Type I interferon-mediated autoinflammation due to DNase II deficiency

Microbial nucleic acid recognition serves as the major stimulus to an antiviral response, implying a requirement to limit the misrepresentation of self nucleic acids as non-self and the induction of autoinflammation. By systematic screening using a panel of interferon-stimulated genes we identify two siblings and a singleton variably demonstrating severe neonatal anemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies. In both families we identify biallelic mutations in DNASE2, associated with a loss of DNase II endonuclease activity. We record increased interferon alpha protein levels using digital ELISA, enhanced interferon signaling by RNA-Seq analysis and constitutive upregulation of phosphorylated STAT1 and STAT3 in patient lymphocytes and monocytes. A hematological disease transcriptomic signature and increased numbers of erythroblasts are recorded in patient peripheral blood, suggesting that interferon might have a particular effect on hematopoiesis. These data define a type I interferonopathy due to DNase II deficiency in humans

Evolution of a shelly beach ridge system over the last decades in a hypertidal open-coast embayment (western Mont-Saint-Michel Bay, NW France)

(IF 1.05 [2018]; Q2)International audienceThe behavior of the shelly beach ridge system forming a more or less continuous barrier lying along the southern coast of the hypertidal Mont-Saint-Michel bay (NW France) is examined using a set of various data including aerial photographs since 1947, sediment cores collected in back-barrier salt marshes, ground penetrating radar profiles, and differential digital elevation models (DEMs). The latter shows that since the middle of the 20th century, the tidal flats extending in front of the ridge system experience erosion and accretion that alternate spatially according to cross-shore corridors. The shelly ridges are better developed on line with the erosional bands. The reasons for this erosion/accretion compartment pattern are not totally elucidated. It probably results from the combined influence of shellfish farms, tidal channels and reef present on the tidal flats on wave and current dynamics. At the decadal to pluri-decadal scale, the shelly beach ridge system behavior as well as its internal organization can partly be related to the fluctuations of hydrodynamic conditions controlled by the 18.6 years nodal tidal cycle. Periods of intense landward migration alternate with periods of relative stability during the peak and the trough of the cycle respectively. This general scheme is complicated due to variations in storm wave dynamics. The most morphogenic events happen potentially during coinciding nodal cycle peaks and enhanced storminess. Such conditions actually occurred around 1995-2000, resulting in the most prominent washover fan deposit preserved within the back-barrier infilling successions. These sediment successions evidence as well that no beach ridge system older than the 19th century is preserved in front of the Medieval dike built during the 11th century on a relict beach ridge, and on which the present-day system is backed. We suggest that the enhanced storminess conditions of the Little Ice Age provoked the reworking of beach ridges formed between the 11th and 19th centuries. Changes in quantity and type of mollusk shells, related to the shellfish farming development during the 20th century are also thought to have had positive consequences on the barrier building and stability

Understanding the role of the hematopoietic niche in Huntington's disease's phenotypic expression: in vivo evidence using a parabiosis model

In a previous study, we have shown that parabiotic coupling of a knock-in mouse model (zQ175) of Huntington's disease (HD) to wild-type (WT) littermates resulted in a worsening of the normal phenotype as seen by detection of mutant huntingtin protein (mHTT) aggregates within peripheral organs and the cerebral cortex as well as vascular abnormalities in WT mice. In contrast, parabiosis improved disease features in the zQ175 mice such as reduction of mHTT aggregate number in the liver and cortex, decrease in blood-brain barrier (BBB) permeability and attenuation of mitochondrial impairments. While the shared circulation mediated these effects, no specific factor was identified. To better understand which blood elements were involved in the aforementioned changes, WT and zQ175 mice underwent parabiotic surgery prior to exposing one of the paired animals to irradiation. The irradiation procedure successfully eliminated the hematopoietic niche followed by repopulation with cells originating from the non-irradiated parabiont, as measured by the quantification of mHTT levels in peripheral blood mononuclear cells. Although irradiation of the WT parabiont, causing the loss of healthy hematopoietic cells, did lead to a few alterations in mitochondrial function in the muscle (TOM40 levels), and increased neuroinflammation in the striatum (GFAP levels), most of the changes observed were likely attributable to the irradiation procedure itself (e.g. mHTT aggregates in cortex and liver; cellular stress in peripheral organs). However, factors such as mHTT aggregation in the brain and periphery, and BBB leakage, which were improved in zQ175 mice when paired to WT littermates in the previous parabiosis experiment, were unaffected by perturbation of the hematopoietic niche. It would therefore appear that cells of the hematopoietic stem cell niche are largely uninvolved in the beneficial effects of parabiosis

One-Year Longitudinal Study of Fatigue, Cognitive Functions, and Quality of Life After Adjuvant Radiotherapy for Breast Cancer

