Endothelial lipase promotes the catabolism of ApoB-containing lipoproteins

Endothelial lipase (EL) has been found to be a key enzyme in high-density lipoprotein (HDL) metabolism in mice, leading to the concept that inhibition of EL could be a novel strategy for raising HDL cholesterol levels. However, mice are "HDL animals" and the effect of EL on atherogenic apoB-containing lipoproteins has not been elucidated. We previously found that EL is capable of hydrolyzing very low-density lipoprotein (VLDL) and LDL lipids ex vivo. To investigate the role of EL in the metabolism of apoB-containing lipoproteins in vivo, we expressed human EL in three mouse models of elevated apoB-containing lipoproteins: apoE-deficient, LDL receptor-deficient, and human apoB transgenic mice. Unexpectedly, hepatic expression of EL resulted in markedly decreased levels of VLDL/LDL cholesterol, phospholipid, and apoB accompanied by significantly increased LDL apolipoprotein and phospholipid catabolism. To determine whether lipolytic activity is required for this effect, we also expressed a catalytically inactive form of human EL (ELS149A); unexpectedly, expression of ELS149A did not lower and in fact increased plasma lipids. Coexpression and coimmunoprecipitation studies suggested that catalytically inactive ELS149A inhibits endogenous mouse EL, accounting for the increased lipid levels. We conclude that (1) in addition to its known effects on HDL metabolism, EL influences the metabolism of apoB-containing particles; (2) catalytic activity of EL is required for its effects on apoB-containing lipoproteins; and (3) overexpressed catalytically inactive EL inhibits endogenous mouse EL, resulting in increased levels of plasma lipids. In light of these results, inhibition of EL has the potential to raise levels of atherogenic lipoproteins in addition to HDL-C levels.     

Collection of peripheral blood stem cells in newly diagnosed myeloma patients without any prior cytoreductive therapy: the first step towards an 'operational cure'?

We have shown that primary therapy with non-myeloablative (140 mg/m(2)) high-dose melphalan (HDM) without hematopoietic support results in high response rates in untreated myeloma and very long-term survival of some patients. This study was designed to see if sufficient CD34 (+) cells can be harvested at presentation in newly diagnosed patients to administer myeloablative HDM (200 mg/m(2); HDM200) with autograft as primary therapy. This may improve outcome by rapid achievement of complete remission (CR) and possible avoidance of late myelodysplasia as a consequence of non-transplant induction chemotherapy. Thirty untreated patients received 1 g/m(2) methylprednisolone daily (days 1-6) and 12-16 micro g/kg G-CSF daily (days 3-6), and underwent leukapheresis on days 6 and 7. The median CD34(+) cell yield was 1.31 x10(6)/kg (range, 0.23-5.63), and was > or =1 x10(6)/kg in 73%. Cell yields were significantly lower than in 82 historical controls apheresed after completion of induction chemotherapy (median 2.16 x 10(6)/kg), and improved in patients who were apheresed again after induction chemotherapy. Three patients received primary therapy with HDM200 and autograft using these cells and attained CR. We conclude that it is possible to harvest stem cells in three-quarters of untreated myeloma patients. Increasing the number of apheresis procedures is needed to improve the number of CD34(+) cells collected.     

p55CDC25 is a nuclear protein required for the initiation of mitosis in human cells.

The cdc25+ gene of fission yeast encodes a phosphotyrosine phosphatase that dephosphorylates tyrosine-15 of p34cdc2 and thereby activates p34cdc2/cyclin to bring about entry into M phase. We have recently cloned a human homolog, CDC25, which rescues the M-phase initiation defect of yeast cdc25 temperature-sensitive mutants. Antibodies raised against the CDC25 gene product specifically recognize human proteins of approximately 55 and approximately 52 kDa. Microinjection of affinity-purified anti-CDC25 antibodies into HeLa cells inhibits entry into mitosis. These observations suggest that the CDC25 gene products are essential for the initiation of mitosis in human cells, similar to their homologs in fission yeast and Drosophila. CDC25 gene products, like p34CDC2, are localized primarily in the nucleus during interphase, suggesting that activation of p34CDC2/cyclin by p52/p55CDC25 occurs within the nucleus.     

