Traumatic Brain Injury (TBI) and persistent post-concussion syndrome (PCS) including chronic migraine (CM) are major health issues for civilians and the military. It is important to understand ...underlying biochemical mechanisms of these conditions, and be able to monitor them in an accurate and minimally invasive manner. This study describes the initial use of a novel serum analytical platform to help distinguish TBI patients, including those with post-traumatic headache (PTH), and to help identify phenotypes at play in these disorders. The hypothesis is that physiological responses to disease states like TBI and PTH and related bodily stresses are reflected in biomolecules in the blood in disease-specific manner. Leave one out (serum sample) cross validations (LOOCV) and sample randomizations were utilized to distinguished serum samples from the following TBI patient groups: TBI +PTSD + CM + severe depression (TBI "most affected" group) vs healthy controls, TBI "most affected" vs TBI, TBI vs controls, TBI + CM vs controls, and TBI + CM vs TBI. Inter-group discriminatory p values were ≤ 10-10, and sample group randomizations resulted in p non-significant values. Peptide/protein identifications of discriminatory mass peaks from the TBI "most affected" vs controls and from the TBI plus vs TBI minus CM groups yielded information of the cellular/molecular effects of these disorders (immune responses, amyloidosis/Alzheimer's disease/dementia, neuronal development). More specific biochemical disease effects appear to involve blood brain barrier, depression, migraine headache, autoimmunity, and autophagy pathways. This study demonstrated the ability for the first time of a novel, accurate, biomarker platform to monitor these conditions in serum, and help identify biochemical relationships leading to better understanding of these disorders and to potential therapeutic approaches.
(Headache 2011;51:33‐51)
Objective and Background.— Amitriptyline is one of the most commonly used medications in migraine prophylaxis. There have been relatively few placebo‐controlled studies of ...amitriptyline in migraine prophylaxis or in treatment of chronic daily headache (CDH). This report deals with a large placebo‐controlled trial of amitriptyline vs placebo of 20 weeks duration that included subjects with intermittent migraine (IM) as well as CDH. The study was carried out between 1976 and 1979; however, results have never been fully reported.
Methods.— Patients with a history of migraine as defined by the 1962 Ad Hoc Committee report were recruited for this study. Subjects had at least 2 headaches per month, and no limit was placed on the number of headaches per month that could be experienced. The study format included a 4‐week baseline period (Period A) in which all subjects received placebo in a dose of 2 pills per day for one week, 3 pills per day for one week and then 4 pills per day for 2 weeks. Subjects with at least 2 migraine headaches in this period were then entered into Period B and randomized into either amitriptyline or placebo tracks. Medication consisted of identical tablets containing either 25 mg amitriptyline or placebo. Period B was 4 weeks in duration with dose titration identical to Period A. The dose could be reduced if necessary to reduce side effects. The minimum dose was one pill per day. Period C was a 12‐week maintenance or stabilization period in which the patient continued the dose established by week 8 with visits at weeks 12, 16, and 20. Patients kept a headache calendar that was used for data collection. Headache frequency (per month), severity, and duration (hours) were the primary measurement parameters employed for data analysis.
Results.— For the entire group, 391 subjects were entered into Period A, 338 were randomized into Period B, 317 (81%) subjects completed the first post‐randomization visit (8 weeks), 255 (65%) completed week 12, 210 (54%) completed week 16, and 186 (48%) completed week 20. Using headache frequency and evaluating parameters of (a) improvement, (b) no change, or (c) worsening relative to baseline, there was a significant improvement in headache frequency for amitriptyline over placebo at 8 weeks (P = .018) but not at 12, 16, or 20 weeks. When amitriptyline and placebo patients were compared for headache frequency at 8, 12, 16, and 20 weeks to their own placebo stabilization period at 4 weeks, statistically significant improvement vs worsening was seen in headache frequency at each evaluation point for both amitriptyline and placebo groups (P ≤ .01) reaching 50% reporting a decrease in frequency in each group and approximately 10% reporting worsening by week 20. There were no significant differences in headache severity or duration between amitriptyline and placebo groups at anytime during the study. Within the study sample, there were 36 amitriptyline and 22 placebo subjects who had headaches ≥17 days/month that fit the current definition of CDH by the Silberstein‐Lipton criteria. These were analyzed separately as a subgroup for comparison of amitriptyline vs placebo using a metric of (1) no change or worsening; (2) up to a 50% improvement; and (3) ≥50% improvement in headache frequency. Amitriptyline was superior to placebo in number with improvement in frequency of ≥50% at 8 weeks (25% vs 5% P = .031) and at 16 weeks (46% vs 9% P = .043). There was a trend for amitriptyline to be superior to placebo at 12 and 20 weeks but this did not reach significance.
