Cognitive decrements in 1991 Gulf War veterans: associations with Gulf War illness and neurotoxicant exposures in the Boston Biorepository, Recruitment, and Integrative Network (BBRAIN) cohorts.

BACKGROUND: During deployment, veterans of the 1991 Gulf War (GW) were exposed to multiple war-related toxicants. Roughly a third of these veterans continue to exhibit neurotoxicant induced symptoms of Gulf War Illness (GWI), a multi-faceted condition that includes fatigue, pain and cognitive decrements. When studied empirically, both deployed veterans with exposures and those who meet the criteria for GWI are more likely to show deficits in the area of neuropsychological functioning. Although studies have shown cognitive impairments in small sample sizes, it is necessary to revisit these findings with larger samples and newer cohorts to see if other areas of deficit emerge with more power to detect such differences. A group of researchers and clinicians with expertise in the area of GWI have identified common data elements (CDE) for use in research samples to compare data sets. At the same time, a subgroup of researchers created a new repository to share these cognitive data and biospecimens within the GWI research community. METHODS: The present study aimed to compare cognitive measures of attention, executive functioning, and verbal memory in a large sample of GWI cases and healthy GW veteran controls using neuropsychological tests recommended in the CDEs. We additionally subdivided samples based on the specific neurotoxicant exposures related to cognitive deficits and compared exposed versus non-exposed veterans regardless of case criteria status. The total sample utilized cognitive testing outcomes from the newly collated Boston, Biorepository, Recruitment, and Integrative Network (BBRAIN) for GWI. RESULTS: Participants included 411 GW veterans, 312 GWI (cases) and 99 healthy veterans (controls). Veterans with GWI showed significantly poorer attention, executive functioning, learning, and short-and-long term verbal memory than those without GWI. Further, GW veterans with exposures to acetylcholinesterase inhibiting pesticides and nerve gas agents, had worse performance on executive function tasks. Veterans with exposure to oil well fires had worse performance on verbal memory and those with pyridostigmine bromide anti-nerve gas pill exposures had better verbal memory and worse performance on an attention task compared to unexposed veterans. CONCLUSIONS: This study replicates prior results regarding the utility of the currently recommended CDEs in determining impairments in cognitive functioning in veterans with GWI in a new widely-available repository cohort and provides further evidence of cognitive decrements in GW veterans related to war-related neurotoxicant exposures.

Genetic association between the APOE ε4 allele, toxicant exposures and Gulf war illness diagnosis.

INTRODUCTION: Exposure to nerve agents, pyridostigmine bromide (PB), pesticides, and oil-well fires during the 1991 Gulf War (GW) are major contributors to the etiology of Gulf War Illness (GWI). Since the apolipoprotein E (APOE) ε4 allele is associated with the risk of cognitive decline with age, particularly in the presence of environmental exposures, and cognitive impairment is one of the most common symptoms experienced by veterans with GWI, we examined whether the ε4 allele was associated with GWI. METHODS: Using a case-control design, we obtained data on APOE genotypes, demographics, and self-reported GW exposures and symptoms that were deposited in the Boston Biorepository and Integrative Network (BBRAIN) for veterans diagnosed with GWI (n = 220) and healthy GW control veterans (n = 131). Diagnosis of GWI was performed using the Kansas and/or Center for Disease Control (CDC) criteria. RESULTS: Age- and sex-adjusted analyses showed a significantly higher odds ratio for meeting the GWI case criteria in the presence of the ε4 allele (Odds ratio [OR] = 1.84, 95% confidence interval [CI = 1.07-3.15], p ≤ 0.05) and with two copies of the ε4 allele (OR = 1.99, 95% CI [1.23-3.21], p ≤ 0.01). Combined exposure to pesticides and PB pills (OR = 4.10 [2.12-7.91], p ≤ 0.05) as well as chemical alarms and PB pills (OR = 3.30 [1.56-6.97] p ≤ 0.05) during the war were also associated with a higher odds ratio for meeting GWI case criteria. There was also an interaction between the ε4 allele and exposure to oil well fires (OR = 2.46, 95% CI [1.07-5.62], p ≤ 0.05) among those who met the GWI case criteria. CONCLUSION: These findings suggest that the presence of the ε4 allele was associated with meeting the GWI case criteria. Gulf War veterans who reported exposure to oil well fires and have an ε4 allele were more likely to meet GWI case criteria. Long-term surveillance of veterans with GWI, particularly those with oil well fire exposure, is required to better assess the future risk of cognitive decline among this vulnerable population.

