscle-derived trophic support caused by axotomy at Postnatal Day 14 (P14) and to increase reactive astrogliosis after traumatic damage to the adult rat striatum. We estimated reactive astrogliosis in facial nuclei at 1, 3, 7, 14, and 21 days after transection of the facial nerve at P14 by two methods: first, by measuring the relative optical density (OD) of GFAP immunoreaction (GFAP-OD) in the facial nuclei and second by determining the relative area of GFAP immunoreactivity (GFAP-AREA) in the same nuclei. Both measures were taken for multiple immunoreacted sections through the length of each facial nuclei by using a control half section at the same brain stem level taken from an unlesioned, age-matched animal. The experimental and control facial nuclear half sections were coimmunoreacted using the "glued" half brain stem method. The facial nerve transections served to axotomize all of the FMns in the ipsilateral facial nuclei. The numbers of surviving FMns were examined at the same time points as above using counts of Nissl-stained somata from serial sections taken through each facial nucleus. We found that FMn loss occurred rapidly after axotomy in saline-treated animals and could be best fitted with a decaying exponential relationship (time constant 2.7 days). In the saline-treated animals, the FMn loss plateaued between 7 and 14 days at 74.8%, and 47% of the FMns were found to be lost within 3 days. Increases in the facial nuclear GFAP-OD values and GFAP-AREA values were evident as early as 1 day following axotomy (2.5 and 3.3 times normal, respectively) and reached maximal levels by 7 days (5.7 and 37.6 times normal, respectively). The administration of (-)-deprenyl slowed the loss of the FMns by 24-48 h (time constant 3.9 days) and increased the number of surviving FMns at 21 days by 2.1 times. Treatment with (-)-deprenyl was found to significantly increase GFAP-OD and GFAP-AREA at Day 1 by 71 and 32%, respectively, and at Day 3 by 22 and 27%, respectively. In contrast, it decreased GFAP-OD and GFAP-AREA by 42 and 19%, respectively, at Day 7, and by 20 and 12%, respectively at Day 21. Accordingly, as estimated by both measures, the drug increases reactive astrogliosis in the facial nucleus during the first 3 days after facial nerve transection and decreases the gliosis thereafter.(ABSTRACT TRUNCATED AT 400 WORDS)

Different rates of age-related loss for four murine monoaminergic neuronal populations.

The age-related loss of locus coeruleus (LC) noradrenergic neurons, substantia nigra compacta (SNc) dopaminergic neurons, dopaminergic retinal amacrine (rAm) neurons and raphe serotonergic neurons, identified using antibodies against tyrosine hydroxylase (TH) and serotonin (5HT) was investigated in C57B1 mice aged 8 to 104 weeks. The neuronal somata were counted and their locations three-dimensionally reconstructed from serial sections alternately immunoreacted or Nissl stained. Nonlinear estimation analysis showed that decaying exponential equations best fitted the plots of neuronal numbers versus age and each subtype was lost according to different exponential constants of -0.015, -0.013, -0.004 and -0.001 for LC TH+, SNc TH+, rAm TH+ and raphe 5HT+ neurons, respectively. Neurons were lost from all different subregions within the nuclei or the retinae. Counts of immediately adjacent TH-immunoreacted and Nissl-stained sections through the LC at different ages indicate that the neuronal loss was due to neuronal death rather than loss of TH immunoreactivity. The markedly different rates of age-related neuronal loss for the four monoaminergic subtypes offer a model to study the underlying molecular and cellular mechanisms.