Conclusions.— In this study, using headache frequency as the primary metric, for the entire group, amitriptyline was superior to placebo in migraine prophylaxis at 8 weeks but, because of a robust placebo response, not at subsequent time points. For the subgroup with CDH, amitriptyline was statistically significantly superior to placebo at 8 weeks and 16 weeks with a similar but nonsignificant trend at 12 and 20 weeks. Compared with placebo amitriptyline is effective in CDH. Amitriptyline was also significantly effective in IM compared intragroup to its own baseline; however, placebo was equally effective in the same analysis. The reason for the robust placebo response in the IM group is not clear, but has been occasionally reported.
Previous results from one-dimensional model studies have demonstrated that large-scale exploitation of the tidal stream resource could have a significant impact on large-scale sediment dynamics. In ...this research, we model the impact that such exploitation would have on the dynamics of headland sand banks. Such sand banks, formed by the large eddies generated by strong tidal flow past headlands, have an important role in natural coastal protection, since they cause waves to refract and dissipate energy. Therefore, a tidal energy converter (TEC) array developed in the vicinity of a headland could alter this natural form of coastal protection. Here, we investigate the impact of TEC array operation on idealised headland sand bank formation, followed by a case study, the Alderney Race: a strait of water between the island of Alderney (Channel Islands) and Cap de la Hague (France). This is achieved through the application of a morphological model that incorporates TEC device operation as an additional bed friction source term in the three-dimensional hydrodynamic module. Through a series of model experiments, we demonstrate the impact that a full-scale (300 MW) TEC array would have on sediment dynamics when sited near a headland. This modelling study demonstrates that a 300 MW TEC array located in the vicinity of a headland could lead to a considerable change in the maintenance of headland sand banks over a spring-neap cycle. If the scale of this change is demonstrated to be significant compared to the natural range of inter-annual and inter-seasonal sand bank variability, then developers of TEC arrays would be advised to examine ways in which they could reduce the environmental impacts of TEC arrays sited near headlands. The most obvious of these is to limit the scale of the array, but if we assume that developers wish to exploit the tidal energy resource to its maximum, the alternative is to site the array strategically (within the bounds of economic feasibility) such that it will not interfere with the natural morphodynamics of the headland system.
► Headland sand banks affect wave energy, and so are important for coastal protection. ► We model the impact of tidal energy converter (TEC) array operation on sand bank dynamics. ► TEC array operation could alter these sand banks. ► TEC arrays should be strategically sited in the vicinity of headlands.
Evaluate the extent and severity of headache following deployment-related TBI (D-TBI) in veterans of the Iraq (OIF) and Afghanistan (OEF) wars over a follow-up period of 4-11 years with comparison to ...age, sex, race, and time of deployment matched controls.
TBI has been recognized as the "signature Injury" of the OEF/OIF campaigns occurring in 14-20% of deployed soldiers. Currently, there are very few data on the longer term follow-up of soldiers with D-TBI. This study deals with prevalence and severity of headache and headache burden at 4-11 years following D-TBI for OEF/OIF veterans with comparison to controls without D-TBI.
This is a matched case controlled-study. All subjects were recruited from Operation New Dawn (OND), a voluntary program for OEF/OIF Veterans at the Oklahoma VAMC designed to assist with re-integrating into civilian life. On entry into OND a medical questionnaire was administered that included a brief screen for D-TBI, and those with a possible D-TBI were referred to a TBI clinic, For this study, the first 500 TBI clinic patients who were found to have had a D-TBI (TBIS) were matched by age, sex, race, and time of deployment to control subjects (CS), drawn from the 4411 OND program members with no D-TBI, creating a pool of 500 TBIS/CS pairs. From this pool, 55 pairs (11%) were randomly selected for this study. Data were collected from both TBIS and CS by telephone interview with questionnaires regarding the DTBI, headache, depression, and PTSD. TBI severity was measured by duration of loss of consciousness (LOC) as: a Very Mild (VMTBI, dazed only, no LOC), b Mild (MTBI, LOC 1-30 minutes), and c Moderate-Severe (MSTBI, LOC > 30 minutes). Intensity for individual headaches was measured by disability produced by the headache as: a Disabling (must be in bed), b Severe (50-90% decrease in activity), or c Mild-Moderate (>50% of usual activity possible). Statistical analysis employed Fisher's exact test and odds ratio.
