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.

DNA repair.

Multiple DNA repair processes are required to maintain the integrity of the cellular genome. Recent advances, including elucidation of three-dimensional structures of DNA repair enzymes, and the cloning and characterization of DNA repair genes implicated in human inherited disease, have given new insights into the surprising complexity of cellular responses to DNA damage.

Neuronal loss in hippocampus induced by prolonged ethanol consumption in rats.

Quantitative neurohistological techniques were used to examine the hippocampal complex of laboratory rats maintained on ethanol-containing or control diets for 5 months followed by a 2-month alcohol-free period. Chronic ethanol consumption resulted in a significant loss of hippocampal pyramidal and dentate gyrus granule cells. This study provides direct evidence that long-term ethanol consumption, in the absence of malnutrition, produces neuronal loss in the central nervous system.

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.

Aberrant DNA repair and DNA replication due to an inherited enzymatic defect in human DNA ligase I.

Two missense mutations in different alleles of the DNA ligase I gene have been described in a patient (46BR) with immunodeficiencies and cellular hypersensitivity to DNA-damaging agents. One of the mutant alleles produces an inactive protein, while the other encodes an enzyme with some residual activity. A subline of identical phenotype that is homozygous (or hemizygous) for the mutant allele encoding this partially active enzyme has facilitated characterization of the enzymatic defect in 46BR. This subline retains only 3 to 5% of normal DNA ligase I activity. The intermediates in the ligation reaction, DNA ligase I-AMP and nicked DNA-AMP, accumulate in vitro and in vivo. The defect of the 46BR enzyme lies primarily in conversion of nicked DNA-AMP into the final ligated DNA product. Assays of DNA repair in 46BR cell extracts and of DNA replication in permeabilized cells have clarified functional roles of DNA ligase I. The initial rate of ligation of Okazaki fragments during DNA replication is apparently normal in 46BR cells, but 25 to 30% of the fragments remain in low-molecular-weight form for prolonged times. DNA base excision repair by 46BR cell extracts shows a delay in ligation and an anomalously long repair patch size that is reduced upon addition of purified normal DNA ligase I.

Phorbol ester provokes insulin-like effects on glucose transport, amino acid uptake, and pyruvate dehydrogenase activity in BC3H-1 cultured myocytes.

We evaluated the possibility that diacylglycerol may function as a second messenger in insulin action. To this end, we employed 12-O-tetradecanoyl phorbol 13-acetate (TPA) to mimic diacylglycerol in BC3H-1 myocytes. Like insulin, TPA provoked rapid increases in 2-deoxyglucose transport and pyruvate dehydrogenase activity in mature insulin-responsive BC3H-1 cultured myocytes. TPA also stimulated amino acid uptake, as evidenced by uptake of alpha-methylaminoisobutyric acid; the relatively slow time course of this effect paralleled that of insulin. In contrast, the effects of TPA were not apparent in undifferentiated BC3H-1 myoblasts, which were also unresponsive to insulin. The insulin-like effects in the myocytes appeared to be specific for TPA, the biologically active phorbol diester which activates protein kinase C, as other tested phorbol derivatives were without effect. Effects of maximally effective concentrations of TPA and insulin were nonadditive. Two synthetic diacylglycerols, 1,2-diolien and 1-oleoyl-2-acetyl-sn-glycerol, also provoked insulin-like effects on 2-deoxyglucose transport. Since insulin rapidly increases diacylglycerol levels in these cells, and TPA mimics diacylglycerol biochemically, it is possible that insulin may control cellular processes through changes in diacylglycerol.

Rapid glucose-dependent increases in phosphatidic acid and phosphoinositides in rat pancreatic islets.

Glucose effects on islet phospholipids were examined during direct incubation or after 3 days of 32P prelabeling in primary culture. In both cases, glucose increased the 32P content of phosphatidic acid (PA), phosphatidylinositol (PI), and polyphosphoinositides (PPI). Glucose-induced increases in PA, PI, and PPI in the culture-prelabeling experiments were evident within 1 min, dose related, and reflective of increases in phospholipid mass, which was confirmed in direct incubations by measurement of PI phosphorus. Thus, in addition to increasing PI-PPI hydrolysis, glucose increases de novo phospholipid synthesis in pancreatic islets. The latter may result from enhanced glycolysis and substrate availability for PA-PI-PPI synthesis, since glyceraldehyde and pyruvic acid also increased PI levels. Our findings raise the possibility that increases in PA, PI, and PPI synthesis could serve as a mechanism to enhance the generation of intracellular mediators, which are purported to regulate insulin secretion.

Sensitization versus tolerance to the dopamine turnover-elevating effects of haloperidol: the effect of regular/intermittent dosing.

Recent clinical research suggests that particular patterns of changes in presynaptic dopamine (DA) turnover accompany the therapeutic response to neuroleptics. We sought to determine whether daily versus weekly dosing of haloperidol for 3 weeks produced distinct effects on DA, dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) concentrations in multiple brain areas. Daily dosing favored the development of tolerance to the DA-turnover elevating effects of haloperidol in the striatum and nucleus accumbens. Weekly dosing favored the development of sensitization in the striatum, posterior olfactory tubercle, and ventral tegmental area. These results suggest that dosing schedules may determine, at least in part, the effects of chronic neuroleptic administration on presynaptic DA function.

Prenatal ethanol exposure permanently reduces the number of pyramidal neurons in rat hippocampus.

