Deletion of the alternatively spliced fibronectin EIIIA domain in mice reduces atherosclerosis

The alternatively spliced and highly conserved EIIIA domain of fibronectin (FN) is included in most FN of the extracellular matrix in embryos. In adults, both extracellular matrix and plasma FN essentially lack EIIIA. In diverse inflammatory situations however, EIIIA is specifically included by regulated RNA splicing. In atherosclerotic lesions, FN, including the EIIIA domain (EIIIA-FN), is abundant, whereas FN in the flanking vessel wall lacks EIIIA. Lesional EIIIA-FN is localized with endothelial cells and macrophage foam cells. To directly test the function of EIIIA-FN, we generated EIIIA-null (EIIIA(-/-)) mice that lack the EIIIA exon and crossed them with apolipoprotein E (ApoE)-null (ApoE(-/-)) mice that develop arterial wall lesions. Compared with ApoE(-/-) controls, EIIIA(-/-)ApoE(-/-) mice had significantly smaller lesions throughout the aortic tree. EIIIA-FN was increased in ApoE(-/-) plasma, and total plasma cholesterol was reduced in EIIIA(-/-)ApoE(-/-) mice, specifically in large lipoprotein particles, suggesting a functional role for plasma EIIIA-FN. To assess a role for macrophage EIIIA-FN in the vessel wall, we conducted in vitro foam cell assays. EIIIA(-/-)ApoE(-/-) macrophages accumulated significantly less intracellular lipid than control ApoE(-/-) cells. These results provide genetic evidence that suggests roles for EIIIA-FN in plasma lipoprotein metabolism and in foam cell formation.     

Calcium scoring of the coronary artery by electron beam CT: how to apply an individual attenuation threshold.

OBJECTIVE: Our aim was to assess the inter- and intraindividual variability of the attenuation threshold used to identify coronary artery calcification on electron beam CT and to illustrate a new threshold method. MATERIALS AND METHODS: We measured the soft-tissue attenuation of regions surrounding the coronary arteries at the level of the left main coronary artery ostium (high level) and at the bottom of the heart (low level) in 48 consecutive patients (22 men, 26 women). Mean +/- 2 standard deviations (SD) of soft-tissue attenuation and variance of soft-tissue density and SDs were calculated at each level for every patient. It was assumed that setting an attenuation threshold greater than or equal to 3 SDs above that of soft tissue at each myocardial level would eliminate 99.5% of all scatter artifacts, allowing precise identification of calcific deposits. RESULTS: For the entire patient cohort, the average soft-tissue attenuation was 41 H and 35 H at the high and low levels, respectively (p < 0.01), indicating a large intraindividual variability. The SDs of soft-tissue attenuation measured by the computer software at the high and low levels were not different (26 H at the high level and 28 H at the low level; p = not significant). However, the calculated SD of the individual mean soft-tissue attenuation was 5 H at the high level and 8 H at the low level, again indicating a large intraindividual variability (p < 0.01). The addition of 3 measured SDs above the mean individual soft-tissue attenuation predicted a mean threshold of 120 and 121 H at the high and low levels, respectively, but with a wide interindividual variability (83-193 H at the high level and 79-242 H at the low level). There was a strong correlation between body weight and SD of soft-tissue attenuation at the low level (r = 0.75, p < 0.001) and a weaker but statistically significant correlation between weight and SD of soft-tissue attenuation at the high level (r = 0.51, p < 0.001). CONCLUSION: For the patients in this study, a threshold of 120 H for the detection of coronary calcification by electron beam CT seemed more appropriate than a threshold of 130 H, which is currently in use. However, given the great inter- and intraindividual variability, a biologic threshold tailored to the individual patient and to each individual imaging level should be used instead of a fixed threshold.     

Bone Density and Microarchitecture: Relationship Between Hand, Peripheral, and Axial Skeletal Sites Assessed by HR-pQCT and DXA in Rheumatoid Arthritis

We assessed the relationship of bone density and microarchitecture between hand, peripheral, and axial skeletal sites using high-resolution peripheral quantitative computed tomography (HR-pQCT) and dual-energy X-ray absorptiometry (DXA) in patients with rheumatoid arthritis (RA) and which factors influence these parameters. This was a cross-sectional study of 100 female patients (53.4?±?9.3?years) with RA. HR-pQCT scans at distal radius and the second metacarpal head were performed to assess cortical and trabecular volumetric bone mineral density (vBMD) and microarchitecture. DXA scans at the hip, lumbar spine, and ultradistal radius were performed to assess areal BMD. There was significant correlation in vBMD and microarchitectural parameters between the second metacarpal head and distal radius (r?=?0.201?0.628). Areal BMD at the axial skeleton was moderately associated with vBMD at the peripheral sites (r?=?0.354–0.558). Factors related to disease severity/chronicity significantly correlated with vBMD and microarchitecture at the distal radius and the second metacarpal head. Factors related to disease activity were more likely to correlate with vBMD and microarchitecture at the second metacarpal head but not those at the distal radius. HR-pQCT is a promising technique that is capable of providing detailed quantitative assessment of disease-associated periarticular bone loss at both cortical and trabecular bone compartments in patients with RA. Future longitudinal studies will be needed to investigate whether assessment by HR-pQCT can be used as a marker of disease activity and a predictor of disease progression in RA.     

