Silent Cerebral Small-Vessel Disease Is Twice as Prevalent in Middle-Aged Individuals With Well-Controlled, Combination Antiretroviral Therapy-Treated Human Immunodeficiency Virus (HIV) Than in HIV-Uninfected Individuals.

Background: Silent cerebral small-vessel disease (CSVD) is defined as white matter hyperintensities, silent brain infarction, or microbleeds. CSVD is responsible for future vascular events, cognitive impairment, frailty, and shorter survival. CSVD prevalence among middle-aged people living with well-controlled human immunodeficiency virus (HIV) infection (PLHIV) is unknown. Methods: The French National Agency for Research on AIDS and Viral Hepatitis (ANRS) EP51 Microvascular Brain Retina and Kidney Study (MicroBREAK; NCT02082574) is a cross-sectional study with prospective enrollment of treated PLHIV, ≥50 years old with viral load controlled for ≥12 months, and frequency age- and sex-matched HIV-uninfected controls (HUCs). It was designed to estimate CSVD prevalence on 3T magnetic resonance imaging (3D fluid-attenuated inversion recovery, transversal T2-weighted gradient-echo imaging and diffusion-weighted imaging), as diagnosed by 2 blinded neuroradiologists. A logistic regression model was used to assess the impact of HIV on CSVD after adjustment for traditional risk factors. Results: Between June 2013 and May 2016, 456 PLHIV and 154 HUCs were recruited. Median age was 56 and 58 years, respectively (P = .001), among whom 84.9% and 77.3%, respectively (P = .030), were men. CSVD was detected in 51.5% of PLHIV and 36.4% of HUCs with an adjusted odds ratio (aOR) of 2.3. The HIV impact differed according to age, with aOR values of 5.3, 3.7, and 1.0 for age groups <54, 54-60, and >60 years, respectively (P = .022). Older age, hypertension, and lower CD4 cell count nadir were independently associated with a higher risk of CSVD among PLHIV. Conclusions: HIV is an independent risk factor for CSVD. Despite sustained immunovirological control, the CSVD prevalence was twice as high among middle-aged PLHIV than HUCs. Clinical Trials Registration: NCT02082574.

Spire-1 contributes to the invadosome and its associated invasive properties.

Cancer cells have an increased ability to squeeze through extracellular matrix gaps that they create by promoting proteolysis of its components. Major sites of degradation are specialized micro-domains in the plasma membrane collectively named invadosomes where the Arp2/3 complex and formin proteins cooperate to spatio-temporally control actin nucleation and the folding of a dynamic F-actin core. At invadosomes, proper coupling of exo-endocytosis allows polarized delivery of proteases that facilitate degradation of ECM and disruption of the cellular barrier. We investigated the contribution of the actin nucleator Spire-1 to invadosome structure and function, using Src-activated cells and cancer cells. We found that Spire-1 is specifically recruited at invadosomes and is part of a multi-molecular complex containing Src kinase, the formin mDia1 and actin. Spire-1 interacts with the Rab3A GTPase, a key player in the regulation of exocytosis that is present at invadosomes. Finally, over- and under-expression of Spire-1 resulted in cells with an increased or decreased potential for matrix degradation, respectively, therefore suggesting a functional interplay of Spire-1 with both actin nucleation and vesicular trafficking that might impact on cell invasive and metastatic behavior.

Toxofilin upregulates the host cortical actin cytoskeleton dynamics, facilitating Toxoplasma invasion.

Toxoplasma gondii, a human pathogen and a model apicomplexan parasite, actively and rapidly invades host cells. To initiate invasion, the parasite induces the formation of a parasite-cell junction, and progressively propels itself through the junction, inside a newly formed vacuole that encloses the entering parasite. Little is known about how a parasite that is a few microns in diameter overcomes the host cell cortical actin barrier to achieve the remarkably rapid process of internalization (less than a few seconds). Using correlative light and electron microscopy in conjunction with electron tomography and three-dimensional image analysis we identified that toxofilin, an actin-binding protein, secreted by invading parasites correlates with localized sites of disassembly of the host cell actin meshwork. Moreover, quantitative fluorescence speckle microscopy of cells expressing toxofilin showed that toxofilin regulates actin filament disassembly and turnover. Furthermore, Toxoplasma tachyzoites lacking toxofilin, were found to be impaired in cortical actin disassembly and exhibited delayed invasion kinetics. We propose that toxofilin locally upregulates actin turnover thus increasing depolymerization events at the site of entry that in turn loosens the local host cell actin meshwork, facilitating parasite internalization and vacuole folding.

