Virus dynamics and drug therapy

The recent development of potent antiviral drugs not only has raised hopes for effective treatment of infections with HIV or the hepatitis B virus, but also has led to important quantitative insights into viral dynamics in vivo. Interpretation of the experimental data depends upon mathematical models that describe the nonlinear interaction between virus and host cell populations. Here we discuss the emerging understanding of virus population dynamics, the role of the immune system in limiting virus abundance, the dynamics of viral drug resistance, and the question of whether virus infection can be eliminated from individual patients by drug treatment.     

Immunohistochemical localization of vascular endothelial growth factor in colonic mucosa of patients with inflammatory bowel disease

BACKGROUND/AIMS: Significantly enhanced serum levels of VEGF (vascular endothelial growth factor) were found in patients with inflammatory bowel disease. Peripheral blood mononuclear cells have been identified as one of the origins of the circulating VEGF. The present investigation examines the localization of VEGF at the site of inflammation in colonic mucosa of patients with Crohn's disease and ulcerative colitis. METHODOLOGY: Immunohistochemical localization of VEGF and immunostaining for leukocytes were performed in colonic mucosal biopsies of 41 patients with Crohn's disease, 26 patients with ulcerative colitis and normal mucosal specimens of 5 patients with irritable bowel syndrome. Measurement of immunohistochemical staining for VEGF and for leukocytes within the epithelium and the lamina propria was performed separately by area morphometry using a computerized cell analysis system. RESULTS: In both patients with Crohn's disease and ulcerative colitis immunohistochemical staining for VEGF within the lamina propria of inflamed colonic mucosa was significantly higher compared with noninflamed mucosa (Crohn's disease: 4.26% vs. 0.07%, P < 0.001; ulcerative colitis: 3.68% vs. 0.32%, P = 0.001). There was a significant correlation between immunostaining for leukocytes and VEGF within the lamina propria in both patients with Crohn's disease (r = 0.73, P < 0.05)) and ulcerative colitis (r = 0.67, P < 0.05). In Crohn's disease immunostaining for VEGF within the epithelium was significantly higher in inflamed mucosa compared with noninflamed mucosa (9.85% vs. 0.63%, P < 0.001). In contrast, strong immunostaining for VEGF has been observed in the epithelium of noninflamed mucosa (7.60%, P < 0.003), as well as in inflamed mucosa of patients with active ulcerative colitis (9.68%, P < 0.002) compared with noninflamed mucosa of patients with inactive ulcerative colitis (1.39%). CONCLUSIONS: The present data indicate, that the increased VEGF expression within the epithelium and the interstitial accumulation of VEGF-producing leukocytes in inflamed mucosa may play an important role in the inflammatory mechanisms of Crohn's disease and ulcerative colitis.     

Cardiovascular effects of long-term central and peripheral administration of urocortin, corticotropin-releasing factor, and adrenocorticotropin in sheep

The neuroendocrine hormones ACTH and corticotropin- releasing factor (CRF), which are involved in the stress response, have acute effects on arterial pressure. New evidence indicates that urocortin (UCN), the putative agonist for the CRF type 2 receptor, has selective cardiovascular actions. The responses to long-term infusions of these hormones, both peripherally and centrally, in conscious animals have not been studied. Knowledge of the long-term effects is important because they may differ considerably from their acute actions, and stress is frequently a chronic stimulus. The present experiments investigated the cardiovascular effects of CRF, UCN, and ACTH in conscious sheep. Infusions were made either into the lateral cerebral ventricles (i.c.v.) or i.v. over 4 d at 5 microg/h. UCN infused i.c.v. or i.v. caused a prolonged increase in heart rate (HR) (P < 0.01) and a small increase in mean arterial pressure (MAP) (P < 0.05). CRF infused i.c.v. or i.v. progressively increased MAP (P < 0.05) but had no effect on HR. Central administration of ACTH had no effect, whereas systemic infusion increased MAP and HR (P < 0.001). In conclusion, long-term administration of these three peptides associated with the stress response had prolonged, selective cardiovascular actions. The striking finding was the large and sustained increase in HR with i.c.v. and i.v. infusions of UCN. These responses are probably mediated by CRF type 2 receptors because they were not reproduced by infusions of CRF.     

