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.

Clinical correlates of DHEA associated with post-traumatic stress disorder.

OBJECTIVE: Increased plasma dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulfate (DHEAS) have been demonstrated in post-traumatic stress disorder (PTSD), but the documented beneficial effects of these steroids in enhancing mood and cognition, as well as neuroprotection, suggest their presence in PTSD may be associated with defensive rather than maladaptive effects. METHOD: We, therefore, examined plasma DHEA, DHEAS, cortisol, and the DHEA/cortisol ratio in 40 male veterans with or without PTSD, and determined their relationships to PTSD symptom severity and symptom improvement. RESULTS: The PTSD group showed significantly higher plasma DHEA and non-significantly higher DHEAS levels as well as a significantly lower cortisol/DHEA ratio, controlling for age. Regression analyses demonstrated that DHEA and DHEAS levels could be predicted by symptom improvement and coping, whereas the cortisol/DHEA ratio was predicted by severity of childhood trauma and current symptom severity. CONCLUSION: That greater symptom improvement was related to DHEA levels may suggest for a role for these hormones in modulating recovery from PTSD.

Variability and severity of depression and anxiety in post traumatic stress disorder and major depressive disorder.

In order to better characterize the similarities in and differences between the nature of the affective disturbance associated with Posttraumatic Stress Disorder (PTSD) and with Major Depressive Disorder (MDD), self-reported mood and anxiety ratings were examined in PTSD subjects, MDD subjects, and subjects without a psychiatric disorder while they were undergoing a chronobiologic study. Based on serial ratings on visual analogue scales over a 24 hr period, PTSD subjects showed comparable levels of depression as the MDD group, as measured by the mean and maximum levels of mood; however, they had greater mood variability, as measured by the range and coefficients of variation of the mood ratings. The MDD but not the PTSD group had significantly lower mood variability than the non-psychiatric group, as measured by the coefficients of variation. The PTSD group reported higher levels of anxiety than the non-psychiatric or MDD group but showed no differences in any measure of variability of anxiety. These findings suggest there are phenomenologic differences in the affective symptoms experienced by patients with PTSD and with MDD and that mood variability may distinguish between them.

Neuroendocrine activity and memory-related impairments in posttraumatic stress disorder.

This article reviews memory-related impairments in trauma survivors with posttraumatic stress disorder and their possible association to neuroendocrine alterations seen in this disorder. The neuroendocrine profile in PTSD first described in chronically ill combat veterans is characterized by lower basal cortisol levels, higher glucocorticoid receptor number, enhanced sensitivity to exogenous steroids, and increased variation in basal cortisol levels over the diurnal cycle. The generalizability and time course of these neuroendocrine alterations are explored in longitudinal studies and studies in other traumatized populations. These studies suggest that at least some aspects of this neuroendocrine profile can also be seen in other populations, including women, children, and victims of childhood trauma. Additionally, the alterations may be present early in the course of illness, perhaps even in the immediate aftermath of trauma, and may continue to be manifest in elderly trauma survivors. The mechanisms by which these neuroendocrine alterations may influence the formation and processing of traumatic memories are discussed.

Sustained attention in combat-related posttraumatic stress disorder.

There is substantial evidence that PTSD patients have information processing abnormalities for stimuli that are highly relevant to the traumas they have endured. The goal of the present study was to examine whether this extends to neutral stimuli as well. Twenty-four male Vietnam combat veterans with PTSD were compared to fifteen normal male comparison subjects on their performance on a sensitive measure of sustained attention, the Continuous Performance Test-Identical Pairs version (CPT-IP). PTSD subjects did not differ from controls in their ability to discriminate target stimuli from background noise on the CPT. Additionally they performed as well as controls, even in the presence of external distraction. Thus, this study did not find a generalized deficit in attention associated with PTSD on the CPT-IP. Nevertheless, further clarification of the nature of the information processing disturbance in PTSD is warranted.

Low serum cholesterol level and attempted suicide.