Macrophagic myofasciitis-associated dysfunctioning: An update of neuropsychological and neuroimaging features.

Macrophagic myofasciitis (MMF) syndrome is a subtype of autoimmune/inflammatory syndrome induced by adjuvants (ASIA) or Shoenfeld's syndrome, characterized by the presence of stereotyped inflammatory lesions at muscle biopsy attesting the long-term persistence of aluminum hydroxide particles at the site of previous immunization. Most frequently reported symptoms are chronic arthromyalgias and fatigue and cognitive complaint. MMF-associated cognitive disorder (MACD) is characterized by the dysfunctioning of attention, executive functions, short-term term and long-term memory, and, in some instances, left ear extinction. MACD is expressed in a chronic, nonevolving, well-defined syndromic framework within which the expression in terms of severity differs from one patient to another. While brain MRI is usually noncontributive, functional imaging using SPECT and PET has revealed the existence of a suggestive pathological pattern with involvement of posterior associative areas, temporal lobes, limbic system, and cerebellum. Put together, neuropsychological and functional neuroimaging investigations support the view that MACD relates to organic central nervous system involvement.

Two Paradigms for Endovascular Thrombectomy After Intravenous Thrombolysis for Acute Ischemic Stroke.

Importance: Intravenous thrombolysis (IVT) followed by mechanical thrombectomy (MT) is recommended to treat acute ischemic stroke (AIS) with a large vessel occlusion (LVO). Most hospitals do not have on-site MT facilities, and most patients need to be transferred secondarily after IVT (drip and ship), which may have an effect on the neurologic outcome. Objective: To compare the functional independence at 3 months between patients treated under the drip-and-ship paradigm and those treated on site (mothership). Design, Setting, and Participants: This study used a prospectively gathered registry of patients with AIS to select patients admitted through the Saint-Antoine and Tenon (drip and ship) or the Fondation Rothschild (mothership) hospitals from January 1, 2013, through April 30, 2016. The study included patients older than 18 years treated with bridging therapy for AIS with LVO of the anterior circulation. Among the 159 patients who received MT at the mothership, 100 had been transferred after IVT from the drip-and-ship hospitals and 59 had received IVT on site. Main Outcomes and Measures: The main outcome was 3-month functional independence (modified Rankin scale score ≤2). Both groups were compared using a multivariate linear model, including variables that were significantly different in the 2 groups. Results: During the study period, 497 patients were hospitalized at the drip-and-ship and mothership hospitals for an AIS eligible to reperfusion therapy; 11 patients had a basilar artery occlusion and were excluded, leaving 100 patients in the drip-and-ship group (mean age, 73 years; age range, 60-81 years; 57 men [57.0%]) and 59 in the mothership group (mean age, 70 years; age range, 58-82 years; 29 men [49.2%]). The proportion of patients with a favorable neurologic outcome at 3 months was similar in both groups (drip and ship, 61 [61.0%]; mothership, 30 [50.8%]; P = .26), even after adjusting the analysis for the baseline National Institutes of Health Stroke Scale score, diffusion-weighted imaging Alberta Stroke Program Early Computed Tomography Score, and general anesthesia (P = .82). Patients had less severe conditions in the drip-and-ship group (median baseline National Institutes of Health Stroke Scale score, 15 vs 17 [P = .03]; median diffusion-weighted imaging Alberta Stroke Program Early Computed Tomography Score, 7.5 vs 7 [P = .05]). Process times were longer in the drip-and-ship group (onset-to-needle time, 150 vs 135 minutes; onset-to-puncture time, 248 vs 189 minutes; and onset-to-recanalization time, 297 vs 240 minutes; P < .001). Both groups were similar in terms of substantial recanalization (Thrombolysis in Cerebral Ischemia scores 2B to 3; drip and ship, 84 [84.0%]; mothership, 47 [79.7%]; P = .49) and symptomatic hemorrhagic transformation (drip and ship, 2 [2.0%]; mothership, 2 [3.4%]; P = .63). Conclusions and Relevance: This study found that patients treated under the drip-and-ship paradigm also benefit from bridging therapy, with no statistically significant difference compared with those treated directly in a comprehensive stroke center.

Mortality and Disability According to Baseline Blood Pressure in Acute Ischemic Stroke Patients Treated by Thrombectomy: A Collaborative Pooled Analysis.

