Precise predictions for V + jets dark matter backgrounds.

High-energy jets recoiling against missing transverse energy (MET) are powerful probes of dark matter at the LHC. Searches based on large MET signatures require a precise control of the Z ( ν ν ¯ ) +  jet background in the signal region. This can be achieved by taking accurate data in control regions dominated by Z ( ℓ + ℓ - ) +  jet, W ( ℓ ν ) +  jet and γ +  jet production, and extrapolating to the Z ( ν ν ¯ ) +  jet background by means of precise theoretical predictions. In this context, recent advances in perturbative calculations open the door to significant sensitivity improvements in dark matter searches. In this spirit, we present a combination of state-of-the-art calculations for all relevant V +  jets processes, including throughout NNLO QCD corrections and NLO electroweak corrections supplemented by Sudakov logarithms at two loops. Predictions at parton level are provided together with detailed recommendations for their usage in experimental analyses based on the reweighting of Monte Carlo samples. Particular attention is devoted to the estimate of theoretical uncertainties in the framework of dark matter searches, where subtle aspects such as correlations across different V +  jet processes play a key role. The anticipated theoretical uncertainty in the Z ( ν ν ¯ ) +  jet background is at the few percent level up to the TeV range.

Inhibitory effect of statins on the proliferation of human breast cancer cells.

OBJECTIVE: Long-term hormone therapy in the postmenopause is associated with a moderate increase in cardiovascular and breast cancer risk. Of great concern, therefore, is the question of how women with menopausal symptoms and enhanced cardiovascular risk can be treated. Evidence is growing that an estrogen/statin combination may be a good choice, since this combination seems to elicit additive beneficial effects on the lipid profile and on the vasculature. METHODS: In the present study, the effect of two statins on the proliferation of breast cancer cells in the presence and absence of estradiol was investigated. RESULTS: Atorvastatin and fluvastatin were able to inhibit the proliferation of MCF-7 cells in the absence of estradiol. This effect seems to depend on an apoptotic statin effect which may be mediated by the down-regulation of the anti-apoptotic protein Bcl-2 rather than up-regulation of Fas-L or p53. However, in the presence of estradiol the inhibitory effect of the statins was less pronounced. CONCLUSIONS: The present data indicate that statins may possess anticancerogenic properties concerning the development of breast cancer in postmenopausal women. Clinical trials are necessary to prove a beneficial statin effect on breast cancer risk when combined with long-term hormone therapy.

Class-specific pro-apoptotic effect of statins on human vascular endothelial cells.

Neonangiogenesis represents an important step in tumor development and propagation. Statins may have anticancerogenic potential by blocking vascular endothelial cell growth. The antiproliferative effect of four statins on human endothelial cells was compared, concomitantly delineating a possible pro-apoptotic process. All four statins tested, i. e. atorvastatin, fluvastatin, lovastatin, and simvastatin inhibited cell proliferation. Nearly complete blocking of cell proliferation was achieved at a concentration of 10 microM. We were able to demonstrate that the antiproliferative effect of the statins is not due to cytotoxicity but rather to an apoptotic effect as demonstrated by comparison of cytotoxicity assay and apoptosis assay. The apoptotic mechanism seems to involve caspases, since the statins significantly enhanced caspase activity at dosages of 10 and 20 microM. Further experiments revealed a downregulation of the pro-apoptotic protein Bcl-2. Our data indicate that statins may class-specific inhibit angiogenesis at high dosages which can contribute to prevention of tumor development and progression.

Influence of infection with non-filarial helminths on the specificity of serological assays for antifilarial immunoglobulin G4.

Serological assays based on the detection of immunoglobulin (Ig) G4 antibodies to crude filarial extracts are widely used for epidemiological and diagnostic purposes. We tested 195 samples collected in 1998 from an area of Brazil where filariasis is not endemic and 13 (6.7%) had levels of antifilarial IgG4 antibodies that were defined as positive. Both Strongyloides infection and the presence of Strongyloides antibody responses were associated with higher antifilarial antibody responses. None of the specimens had a positive response to the Brugia malayi recombinant antigen (Bm14). These data suggest that serodiagnostic assays based on the use of crude filarial antigens should be interpreted with caution because of the potential for cross-reactivity with Strongyloides.

A conformational C4 peptide polymer vaccine coupled with live recombinant vector priming is immunogenic but does not protect against rectal SIV challenge.

