Zoonotic infections in communities of the James Bay Cree territory: An overview of seroprevalence

The Cree communities of James Bay are at risk for contracting infectious diseases transmitted by wildlife. Data from serological testing for a range of zoonotic infections performed in the general population (six communities), or trappers and their spouses (one community), were abstracted from four population-based studies conducted in Cree territory (Quebec) between 2005 and 2009. Evidence of exposure to Trichinella species, Toxoplasma gondii, Toxocara canis, Echinococcus granulosus, Leptospira species, Coxiella burnetii and Francisella tularensis was verified in all communities, whereas antibodies against Sin Nombre virus and California serogroup viruses (Jamestown Canyon and snowshoe hare viruses) were evaluated in three and six communities, respectively. Seroprevalence varied widely among communities: snowshoe hare virus (1% to 42%), F tularensis (14% to 37%), Leptospira species (10% to 27%), Jamestown Canyon virus (9% to 24%), C burnetii (0% to 18%), T gondii (4% to 12%), T canis (0% to 10%), E granulosus (0% to 4%) and Trichinella species (0% to 1%). No subject had serological evidence of Sin Nombre virus exposure. These data suggest that large proportions of the Cree population have been exposed to at least one of the targeted zoonotic agents. The Cree population, particularly those most heavily exposed to fauna, as well as the medical staff living in these regions, should be aware of these diseases. Greater awareness would not only help to decrease exposures but would also increase the chance of appropriate diagnostic testing.     

Fever caused by metapramine. Diagnosis of fever caused by psychotropic drugs

Because of two hyperthermias, due to metapramine a french antidepressives of the tricyclic family, international literature concerning drug fever induced by psychotropics was reviewed. This study stresses the fact that apart from neuroleptics which are frequently involved in that type of accident, other psychotropics are very rarely responsible of hyperthermia. One hundred and five cases published since 1970 and sufficiently well documented to be analysed according to Dangoumeau's french method of imputation of side effects of drugs, were reviewed. Among these cases, one hundred (95%) corresponded to malignant syndrome of neuroleptics, 89 concerned neuroleptics alone, and 11, neuroleptics associated with other psychotropics. Regarding the different mechanisms which can explain drug fever as described by Lipsky, it seems that concerning psychotropics two types may be retained: Fever due to central dysregulation directly induced by drugs, and mainly, immunoallergic fever, the most frequently seen as described in our two cases.     

Dynamic history of low-grade gliomas before and after temozolomide treatment

OBJECTIVE: To evaluate the natural progression and the impact of temozolomide in low-grade gliomas and to correlate these changes with the profile of genetic alterations. METHODS: The mean tumor diameter (MTD) of low-grade gliomas was evaluated on serial magnetic resonance images before (n = 39), during, and after (n = 107) treatment with neoadjuvant temozolomide. MTD growth curves were correlated with chromosomes 1p-19q loss and p53 overexpression in the tumors. RESULTS: Before temozolomide onset, MTD increased linearly over time, indicating a continuous growth that was significantly slower in 1p-19q deleted tumors (3.4 vs 5.9mm/year; p = 0.0016) and in tumors that did not overexpress p53 (4.2 vs 6.3mm/year; p = 0.05). During temozolomide treatment, almost all patients (92%) experienced initial decrease of MTD. Subsequently, some tumors started to resume growth despite continuous administration of temozolomide, with a lower rate of relapse in 1p-19q deleted tumors (16.6 vs 58%; p = 0.0004) and in tumors that did not overexpress p53 (26 vs 68%; p = 0.003). When temozolomide was discontinued in the absence of tumor progression, a majority of tumors resumed their progressive growth within a year. INTERPRETATION: Untreated low-grade gliomas grow continuously at a rate that is influenced by the genetic alterations of the tumors. Temozolomide reverses this pattern at the onset, but this effect is often brief in patients whose tumors overexpress p53 and do not harbor the 1p-19q codeletion, suggesting acquired chemoresistance. A majority of tumors will resume their growth when treatment is discontinued, raising the issue of the optimal duration of treatment in continuously responding patients.     