Boston biorepository, recruitment and integrative network (BBRAIN): A resource for the Gulf War Illness scientific community.

AIMS: Gulf War Illness (GWI), a chronic debilitating disorder characterized by fatigue, joint pain, cognitive, gastrointestinal, respiratory, and skin problems, is currently diagnosed by self-reported symptoms. The Boston Biorepository, Recruitment, and Integrative Network (BBRAIN) is the collaborative effort of expert Gulf War Illness (GWI) researchers who are creating objective diagnostic and pathobiological markers and recommend common data elements for GWI research. MAIN METHODS: BBRAIN is recruiting 300 GWI cases and 200 GW veteran controls for the prospective study. Key data and biological samples from prior GWI studies are being merged and combined into retrospective datasets. They will be made available for data mining by the BBRAIN network and the GWI research community. Prospective questionnaire data include general health and chronic symptoms, demographics, measures of pain, fatigue, medical conditions, deployment and exposure histories. Available repository biospecimens include blood, plasma, serum, saliva, stool, urine, human induced pluripotent stem cells and cerebrospinal fluid. KEY FINDINGS: To date, multiple datasets have been merged and combined from 15 participating study sites. These data and samples have been collated and an online request form for repository requests as well as recommended common data elements have been created. Data and biospecimen sample requests are reviewed by the BBRAIN steering committee members for approval as they are received. SIGNIFICANCE: The BBRAIN repository network serves as a much needed resource for GWI researchers to utilize for identification and validation of objective diagnostic and pathobiological markers of the illness.

Understanding the Scientific Basis of Post-traumatic Stress Disorder (PTSD): Precision Behavioral Management Overrides Stigmatization.

Post-traumatic stress disorder (PTSD) is a severe polygenic disorder triggered by environmental factors. Many polymorphic genes, particularly the genetic determinants of hypodopaminergia (low dopamine function), associate with a predisposition to PTSD as well as substance use disorder. Support from the National Institutes of Health for neuroimaging research and molecular, genetic applied technologies has improved understanding of brain reward circuitry functions that have inspired the development of new innovative approaches to their early diagnosis and treatment of some PTSD symptomatology and addiction. This review presents psychosocial and genetic evidence that vulnerability or resilience to PTSD can theoretically be impacted by dopamine regulation. From a neuroscience perspective, dopamine is widely accepted as a major neurotransmitter. Questions about how to modulate dopamine clinically in order to treat and prevent PTSD and other types of reward deficiency disorders remain. Identification of genetic variations associated with the relevant genotype-phenotype relationships can be characterized using the Genetic Addiction Risk Score (GARS®) and psychosocial tools. Development of an advanced genetic panel is under study and will be based on a new array of genes linked to PTSD. However, for now, the recommendation is that enlistees for military duty be given the opportunity to voluntarily pre-test for risk of PTSD with GARS, before exposure to environmental triggers or upon return from deployment as part of PTSD management. Dopamine homeostasis may be achieved via customization of neuronutrient supplementation "Precision Behavioral Management" (PBM™) based on GARS test values and other pro-dopamine regulation interventions like exercise, mindfulness, biosensor tracking, and meditation.

Influence of different surface treatments of poly(n-butyl acrylate) networks on fibroblasts adhesion, morphology and viability.

