Ryanodine action at calcium release channels. 1. importance of hydroxyl substituents

Ryanodine (1) and dehydroryanodine (2) have a polar face formed by cis-hydroxyls at C-2, C-4, C-6, and C-12. The importance of the hydroxyls to the action of 1 and 2 at the ryanodine receptor (ryr) of calcium release channels is examined at [3H]-1 binding sites in brain and skeletal muscle and in heart membranes relative to cardiac contractility, a pharmacologic response which appears to be mediated by the ryr. Five types of changes are considered: blocking the 4- and 6-hydroxyls as cyclic borates and boronates; blocking the 10- and 12-hydroxyls as cyclic phosphates, phosphonates, and phosphoramidates; methylation at nitrogen or hydroxyls at C-4 and C-10; dehydration of the C-2 hydroxyl; additional data for a 4,12-oxygen-bridged series. The first change has little effect on potency possibly due to the lability of the boron protective groups whereas the cyclic phosphorus compounds have reduced activity. Methylation reduces potency the least at nitrogen and the C-4 hydroxyl. Dehydration of 1 to 2-deoxy-2(13)-dehydro-1 allows the restoration of oxygen at C-2 by conversion to epoxides or a diol. One of the epoxides and 2-deoxy-2(13)-dehydro-2 retain 8-31% of ryanodine's potency in the ryr assays and 81% in the cardiac contractility system. In the 4,12-oxygen-bridged series, high potency at the receptor and cardiac muscle is retained in the 4-hydroxy ketal.     

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.     

Edible vaccine protects mice against Escherichia coli heat-labile enterotoxin (LT): potatoes expressing a synthetic LT-B gene

The authors have designed and constructed a plant-optimize synthetic gene encoding the Escherichia coli heat-labile enterotoxin B subunit (LT-B), for use in transgenic plants as an edible vaccine against enterotoxigenic E. coli. Expression of the synthetic LT-B gene in potato plants under the control of a constitutive promoter yielded increased accumulation of LT-B in leaves and tubers, as compared to the bacterial LT-B gene. The plant-derived LT-B assembled into native pentameric structures as evidenced by its ability to bind ganglioside. The authors demonstrated immunogenicity by feeding mice the raw tubers and comparing the anti-LT-B serum IgG and faecal IgA to that produced in mice gavaged with bacterial LT-B. Mice were fed three weekly doses of 5 g tuber tissue containing either 20 or 50 micrograms LT-B, or gavaged weekly with 5 micrograms of LT-B from recombinant E. coli. One week after the third dose, mice immunized with potato LT-B had higher levels of serum and mucosal anti-LT-B than those gavaged with bacterial LT-B. Mice were challenged by oral administration of 25 micrograms LT, and protection assessed by comparing the gut/carcass mass ratios. Although none of the mice were completely protected, the higher dose potato vaccine compared favourably with the bacterial vaccine. These findings show that an edible vaccine against E. coli LT-B is feasible.     

Evolution of consanguinity in the Archbishopric of Santiago de Compostela (Spain) during 1900-1979

Continuous intracameral infusions of a balanced salt solution (0.175 microliter min-1) have been reported to raise intraocular pressure (IOP) in anesthetized rats. Palm et al. (1995) previously reported that this effect was attenuated significantly by inclusion of arginine-vasopressin (AVP, 10 ng 0.175 microliter-1) in the infusate. This study used experimental and computer simulation methods to investigate factors underlying these changes in IOP. First, constant intracameral infusions of artificial cerebrospinal fluid (aCSF) at different fixed rates (0.049-0.35 microliter min-1) were used to estimate the outflow resistance. Secondly, IOP responses were measured during an 2 hr intracameral infusion of either aCSF or AVP that was the sum of a small constant component (0.05 microliter min-1) and a larger periodic component (0.25 microliter min-1, cycling for 4 min on, then 4 min off); the mean infusion rate was 0.175 microliter min-1. As shown previously for 0.175 microliter min-1 constant infusions, the periodic aCSF infusion induced a significant rise in IOP that was attenuated by AVP administration. Complex demodulation analysis and the estimated gain parameter of a second order transfer function fit to the periodic responses indicated that outflow resistance increased significantly during the infusions in both aCSF and AVP groups, but that the indices of resistance did not differ significantly between aCSF and AVP infused eyes. This finding implies that changes in outflow resistance do not explain the difference in IOP responses to intracameral aCSF and AVP. The two responses differed significantly, though, in damping factors, such that the aCSF responses were considerably more underdamped than the AVP responses. It is hypothesized that aCSF-induced increase in IOP reflects both (1) a small component reflecting increased outflow resistance and (2) a larger non-resistive component. Since the non-resistive component is insensitive to pretreatment with acetazolamide, it is suggested that the aCSF-induced elevation in IOP reflects primarily vascular perfusion changes that are reduced by local vasoconstrictor actions of AVP. The latter mechanism likely maintains vascular perfusion of the globe when intraocular hypertension develops.     

Activation of the mitogen-activated protein kinase pathway is involved in and sufficient for megakaryocytic differentiation of CMK cells

Activation of the mitogen-activated protein (MAP) kinase pathway has been associated with both cell proliferation and differentiation. Constitutively activated forms of Mek (MAP kinase/Erk kinase) and Erk (MAP kinase) have been previously shown capable of inducing differentiation or proliferation in nonhematopoietic cells. To specifically examine the role of Erk activation in megakaryocytic growth and development, we activated the MAP kinase pathway by the transfection of constitutively activated Mek or Erk cDNA into a human megakaryoblastic cell line, CMK, by electroporation. The CMK transfectant clones that expressed constitutively activated Mek or Erk showed morphologic changes of differentiation. Transfected cells also showed expression of mature megakaryocytic cell surface markers. The MAP kinase pathway was also activated by treatment of the hematopoietic cells with a cytokine that activates Erk. The treatment of CMK cells with stem cell factor (SCF ) caused MAP kinase activation and induced differentiation by the expression of mature megakaryocytic cell surface markers. The effects of the SCF treatment were inhibited by pretreatment with a specific inhibitor of the MAP kinase pathway, PD98059. In this report, we conclude that activation of the MAP kinase pathway was both necessary and sufficient to induce differentiation in this megakaryoblastic cell line.     

