Exercise cardiac MRI unmasks right ventricular dysfunction in acute hypoxia and chronic pulmonary arterial hypertension

Background - Coupling of right ventricular (RV) contractility to afterload is maintained at rest in the early stages of pulmonary arterial hypertension (PAH), but exercise may unmask depleted contractile reserves. We assessed whether elevated afterload reduces RV contractile reserve despite compensated resting function using non-invasive exercise imaging. Methods and Results - Fourteen patients with PAH (mean age 39.1 years, 10 females) and 34 healthy control subjects (mean age 35.6 years, 17 females) completed real-time cardiac magnetic resonance imaging during sub-maximal exercise breathing room-air. Controls were then also exercised during acute normobaric hypoxia (FiO2 12%). RV contractile reserve was assessed by the effect of exercise on ejection fraction (RVEF). In control subjects the increase in RVEF on exercise was less during hypoxia (P=0.017), but the response of left ventricular ejection fraction to exercise did not change. Patients with PAH had impaired RV reserve with half demonstrating a fall in RVEF on exercise despite comparable resting function to controls (PAH: rest 53.6{plus minus}4.3% vs exercise 51.4{plus minus}10.7%; controls: rest 57.1{plus minus}5.2% vs exercise 69.6{plus minus}6.1%, P<0.0001). In control subjects the increase in stroke volume index (SVi) on exercise was driven by reduced RV end-systolic volume, whereas PAH patients did not augment SVi, with increases in both end-diastolic and end-systolic volumes. From baseline hemodynamic and exercise capacity variables only VE/VCO2 was an independent predictor of RV functional reserve (P=0.021). Conclusions - Non-invasive cardiac imaging during exercise unmasks depleted RV contractile reserves in healthy adults under hypoxic conditions and PAH patients under normoxic conditions despite preserved ejection fraction

Identification of targets of CD8⁺ T cell responses to malaria liver stages by genome-wide epitope profiling.

CD8⁺ T cells mediate immunity against Plasmodium liver stages. However, the paucity of parasite-specific epitopes of CD8⁺ T cells has limited our current understanding of the mechanisms influencing the generation, maintenance and efficiency of these responses. To identify antigenic epitopes in a stringent murine malaria immunisation model, we performed a systematic profiling of H(2b)-restricted peptides predicted from genome-wide analysis. We describe the identification of Plasmodium berghei (Pb) sporozoite-specific gene 20 (S20)- and thrombospondin-related adhesive protein (TRAP)-derived peptides, termed PbS20₃₁₈ and PbTRAP₁₃₀ respectively, as targets of CD8⁺ T cells from C57BL/6 mice vaccinated by whole parasite strategies known to protect against sporozoite challenge. While both PbS20₃₁₈ and PbTRAP₁₃₀ elicit effector and effector memory phenotypes in both the spleens and livers of immunised mice, only PbTRAP₁₃₀-specific CD8⁺ T cells exhibit in vivo cytotoxicity. Moreover, PbTRAP₁₃₀-specific, but not PbS20₃₁₈-specific, CD8⁺ T cells significantly contribute to inhibition of parasite development. Prime/boost vaccination with PbTRAP demonstrates CD8⁺ T cell-dependent efficacy against sporozoite challenge. We conclude that PbTRAP is an immunodominant antigen during liver-stage infection. Together, our results underscore the presence of CD8⁺ T cells with divergent potencies against distinct Plasmodium liver-stage epitopes. Our identification of antigen-specific CD8⁺ T cells will allow interrogation of the development of immune responses against malaria liver stages

Connections between the zona incerta and superior colliculus in the monkey and squirrel

The zona incerta contains GABAergic neurons that project to the superior colliculus in the cat and rat, suggesting that it plays a role in gaze changes. However, whether this incertal connection represents a general mammalian pattern remains to be determined. We used neuronal tracers to examine the zona incerta connections with the midbrain tectum in the gray squirrel and macaque monkey. Collicular injections in both species revealed that most incertotectal neurons lay in the ventral layer, but anterogradely labeled tectoincertal terminals were found in both the dorsal and ventral layers. In the monkey, injections of the pretectum also produced retrograde labeling, but mainly in the dorsal layer. The dendritic fields of incertotectal and incertopretectal cells were generally contained within the layer inhabited by their somata. The macaque, but not the squirrel, zona incerta extended dorsolaterally, within the external medullary lamina. Zona incerta injections produced retrogradely labeled neurons in the superior colliculus of both species. In the squirrel, most cells inhabited the lower sublamina of the intermediate gray layer, but in the monkey, they were scattered throughout the deeper layers. Labeled cells were present among the pretectal nuclei in both species. Labeled terminals were concentrated in the lower sublamina of the intermediate gray layer of both species, but were dispersed among the pretectal nuclei. In summary, an incertal projection that is concentrated on the collicular motor output layers and that originates in the ventral layer of the ipsilateral zona incerta is a common mammalian feature, suggesting an important role in collicular function

Coupling Social Solidarity and Social Harmony in Hong Kong

Social solidarity, Social harmony, Resource exchange theory,