The conserved, immunogenic CD4 binding site on the viral envelope is an attractive HIV or SIV vaccine candidate. Polymerization of an 18 amino acid segment derived from the C4 domain of SIV gp120 produced a peptide polymer or "peptomer," having an alpha-helical conformation possibly mimicking a proposed structure of the C4 domain in the unbound native protein. The SIV peptomer and native gp120 were compared as subunit boosts following two adenovirus type 5 host range (Ad5hr)-SIVenv recombinant priming immunizations. Both vaccine regimens successfully elicited SIV-specific CTL responses in five of six immunized macaques. Peptomer-boosted macaques exhibited significantly higher envelope-specific T cell proliferative responses than either the gp120-boosted macaques or controls. Peptomer immunization also elicited peptomer and SIV gp120-specific binding antibodies, but only native gp120 boosting elicited SIV neutralizing antibodies. Upon intrarectal challenge with SIVmac32H, all nine macaques became infected. The solely envelope-based vaccine conferred no protection. However, changing the boosting immunogen to the C4 peptomer did not improve protective efficacy in spite of its elicitation of humoral and cellular immune responses, including robust T-helper activity. In spite of the peptomer's strong immunogenicity and potential for induction of broadly protective immune responses, it was not effective as a subunit vaccine.

Electrochemical methods for monitoring of environmental carcinogens.

The use of modern electroanalytical techniques, namely differential pulse polarography, differential pulse voltammetry on hanging mercury drop electrode or carbon paste electrode, adsorptive stripping voltammetry and high performance liquid chromatography with electrochemical detection for the determination of trace amounts of carcinogenic N-nitroso compounds, azo compounds, heterocyclic compounds, nitrated polycyclic aromatic hydrocarbons and aromatic and heterocyclic amines is discussed. Scope and limitations of these methods are described and some practical applications based on their combination with liquid-liquid or solid phase extraction are given.

Acute improvement of peripheral endothelial function in postmenopausal women with coronary artery disease after single oral intake of 17beta-estradiol valerate.

Chronic estrogen supplementation is known to improve endothelial function in postmenopausal women. We studied the acute effect of a single dose of orally administered 17beta-estradiol valerate (E2) on the peripheral endothelial dependent and independent vasodilatation in postmenopausal women with coronary artery disease (CAD). 20 postmenopausal women (age: 64.9 (7.2) y, height: 1.61 (0.04) m. weight: 68.6 (10.6) kg) with angiographically confirmed CAD were randomly examined for flow-associated vasodilatation (= FAD%, a marker for endothelial dependent vasodilatation) and for glyceryltrinitrate (400 microg, p.o.) induced vasodilatation (= GTN%, representing endothelial independent vasodilatation) two hours after placebo controlled, randomized crossover intake of 4 mg E2 p.o. After placebo FAD% was impaired (3.5 (1.7)%) compared to historic controls. After the oral intake of 4 mg E2, FAD% improved to 5.0 (2.8)% (P=0.02). GTN% was not significantly influenced by the oral E2 (E2: 12.6 (5.7) v placebo: 11.2 (6.9)%, P=0.14). Endothelial dysfunction can partially be restored by a single oral dose of 4 mg E2. This indicates an acute vasoprotective effect of E2 beyond its genomic and lipid modifying actions. It remains to be investigated if estrogen might play a beneficial role in the acute treatment of symptomatic coronary artery disease such as angina pectoris or preinfarct syndrome.

Continuous-combined treatment of the menopause with combinations of oestradiol valerate and dienogest - a dose-ranging study.

OBJECTIVES: To determine the progestational efficacy of continuous treatment with various doses of dienogest, combined with oestradiol valerate, on the basis of endometrial histology, effect on climacteric symptoms and bleeding profile in postmenopausal women. METHODS: Patients were randomised to one of five fixed-combination treatments, oestradiol valerate 2.0 mg plus dienogest 0.5, 1.0, 2.0, 3.0 or 4.0 mg. Efficacy was assessed by endometrial biopsy, menstrual charts and change in climacteric symptoms. RESULTS: The endometrium was classified as atrophic in 20.0, 31.3, 25.0, 55.6 and 57.1% of patients in the 0.5, 1.0, 2.0, 3.0 and 4.0 mg dienogest groups, respectively. The frequency of uterine bleeding was dose-dependent. The most favourable bleeding profile was seen in the 3.0 mg dienogest group, whereas the lower doses of dienogest had advantages with respect to the efficacy of the combined preparation. CONCLUSIONS: Dienogest 2.0 and 3.0 mg are the optimal doses for combination with 2.0 mg oestradiol valerate for continuous-combined hormone replacement therapy.

