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.     

Epidemiological aspects of rotavirus infection in Ahwaz, Iran

Rotavirus is the major cause of diarrhoea in children worldwide. In this study, conducted in the city of Ahwaz, Iran, during November 2001-March 2002, stool samples from 200 inpatient (n=63) and outpatient (n=137) children aged 1-24 month(s) were analyzed. Polyacrylamide gel electrophoresis was used for isolating rotavirus. Rotavirus was isolated from 36 (26.3%) of the 137 stool samples of outpatients and from 23 (36.5%) of the 63 stool samples of inpatients. The overall frequency of rotavirus in this population was 29.5%. The highest detection of rotavirus was made in children aged 7-12 months, which demonstrated that the relationship between age and rate of rotaviral infection was statistically significant (p < 0.05). The predominant electrophoretic pattern detected was the long (L) electrophoretype (46 of 59; 78%), followed by the short (S) electrophoretype (12 of 59; 20.3%). One strain had a mixed pattern. Such analysis throughout Iran would assist in developing sound guidelines for the prevention of rotavirus infections.     

Sudden reversible vitritis after keratoprosthesis: an immune phenomenon?

PURPOSE: To report our experience with late vitritis associated with keratoprosthesis (KPro). METHODS: Between 1990 and 2003, 218 patients underwent an all-polymethylmethacrylate, collar button-shaped KPro surgery. Eight patients developed a total of 12 episodes of sudden, massive vitritis. Five of these patients had an Ahmed shunt implant, 3 had anterior vitrectomy during surgery, and 4 had a soft contact lens in place. Preoperative diagnoses were multiple graft failures, chemical burn, Stevens-Johnson syndrome, or ocular cicatricial pemphigoid. All patients were maintained on prophylactic topical ofloxacin 0.3% or polymyxin-B/trimethoprim, as well as prednisolone acetate 1% (in 2 cases, medroxyprogesterone 1%), at least twice daily. Vancomycin (14 mg/mL) was also given twice daily in 2 patients. RESULTS: Vitritis occurred in 8 patients (12 episodes), 2 to 23 months postoperatively. All patients presented with sudden, very marked decrease in vision, with little or no pain, tenderness, conjunctival redness, or discharge. Eight of the 12 events were subjected to vitreous tap and injection of antibiotics and steroids on the day of presentation. Cultures grew Staphylococcus epidermidis, only in liquid (broth) media, in 3 cases; the other 5 showed no growth. The vitritis episodes resolved after 2 to 9 weeks. Full recovery to pre-episode status of a quiet eye with clear vitreous was seen in all patients. Visual acuity recovered almost completely or completely (mental debilitation in one patient made accurate assessment uncertain). CONCLUSIONS: This phenomenon of sudden vitritis after KPro, with few other symptoms and with complete recovery, would be uncharacteristic of a bacterial endophthalmitis. It may represent a uveitic immune phenomenon.