Catalytic degradation of Orange II in aqueous solution using diatomite-supported bimetallic Fe/Ni nanoparticles

A functional diatomite-supported Fe/Ni nanocomposite successfully remediated Orange II contaminant in aqueous solution. The hypothesis was that diatomite-supported Fe/Ni would not only be more effective than Fe/Ni but also require less metallic loading to effect the catalytic reaction. Batch experiments indicate that 99.00% of Orange II was removed using diatomite-supported Fe/Ni, while only 86.64 and 3.59% of Orange II were removed using bimetallic Fe/Ni nanoparticles and diatomite, after 6 h of reaction, respectively. Characterisation by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM) and scanning electron microscopy (SEM) indicates that the use of diatomite as a support material reduced the aggregation of bimetallic Fe/Ni nanoparticles, thereby resulting in an enhancement in the reactivity. A synergistic mechanism for the removal of Orange II by diatomite-supported Fe/Ni was proposed which involves adsorption, followed by catalytic reduction. This study has demonstrated that diatomite may be a suitable support material for stabilizing and dispersing bimetallic Fe/Ni nanoparticles and the resulting diatomite-supported Fe/Ni composite could be a promising catalyst for the remediation of dye-contaminated wastewater.

A functional diatomite-supported Fe/Ni nanocomposite successfully remediated Orange II contaminant in aqueous solution.     

Pilot Randomized Controlled Trial of Motivational Interviewing with Sexual Minority Male Couples to Reduce Drug Use and Sexual Risk: The Couples Health Project

AIDS and Behavior - A randomized controlled trial evaluated the preliminary efficacy of a dyadically-delivered motivational interviewing (MI) intervention to reduce drug use and sexual risk in a...     

Luteinizing hormone release from chicken pituitary cells: synergism between calcium and protein kinase C and its inhibition by calmodulin antagonists

Continuous stimulation of cultured chicken pituitary cells with a native chicken hypothalamic GnRH, Gln8-GnRH, caused LH release, followed by rapid desensitization. Continuous exposure to calcium ionophore A23187 also produced a short-lived LH response, followed by desensitization. In contrast, continuous stimulation with a phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), caused prolonged release of LH, reaching maximum amplitude after 1 h and slowly decreasing thereafter. Cells desensitized to GnRH remained fully responsive to A23187 and TPA, indicating that GnRH-mediated desensitization occurs at a level before protein kinase C activation and calcium mobilization. Simultaneous addition of A23187 and TPA resulted in a synergistic response which was independent of the order of addition of the two compounds. Synergism was also demonstrated between depolarizing concentrations of potassium and TPA and between veratridine and TPA, indicating that calcium entering via voltage-dependent channels also synergizes with phorbol ester. Despite the prolonged action of TPA, rapid pulsatile changes in LH release could be induced in cells treated with TPA and veratridine by rapidly changing the extracellular calcium concentration. This suggest that protein kinase C could function as an amplifier of the calcium signal generated by GnRH. Synergism between calcium and TPA was blocked by trifluoperazine, chlorpromazine, and W-7 [N-(6-aminohexyl)5-chloro-1-napthalenesulfonamide] at concentrations that had no effect on LH release mediated by TPA alone. This suggests that synergism is mediated via calmodulin and not a direct effect of calcium on protein kinase C.     

Identification and quantification of apneas by computer-based analysis of oxygen saturation

Manual detection and quantitation of apneas from an all-night polysomnogram is very time-consuming. Because SaO2 changes with virtually every apnea event, we reasoned that by identifying cyclical SaO2 changes, we could calculate (1) an apnea-hypopnea index that would correlate very well with the manually derived apnea-hypopnea index, and (2) the duration of apnea-hypopnea events. We developed a computer algorithm to scan and detect dips in SaO2 data digitally stored as a time series by computer throughout overnight studies. Desaturations detected by computer were compared with the events detected manually in 9 all-night polysomnograms from 6 patients with typical obstructive sleep apnea. Events detected by one method but not the other were subsequently verified to determine the overall number of apnea-hypopnea events present and to determine false positive and false negative rates for the 2 methods of detection. The total number of apneas was 4,008. Both methods agreed on 3,639 of them. Of 77 manually recorded apneas not detected by computer, 24 were subsequently discounted (manual false positives, 24 of 4,007 = 0.6%) and 53 confirmed (computer false negatives, 1.32%). Of 358 events not detected manually, 316 were confirmed (manual false negatives, 7.9%) and 42 discounted (computer false positives, 1.1%). Using the final manual scoring as the reference, the computer program detected apneas with a sensitivity of 97.9%, and the predictive value of a computer-detected event was 90.8%. For event duration, a regression was performed on 3,623 matched apneas-hypopnea events, giving a coefficient of r = 0.9431, p less than 10(-6).(ABSTRACT TRUNCATED AT 250 WORDS)     

