IFN-free therapy is associated with restoration of type I IFN response in HIV-1 patients with acute HCV infection who achieve SVR.

Interferon (IFN)-free direct-acting antiviral agents (DAAs) have revolutionized chronic hepatitis C virus (HCV) treatment; early studies suggest excellent efficacy in acute HCV. However, changes in innate immune responses during DAA therapy for acute HCV are unknown. We studied interferon-stimulated gene (ISG) expression and related cytokines/chemokines in HIV-infected patients with acute HCV receiving sofosbuvir plus ribavirin (SOF+RBV) as part of the A5327 clinical trial. ISG expression was determined from PBMCs, and circulating cytokines/chemokines were quantified from serum from study participants. The overall sustained virologic response (SVR) was 57%; all treatment failures were due to virologic relapse. Apart from NOS2a, baseline ISG/chemokine/cytokine levels were similar irrespective of treatment outcome. Downregulation of ISGs was observed at treatment week four and end of treatment (EOT), implicating HCV in establishing elevated ISGs early during HCV infection. Levels of many of these ISGs increased at post-treatment week 12 (PTW12) in relapsers only, coinciding with recurrent HCV RNA. Eleven ISGs were differentially expressed in responders vs relapsers. On-treatment viral suppression was also associated with a reduction in IP-10, CXCL11 and MIP-1ß levels. In contrast, circulating IFN-α levels were significantly higher at EOT and PTW12 in responders vs relapsers. Upregulation of peripheral ISG expression is established early in the course of HCV infection during acute HCV infection, but did not predict subsequent treatment outcome with SOF+RBV. ISGs were downregulated during therapy and increased post-therapy in relapsers. IFN-α levels were higher in responders at EOT/PTW12, suggesting that impaired type I IFN production/secretion may contribute to relapse.

Does IL28B genotyping still have a role in the era of direct-acting antiviral therapy for chronic hepatitis C infection?

IL28B genotype has been shown to be the strongest pretreatment predictor of sustained virological response (SVR) in patients with genotype 1 chronic hepatitis C infection (CHC) treated with pegylated interferon (peg-IFN) and ribavirin (RBV). Patients carrying the good response genotype have a two- to threefold higher chance of SVR than those with a poor response genotype, manifest as dramatically improved early viral kinetics. However, the treatment paradigm for CHC is changing with the introduction of potent direct-acting antivirals (DAAs). IL28B genotype remains relevant to both telaprevir and boceprevir treatment regimens, although the strength of association with virological response is attenuated. The association between IL28B genotype and outcomes of treatment regimens that involve peg-IFN plus combination DAA therapy, or IFN-free regimens, is currently being evaluated. IL28B genotype may remain relevant to individualizing the choice of treatment regimen in the future.

Impacts of Heterogeneous Chemistry on Vertical Profiles of Martian Ozone.

We show a positive vertical correlation between ozone and water ice using a vertical cross-correlation analysis with observations from the ExoMars Trace Gas Orbiter's Nadir and Occultation for Mars Discovery instrument. This is particularly apparent during L S = 0°-180°, Mars Year 35 at high southern latitudes, when the water vapor abundance is low. Ozone and water vapor are anti-correlated on Mars; Clancy et al. (2016, https://doi.org/10.1016/j.icarus.2015.11.016) also discuss the anti-correlation between ozone and water ice. However, our simulations with gas-phase-only chemistry using a 1-D model show that ozone concentration is not influenced by water ice. Heterogeneous chemistry has been proposed as a mechanism to explain the underprediction of ozone in global climate models (GCMs) through the removal of HO x . We find improving the heterogeneous chemical scheme by creating a separate tracer for the HO x adsorbed state, causes ozone abundance to increase when water ice is present (30-50 km), better matching observed trends. When water vapor abundance is high, there is no consistent vertical correlation between observed ozone and water ice and, in simulated scenarios, the heterogeneous chemistry has a minor influence on ozone. HO x , which are by-products of water vapor, dominate ozone abundance, masking the effects of heterogeneous chemistry on ozone, and making adsorption of HO x have a negligible impact on ozone. This is consistent with gas-phase-only modeled ozone, showing good agreement with observations when water vapor is abundant. Overall, the inclusion of heterogeneous chemistry improves the ozone vertical structure in regions of low water vapor abundance, which may partially explain GCM ozone deficits.

