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To forecast geomagnetic storms, we had examined initially observed parameters of coronal mass ejections (CMEs) and introduced an empirical storm forecast model in a previous study. Now we suggest a two-step forecast considering not only CME parameters observed in the solar vicinity but also solar wind conditions near Earth to improve the forecast capability. We consider the empirical solar wind criteria derived in this study (Bz ≤ -5 nT or Ey ≥ 3 mV/m for t≥ 2 h for moderate storms with minimum Dst less than -50 nT) and a Dst model developed by Temerin and Li (2002, 2006) (TL model). Using 55 CME-Dst pairs during 1997 to 2003, our solar wind criteria produce slightly better forecasts for 31 storm events (90%) than the forecasts based on the TL model (87%). However, the latter produces better forecasts for 24 nonstorm events (88%), while the former correctly forecasts only 71% of them. We then performed the two-step forecast. The results are as follows: (i) for 15 events that are incorrectly forecasted using CME parameters, 12 cases (80%) can be properly predicted based on solar wind conditions; (ii) if we forecast a storm when both CME and solar wind conditions are satisfied (∩), the critical success index becomes higher than that from the forecast using CME parameters alone, however, only 25 storm events (81%) are correctly forecasted; and (iii) if we forecast a storm when either set of these conditions is satisfied (∪), all geomagnetic storms are correctly forecasted.

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Mutations in the Wnt signalling cascade are believed to cause aberrant proliferation of colorectal cells through T-cell factor-4 (TCF4) and its downstream growth-modulating factors. HOXB13 is exclusively expressed in prostate and colorectum. In prostate cancers, HOXB13 negatively regulates beta-catenin/TCF4-mediated transactivation and subsequently inhibits cell growth. To study the role of HOXB13 in colorectal tumorigenesis, we evaluated the expression of HOXB13 in 53 colorectal tumours originated from the distal left colon to rectum with their matching normal tissues using quantitative RT-PCR analysis. Expression of HOXB13 is either lost or diminished in 26 out of 42 valid tumours (62%), while expression of TCF4 RNA is not correlated with HOXB13 expression. TCF4 promoter analysis showed that HOXB13 does not regulate TCF4 at the transcriptional level. However, HOXB13 downregulated the expression of TCF4 and its target gene, c-myc, at the protein level and consequently inhibited beta-catenin/TCF-mediated signalling. Functionally, forced expression of HOXB13 drove colorectal cancer (CRC) cells into growth suppression. This is the first description of the downregulation of HOXB13 in CRC and its mechanism of action is mediated through the regulation of TCF4 protein stability. Our results suggest that loss of HOXB13 may be an important event for colorectal cell transformation, considering that over 90% of colorectal tumours retain mutations in the APC/beta-catenin pathway.

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The authors tested the cognitive vulnerability hypotheses of depression with a retrospective behavioral high-risk design. Individuals without current Axis I diagnoses who exhibited either negative or positive cognitive styles were compared on lifetime prevalence of depressive and other disorders and the clinical parameters of depressive episodes. Consistent with predictions, cognitively high-risk participants had higher lifetime prevalence than low-risk participants of major and hopelessness depression and marginally higher prevalence of minor depression. These group differences were specific to depressive disorders. The high-risk group also had more severe depressions than the low-risk group, but not longer duration or earlier onset depressions. The risk group differences in prevalence of depressive disorders were not mediated by current depressive symptoms.

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Previously, we demonstrated that transforming growth factor-beta (TGF-beta) pretreatment protects neuroblastoma cell lines, human hNT neurons, and primary rat embryo hippocampal neurons (REHIPs) from degeneration caused by incubation with beta-amyloid peptide (Abeta). Here we present evidence suggesting that TGF-beta interferes with an apoptotic pathway induced by Abeta. TGF-beta preteatment decreases the amount of DNA laddering seen following Abeta treatment in neuroblastoma cells, while in REHIPs, TGF-beta decreases the number of positive cells detected in situ by Klenow labelling following Abeta treatment. RT-PCR shows that in REHIPs, Abeta decreases mRNA expression of Bcl-2, as well as the ratio of Bcl-xL/Bcl-xS, with little effect on Bax expression. These changes are expected to promote apoptosis. When REHIPs are incubated with TGF-beta before addition of Abeta, the Bcl-xL/Bcl-xS ratio and Bcl-2 levels are increased compared to cells treated with Abeta alone. Again there is little effect on Bax expression. Western blotting and immunohistochemistry experiments also show that TGF-beta maintains increased levels of Bcl-2 and Bcl-xL protein in REHIPs even in the presence of Abeta. This pattern of gene expression should function to decrease apoptosis. Similarly, RT-PCR analysis of mRNA prepared from hNT cells shows that TGF-beta pretreatment before addition of Abeta maintains a higher level of Bcl-2 expression and an increased Bcl-xL/Bcl-xS ratio as compared to cells treated with Abeta alone. In neuronal cell types treated with Abeta, TGF-beta appears to regulate expression of genes in the Bcl-2 family to favor an anti-apoptotic pathway.

