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ABSTRACTOur objective was to evaluate the interaction of supplemental essential oils (EO) and monensin (MON) on performance and digestion. Two levels of EO (0 vs 0.011% Xtract®) and two levels of MON (0 vs 33 mg/kg) were evaluated in a 2 × 2 factorial arrangement. Treatment effects on 216-d growth performance were evaluated in 96 Holstein steers. Supplemental MON enhanced (P ≤ 0.05) ADG, DMI and gain efficiency. Without EO, MON improved (P < 0.05) gain efficiency and dietary NE. However, in diets with both EO and MON, gain efficiency and dietary NE were not different from non-supplemented diets (interaction, P < 0.10). Treatment effects on characteristics of digestion were evaluated using four cannulated steers. Ruminal digestion of OM and N were greater for MON alone. Ruminal digestion of OM and N were similar for EO-alone vs MON-alone, but not by the combination of the two (interaction P ≤ 0.02). Supplemental MON enhanced (P ≤ 0.02) total tract digestion of OM and N. We conclude that supplemental EO-alone or MON-alone may enhance gain efficiency and NE value of the diet. However, effects are negated when fed in combination. Treatment effects on performance are consistent with digestion measures.

ABSTRACTOne hundred and sixty-eight crossbred steers (133 ± 7 kg) were used in a 336-d experiment to evaluate the effects of enzymatically hydrolysed yeast cell wall plus yeast culture (EHY) supplementation on growth performance and carcass characteristics. Treatments consisted of steam-flaked corn-based diet supplemented with 0, 195, 390 or 585 mg/kg EHY. Supplemental EHY enhanced overall (336-d) dry matter intake (DMI, P < .01), averagde daily gain (ADG, P = .04), and final carcass weight (P = .04). Responses were maximal (quadratic effect, P ≤ .02) at the 195 mg/kg level of EHY supplementation. Feed intake enhancements were observed throughout each 112-d period of the study. Improvements in ADG were largely the result of increased DMI, as gain efficiency and estimated dietary net energy (NE) were not affected by EHY supplementation. Effects of supplemental EHY on other carcass measures were not appreciable (P > .20), except for a slight lowering (0.7%, P = .04) in carcass yield. We conclude that throughout the growing-finishing period, supplemental EHY will enhance ADG, resulting in marked increases in final carcass weight. This effect is due to consistent increases in DMI, as supplementation did not affect gain efficiency or estimated dietary NE.

ABSTRACTA feedlot growth-performance trial was conducted to evaluate the relative response to tempering when flake density (FD) of corn is increased from 0.31 kg/L (24 lb/bushel) to 0.39 kg/L (30 lb/bushel). Treatments were (1) non-tempered, FD = 0.31 kg/L; (2) non-tempered, FD = 0.39 kg/L; (3) tempered, FD = 0.31 kg/L and (4) tempered, FD = 0.39 kg/L. Tempering prior to flaking increased (21%, P < .01) the moisture content of corn as it exited the rolls and decreased (14%, P = .02) the starch enzymatic reactivity. Increasing roll tension to reduce FD decreased flake thickness (24%, P < .01) and increased starch reactivity (43%, P < .01). Increasing FD decreased (P = .03) estimated dietary NEm and NEg, and the estimated NEm and NEg values of steam-flaked corn by 2.3% and 2.9%, respectively. We conclude that whereas tempering corn grain before steam flaking increases the moisture content of corn as it exits the roles, it has minimal influence on the feeding value for corn for feedlot cattle. Increasing FD from 0.31 to 0.39 kg/L decreases starch reactivity and the net energy value of corn, but does not affect daily weight gain or carcass characteristics.