Intraoperative hypercyanosis in a patient with pulmonary artery band: case report and review of the literature

A case of intraoperative cyanosis in a patient with a common atrioventricular canal palliated with a pulmonary artery (PA) band is presented. The patient's physiology was consistent with cyanosis due to inadequate pulmonary blood flow, and responded quickly to typical interventions used for a hypercyanotic episode in a patient with unrepaired Tetralogy of Fallot. Differences and similarities in the physiology of PA banding compared with Tetralogy of Fallot are presented, including a rationale for treatment options for hemodynamic decompensation occurring in the setting of anesthesia and surgery.     

Lactate and base deficit in trauma: does alcohol or drug use impair their predictive accuracy?

BACKGROUND: Abnormal blood lactate and base deficit (BD) reflect hypoperfusion and have been documented to predict outcome in trauma. Alcohol and drug use may also induce metabolic acidosis in trauma victims, potentially diminishing the predictive accuracy of lactate and BD. We, therefore, sought to examine the effect of alcohol and drug use on the predictive accuracy of admission blood lactate and BD in trauma. METHODS: Prospective data were collected on 15,179 patients admitted to the R Adams Cowley Shock Trauma Center over a 3-year period from 1998 to 2000. Patients were stratified by age, gender, race, injury severity score (ISS), Glasgow coma score (GCS), alcohol concentration and illicit drug use. Multiple regression analyses were used to assess admission blood lactate and BD as independent risk factors for mortality, intensive care unit (ICU) admission, and ICU and hospital length of stay (LOS) controlling for alcohol and drug use [cocaine, phencyclidine and methamphetamines] by measured serum concentrations. RESULTS: The mean age of the study cohort was 37 +/- 19 years, mean ISS was 9 +/- 10, mean GCS 14.1 +/- 2.7, 71% were male and 77% sustained blunt trauma. Alcohol testing was completed in 13,102 of 15,179 (86.3%) of patients. Alcohol screen was positive in 27% (n = 3536) of the total cohort tested (n = 13,102) with a mean blood alcohol concentration of 141 +/- 95 mg/dL; 7% (n = 992) had positive drug screens. Increasing injury severity was associated with significantly increased admission blood lactate and BD (p < 0.001). Patients with positive alcohol and drug screens had significantly increased admission blood lactate, BD and injury severity compared with patients with negative alcohol and drug screens (p < 0.01). Patients with positive alcohol and drug screens had a significant increase in admission to the ICU (p < 0.05), but no significant increase in mortality, ICU or hospital LOS compared with patients with negative screens. Multiple logistic and linear regression analyses confirmed admission lactate and BD as significant independent predictors of mortality, ICU and hospital LOS (p < 0.01). These results were unchanged after controlling for alcohol and drug use as covariates in the logistic and linear regression analyses. CONCLUSION: Alcohol and drug use are common in trauma, but do not impair the predictive accuracy of admission lactate and BD in trauma outcome. Admission lactate and BD are therefore confirmed as significant independent predictors of trauma outcome in patients with acute alcohol and drug use in this largest clinical study to date.     

Racial differences in rate of decline in bone mass in older men: the Baltimore men's osteoporosis study.

Older black men have higher adjusted BMD than older white men. Using data from a longitudinal cohort study of older men followed for a mean of 18.8 +/- 6.5 (SD) months, we found that older black men have a higher rate of decline in femoral neck and total hip BMD and femoral neck BMAD than older white men. INTRODUCTION: Older black men have higher adjusted BMD compared with older white men. The difference in BMD may be caused by having attained higher peak bone mass as young adults and/or having a slower rate of decline in bone mass as adults. There are few published longitudinal data on change in bone mass in older white men and no published data for older black men. MATERIALS AND METHODS: Three hundred forty-nine white men and 119 black men 65 of age (mean age, 75 +/- 5.7 and 72 +/- 5.6 years, respectively) who participated in the longitudinal component of the Baltimore Men's Osteoporosis Study returned for a second visit after a mean of 18.8 +/- 6.5 (SD) months and were not taking medications used to treat low bone mass at either visit. BMD was measured at the femoral neck and total hip by Hologic-certified technicians using a QDR 2000 at the baseline visit (V1) and QDR 4500 at the first follow-up visit (V2). Participants also completed self-administered and interviewer-administered questionnaires and underwent standardized clinic examinations. Bone mineral apparent density (BMAD) at the femoral neck was calculated as an estimate of volumetric BMD. Annual crude and multiple variable adjusted percent changes in BMD and BMAD were calculated. RESULTS: In univariate analyses, black men had lower percent decline in femoral neck and total hip BMD and femoral neck BMAD than white men. In addition, older age at baseline, lower baseline weight, current smoking, and lower baseline BMD were associated with greater percent decline per year in femoral neck BMD; older age at baseline, current smoking, and lower baseline BMD were associated with greater percent decline per year in total hip BMD; and older age at baseline and lower baseline femoral neck BMAD were associated with greater percent decline per year in femoral neck BMAD. Racial differences in bone loss persisted in multiple variable models that controlled for other factors associated with change in BMD and BMAD. CONCLUSIONS: Older black men seem to lose bone mass at a slower rate than older white men. These differences in the rate of bone loss may account, in part, for the racial disparities in BMD and BMAD and risk of osteoporotic fractures among older men.     