Global Variations in Water Vapor and Saturation State Throughout the Mars Year 34 Dusty Season.

To understand the evolving martian water cycle, a global perspective of the combined vertical and horizontal distribution of water is needed in relation to supersaturation and water loss and how it varies spatially and temporally. The global vertical water vapor distribution is investigated through an analysis that unifies water, temperature and dust retrievals from several instruments on multiple spacecraft throughout Mars Year (MY) 34 with a global circulation model. During the dusty season of MY 34, northern polar latitudes are largely absent of water vapor below 20 km with variations above this altitude due to transport from mid-latitudes during a global dust storm, the downwelling branch of circulation during perihelion season and the intense MY 34 southern summer regional dust storm. Evidence is found of supersaturated water vapor breaking into the northern winter polar vortex. Supersaturation above around 60 km is found for most of the time period, with lower altitudes showing more diurnal variation in the saturation state of the atmosphere. Discrete layers of supersaturated water are found across all latitudes. The global dust storm and southern summer regional dust storm forced water vapor at all latitudes in a supersaturated state to 60-90 km where it is more likely to escape from the atmosphere. The reanalysis data set provides a constrained global perspective of the water cycle in which to investigate the horizontal and vertical transport of water throughout the atmosphere, of critical importance to understand how water is exchanged between different reservoirs and escapes the atmosphere.

Global Vertical Distribution of Water Vapor on Mars: Results From 3.5 Years of ExoMars-TGO/NOMAD Science Operations.

We present water vapor vertical distributions on Mars retrieved from 3.5 years of solar occultation measurements by Nadir and Occultation for Mars Discovery onboard the ExoMars Trace Gas Orbiter, which reveal a strong contrast between aphelion and perihelion water climates. In equinox periods, most of water vapor is confined into the low-middle latitudes. In aphelion periods, water vapor sublimated from the northern polar cap is confined into very low altitudes-water vapor mixing ratios observed at the 0-5 km lower boundary of measurement decrease by an order of magnitude at the approximate altitudes of 15 and 30 km for the latitudes higher than 50°N and 30-50°N, respectively. The vertical confinement of water vapor at northern middle latitudes around aphelion is more pronounced in the morning terminators than evening, perhaps controlled by the diurnal cycle of cloud formation. Water vapor is also observed over the low latitude regions in the aphelion southern hemisphere (0-30°S) mostly below 10-20 km, which suggests north-south transport of water still occurs. In perihelion periods, water vapor sublimated from the southern polar cap directly reaches high altitudes (>80 km) over high southern latitudes, suggesting more effective transport by the meridional circulation without condensation. We show that heating during perihelion, sporadic global dust storms, and regional dust storms occurring annually around 330° of solar longitude (L S) are the main events to supply water vapor to the upper atmosphere above 70 km.

Linkage group XIX of Chlamydomonas reinhardtii has a linear map.

Linkage group XIX (or the UNI linkage group) of Chlamydomonas reinhardtii has been reported to show a circular meiotic recombination map. A circular map predicts the existence of strong chiasma and chromatid interference, which would lead to an excess number of two-strand double crossovers during meiosis. We have tested this prediction in multipoint crosses. Our results are consistent with a linear linkage group that shows positive chiasma interference and no chromatid interference. Chiasma interference occurs both within arms and across the centromere. Of the original loci that contributed to the circular map, we find that two map to other linkage groups and a third cannot be retested because the mutant strain that defined it has been lost. A second reported unusual property for linkage group XIX was the increase in meiotic recombination with increases in temperature during a period that precedes the onset of meiosis. Although we observed changes in recombination frequencies in some intervals on linkage group XIX in crosses to CC-1952, and in strains heterozygous for the mutation ger1 at 16 degrees, we also show that our strains do not exhibit the previously observed patterns of temperature-sensitive recombination for two different pairs of loci on linkage group XIX. We conclude that linkage group XIX has a linear genetic map that is not significantly different from other Chlamydomonas linkage groups.