Dynamical evidence for causality between galactic cosmic rays and interannual variation in global temperature

As early as 1959, it was hypothesized that an indirect link between solar activity and climate could be mediated by mechanisms controlling the flux of galactic cosmic rays (CR) [Ney ER (1959) Nature 183:451–452]. Although the connection between CR and climate remains controversial, a significant body of laboratory evidence has emerged at the European Organization for Nuclear Research [Duplissy J, et al. (2010) Atmos Chem Phys 10:1635–1647; Kirkby J, et al. (2011) Nature 476(7361):429–433] and elsewhere [Svensmark H, Pedersen JOP, Marsh ND, Enghoff MB, Uggerhøj UI (2007) Proc R Soc A 463:385–396; Enghoff MB, Pedersen JOP, Uggerhoj UI, Paling SM, Svensmark H (2011) Geophys Res Lett 38:{"type":"entrez-nucleotide","attrs":{"text":"L09805","term_id":"177519"}}L09805], demonstrating the theoretical mechanism of this link. In this article, we present an analysis based on convergent cross mapping, which uses observational time series data to directly examine the causal link between CR and year-to-year changes in global temperature. Despite a gross correlation, we find no measurable evidence of a causal effect linking CR to the overall 20th-century warming trend. However, on short interannual timescales, we find a significant, although modest, causal effect between CR and short-term, year-to-year variability in global temperature that is consistent with the presence of nonlinearities internal to the system. Thus, although CR do not contribute measurably to the 20th-century global warming trend, they do appear as a nontraditional forcing in the climate system on short interannual timescales.The basic principles behind a possible connection between galactic cosmic rays (CR) and global temperature (GT) are as follows: It has been known since the invention of the cloud chamber in 1911 by Charles Thomson Rees Wilson that ionizing radiation leads to atmospheric cloud nucleation. Although the prime source of ionizing radiation in the global troposphere is CR, the flux of CR reaching the troposphere depends on the solar wind. The solar wind is a stream of ionized gases that blows outward from the Sun, and its intensity varies strongly with the level of surface activity on the Sun. The Earth''s magnetic field shields the planet from much of the solar wind, deflecting that wind like water around the bow of a ship. When solar activity is great, the solar wind is strong, swiping away CR arriving at the top of the atmosphere. These CR are hypothesized to affect cloud formation and cloudiness, and therefore GT. The net radiative effect of cloudiness depends on the difference between incoming solar radiation and outgoing long-wave radiation. Increased cloudiness in the upper troposphere reduces outgoing long-wave radiation, thereby resulting in warming of the planet. Increased cloudiness in the lower troposphere causes less incoming radiation, and therefore cooling of the planet. Data suggest (6) that the amount of CR is positively correlated with the amount of low-level clouds but has no effect on middle- or high-level clouds. Although this is still an open question (7, 8), the reduction in flux in CR in times of high solar activity is hypothesized to result in less cloud nucleation and fewer cloud condensation nuclei, and consequently, reduced low-level cloud amounts. This, in turn, leads to a higher solar radiation flux at the Earth’s surface, and warmer temperatures. Conversely, a weaker solar wind results in cooler temperatures. The actual chemical processes and reactions involved in this problem are complex, but a growing body of experimental and theoretical work has uncovered a chemical pathway by which CR ionization may increase nucleation rates to levels appropriate for cloud condensation nuclei (2–5, 9–11 and references therein). This suggests a superficially simple network linking the Sun, CR, and global climate, with the interaction between the Sun and CR having a potential influence on the climate system. However reasonable this may be, as described in a 2006 review (12), “The suggested mechanisms are, however, too complex to evaluate meaningfully at present.”     

Effect of weight loss,with or without exercise,on body composition and sex hormones in postmenopausal women: the SHAPE-2 trial

Introduction

Physical inactivity and overweight are risk factors for postmenopausal breast cancer. The effect of physical activity may be partially mediated by concordant weight loss. We studied the effect on serum sex hormones, which are known to be associated with postmenopausal breast cancer risk, that is attributable to exercise by comparing randomly obtained equivalent weight loss by following a hypocaloric diet only or mainly by exercise.

