Medical and Psychiatric Risk Factors for Dementia in Veterans with and without Traumatic Brain Injury (TBI): A Nationwide Cohort Study.

BACKGROUND: Traumatic brain injury (TBI) is a risk factor for dementia and is common, especially among Veterans. It is unknown whether TBI exposure moderates the effect of other common medical/psychiatric comorbidities that are also risk factors for dementia. If treatable or preventable risk factors have a different impact on TBI-exposed Veterans, then this may have important public health implications for dementia prevention. OBJECTIVES: Determine prevalence of common medical/psychiatric comorbidities and associated risk of dementia in Veterans with versus without TBI. DESIGN: Observational cohort. SETTING: Nationwide Veterans Health Administrative data 2001-2019. PARTICIPANTS: After excluding baseline dementia, Veterans age ≥55 years with TBI (N=95,139) were age/sex/race-matched 1:2 with Veterans without TBI (N=190,278). MEASUREMENTS: We compared prevalence of hypertension, coronary artery disease (CAD), diabetes, cerebrovascular disease (CVD), epilepsy, depression, and post-traumatic stress disorder (PTSD) among Veterans with and without TBI. We calculated risk of incident dementia associated with each comorbidity using multivariable hazard ratios (HR) with Fine-Grey competing risk of death adjusted for baseline demographics. We estimated population attributable fraction (PAF) of dementia due to each comorbidity among Veterans with versus without TBI. RESULTS: Prevalence of all comorbidities were significantly more prevalent (5.7% to 21.5% higher) among Veterans compared to those without TBI. All comorbidities were associated with increased risk of dementia in both groups. There were significant interactions between comorbidities and TBI in which HRs were slightly lower among Veterans with TBI (adjusted HRs 1.08-1.37) compared to those without TBI (adjusted HRs 1.12-2.13). Nevertheless, PAFs for dementia due to depression, hypertension, CAD, CVD, and epilepsy were slightly higher in Veterans with TBI due to their high prevalence in this group. CONCLUSIONS: Targeting depression, hypertension, CAD, CVD, and epilepsy may be especially important for dementia risk reduction among Veterans with TBI.

Experience of angiosarcoma in the North of England Bone and Soft Tissue Tumour Service.

INTRODUCTION: Angiosarcomas are rare aggressive sarcomas of vascular endothelial origin. These tumours have the potential to be multicentric and are associated with high rates of local recurrence, which makes treatment challenging. The gold-standard is that these patients are managed in specialist centres by a multidisciplinary team. We present our experience of managing patients with angiosarcoma in the North of England Bone and Soft Tissue Tumour Service and a review of the literature. METHODS: A prospectively collated electronic database was used to identify patients with angiosarcoma treated between 2000 and 2008, and an analysis performed of demographics, anatomical site, surgical excision and reconstruction, local disease recurrence and metastatic disease. RESULTS: Fifteen patients (ten female, five male, mean age 71 years) were identified. Eight patients developed tumours in a previously irradiated area, after a mean of 11 years. Six patients had metastatic disease at presentation. Fourteen patients underwent wide surgical excision of the tumour, of which nine required defect reconstruction (five free latissimus dorsi flaps, two free anterolateral thigh flaps, two pedicled latissimus dorsi flaps). One patient was treated with chemotherapy only. Five of 14 patients received adjuvant radiotherapy, and one received adjuvant chemotherapy. Two out of 14 patients developed local recurrence. Eight patients developed metastases, the majority of which were pulmonary. Estimated five-year survival was calculated as 33% in our patient cohort. CONCLUSIONS: Angiosarcomas are aggressive, difficult to treat tumours, which can occur secondary to a multitude of causes. Clinical suspicion, biopsy and early diagnosis are essential to allow optimum treatment, which currently consists of radical surgery, together with adjuvant radiotherapy and chemotherapy.

Predicting risk of dementia in older adults: The late-life dementia risk index.