Two experiments were conducted to examine the influence of protein and virginiamycin (VM) supplementation on feedlot growth performance, digestion, and metabolizable AA (MAA) supply of calf-fed Holstein steers. Growth performance and dietary energetics were evaluated in 120 Holstein steers (127 ± 9 kg). During the initial 112-d feeding period, a steam-flaked corn-based diet was balanced to meet either 100% (MAB) or 87% (UREA) of MAA requirements. Diets were supplemented with or without 22.5 mg/kg VM in a 2 × 2 factorial arrangement. Subsequently (d 112 to 308), all steers received the UREA diet with or without VM. During the initial 112-d, MAB increased ADG, G:F, and dietary NE (P< 0.01). Thereafter, when all steers received the UREA diet, ADG, G:F, and dietary NE were not different (P> 0.10) across initial supplementation treatments. Overall (d 1 to 308), MAB did not affect ADG (P> 0.10) but enhanced G:F efficiency (P= 0.03) and dietary NE (P= 0.05). During the initial 112-d period and through the remainder of the experiment, VM increased G:F (P< 0.01) and dietary NE (P< 0.01). Four Holstein steers (146 ± 4 kg) with cannulas in the rumen and proximal duodenum were used in a 4 × 4 Latin square design to evaluate initial 112-d treatment effects on digestive function. There were no treatment effects (P> 0.10) on ruminal digestion of OM, NDF, starch, microbial efficiency, or total tract digestion of OM and NDF. The MAB increased indispensable AA flow to the small intestine (P< 0.01) and total tract digestion of N (P< 0.01) and starch (P= 0.04). Observed AA supply to small intestine was in agreement with expected supply (r2= 0.96). Virginiamycin decreased (P= 0.04) nonammonia N flow to the small intestine and did not affect (P> 0.10) total tract N digestion. Extrapolating from AA supplies in the metabolism study, MAB satisfied indispensable AA requirements during the initial 112-d period, whereas the UREA diet met 73.5% and 79.2% of methionine and lysine requirements, respectively. During the subsequent periods (d 112 to 308) indispensable AA supplies exceeded theoretical requirements. We conclude that enhancements in energy utilization when diets are balanced to meet MAA requirements of calf-fed Holstein steers during the initial 112-d feedlot period remain appreciable throughout time on feed. Virginiamycin enhanced efficiency of energy utilization throughout the feedlot growing-finishing period.

Purpose Adjuvant chemotherapy improves survival of patients with gastric cancer. Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S) was a phase III study comparing sequential FOLFIRI followed by docetaxel/cisplatin versus 5-fluorouracil monotherapy. The intensive regimen was not superior in terms of disease-free survival (DFS) and overall survival (OS).Methods The treatment was to be started within 8 weeks from surgery. This analysis evaluates the impact of time from surgery to chemotherapy start (TSC) on outcomes.Results Out of 1,106 randomized, 1,072 patients without major violations of eligibility criteria and receiving at least one treatment cycle were analyzed. Median TSC was 50 days. Chemotherapy was interrupted in 201 (18.8%) cases, whereas it was completed without or with modifications in 277 (25.8%) and 594 (55.4%), respectively. At a median follow-up of 56.9 months, 513 progressions and 472 deaths occurred. A longer TSC was significantly associated with longer DFS (hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.89-1.00; p = 0.05) and OS (HR 0.91; 95% CI 0.86-0.97; p = 0.004), after adjustment for treatment arm, age, sex, primary tumor site, number of resected nodes, and tumor stage. Better treatment compliance was associated with improved survival.Conclusions Our findings suggest that longer TSC had at least no detrimental effect on DFS and OS, whereas treatment completion had a protective effect. Our findings need to be confirmed prospectively.