Efficient method for preparation of highly purified lipopolysaccharides by hydrophobic interaction chromatography.

A method for the efficient preparation of highly purified lipopolysaccharides (LPSs) by hydrophobic interaction chromatography (HIC) has been developed. The procedure can be used for the purification of cell wall bound LPSs after hot phenol-water extraction and for the isolation of extracellular LPSs from the supernatant, respectively. The method described has been tested with artificial mixtures containing LPSs, polysaccharide, protein and RNA and subsequently employed for the preparative purification of two LPSs of different origin, namely the extracellular LPS secreted by Escherichia coli E49 into the culture medium, and the cell wall bound LPS from Pseudomonas aeruginosa VA11465/1. Compared to currently used methods for LPS purification such as enzymatic digestion and ultracentrifugation, the chromatographic separation reported here combines superior purity with minimal loss of LPS, high reproducibility and simple handling. The removal of contaminants such as protein, RNA and polysaccharides and the recovery of LPSs were monitored by appropriate assays.

Estradiol concentrations in premenopausal women with coronary heart disease.

BACKGROUND: Because of the beneficial effects of estrogen, premenopausal women are normally protected against coronary heart disease (CHD) and are at lower risk for myocardial infarction; consequently, CHD occurs very rarely in menstrually active women. Given this background, the aim of the present study was to test the hypothesis that decreased concentrations of estrogen are associated with CHD in premenopausal women. METHODS: Fourteen premenopausal women with CHD were investigated and compared with a healthy control group comparable for age and cardiovascular risk factors. Relevant characteristics of patients and controls were assessed: age, blood pressure, body mass index, total cholesterol and high-density lipoprotein cholesterol, triglycerides, former pregnancies, ovariectomy and related surgical interventions, smoking history and former use of oral contraceptives. To ensure the premenopausal status of the participants, the regularity of the menstrual cycle and the follicle-stimulating hormone concentrations were also assessed. Plasma estradiol and progesterone and urine estrone concentrations (24 h urine collection) were measured at day 6 after estimated ovulation to assess the relative increase in plasma estradiol and progesterone during the second half of the menstrual cycle. RESULTS: Compared with the control group, premenopausal women with CHD had significantly lower concentrations of plasma estradiol (408.9 +/- 141 pmol/l and 287.8 +/- 109 pmol/l respectively; P = 0.0228) and total estrogen (2061 +/- 693 pg/mumol creatinine and 1607 +/- 448 pg/mumol creatinine respectively; P = 0.025) in the urine. However, the progesterone concentrations were not significantly different between the groups. These findings might be explained by a partial ovarian dysfunction, as the patient group had a significantly higher number of tubal sterilizations (eight compared with one). CONCLUSION: Our data provide support for the hypothesis that decreased concentrations of estradiol might be an additional pathogenetic factor for the development of CHD in menstrually active premenopausal women.

Effect of 17 alpha-ethinylestradiol, levonorgestrel, 3-keto-desogestrel, and gestodene on calcium influx via voltage-gated calcium channels in human aortic smooth muscles.

The effect of the synthetic estradiol, 17 alpha-ethinylestradiol, and three progestogens on calcium influx was investigated in cell cultures of human aortic smooth muscle. Neither the synthetic estrogen nor the progestogens levonorgestrel, 3-keto-desogestrel, and gestodene showed, in the concentration range of 10(-9) to 10(-6) M, a significant effect on calcium influx both alone or in equimolar estrogen-gestagen combinations. The results indicate that these substances, commonly used in contraceptive pills, do not change vasotonus interfering with calcium homeostasis.

Different effects of estrogen and progesterone on experimental atherosclerosis in female versus male rabbits. Quantification of cellular proliferation by bromodeoxyuridine.

