Oxygen tension and gradient measurements in the retinal microvasculature of rats

Background  

Oxygen delivery from the retinal vasculature plays a crucial role in maintaining normal retinal metabolic function. Therefore, measurements of retinal vascular oxygen tension (PO₂) and PO₂ longitudinal gradients (gPO₂) along retinal blood vessels may help gain fundamental knowledge of retinal physiology and pathological processes.     

Hematopoiesis and RAS-driven myeloid leukemia differentially require PI3K isoform p110α

The genes encoding RAS family members are frequently mutated in juvenile myelomonocytic leukemia (JMML) and acute myeloid leukemia (AML). RAS proteins are difficult to target pharmacologically; therefore, targeting the downstream PI3K and RAF/MEK/ERK pathways represents a promising approach to treat RAS-addicted tumors. The p110α isoform of PI3K (encoded by Pik3ca) is an essential effector of oncogenic KRAS in murine lung tumors, but it is unknown whether p110α contributes to leukemia. To specifically examine the role of p110α in murine hematopoiesis and in leukemia, we conditionally deleted p110α in HSCs using the Cre-loxP system. Postnatal deletion of p110α resulted in mild anemia without affecting HSC self-renewal; however, deletion of p110α in mice with KRAS^G12D-associated JMML markedly delayed their death. Furthermore, the p110α-selective inhibitor BYL719 inhibited growth factor–independent KRAS^G12D BM colony formation and sensitized cells to a low dose of the MEK inhibitor MEK162. Furthermore, combined inhibition of p110α and MEK effectively reduced proliferation of RAS-mutated AML cell lines and disease in an AML murine xenograft model. Together, our data indicate that RAS-mutated myeloid leukemias are dependent on the PI3K isoform p110α, and combined pharmacologic inhibition of p110α and MEK could be an effective therapeutic strategy for JMML and AML.     

Social capital and neo-materialist contextual determinants of sense of insecurity in the neighbourhood: a multilevel analysis in Southern Sweden

BACKGROUND: The aim of this study was to investigate the influence of contextual (social capital and neo-materialist) and individual factors on sense of insecurity in the neighbourhood. METHODS: The 2000 public health survey in Scania is a cross-sectional study. A total of 13,715 persons answered a postal questionnaire, which is 59% of the random sample. A multilevel logistic regression model, with individuals at the first level and municipalities at the second, was performed. The effect (median odds ratios, intra-class correlation, cross-level modification and odds ratios) of individual and municipality/city quarter (social capital and police district) factors on sense of insecurity was analysed. RESULTS: The crude variance between municipalities/city quarters was not affected by individual factors. The introduction of administrative police district in the model reduced the municipality variance, although some of the significant variance between municipalities remained. The introduction of social capital did not affect the municipality variance. CONCLUSIONS: This study suggests that the neo-materialist factor administrative police district may partly explain the individual's sense of insecurity in the neighbourhood.     

Nerve fiber layer thickness in glaucoma patients with asymmetric hemifield visual field loss

PURPOSE: To investigate the presence of retinal nerve fiber layer (RNFL) thinning and determine the relationship between RNFL thickness and visual field sensitivity loss in glaucoma patients with asymmetric hemifield visual field loss. PATIENTS AND METHODS: Thirty glaucoma patients with asymmetric hemifield visual field loss and 30 normal control subjects were included in the study. RNFL thickness was measured by optical coherence tomography and visual field sensitivity was measured by automated perimetry. Glaucoma patients with advanced visual field loss restricted to 1 hemifield and early or absent glaucomatous field loss in the other hemifield on the basis of the visual field data were included. Visual field sensitivity and mean deviation (MD) were averaged separately in each of the 2 hemifields. The hemifields in each eye were categorized as early (MD>or=-6 dB) and advanced (MD<-6 dB) glaucomatous hemifields. RESULTS: RNFL thickness measurements in corresponding (eg, superior peripapillary quadrant with inferior hemifield) advanced glaucomatous hemifields (59+/-16 microm) were significantly (P<0.001) lower than in corresponding early glaucomatous hemifields (90+/-25 microm). The mean RNFL thickness in corresponding advanced and early glaucomatous hemifields were significantly lower than in normal control subjects (P<0.0001). On the basis of the normative database supplied by optical coherence tomography software, 100% and 43% of eyes had abnormal RNFL thickness in corresponding advanced and early glaucomatous hemifields, respectively. A linear correlation was found between RNFL thickness and MD in the early (r=0.6; P<0.001) and advanced (r=0.5; P=0.007) glaucomatous hemifields. CONCLUSIONS: RNFL thinning was present in corresponding hemifields of glaucomatous eyes with minimal visual field defect and correlated with visual field sensitivity loss. Measurement of RNFL thickness has potential for detection of early nerve fiber loss owing to glaucoma.     

Chorioretinal vascular oxygen tension changes in response to light flicker

PURPOSE: To investigate oxygen tension (P(O2)) changes in the retinal and choroidal vasculatures in response to visual stimulation by light flicker. METHODS: A previously developed optical section phosphorescence imaging system was used to measure P(O2) separately in the retinal veins, arteries, and capillaries and in the choroid before and during light flicker. Imaging was performed in rats during light flicker at frequencies between 0 and 14 Hz. Light flicker-induced changes in the chorioretinal vasculature P(O2) and arteriovenous P(O2) differences were determined. Retinal arterial and venous P(O2) were measured along blood vessels as a function of the distance from the optic nerve head. RESULTS: Retinal arterial P(O2) and arteriovenous P(O2) differences increased with increasing light flicker at frequencies up to 10 Hz, after which no further increase was observed. Significant increases in retinal arterial P(O2) (P = 0.009; n =10) and in retinal capillary P(O2) (P = 0.04, n = 10) were measured in response to light flicker at 10 Hz. Retinal arteriovenous P(O2) differences during light flicker were significantly greater than differences before light flicker (P = 0.01; n = 10). Retinal arterial P(O2) decreased significantly with increased distance from the optic nerve head (P < or = 0.004), whereas retinal venous P(O2) remained relatively unchanged (P > or= 0.4). CONCLUSIONS: Measurement of changes in the chorioretinal vasculature P(O2) can potentially advance the understanding of oxygen dynamics in challenged physiological states and in animal models of human retinal diseases.