The postantibiotic effect in the treatment of experimental meningitis caused by Streptococcus pneumoniae in rabbits

The relevance of a postantibiotic effect in the treatment of pneumococcal meningitis was evaluated in a rabbit model. After administration of a single intravenous bolus of ampicillin at various dosages, such an effect was observed in all animals. The duration of this effect in vivo (2.5-18 hr) was consistently longer than that in vitro (1-4.3 hr); however, in rabbits the postantibiotic effect was eliminated by the administration of intravenous plus intracisternal beta-lactamase. In an assessment of the potential therapeutic benefit of the postantibiotic effect, the efficacy to two regimens of treatment with different intervals between doses was compared. One group of animals received ampicillin every 4 hr and another every 12 hr. With sufficiently high doses, drug concentrations in cerebrospinal fluid exceeded the minimal bactericidal concentration for most of the 4-hr interval but for only about one-third of the 12-hr interval. The rate of cure was similar for the two regimens and approximated 100% when peak drug concentrations in cerebrospinal fluid exceeded the minimal bactericidal concentration by at least 10-fold.

The potential effect of population development, smoking and antioxidant supplementation on the future epidemiology of age-related macular degeneration in Switzerland

BACKGROUND: Due to the predicted age shift of the population an increase in the number of patients with late AMD is expected. At present smoking represents the only modifiable risk factor. Supplementation of antioxidants in patients at risk is the sole effective pharmacological prevention. The aim of this study is to estimate the future epidemiological development of late AMD in Switzerland and to quantify the potential effects of smoking and antioxidants supplementation. METHODS: The modelling of the future development of late AMD cases in Switzerland was based on a meta-analysis of the published data on AMD-prevalence and on published Swiss population development scenarios until 2050. Three different scenarios were compared: low, mean and high. The late AMD cases caused by smoking were calculated using the "population attributable fraction" formula and data on the current smoking habits of the Swiss population. The number of potentially preventable cases was estimated using the data of the Age-Related Eye Disease Study (AREDS). RESULTS: According to the mean population development scenario, late AMD cases in Switzerland will rise from 37 200 cases in 2005 to 52 500 cases in 2020 and to 93 200 cases in 2050. Using the "low" and the "high" scenarios the late AMD cases may range from 49 500 to 56 000 in 2020 and from 73 700 to 118 400 in 2050, respectively. Smoking is responsible for approximately 7 % of all late AMD cases, i. e., 2600 cases in 2005, 3800 cases in 2020, 6600 cases in 2050 ("mean scenario"). With future antioxidant supplementation to all patients at risk another 3100 cases would be preventable until 2020 and possibly 23 500 cases until 2050. CONCLUSION: Due to age shift in the population a 2.5-fold increase in late AMD cases until 2050 is expected, representing a socioeconomic challenge. Cessation of smoking and supplementation of antioxidants to all patients at risk has the potential to reduce this number. Unfortunately, public awareness is low. These data may support health-care providers and public opinion leaders when developing public education and prevention strategies.

The Staining Effect of the Hydrochloric Acid-Chromate Trioxide Solution on the Minerals of the Chalcocite-Stibnite-Galena Ternary System.

The object of this work has been to devise a method by which the different phases in the chalcocite-stibnite-galena ternary system may be identified. As the mineralogists have no precise methods for the identification of these phases, a hydrochloric acid-chromate trioxide staining solution was employed.

The moderating effect of personal mastery and the relations between stress and Plasminogen Activator Inhibitor-1 (PAI-1) antigen

OBJECTIVE: This study tested whether feelings of personal control over one's life circumstances (i.e., personal mastery) would attenuate the relations between stress (i.e., negative life events and caregiving distress) and Plasminogen Activator Inhibitor (PAI)-1 antigen, an inhibitor of fibrinolysis implicated in the development of cardiovascular disease. DESIGN: Seventy-one spousal dementia caregivers were assessed for plasma levels of PAI-1 antigen, negative life events, caregiver distress, and feelings of personal mastery. Regression analysis was used to determine if personal mastery moderated the relations between stress (i.e., life stress and caregiving distress) and PAI-1 antigen levels. MAIN OUTCOME MEASURE: Plasminogen activator inhibitor (PAI)-1 antigen in plasma. RESULTS: After controlling for other factors associated with PAI-1 antigen levels, negative life events were positively associated with plasma PAI-1 antigen concentrations in participants low in personal mastery (beta = .31; p = .050) but not in individuals high in personal mastery (beta = .22; p = .184). The moderating effect of mastery on the relations between caregiving distress and PAI-1 antigen did not reach statistical significance (p = .091). CONCLUSIONS: These data suggest that mastery may protect individuals from some of the alterations in hemostatic factors that have been linked to cardiovascular risk.

Holocene climatic change and the development of the lake-effect snowbelt in Michigan, USA