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A prospective study of 69 patients (138 knees) who had a primary simultaneous bilateral total knee replacement was conducted to assess the effect of postoperative suction drainage on wound healing and infection. A suction drain was placed by randomization of side for the drained versus nondrained side. The same operative technique was used in all wounds of total knee arthroplasty. The knees that had no drains had a higher incidence of drainage from the wound, had soaked dressings requiring dressing reinforcements, and had more ecchymosis and erythema around the wound. However, the final results regarding quadriceps strength, range of motion, and wound complications were not affected significantly by nonuse of closed suction drainage. Although the incidence of infection in the two groups is not statistically different, the development of infection in two knees in which drains were not used suggests that suction drainage may reduce deep infection.

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A prospective study of 48 patients (96 hips) who had undergone primary simultaneous bilateral total hip arthroplasty was conducted to assess the effect of postoperative suction drainage on wound healing and infection. A suction drain was placed by randomization of the drained versus undrained side. The same surgical technique was used in all total hip arthroplasty wounds. Statistical analysis of the results showed significant differences with respect to drainage from the wound, soaked dressings requiring reinforcements, ecchymosis, and erythema about the wound in the group without drainage. There was no specific correlation between the incidence of wound complications and infection after total hip arthroplasty and the use or nonuse of closed-suction drainage. The hip score and range of motion of the hip were unaffected by the use or nonuse of the drains. The cost of 1 set of hemovac drains is $135 and the cost for 4-5 dressings and bed sheet changes is about $50. Although the hemovac is more expensive, the authors recommend the routine use of suction drains for wounds after primary total hip arthroplasty to reduce drainage, soaked dressings requiring reinforcement, ecchymosis and erythema around the wound, and psychological impact on the patient's fear of bleeding.

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The active components of Aloe vera gel that can prevent ultraviolet B (UVB)-induced suppression of accessory cell function of Langerhans cells (LC) were purified by activity-guided sequential fractionation followed by in vitro functional assay. The functional assay was based on the fact that exposure of freshly isolated murine epidermal cells (EC) to UVB radiation resulted in impairment of accessory cell function of LC, as measured by their ability to support anti-CD3 monoclonal antibody (mAb)-primed T-cell mitogenesis. This UVB-suppressed LC accessory cell function was prevented by addition of partially purified Aloe gel components to cultures of UVB-irradiated EC. The Aloe gel components appeared to prevent events occurring within the first 24 h after UVB irradiation that lead to the impairment of accessory cell function. The Aloe gel components did not cause proliferation of anti-CD3 mAb-primed T-cells, nor did induce proliferation of normal EC. The activity-guided final purification of Aloe gel components resulted in the isolation of two components. Both of the components were small molecular weight (MW) substances with an apparent MW of less than 1,000 Da but different from each other in net charge characteristics at pH 7.4. These results suggest that Aloe vera gel contains at least two small molecular weight immunomodulators that may prevent UVB-induced immune suppression in the skin.

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Post-mitotic, human neurons (hNT cells) which have a phenotype similar to that of terminally differentiated neurons of the central nervous system were generated by treating the NT2/D1 human teratocarcinoma cell line with retinoic acid. Treatment of both hNT and NT2/D1 cells with 10(-5) M beta-amyloid peptide fragment 25-35 (A beta P) for 24 h resulted in a decrease in cell viability as determined by MTT incorporation and Trypan blue exclusion, and also induced an apoptotic morphology in hNT cells. Pre-treatment of cells for 24 h with 10 ng/ml TGF-beta 1 or 2 before addition of A beta P reduced the apoptotic morphology of hNT cells and increased cell viability in hNT cells, but not in NT2/D1 cells. Results of RT-PCR, immunohistochemistry and analysis of receptor cross-linking of [125I]TGF-beta 1 to the cell membrane, all showed that the TGF-beta type II receptor is expressed by hNT cells, but not NT2/D1 cells. These results suggest that TGF-beta can protect human, terminally differentiated, TGF-beta type II receptor-positive neurons from A beta P toxicity. We propose that the increased expression of TGF-beta in brains of patients with Alzheimer's disease may offer some degree of neuroprotection if neurons also express a functional TGF-beta type II receptor.

