Genotype specific pathogenicity of hepatitis E virus at the human maternal-fetal interface.

Hepatitis E virus (HEV) infection, particularly HEV genotype 1 (HEV-1), can result in fulminant hepatic failure and severe placental diseases, but mechanisms underlying genotype-specific pathogenicity are unclear and appropriate models are lacking. Here, we model HEV-1 infection ex vivo at the maternal-fetal interface using the decidua basalis and fetal placenta, and compare its effects to the less-pathogenic genotype 3 (HEV-3). We demonstrate that HEV-1 replicates more efficiently than HEV-3 both in tissue explants and stromal cells, produces more infectious progeny virions and causes severe tissue alterations. HEV-1 infection dysregulates the secretion of several soluble factors. These alterations to the cytokine microenvironment correlate with viral load and contribute to the tissue damage. Collectively, this study characterizes an ex vivo model for HEV infection and provides insights into HEV-1 pathogenesis during pregnancy that are linked to high viral replication, alteration of the local secretome and induction of tissue injuries.

ZIKA virus reveals broad tissue and cell tropism during the first trimester of pregnancy.

The outbreak of the Zika Virus (ZIKV) and its association with fetal abnormalities have raised worldwide concern. However, the cellular tropism and the mechanisms of ZIKV transmission to the fetus during early pregnancy are still largely unknown. Therefore, we ex vivo modeled the ZIKV transmission at the maternal-fetal interface using organ culture from first trimester pregnancy samples. Here, we provide evidence that ZIKV strain circulating in Brazil infects and damages tissue architecture of the maternal decidua basalis, the fetal placenta and umbilical cord. We also show that ZIKV replicates differentially in a wide range of maternal and fetal cells, including decidual fibroblasts and macrophages, trophoblasts, Hofbauer cells as well as umbilical cord mesenchymal stem cells. The striking cellular tropism of ZIKV and its cytopathic-induced tissue injury during the first trimester of pregnancy could provide an explanation for the irreversible congenital damages.

Natural cytotoxicity receptor splice variants orchestrate the distinct functions of human natural killer cell subtypes.

The natural cytotoxicity receptors NKp46/NCR1, NKp44/NCR2 and NKp30/NCR3 are critical for natural killer (NK) cell functions. Their genes are transcribed into several splice variants whose physiological relevance is not yet fully understood. Here we report that decidua basalis NK (dNK) cells of the pregnant uterine mucosa and peripheral blood NK (pNK) cells, two functionally distinct subsets of the physiological NK cell pool, display differential expression of NKp30/NCR3 and NKp44/NCR2 splice variants. The presence of cytokines that are enriched within the decidual microenvironment is sufficient to convert the splice variant profile of pNK cells into one similar to that of dNK cells. This switch is associated with decreased cytotoxic function and major adaptations to the secretome, hallmarks of the decidual phenotype. Thus, NKp30/NCR3 and NKp44/NCR2 splice variants delineate functionally distinct NK cell subsets. To our knowledge, this is the first conclusive evidence underlining the physiological importance of NCR splice variants.

Vocal response times to real and imagined stimuli in spatial neglect: A group study and single-case report.

The relationships between spatial neglect for perceptual objects and representational for imagined items are difficult to explore because of several methodological problems, including the dearth of comparable tests for real and imagined scenes. We asked 19 patients with right brain damage and 12 healthy controls to say whether an auditorily presented French geographical location was left or right of Paris, and recorded their vocal response times. Afterwards, participants performed a similar test with visually presented items. Although several patients had asymmetries of performance on the perceptual version of the test, only one patient was more accurate for right-sided than for left-sided imagined stimuli, thus showing evidence for imaginal neglect. However, this patient performed normally on place description and on mental number line bisection, perhaps as a consequence of different strategies he employed for these tasks. Overall, our results confirm previous evidence showing that imaginal neglect is less frequent than, and often occurs in association with, perceptual neglect. Imaginal neglect may result from the contribution of deficits partly distinct from those implicated in perceptual neglect, such as impaired endogenous orienting of attention or deficits of spatial working memory.

Migraine with aura and brain magnetic resonance imaging abnormalities in patients with CADASIL.