OBJECTIVE: To develop a late-life dementia risk index that can accurately stratify older adults into those with a low, moderate, or high risk of developing dementia within 6 years. METHODS: Subjects were 3,375 participants in the Cardiovascular Health Cognition Study without evidence of dementia at baseline. We used logistic regression to identify those factors most predictive of developing incident dementia within 6 years and developed a point system based on the logistic regression coefficients. RESULTS: Subjects had a mean age of 76 years at baseline; 59% were women and 15% were African American. Fourteen percent (n = 480) developed dementia within 6 years. The final late-life dementia risk index included older age (1-2 points), poor cognitive test performance (2-4 points), body mass index <18.5 (2 points), > or =1 apolipoprotein E epsilon4 alleles (1 point), cerebral MRI findings of white matter disease (1 point) or ventricular enlargement (1 point), internal carotid artery thickening on ultrasound (1 point), history of bypass surgery (1 point), slow physical performance (1 point), and lack of alcohol consumption (1 point) (c statistic, 0.81; 95% confidence interval, 0.79-0.83). Four percent of subjects with low scores developed dementia over 6 years compared with 23% of subjects with moderate scores and 56% of subjects with high scores. CONCLUSIONS: The late-life dementia risk index accurately stratified older adults into those with low, moderate, and high risk of developing dementia. This tool could be used in clinical or research settings to target prevention and intervention strategies toward high-risk individuals.

Preclinical cognitive decline and subsequent sleep disturbance in older women.

OBJECTIVE: To determine whether longitudinal cognitive decline is associated with increased risk of sleep disturbance in older, nondemented, community-dwelling women. METHODS: We studied 2,474 women (mean age 68.9 years) who were part of a prospective study started in 1986; women with baseline or follow-up evidence of possible dementia were excluded. Cognitive data were gathered over 15 years for modified Mini-Mental State Examination (mMMSE) and 13 years for Trails B; cognitive decline was defined as declining >1.5 SDs on the mMMSE (> or =3 points) or Trails B (>92 seconds). Sleep disturbance was measured objectively using actigraphy (Sleepwatch-O, Ambulatory Monitoring) at the 15-year follow-up visit; measures included total sleep hours, sleep efficiency, sleep latency, napping, and time awake after sleep onset (WASO). RESULTS: During follow-up, 11% of women declined on mMMSE and 15% on Trails B. Cognitive decliners were more likely than non-decliners to experience sleep disturbance at follow-up on most measures. For women who declined on mMMSE, adjusted ORs (aOR) (95% CI) were 1.71 (1.24, 2.37) for sleep efficiency <70%, 1.57 (1.12, 2.21) for sleep latency > or =1 hour, and 1.43 (1.07, 1.92) for WASO > or =90 minutes. Results were similar for women who declined on Trails B; in addition, these women were more likely to nap >2 hours per day (aOR: 1.73; 95% CI: 1.28, 2.33). Cognitive decline on either test was not associated with total sleep time. CONCLUSIONS: Cognitive decline is associated with sleep disturbance in nondemented community-dwelling elderly women.

Age-related and tissue-specific accumulation of oxidative DNA base damage in 7,8-dihydro-8-oxoguanine-DNA glycosylase (Ogg1) deficient mice.

Mutations that influence the repair of oxidative DNA modifications are expected to increase the steady-state (background) levels of these modifications and thus create a mutator phenotype that predisposes to malignant transformation. We have analysed the steady-state levels and repair kinetics of oxidative DNA modifications in cells of homozygous ogg1(-/-) null mice, which are deficient in Ogg1 protein, a DNA repair glycosylase that removes the miscoding base 8-hydroxyguanine (8-oxoG) from the genome. Oxidative purine modifications including 8-oxoG were quantified by means of an alkaline elution assay in combination with Fpg protein, the bacterial functional analogue of Ogg1 protein. In primary hepatocytes of adult ogg1(-/-) mice aged 9-12 months, the steady-state level of the lesions was 2.8-fold higher than in wild-type control mice. In contrast, no difference between ogg1(-/-) and wild-type mice was observed in splenocytes, spermatocytes and kidney cells. In hepatocytes of ogg1(-/-) mice, but not in wild-type controls, the steady-state levels increased continuously over the whole lifespan. No significant accumulation of the oxidative base modifications was observed in ogg1(-/-) fibroblasts in culture when they were kept confluent for 8 days. Both in confluent and proliferating ogg1(-/-) fibroblasts, the global repair of additional oxidative base modifications induced by photosensitization was 4-fold slower than in wild-type cells. The results suggest that the consequences of an Ogg1 defect are restricted to slowly proliferating tissues with high oxygen metabolism such as liver, because of a back-up mechanism for the repair of 8-oxoG residues that is independent of transcription and replication.

Excision of deaminated cytosine from the vertebrate genome: role of the SMUG1 uracil-DNA glycosylase.