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The basidiocarps of Ganoderma lucidum have been used for prevention and treatment of various diseases in the Orient. Methanolic extracts of this mushroom were applied to human peripheral blood mononuclear cell (PBMC) culture systems in the presence of various immunostimulating or immunosuppressive agents. Phytohemagglutinin-induced cell proliferation was reduced to 14% of that of the control by a GLE fraction that is the neutral component of the methanolic extracts of the carpophores. 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced cell proliferation was inhibited by the fractions of GLA, GLC, GLE and GLG. However none of these fractions inhibited proliferation of the PBMCs stimulated with TPA plus ionomycin (IM). Treatment of the PBMCs with cyclosporin A (CsA) led to blockage of the cell proliferation to 9% of that of the control. When the cells were cultured with the methanolic fractions in the presence of CsA, concentration dependent inhibition of the cell proliferation was observed by the addition of GLE and GLG fractions. On the contrary, the GLH fraction recovered the CsA induced inhibition of the cell proliferation. Taken together, among the methanolic fractions, GLE showed the highest inhibitory activity. This fraction might inhibit the protein kinase C signal pathway and accelerate the CsA signal pathway.

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The antiproliferative properties of three 21-aminosteroid antioxidants (lazaroids), 21-[4-[5,6-bis(diethylamino)-2-pyridinyl]-1- piperazinyl]-16 alpha-methylpregna-1,4,9(11)triene-3,20-dione, hydrochloride (U74500A), 21-[4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piper- azinyl]-pregna-1,4,9(11)-triene-3,20-dione, monomethanesulfonate (U74389F), 2H-1-benzopyran-6-ol, 2-[[4-[3-(ethylamino)-2-pyridinyl]-1-piperzinyl]methyl]-3,4- dihydro-2,5,7,8-tetramethyl-, (Z)-2-buten dioate (U78518F), on human breast cancer cells are described. U74500A inhibited cell proliferation in a dose-dependent manner with IC50 values of approximately 1.7 and 1.2 microM when cells were exposed to the drug for 3 and 5 days, respectively. The non-steroid antioxidants, alpha-tocopherol and nordihydroguaiaretic acid, showed weak or no activity at the same dose range. All three lazaroids inhibited, dose dependently, the proliferation of mouse lymphocytes but only at IC50 values ranging between 20-30 microM. The specificity of action was studied by including other steroids: progesterone, testosterone and hydrocortisone. Both sex hormones stimulated cell proliferation at low (less than 10(-5) M) concentrations but inhibited at higher doses with IC50 values of 26 (progesterone) and 80 (testosterone) microM. Hydrocortisone (IC50 0.17 microM), on the other hand, inhibited cell proliferation by 70% over a wide range of doses. Human breast cancer cells appear to have a greater sensitivity than the mouse lymphocytes to lazaroids. The antiproliferative effects of lazaroids in cancer cells may be, at least in part, due to an interaction with glucocorticoid receptors.

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Four human colon adenocarcinoma cell lines, SNU-C1, SNU-C4, SNU-C5, and NCI-H716, that are capable of proliferating autonomously in serum-free medium containing no added peptide growth factors were identified. All four cell lines show epidermal growth factor (EGF) receptors (EGFRs), express transforming growth factor alpha (TGF-alpha) messenger RNA, and release anti-TGF-alpha-immunoreactive molecules. The blocking anti-EGFR monoclonal antibody (mAb) 225 blocks autonomous proliferation of SNU-C1 and SNU-C4 cells. In both of these cell lines, the inhibitory effect of mAb 225 is reversible by the addition of EGF, TGF-alpha, or conditioned medium from any of the four cell lines. In contrast, autonomous proliferation of SNU-C5 and NCI-H716 cells is not inhibited by mAb 225 and is not affected by exogenous EGF, TGF-alpha, or conditioned medium. Together, these data confirm the previous finding that anti-EGFR antibodies can inhibit the proliferation of some carcinoma cell lines that coexpress TGF-alpha and EGFR. However, here it is shown that the mechanisms of autonomous proliferation of colon carcinoma cell lines are heterogeneous and not always sensitive to antibody disruption of TGF-alpha/EGFR autocrine interactions.