Loss of spatial control of the mitotic spindle apparatus in a Chlamydomonas reinhardtii mutant strain lacking basal bodies.

The bld2-1 mutation in the green alga Chlamydomonas reinhardtii is the only known mutation that results in the loss of centrioles/basal bodies and the loss of coordination between spindle position and cleavage furrow position during cell division. Based on several different assays, bld2-1 cells lack basal bodies in > 99% of cells. The stereotypical cytoskeletal morphology and precise positioning of the cleavage furrow observed in wild-type cells is disrupted in bld2-1 cells. The positions of the mitotic spindle and of the cleavage furrow are not correlated with respect to each other or with a specific cellular landmark during cell division in bld2-1 cells. Actin has a variable distribution during mitosis in bld2-1 cells, but this aberrant distribution is not correlated with the spindle positioning defect. In both wild-type and bld2-1 cells, the position of the cleavage furrow is coincident with a specialized set of microtubules found in green algae known as the rootlet microtubules. We propose that the rootlet microtubules perform the functions of astral microtubules and that functional centrioles are necessary for the organization of the cytoskeletal superstructure critical for correct spindle and cleavage furrow placement in Chlamydomonas.

Topoisomerase II alpha expression in acute myeloid leukaemia and its relationship to clinical outcome.

The treatment of acute myeloid leukaemia (AML) is often complicated by resistance to chemotherapeutic drugs. Many of the most effective drugs used to treat haematological malignancies target the nuclear enzyme topoisomerase II. Resistance to these drugs in vitro has been associated with quantitative and qualitative changes in the enzyme. In this study, we have investigated topoisomerase II mRNA expression in leukaemic blasts from 23 AML patients. Expression levels ranged from 1-47% relative to the haemopoietic cell line HL60 in 16 evaluable patients. Thirteen of 16 patients achieved complete remission (CR). We have therefore chosen ease of entry into CR as the most sensitive clinical correlate. Decreased topoisomerase II mRNA expression in vitro results in drug resistance. The clinical relevance of reduced expression is not known. All cases of AML and de novo AML have been studied separately. We are unable to identify a correlation between topoisomerase II mRNA levels and ease of entry into CR in either of these groups. Taking these findings into account, group size calculations have been undertaken and indicate that a multi-centre study of this question is warranted.

Topoisomerase II expression in normal haemopoietic cells and chronic lymphocytic leukaemia: drug sensitivity or resistance?

Chronic lymphocytic leukaemia (CLL) is a progressive disease, commonly treated in its early stage with alkylating agents. A multi-agent regimen which includes anthracyclines is used to treat advanced disease. Despite chemotherapy, the disease remains incurable. There is now considerable evidence to suggest that anthracyclines exert their effect via the nuclear enzyme topoisomerase II and that alterations in amount or activity of this enzyme may mediate drug resistance. We have investigated topoisomerase II mRNA expression in 34 CLL patients and in haemopoietic cells from 10 normal donors. Expression was found to be low but detectable in all patients and normals. Such low levels may contribute to the toxicity of alkylating agents, but could severely limit the effect of anthracyclines.

Is the mdr 1 gene relevant in chronic lymphocytic leukemia?