The effect of prenatal ethanol exposure in the rat on the development of dorsal hippocampal pyramidal and dentate gyrus granule cells was examined. Ethanol was administered in a nutritionally adequate liquid diet to pregnant rats during days 10--21 of gestation. Control groups were either pair-fed the same liquid diet, except for equicaloric substitution of sucrose for ethanol, or received free access to pelleted laboratory food. The brains of 60-day-old offspring exposed to ethanol during gestation were found to have 20% fewer dorsal hippocampal pyramidal cells than did those of controls. Prenatal ethanol exposure, however, did not affect the number of dentate gyrus granule cells. Prenatal exposure to ethanol permanently reduced the number of prenatally formed hippocampal neurons without altering physical growth, which suggested that the developing nervous system is particularly sensitive to the toxic effects of ethanol.

Estimation of haloperidol concentrations in rat striatum after chronic treatment.

3H-Spiroperidol association and dissociation rate constants were determined in rat striatal homogenates in the presence of known concentrations of unlabelled haloperidol. The rate of 3H-spiroperidol association was progressively decreased in the presence of increasing concentrations of haloperidol and no changes were seen in 3H-spiroperidol dissociation rate constants. Measuring changes in 3H-spiroperidol association rate constants permitted detection of 0.1 pmol/ml unlabelled haloperidol in assay homogenates. Then, male Sprague-Dawley rats received daily injections of haloperidol (1.5 mg/kg) for 1-21 days. Twenty-four hours after the last injection, 3H-spiroperidol kinetic rate constants and Kd values were measured and found to be unchanged in all treatment groups. These findings suggest that, under these conditions of drug withdrawal and tissue preparation, which are widely employed in studies of chronic neuroleptic administration, residual haloperidol does not interfere with the estimation of 3H-spiroperidol binding parameters.

Interrelationships between plasma homovanillic acid and indices of dopamine turnover in multiple brain areas during haloperidol and saline administration.

Haloperidol or saline was administered to rats daily for 1, 8, 15 or 22 days. During haloperidol, but not saline administration, changes in plasma homovanillic acid (HVA) concentrations were correlated with changes in nucleus accumbens HVA. Haloperidol administration also had a significant effect on the intercorrelation of dopamine (DA) concentrations and indices of DA turnover across multiple brain areas. In particular, intercorrelations of HVA concentrations among DA terminal brain areas (i.e. striatum, nucleus accumbens, and olfactory tubercle) occurred only during haloperidol treatment.

Particle repositioning maneuver for benign paroxysmal positional vertigo.

The recent demonstration of free-floating particles in the endolymph of the posterior semicircular canal in patients with benign paroxysmal positional vertigo (BPPV) has renewed interest in the physiology and treatment of this entity. The particle repositioning maneuver (PRM) relocates the free-floating particles from the posterior semicircular canal back into the utricle, relieving the patient of bothersome, often long-standing vertigo. This report represents a prospective study of 27 consecutive patients seen with a diagnosis of BPPV. Eighty-four percent of the patients treated with the particle repositioning maneuver who had no other associated pathology were cured or significantly improved with this new technique. Two patients who failed conservative management went on to surgical intervention with the posterior semicircular canal occlusion. The authors find the particle repositioning maneuver effective for many patients with benign positional vertigo and recommend it as the first-line treatment modality for BPPV.

Sensitization versus tolerance to haloperidol-induced catalepsy: multiple determinants.

The effects of dose, administration frequency, and behavioral testing conditions on the development of tolerance versus sensitization to haloperidol-induced catalepsy were tested in rats. Animals received daily or weekly injections of haloperidol (0.05-5.00 mg/kg SC) for up to 22 days. Catalepsy assessments were made either once or repeatedly using two tests: the horizontal bar and the inclined screen. Tolerance was found only in animals treated daily with haloperidol (1.5 mg/kg) and tested repeatedly on the horizontal bar. In contrast, sensitization was observed with various haloperidol doses, daily or weekly administration schedules (for most doses), either horizontal bar or inclined screen catalepsy tests, and repeated or single testing. Sensitization developed most strongly following weekly drug administration and repeated testing on the horizontal bar. No single experimental variable produced a definitive pattern of change in catalepsy over time. Dose, drug administration schedule, and behavioral test conditions all influenced the evolution of catalepsy during chronic haloperidol treatment.

Gender influences subsite of origin of laryngeal carcinoma.

The relationship of gender to laryngeal cancer is not well understood. We analyzed 688 laryngeal cancers diagnosed in Kansas from 1980 through 1989 for sex differences in subsite distribution (glottis, supraglottis, subglottis, and laryngeal cartilage) as well as survival, histologic grade, and age at diagnosis. The ratio of glottic to supraglottic tumors was 22.12:1 in men and 0.56:1 in women, a highly significant difference. Survival in glottic tumors was significantly better than in supraglottic tumors, but survival was not significantly better for women than it was for men. Glottic tumors were significantly more likely than were supraglottic tumors to be of low-grade malignancy for all subjects and for male subjects alone, but not for female subjects alone. Women were younger at time of diagnosis than were men, but not significantly so. Gender is an important factor in the genesis of laryngeal cancer.

Acoustic stimulation of the semicircular canals.

Stimulation of the semicircular canals provides an alternative method of vibratory stimulation of the auditory system. The frequency response characteristics of stimulation of the tympanic membrane, malleus, stapes, round window, and fenestrated semicircular canal are presented in this article.

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.