The sialylation of plasma lipoproteins

Sialic acids are a family of amino sugars that are commonly found as terminal oligosaccharide residues on glycoproteins and glycolipids. Plasma lipoproteins are sialylated on their apolipoprotein and glycolipid constituents. The function of sialic acid on apolipoproteins is not completely understood but has been associated with secretion, lipid-binding, and plasma clearance for some apolipoproteins. The sialic acid content of individual apolipoproteins can vary in response to physiological conditions while the sialic acid content of individual sialylated glycolipids (gangliosides) is constant. Thus, the sialic acid content of plasma lipoproteins can differ considerably as a result of (1) variations in the sialylation of their apolipoprotein constituents, (2) variations in their content of sialylated apolipoproteins and gangliosides, and (3) modifications of the sialic acid on lipoprotein constituents while circulating in plasma. The significance of sialic acid on lipoproteins is not fully understood although associations have been made between sialic acid and charge (very low density lipoprotein), lipoprotein solubility, receptor binding and uptake, and interactions with vascular matrix (low density lipoprotein and Lp(a)) and with cholesterol efflux (high density lipoprotein). Further studies identifying sites of sialylation on apolipoproteins and characterizing the structures of sialylated oligosaccharides will aid in determining the enzymes responsible for their sialylation. Manipulations of the sialylation of apolipoproteins and of the quantity of apolipoproteins and gangliosides on lipoproteins will be useful methods in determining the role of lipoprotein sialic acid in the development of atherosclerosis.     

The effect of oxygen on respiration and sleep in patients with congestive heart failure

STUDY OBJECTIVE: To determine the effect of supplemental oxygen on Cheyne-Stokes respiration, nocturnal oxygen saturation (SaO2), and sleep in male patients with severe, stable congestive heart failure. DESIGN: Randomized, single-blind, placebo-controlled crossover study. SETTING: Patients referred from outpatient cardiology clinics of two teaching hospitals. PATIENTS: Sequential sample of nine outpatients with severe, stable congestive heart failure. INTERVENTIONS: For each patient, sleep studies (after an adaptation night) from two consecutive randomized nights were compared; one study was done while the patient breathed compressed air and the other while the patient breathed oxygen (O2). Compressed air and oxygen were both administered through nasal cannulae at 2 to 3 L/min. MEASUREMENTS AND MAIN RESULTS: Cheyne-Stokes respiration, defined as periodic breathing with apnea or hypopnea, was found in all patients. Low-flow oxygen significantly reduced the duration of Cheyne-Stokes respiration (50.7% +/- 12.0% to 24.2% +/- 5.4% total sleep time), mainly during stage 1 NREM (non-rapid eye movement) sleep (21.3% +/- 7.1% to 6.7% +/- 2.3% total sleep time) with no significant change during stage 2 sleep, slow-wave sleep, or REM (rapid eye movement) sleep. Although patients had normal SaO2 (96.0% +/- 1.7%) while awake, severe sleep hypoxemia was common; breathing oxygen reduced the amount of time that SaO2 was less than 90% from 22.3% +/- 8.0% to 2.41% +/- 1.93% of total sleep time. Sleep, disrupted to a variable extent in all patients, improved with oxygen therapy: There was an increase in total sleep time from 275.3 min +/- 36.6 to 324.6 min +/- 23.3; a reduction in the proportion of stage 1 sleep (27.6% +/- 5.8% total sleep time to 15.2% +/- 2.6% total sleep time); and a reduction in the number of arousals (30.4/h +/- 8.0 to 13.8/h +/- 1.9). The apnea-hypopnea index was reduced from 30.0 +/- 4.7 to 18.9 +/- 2.4 with oxygen breathing. CONCLUSION: In severe, stable congestive heart failure, nocturnal oxygen therapy reduces Cheyne-Stokes respiration, corrects hypoxemia, and consolidates sleep by reducing arousals caused by the hyperpneic phase of Cheyne-Stokes respiration. Correction of nocturnal hypoxemia and sleep disruption may improve the clinical status of these patients.