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The cytotoxic effect of aldehydic metabolites of linoleic acid, 13-oxo-tridecadienoic acids, on MCF-7 human breast cancer cells was investigated. The metabolites inhibited the growth of the cancer cells and the effect was dependent on both time of exposure and concentration of the metabolites; 50% growth inhibition occurred at approximately 55 and 33 microM, after 3- and 5-day incubations, respectively. The metabolites had greater cytotoxicity than parent linoleic acid or other polyunsaturated fatty acids tested. The antiproliferative effect was partially reversed by 10 microM of dithiothreitol suggesting that attack on thiol groups in cancer cells by highly reactive alpha, beta-unsaturated carbonyl moiety in the metabolites was responsible for the cytotoxic actions.

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The synthesis of the glucoside, 3 beta-[(beta-D-glucopyranosyl)oxy]-14-hydroxy-14 beta-pregn-4-en-20-one, a 14 beta-hydroxyprogesterone glucoside (14 beta-OHP-glu), is described. This compound has an IC50 of 1 microM in a [3H]ouabain binding assay, and is about 10 times more potent than the aglycone. Like 14 beta-hydroxyprogesterone, the glucoside enhances contractility of isolated cardiac muscle. 14 beta-OHP-glu or ouabain, when infused at comparable doses into the renal artery of the anesthetized rat, markedly increases urine volume. Whereas ouabain significantly enhances urinary potassium excretion with little or no effect on sodium excretion, 14 beta-OHP-glu promotes a marked natriuresis with no significant effect on potassium excretion.

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We demonstrated previously that products of linoleic and arachidonic acids, arising from enzymatic or non-enzymatic oxidation, inhibit ATP-dependent calcium accumulation into and promote release of calcium from vesicles derived from sarcoplasmic reticulum of guinea-pig heart. In the present study, direct enzymatic peroxidation of cardiac membrane lipids was performed and the effect on calcium transport was examined. Vesicles were preincubated at 37 degrees C with soybean lipoxygenase-1 (linoleate:oxygen oxidoreductase, EC 1.13.11.12) for up to 1 h prior to the initiation of calcium accumulation. The extent of membrane peroxidation was assessed by monitoring the production of malondialdehyde. Pretreatment of vesicles with lipoxygenase for 40 and 60 min markedly depressed calcium accumulation. The lipoxygenase-induced suppression of calcium transport was completely antagonized by nordihydroguaiaretic acid (1 microM), not at all by indomethacin (1 microM), and only partially by 5,8,11,14-eicosatetraynoic acid (0.3 microM). Low concentrations of calcium (10(-5)-5 X 10(-5) M) enhanced, and a high concentration (10(-3) M) inhibited lipoxygenase-induced peroxidation of membrane lipids. The calcium-accumulating ability of the vesicles was inversely related to the extent of membrane peroxidation. The vesicles which showed the highest degree of peroxidation in the presence of 5 X 10(-5) M calcium, accumulated the lowest amount of calcium. In contrast, calcium at 10(-3) M suppressed lipid peroxidation, resulting in higher calcium uptake than in vesicles peroxidized in the absence of calcium. Thus, calcium transport is depressed in microsomes undergoing lipoxygenase-induced peroxidation, a process which in turn is modulated by calcium.

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The effect of linoleic and arachidonic acid derivatives on ATP-dependent calcium transport was studied in the isolated vesicles from cardiac sarcoplasmic reticulum of guinea-pigs. Oxidation products of linoleic and arachidonic acids, obtained either by autoxidation or incubation with soybean lipoxygenase, effectively blocked in a dose-dependent manner, the net influx of calcium in the absence or presence of 5 mM of oxalate. Unoxidized fatty acids were much weaker at lower concentrations as compared to their oxidized counterparts, except the lipoxygenase-generated product of arachidonic acid which had only a marginal effect even at high concentrations. Autoxidation products of arachidonic acid were the most potent inhibitors of calcium transport. Likewise, autoxidation products of linoleic and arachidonic acids and lipoxygenase-generated products of linoleic acid induced a dose-dependent release of calcium from vesicles previously loaded with 45Ca, and release was further enhanced in the presence of 0.5 mM of EGTA. In contrast, lipoxygenase metabolites of arachidonic acid caused a transient increase in net calcium content. The effect of the fatty acid derivatives on calcium transport did not appear to be due either to the inhibition of Ca2+-ATPase activity or to a non-specific detergent-like action. The effects of oxidized fatty acids, on ATP-dependent calcium accumulation into and release from cardiac microsomal fraction were similar but less potent than those of classical calcium ionophores, X537A or A23187.