BACKGROUND: Migraine with aura (MA) is one of the clinical hallmarks of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a small vessel disease of the brain caused by mutations in the NOTCH3 gene, but its exact mechanisms are unknown. OBJECTIVES: To describe the patterns of MA in CADASIL and to compare brain magnetic resonance signal abnormalities between CADASIL patients with and without MA. DESIGN: Comparison of brain magnetic resonance signal abnormalities between cases and controls. SETTING: Patients with CADASIL seen at Lariboisière Hospital. PATIENTS: Forty-one CADASIL patients with MA and 31 age-matched CADASIL controls without MA. RESULTS: The mean age at onset of MA was significantly younger in women compared with men and occurred a mean of 15 years prior to stroke onset. A majority of patients (56%) reported at least 1 migraine attack with atypical aura. All CADASIL patients either with or without MA had white matter signal abnormalities on T2-weighted imaging. There was no difference in the frequency and distribution of brain signal abnormalities between CADASIL patients with and without MA. CONCLUSIONS: In CADASIL, MA is characterized by an unusually high frequency of attacks of migraine with atypical aura. The distribution and extent of magnetic resonance signal abnormalities did not differ according to migraine phenotype.

Nevirapine or lamivudine plus stavudine and indinavir: examples of 2-class versus 3-class regimens for the treatment of human immunodeficiency virus type 1.

We compared use of a 3-class regimen (nevirapine [Nvp], stavudine [d4T], and indinavir [Idv; 1000 mg 3 times daily]) with use of a 2-class regimen (lamivudine [3TC], d4T, and Idv [800 mg 3 times daily]) for 145 patients infected with human immunodeficiency virus type 1 (HIV-1). At week 72, the plasma HIV-1 RNA level was undetectable in 52% of Nvp recipients versus 79% of 3TC recipients (P<.001). Idv trough levels were 81 ng/mL in the Nvp group and 99 ng/mL in the 3TC group (P=.012). In the Nvp group, 42.5% of patients discontinued the study regimen; in the 3TC group, 22.5% of patients discontinued therapy (P=.013). The rate of resistance to nonnucleoside analogue reverse-transcriptase inhibitors among patients in the Nvp group with virological failure was not different from the rate of resistance to 3TC among patients in the 3TC group with virological failure. These results do not support the use of a 3-class regimen that includes Nvp for patients with no or limited exposure to nucleoside analogues.

Longitudinal study of carotid atherosclerosis and white matter hyperintensities: the EVA-MRI cohort.

BACKGROUND AND PURPOSE: White matter hyperintensities (WMHs) are often observed on cerebral magnetic resonance imaging (MRI) of elderly individuals. Epidemiological studies have shown that age and hypertension are associated with WMHs, suggesting a vascular mechanism in WMH pathogenesis. In a population-based prospective study, we examined the association of carotid atherosclerosis measured at baseline and 4-year follow-up with severity of WMHs assessed at 4-year follow-up. METHODS: The sample consisted of 640 healthy subjects aged 59-71 years at entry enrolled in the prospective EVA Study. Systolic and diastolic blood pressures were measured at each wave. Ultrasonographic measures of intima-media thickness (IMT) of the common carotid arteries and plaques were made at baseline and at 4-year follow-up examination. An MRI examination was performed at 4-year follow-up. The presence and severity of WMHs were evaluated by a single radiologist. RESULTS: After adjusting for age, gender, and hypertension, the presence of carotid plaques at baseline was significantly associated with the presence of severe WMHs 4 years later [odds ratio (OR) = 1.70; 95% confidence interval (CI): 1.05-2.74]. The association was stronger in men than in women. A 0.1-mm increase of baseline IMT was associated with an increased risk of severe WMHs in both sexes (adjusted OR = 1.17; 95% CI: 0.96-1.41), but the association was not significant (p = 0.12). Cross-sectional relationships between carotid plaques and severe WMHs at 4-year follow-up showed that the risk of having severe WMHs was stronger in the group of subjects who had already plaques at study entry compared to the group of subjects whose plaques occurred during 4-year follow-up. CONCLUSION: This study confirmed an association between carotid atherosclerosis and WMHs independently of age and hypertension. It also suggested that the older the carotid plaques, the higher the risk of having severe WMHs.