ABSTRACTFifty-four Holstein steer calves, divided in two weight groupings (141.2 ± 4.9 kg and 454.2 ± 7.0 kg respectively), were used in a 56-day study to evaluate the influence of supplemental vitamin E on growth performance and plasma vitamin concentrations. Steers were assigned within body weight groupings to 18 pens, 3 steers/pen. Dietary treatments consisted of a steam-flaked corn-based growing-finishing diet supplemented to provide 0, 250, or 500 IU/d of vitamin E as all racemic α-tocopherol. No morbidity was apparent during the course of the study. Calves in the heavier weight grouping had greater average daily gain (24.4%, P < .01), dry matter intake (54.3%, P < .01), and lower gain efficiency (40.7%, P < .01). Vitamin E supplementation did not affect (P > .10) feedlot growth performance. Initial and 56-day plasma tocopherol were not influenced (P > .10) by weight grouping. Final 56-day plasma tocopherol increased linearly (P < .01) with level of vitamin E supplementation. Plasma tocopherol of non-supplemented steers decreased (P = .01) from an average initial concentration of 1.66–1.16 ug/mL at day 56. It is concluded that vitamin E supplementation of calf-fed Holstein steers receiving a conventional steam-flaked corn-based growing-finishing diet is not expected to enhance growth performance.

Two experiments were conducted to evaluate the comparative feeding value of dried shredded sugarbeets (DSSB; 0, 20, and 40% of diet DM) as a replacement for steam-flaked corn (SFC) in finishing diets for feedlot cattle. In Exp. 1, 60 calf-fed Holstein steers (476 ± 6.3 kg) were used in a 97-d finishing trial. Substitution of SFC with DSSB did not affect ADG or DMI (P > 0.20). Increasing DSSB decreased gain efficiency (ADG:DMI; linear effect, P = 0.04) and dietary NE (linear effect, P = 0.03). Given that SFC has a NE(m) value of 2.38 Mcal/kg, the replacement NE(m) and NE(g) values for DSSB were 1.94 and 1.29 Mcal/kg, respectively. There were no treatment effects (P > 0.20) on carcass characteristics. In Exp. 2, 6 cannulated Holstein steers (205 kg) were used in a replicated 3 × 3 Latin square design to evaluate treatment effects on digestion. Ruminal digestion of starch, NDF, and feed N were not affected (P > 0.10) by DSSB, although ruminal OM digestion tended to increase (linear effect, P < 0.08). Replacing SFC with DSSB decreased flow of starch to the small intestine, but it increased flow of microbial N (linear effect, P = 0.05). There were no treatment effects (P > 0.14) on postruminal digestion of OM, NDF, starch, or feed N or total tract digestion of OM, starch, and N. Substitution of DSSB increased (linear effect, P = 0.05) total tract NDF digestion and decreased (linear effect, P = 0.05) dietary DE (Mcal/kg). Given that SFC has a DE value of 4.19 Mcal/kg, the replacement DE value of DSSB was 3.68 Mcal/kg. There were no treatment effects (P > 0.12) on ruminal pH or total VFA; however, DSSB decreased propionate (linear effect, P = 0.05) and increased acetate (linear effect, P = 0.07), butyrate (linear effect, P = 0.05), valerate (linear effect, P = 0.04), and estimated methane production (linear effect, P = 0.05). We concluded that DSSB may replace SFC in finishing diets at levels of up to 40% without detrimental effects on ADG and carcass characteristics. The NE value of DSSB is 82% that of SFC (DM basis). Partial replacement of SFC with DSSB alters ruminal VFA patterns, increasing estimated methane energy loss and slightly decreasing the efficiency of DE utilization.

Food may be either contaminated with a range of industrial chemicals or contain naturally produced toxic compounds. Even the most sophisticated chemical analyses are not able to perform or contribute to an effect assessment of food constituents. While in environmental research the application of “effect directed analysis” (EDA) and “toxicity identification and evaluation” (TIE) has been widely accepted and applied, these concepts had been hardly applied for toxicity characterization to food matrices. It has been nevertheless used in the areas of botanical chemistry, pharmacology and ethno-pharmacology, focusing on new drug discovery and in the search for new ingredients. Within this review a scheme for EDA application to food items is formulated based on experiences from environmental toxicology, the few experiences of in vitro effect-directed analysis of food items with a related epidemiological risk are described and discussed. A wider use of EDA for food toxicity characterization is strongly emphasized.