Gene-targeted mice deficient in the evolutionarily conserved uracil-DNA glycosylase encoded by the UNG gene surprisingly lack the mutator phenotype characteristic of bacterial and yeast ung(-) mutants. A complementary uracil-DNA glycosylase activity detected in ung(-/-) murine cells and tissues may be responsible for the repair of deaminated cytosine residues in vivo. Here, specific neutralizing antibodies were used to identify the SMUG1 enzyme as the major uracil-DNA glycosylase in UNG-deficient mice. SMUG1 is present at similar levels in cell nuclei of non-proliferating and proliferating tissues, indicating a replication- independent role in DNA repair. The SMUG1 enzyme is found in vertebrates and insects, whereas it is absent in nematodes, plants and fungi. We propose a model in which SMUG1 has evolved in higher eukaryotes as an anti-mutator distinct from the UNG enzyme, the latter being largely localized to replication foci in mammalian cells to counteract de novo dUMP incorporation into DNA.

BRCT domain interactions in the heterodimeric DNA repair protein XRCC1-DNA ligase III.

Proteins involved in DNA repair, or its coordination with DNA replication and mitosis through cell cycle checkpoints, are vital in the concerted cellular response to DNA damage that maintains the integrity of the genome. The "BRCT" domain (BRCA1 carboxy terminal) was noted as a putative protein-protein interaction motif in the breast cancer suppressor gene, BRCA1, and subsequently identified in over 50 proteins involved in DNA repair, recombination, or cell cycle control. The heterodimer of the DNA repair proteins, XRCC1 and DNA ligase III, was the first example of a functional interaction via BRCT modules. The only three-dimensional crystal structure of a BRCT domain was solved for this region of XRCC1. Key amino acid residues mediating the interaction with DNA ligase III were identified here by targeted mutagenesis of the XRCC1 BRCT domain. The consequences of these mutations on protein folding were assessed. A structural model of the DNA ligase III BRCT domain was constructed and similarly tested by mutation of corresponding residues required for the interaction with XRCC1. These data identify the XRCC1-DNA ligase III heterodimer interface and provide the first demonstration of the surface contacts coordinating a functional BRCT-BRCT protein interaction.

Defective neurogenesis resulting from DNA ligase IV deficiency requires Atm.

Ataxia telangiectasia results from mutations of ATM and is characterized by severe neurodegeneration and defective responses to DNA damage. Inactivation of certain DNA repair genes such as DNA ligase IV results in massive neuronal apoptosis and embryonic lethality in the mouse, indicating the occurrence of endogenously formed DNA double-strand breaks during nervous system development. Here we report that Atm is required for apoptosis in all areas of the DNA ligase IV-deficient developing nervous system. However, Atm deficiency failed to rescue deficits in immune differentiation in DNA ligase IV-null mice. These data indicate that ATM responds to endogenous DNA lesions and functions during development to eliminate neural cells that have incurred genomic damage. Therefore, ATM could be important for preventing accumulation of DNA-damaged cells in the nervous system that might eventually lead to the neurodegeneration observed in ataxia telangiectasia.

Transcription coupled repair of 8-oxoguanine in murine cells: the ogg1 protein is required for repair in nontranscribed sequences but not in transcribed sequences.

To assess the role of the Ogg1 DNA glycosylase in the transcription-coupled repair (TCR) of the mutagenic lesion, 7, 8-dihydro-8oxoguanine (8-OxoG), we have investigated the removal of this lesion in wild-type and ogg1(-/-) null mouse embryo fibroblast (MEF) cell lines. We used nonreplicating plasmids containing a single 8-OxoG.C base pair in a different assay that allowed us to study the removal of 8-OxoG located in a transcribed sequence (TS) or in a nontranscribed sequence (NTS). The results show that the removal of 8-OxoG in a wild-type MEF cell line is faster in the TS than in the NTS, indicating TCR of 8-OxoG in murine cells. In the homozygous ogg1(-/-) MEF cell line, 8-OxoG was not removed from the NTS whereas there was still efficient 8-OxoG repair in the TS. Expression of the mouse Ogg1 protein in the homozygous ogg1(-/-) cell line restored the ability to remove 8-OxoG in the NTS. Therefore, we have demonstrated that Ogg1 is essential for the repair of 8-OxoG in the NTS but is not required in the TS. These results indicate the existence of an Ogg1-independent pathway for the TCR of 8-OxoG in vivo.

Uracil-DNA glycosylase (UNG)-deficient mice reveal a primary role of the enzyme during DNA replication.