Efficacy of the lithium compound with prolonged action during "reserpine depression"]

Being a foreign body, intrauterine coil causes decubitus and inflammation of the adjacent tissues. Long-term carriage of the coil may give rise to endometritis, myometritis, parametritis, salpingo-oophoritis, tubo-ovarian inflammatory infiltrates. These infiltrates invade retroperitoneal pelvic fat and may obstruct pelvic ureters. Ureteral obstruction may bring about ureterohydronephrosis, pyelonephritis and renal calculi. The coil may be also responsible for chronic pyelonephritis. The authors have treated 64 females aged 18-45 years with urological complications due to intrauterine coils which stayed from 6 months to 14 years. 34 of them presented with attack of acute pyelonephritis, 29 with renal colic and acute pyelonephritis, 26 with renal calculi. To arrest renal colic and attack of acute pyelonephritis ureteral catheterization and renal pelvis drain were performed in 31 patients. One patient has undergone ureterolithotomy. 8 patients rejected removal of the coil and had recurrent renal colics and acute pyelonephritis attacks. Removal of the coil arrested pyelonephritis and lithogenesis in the kidney. In one case of coil removal there was injury to the uterine cervix and urinary bladder eventuating in vesicovaginal fistula.     

Loss of H19 imprinting and up-regulation of H19 and SNRPN in a case with malignant mixed Müllerian tumor of the uterus

An unusual clinical presentation of a patient with neuronal intestinal dysplasia is presented. A 46-year-old male noted a palpable mass in the right lower quadrant of his abdomen for two months. A computed axial tomographic scan showed a thickened wall of the cecum with a tumor-like appearance. The excised specimen consisted of a mass caused by the thickened, edematous wall of the dilated cecum and appendix. The wall of the cecum and appendix measured up to 2.5 and 0.8 cm, respectively, in thickness. Microscopic studies showed extensive hyperplasia and hypertrophy of the ganglia and nerve plexuses and hypertrophy of the muscularis propria, consistent with neuronal intestinal dysplasia.     

离子束增强沉积氮化硅膜及TiAl抗高温氧化性能的改善

用离子束增强沉积（ＩＢＥＤ）方法在金属间化合物ＴｉＡｌ上合成厚度为０．５，１，和２μｍ的氮化硅薄膜。所形成的薄膜为非晶态，膜与基底间存在混合的过渡区，膜与基底结合紧密用ＡＥＳ，ＸＲＤ和ＸＰＳ研究薄膜的组成和结构，高温循环氧化结果表明，经沉积膜的ＴｉＡｌ试样的抗氧化性能显著提高其中沉积０．５μｍ薄膜的试样表现出极好的抗循环氧化性能由ＳＥＭ及ＥＤＳ分析得出，良好的高温稳定性能、高的膜／基底结合力和形成富Ａｌ２Ｏ３和硅化物的保护层是提高ＴｉＡｌ抗高温氧化性能的主要因素．     

不同比例LA/ALA对HepG2细胞炎症因子的影响

选取植物油中典型的多不饱和脂肪酸亚油酸(LA)和α-亚麻酸(ALA)为原料,分为7个不同摩尔浓度配比实验组(组1,LA;组2,10∶1 LA/ALA;组3,5∶1 LA/ALA;组4,1∶1 LA/ALA;组5,1∶5 LA/ALA;组6,1∶10 LA/ALA;组7,ALA)体外评估不同比例n-6/n-3 PUFAs对HepG2细胞炎症因子的影响。结果表明:60μmol/L各实验组均可降低HepG2细胞产生的促炎因子TNF-α和IL-6水平,提高抗炎因子IL-10和抗炎介质LXA4水平,其中组4(1∶1 LA/ALA)作用最显著。     

Resuspension of coal and coal/municipal sewage sludge combustion generated fine particles for inhalation health effects studies

Airborne particulate matter (PM) is an important environmental issue because of its association with acute respiratory distress in humans, although the specific particle characteristics that cause lung damage have yet to be identified. Particle size, acid aerosols, water-soluble transition metals (e.g. Cu, Fe, V, Ni and Zn), polyaromatic hydrocarbons, and particle composition are the focus of several popular hypotheses addressing respiratory distress. All of the above mentioned characteristics are contained in PM generated from the combustion of both pulverized coal, and biomass, including dried municipal sewage sludge (MSS). In this investigation, we report results from collaborative interdisciplinary research on the inhalation health risks caused by particles emitted from the co-combustion of municipal sewage sludge (MSS) and coal. A solid particle resuspension system was implemented to resuspend ash particles. Mice were exposed to resuspended coal and MSS/coal ash particles. Mice exposed to MSS/coal ash particulate demonstrated significant increases in lung permeability, a marker of the early stages of pathological lung injury, while the mice exposed to coal-only ash did not. These results show that the composition of particles actually inhaled is important in determining lung damage. Zinc was significantly more concentrated in the MSS/coal ash than coal ash particles and the pH of these particles did not differ significantly. Specifically, an MSS/coal mixture, when burned, emits particles that may cause significantly more lung damage than coal alone, and that consequently, the use of MSS as a 'green', CO2-neutral replacement fuel should be carefully considered.