Chronic lymphocytic leukemia (CLL) is a progressive disease in which chemotherapy may result in temporary suppression of the peripheral blood lymphocyte count, but cure is not usually possible. Drug resistance mechanisms and the multidrug resistant (MDR) phenotype may be relevant to the therapeutic response. We have studied 34 patients with CLL (seven untreated, 27 treated), screening both DNA and RNA with the mdr 1 gene probe. In pure lymphocyte populations from 10 normal subjects, low levels of mdr 1 RNA expression were found. Eighteen CLL patients (four untreated, 14 treated) had levels of mdr 1 RNA expression above the normal range. No evidence of mdr 1 gene amplification could be found in these patients. Sequential estimations of RNA levels in three patients suggest that malignant lymphocytes in CLL can increase mdr 1 expression in response to chemotherapy and return to basal levels on withdrawal of the treatment. Such data raise important questions about the type of timing of cytotoxic therapy in CLL.

The relationships between IFNL4 genotype, intrahepatic interferon-stimulated gene expression and interferon treatment response differs in HCV-1 compared with HCV-3.

BACKGROUND: The biological mechanism underlying the association between IFNL4/IFNL3 polymorphism and peginterferon/ribavirin (PR) response in HCV-1 is thought to involve differential intrahepatic interferon-stimulated gene expression. HCV-3 is more sensitive to PR, but there are no studies of the association between IFNL4 polymorphism, PR treatment response and liver interferon-stimulated gene expression in HCV-3. AIM: We evaluated the association between IFNL4/IFNL3 genotypes, PR treatment outcomes and intrahepatic interferon-stimulated gene expression, according to HCV genotype. METHODS: HCV-1 and HCV-3 patients who received PR therapy were identified. IFNL3 (rs12979860) and IFNL4 genotype (rs368234815) were determined. A second cohort with stored liver specimens was identified. Expression of ISGs was measured by rt-PCR. RESULTS: Two hundred and fifty-nine patients were identified: 55% HCV-1, 45% HCV-3. IFNL4 genotype frequency was TT/TT 44%, TT/ΔG 42% andΔG/ΔG 14%. Linkage disequilibrium with IFNL3 genotype was high (r(2) = 0.98). The association between IFNL4 genotype and PR response was attenuated in HCV-3 vs. HCV-1 (HCV-3: SVR 89% vs. 76% vs. 72% for TT/TT vs. TT/ΔG vs. ΔG/ΔG, P = 0.09; HCV-1: SVR: 82% vs. 29% vs. 24%, P < 0.001). Intrahepatic ISG expression was evaluated in 92 patients; 61% HCV-1. The association between IFNL4 genotype and liver ISG expression was significantly different for HCV-3 vs. HCV-1 (P-value for interaction = 0.046), with levels of interferon-stimulated gene expression being highest in HCV-1 patients who carried a poor-response IFNL4 genotype. CONCLUSIONS: The relationship between IFNL4 genotype and PR treatment response as well as intrahepatic interferon-stimulated gene expression differs between HCV-1 and HCV-3. These data suggest fundamental differences in host-virus interactions according to HCV genotype.

Autoantibody analysis in chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) bears clinical similarities to connective tissue diseases which are characterized by a spectrum of autoantibody formation. A wide range of autoantibody analyses in 19 allogeneic and 16 autologous bone marrow transplant (BMT) patients has determined that the most commonly detected antibody is IgM anti-cytoplasmic factor (ACF) occurring in 37% and 20% of allogeneic and autologous group respectively and of a type not normally seen in connective tissue disease. The antigen is as yet unidentified. These results suggest that autoantibody formation post-BMT is unrelated to the graft-versus-host process. Ophthalmic examination revealed evidence of a Sjögren-like syndrome in 20% autologous and 47% allogeneic patients, suggesting that the development of dry eyes post-BMT is not uniquely a feature of cGVHD.

Quality of life in long-term survivors of marrow transplantation: comparison with a matched group receiving maintenance chemotherapy.

