Brain Magnetic Resonance Imaging Reveals Different Courses of Disease in Pediatric and Adult Cerebral Malaria.

BACKGROUND: Cerebral malaria is a common presentation of severe Plasmodium falciparum infection and remains an important cause of death in the tropics. Key aspects of its pathogenesis are still incompletely understood, but severe brain swelling identified by magnetic resonance imaging (MRI) was associated with a fatal outcome in African children. In contrast, neuroimaging investigations failed to identify cerebral features associated with fatality in Asian adults. METHODS: Quantitative MRI with brain volume assessment and apparent diffusion coefficient (ADC) histogram analyses were performed for the first time in 65 patients with cerebral malaria to compare disease signatures between children and adults from the same cohort, as well as between fatal and nonfatal cases. RESULTS: We found an age-dependent decrease in brain swelling during acute cerebral malaria, and brain volumes did not differ between fatal and nonfatal cases across both age groups. In nonfatal disease, reversible, hypoxia-induced cytotoxic edema occurred predominantly in the white matter in children, and in the basal ganglia in adults. In fatal cases, quantitative ADC histogram analyses also demonstrated different end-stage patterns between adults and children: Severe hypoxia, evidenced by global ADC decrease and elevated plasma levels of lipocalin-2 and microRNA-150, was associated with a fatal outcome in adults. In fatal pediatric disease, our results corroborate an increase in brain volume, leading to augmented cerebral pressure, brainstem herniation, and death. CONCLUSIONS: Our findings suggest distinct pathogenic patterns in pediatric and adult cerebral malaria with a stronger cytotoxic component in adults, supporting the development of age-specific adjunct therapies.

Fishing in greener waters: Understanding the impact of harmful algal blooms on Lake Erie anglers and the potential for adoption of a forecast model.

Harmful algal blooms (HABs) pose public health risks worldwide, because of the toxins that they can produce. Researchers have explored the impact of HABs on local economies, but know relatively little about the decision-making that informs these behaviors that lead to financial losses. Understanding the factors that inform this decision-making is critical to developing mitigative solutions. This study seeks to understand how HABs in Western Lake Erie affect angler decision-making, before evaluating a possible decision-support tool-a harmful algal bloom forecast known as the Experimental Lake Erie HAB Tracker. The HAB Tracker provides a nowcast and five-day forecast of the spatial distribution and transport of Microcystis, the predominant species of harmful algae in Western Lake Erie. Data collected using focus groups and surveys were coded to identify key themes that influence angler decision-making. The theory of the diffusion of innovations provides an analytical framework to evaluate the potential for widespread adoption of the HAB forecast among Lake Erie anglers. Analysis of emerging themes revealed that Lake Erie anglers face three key decision-points when fishing in HABs: whether to fish, where to fish, and whether to eat the fish. Five primary variables factored into angler decisions on where and whether to fish including 1) perceptions of HAB aesthetics, 2) perceptions of the impact of HABs on angler health, 3) perceptions of the impact of HABs on fish, 4) communication methods, 5) perceptions of HABs by customers of charter captains. Most participants in this study sought to avoid fishing in HABs primarily for aesthetic reasons. Recreational anglers are more likely than charter captains to adopt the HAB Tracker as a decision-support tool, because it is compatible with their information needs and provides a relative advantage over existing sources of information. Charter captains are less likely to adopt the HAB Tracker, because they rely on their existing knowledge and social network for HAB information. If researchers can reduce the complexity of forecast information while increasing its accessibility and reliability, then all anglers will be more likely to adopt a HAB forecast as a decision-support tool while fishing in Lake Erie during bloom season.

α7 nicotinic acetylcholine receptor signaling inhibits inflammasome activation by preventing mitochondrial DNA release.

The mammalian immune system and the nervous system coevolved under the influence of cellular and environmental stress. Cellular stress is associated with changes in immunity and activation of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, a key component of innate immunity. Here we show that α7 nicotinic acetylcholine receptor (α7 nAchR)-signaling inhibits inflammasome activation and prevents release of mitochondrial DNA, an NLRP3 ligand. Cholinergic receptor agonists or vagus nerve stimulation significantly inhibits inflammasome activation, whereas genetic deletion of α7 nAchR significantly enhances inflammasome activation. Acetylcholine accumulates in macrophage cytoplasm after adenosine triphosphate (ATP) stimulation in an α7 nAchR-independent manner. Acetylcholine significantly attenuated calcium or hydrogen oxide-induced mitochondrial damage and mitochondrial DNA release. Together, these findings reveal a novel neurotransmitter-mediated signaling pathway: acetylcholine translocates into the cytoplasm of immune cells during inflammation and inhibits NLRP3 inflammasome activation by preventing mitochondrial DNA release.

Correlation of E-cadherin Immunohistochemical Expression with Histopathological Grading of Oral Squamous Cell Carcinoma.

OBJECTIVES: The current research was undertaken with an aim to correlate the expression of E-cadherin with histopathological grading in oral squamous cell carcinoma (OSCC) patients. Further, the objectives of the study were to evaluate the qualitative and quantitative expressions of E-cadherin in OSCC and to correlate the number of tumor cells of OSCC, immunopositive for E-cadherin with histopathological grading of OSCC. MATERIALS AND METHODS: Immunoexpression of E-cadherin antibody was evaluated in previously diagnosed, paraffin-embedded sections of 20 tissues each of well-differentiated and moderately differentiated OSCC, 17 tissues of poorly differentiated OSCC, and 10 tissues of normal oral mucosa; Chi-square test, analysis of variance, and Tukey's honestly significant difference test were employed for statistical analysis. RESULTS: E-cadherin immunoreactivity was inversely correlated to the loss of cell differentiation. There was a significant decrease in expression of E-cadherin (P < 0.0001) in advanced cases of OSCC. Furthermore, there was a significant reduction in intensity of E-cadherin expression with advancing histological grades of OSCC. CONCLUSION: From the present study, it is concluded that the reduced expression of E-cadherin may be a reliable indicator of increase in the invasiveness of OSCCs.