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Prospective Evaluation of the Impact of Antiangiogenic Treatment on Cognitive Functions in Metastatic Renal Cancer

International audienceBACKGROUND:Little is known about the cognitive effects of antiangiogenic therapies (AATs) in metastatic renal cell carcinoma (mRCC) and their relation with fatigue.OBJECTIVE:To evaluate the impact of AATs on cognition and its connection with fatigue and quality of life (QoL) in patients with mRCC.DESIGN, SETTING, AND PARTICIPANTS:This prospective study enrolled 75 patients starting AAT as first or second line for mRCC and assessed them at 3 mo (n=58) and 6 mo (n=50).OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:We assessed objective cognitive decline with a neuropsychological battery of tests and cognitive complaint, fatigue, and QoL with validated self-reported questionnaires using the Fisher exact test, Wilcoxon test, and Spearman correlation coefficient.RESULTS AND LIMITATIONS:A decline of cognitive functions was observed in 18 patients (31%) including 13 without cognitive impairment at baseline. The score of fatigue was increased in all patients except one. A relationship between cognitive complaints and fatigue was observed (p<0.05) but not with objective cognitive decline. Cognitive complaints and fatigue had a significant impact on most of the domains of QoL (p<0.01). A positive correlation was found between fatigue and inflammatory markers but not with cognition. The main limitation of this study is the absence of a control group.CONCLUSIONS:AAT induced cognitive decline in patients with mRCC independently of fatigue. These side effects affecting QoL should be better assessed in clinical trials and taken into account in routine practice.PATIENT SUMMARY:Fatigue is a well-known effect of antiangiogenic therapies (AATs) of cancer. The study performed in patients with treated metastatic renal cancer shows a decline of cognitive functions induced by AATs, such as information-processing speed or working memory, in a third of patients, independently of fatigue. Patients on AATs should be informed of these possible adverse effects

Analysis of Transfusion-Related Acute Lung Injury and Possible Transfusion-Related Acute Lung Injury Reported to the French Hemovigilance Network From 2007 to 2013

International audienceUsing the French Hemovigilance Network database from 2007 to 2013, we provide information on demographics, incidence, and risk factors of reported transfusion-related acute lung injury (TRALI) and possible TRALI, analyze TRALI mitigation efforts for fresh frozen plasma and platelet concentrates, and consider the impact of platelet additive solutions on TRALI incidence. We applied the Toronto consensus conference definitions for TRALI and possible TRALI. Two TRALI subgroups were considered: “antibody positive” when a donor has human leukocyte antigen (class I or II) and/or human neutrophil antigen antibodies and the recipient has cognate antigen, and “antibody negative” when immunological investigation is negative or not done. The analysis targeted 378 cases, divided into antibody-positive TRALI (n=75), antibody-negative TRALI (n=100), and possible TRALI (n=203). TRALI patientswere younger and receivedmore blood components than the general population of transfused patients.Moreover,we identified the following clinical conditionswhere patients seemed to be at higher risk to develop TRALI: postpartum hemorrhage, acute myeloid leukemia, liver transplantation, allogeneic and autologous hematopoietic stem cells transplantation, polytrauma, and thrombotic microangiopathy. Policy measures intended to reduce antibody-positive TRALI were found effective for apheresis platelet concentrates and fresh frozen plasma but not forwhole blood–derived platelet concentrates. The use of platelet additive solutions was associated with a significant reduction in the incidence of TRALI following transfusion of buffy coat–derived platelet concentrates but not following transfusion of apheresis platelets. Our data reinforce the concept that possible TRALI and TRALI, as defined in the Canadian consensus conference, share many characteristics. No specific policy measures are currently directed at mitigation of possible TRALI despite its impact on transfusion safety. Despite TRALI mitigationmeasures, the overall incidence of TRALI cases reported to the French Hemovigilance system was not significantly reduced. Therefore, additional research is needed to reduce, if not eradicate, all TRALI categories

Sexual Disorders of Patients With Metastatic Renal Cell Carcinoma (mRCC) Treated With Antiangiogenic Therapies