BACKGROUND: Physical and chemical characteristics of implant materials determine the fate of long-term cardiovascular devices. However, there is still a lack of fundamental understanding of the molecular mechanisms occurring in the material-tissue interphase. In a previous study, soft covalently crosslinked poly(n-butyl acrylate) networks (cPnBA) were introduced as sterilizable, non-toxic and immuno-compatible biomaterials with mechanical properties adjustable to blood vessels. Here we study the influence of different surface treatments in particular oxygen plasma modification and fibrinogen deposition as well as a combinatorial approach on the adhesion and viability of fibroblasts. MATERIAL AND METHODS: Two types of cPnBA networks with Young's moduli of 0.19±0.01 MPa (cPnBA04) and 1.02±0.01 MPa (cPnBA73) were synthesized and post-modified using oxygen plasma treatment (OPT) or fibrinogen coating (FIB) or a combination of both (OPT+FIB). The water contact angles of the differently post-treated cPnBAs were studied to monitor changes in the wettability of the polymer surfaces. Because of the key role of vascular fibroblasts in regeneration processes around implant materials, here we selected L929 fibroblasts as model cell type to explore morphology, viability, metabolic activity, cell membrane integrity as well as characteristics of the focal adhesions and cell cytoskeleton on the cPnBA surfaces. RESULTS: Compared to non-treated cPnBAs the advancing water-contact angles were found to be reduced after all surface modifications (p < 0.05, each), while lowest values were observed after the combined surface treatment (OPT+FIB). The latter differed significantly from the single OPT and FIB. The number of adherent fibroblasts and their adherence behavior differed on both pristine cPnBA networks. The fibroblast density on cPnBA04 was 743±434 cells·mm-2, was about 6.5 times higher than on cPnBA73 with 115±73 cells·mm-2. On cPnBA04 about 20% of the cells were visible as very small, round and buckled cells while all other cells were in a migrating status. On cPnBA73, nearly 50% of fibroblasts were visible as very small, round and buckled cells. The surface functionalization either using oxygen plasma treatment or fibrinogen coating led to a significant increase of adherent fibroblasts, particularly the combination of both techniques, for both cPnBA networks. It is noteworthy to mention that the fibrinogen coating overruled the characteristics of the pristine surfaces; here, the fibroblast densities after seeding were identical for both cPnBA networks. Thus, the binding rather depended on the fibrinogen coating than on the substrate characteristics anymore. While the integrity of the fibroblasts membrane was comparable for both polymers, the MTS tests showed a decreased metabolic activity of the fibroblasts on cPnBA. CONCLUSION: The applied surface treatments of cPnBA successfully improved the adhesion of viable fibroblasts. Under resting conditions as well as after shearing the highest fibroblast densities were found on surfaces with combined post-treatment.

Comparative assessment of the incidence of vertical root fractures between conventional versus surgical endodontic retreatment.

OBJECTIVES: Vertical root fractures (VRFs) are a common cause of tooth loss. Little evidence exists though, relating the incidence of VRFs to the type of endodontic retreatment. This retrospective study aimed at evaluating the impact of conventional versus surgical endodontics on root canal-filled teeth with VRFs. MATERIALS AND METHODS: Over a period of 13 years, 200 endodontically retreated teeth from 192 patients with VRFs were extracted and further examined. VRFs were assessed in relation to age, gender, tooth group, clinical signs, extension on the root surface, patency, as well as type of endodontic retreatment and restoration. Statistical analysis was conducted using a Cox PH Model, Chi-squared, Wilcoxon rank-sum, and Log rank tests at a significance level of 5 %. RESULTS: The majority of teeth with VRFs (62.31 %) had undergone the combination of conventional root canal retreatment and apical surgery. Women (64.06 %) presented VRFs more frequently than men (35.94 %) at the mean age of 51.1 and 55.1 years, respectively. Maxillary first (17.5 %) and second (16.5 %) premolars, restored by a resin-based material without a post (56.28 %) were more susceptible to VRFs. Apically initiated (84.1 %) VRFs could be diagnosed more easily on radiographs. CONCLUSIONS: The type of endodontic treatment strongly correlated with VRFs. The prevalence of VRFs in teeth having undergone both conventional and surgical endodontic retreatment could be attributed, among others, to additive dentin damage related to the aforementioned endodontic procedures. CLINICAL RELEVANCE: The possible involvement of endodontic retreatment in the multifactorial etiology of VRFs needs to be taken into consideration in clinical practice.