Methods

Overweight, insufficiently active women were randomised to a diet (N = 97), mainly exercise (N = 98) or control group (N = 48). The goal of both interventions was to achieve 5–6 kg of weight loss by following a calorie-restricted diet or an intensive exercise programme combined with only a small caloric restriction. Primary outcomes after 16 weeks were serum sex hormones and sex hormone-binding globulin (SHBG). Body fat and lean mass were measured by dual-energy X-ray absorptiometry.

Results

Both the diet (−4.9 kg) and mainly exercise (−5.5 kg) groups achieved the target weight loss. Loss of body fat was significantly greater with exercise versus diet (difference −1.4 kg, P < 0.001). In the mainly exercise arm, the reduction in free testosterone was statistically significantly greater than that of the diet arm (treatment effect ratio [TER] 0.92, P = 0.043), and the results were suggestive of a difference for androstenedione (TER 0.90, P = 0.064) and SHBG (TER 1.05, P = 0.070). Compared with the control arm, beneficial effects were seen with both interventions, diet and mainly exercise, respectively, on oestradiol (TER 0.86, P = 0.025; TER 0.83, P = 0.007), free oestradiol (TER 0.80, P = 0.002; TER 0.77, P < 0.001), SHBG (TER 1.14; TER 1.21, both P < 0.001) and free testosterone (TER 0.91, P = 0.069; TER = 0.84, P = 0.001). After adjustment for changes in body fat, intervention effects attenuated or disappeared.

Conclusions

Weight loss with both interventions resulted in favourable effects on serum sex hormones, which have been shown to be associated with a decrease in postmenopausal breast cancer risk. Weight loss induced mainly by exercise additionally resulted in maintenance of lean mass, greater fitness, greater fat loss and a larger effect on (some) sex hormones. The greater fat loss likely explains the observed larger effects on sex hormones.

Trial registration

ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT01511276","term_id":"NCT01511276"}}NCT01511276. Registered on 12 January 2012.

Electronic supplementary material

The online version of this article (doi:10.1186/s13058-015-0633-9) contains supplementary material, which is available to authorized users.     

Helios,and not FoxP3, is the marker of activated Tregs expressing GARP/LAP

Regulatory T cells (Tregs) are key players of immune regulation/dysregulation both in physiological and pathophysiological settings. Despite significant advances in understanding Treg function, there is still a pressing need to define reliable and specific markers that can distinguish different Treg subpopulations. Herein we show for the first time that markers of activated Tregs [latency associated peptide (LAP) and glycoprotein A repetitions predominant (GARP, or LRRC32)] are expressed on CD4⁺FoxP3⁻ T cells expressing Helios (FoxP3⁻Helios⁺) in the steady state. Following TCR activation, GARP/LAP are up-regulated on CD4⁺Helios⁺ T cells regardless of FoxP3 expression (FoxP3^+/−Helios⁺). We show that CD4⁺GARP^+/−LAP⁺ Tregs make IL-10 immunosuppressive cytokine but not IFN-γ effector cytokine. Further characterization of FoxP3/Helios subpopulations showed that FoxP3⁺Helios⁺ Tregs proliferate in vitro significantly less than FoxP3⁺Helios⁻ Tregs upon TCR stimulation. Unlike FoxP3⁺Helios⁻ Tregs, FoxP3⁺Helios⁺ Tregs secrete IL-10 but not IFN-γ or IL-2, confirming they are bona fide Tregs with immunosuppressive characteristics. Taken together, Helios, and not FoxP3, is the marker of activated Tregs expressing GARP/LAP, and FoxP3⁺Helios⁺ Tregs have more suppressive characteristics, compared with FoxP3⁺Helios⁻ Tregs. Our work implies that therapeutic modalities for treating autoimmune and inflammatory diseases, allergies and graft rejection should be designed to induce and/or expand FoxP3⁺Helios⁺ Tregs, while therapies against cancers or infectious diseases should avoid such expansion/induction.