ITPA Polymorphisms Are Associated with Hematological Side Effects during Antiviral Therapy for Chronic HCV Infection

Background/ObjectiveGenetic polymorphisms in the inosine triphosphatase (ITPA) gene have been associated with the protection from early ribavirin(RBV)-induced hemolytic anemia among patients with chronic hepatitis C virus (HCV) infection. The aim of the present study was to investigate the association between the functional ITPA variants and hematological side effects during antiviral therapy with pegylated interferon (PegIFN) and RBV.ResultsIn total, 213 patients were included. The predicted ITPase activity was normal among 152 (71%) patients; 61 (29%) patients had ITPase deficiency. By multivariable linear regression, RBV dose in mg per kilogram (Beta 0.09, 95%CI 0.04–0.13, p<0.001) and normal ITPase activity (Beta 0.89, 95%CI 0.64–1.14, p<0.001) were associated with more Hb decline at week 4 of treatment. Patients with normal ITPase activity underwent more dose adjustments of RBV than patients with ITPase deficiency (19(13%) vs 1(2%),p = 0.014) and received erythropoietin more frequently (12 (8%) vs 0 (0%),p = 0.024).ConclusionGenetic variants in the ITPA gene protected against RBV treatment-induced anemia among Caucasian patients with chronic HCV infection. Patients with normal ITPase activity underwent more dose reductions of RBV and received erythropoietin more frequently.     

Genetic counselling for pulmonary arterial hypertension: a matter of variable variability

We report three cases which highlight the complex considerations surrounding genetic counselling for pulmonary arterial hypertension (PAH). The first counselee developed PAH symptoms shortly after his daughter’s death from PAH and was diagnosed with a delay of 1 year. An early diagnosis of familial PAH was established in the second counselee. Oral therapy was initiated immediately, and her functional status has since remained stable. The third counselee was a healthy woman who struggled to cope with her risk for familial PAH, having lost two siblings from the disease. These cases show that incomplete penetrance and variable expression need particular attention during clinical assessment and genetic counselling of heritable PAH patients and family members.     

The stress of Arctic warming on polar bears

Arctic ecosystems are changing rapidly in response to climate warming. While Arctic mammals are highly evolved to these extreme environments, particularly with respect to their stress axis, some species may have limited capacity to adapt to this change. We examined changes in key components of the stress axis (cortisol and its carrier protein—corticosteroid binding globulin [CBG]) in polar bears (Ursus maritimus) from western Hudson Bay (N = 300) over a 33 year period (1983–2015) during which time the ice‐free period was increasing. Changing sea ice phenology limits spring hunting opportunities and extends the period of onshore fasting. We assessed the response of polar bears to a standardized stressor (helicopter pursuit, darting, and immobilization) during their onshore fasting period (late summer–autumn) and quantified the serum levels of the maximum corticosteroid binding capacity (MCBC) of CBG, the serum protein that binds cortisol strongly, and free cortisol (FC). We quantified bear condition (age, sex, female with cubs or not, fat condition), sea ice (breakup in spring–summer, 1 year lagged freeze‐up in autumn), and duration of fasting until sample collection as well as cumulative impacts of the latter environmental traits from the previous year. Data were separated into “good” years (1983–1990) when conditions were thought to be optimal and “poor” years (1991–2015) when sea ice conditions deteriorated and fasting on land was extended. MCBC explained 39.4% of the variation in the good years, but only 28.1% in the poor ones, using both biological and environmental variables. MCBC levels decreased with age. Changes in FC were complex, but more poorly explained. Counterintuitively, MCBC levels increased with increased time onshore, 1 year lag effects, and in poor ice years. We conclude that MCBC is a biomarker of stress in polar bears and that the changes we document are a consequence of climate warming.     

