Jonathan L. Chang

Podoplanin-Rich Stromal Networks Induce Dendritic Cell Motility via Activation of the C-type Lectin Receptor CLEC-2

Summary To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces.

B cell homeostasis and follicle confines are governed by fibroblastic reticular cells

Fibroblastic reticular cells (FRCs) are known to inhabit T cell–rich areas of lymphoid organs, where they function to facilitate interactions between T cells and dendritic cells. However, in vivo manipulation of FRCs has been limited by a dearth of genetic tools that target this lineage. Here, using a mouse model to conditionally ablate FRCs, we demonstrated their indispensable role in antiviral T cell responses. Unexpectedly, loss of FRCs also attenuated humoral immunity due to impaired B cell viability and follicular organization. Follicle-resident FRCs established a favorable niche for B lymphocytes via production of the cytokine BAFF. Thus, our study indicates that adaptive immunity requires an intact FRC network and identifies a subset of FRCs that control B cell homeostasis and follicle identity.

Anorexia Nervosa and Exercise

ConclusionRecently, the potential abuses of excessive exercise have received a great deal of attention. Several researchers, most notably Yates and colleagues (1983), have suggested that the habitual runner resembles the male equivalent of the patient with anorexia nervosa. Our review of the two modes of behaviour, however, provided little empirical support for the proposed analogy. Indeed, most evidence suggests that while anorexia nervosa represents a serious medical disorder, running is generally an adaptive form of behaviour that often serves to enhance physical and psychological functioning. Instead of a disease model of running, we propose that running represents one method by which individuals learn to regulate their emotional states.

Lymph node metastases can invade local blood vessels, exit the node, and colonize distant organs in mice

An alternate route for metastatic cells Metastatic tumor cells are thought to reach distant organs by traveling through the blood circulation or the lymphatic system. Two studies of mouse models now suggest a hybrid route for tumor cell dissemination. Pereira et al. and Brown et al. used distinct methodologies to monitor the fate of tumor cells in lymph nodes. They found that tumor cells could invade local blood vessels within a node, exit the node by entering the blood circulation, then go on to colonize the lung. Whether this dissemination route occurs in cancer patients is unknown; the answer could potentially change the way that affected lymph nodes are treated in cancer. Science, this issue p. 1403, p. 1408 In mice, tumor cells can metastasize to distant organs by entering blood vessels within the local lymph node. Lymph node metastases in cancer patients are associated with tumor aggressiveness, poorer prognoses, and the recommendation for systemic therapy. Whether cancer cells in lymph nodes can seed distant metastases has been a subject of considerable debate. We studied mice implanted with cancer cells (mammary carcinoma, squamous cell carcinoma, or melanoma) expressing the photoconvertible protein Dendra2. This technology allowed us to selectively photoconvert metastatic cells in the lymph node and trace their fate. We found that a fraction of these cells invaded lymph node blood vessels, entered the blood circulation, and colonized the lung. Thus, in mouse models, lymph node metastases can be a source of cancer cells for distant metastases. Whether this mode of dissemination occurs in cancer patients remains to be determined.

Stroke in Human Immunodeficiency Virus-infected Individuals in Sub-Saharan Africa (SSA): A Systematic Review

BACKGROUND Human immunodeficiency virus (HIV) infection is associated with worse outcomes after stroke, but this association is less well-described in sub-Saharan Africa (SSA). We reviewed literature on stroke among people living with HIV (PLWH) in SSA. METHODS We systematically reviewed published literature for original clinical stroke studies conducted in SSA that included PLWH. We included studies that reported data on presenting characteristics, risk factors, and/or outcomes after stroke. RESULTS Seventeen studies (N = 478) met inclusion criteria. At the time of stroke presentation, PLWH had a median age ranging from 32 to 43 years. Subjects had low CD4 counts (median CD4, 108-225 cells/µl), and most were antiretroviral therapy-naïve. Fever, seizures, and concurrent opportunistic infections were common at presentation. Ischemic stroke accounted for up to 96% of strokes, which were mostly located in the anterior circulation territory. In studies comparing PLWH with HIV-uninfected individuals, PLWH had more frequent coagulopathy, greater stroke severity, (72% versus 36% National Institutes of Health Stroke Scale >13, P = .02), longer hospital length of stay (30.5 versus <10 days), and a higher 30-day mortality rate (23% versus 10.5%, P = .007). CONCLUSION Stroke in PLWH in SSA occurs at a young age, in those with advanced disease, and is associated with worse outcomes than in HIV-uninfected comparators. Stroke in young individuals in the region should prompt HIV testing, and ongoing efforts to promote early antiretroviral therapy initiation might also help decrease stroke incidence, morbidity, and mortality in the region.

Who Stays and Who Goes: Predictors of Admission among Patients Presenting with Febrile Illness and a Positive Malaria Rapid Diagnostic Test in a Rural Ugandan Health Center

Not much is known about clinical decision-making in rural, low-resource settings regarding fever, a common reason for presentation to care. In this prospective cohort study of patients presenting with febrile illness to a rural Ugandan health center, we examined demographic and clinical factors predictive of an initial disposition of inpatient admission after clinical evaluation, but before laboratory testing. We then assessed the association of laboratory results and system factors with a change between initial and final disposition plans. Four thousand nine hundred twenty-four patients with suspected febrile illness were included in the primary analysis. The strongest predictors for an initial disposition of admission after clinical examination were impaired consciousness (adjusted risk ratio [aRR], 3.21; 95% confidence interval [CI]: 2.44-4.21) and fever on examination (aRR, 2.27; 95% CI: 1.79-2.87). Providers initially planned to discharge patients with significant vital sign abnormalities, including tachypnea (3.6%) and hypotension (1.3%). Anemia strongly predicted a final disposition of admission after an initial disposition of discharge (aRR, 48.34; 95% CI: 24.22-96.49); other laboratory abnormalities, including hypoglycemia and acidosis, did not change disposition planning. In those with an initial disposition of admission, living farther than the two neighboring villages was associated with a final disposition of discharge (aRR, 2.12; 95% CI: 1.10-4.12). A concerning number of patients with abnormal vital signs and laboratory results were not admitted for inpatient care. Geographic factors may influence a patients final disposition contrary to a providers initial disposition plan. Future work should assess longer term outcomes after discharge and a broader study population.