OBJECTIVE: Several studies suggest that a low cholesterol concentration is associated with a greater than normal risk of mortality from suicide. The authors sought to determine whether a low cholesterol level is associated with a history of serious suicide attempts among psychiatric inpatients. METHOD: Lifetime history of attempted suicide of 650 patients, aged 18-59 years, consecutively admitted to a psychiatric hospital was assessed by semistructured interview. The seriousness of an attempt was rated on the basis of the resulting medical injury. Serum cholesterol levels, obtained from the admission biochemical profiles, were divided into quartiles. RESULTS: Compared to men with low cholesterol levels (defined as less than or equal to the 25th percentile), men with cholesterol levels above the 25th percentile were less likely to have ever made a serious suicide attempt when age, weight, race, socioeconomic status, alcohol use, and depression were controlled for. There was no association between cholesterol level and attempted suicide in women. CONCLUSIONS: Male psychiatric patients with low cholesterol levels were twice as likely to have ever made a medically serious suicide attempt than men with cholesterol levels above the 25th percentile. Low cholesterol concentration should be further investigated as a potential biological marker of suicide risk.

Cloning and sequence analysis of the VH and VL regions of an anti-myelin/DNA antibody from a patient with peripheral neuropathy and chronic lymphocytic leukemia.

We have cloned and determined the nucleotide sequence of the Ig VH and VL region genes of an IgM kappa mAb that binds to denatured DNA and myelin from a patient (POP) with chronic lymphocytic leukemia and peripheral neuropathy. Sequence analysis indicates that the V region of the kappa L chain gene (PopVK) has 99% homology to a V kappa IIIa germ-line gene and the V region of the mu H chain gene (PopVH) has 96% homology to the VH26 germ-line gene that is a member of the VH3 gene family. It is likely the V kappa and VH genes arose from these respective germ-line genes via somatic mutation or from closely related genes. V kappa III genes have frequently been used by other IgMk mAb especially those with rheumatoid factor activity, and the VH26 gene with no somatic mutation has been used by several anti-DNA antibodies, suggesting the possibility of preferential association of these or related germ-line genes with autoantibodies. The minor differences between the sequences of POP's VH and V kappa genes and sequences used by other autoantibodies, may be responsible for this antibody's crossreactivity with myelin and, as a result, the autoimmune neuropathy.

Molecular cloning of human myelin-associated glycoprotein.

The nucleotide sequence for human myelin-associated glycoprotein (MAG) and its deduced amino acid sequence, obtained by analysis of two overlapping cDNA clones isolated from a human brain cDNA library, is presented and compared to that reported for rat MAG. The sequence provides an open reading frame of 1,878 nucleotides encoding a peptide of 626 amino acids with a calculated molecular weight of 69.1 kD. It is 89% homologous in nucleotide sequence to the large isoform of rat MAG, with 95% homology in the amino acid sequence. It contains 9 potential glycosylation sites, one more than in rat, and shares other key features with rat MAG, including 5 immunoglobulin-like regions of internal homology, an RGD sequence, and potential phosphorylation sites. Its structure appears to be highly conserved in evolution, possibly suggesting a close interdependence between its structure and function. The human gene is located on the proximal long arm of chromosome 19 (19q12----q13.2).

Specificity of mouse and human monoclonal antibodies to myelin-associated glycoprotein.

Some patients with neuropathy have IgM M-proteins that bind to myelin and to myelin-associated glycoprotein (MAG). We compared the binding properties of a human anti-MAG M-protein with three mouse monoclonal anti-MAG antibodies (GEN-S1, GEN-S3, GEN-S8) and with a mouse monoclonal antibody (HNK-1) that binds to both MAG and to human natural killer cells. The antibodies GEN-S1, GEN-S3, and GEN-S8 bound to different epitopes in the polypeptide portion of MAG as shown by peptide mapping, deglycosylation and competitive binding studies. The M-protein and HNK-1 bound to both CNS and PNS MAG and to several additional protein bands of 70K, 30K, 26K, and 23K daltons in peripheral, but not in central myelin; they did not bind to deglycosylated MAG. The M-protein and HNK-1 immunostained myelin diffusely, whereas GEN-S8 immunostained only the periaxonal and outer regions of myelin sheath, and there was no staining with GEN-S1 or GEN-S3. The human M-proteins probably bind to a carbohydrate moiety in MAG that is also present in other PNS myelin proteins. This may explain the observed differences in immunostaining and the sparing of the CNS in patients with anti-MAG M-proteins.