BACKGROUND: High blood pressure (BP) is associated with worse clinical outcomes in the setting of acute ischemic stroke, but the optimal blood pressure target is still a matter of debate. We aimed to study the association between baseline BP and mortality in acute ischemic stroke patients treated by mechanical thrombectomy. METHODS AND RESULTS: A total of 1332 acute ischemic stroke patients treated by mechanical thrombectomy were enrolled (from January 2012 to June 2016) in the ETIS (Endovascular Treatment in Ischemic Stroke) registry. Linear and polynomial logistic regression models were used to assess the association between BP and mortality and functional outcome at 90 days. Highest mortality was found at lower and higher baseline systolic blood pressure (SBP) values following a J- or U-shaped relationship, with a nadir at 157 mm Hg (95% confidence interval 143-170). When SBP values were categorized in 10-mm Hg increments, the odds ratio for all-cause mortality was 3.78 (95% confidence interval 1.50-9.55) for SBP<110 mm Hg and 1.81 (95% confidence interval 1.01-3.36) for SBP≥180 mm Hg using SBP≥150 to 160 mm Hg as reference. The rate of favorable outcome was the highest at low SBP values and lowest at high SBP values, with a nonlinear relationship; in unplanned exploratory analysis, an optimal threshold SBP≥177 mm Hg was found to predict unfavorable outcome (adjusted odds ratio 0.47; 95% confidence interval 0.31-0.70). CONCLUSION: In acute ischemic stroke patients treated by mechanical thrombectomy, baseline SBP is associated with all-cause mortality and favorable outcome. In contrast to mortality, favorable outcome rate was the highest at low SBP values and lowest at high SBP values. Further studies are warranted to confirm these findings.

The Capillary Index Score before thrombectomy: an angiographic correlate of favorable outcome.

BACKGROUND AND PURPOSE: The angiography based Capillary Index Score (CIS) has recently emerged as a potential surrogate marker of cerebral perfusion before intra-arterial thrombolysis. We assessed the prevalence of a favorable CIS (f-CIS) and its relationship with clinical outcome in patients treated by mechanical thrombectomy (MT). METHODS: Data from consecutive patients treated by MT from acute middle cerebral artery (MCA) occlusion were retrospectively analyzed. CIS was calculated from a pre-intervention cerebral angiogram. Association with favorable clinical outcome (modified Rankin Scale score ≤2) at 3 months was assessed in multivariate analysis. RESULTS: 146 patients were included in the study. f-CIS was observed in 106/146 (72%) patients with an acceptable inter-rater agreement (κ=0.73, p<0.001). It was associated with a lower pretreatment National Institutes of Health Stroke Scale (NIHSS) score (p=0.014), an isolated M1/M2 occlusion without internal carotid occlusion (p=0.042), and an Alberta Stroke Program Early CT Score (ASPECTS) >4 (p=0.004). In binary regression, a favorable outcome was independently associated with f-CIS (OR (-95% CI, +95% CI)=3.8 (1.3 to 10.9), p=0.013), as well as NIHSS (p=0.007), ASPECTS (p=0.005), isolated M1/M2 occlusion (p=0.013), and age (p=0.032). The positive predictive value of f-CIS for a favorable outcome was 67%. CONCLUSIONS: f-CIS was strongly associated with a favorable outcome after MT of acute MCA occlusion. As an easy surrogate marker of cerebral perfusion, it may be a useful-albeit not sufficient-diagnostic test to select patients just before an MT or to manage them after recanalization.

A Toxoplasma type 2C serine-threonine phosphatase is involved in parasite growth in the mammalian host cell.

Toxoplasma gondii is a human protozoan parasite that belongs to the phylum of Apicomplexa and causes toxoplasmosis. As the other members of this phylum, T. gondii obligatory multiplies within a host cell by a peculiar type of mitosis that leads to daughter cell assembly within a mother cell. Although parasite growth and virulence have been linked for years, few molecules controlling mitosis have been yet identified and they include a couple of kinases but not the counteracting phosphatases. Here, we report that in contrast to other animal cells, type 2C is by far the major type of serine threonine phosphatase activity both in extracellular and in intracellular dividing parasites. Using wild type and transgenic parasites, we characterized the 37kDa TgPP2C molecule as an abundant cytoplasmic and nuclear enzyme with activity being under tight regulation. In addition, we showed that the increase in TgPP2C activity significantly affected parasite growth by impairing cytokinesis while nuclear division still occurred. This study supports for the first time that type 2C protein phosphatase is an important regulator of cell growth in T. gondii.