International audienceBackground :Targeted therapies, in particular antiangiogenic therapies (AATs), have become the standard of treatment for metastatic renal cell carcinoma (mRCC). Although common adverse effects like fatigue have been well-established, sexual disorders induced by these treatments, although often reported, have been poorly evaluated. The aim of this study was to evaluate the impact of AATs on the sexual life of patients with mRCC and the relationships with quality of life (QoL), fatigue, and biologic parameters.Patients and Methods :This longitudinal study included patients with mRCC on first- or second-line AATs. Sexuality was evaluated by the French version of Changes in Sexual Functioning Questionnaire short-Form (CSFQ); QoL and fatigue were measured by the Functional Assessment of Cancer Therapy General (FACT-G) and the Multidimensional Fatigue Inventory (MFI-20), respectively. Biologic parameters were also assessed.Results :Among 75 patients included in the study, 39 agreed to respond to the sexual functioning questionnaire (CSFQ). At baseline, all patients had at least 1 sexual dysfunction. No relationship with QoL, fatigue, and biologic parameters was shown. After 3 months of treatment, a decrease in at least 1 sexual dimension was observed in 69% of patients. The most affected sexual dimensions were pleasure (34%) and desire/interest (38%). No significant relationship between sexual dysfunctions and biologic parameters was found. The percentage of non-participants (50%) and the absence of a control arm are the main limitations.Discussion :Patients with mRCC exhibit sexual dysfunction that could be increased by AATs independently of the impact on fatigue and QoL. Further studies aiming to define the role of biologic parameters like inflammatory markers and thyroid parameters are warranted.Conclusion :Sexual disorders induced or degraded by AAT are an independent side effect that should be taken into account in oncology supportive care departments

Decline in Cognitive Function in Older Adults With Early-Stage Breast Cancer After Adjuvant Treatment

International audienceBackground. The impact of chemotherapy on cognition among elderly patients has received little attention, although such patients are more prone to presenting with age-related cognitive deficits and/or cognitive decline during chemotherapy. The present study assessed the cognitive function in older adults treated for early-stage breast cancer (EBC). Patients and Methods. The participants were newly diagnosed EBC patients aged $65 years without previous systemic treatment or neurological or psychiatric disease and matched healthy controls. They underwent two assessments: before starting adjuvant therapy and after the end of chemotherapy (including doxorubicin 6 docetaxel [CT1 group], n 5 58) or radiotherapy for patients who did not receive chemotherapy (CT2 group, n 5 61), and at the same interval for the healthy controls (n 5 62). Neuropsychological and geriatric assessments were performed. Neuropsychological data were analyzed using the Reliable Change Index. Results. Forty-nine percent of the patients (mean age, 70 6 4 years) had objective cognitive decline after adjuvant treatment that mainly concerned working memory. Among these patients, 64% developed a cognitive impairment after adjuvant treatment. Comorbidity was not associated with cognitive decline. No significant difference in objective cognitive decline was found between the two groups of patients; however, the CT1 group had more subjective cognitive complaints after treatment (p 5 .008). The oldest patients (aged 70–81 years) tended to have more objective decline with docetaxel (p 5 .05). Conclusion. This is the largest published study assessing cognitive function in older adults with EBC that included a group of patients treated with modern chemotherapy regimens. Approximately half the patients had objective cognitive decline after adjuvant treatment. The oldest patients were more likely to have cognitive decline with chemotherapy, particularly with docetaxel. The Oncologist 2016;21:1–12 Implications for Practice: This is the largest published study assessing cognitive function in older adults with early-stage breast cancer that included a group of patients treated with modern chemotherapy regimens. Approximately half the patients had objective cognitive decline after adjuvant treatment. The oldest patients were more likely to have cognitive decline with che-motherapy, particularly with docetaxel. Cognitive deficits could affect patients' quality of life and their compliance to treatment. Assessing cognitive dysfunctions in the elderly cancer population is a challenge in clinical practice, but it could influence the choice of the most appropriate therapy, including the use of oral drugs

Baseline cognitive functions among elderly patients with localised breast cancer

International audiencePURPOSE: Cognitive deficits (CD) are reported among cancer patients receiving chemotherapy, but may also be observed before treatment. Though elderly patients are expected to be more prone to present age-related CD, poor information is available regarding the impact of cancer and chemotherapy on this population. This study assessed baseline cognitive functions (before adjuvant treatment) in elderly early stage breast cancer (EBC) patients. METHODS: Women >65years-old with newly diagnosed EBC were included in this prospective study. Episodic memory, working memory, executive functions and information processing speed were assessed by neuropsychological tests. Questionnaires were used to assess subjective CD, anxiety, depression, fatigue, quality of life and geriatric profile. Objective CD were defined using International Cognition and Cancer Task Force criteria. A group of elderly women without cancer coupled with published data related to healthy women were used for comparison (respectively to subjective and objective CD). RESULTS: Among the 123 elderly EBC patients (70±4years) included, 41% presented objective CD, which is greater than expected in healthy population norms (binomial test P<.0001). Verbal episodic memory was mainly impaired (21% of patients). No correlation was observed between objective CD and cancer stage or geriatric assessment. Subjective CD only correlated with verbal episodic memory (P=.01). CONCLUSIONS: This is the first large series assessing baseline cognitive functions in elderly EBC patients. More than 40% presented objective CD before any adjuvant therapy, which is higher than what is reported among younger patients. Our results reinforce the hypothesis that age is a risk factor for CD in EBC patients