Assessment of carotid plaque vulnerability using structural and geometrical determinants

BACKGROUND: Because many acute cerebral ischemic events are caused by rupture of vulnerable carotid atheroma and subsequent thrombosis, the present study used both idealized and patient-specific carotid atheromatous plaque models to evaluate the effect of structural determinants on stress distributions within plaque. METHODS AND RESULTS: Using a finite element method, structural analysis was performed using models derived from in vivo high-resolution magnetic resonance imaging (MRI) of carotid atheroma in 40 non-consecutive patients (20 symptomatic, 20 asymptomatic). Plaque components were modeled as hyper-elastic materials. The effects of varying fibrous cap thickness, lipid core size and lumen curvature on plaque stress distributions were examined. Lumen curvature and fibrous cap thickness were found to be major determinants of plaque stress. The size of the lipid core did not alter plaque stress significantly when the fibrous cap was relatively thick. The correlation between plaque stress and lumen curvature was significant for both symptomatic (p=0.01; correlation coefficient: 0.689) and asymptomatic patients (p=0.01; correlation coefficient: 0.862). Lumen curvature in plaques of symptomatic patients was significantly larger than those of asymptomatic patients (1.50+/-1.0 mm(-1) vs 1.25+/-0.75 mm(-1); p=0.01). CONCLUSION: Specific plaque morphology (large lumen curvature and thin fibrous cap) is closely related to plaque vulnerability. Structural analysis using high-resolution MRI of carotid atheroma may help in detecting vulnerable atheromatous plaque and aid the risk stratification of patients with carotid disease.     

Inequality in science and the case for a new agenda

The history of the scientific enterprise demonstrates that it has supported gender, identity, and racial inequity. Further, its institutions have allowed discrimination, harassment, and personal harm of racialized persons and women. This has resulted in a suboptimal and demographically narrow research and innovation system, a concomitant limited lens on research agendas, and less effective knowledge translation between science and society. We argue that, to reverse this situation, the scientific community must reexamine its values and then collectively embark upon a moonshot-level new agenda for equity. This new agenda should be based upon the foundational value that scientific research and technological innovation should be prefaced upon progress toward a better world for all of society and that the process of how we conduct research is just as important as the results of research. Such an agenda will attract individuals who have been historically excluded from participation in science, but we will need to engage in substantial work to overcome the longstanding obstacles to their full participation. We highlight the need to implement this new agenda via a coordinated systems approach, recognizing the mutually reinforcing feedback dynamics among all science system components and aligning our equity efforts across them.     

Optimization of infusional calcium gluconate for prevention of hypocalcemic reactions during therapeutic plasma exchange

We sought to optimize direct intravenous infusion of calcium gluconate (CaGlu) for maintaining plasma ionized calcium concentration ([Ca²⁺]) and preventing hypocalcemic reactions during 34 consecutive 1-volume therapeutic plasma exchanges (TPEs) in eight patients. CaGlu, 2 g in 50 mL of 0.9% NaCl, was prepared by our hospital pharmacy and infused at either 1.0 or 1.6 g/h during alternate TPE. Plasma [Ca²⁺] was monitored at intervals of 20 to 30 minutes. At 1 g/h of CaGlu, plasma [Ca²⁺] fell by 8.35% after 40 to 50 minutes and then plateaued. At 1.6 g/h of CaGlu, plasma [Ca²⁺] fell by 6% after 20 to 30 minutes and then plateaued. The difference at 40 to 50 minutes was significant (P = .015). Hypocalcemic reactions were noted in three patients during 5 of 17 TPE at 1.0 g/h (all after 40 to 60 minutes) but 0 of 17 TPE at 1.6 g/h (P = .044). CaGlu at 1.6 g/h stabilized plasma [Ca²⁺] and appears to prevent hypocalcemic reactions during TPE.     

The impact of diabetes on periodontal diseases

The susceptibility and severity of periodontal diseases is made more severe by diabetes, with the impact on the disease process inversely proportional to the level of glycemic control. Although type 1 diabetes mellitus and type 2 diabetes mellitus have different etiologies, and their impact on bone is not identical, they share many of the same complications. Studies in animals and humans agree that both forms of diabetes increase inflammatory events in periodontal tissue, impair new bone formation, and increase expression of RANKL in response to bacterial challenge. High levels of glucose, reactive oxygen species, and advanced glycation end-products are found in the periodontium of diabetic individuals and lead to increased activation of nuclear factor-kappa B and expression of inflammatory cytokines such as tumor necrosis factor and interleukin-1. Studies in animals, moreover, suggest that there are multiple cell types in periodontal tissues that are affected by diabetes, including leukocytes, vascular cells, mesenchymal stem cells, periodontal ligament fibroblasts, osteoblasts, and osteocytes. The etiology of periodontal disease involves the host response to bacterial challenge that is affected by diabetes, which increases the expression of RANKL and reduces coupled bone formation. In addition, the inflammatory response also modifies the oral microbiota to render it more pathogenic, as demonstrated by increased inflammation and bone loss in animals where bacteria are transferred from diabetic donors to germ-free hosts compared with transfer from normoglycemic donors. This approach has the advantage of not relying upon limited knowledge of the specific bacterial taxa to determine pathogenicity, and examines the overall impact of the microbiota rather than the presumed pathogenicity of a few bacterial groups. Thus, animal studies have provided new insights into pathogenic mechanisms that identify cause-and-effect relationships that are difficult to perform in human studies.     

