Most patients with cerebral malaria (CM) sustain cerebral microvascular sequestration of Plasmodium falciparum-infected red blood cells (iRBCs). Although many young children are infected with P. falciparum, CM remains a rare outcome; thus, we hypothesized that specific host conditions facilitate iRBC cerebral sequestration. To identify these host factors, we compared the peripheral whole-blood transcriptomes of Malawian children with iRBC cerebral sequestration, identified as malarial-retinopathy-positive CM (Ret+CM), to the transcriptomes of children with CM and no cerebral iRBC sequestration, defined as malarial-retinopathy-negative CM (Ret-CM). Ret+CM was associated with upregulation of 103 gene set pathways, including cytokine, blood coagulation, and extracellular matrix (ECM) pathways (P < 0.01; false-discovery rate [FDR] of <0.05). Neutrophil transcripts were the most highly upregulated individual transcripts in Ret+CM patients. Activated neutrophils can modulate diverse host processes, including the ECM, inflammation, and platelet biology to potentially facilitate parasite sequestration. Therefore, we compared plasma neutrophil proteins and neutrophil chemotaxis between Ret+CM and Ret-CM patients. Plasma levels of human neutrophil elastase, myeloperoxidase, and proteinase 3, but not lactoferrin or lipocalin, were elevated in Ret+CM patients, and neutrophil chemotaxis was impaired, possibly related to increased plasma heme. Neutrophils were rarely seen in CM brain microvasculature autopsy samples, and no neutrophil extracellular traps were found, suggesting that a putative neutrophil effect on endothelial cell biology results from neutrophil soluble factors rather than direct neutrophil cellular tissue effects. Meanwhile, children with Ret-CM had lower levels of inflammation, higher levels of alpha interferon, and upregulation of Toll-like receptor pathways and other host transcriptional pathways, which may represent responses that do not favor cerebral iRBC sequestration.

Copines make up a family of soluble, calcium-dependent, membrane binding proteins found in a variety of eukaryotic organisms. In an earlier study, we identified six copine genes in the Dictyostelium discoideum genome and focused our studies on cpnA. Our previous localization studies of green fluorescent protein-tagged CpnA in Dictyostelium suggested that CpnA may have roles in contractile vacuole function, endolysosomal trafficking, and development. To test these hypotheses, we created a cpnA ؊ knockout strain, and here we report the initial characterization of the mutant phenotype. The cpnA ؊ cells exhibited normal growth rates and a slight cytokinesis defect. When placed in starvation conditions, cpnA ؊ cells appeared to aggregate into mounds and form fingers with normal timing; however, they were delayed or arrested in the finger stage. When placed in water, cpnA ؊ cells formed unusually large contractile vacuoles, indicating a defect in contractile vacuole function, while endocytosis and phagocytosis rates for the cpnA ؊ cells were similar to those seen for wild-type cells. These studies indicate that CpnA plays a role in cytokinesis and contractile vacuole function and is required for normal development, specifically in the later stages prior to culmination. We also used real-time reverse transcription-PCR to determine the expression patterns of all six copine genes during development.

Objective: Perfusion imaging identifies anterior circulation stroke patients who respond favorably to endovascular thrombectomy (ET), but its role in basilar artery occlusion (BAO) is unknown. We hypothesized that BAO patients with limited regions of severe hypoperfusion (time to reach maximum concentration in seconds [Tmax] > 10) would have a favorable response to ET compared to patients with more extensive regions involved. Methods: We performed a multicenter retrospective cohort study of BAO patients with perfusion imaging prior to ET. We prespecified a Critical Area Perfusion Score (CAPS; 0-6 points), which quantified severe hypoperfusion (Tmax > 10) in cerebellum (1 point/hemisphere), pons (2 points), and midbrain and/or thalamus (2 points). Patients were dichotomized into favorable (CAPS ≤ 3) and unfavorable (CAPS > 3) groups. The primary outcome was a favorable functional outcome 90 days after ET (modified Rankin Scale = 0-3). Results: One hundred three patients were included. CAPS ≤ 3 patients (87%) had a lower median National Institutes of Health Stroke Scale score (NIHSS; 12.5, interquartile range [IQR] = 7-22) compared to CAPS > 3 patients (13%; 23, IQR = 19-36; p = 0.01). Reperfusion was achieved in 84% of all patients, with no difference between CAPS groups (p = 0.42). Sixty-four percent of reperfused CAPS ≤ 3 patients had a favorable outcome compared to 8% of nonreperfused CAPS ≤ 3 patients (odds ratio [OR] = 21.0, 95% confidence interval [CI] = 2.6-170; p < 0.001). No CAPS > 3 patients had a favorable outcome, regardless of reperfusion. In a multivariate regression analysis, CAPS ≤ 3 was a robust independent predictor of favorable outcome after adjustment for reperfusion, age, and pre-ET NIHSS (OR = 39.25, 95% CI = 1.34->999, p = 0.04). Interpretation: BAO patients with limited regions of severe hypoperfusion had a favorable response to reperfusion following ET. However, patients with more extensive regions of hypoperfusion in critical brain regions did not benefit from endovascular reperfusion.