A retrospective descriptive study was designed to assess the quality of life (QoL) and psychosocial adjustment in long-term BMT survivors compared with a group of patients with haematological malignancies receiving maintenance chemotherapy (MC), matched for age, post-treatment time, sociodemographic and disease characteristics. The sample consisted of 91 long-term BMT survivors and 73 MC patients from three teaching hospitals in the UK. The results indicated that most of the BMT subjects had a good to excellent quality of life and, in some domains, even better adjustment than the MC patients. However, 20% of the BMT subjects had failed to return to full-time employment at a mean post-BMT time of almost 40 months. A significant number of BMT subjects were also identified with symptoms of anxiety and depression. The physical symptomatology had an association with psychological status. Impotence-related difficulties, decreased sexual satisfaction and altered body image were the main characteristics of psychosexual dysfunction in the BMT group. Poorer quality of life was predicted by the presence of depressive symptoms, low affirmation, and impoverished social adjustment.

The activity of deoxyspergualin in multidrug-resistant cells.

Deoxyspergualin, a synthetic analogue of the immunosuppressive anti-tumour antibiotic spergualin, has been shown to possess potent in vitro and in vivo anti-tumour activity and is currently in the National Cancer Institute (NCI) decision network. Deoxyspergualin shows similarities in properties and mechanisms of action to the natural-product immunosuppressive agents cyclosporin A and FK506, each of which can act as a modifier of multidrug resistance. We therefore decided to examine the comparative activity of deoxyspergualin in parent and multidrug-resistant cells. Deoxyspergualin contains the polyamine spermidine within its structure. Bovine serum copper amine oxidase catalyses the oxidative deamination of spermidine to produce an aminoaldehyde, ammonia and hydrogen peroxide. These aminoaldehydes are believed to be responsible for the toxicity of polyamines in vitro in the presence of bovine serum. For this reason, all experiments were carried out in medium containing bovine serum and in medium containing horse serum (which is low in copper amine oxidase content). We used the tetrazolium (MTT) colorimetric assay to determine drug sensitivity and tritiated daunorubicin accumulation together with inhibition of azidopine binding to study specific mechanisms of resistance modulation. The murine cell lines EMT6/P and EMT6/AR1.0 and the human cell lines H69/P and H69/LX4 were, respectively, 32-, 32-, 372- and 483-fold more sensitive to spermidine and 175-, 133-, 321- and 444-fold more sensitive to spermine in the presence of calf serum than in the presence of horse serum. However, these large differential effects were not seen for deoxyspergualin. It appears that in the presence of horse serum, deoxyspergualin may exert its effect by a mechanism other than polyamine oxidation. Deoxyspergualin did not enhance the accumulation of [3H]-daunorubicin in EMT6/AR1.0 cells. Furthermore, deoxyspergualin (1-20 microM) did not restore the sensitivity of EMT6/AR1.0 or H69/LX4 cells to that of the parent lines. P-glycoprotein (Pgp) in membranes prepared from H69/LX4 cells was photo-affinity-labeled with [3H]-azidopine. Deoxyspergualin did not inhibit this labeling. Although deoxyspergualin appears to exert its immunosuppressive effect via a mechanism similar to that of cyclosporin A and FK506, it does not share their ability to modify Pgp-mediated multidrug resistance. However, its lack of cross-resistance and potent in vivo anti-tumour activity make deoxyspergualin a promising candidate for development as an anti-cancer agent.

Multidrug Resistance in Leukaemia.

The treatment of many haematological malignancies is complicated by the development of resistance to cytotoxic agents. Cells which acquire the multidrug resistant (MDR) phenotype lose sensitivity to a spectrum of structurally unrelated chemotherapeutic drugs. Several distinct drug resistance mechanisms are now recognised which may be involved in clinically resistant leukaemia. It is possible that leukaemic cells may utilise one or more of these resistance processes as a survival mechanism and to maintain a proliferative advantage. If relevance of resistance mechanisms can be established, then the potential therapeutic benefit by circumvention of MDR is considerable with patients rendered chemosensitive and curable. There are many drugs which in vitro can reverse resistance processes, but their efficacy in vivo is yet to be fully demonstrated. It is likely that the final picture of the involvement of drug resistance in leukaemia will be complicated. Further investigation is warranted as the potential rewards are high.