The 55 TBIS/CS pairs were segregated by severity of TBI for the TBIS. For the TBIS there were no significant differences among these three subgroups as to mechanism producing the TBI (blast injury or direct head trauma). Comparing TBIS vs CS for phenotypic classification of headaches, for TBIS - 89% had migraine, 2% probable migraine, 9% had tension, and 0% had no headaches, while for CS - 36% had migraine, 15% probable migraine, 27% tension, and 22% no headache (P < .0001). Migraine with aura occurred in 38% of TBIS and 6% of CS (P < .0001). As to headache frequency, for TBIS - chronic daily headache (CDH) occurred in 44%, frequent headache in 33%, and infrequent or no headache in 23%, while for CS - CDH occurred in 7%, frequent headache in 13%, and infrequent or no headache in 80% (P < .0001). For TBIS, 54% had severe or disabling headache ≥2 days/week as opposed to only 16% of CS (OR 6.13 2.5-14.9). As to onset of most severe and frequent headaches, this occurred shortly after TBI in 89% of TBIS while only 27% of CS reported most severe headaches starting during deployment. There was no correlation of severity of headache problem with severity of TBI. Comparing TBIS at 4-7 vs 8-11 years after injury, there was no difference in frequency or severity of headache between these groups.
At 4-11 years after D-TBI for TBIS, or after deployment for CS, the TBIS as compared to CS suffered much more frequent and severe headaches. For TBIS, there was no relation of headache intensity or phenotype to severity or cause of the TBI, and the Headache Burden has not improved over time up to 11 years after D-TBI. The process initiated by the D-TBI that relates to the headache has a prolonged effect up to and beyond 11 years.
It is important to develop minimally invasive biomarker platforms to help in the identification and monitoring of patients with Alzheimer's disease (AD). Assisting in the understanding of biochemical ...mechanisms as well as identifying potential novel biomarkers and therapeutic targets would be an added benefit of such platforms. This study utilizes a simplified and novel serum profiling platform, using mass spectrometry (MS), to help distinguish AD patient groups (mild and moderate) and controls, as well as to aid in understanding of biochemical phenotypes and possible disease development. A comparison of discriminating sera mass peaks between AD patients and control individuals was performed using leave one serum sample out cross validation (LOOCV) combined with a novel peak classification valuation (PCV) procedure. LOOCV/PCV was able to distinguish significant sera mass peak differences between a group of mild AD patients and control individuals with a
value of 10
. This value became non-significant (
= 0.09) when the same sera samples were randomly allocated between the two groups and reanalyzed by LOOCV/PCV. This is indicative of physiological group differences in the original true-pathology binary group comparison. Similarities and differences between AD patients and traumatic brain injury (TBI) patients were also discernable using this novel LOOCV/PCV platform. MS/MS peptide analysis was performed on serum mass peaks comparing mild AD patients with control individuals. Bioinformatics analysis suggested that cell pathways/biochemical phenotypes affected in AD include those involving neuronal cell death, vasculature, neurogenesis, and AD/dementia/amyloidosis. Inflammation, autoimmunity, autophagy, and blood-brain barrier pathways also appear to be relevant to AD. An impaired VWF/ADAMTS13 vasculature axis with connections to F8 (factor VIII) and LRP1 and NOTCH1 was indicated and is proposed to be important in AD development.
ObjectivesThe US Occupational Safety and Health Administration (OSHA) recently proposed a permissible exposure limit of 0.2 µg/m3 for beryllium, based partly on extrapolated estimates of lung cancer ...risk from a pooled occupational cohort. The purpose of the present analysis was to evaluate whether cohort members exposed at lower levels to mainly insoluble forms of beryllium exhibit increased risk of lung cancer.MethodsWe conducted Cox proportional hazards regression analyses among 75 lung cancer cases in age-based risk sets within two lower exposure plants in the pooled cohort followed from 1940 to 2005. We used categorical and power models to evaluate exposure–response patterns for mean and cumulative beryllium exposures in the two-plant cohort, comparing findings with the full pooled cohort. We also evaluated the distribution of exposure-years in each cohort by solubility class (soluble, insoluble and mixed).Results98% of workers in the two-plant cohort were hired between 1955 and 1969. The mean beryllium exposure averaged 1.3 µg/m3 and the predominant form was insoluble. Adjusting for confounders, we observed a monotonic increase in lung cancer mortality across exposure categories in the two-plant cohort. The exposure–response coefficients (per unit ln exposure) were 0.270 (p=0.061) for mean exposure and 0.170 (p=0.033) for cumulative exposure, compared with 0.155 and 0.094 (respectively) in the full cohort.ConclusionThe low-exposure levels at these two plants and the predominance of insoluble beryllium suggest that the overall pooled cohort findings on which OSHA’s lung cancer risk assessment is based are relevant for current workers exposed to any form of beryllium.