BackgroundCerebral malaria (CM) remains a significant cause of morbidity and mortality in children in sub-Saharan Africa. CM mortality has been associated with increased brain volume, seen on neuroimaging studies.MethodsTo examine the potential role of blood metabolites and inflammatory mediators in increased brain volume in Malawian children with CM, an association study was performed between plasma metabolites, cytokine levels and phospholipase A2 (PLA2) activity with brain volume.ResultsThe metabolomics analysis demonstrated arachidonic acid and other lysophospholipids to be positively associated with brain swelling. These lipids are products of the PLA2 enzyme and an association of plasma PLA2 enzymatic activity with brain swelling was confirmed. TNFα, which can upregulate PLA2 activity, was associated with brain volume. In addition, CCL2 and IL-8 were also associated with brain volume. Some of these cytokines can alter endothelial cell tight junction proteins and increase blood brain barrier permeability.ConclusionsTaken together, paediatric CM brain volume was associated with products of the PLA2 pathway and inflammatory cytokines. Their role in causality is unknown. These molecules will need to undergo testing in vitro and in animal models to understand their role in processes of increased brain volume. These observations provide novel data on host physiology associated with paediatric CM brain swelling, and may both inform pathogenesis models and suggest adjunct therapies that could improve the morbidity and mortality associated with paediatric CM.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-1036-1) contains supplementary material, which is available to authorized users.

Objectives Despite the availability of effective anti-malarial prophylaxis, imported adult and pediatric malaria occurs in the United States and this can pose diagnostic issues. We examined the clinical characteristics and diagnostic challenges of imported malaria requiring adult or pediatric inpatient admission at Montefiore Medical Center (MMC) in the Bronx which provides care for a large population of immigrants from malaria endemic areas. Study Design We conducted a retrospective single center review of patients admitted with a diagnosis of malaria at MMC from 2005 through 2012. We extracted historical, clinical, and laboratory values from the electronic medical record and patient charts. Results We identified 95 patients who were diagnosed and hospitalized with malaria from 2005–2012, 33 (35%) of them children and 17 (18%) with severe malaria. Most patients contracted malaria while visiting friends and relatives (VFR) in West Africa. Only 38% of travelers took prophylaxis, and fewer than half reported taking it as prescribed. Misdiagnosis by emergency room or primary care doctors was observed in almost one quarter of all of the patients. Misdiagnosis occurred significantly more frequently in children (43%) compared to adults (13%) (p=0.002). Pediatric patients were more likely to present with abdominal pain (42% vs 15%, p=0.005). Conclusions Pediatric patients admitted for imported malaria at MMC had a higher rate of misdiagnosis and presented with more gastrointestinal symptoms than hospitalized adults. By describing the clinical characteristics of patients with imported malaria, we hope to improve diagnostic accuracy by healthcare workers and raise awareness that VFRs may require more intensive pre-travel counseling.