Retention of CD4+ CD25+ FoxP3+ regulatory T cells in the liver after therapy-induced hepatitis C virus eradication in humans

Following infection with the hepatitis C virus (HCV), in most cases immunity fails to eradicate the virus, resulting in slowly progressing immunopathology in the HCV-infected liver. We are the first to examine intrahepatic T cells and CD4(+) CD25(+) FoxP3(+) regulatory T cells (Treg) in patients chronically infected with HCV (chronic HCV patients) during and after antiviral therapy by collecting multiple aspiration biopsy samples from the liver at different time points. We found that intrahepatic Treg frequencies were increased upon alpha interferon and ribavirin administration in about 50% of chronic HCV patients, suggesting stronger regulation of intrahepatic immunity by Treg during antiviral therapy. After cessation of antiviral therapy, the frequency of intrahepatic Treg remained above baseline in the large majority of livers of individuals who successfully cleared the virus. The phenotype of those Treg that were retained in the liver months after therapy-induced clearance of HCV RNA indicated a reduced contribution of effector memory cells. Our findings, gathered by multiple samplings of the liver, indicate that successful antiviral therapy of chronic HCV patients does not lead to normalization of the local immune response to a resting state comparable to that for healthy livers. The continuous presence of high numbers of Treg, with a phenotype reflecting a relatively weak suppressive activity, suggests ongoing residual regulation of immunopathology. These findings provide important insight into the dynamics of the immune response to HCV, as well as the effect of therapy on intrahepatic immunity.     

From process to pattern: how fluctuating predation risk impacts the stress axis of snowshoe hares during the 10-year cycle

Predation is a central organizing process affecting populations and communities. Traditionally, ecologists have focused on the direct effects of predation—the killing of prey. However, predators also have significant sublethal effects on prey populations. We investigated how fluctuating predation risk affected the stress physiology of a cyclic population of snowshoe hares (Lepus americanus) in the Yukon, finding that they are extremely sensitive to the fluctuating risk of predation. In years of high predator numbers, hares had greater plasma cortisol levels at capture, greater fecal cortisol metabolite levels, a greater plasma cortisol response to a hormone challenge, a greater ability to mobilize energy and poorer body condition. These indices of stress had the same pattern within years, during the winter and over the breeding season when the hare:lynx ratio was lowest and the food availability the worst. Previously we have shown that predator-induced maternal stress lowers reproduction and compromises offspring’s stress axis. We propose that predator-induced changes in hare stress physiology affect their demography through negative impacts on reproduction and that the low phase of cyclic populations may be the result of predator-induced maternal stress reducing the fitness of progeny. The hare population cycle has far reaching ramifications on predators, alternate prey, and vegetation. Thus, predation is the predominant organizing process for much of the North American boreal forest community, with its indirect signature—stress in hares—producing a pattern of hormonal changes that provides a sensitive reflection of fluctuating predator pressure that may have long-term demographic consequences.     

Multiple measures elucidate glucocorticoid responses to environmental variation in predation threat

Predator-induced changes in the glucocorticoid responses of prey have been proposed to mediate indirect predator effects on prey demography. Ambiguities exist, however, as to whether differences in predation threat in the environment at large affect the mean glucocorticoid response in wild birds and mammals, and whether this is likely to affect reproduction. Most studies to date that have examined glucocorticoid responses to environmental variation in predation threat have evaluated just one of the several potential measures of the glucocorticoid response, and this may be the source of many ambiguities. We evaluated multiple measures of the glucocorticoid response [plasma total CORTicosterone, corticosteroid binding globulin (CBG) and free CORT] in male and female song sparrows (Melospiza melodia) sampled at locations differing in predation threat in the environment at large, where we have previously reported reproductive differences suggestive of indirect predator effects. Total CORT varied markedly with predation threat in males but not females whereas the opposite was true for CBG, and both sexes demonstrated the same moderately significant free CORT response. Considering all three indices, a glucocorticoid response to environmental variation in predation threat was evident in both sexes, whereas there were ambiguities considering each index singly. We conclude that collecting multiple physiological measures and conducting multivariate analyses may provide a preferable means of assessing glucocorticoid responses to environmental variation in predation threat, and so help clarify whether such glucocorticoid changes affect reproduction in wild birds and mammals.