Per and neuropeptide expression in the rat suprachiasmatic nuclei: compartmentalization and differential cellular induction by light

Per1 and Per2, two clock genes rhythmically expressed in the suprachiasmatic nucleus (SCN), are implicated in the molecular mechanism of the circadian pacemaker and play a major role in its entrainment by light. To date, it is not known if every cell of the SCN, a heterogeneous structure in respect of neuropeptide content, expresses clock genes equally. The aim of this study was to identify, by single and double non-radioactive and/or radioactive hybridizations, the cell types (AVP, VIP and GRP) expressing Per1 or Per2 in the SCN of rats, (1) when Per are highly expressed during the daytime, and (2) after induction of Per expression by a light pulse at night. Our results indicate that, during the daytime, Per1 and Per2 genes are both mainly expressed in the AVP cells of the dorso-median part of the SCN, whereas only a few VIP cells in the ventral part of the SCN exhibit Per gene expression. In contrast, following a light pulse at night, there is differential induction of the two Per genes. Per1 expression essentially occurs in the ventro-lateral GRP cells, while Per2 expression is not restricted to the retinorecipient part of the SCN as it also occurs in AVP cells. Altogether, our results suggest that Per1 and Per2 are mainly expressed in AVP cells during the daytime and suggest that GRP cells play an important role in resetting of the clock by light.     

Continuous growth of mean tumor diameter in a subset of grade II gliomas

Serial magnetic resonance images of 27 patients with untreated World Health Organization grade II oligodendrogliomas or mixed gliomas were reviewed retrospectively to study the kinetics of tumor growth before anaplastic transformation. Analysis of the mean tumor diameters over time showed constant growth. Linear regression, using a mixed model, found an average slope of 4.1mm per year (95% confidence interval, 3.8-4.4mm/year). Untreated low-grade oligodendrogliomas or mixed gliomas grow continuously during their premalignant phase, and their pattern of growth can be predicted within a relatively narrow range. These findings could be of interest to optimize patients management and follow-up.     

Macroautophagy in lymphatic endothelial cells inhibits T cell–mediated autoimmunity

Lymphatic endothelial cells (LECs) present peripheral tissue antigens to induce T cell tolerance. In addition, LECs are the main source of sphingosine-1-phosphate (S1P), promoting naive T cell survival and effector T cell exit from lymph nodes (LNs). Autophagy is a physiological process essential for cellular homeostasis. We investigated whether autophagy in LECs modulates T cell activation in experimental arthritis. Whereas genetic abrogation of autophagy in LECs does not alter immune homeostasis, it induces alterations of the regulatory T cell (T reg cell) population in LNs from arthritic mice, which might be linked to MHCII-mediated antigen presentation by LECs. Furthermore, inflammation-induced autophagy in LECs promotes the degradation of Sphingosine kinase 1 (SphK1), resulting in decreased S1P production. Consequently, in arthritic mice lacking autophagy in LECs, pathogenic Th17 cell migration toward LEC-derived S1P gradients and egress from LNs are enhanced, as well as infiltration of inflamed joints, resulting in exacerbated arthritis. Our results highlight the autophagy pathway as an important regulator of LEC immunomodulatory functions in inflammatory conditions.     

Usefulness of tricuspid annular displacement (TAD) to identify right ventricular dysfunction in normotensive patients with acute pulmonary embolism

Background

Echocardiographic criteria of right ventricular dysfunction (RVD) in acute pulmonary embolism (PE) differ among published studies. Assessment of RV systolic function remains difficult because of the RV's complex shape. We aimed to evaluate RV systolic function with TAD in patients (pts) with acute PE. TAD (QLAB, Philips Medical Imaging) was based on a tissue-tracking algorithm that is ultrasound beam angle independent for automated detection of tricuspid annular displacement.

Design

Prospective and observational study.

Methods

All adults’ pts who were diagnosed with PE from December 2008 to December 2009 at Princess Grace Hospital, Monaco were eligible for this study after exclusion of history of heart failure. We evaluated 36 consecutive pts with PE (18 male, mean age 62.7 years), which underwent echocardiography, plasma BNP titration during the first day after admission, and a second echocardiography obtained within 48 hours before discharge.