BACKGROUND: The aim of the present study was to compare the effect of estrogen and progesterone on the development of experimental atherosclerosis in female versus male rabbits to assess possible sex-specific differences. METHODS AND RESULTS: A total of 32 female and 32 male New Zealand White rabbits were ovariectomized or castrated. In addition to a 0.5% cholesterol diet, the rabbits received estradiol alone (1 mg/kg body wt [BW] per week), progesterone alone (25 mg/kg BW per week), or combined estradiol-progesterone in these dosages during 12 weeks. Ovariectomized female and castrated male rabbits served as control groups without hormone treatment. Before excision of the vessels, bromodeoxyuridine labeling was performed to determine the extent of cellular proliferation in the atherosclerotic lesions. The aortic arch was analyzed immunohistologically and morphometrically. An inhibitory effect of estrogen on intimal plaque size was found in female rabbits compared with the ovariectomized control group (0.7 +/- 0.5 versus 3.7 +/- 2.5 mm2, P < .002; proliferating cells, 3.1 +/- 1.8% versus 8.5 +/- 2.6%, P < .002). In combination with progesterone, however, estrogen was not able to reduce intimal plaque size or cellular proliferation. In contrast, estradiol in castrated male rabbits was not associated with an inhibitory effect on cellular proliferation or intimal thickening compared with controls (estrogen treatment, 7.6 +/- 2.1% proliferating cells and 2.8 +/- 1.0 mm2 neointima; control group, 7.2 +/- 2.1% cellular proliferation and 2.9 +/- 1.2 mm2 intimal thickening). CONCLUSIONS: Our data suggest that the atheroprotective effect of estrogen is probably due to a mechanism that is present in female rabbits only.

Serotonin metabolite excretion after postmenopausal estradiol therapy.

Serotonin, known for its beneficial action on mood and well-being, is also involved in cardiovascular functions. Thus the current work was undertaken to study the effect of hormone replacement therapy on serotonin turnover in postmenopausal women. Eighteen women received estradiol transdermally and 17 women estradiol valerate orally for 4 weeks. The serotonin metabolite 5-hydroxyindole acetic acid (5-HIAA) was determined in the urine before, and after 2 and 4 weeks' estradiol treatment. With both administration routes estradiol produced a significant increase in urinary 5-HIAA excretion, greatest with transdermal estradiol after 28 days of treatment. The enhancement of serotonin turnover may contribute not only to an improvement of mood and well-being but also to a cardioprotective effect of estradiol observed after hormone substitution in postmenopausal women.

Does melatonin affect calcium influx in human aortic smooth muscle cells and estradiol-mediated calcium antagonism?

The pineal hormone melatonin showed no effect on voltage-gated calcium channels in cultured human aortic smooth muscle cells. In combination with estradiol, which blocked calcium channels, melatonin did not antagonize the effect of estradiol. It is concluded that melatonin seems to have different effects on voltage-gated calcium channels of divergent cell types since the positive action of melatonin previously observed on rat cardiac membranes by other authors could not be seen in the present investigations with human vascular smooth muscle cells.

Inhibition of the protective effect of estrogen by progesterone in experimental atherosclerosis.

The aim of the present study was to determine the effect of progesterone on the action of estrogen in the development of atherosclerosis. A total of 48 female New Zealand white (NZW) rabbits were ovariectomized. The animals were separated into 6 groups of 8 animals each and received subsequently a 0.5% cholesterol diet for 12 weeks. During this cholesterol feeding period, either estradiol (1 mg/kg body weight (BW)/week), progesterone (25 mg/kg BW/week), or combined estradiol/progesterone (in above dosages) was administered intramuscularly in each group (n = 8 each) of ovariectomized rabbits. One additional group of 8 animals received a combined estrogen/ progesterone regimen, but with progesterone at one third of the above mentioned dosage. In another 8 rabbits, progesterone was reduced to one ninth of the maximum dosage above, whereas estrogen was kept the same, at 1 mg/kg BW/week. Eight ovariectomized animals served as the control group and received no hormone treatment. After 12 weeks, the animals were sacrificed and the proximal aortic arch was removed for further histological examination. An inhibitory effect of estrogen of intimal thickening was found, in comparison to the control group (intimal area: 0.7 +/- 0.5 mm2 vs. 3.7 +/- 2.5 mm2, P < 0.01), whereas progesterone alone did not show a significant effect on intimal plaque size (intimal area: 4.0 +/- 2.3 mm2). In combination with progesterone (high dose), estrogen was not able to reduce intimal atherosclerosis (intimal area: 3.4 +/- 2.4 mm2). However, the beneficial effect of estrogen was not affected by progesterone, when this was reduced respectively to one third (intimal area: 0.8 +/- 0.7 mm2), or to one ninth of the highest dosage (intimal area: 0.6 +/- 0.4 mm2). Interestingly, these differences in atherosclerotic plaque development were observed without significant changes in plasma cholesterol concentrations by the administered hormones. In conclusion, progesterone was dose-dependently able to completely inhibit the beneficial effect of estrogen in experimental atherosclerosis, suggesting that progesterone exerts a direct inhibitory effect on the athero-protective action of estrogen. In the context of recently published data, the present work confirms the importance of the 'non-lipid-mediated', anti-atherosclerotic effect of estrogen, probably due to an interaction with six hormone receptors in vascular smooth muscle cells (VSMC).