Beta amyloid PET scans are a minimally invasive biomarker that may inform Alzheimer's disease (AD) diagnosis. The Caregiver's Reactions and Experience (CARE) study, an IDEAS supplement, aimed to ...understand experiences of PET scan recipients and their care partners regarding motivations for scans, reporting and interpreting results, and impact of results. Patients with mild cognitive impairment or dementia who agreed to join the CARE-IDEAS study and their care partners participated in a baseline survey and follow-up survey approximately 18 months later, supplemented by in-depth qualitative interviews with subsets of participants. Patients who received scans and volunteered for follow-up research were more likely to be male, better educated, and have higher income than the general population. Survey information was merged with Medicare data. This article integrates findings from several CARE-IDEAS publications and provides implications for practice and research. Although most participants accurately reported scan results, they were often confused about their meaning for prognosis. Some participants reported distress with results, but there were no significant changes in measured depression, burden, or economic strain over time. Many respondents desired more information about prognosis and supportive resources. Scan results were not differentially associated with changes in service use over time. Findings suggest a need for carefully designed and tested tools for clinicians to discuss risks and benefits of scans and their results, and resources to support patients and care partners in subsequent planning. Learning of scan results provides a point-of-contact that should be leveraged to facilitate shared decision-making and person-centered longitudinal AD care.
Tyr142, the C-terminal amino acid of histone variant H2A.X is phosphorylated by WSTF (Williams-Beuren syndrome transcription factor), a component of the WICH complex (WSTF-ISWI chromatin-remodeling ...complex), under basal conditions in the cell. In response to DNA double-strand breaks (DSBs), H2A.X is instantaneously phosphorylated at Ser139 by the kinases ATM and ATR and is progressively dephosphorylated at Tyr142 by the Eya1 and Eya3 tyrosine phosphatases, resulting in a temporal switch from a postulated diphosphorylated (pSer139, pTyr142) to monophosphorylated (pSer139) H2A.X state. How mediator proteins interpret these two signals remains a question of fundamental interest. We provide structural, biochemical, and cellular evidence that Microcephalin (MCPH1), an early DNA damage response protein, can read both modifications via its tandem BRCA1 C-terminal (BRCT) domains, thereby emerging as a versatile sensor of H2A.X phosphorylation marks. We show that MCPH1 recruitment to sites of DNA damage is linked to both states of H2A.X.
Depression and cognitive impairment commonly co-occur, and it has been hypothesized that the two share pathological processes. Our objective for this study was to determine the relationship between ...elevated β-amyloid level and the prevalence and incidence of depressive symptoms and diagnosed depression over two years among fee-for-service Medicare beneficiaries with cognitive impairment.
We utilized data from the CARE-IDEAS cohort study (N = 2078) including two measures of depressive symptoms (PHQ-2) and administrative claims data to identify pre-scan and incident depression diagnosis in subsample of fee-for-service Medicare beneficiaries (N = 1443). We used descriptive statistics and Poisson regression models with robust covariance.
Beneficiaries whose scan results indicated not-elevated β-amyloid were significantly more likely to have been diagnosed with depression pre-scan (46.4 % vs. 33.1 %). There was no significant association between elevated amyloid and the incidence of depressive symptoms or diagnosed depression.
The sample was limited to Medicare beneficiaries with cognitive impairment. Race/ethnic composition and education levels were not representative of the general population and there was substantial loss to follow-up. Mixed depressive / anxious episodes were captured as diagnoses of depression, potentially overestimating depression in this population.
There was a high prevalence and incidence of diagnosed depression in this cohort of Medicare beneficiaries, but the incidence of depressive symptoms and diagnosed depression was not associated with elevated β-amyloid.
•Depressive symptoms and cognitive impairment commonly co-occur.•Amyloid-β scans are increasingly used as part of diagnostic screening for Alzheimer’s.•Relationship between β-amyloid level and incidence of depressive symptoms is unclear.•Findings show no association between β-amyloid levels, depressive symptoms incidence.
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