Treatment of spondylodiscitis in human immunodeficiency virus-infected patients: a comparison of conservative and operative therapy.

STUDY DESIGN: Multicenter retrospective case series. OBJECTIVE: To determine relevant clinical presentation and outcome of human immunodeficiency virus (HIV)-positive patients with spondylodiscitis as a function of the treatment. SUMMARY OF BACKGROUND DATA: This is the first study comparing the clinical outcome of HIV-positive patients with spondylodiscitis as a function of the treatment. METHODS: We performed a national multicenter retrospective case series comparing operatively versus conservatively treated HIV-positive patients with spondylodiscitis presenting between 1991 and 2007. RESULTS: Twenty patients were included in the study. The average age of the patients at the time of admission was 43.0 years. The sex ratio m:w resulted in 2.3:1. On admission, 50% of the patients were in CDC stage C3. The CD4 T-cell count was determined as being 237.5/microL on average. At the occurrence of spondylodiscitis HIV had been known for a mean 8.5 years. In altogether 75% of the cases a pathogen was found. In 3 cases, mixed infections were present. Half of the patients received surgery. In none of these patients a wound infection or a delay of wound healing could be observed. One patient died during in-patient stay. Eleven of the 19 patients could be followed up a mean 13 months after discharge. In the follow-up period further 3 patients died on an average of 45 months after discharge. CONCLUSION: The occurrence of spondylodiscitis in HIV-positive patients is associated with a low CD4 T-cell count. The probability of mixed infections rises with a CD4 T-cell count <100/microL. The occurrence of spondylodiscitis in HIV-positive patients is accompanied by high mortality. Operative therapy of spondylodiscitis in HIV-positive patients is not associated with an increased surgical complication rate. HIV infection or AIDS should not have an influence on decision-making regarding conservative or operative therapy of spondylodiscitis.

Neuropsychological function in Gulf War veterans: relationships to self-reported toxicant exposures.

BACKGROUND: The present study was aimed at (1) exploring evidence of central nervous system (CNS) dysfunction among Gulf War (GW) veterans on neuropsychological tests and (2) examining whether performance on neuropsychological tests was related to specific neurotoxicant exposures experienced in the Gulf. METHODS: The GW-deployed groups were selected using stratified random sampling methods from two distinct cohorts of GW veterans. A comparison group that had been called up for GW service but deployed to Germany rather than the Gulf also was examined. Neuropsychological function was assessed using a pre-determined battery chosen to include tests known to be highly sensitive to the behavioral effects of the neurotoxicants thought to have been present in the Gulf. RESULTS: Self-reported exposures were related to neuropsychological test performance controlling for post-traumatic stress disorder, major depression, and other known covariates of neuropsychological test performance. Results showed that GW-deployed veterans performed more poorly than the Germany-deployed veterans on several specific neuropsychological tests, but after adjustment for multiple comparisons, only the differences in mood complaints remained significant. Within the GW-deployed group, self-reported exposure to chemical warfare agents was associated with poorer performance on cognitive tests involving specific functional domains. CONCLUSIONS: Results provide evidence that there are subtle differences in CNS function among GW-deployed veterans who report chemical warfare agent exposure while in the GW theater.

Are there cognitive subtypes in adult attention deficit/hyperactivity disorder?