Differential effects of avoidant and attentional coping strategies on adaptation to chronic and recent-onset pain.

Examined the effectiveness of attentional and avoidant coping strategies for somatic, behavioral, and psychological adaptation to clinical pain. Subjects were 30 chronic and 30 recent-onset pain patients who used either attentional or avoidant coping strategies in response to their pain. Based on a review of the coping literature, it was hypothesized that subjects with recent-onset pain would demonstrate greater adaptation (lower anxiety, depression, lower pain severity and somatization ratings, and higher levels of social activity) when employing avoidant rather than attentional strategies. Chronic pain subjects using attentional strategies were predicted to demonstrate greater adaptation than chronic pain subjects using avoidant strategies. The results supported this "time x strategy" hypothesis. Implications for pain treatment programs are discussed, and suggestions are made for matching pain duration with patient coping style.

Erector spinae activation and movement dynamics about the lumbar spine in lordotic and kyphotic squat-lifting.

Activation of the erector spinae during squat lifts depends on the initial posture of the lumbar spine. The authors assessed erector spinae activation by electromyography during squat lifts from lordotic and kyphotic postures, measured kinematics of the lifts from digitized video images, and inferred torques from the kinematics, using a two-dimensional model of a human lifting in the sagittal plane, with a joint at L3. Lifts from the lordotic initial posture had peak electromyographic signals early in the lift, whereas lifts from kyphotic initial posture had an initial "flexor relaxation," and peak activity in the middle of the lift. Lumbar flexion was much greater in lifts from kyphotic initial position. Torques required about L3 were similar between the two postures, though somewhat larger initially in lifts from kyphosis. The largest torques were therefore sustained by flexed lumbar spines, during periods of little or no erector spinae activity, in lifts made from kyphotic initial position. A sizable portion of the early torque is inertial, and therefore strongly dependent on movement time. Movements with a 30-lb load in the hands were similar, in kinematics and electromyography, to unloaded lifts, though longer in duration. The clinical implications of the differences in activation with posture, the practical implications of the inertial component of torque, and the need for consideration of lumbar posture in future modeling of squat lifting are discussed.

Completing the picture: adolescents talk about what's missing in sexual health services.

This qualitative study was conducted to learn adolescents' opinions about sexual health services and strategies to improve their delivery. Sixteen 1.5-hour, same-sex focus groups were conducted in one rural and one urban high school in each of two Ontario regions. In total, 83 students (49 females and 34 males) participated in the study. Topics were: sources and quality of sexual health information, knowledge and use of sexual health services, gender differences, factors that influence sexual behaviour, and suggestions for improving sexual health services. The adolescents reported that sex education focussed too much on "plumbing" and was often provided by teachers with whom they felt uncomfortable discussing sexual issues. Peers and media were their main sources of information although they acknowledged that these were not always accurate. The participants had limited knowledge of the services available. Many of their comments reflected traditional gender differences. Peers, and for females, partners and parents influenced sexual decision-making. The participants made numerous suggestions for improving sexual health services.

The relationship between type of antidepressant and neurovegetative symptoms in adult unipolar nonpsychotic depression: an opinion survey.

The bi-directional nature of the neurovegetative symptoms of depression, as well as the differential response to antidepressant medications, underscore the existence of possible subtypes of this disorder. This study surveyed 56 physicians practicing psychiatry in Hawaii for opinions regarding the most effective antidepressant medication for the following symptoms: hypersomnia vs. insomnia, psychomotor agitation vs. retardation, and gain vs. loss of appetite or weight. Fluoxetine was found to be the drug of choice for weight and appetite gain, hypersomnia, and psychomotor retardation. Mirtazapine was viewed as most effective for weight and appetite loss. Trazodone was found most effective for insomnia and nefazodone for psychomotor agitation. It is concluded that subtyping of depression should be investigated at the symptom level and the generalizability of the effects of each specific compound should be tested.