Two experiments were conducted to evaluate the influence of dry-rolling (DRS) and tempering agent (TA) addition during the steam-flaking of grain sorghum (SFS) for feedlot cattle. Five dietary treatments were compared: 1) DRS; 2) SFS, no TA; 3) SFS, 0.275 mg/kg of TA; 4) SFS, 1.375 mg/kg of TA; and 5) SFS, 2.750 mg/kg of TA. Bulk densities of DRS and SFS were 0.48 and 0.36 kg/L, respectively. Diets contained 70.6% grain sorghum (DM basis). One hundred fifty crossbred steers (336 kg of BW) were used in a 115-d finishing experiment to evaluate treatment effects on feedlot performance. Body weight gain averaged 1.49 kg/d and was not affected (P= 0.47) by treatments. The SFS reduced (P< 0.01) DMI (9%) and enhanced (P< 0.01) G:F (13%) and the NEmand NEgvalue of the diet (9 and 11%, respectively). Use of a TA before flaking sorghum did not influence (P> 0.20) cattle growth performance or NEmor NEgvalue of the diet. Given that the NEmand NEgvalues of DRS are 2.00 and 1.35 Mcal/kg, respectively (NRC, 1996), the corresponding values for SFS were 2.28 and 1.59 Mcal/kg. Five steers (397 kg of BW) with ruminal and duodenal cannulas were used in a 5 × 5 Latin square design to evaluate treatment effects on digestive function. Ruminal digestion of OM and starch was greater (14 and 16%, respectively; P< 0.01) for SFS vs. DRS. Steam-flaking sorghum increased (P< 0.01) postruminal digestion of OM (11%), N (10%), and starch (25%) and total tract digestion (P< 0.01) of OM (8.3%), N (8.2%), and starch (8.9%). Grain processing did not affect (P> 0.20) ruminal pH or VFA molar proportions. There was a cubic component (P< 0.10) to level of TA on ruminal pH and VFA molar proportions, with values being optimal at 1.375 mg/kg of tempering agent. It is concluded that steam-flaking grain sorghum will increase its NE value for maintenance and gain (14 and 18%, respectively) and enhance the MP value of the diet due to greater intestinal N digestion. The use of a TA to enhance the mechanical efficiency of the flaking process may not otherwise benefit the feeding value of sorghum.

The association between sexual activity and human herpes virus‐8 (HHV‐8) infection has been established, but the mode of acquisition is still unclear. Blood samples from 238 individuals from Northern Cameroon were tested to evaluate the incidence of herpes simplex virus‐2 (HSV‐2), human immunodeficiency virus (HIV), Treponema pallidum, and HHV‐8 infections and to identify their possible association. The presence of HSV‐2 antibodies was associated significantly with gender, age, and HIV, HHV‐8 antilatent, and T. pallidumantibodies, but not with HHV‐8 antilytic antibodies. In a multivariate model older age, female gender, seropositivity for HIV, for HHV‐8 latent antigens and for T. pallidumwere associated independently with seropositivity for HSV‐2. HSV‐2‐seropositive individuals had significantly higher titers of antibodies to both lytic (P= 0.019) and latent (P= 0.021) HHV‐8 antigens. These results suggest that HSV‐2 infection can contribute to sexual transmission of HHV‐8 infection. J. Med. Virol. 74:467–472, 2004. © 2004 Wiley‐Liss, Inc.

A longitudinal study of the replication capacity of HIV strains isolated from 18 patients failing highly active antiretroviral therapy (HAART) was undertaken at the time of genotypic guided change of therapy and after 12 months. Patients were divided in two groups according to the response to therapy: immune responders (12 patients with immune recovery defined as having more than 100 CD4 cells compared to baseline value), and failing patients (six patients without immune recovery). At enrolment no significant difference in terms of CD4 cell count and HIV plasma viremia was detected between the two groups. One year after change of therapy, all patients experienced a decrease in the replication capacity of HIV strains. The HIV replication capacity of the failing and of immune‐responder patients decreased from 60% (range 14–96%) to 26.4% (range 0.4–74.5) and from 46.8% (range 15–98%) to 3.6% (range 0.1–26.8%), respectively. At month 12, the difference of HIV replication capacity between the two groups reached a statistical significance (P< 0.03). After the change of therapy, an increase in the number of drug resistance mutations in the protease gene was detected in both groups with a higher prevalence of M36I mutation in immune responders. The HIV strains of patients failing HAART showed a progressive impaired replication capacity. The degree of the impairment in viral replication correlated with the viro‐immunological discordant response to HAART and with the acquisition of new drug resistant mutations in the protease gene. In patients failing HAART, the impaired replication capacity of HIV strains could justify the persistence of an immune recovery. J. Med. Virol. 72:511–516, 2004. © 2004 Wiley‐Liss, Inc.