There has been increasing knowledge of the treatment, diagnosis, and demographics of adults with residual attention deficit/hyperactivity disorder (ADHD). However, less is known about the neuropsychological functioning in adults with residual ADHD. In comparing the clinical neuropsychological test performance of a group of adult clinic patients with residual ADHD (N = 30) with that of normal controls (N = 10), we found the patients performed worse on the Trail Making Test, a visual continuous performance test, and the "Brown-Peterson" Auditory Consonant Trigrams Test, but not on any other neuropsychological measures. This pattern indicated a deficit in the area of executive control type functioning, a functional deficit that could be linked to dysregulation of frontal lobe brain systems. Of equal interest was that patients diagnosed with ADHD/hyperactive impulsive type (ADHD+) and patients diagnosed with ADHD/inattentive type (ADHD-) had different types of executive system deficits. ADHD+ was associated with relative deficiency on the Wisconsin Card Sorting Test. ADHD- was associated with relative deficiency on the "Brown-Peterson" Auditory Consonant Trigrams Test, a measure of working memory, as well as less olfactory identification on a smell identification test. The data are discussed in terms of recent localization theories of frontal lobe function. The preliminary data suggest that the different cognitive weaknesses of ADD subtypes may be linked to dysregulation of separate frontal brain regions and/or neurotransmitter systems.

A comparison of NES2 and traditional neuropsychological tests in a neurologic patient sample.

The Neurobehavioral Evaluation System (NES), a computer-assisted battery of behavioral tests, has been widely used to detect central nervous system dysfunction in occupational and environmental settings and has recently been adapted for testing of neurological patients. The purpose of the present study was to assess the relationship between NES tasks and the traditional neuropsychological tests from which many of the NES tests were developed. For this purpose, comparisons were made between scores on NES tests and traditional neuropsychological tests designed to measure functioning in the same cognitive domains in a sample of patients with idiopathic Parkinson's disease (PD). As has been found in prior studies with normal subjects, correlations between traditional and NES2 tests varied from low to moderate. Correlations tended to be low when the modality of stimulus presentation or responses was different in the NES tests from the traditional tasks (e.g., verbal rather than visual) or when divergent and highly specific cognitive functions were being measured by the tests.

Validation of the NES2 in patients with neurologic disorders.

Performance on the Neurobehavioral Evaluation System (NES) has been demonstrated to be affected by exposure to a variety of neurotoxicants. However, the relation of NES subtests to CNS function has not yet been documented in patients diagnosed with neurologic disorders known to implicate specific brain substrates. A validation study of the NES2 was carried out in patients with multiple sclerosis (MS) and Parkinson's disease (PD), disorders exhibiting neuropathology at loci (white matter in MS, basal ganglia in PD) believed to be the sites of action of several known neurotoxicants. The results indicated that performance on certain NES2 subtests was affected in expected ways in both types of patients. However, performance on many more subtests was impaired, relative to controls, in MS than in PD. The relative insensitivity to PD suggests that expansion and refinement of the battery are required if it is to serve well in detecting the effects of toxicants in subjects without frank physical symptoms. These are the goals of a new version of the instrument currently under development (NES3).

Evoked potential augmenting and reducing: the methodological and theoretical significance of new electrophysiological observations.

Buchsbaum's (1976) evoked potential (EP) procedure reveals differences in the slope of P100-N140 amplitude changes with variation of stimulus luminance. Subjects are classed 'augmenters' or 'reducers', respectively, if their slopes are positive or negative. Psychological correlates of this slope index have been reported and it has distinguished psychiatric patient populations from healthy subjects. Data are presented which indicate that the augmenting-reducing slope differences are due to an early slow-wave. For augmenters, the major slow-wave deflection is of positive polarity. At the highest luminance, with a correspondingly shorter latency, the slow-wave increases the positive-going P100 deflection. At the lowest luminance, with a longer latency, it reduces the negative-going N140 deflection. This results in positive slopes. For reducers, the major slow-wave deflection is of negative polarity. This influences the measured P100 and N140 amplitudes in a manner opposite to that described for augmenters and results in negative slopes. Since these findings provide new insights concerning the nature of the Buchsbaum augmenting-reducing phenomenon, they have methodological and theoretical implications. It is concluded that the Buchsbaum procedure is an effective measure of slow-wave differences but that the reducing effect is difficult to explain in terms of Pavlov's concept of protective inhibition. An alternative 'opponent-process' explanation is offered.