Critical role for the chemokine receptor CXCR6 in NK cell-mediated antigen-specific memory of haptens and viruses.

Hepatic natural killer (NK) cells mediate antigen-specific contact hypersensitivity (CHS) in mice deficient in T cells and B cells. We report here that hepatic NK cells, but not splenic or naive NK cells, also developed specific memory of vaccines containing antigens from influenza, vesicular stomatitis virus (VSV) or human immunodeficiency virus type 1 (HIV-1). Adoptive transfer of virus-sensitized NK cells into naive recipient mice enhanced the survival of the mice after lethal challenge with the sensitizing virus but not after lethal challenge with a different virus. NK cell memory of haptens and viruses depended on CXCR6, a chemokine receptor on hepatic NK cells that was required for the persistence of memory NK cells but not for antigen recognition. Thus, hepatic NK cells can develop adaptive immunity to structurally diverse antigens, an activity that requires NK cell-expressed CXCR6.

The value of intraoperative ultrasound in oblique corpectomy for cervical spondylotic myelopathy and ossified posterior longitudinal ligament.

Intraoperative ultrasound (IOUS) has been described to be useful during central corpectomy for compressive cervical myelopathy. This study aimed at documenting the utility of IOUS in oblique cervical corpectomy (OCC). Prospective data from 24 patients undergoing OCC for cervical spondylotic myelopathy and ossified posterior longitudinal ligament (OPLL) were collected. Patients had a preoperative cervical spine magnetic resonance (MR) image, IOUS and a postoperative cervical CT scan. Retrospective data from 16 historical controls that underwent OCC without IOUS were analysed to compare the incidence of residual compression between the two groups. IOUS identified the vertebral artery in all cases, detected residual cord compression in six (27%) and missed compression in two cases (9%). In another two cases with OPLL, IOUS was sub-optimal due to shadowing. IOUS measurement of the corpectomy width correlated well with these measurements on the postoperative CT. The extent of cord expansion noted on IOUS after decompression showed no correlation with immediate or 6-month postoperative neurological recovery. No significant difference in residual compression was noted in the retrospective and prospective groups of the study. Craniocaudal spinal cord motion was noted after the completion of the corpectomy. IOUS is an inexpensive and simple real-time imaging modality that may be used during OCC for cervical spondylotic myelopathy. It is helpful in identifying the vertebral artery and determining the trajectory of approach, however, it has limited utility in patients with OPLL due to artifacts from residual ossification.

Elemental (C/N ratios) and isotopic (δ15N(org), δ13C(org)) compositions of sedimentary organic matter from a high-altitude mountain lake (Meidsee, 2661 m a.s.l., Switzerland): Implications for Lateglacial and Holocene Alpine landscape evolution

The deposition of Late Pleistocene and Holocene sediments in the high-altitude lake Meidsee (located at an altitude of 2661 m a.s.l. in the Southwestern Alps) strikingly coincided with global ice-sheet and mountain-glacier decay in the Alpine forelands and the formation of perialpine lakes. Radiocarbon ages of bottom-core sediments point out (pre-) Holocene ice retreat below 2700 m a.s.l., at about 16, 13, 10, and 9 cal. kyr BP. The Meidsee sedimentary record therefore provides information about the high-altitude Alpine landscape evolution since the Late Pleistocene/Holocene deglaciation in the Swiss Southwestern Alps. Prior to 5 cal. kyr BP, the C/N ratio and the isotopic composition of sedimentary organic matter (delta N-15(org), delta C-13(org)) indicate the deposition of algal-derived organic matter with limited input of terrestrial organic matter. The early Holocene and the Holocene climatic optimum (between 7.0 and 5.5 cal. kyr BP) were characterized by low erosion (decreasing magnetic susceptibility, chi) and high content of organic matter (C-org > 13 wt.%), enriched in C-13(org) (>-18 parts per thousand) with a low C/N (similar to 10) ratio, typical of modern algal matter derived from in situ production. During the late Holocene, there was a long-term increasing contribution of terrestrial organic matter into the lake (C/N > 11), with maxima between 2.4 and 0.9 cal. kyr BP. A major environmental change took place 800 years ago, with an abrupt decrease in the relative contribution of terrestrial organic material into the lake compared with aquatic organic material which subsequently largely dominated (C/N drop from 16 to 10). Nonetheless, this event was marked by a rise in soil erosion (chi), in nutrients input (N and P contents) and in anthropogenic lead deposition, suggesting a human disturbance of Alpine ecosystems 800 years ago. Indeed, this time period coincided with the migration of the Walser Alemannic people in the region, who settled at relatively high altitude in the Southwestern Alps for farming and maintaining Alpine passes.