-Is prevention of pre-eclampsia with low dosage aspirin possible? Critical assessment of available studies-. / Ist mit niedrigdosierter Aspirinbehandlung eine Prophylaxe der Pr-aeklampsie m"oglich? Kritische Betrachtung der vorliegenden Studien.

The efficacy of low-dose aspirin treatment to prevent preeclampsia was assessed by reviewing studies of the available literature. 9 studies were performed examining nearly 13,000 pregnant women. Aspirin treatment compared with untreated control groups led to a significant reduction of preeclampsia in 5 small-scale studies. However, no prophylaxis could be achieved in 4 studies comprising more than 12,000 pregnant women. A assessment of low-dose aspirin treatment is difficult, since no dose-response study was performed to determine the optimal dose; the duration of treatment--beginning and end--was not defined and the drug risk for mother and child was not documented in accordance with GCP guidelines. The major problem of all studies, however, consisted in the recruitment of the patients since there are no easily performable and well-recognised screening tests available to estimate the risk of preeclampsia. In conclusion, at present no statement is possible if and under which conditions low-dose aspirin treatment will be able to prevent preeclampsia.

[Treatment of estrogen deficiency-induced sex disorders]. / Die Behandlung östrogenmangelinduzierter Sexualstörungen.

OBJECTIVE: Is it possible to successfully treat sexual disturbances related to an estrogen deficiency syndrome with estrogens? METHODS: For 4 months, sexual dysfunctions (loss of libido, dyspareunia, difficulties in experiencing orgasm) were treated with a transdermal system-the estrogen patch-in one group cyclically and in a second continually. Women with uterus got 1 mg/day norethisterone acetate for 12 days a month. RESULTS: By estrogen therapy alone, success was seen in 40/41% for loss of libido, in 75/56% for dyspareunia and in 47/25% for difficulties of orgasm. CONCLUSIONS: In spite of the complexity of the biopsychosocial causes of the sexual disturbances in relation with an estrogen deficiency syndrome, the replacement therapy is successful in many cases.

[Serum lipids in treatment with transdermal estradiol and oral norethisterone acetate]. / Serumlipide unter Behandlung mit transdermalem Ostradiol und oralem Norethisteronacetat.

With transdermal estradiol substitution the so called "primary liver passage" is avoided. Taking into account also the low dose of estradiol the risk of hepatic side effects can be reduced. On the other hand, it was assumed that for the same reason desirable lipid effects regarding cardiovascular protection may also not be possible, in contrast to oral estrogen treatment. Treating 26 postmenopausal women with the estradiol patch releasing 0.05 mg daily and with 1 mg oral norethisterone acetate, added at least during 10 days in each cycle, a significant reduction was observed in total cholesterol as well as in LDL- and VLDL-cholesterol of about 15-20%. HDL-cholesterol first showed a decrease and thereafter it increased again to basic level. It is supposed that the reason for this may be different effects on subfractions of HDL-cholesterol. The triglycerides were lowered to about 20%. This result is thought to be important because oral estrogens have been associated with increases in triglycerides. By lowering LDL-cholesterol as well as triglycerides, both serum lipids, most important with respect to cardiovascular protection, are shown to be influenced positively.

The effect of estradiol on the production of melatonin in postmenopausal women.

The influence of two routes of estradiol administration on pineal melatonin production in postmenopausal women was investigated. Both transdermal and oral estradiol treatment led to an increase as well as decrease of melatonin production in different patients. The reason why individuals respond either in a stimulatory or inhibitory manner is unknown and requires to be evaluated in further more extensive studies.