Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S)

BACKGROUND: The Scandinavian Simvastatin Survival Study (4S) randomized 4444 patients with coronary heart disease (CHD) and serum cholesterol 5.5 to 8.0 mmol/L (213 to 310 mg/dL) with triglycerides < or =2.5 mmol/L (220 mg/dL) to simvastatin 20 to 40 mg or placebo once daily. Over the median follow-up period of 5.4 years, one or more major coronary events (MCEs) occurred in 622 (28%) of the 2223 patients in the placebo group and 431 (19%) of the 2221 patients in the simvastatin group (34% risk reduction, P<.00001). Simvastatin produced substantial changes in several lipoprotein components, which we have attempted to relate to the beneficial effects observed. METHODS AND RESULTS: The Cox proportional hazards model was used to assess the relationship between lipid values (baseline, year 1, and percent change from baseline at year 1) and MCEs. The reduction in MCEs within the simvastatin group was highly correlated with on-treatment levels and changes from baseline in total and LDL cholesterol, apolipoprotein B, and less so with HDL cholesterol, but there was no clear relationship with triglycerides. We estimate that each additional 1% reduction in LDL cholesterol reduces MCE risk by 1.7% (95% CI, 1.0% to 2.4%; P<.00001). CONCLUSIONS: These analyses suggest that the beneficial effect of simvastatin in individual patients in 4S was determined mainly by the magnitude of the change in LDL cholesterol, and they are consistent with current guidelines that emphasize aggressive reduction of this lipid in CHD patients.     

The Homothorax homeoprotein activates the nuclear localization of another homeoprotein, extradenticle, and suppresses eye development in Drosophila

The Extradenticle (Exd) protein in Drosophila acts as a cofactor to homeotic proteins. Its nuclear localization is regulated. We report the cloning of the Drosophila homothorax (hth) gene, a homolog of the mouse Meis1 proto-oncogene that has a homeobox related to that of exd. Comparison with Meis1 finds two regions of high homology: a novel MH domain and the homeodomain. In imaginal discs, hth expression coincides with nuclear Exd. hth and exd also have virtually identical, mutant clonal phenotypes in adults. These results suggest that hth and exd function in the same pathway. We show that hth acts upstream of exd and is required and sufficient for Exd protein nuclear localization. We also show that hth and exd are both negative regulators of eye development; their mutant clones caused ectopic eye formation. Targeted expression of hth, but not of exd, in the eye disc abolished eye development completely. We suggest that hth acts with exd to delimit the eye field and prevent inappropriate eye development.     

Histological and biomechanical analysis of bone and interface reactions around hydroxyapatite-coated intramedullary implants of different stiffness: a pilot study on the goat

We hypothesized that reduced stem stiffness of orthopaedic implants contributes to a high risk of loosening, since interface stresses and relative motions may exceed a tolerable range. To study this hypothesis, three types of load-bearing implant with different stiffnesses were inserted into the tibia of the goat. Histological analysis was performed of bone repair after insertion of the implant, bone ingrowth, interface disruption and loosening. A finite element model of the configuration provided the quantitative range of interface stresses and relative motions for the present experiment. The implants were made out of stainless steel, hollow titanium and a thin titanium core covered with a polyacetal coating. The stiffness ratios of these implants were approximately 10:4:1, respectively. All implants were coated with a layer of hydroxyapatite (HA) in order to minimize the possible biological effects of the different implant materials. Irrespective of the type of implant, there was a repair phase that lasted 6-12 weeks. The stiff implants functioned well. Large areas of bone bonding to the HA layer were found after the repair phase at 12 weeks postoperatively. After 24 weeks, some signs of loosening were observed. More loosening occurred with the hollow titanium and polyacetal implants, mainly during the repair phase. Three hollow titanium and three polyacetal coated implants survived this period, and were killed after 24 weeks. The integrity of the HA layer at the bone-implant interface of the titanium implants was good. In the polyacetal implants, the repair reaction of the cortical bone was incomplete. Bone ingrowth into HA was largely lacking. In conclusion, we found significant differences in the repair and interface reactions around implants of different stiffness. Stiff implants showed favourable initial interface conditions for bone ingrowth. Intermediate and flexible implants provoked unfavourable interface conditions for initial bone ingrowth. The finite element study showed that the flexible stems produce larger micromotions and higher interface stresses at the bone-prosthesis interface than the stiff stems, indicating an explanation for the histological findings.     