Nonclassical NK cell education.

Diseased host cells are eliminated more effectively when natural killer cells grow up in the presence of classical major histocompatibility complex (MHC) class I molecules. The nonclassical MHC class I molecule H2-M3 can exert an analogous effect.

Partial protection and intrathecal invasion of CD8(+) T cells in acute canine distemper virus infection.

Initial non-inflammatory demyelination in canine distemper virus infection (CDV) develops against a background of severe immunosuppression and is therefore, thought to be virus-induced. However, recently we found a marked invasion of T cells throughout the central nervous system (CNS) in dogs with acute distemper despite drastic damage to the immune system. In the present study, this apparent paradox was further investigated by immunophenotyping of lymphocytes, following experimental CDV challenge in vaccinated and non-vaccinated dogs. In contrast to CDV infected, unprotected dogs, vaccinated dogs did not become immunosuppressed and exhibited a strong antiviral immune response following challenge with virulent CDV. In unprotected dogs rapid and drastic lymphopenia was initially due to depletion of T cells. In peripheral blood, CD4(+) T cells were more sensitive and depleted earlier and for a longer time than CD8(+) cells which recovered soon. In the cerebrospinal fluid (CSF) we could observe an increase in the T cell to B cell and CD8(+) to CD4(+) ratios. Thus, partial protection of the CD8(+) cell population could explain why part of the immune function in acute distemper is preserved. As found earlier, T cells invaded the CNS parenchyma in these dogs but also in the protected challenged dogs, which did not develop any CNS disease at all. Since markers of T cell activation were upregulated in both groups of animals, this phenomenon could in part be related to non-specific penetration of activated T cells through the blood brain barrier. However, in diseased animals much larger numbers of T cells were found in the CNS than in the protected dogs, suggesting that massive invasion of T cells in the brain requires CDV expression in the CNS.

Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: a literature review and meta-analysis of individual patient data.

BACKGROUND: Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses a major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan African countries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs). METHODS: A literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials (uncontrolled trials, controlled trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa, between 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial Resistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting early parasitological response were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in included studies was evaluated based on study design, methodology and missing data. RESULTS: In total, 29,493 patients from 84 clinical trials were included in the analysis, treated with artemether-lumefantrine (n = 13,664), artesunate-amodiaquine (n = 11,337) and dihydroartemisinin-piperaquine (n = 4,492). The overall parasite clearance rate was rapid. The parasite positivity rate (PPR) decreased from 59.7 % (95 % CI: 54.5-64.9) on day 1 to 6.7 % (95 % CI: 4.8-8.7) on day 2 and 0.9 % (95 % CI: 0.5-1.2) on day 3. The 95th percentile of observed day 3 PPR was 5.3 %. Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16 (95 % CI: 1.08-1.25); per 2-fold increase in parasite density, P <0.001); fever (>37.5 °C) (AOR = 1.50 (95 % CI: 1.06-2.13), P = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21-3.44), P = 0.008); areas of low/moderate transmission setting (AOR = 2.71 (95 % CI: 1.38-5.36), P = 0.004); and treatment with the loose formulation of artesunate-amodiaquine (AOR = 2.27 (95 % CI: 1.14-4.51), P = 0.020, compared to dihydroartemisinin-piperaquine). CONCLUSIONS: The three ACTs assessed in this analysis continue to achieve rapid early parasitological clearance across the sites assessed in Sub-Saharan Africa. A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50 patients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold of 10 % to trigger further investigation of artemisinin susceptibility.

Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation.

Stromal fibroblast senescence has been linked to ageing-associated cancer risk. However, density and proliferation of cancer-associated fibroblasts (CAFs) are frequently increased. Loss or downmodulation of the Notch effector CSL (also known as RBP-Jκ) in dermal fibroblasts is sufficient for CAF activation and ensuing keratinocyte-derived tumours. We report that CSL silencing induces senescence of primary fibroblasts from dermis, oral mucosa, breast and lung. CSL functions in these cells as a direct repressor of multiple senescence- and CAF-effector genes. It also physically interacts with p53, repressing its activity. CSL is downmodulated in stromal fibroblasts of premalignant skin actinic keratosis lesions and squamous cell carcinomas, whereas p53 expression and function are downmodulated only in the latter, with paracrine FGF signalling as the probable culprit. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances expression of CAF effectors and promotes stromal and cancer cell expansion. The findings support a CAF activation-stromal co-evolution model under convergent CSL-p53 control.