Isolated and silent spinal neurocysticercosis associated with pseudotumor cerebri.

Incidence of spinal neurocysticercosis (NCC) is rare. Isolated spinal NCC is still rarer. We present here a case report where a young lady presented with all the clinical features of pseudotumor cerebri (PTC), where medical treatment for PTC failed and the presence of cysticercous in spinal canal was detected only on the operation table, while doing a lumbo-peritoneal shunt (LP shunt) to save her vision. Diagnosis could be confirmed only after the histopathology report was received. She did not have any direct evidence of spinal involvement, thereby eluding correct diagnosis. In English literature, we could not find any report of isolated and silent spinal NCC associated with PTC. In addition, we could not find any report of recovery of cysticercous larva through the Touhey's needle injury, although this was an incidental finding. In endemic areas, isolated spinal NCC should be suspected in patients presenting with PTC.

Magnetic Resonance Imaging of Cerebral Malaria Patients Reveals Distinct Pathogenetic Processes in Different Parts of the Brain.

The mechanisms underlying the rapidly reversible brain swelling described in patients with cerebral malaria (CM) are unknown. Using a 1.5-Tesla (T) magnetic resonance imaging (MRI) scanner, we undertook an observational study in Rourkela, India, of 11 Indian patients hospitalized with CM and increased brain volume. Among the 11 cases, there were 5 adults and 6 children. All patients had reduced consciousness and various degrees of cortical swelling at baseline. The latter was predominately posterior in distribution. The findings on diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps were consistent with vasogenic edema in all cases. Reversibility after 48 to 72 h was observed in >90% of cases. DWI/ADC mismatch suggested the additional presence of cytotoxic edema in the basal nuclei of 5 patients; all of these had perfusion parameters consistent with vascular engorgement and not with ischemic infarcts. Our results suggest that an impairment of the blood-brain barrier is responsible for the brain swelling in CM. In 5 cases, vasogenic edema occurred in conjunction with changes in the basal nuclei consistent with venous congestion, likely to be caused by the sequestration of Plasmodium falciparum-infected erythrocytes. While both mechanisms have been individually postulated to play an important role in the development of CM, this is the first demonstration of their concurrent involvement in different parts of the brain. The clinical and radiological characteristics observed in the majority of our patients are consistent with posterior reversible encephalopathy syndrome (PRES), and we show for the first time a high frequency of PRES in the context of CM. IMPORTANCE The pathophysiology and molecular mechanisms underlying cerebral malaria (CM) are still poorly understood. Recent neuroimaging studies demonstrated that brain swelling is a common feature in CM and a major contributor to death in pediatric patients. Consequently, determining the precise mechanisms responsible for this swelling could open new adjunct therapeutic avenues in CM patients. Using an MRI scanner with a higher resolution than the ones used in previous reports, we identified two distinct origins of brain swelling in both adult and pediatric patients from India, occurring in distinct parts of the brain. Our results support the hypothesis that both endothelial dysfunction and microvascular obstruction by Plasmodium falciparum-infected erythrocytes make independent contributions to the pathogenesis of CM, providing opportunities for novel therapeutic interventions.

Hypoxia promotes colon cancer dissemination through up-regulation of cell migration-inducing protein (CEMIP).

Hypoxic stress drives cancer progression by causing a transcriptional reprogramming. Recently, KIAA1199 was discovered to be a cell-migration inducing protein (renamed CEMIP) that is upregulated in human cancers. However, the mechanism of induction of CEMIP in cancer was hitherto unknown. Here we demonstrate that hypoxia induces CEMIP expression leading to enhanced cell migration. Immunohistochemistry of human colon cancer tissues revealed that CEMIP is upregulated in cancer cells located at the invasive front or in the submucosa. CEMIP localization inversely correlated with E-cadherin expression, which is characteristic of the epithelial-to-mesenchymal transition. Mechanistically, hypoxia-inducible-factor-2α (HIF-2α), but not HIF-1α binds directly to the hypoxia response element within the CEMIP promoter region resulting in increased CEMIP expression. Functional characterization reveals that CEMIP is a downstream effector of HIF-2α-mediated cell migration. Expression of CEMIP was demonstrated to negatively correlate with the expression of Jarid1A, a histone demethylase that removes methyl groups from H3K4me3 (an activation marker for transcription), resulting in altered gene repression. Low oxygen tension inhibits the function of Jarid1A, leading to increased presence of H3K4me3 within the CEMIP promoter. These results provide insight into the upregulation of CEMIP within cancer and can lead to novel treatment strategies targeting this cancer cell migration-promoting gene.

Reversibility of retinal microvascular changes in severe falciparum malaria.

Malarial retinopathy allows detailed study of central nervous system vascular pathology in living patients with severe malaria. An adult with cerebral malaria is described who had prominent retinal whitening with corresponding retinal microvascular obstruction, vessel dilatation, increased vascular tortuosity, and blood retinal barrier leakage with decreased visual acuity, all of which resolved on recovery. Additional study of these features and their potential role in elucidating the pathogenesis of cerebral malaria is warranted.