Soil nutrient evaluation from swine effluent application to five forage-system practices

Many contract swine producers are located in the southeastern U.S. In this region almost all of the swine effluent from swine production is applied to warm-season perennial species such as bermudagrass [Cynodon dactylon (L.) Pers.] which is widely grown for summer grazing and hay production. A 3-yr study was conducted to investigate the impact of forage double-cropping on nutrient accumulation and leaching in Mantachie fine loam soil fertilized with swine (Sus scrofa domesticus) lagoon effluent as the source of plant nutrients. Plots of previously established Tifton 44 bermudagrass were overseeded in the fall with one of four winter annuals: berseem clover (Trifolium alexandrinum L.); crimson clover (T. incarnatum L.); ryegrass (Lolium multiflorum L.); or wheat (Triticum aestivum L.). Four plots of bermudagrass were not overseeded and considered as control. Plots were harvested in spring for cool-season annual hay and in summer for bermudagrass hay. Swine effluent was applied during spring and summer on a need base. Suction lysimeters were installed in selected plots at two depths to monitor nutrient leaching. Surface soil samples were taken to determine baseline nutrient contents, followed by three other sampling dates during the study. Bermudagrass dry matter production (3-yr average = 9.8 Mg ha⁻¹) was not adversely affected by the overseeding treatments. Greatest dry matter production was achieved with bermudagrass overseeded with ryegrass (3-yr average  = 11.3 Mg ha⁻¹). Soil pH decreased by almost one unit by the end of the study. While total P (TP) did not change much, Mehlich-3 P (M3-P), K, Cu, and Zn increased significantly, Mg and Mn concentrations decreased by 2002 compared to the baseline levels. Soil P, Mg, K, Fe, Mn, and Zn accumulation were greater under bermudagrass/wheat combination. In general, the influence of double cropping on soil nutrient accumulation was not conclusive, however, this practice provides the year-round green forage for grazing and haying. Nutrient concentrations in soil and lysimeter leachate were directly related to the quantity of effluent applied. Results also demonstrated that effluent application must be coordinated with the nutrient requirements of the growing forages in order to minimize accumulation and leaching.     

Quantitative analysis of mitoxantrone by surface-enhanced resonance Raman scattering

Mitoxantrone is an anticancer agent for which it is important to know the concentration in blood during therapy. Current methods of analysis are cumbersome, requiring a pretreatment stage. A method based on surface-enhanced resonance Raman scattering (SERRS) has been developed using a flow cell and silver colloid as the SERRS substrate. It is simple, sensitive, fast, and reliable. Both blood plasma and serum can be analyzed directly, but fresh serum is preferred here due to reduced fluorescence in the clinical samples available. Fluorescence is reduced further by the dilution of the serum in the flow cell and by quenching by the silver of surface-adsorbed material. The effectiveness of the latter process is dependent on the contact time between the serum and the silver. The linear range encompasses the range of concentrations detected previously in patient samples using HPLC methods. In a comparative study of a series of samples taken from a patient at different times, there is good agreement between the results obtained by HPLC and SERRS with no significant difference between them at the 95% limit. The limit of detection in serum using the final optimized procedure for SERRS was 4.0 x 10(-11) M (0.02 ng/mL) mitoxantrone. The ease with which the SERRS analysis can be carried out makes it the preferred choice of technique for mitoxantrone analysis.     

Tool Building Requirements for an API to First-Order Solvers

Effective formal verification tools require that robust implementations of automatic procedures for first-order logic and satisfiability modulo theories be integrated into expressive interactive frameworks for logical deduction, such as higher-order logic theorem provers. This paper states some pragmatic requirements for implementations of decision procedures that make them well-suited to integration into such frameworks. The aim is to open a dialogue with the designers of decision procedure software that will lead to greater and easier uptake of their implementations by verification users.     

Hairline lowering during foreheadplasty

Many patients seeking rejuvenation of their foreheads have high hairlines and are troubled by the prospect that surgery will worsen the deformity. Hairline elevation occurs in both coronal and endoscopic foreheadplasty techniques and is at least part of the reason that many surgeons do not always recommend these procedures when otherwise indicated. Although a pretrichial "hairline" incision prevents hairline retro-displacement, it results in forehead shortening only and not true hairline lowering. When a pretrichial incision is used in combination with a posterior scalp advancement flap, however, true hairline lowering is possible. Experience with this technique encompasses 27 procedures performed over a 5-year period. Patients ranged in age from 35 to 71 years. A significant improvement was demonstrable in all cases and corresponded with a high degree of patient satisfaction. No serious complications were seen. A high hairline must be recognized as the source of both a disproportionate and aged appearance. The ability to lower the hairline and place it in a more proportionate, youthful relationship with the rest of the face adds a new dimension to foreheadplasty equal to or greater in importance to an overall improved appearance as other maneuvers typically performed during the procedure. For many patients, the benefits of hairline lowering far outweigh the trade-off of a more anteriorly situated, and possibly more visible, scar.