Gene-targeted knockout mice have been generated lacking the major uracil-DNA glycosylase, UNG. In contrast to ung- mutants of bacteria and yeast, such mice do not exhibit a greatly increased spontaneous mutation frequency. However, there is only slow removal of uracil from misincorporated dUMP in isolated ung-/- nuclei and an elevated steady-state level of uracil in DNA in dividing ung-/- cells. A backup uracil-excising activity in tissue extracts from ung null mice, with properties indistinguishable from the mammalian SMUG1 DNA glycosylase, may account for the repair of premutagenic U:G mispairs resulting from cytosine deamination in vivo. The nuclear UNG protein has apparently evolved a specialized role in mammalian cells counteracting U:A base pairs formed by use of dUTP during DNA synthesis.

Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage.

DNA damage generated by oxidant byproducts of cellular metabolism has been proposed as a key factor in cancer and aging. Oxygen free radicals cause predominantly base damage in DNA, and the most frequent mutagenic base lesion is 7,8-dihydro-8-oxoguanine (8-oxoG). This altered base can pair with A as well as C residues, leading to a greatly increased frequency of spontaneous G.C-->T.A transversion mutations in repair-deficient bacterial and yeast cells. Eukaryotic cells use a specific DNA glycosylase, the product of the OGG1 gene, to excise 8-oxoG from DNA. To assess the role of the mammalian enzyme in repair of DNA damage and prevention of carcinogenesis, we have generated homozygous ogg1(-/-) null mice. These animals are viable but accumulate abnormal levels of 8-oxoG in their genomes. Despite this increase in potentially miscoding DNA lesions, OGG1-deficient mice exhibit only a moderately, but significantly, elevated spontaneous mutation rate in nonproliferative tissues, do not develop malignancies, and show no marked pathological changes. Extracts of ogg1 null mouse tissues cannot excise the damaged base, but there is significant slow removal in vivo from proliferating cells. These findings suggest that in the absence of the DNA glycosylase, and in apparent contrast to bacterial and yeast cells, an alternative repair pathway functions to minimize the effects of an increased load of 8-oxoG in the genome and maintain a low endogenous mutation frequency.

Why review articles on the health effects of passive smoking reach different conclusions.

OBJECTIVE: To determine whether the conclusions of review articles on the health effects of passive smoking are associated with article quality, the affiliations of their authors, or other article characteristics. DATA SOURCES: Review articles published from 1980 to 1995 were identified through electronic searches of MEDLINE and EMBASE and from a database of symposium proceedings on passive smoking. ARTICLE SELECTION: An article was included if its stated or implied purpose was to review the scientific evidence that passive smoking is associated with 1 or more health outcomes. Articles were excluded if they did not focus specifically on the health effects of passive smoking or if they were not written in English. DATA EXTRACTION: Review article quality was evaluated by 2 independent assessors who were trained, followed a written protocol, had no disclosed conflicts of interest, and were blinded to all study hypotheses and identifying characteristics of articles. Article conclusions were categorized by the 2 assessors and by one of the authors. Author affiliation was classified as either tobacco industry affiliated or not, based on whether the authors were known to have received funding from or participated in activities sponsored by the tobacco industry. Other article characteristics were classified by one of the authors using predefined criteria. DATA SYNTHESIS: A total of 106 reviews were identified. Overall, 37% (39/106) of reviews concluded that passive smoking is not harmful to health; 74% (29/39) of these were written by authors with tobacco industry affiliations. In multiple logistic regression analyses controlling for article quality, peer review status, article topic, and year of publication, the only factor associated with concluding that passive smoking is not harmful was whether an author was affiliated with the tobacco industry (odds ratio, 88.4; 95% confidence interval, 16.4-476.5; P<.001). CONCLUSIONS: The conclusions of review articles are strongly associated with the affiliations of their authors. Authors of review articles should disclose potential financial conflicts of interest, and readers of review articles should consider authors' affiliations when deciding how to judge an article's conclusions.

Targeted disruption of the gene encoding DNA ligase IV leads to lethality in embryonic mice.

DNA ligase IV is the most recently identified member of a family of enzymes joining DNA strand breaks in mammalian cell nuclei [1] [2]. The enzyme occurs in a complex with the XRCC4 gene product [3], an interaction mediated via its unique carboxyl terminus [4] [5]. Cells lacking XRCC4 are hypersensitive to ionising radiation and defective in V(D)J recombination [3] [6], implicating DNA ligase IV in the pathway of nonhomologous end-joining (NHEJ) of DNA double-strand breaks mediated by XRCC4, the Ku70/80 heterodimer and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) in mammalian cells (reviewed in [7]). The phenotype of a null mutant of the Saccharomyces cerevisiae DNA ligase IV homologue indicates that the enzyme is non-essential and functions in yeast NHEJ [8] [9] [10]. Unlike other mammalian DNA ligases for which cDNAs have been characterised, DNA ligase IV is encoded by an intronless gene (LIG4). Here, we show that targeted disruption of LIG4 in the mouse leads to lethality associated with extensive apoptotic cell death in the embryonic central nervous system. Thus, unlike Ku70/80 and DNA-PKcs [11] [12] [13] [14], DNA ligase IV has an essential function in early mammalian development.