The current AIDS pandemic represents the uneven spread of multiple genetically related subtypes (A to J) of human immunodeficiency virus type 1 (HIV-1). Notably, HIV-1 E in southeast Asia and HIV-1 C in sub-Saharan Africa are expanding faster and are likely of greater global significance than the HIV-1 B subtype prevalent in the United States and Europe. While many studies have focused on genetic variation among structural genes, we chose to conduct a comparative analysis of the long terminal repeats of HIV-1 E and HIV-1 C isolates and report subtype-specific differences in enhancer copy numbers and sequences, as well as divergent activation in response to the cellular transcriptional activators Rel-p65 and NFATc and viral Tat. This study is the first to identify functional distinctions in promoter architecture between HIV-1 subtypes and raises the possibility that regulatory divergence among the subtypes of HIV-1 has occurred. Divergent transcriptional regulation may explain some of the epidemiologically observed differences in transmission and pathogenesis and underscores the need for further comparative analysis of HIV-1 regulation.

We have previously reported that antiestrogens stimulate quinone reductase (NAD(P)H:(quinone-acceptor) oxidoreductase (QR or NQO1); EC 1.6.99.2) enzymatic activity, an action that may provide protective effects against the toxicity and mutagenicity caused by quinones. We have now investigated the transcriptional regulation of the QR gene by antiestrogens. In transfection experiments employing the 5'-flanking (863-base pair) region of the human QR gene promoter with its electrophile/antioxidant response element (EpRE/ARE) or deleted or mutated constructs, we observe that antiestrogens induced an increase in QR gene promoter reporter activity in estrogen receptor (ER) negative breast cancer and endometrial cancer cells transfected with ER, and this induction by antiestrogens was repressed by estradiol. The stimulation of QR transcriptional activity required the 31-base pair electrophile-responsive region from the human QR gene promoter and a functional ER. Intriguingly, antiestrogens were stronger activators of the QR EpRE via the ER subtype ERbeta than ERalpha. Oligonucleotide gel mobility and antibody shift assays reveal that the ER binds to the EpRE but is only a minor component of the proteins bound to the EpRE in ER-containing MCF-7 breast cancer cells. While binding of ERbeta to the estrogen response element was weaker when compared with ERalpha, ERbeta and ERalpha showed similar binding to the EpRE. Together these findings provide evidence that QR gene regulation by the antiestrogen-occupied ER is mediated by the EpRE-containing region of the human QR gene and indicate that the ER is one of the complex of proteins that binds to the EpRE. In addition, that ERbeta is a more potent activator at EpRE elements than is ERalpha suggests that the different levels of these two receptors in various estrogen target cells could impact importantly on the antioxidant potency of antiestrogens in different target cells. These findings have broad implications regarding the potential beneficial effects of antiestrogens since EpREs mediate the transcriptional induction of numerous genes, including QR, which encode chemoprotective detoxification enzymes.