Newly born granule cells in the dentate gyrus rapidly extend axons into the hippocampal CA3 region following experimental brain injury

We investigated whether new neurons generated in the adult rat brain following lateral fluid percussion traumatic brain injury (TBI) are capable of projecting axons along the mossy fiber pathway to the CA3 region of the hippocampus. Dividing cells were labeled by intraperitoneal injection of bromodeoxyuridine (BrdU) on the day of surgery/injury, and neurons that extended axons to the CA3 region were retrogradely labeled by fluorescent tracers (FluoSpheres), stereotactically injected into the CA3 region of both the ipsi- and contralateral hippocampus at 1 or 12 days following TBI (n = 12) or sham injury (n = 12) in anaesthetized rats. Animals (n = 6 injured and n = 6 sham-injured controls per time point) were sacrificed at either 3 or 14 days post-injury. Another group of animals (n = 3) was subjected to experimental TBI and BrdU administration and sacrificed 3 days after TBI to be processed for BrdU and immunohistochemistry for polysialylated neural cell adhesion molecule (PSA-NCAM), a growth-related protein normally observed during CNS development. A fivefold bilateral increase in the number of mitotically active (BrdU+) cells was noted within the dentate gyrus when compared to uninjured controls as early as 3 days following TBI. A subgroup of dividing cells was also immunoreactive for PSA-NCAM at 3 days following TBI. By 2 weeks post-injury the number of BrdU+ cells within the dentate gyrus was increased twofold compared to the uninjured counterparts and a proportion of these newly generated cells showed cytoplasmic staining for the fluorescent tracer. These findings document rapid neurogenesis following TBI and show, for the first time, that newly generated granule neurons are capable of extending projections along the hippocampal mossy fiber pathway in the acute post-traumatic period.     

Bone marrow biopsy involvement by non-Hodgkin's lymphoma: frequency of lymphoma types, patterns, blood involvement, and discordance with other sites in 450 specimens

To evaluate the features of bone trephine biopsy involvement by non-Hodgkin lymphoma, 450 specimens were evaluated for percentage of marrow involvement, pattern of involvement, presence of germinal centers or follicular structures, and discordance with other involved sites. A subset of 197 cases was evaluated for evidence of concurrent peripheral blood involvement. Follicular grade 1 lymphoma (30.4%) was the most common type to involve the marrow, followed by diffuse large B-cell lymphoma (16.0%), mantle cell lymphoma (9.3%), low-grade B-cell lymphoma, not otherwise specified (8.7%), lymphoplasmacytic lymphoma (8.4%), follicular grade 2 lymphoma (7.1%), and mature T- and NK-cell lymphomas (6.4%). A mixed pattern of infiltration was most common, followed by paratrabecular, nodular, diffuse, and interstitial patterns. Greater than 90% of follicular lymphomas had at least a focal paratrabecular infiltration pattern, but this pattern was also seen with other lymphoma types. Interstitial disease infiltration tended to correlate with lymphoplasmacytic lymphoma but was also not specific. The presence of germinal centers or follicular structures was associated with follicular lymphoma in 88% of cases. Discordance between the bone marrow morphology and other tissue sites was observed in 24.9% of cases and was most often seen with follicular or diffuse large B-cell lymphoma. Peripheral blood involvement by lymphoma was observed in 29% of cases, found in all disease groups except for follicular grade 3 lymphoma. This study highlights the frequency of different lymphoma patterns in the marrow, limitations of primary lymphoma classification on biopsy material alone, and the relative frequency of marrow discordance and peripheral blood involvement by marrow lymphoma.     

Effectiveness of an intensive stress intervention workshop for senior managers

This study investigates the efficacy of an intensive, integrated approach to stress reduction and coping enhancement directed towards an educated, upper level management population. Ninety‐five US governmental senior managers participated in a 35‐h stress management retreat held over a 3.5‐day period. The retreat combined didactic and experiential activities that were designed to increase participants' knowledge of stress liabilities and coping skills. Participants were encouraged to make positive lifestyle changes and to create specific action plans for the year following the workshop. Evaluations of participant satisfaction were completed at the close of the workshop. Eighty‐three participants completed baseline and follow‐up Stress and Coping Inventory (SCI) assessments in order to identify durable changes in these measures. Across 10 months, participants showed significant improvements in their overall Global Balance scores, psychological symptoms, depression symptoms, and all major coping scales, including Health Habits, Social Support, Responses to Stress and Life Satisfactions. Therefore, an intensive, multifaceted approach to stress intervention is a viable option for encouraging sustained behavioural change. Copyright © 2003 John Wiley & Sons, Ltd.