Beverage choice among native american and african american urban women

BACKGROUND: Little is known about beverage preference, especially among understudied urban minority populations. Also, most studies do not differentiate between beer and malt liquor or among wine, wine coolers, and fortified wine. This article examines whether ethnicity or drinking frequency are associated with beverage choice, considering six types of alcoholic beverages: beer, wine, spirits, malt liquor, fortified wine, and wine coolers. METHODS: Data were analyzed from Native American (n = 70) and African American (n = 129) urban pregnant women who reported drinking in the 12 months before an index pregnancy. A small comparison group of white women (n = 22) was included. Women were queried about their consumption of each of six beverage types during the 12 months before pregnancy. RESULTS: The alcoholic beverage most often used, adjusted for other beverages consumed, was beer, followed in order by spirits, wine coolers, malt liquor, wine, and fortified wine. The Native American women preferred beer, which accounted for one third of total intake. In contrast, malt liquor and spirits each accounted for approximately a quarter of intake among African Americans. Compared with other drinkers, women who drank daily were significantly more likely to choose the beer and wine products with a higher alcohol content. In general, these bivariate results were borne out by multivariate analyses that controlled for age, marital status, and education. CONCLUSIONS: These findings suggest that when accuracy is desired, alcohol studies focusing on urban African American samples (and, to a lesser degree, Native American respondents) should consider not just beer, wine, and spirits consumption, but also stronger beer products, such as malt liquor; stronger wine products, such as fortified wine; and sweeter products, such as wine coolers.     

Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization

Activation of p53 tumor suppressor by antagonizing its negative regulator murine double minute (MDM)2 has been considered an attractive strategy for cancer therapy and several classes of p53-MDM2 binding inhibitors have been developed. However, these compounds do not inhibit the p53-MDMX interaction, and their effectiveness can be compromised in tumors overexpressing MDMX. Here, we identify small molecules that potently block p53 binding with both MDM2 and MDMX by inhibitor-driven homo- and/or heterodimerization of MDM2 and MDMX proteins. Structural studies revealed that the inhibitors bind into and occlude the p53 pockets of MDM2 and MDMX by inducing the formation of dimeric protein complexes kept together by a dimeric small-molecule core. This mode of action effectively stabilized p53 and activated p53 signaling in cancer cells, leading to cell cycle arrest and apoptosis. Dual MDM2/MDMX antagonists restored p53 apoptotic activity in the presence of high levels of MDMX and may offer a more effective therapeutic modality for MDMX-overexpressing cancers.     

Naturally occurring antibodies to an epitope on Plasmodium falciparum gametes detected by monoclonal antibody-based competitive enzyme-linked immunosorbent assay.

The antibody response to an epitope on gamete antigens of Plasmodium falciparum in persons naturally exposed to malaria has been investigated by competitive enzyme-linked immunosorbent assay. The assay detects antibodies to an epitope on the 48/45-kilodalton (kDa) gamete surface antigen by competition with horseradish peroxidase-labeled monoclonal antibody IIC5-B10. Five sera previously shown to immunoprecipitate the 230- and 48/45-kDa antigens significantly inhibited IIC5-B10 binding to an average of 24.2% of control. The one serum which precipitated only the 48/45-kDa antigen did not inhibit IIC5-B10 binding. For 26 sera which were negative by immunoprecipitation, mean binding in the assay was 112.7% of control (pooled London nonimmune sera). Recognition of both 230-kDa and 48/45-kDa antigens was associated with a titer of 1:9 or greater (reciprocal geometric mean titer, 27.6) for inhibition to more than 2 standard deviations from the mean of the negative sera. The results show that the IIC5-B10 binding site is a naturally immunogenic epitope recognized by the majority of persons who had antibodies to the 48/45-kDa protein. An additional finding was enhancement of binding of IIC5-B10 to an average of 154.4% of control by five sera which recognized only the 230-kDa antigen, presumably due to conformational alteration of the gamete antigen complex.     

Nonspecific cytotoxic cells in fish (Ictalurus punctatus). IV. Target cell binding and recycling capacity

The morphology of nonspecific cytotoxic cells (NCC) was identified. NCC were purified by target cell conjugate formation and density gradient separation. NCC are monocyte-like. They have reniform nuclei and a low nucleus/cytoplasm ratio. Cytoplasmic granules were not seen after giemsa staining. Scanning electron microscopy demonstrated moderate surface villi and target cell attachment occurred via long membraneous filament-like surface projections extending to the target cell membranes. Transmission electron microscopy of effector:target cell conjugates revealed membrane contact areas without fusion or fragmentation. The nucleus of the NCC had accentuated peripheral chromation and a prominent Golgi apparatus; the cytoplasm contained osmiophilic granules. Michaelis-Menten and Lineweaver-Burk transformation of target cell binding revealed a Vmax of 11-15,000 and a Km of 40,000. The percentage of NCC bound to target cells was 16-18%. Results of these studies were combined with the conjugate experiment to obtain an estimated percentage of active NCC (5-7%). A maximum recycling capacity of .16-.30 indicated that once attachment by NCC to the target cell occurred (and a lethal signal delivered by an effector cell), either the NCC did not recycle or a long lag period was required to restore its cytotoxic capability.     

Evaluation of the Directigen Group A Strep test kit

The Directigen Group A Strep test kit (Hynson, Wescott, and Dunning, Baltimore, Md.) was tested for its ability to detect group A streptococci directly from 147 throat swabs. The results were compared with results from conventional culture and Lancefield serological grouping tests. The data showed that 121 of 124 culture-negative throat specimens were also Directigen negative (98%) and that 21 of 23 culture-positive specimens were Directigen positive (91%). If specimens that provided less than 10 colonies per plate of beta-hemolytic streptococci were eliminated, all of the culture-positive specimens were Directigen positive. Positive or negative results were available within 65 to 70 min of testing. The Directigen method is relatively simple to perform and easy to interpret and provides accurate assessment of the presence or absence of group A streptococci in throat swabs, with little or no cross-reactivity with other beta-hemolytic groups.