The global diversity of human immunodeficiency virus type 1 (HIV-1) genotypes, termed subtypes A to J, is considerable and growing. However, relatively few studies have provided evidence for an associated phenotypic divergence. Recently, we demonstrated subtype-specific functional differences within the long terminal repeat (LTR) region of expanding subtypes (M. A. Montano, V. A. Novitsky, J. T. Blackard, N. L. Cho, D. A. Katzenstein, and M. Essex, J. Virol. 71:8657-8665, 1997). Notably, all HIV-1E isolates were observed to contain a defective upstream NF-kappaB site and a unique TATA-TAR region. In this study, we demonstrate that tumor necrosis factor alpha (TNF-alpha) stimulation of the HIV-1E LTR was also impaired, consistent with a defective upstream NF-kappaB site. Furthermore, repair of the upstream NF-kappaB site within HIV-1E partially restored TNF-alpha responsiveness. We also show, in gel shift assays, that oligonucleotides spanning the HIV-1E TATA box displayed a reduced efficiency in the assembly of the TBP-TFIIB-TATA complex, relative to an HIV-1B TATA oligonucleotide. In transfection assays, the HIV-1E TATA, when changed to the canonical HIV-1B TATA sequence (ATAAAA-->ATATAA) unexpectedly reduces both heterologous HIV-1B Tat and cognate HIV-1E Tat activation of an HIV-1E LTR-driven reporter gene. However, Tat activation, irrespective of subtype, could be rescued by introducing a cognate HIV-1B TAR. Collectively, these observations suggest that the expanding HIV-1E genotype has likely evolved an alternative promoter configuration with altered NF-kappaB and TATA regulatory signals in contradistinction with HIV-1B.

Circulating estradiol is assumed not to contribute to sexual differentiation of the brain or other estrogen target tissues. The only estradiol available for binding to estrogen receptors is thought to be produced within brain cells by the aromatization of testosterone to estradiol as part of the action of androgen in the brain. However, we report that the concentration of free, biologically active serum estradiol (the concentration not bound to plasma proteins) was 0.54–2.17 pg/ml during the fetal and early neonatal period of sexual differentiation. These values were within the same concentration range for free estradiol observed in adult female rats throughout the estrous cycle (diestrus = 0.53 pg/ml; proestrus = 2.26 pg/ml), and estradiol clearly has physiological effects during diestrus as well as proestrus in adult females. When a stable, physiological blood concentration of [3H]estradiol of 49 pg/ml total (0.61 pg/ml free) was achieved with Silastic capsules in 2-day-old female pups, [3H]estradiol was recovered specifically bound to brain cell nuclei at approximately 2.7 fmol per pup brain or 12.4 fmol/mg DNA. The finding of brain uptake of circulating estradiol is contrary to current hypotheses. These findings suggest that estradiol in the fetal and neonatal circulation may be able to interact with testosterone and its metabolites to regulate sexual differentiation of the brain and other estrogen target tissues.

The effect of changes in maternal corticosterone concentrations, induced by maternal stress, maternal adrenalectomy or both, on concentration of corticosterone in serum and in adrenals of mouse (Mus domesticus) fetuses was examined. Higher baseline serum corticosterone concentrations were found in female fetuses than in male fetuses; however, there was no sex difference in the content of corticosterone in adrenals collected from these fetuses. Sex differences were observed in the fetal response to changes in maternal concentrations of serum corticosterone resulting from stress (bright light and heat) or adrenalectomy, and both factors eliminated the sex difference in corticosterone in fetal serum. When females were injected i.v. with [3H]corticosterone on day 17 of pregnancy, significantly more 3H was recovered from the serum of female than of male fetuses 15 min after the injection, while more 3H was recovered from placentae of male fetuses. This finding suggests that the difference in serum corticosterone in male and female mouse fetuses is due to greater transport of corticosterone from maternal blood across the placenta of female than of male fetuses.

ABSTRACTAfter interruption of highly active antiretroviral therapy, 15 out of 53 patients with the X4 HIV strain had a significantly larger decrease in CD4+T cell count (P= 0.001) and shorter length of treatment interruption (P= 0.02) than patients with the R5 strain. At treatment resumption, HIV inferred tropism switched from the X4 strain to the R5 variant in 9 patients (60%). These patients had a prolonged length of treatment interruption compared to that of those who still carried the X4 strain.