A prognostic score to identify low-risk outpatients with acute deep vein thrombosis in the upper extremity.

BACKGROUND: No studies have identified which patients with upper-extremity deep vein thrombosis (DVT) are at low risk for adverse events within the first week of therapy. METHODS: We used data from Registro Informatizado de la Enfermedad TromboEmbólica to explore in patients with upper-extremity DVT a prognostic score that correctly identified patients with lower limb DVT at low risk for pulmonary embolism, major bleeding, or death within the first week. RESULTS: As of December 2014, 1135 outpatients with upper-extremity DVT were recruited. Of these, 515 (45%) were treated at home. During the first week, three patients (0.26%) experienced pulmonary embolism, two (0.18%) had major bleeding, and four (0.35%) died. We assigned 1 point to patients with chronic heart failure, creatinine clearance levels 30-60 mL min(-1) , recent bleeding, abnormal platelet count, recent immobility, or cancer without metastases; 2 points to those with metastatic cancer; and 3 points to those with creatinine clearance levels < 30 mL min(-1) . Overall, 759 (67%) patients scored ≤ 1 point and were considered to be at low risk. The rate of the composite outcome within the first week was 0.26% (95% confidence interval [CI] 0.004-0.87) in patients at low risk and 1.86% (95% CI 0.81-3.68) in the remaining patients. C-statistics was 0.73 (95% CI 0.57-0.88). Net reclassification improvement was 22%, and integrated discrimination improvement was 0.0055. CONCLUSIONS: Using six easily available variables, we identified outpatients with upper-extremity DVT at low risk for adverse events within the first week. These data may help to safely treat more patients at home.

La fureur divine et son détournement en Nb 25

The story Numbers of 25 which reports the incident of Baal Peor is one among several texts in the book of Numbers focusing on divine wrath, its cause and its consequences. The present article offers a detailed analysis of the account which is difficult to understand because of certain jumps in the plot and because of its allusive style. Scholars mostly agree with the idea that the story grew in two or three stages. A lot of commentators believe that the original story contains only the apostasy of Peor caused by the Moabites (vv. 1-5). A subsequent story would focus on Pinchas' action against Zimri and Kospi, and a third layer is linked to the story of the war between Israel and Midian (Numbers 31). The problem of this theory however is that it seems impossible to reconstruct an original story about the matter of Peor; one does not find a satisfying end within vv. 1-5. Furthermore, v. 5, which belongs to the first, "Moabite", section, is already linked to the theme of Midian which dominates the second and the third passage. Moreover, the assemblage of different themes and motifs seem having been done with care: Regarding the two abuses of Israel reported in the story--idolatry and intermarriage--, they often go together in late polemical Deuteronomistic and post-Deuteronomistic layers (Ezra-Nehemiah). The double focus on Midian and Moab could both be polemically directed against certain Moses traditions found in the books of Exodus and Deuteronomy (concerning Moses' marriage with a Midianite women on the one hand and his stay and death and burial in Moab - in the vicinity of Beth Peor - on the other hand). As in several ANE traditions also in the Hebrew Bible the motif of "divine wrath" serves to interpret fatal historical events; in Num 25 as in other Biblical stories however it is doubtful whether the alleged incident (the plague) really have taken place and the story's plot is anchored in ancient Israel's history.

Evidence for Parachlamydia in bovine abortion.

Bovine abortion of unknown infectious aetiology still remains a major economic problem. In this study, we focused on a new possible abortigenic agent called Parachlamydia acanthamoebae. Retrospective samples (n=235) taken from late-term abortions in cattle were investigated by real-time diagnostic PCR for Chlamydiaceae and Parachlamydia spp., respectively. Histological sections of cases positive by real-time PCR for any Chlamydia-related agent were further examined by immunohistochemistry using specific antibodies. Chlamydophila abortus was detected only in three cases (1.3%) by real-time PCR and ArrayTube Microarray playing a less important role in bovine abortion compared to the situation in small ruminants in Switzerland. By real-time PCR as many as 43 of 235 (18.3%) cases turned out to be positive for Parachlamydia. The presence of Parachlamydia within placental lesions was confirmed in 35 cases (81.4%) by immunohistochemistry. The main histopathological feature in parachlamydial abortion was purulent to necrotizing placentitis (25/43). Parachlamydia should be considered as a new abortigenic agent in Swiss cattle. Since Parachlamydia may be involved in lower respiratory tract infections in humans, bovine abortion material should be handled with care given the possible zoonotic risk.