Lake-effect snow is an important constraint on ecological and socio-economic systems near the North American Great Lakes. Little is known about the Holocene history of lake-effect snowbelts, and it is difficult to decipher how lake-effect snowfall abundance affected ecosystem development. We conducted oxygen-isotope analysis of calcite in lake-sediment cores from northern Lower Michigan to infer Holocene climatic variation and assess snowbelt development. The two lakes experience the same synoptic-scale climatic systems, but only one of them (Huffman Lake) receives a significant amount of lake-effect snow. A 177-cm difference in annual snowfall causes groundwater inflow at Huffman Lake to be 18O-depleted by 2.3‰ relative to O'Brien Lake. To assess when the lake-effect snowbelt became established, we compared calcite-δ18O profiles of the last 11,500 years from these two sites. The chronologies are based on accelerator-mass-spectrometry 14C ages of 11 and 17 terrestrial-plant samples from Huffman and O'Brien lakes, respectively. The values of δ18O are low at both sites from 11,500 to 9500 cal yr BP when the Laurentide Ice Sheet (LIS) exerted a dominant control over the regional climate and provided periodic pulses of meltwater to the Great Lakes basin. Carbonate δ18O increases by 2.6‰ at O'Brien Lake and by 1.4‰ at Huffman Lake between 9500 and 7000 cal yr BP, suggesting a regional decline in the proportion of runoff derived from winter precipitation. The Great Lakes snowbelt probably developed between 9500 and 5500 cal yr BP as inferred from the progressive 18O-depletion at Huffman Lake relative to O'Brien Lake, with the largest increase of lake-effect snow around 7000 cal yr BP. Lake-effect snow became possible at this time because of increasing contact between the Great Lakes and frigid arctic air. These changes resulted from enhanced westerly flow over the Great Lakes as the LIS collapsed, and from rapidly rising Great Lakes levels during the Nipissing Transgression. The δ18O difference between Huffman and O'Brien lakes declines after 5500 cal yr BP, probably because of a northward shift of the polar vortex that brought increasing winter precipitation to the entire region. However, δ18O remains depleted at Huffman Lake relative to O'Brien Lake because of the continued production of lake-effect snow.

The bivalency effect represents an interference-triggered adjustment of cognitive control: an ERP study

When bivalent stimuli (i.e., stimuli with relevant features for two different tasks) occur occasionally among univalent stimuli, performance is slowed on subsequent univalent stimuli even if they have no overlapping stimulus features. This finding has been labeled the bivalency effect. It indexes an adjustment of cognitive control, but the underlying mechanism is not well understood yet. The purpose of the present study was to shed light on this question, using event-related potentials. We used a paradigm requiring predictable alternations between three tasks, with bivalent stimuli occasionally occurring on one task. The results revealed that the bivalency effect elicited a sustained parietal positivity and a frontal negativity, a neural signature that is typical for control processes implemented to resolve interference. We suggest that the bivalency effect reflects interference, which may be caused by episodic context binding.

The devaluation effect: activating a need devalues unrelated objects

It is commonly assumed that an object capable of satisfying a need will be perceived as subjectively more valuable as the need for it intensifies. For example, the more active the need to eat, the more valuable food will become. This outcome could be called a valuation effect. In this article, we suggest a second basic influence of needs on evaluations: that activating a focal need (e.g., to eat) makes objects unrelated to that need (e.g., shampoo) less valuable, an outcome we refer to as the devaluation effect. Two existing studies support the existence of a devaluation effect using manipulations of the need to eat and to smoke and measuring attractiveness of consumer products and willingness to purchase raffle tickets. Furthermore, the evidence suggests that consumers are not aware of the devaluation effect and its influence on their preferences.

Increasing the Antitumor Effect of an EpCAM-Targeting Fusion Toxin by Facile Click PEGylation

Fusion toxins used for cancer-related therapy have demonstrated short circulation half-lives, which impairs tumor localization and, hence, efficacy. Here, we demonstrate that the pharmacokinetics of a fusion toxin composed of a designed ankyrin repeat protein (DARPin) and domain I–truncated Pseudomonas Exotoxin A (PE40/ETA″) can be significantly improved by facile bioorthogonal conjugation with a polyethylene glycol (PEG) polymer at a unique position. Fusion of the anti-EpCAM DARPin Ec1 to ETA″ and expression in methionine-auxotrophic E. coli enabled introduction of the nonnatural amino acid azidohomoalanine (Aha) at position 1 for strain-promoted click PEGylation. PEGylated Ec1-ETA″ was characterized by detailed biochemical analysis, and its potential for tumor targeting was assessed using carcinoma cell lines of various histotypes in vitro, and subcutaneous and orthotopic tumor xenografts in vivo. The mild click reaction resulted in a well-defined mono-PEGylated product, which could be readily purified to homogeneity. Despite an increased hydrodynamic radius resulting from the polymer, the fusion toxin demonstrated high EpCAM-binding activity and retained cytotoxicity in the femtomolar range. Pharmacologic analysis in mice unveiled an almost 6-fold increase in the elimination half-life (14 vs. 82 minutes) and a more than 7-fold increase in the area under the curve (AUC) compared with non-PEGylated Ec1-ETA″, which directly translated in increased and longer-lasting effects on established tumor xenografts. Our data underline the great potential of combining the inherent advantages of the DARPin format with bioorthogonal click chemistry to overcome the limitations of engineering fusion toxins with enhanced efficacy for cancer-related therapy.

Age affects the adjustment of cognitive control after a conflict: evidence from the bivalency effect

Age affects cognitive control. When facing a conflict, older adults are less able to activate goal-relevant information and inhibit irrelevant information. However, cognitive control also affects the events after a conflict. The purpose of this study was to determine whether age affects the adjustment of cognitive control following a conflict. To this end, we investigated the bivalency effect, that is, the performance slowing occurring after the conflict induced by bivalent stimuli (i.e., stimuli with features for two tasks). In two experiments, we tested young adults (aged 20-30) and older adults (aged 65-85) in a paradigm requiring alternations between three tasks, with bivalent stimuli occasionally occurring on one task. The young adults showed a slowing for all trials following bivalent stimuli. This indicates a widespread and long-lasting bivalency effect, replicating previous findings. In contrast, the older adults showed a more specific and shorter-lived slowing. Thus, age affects the adjustment of cognitive control following a conflict.