Results

TAD value were significantly lower in pts with abnormal RV function by echocardiogram (15.9 ± 0.3 vs. 12.7 ± 0.2 ; P = 0.026). Pts with a normal BNP (< 80 pg/ml) had an elevated TAD (16.4 ± 0.2 vs. 11.2 ± 0.3 mm ; P < 0.0001). At discharge, echocardiographic data were obtained from 33 pts (mean: 8.3 ± 3.5 days). RV end diastolic diameter, RV to LV diameter, pulmonary arterial systolic pressure, mean pulmonic valve acceleration time, RV FAC, Sa and TAD were significantly improved. There was no difference between TAD among pts with echocardiographic RVD at baseline vs. pts without RVD (14.9 ± 3.7 vs. 16.1 ± 2.9 mm ; P = 0.3). Four pts who deteriorated during short-term observation had substantially lower TAD values than those with uncomplicated courses (7.7 ± 0.4 mm vs. 14.6 ± 0.2 mm ; P = 0.001). In conclusion, impaired TAD was associated with decreased RV systolic function in pts with acute PE. To identify the clinical meaning of decreased TAD, larger trials with longer follow-up periods are needed.     

Next-Generation Sequencing of CYP2C19 in Stent Thrombosis: Implications for Clopidogrel Pharmacogenomics

Purpose

Describe CYP2C19 sequencing results in the largest series of clopidogrel-treated cases with stent thrombosis (ST), the closest clinical phenotype to clopidogrel resistance. Evaluate the impact of CYP2C19 genetic variation detected by next-generation sequencing (NGS) with comprehensive annotation and functional studies.

Methods

Seventy ST cases on clopidogrel identified from the PLATO trial (n =?58) and Mayo Clinic biorepository (n =?12) were matched 1:1 with controls for age, race, sex, diabetes mellitus, presentation, and stent type. NGS was performed to cover the entire CYP2C19 gene. Assessment of exonic variants involved measuring in vitro protein expression levels. Intronic variants were evaluated for potential splicing motif variations.

Results

Poor metabolizers (n =?4) and rare CYP2C19*8, CYP2C19*15, and CYP2C19*11 alleles were identified only in ST cases. CYP2C19*17 heterozygote carriers were observed more frequently in cases (n =?29) than controls (n =?18). Functional studies of CYP2C19 exonic variants (n =?11) revealed 3 cases and only 1 control carrying a deleterious variant as determined by in vitro protein expression studies. Greater intronic variation unique to ST cases (n =?169) compared with controls (n =?84) was observed with predictions revealing 13 allele candidates that may lead to a potential disruption of splicing and a loss-of-function effect of CYP2C19 in ST cases.

Conclusion

NGS detected CYP2C19 poor metabolizers and paradoxically greater number of so-called rapid metabolizers in ST cases. Rare deleterious exonic variation occurs in 4%, and potentially disruptive intronic alleles occur in 16% of ST cases. Additional studies are required to evaluate the role of these variants in platelet aggregation and clopidogrel metabolism.

     

Peroxide bond-dependent antiplasmodial specificity of artemisinin and OZ277 (RBx11160)

Using nonperoxidic analogs of artemisinin and OZ277 (RBx11160), the strong in vitro antiplasmodial activities of the latter two compounds were shown to be peroxide bond dependent. In contrast, the weak activities of artemisinin and OZ277 against six other protozoan parasites were peroxide bond independent. These data support the iron-dependent artemisinin alkylation hypothesis.     

Prevalence of Toscana virus antibodies in volunteer blood donors and patients with central nervous system infections in southeastern France

Toscana virus (TOSV) is a sandfly-borne phlebovirus causing meningitis and encephalitis during the summer period. A significant proportion of infection results in asymptomatic or pauci-symptomatic forms. Although seroprevalence studies had been conducted in Italy, Spain, Greece, and Cyprus, no data were available from France at the outset of this study. We present here results of seroprevalence studies conducted in volunteer blood donors and in patients presenting with central nervous system (CNS) infections. Twelve percent of sera from blood donors and 18.9% of sera from patients hospitalized for CNS infection contained immunoglobulin G (IgG) reacting against TOSV or TOSV-related phleboviruses. This study confirms that TOSV and possibly TOSV-related phleboviruses actively circulates in southeastern France and demonstrates that a significant proportion of healthy blood donors and patients with CNS infections have a history of TOSV or TOSV-related phlebovirus infection.