High-impact genetic variants associated with neurodevelopmental disorders provide biologically defined entry points for etiological discovery. The 3q29 deletion (3q29Del) is one such variant that confers a ~40-fold increased risk for schizophrenia, and a ~30-fold increased risk for autism. However, the specific neural mechanisms underlying this link remain largely unknown. Here, we report the first in vivo quantitative neuroimaging study in 3q29Del subjects (N = 24) and healthy controls (N = 1,608) using structural MRI. Given prior reports of posterior fossa abnormalities in 3q29Del, we focus our investigation on the cerebellum and its primary tissue-types. Additionally, we compare the prevalence of cystic/cyst-like malformations of the posterior fossa between 3q29Del subjects and controls, and examine the association between neuroanatomical findings and standardized behavioral measures to probe gene-brain-behavior relationships. 3q29Del subjects had smaller cerebellar cortex volumes than controls, both before and after correction for intracranial volume (ICV). 3q29Del subjects also had larger cerebellar white matter volumes than controls following ICV-correction. The 3q29Del group displayed an elevated rate of posterior fossa arachnoid cysts and mega cisterna magna findings independent of cerebellar volume. Sex played a moderating role in a subset of findings. Cerebellar white matter volume was positively associated with visual-motor integration skills and cognitive ability, while cystic/cyst-like malformations yielded no behavioral link. Abnormal development of posterior fossa structures may represent neuroimaging-based biomarkers in 3q29Del. Results reveal cerebellar associations with sensorimotor and cognitive deficits in 3q29Del and present a novel point of genetic convergence with cerebellar pathology reported in idiopathic forms of neurodevelopmental disease.

The generalization of perfusion-based, anterior circulation large vessel occlusion selection criteria to posterior circulation stroke is not straightforward due to physiologic delay, which we posit produces physiologic prolongation of the posterior circulation perfusion time-to-maximum (Tmax). To assess normative Tmax distributions, patients undergoing CTA/CTP for suspected ischemic stroke between 1/2018-3/2019 were retrospectively identified. Subjects with any cerebrovascular stenoses, or with follow-up MRI or final clinical diagnosis of stroke were excluded. Posterior circulation anatomic variations were identified. CTP were processed in RAPID and segmented in a custom pipeline permitting manually-enforced arterial input function (AIF) and perfusion estimations constrained to pre-specified vascular territories. Seventy-one subjects (mean 64 ± 19 years) met inclusion. Median Tmax was significantly greater in the cerebellar hemispheres (right: 3.0 s, left: 2.9 s) and PCA territories (right: 2.9 s; left: 3.3 s) than in the anterior circulation (right: 2.4 s; left: 2.3 s, p < 0.001). Fetal PCA disposition eliminated ipsilateral PCA Tmax delays (p = 0.012). Median territorial Tmax was significantly lower with basilar versus any anterior circulation AIF for all vascular territories (p < 0.001). Significant baseline delays in posterior circulation Tmax are observed even without steno-occlusive disease and vary with anatomic variation and AIF selection. The potential for overestimation of at-risk volumes in the posterior circulation merits caution in future trials.

BackgroundHigh-resolution vessel wall MRI (VWI) is increasingly used to characterize intramural disorders of the intracranial vasculature unseen by conventional arteriography.ObjectiveTo evaluate the use of VWI for surveillance of flow diverter (FD) treated aneurysms.Materials and methodsRetrospective study of 28 aneurysms (in 21 patients) treated with a FD (mean 57 years; 14 female). All examinations included VWI and a contemporaneously obtained digital subtraction angiogram. Multiplanar pre- and post-gadolinium 3D, variable flip-angle T1 black-blood VWI was obtained using delay alternating nutation for tailored excitation (DANTE) at 3T. 3D time-of-flight MR angiography (MRA) was also carried out. Images were assessed for in-stent stenosis, aneurysm occlusion, presence and pattern/distribution of aneurysmal or parent vessel gadolinium enhancement.ResultsThe VWI-MRI was performed on average at 361±259 days after the intervention. Follow-up DSA was performed at 338±254 days postintervention. Good or excellent black-blood angiographic quality was recorded in 22/28 (79%) pre-contrast and 21/28 (75%) post-contrast VWI, with no cases excluded for image quality. Aneurysm enhancement was noted in 24/28 (85.7%) aneurysms, including in 79% of angiographically occluded aneurysms and 100% of angiographically non-occluded aneurysms. Enhancement of the stented parent-vessel wall occurred significantly more often when aneurysm enhancement was present (92% vs 33%, p=0.049).ConclusionAdvanced VWI produces excellent depiction of FD-treated aneurysms, with robust evaluation of the parent vessel and aneurysm wall to an extent not achievable with conventional MRI/MRA. Gadolinium enhancement may, however, continue even after enduring catheter angiographic occlusion, confounding interpretation, and requiring cognizance of this potentially prolonged effect in such patients.