Scientific quality of original research articles on environmental tobacco smoke.

OBJECTIVE: To evaluate the scientific quality of original research articles on the health effects of environmental tobacco smoke; to determine whether poor article quality is associated with publication in non-peer-reviewed symposium proceedings or with other article characteristics. DESIGN: Cross sectional study of original research articles on the health effects of environmental tobacco smoke published in peer reviewed journals and non-peer-reviewed symposium proceedings from 1980 to 1994. Article quality was assessed by two independent reviewers who used a valid and reliable instrument, were unaware of study hypotheses, were blinded to identifying characteristics of articles, and had no disclosed conflicts of interest. PARTICIPANTS: All symposium articles (n = 68) and a random sample of peer reviewed journal articles (n = 68) that satisfied inclusion/exclusion criteria. MAIN OUTCOME MEASURE: Mean quality scores, which could range from 0 (lowest quality) to 1 (highest quality). RESULTS: Using multivariate regression analysis, symposium articles were of poorer scientific quality than peer reviewed journal articles when controlling simultaneously for the effects of study design, article conclusion, article topic, and source of funding acknowledged (P = 0.027). Article quality was not associated with either source of funding acknowledged or article conclusion in multivariate analyses. CONCLUSIONS: In published reports on environmental tobacco smoke, non-peer-reviewed symposium articles tend to be of poor quality. These articles should not be used in scientific, legal, or policy settings unless their quality has been independently assessed.

Specific function of DNA ligase I in simian virus 40 DNA replication by human cell-free extracts is mediated by the amino-terminal non-catalytic domain.

The joining of Okazaki fragments during lagging strand DNA replication in mammalian cells is believed to be due to DNA ligase I. This enzyme is composed of a 78-kDa carboxyl-terminal catalytic domain and a 24-kDa amino-terminal region that is not required for ligation activity in vitro. Extracts of the human cell line 46BR.1G1, in which DNA ligase I is mutationally altered, supported aberrant in vitro SV40 DNA replication; the joining of Okazaki fragments was defective, and unligated intermediates were unstable. Human DNA ligase I, but not DNA ligase III or bacteriophage T4 DNA ligase, complemented both defects in 46BR.1G1 extracts. The catalytic domain of DNA ligase I was 10-fold less effective in complementation experiments than the full-length protein, indicating that the amino-terminal region of the enzyme is required for efficient lagging strand DNA replication. Moreover, in vitro SV40 DNA replication in normal human cell extracts was inhibited by an excess of either full-length DNA ligase I or the amino-terminal region of the protein, but not by the catalytic domain. This inhibition may be mediated by the interaction of the amino-terminal region of DNA ligase I with other replication proteins.

XRCC1 protein interacts with one of two distinct forms of DNA ligase III.

Human DNA ligase III (103 kDa) has been shown to interact directly with the 70 kDa DNA repair protein, XRCC1. Here, the binding sites have been defined. Subcloned fragments of XRCC1 have been expressed and assayed for their ability to associate with DNA ligase III by far Western and affinity precipitation analyses. The C-terminal 96 amino acids of XRCC1 are necessary and sufficient for the specific interaction with DNA ligase III. A similar approach with the 103 kDa DNA ligase III has identified the C-terminal 148 amino acids of this enzyme as containing the binding site for XRCC1. An alternative 96 kDa form of DNA ligase III, abundant in testes, has been described [Chen, J., et al. (1995) Mol. Cell. Biol. 15, 5412-5422]. These two forms of DNA ligase III have identical N-terminal regions but differ toward their C termini and may be alternatively spliced products of the same gene. Antipeptide antibodies directed against the different C termini of the two forms of the enzyme indicate that both of them occur in vivo. The C-terminal region of the 96 kDa derivative of DNA ligase III is not able to interact with XRCC1. These findings indicate that only the larger form of DNA ligase III acts together with XRCC1, suggesting a role for this isoform of the enzyme in base excision repair.