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Oxidation profiles of polyunsaturated fatty acids, their esters, and fatty alcohols were compared by several commonly employed analytical procedures. The extent of lipid peroxidation varied with the structure of the specific lipid class. The rate of oxidation was greater for polyenoic lipids than for dienoic counterparts. In general, the maximum diene conjugation and thiobarbituric acid reactivity occurred earlier for acids than for esters or alcohols containing identical numbers of carbon chains and double bonds. For each homologous series there were, initially, increasing levels of conjugated dienes and thiobarbituric acid-reactive products, which then diminished in association with rising levels of carbonyl and fluorescent products. At late stages of oxidation, conjugated diene or thiobarbituric acid reactivity was not indicative of total peroxidation products. Thus, supplementary measurements are required to detect secondary degradation products of polyunsaturated fatty acids.

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The synthesis of 14-hydroxy-14 beta-pregn-4-ene-3,20-dione (14 beta-hydroxyprogesterone) is described. This novel steroid is about 10 times more potent than progesterone and one-tenth as potent as ouabagenin in an [3H]ouabain radioligand binding assay and is the first in a series of progesterone congeners that interact at the cardiac glycoside receptor both to possess the C/D cis ring junction and to enhance contractility of isolated cardiac tissue.

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The profiles of lipid peroxidation products in liver homogenates or microsomal membranes prepared from CCl4-intoxicated mice were determined by several commonly employed methods. The level of conjugated dienes peaked within 30 min and then decreased, suggesting the transitory nature of lipid peroxides in vivo. Values for thiobarbituric acid positive material peaked 30 min after CCl4 treatment, diminished thereafter for a time, and gradually rose to a new maximum at 24 h; the first peak appears to represent lipid peroxides and the second represents further degradation products including malondialdehyde. Fluorescence intensity (excitation, 360 nm; emission, 430 nm) was closely correlated with the second peak. Our findings support the involvement of lipid peroxidation in CCl4-induced hepatotoxicity in mice and emphasize the necessity for several analytical indices of lipid peroxidation performed at different time intervals.

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A number of progesterone derivatives, having a 17 alpha-acetoxy group and various functions at C-3 and C-6, interact at the cardiac glycoside (CG) binding site, using [3H]ouabain in a radioligand binding assay (RBA) with membranes from dog myocardium. We now report on results of structure-activity studies concerned with modification of the A and B rings as they influence potency in the RBA. Some progesterone derivatives with 5 alpha- or 5 beta-stereochemistry show weak receptor competing activity. Among the congeners highest potency is associated with the presence of C-4 or C-4,6 unsaturation and a C-6 substituent (CH3, Cl, Br) whose importance appears to reside in its steric rather than electronic character. The C-3 function may be carbonyl, 3 beta-hydroxy or 3 beta-acetoxy when associated with C-4 or C-4,6 unsaturation. In compounds with other substituents that promote activity, C-6 alpha substitution with -CH3, -Cl, or -Br strongly enhances activity; -F, -OCH3, carbonyl, or the unsubstituted compound promotes weak binding; and -OC2H5, -OAc, -OCOOCH3, or -OH eliminates binding activity. Receptor interaction with the double bond at C-4, but not C-5, appears to be particularly important for binding. The most potent analog identified thus far is chlormadinone acetate (17 alpha-acetoxy-6-chloropregna-4,6-diene-3,20-dione), which has 1/20 the potency of ouabain in the RBA. Studies to determine optimal structural requirements for CG-receptor binding by these hormonal steroid congeners, in conjunction with appropriate biological assays, may provide insight into the nature of a putative endogenous counterpart, lead to a better understanding of the mode of action of the CG and yield CG-like compounds with superior therapeutic properties.

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