Genetically attenuated Plasmodium berghei liver stages induce sterile protracted protection that is mediated by major histocompatibility complex Class I-dependent interferon-gamma-producing CD8+ T cells

At present, radiation-attenuated plasmodia sporozoites ( gamma -spz) is the only vaccine that induces sterile and lasting protection in malaria-naive humans and laboratory rodents. However, gamma -spz are not without risks. For example, the heterogeneity of the gamma -spz could explain occasional breakthrough infections. To avoid this possibility, we constructed a double-knockout P. berghei parasite by removing 2 genes, UIS3 and UIS4, that are up-regulated in infective spz. We evaluated the double-knockout Pbuis3(-)/4(-) parasites for protective efficacy and the contribution of CD8(+) T cells to protection. Pbuis3(-)/4(-) spz induced sterile and protracted protection in C57BL/6 mice. Protection was linked to CD8(+) T cells, given that mice deficient in beta (2)m were not protected. Pbuis3(-)/4(-) spz-immune CD8(+) T cells consisted of effector/memory phenotypes and produced interferon- gamma . On the basis of these observations, we propose that the development of genetically attenuated P. falciparum parasites is warranted for tests in clinical trials as a pre-erythrocytic stage vaccine candidate.     

Myocardial asynchrony in patients with postinfarction intraventricular conduction defects

BACKGROUND: Postinfarction intraventricular conduction defects lead to asynchronous activation of the myocardium.Hypothesis: The aim of the current study is to evaluate contraction asynchrony in postinfarction patients with intraventricular conduction defects. METHODS: A total of 158 patients 6 months postmyocardial infarction and 15 healthy subjects underwent echocardiography to evaluate atrioventricular, interventricular, intraventricular asynchrony, and myocardial performance index (MPI). A subgroup of 126 patients had intraventricular conduction defects in ECG, whereas 32 with normal QRS complex served as controls. RESULTS: All patients postmyocardial infarction showed intraventricular asynchrony and markedly higher MPI. Comparing groups with and without intraventricular conduction defects postmyocardial infarction, those with left bundle branch block (BBB) had significantly higher parameters of all asynchrony types; those with right BBB and left posterior hemiblock (LPH) had significantly higher interventricular asynchrony parameters; those with left anterior hemiblock did not show significant differences in asynchrony parameters as compared with subjects without postinfarction conduction defects. CONCLUSIONS: (1) Patients 6 months postmyocardial infarction show intraventricular asynchrony and markedly higher MPI. (2) Postinfarction patients with LBBB have the highest parameters of atrioventricular, interventricular and intraventricular asynchrony as compared with postinfarction patients with other and without conduction defects. (3) In postinfarction patients with RBBB or LPH parameters of interventricular asynchrony are significantly higher as compared with postinfarction patients without intraventricular conduction defects.     

507 A Novel Mechanism of Fas Signaling Suppression by PMLRARα in Acute Promyelocytic Leukemia

Presence of potential inhibitors of Fas could block Fas signaling and explain cancer cells resistance to apoptosis. In this study, we found that PMLRARα binds to Fas and blocks Fas-mediated apoptosis through recruiting c-FLIP in APL. Targeting tissue-specific inhibitors of Fas such as PMLRARα would improve cancer therapy.

Full Abstract

Fas plays a critical role in cell proliferation and in the selective killing of autoreactive lymphocytes and abnormal cells, including infected cells. To explain the common expression of Fas and the resistance to the Fas-induced apoptosis observed in some normal and cancer cells, we have screened cells for potential regulators of the Fas death receptor. By using mass spectrometry analysis of Fas-associated proteins, we identified peptides derived from promyelocytic leukemia (PML).PML enhances

     

A seed coat bedding assay shows that RGL2-dependent release of abscisic acid by the endosperm controls embryo growth in Arabidopsis dormant seeds

Seed dormancy is an ecologically important adaptive trait in plants whereby germination is repressed even under favorable germination conditions such as imbibition with water. In Arabidopsis and most plant species, dormancy absolutely requires an unidentified seed coat germination-repressive activity and constitutively higher abscisic acid (ABA) levels upon seed imbibition. The mechanisms underlying these processes and their possible relationship are incompletely understood. We developed a "seed coat bedding" assay monitoring the growth of dissected embryos cultured on a layer of seed coats, allowing combinatorial experiments using dormant, nondormant, and various genetically modified seed coat and embryonic materials. This assay, combined with direct ABA measurements, revealed that, upon imbibition, dormant coats, unlike nondormant coats, actively produce and release ABA to repress embryo germination, whatever the embryo origin, i.e., from dormant, nondormant, or never dormant aba seeds, unable to synthesize ABA. The persistent high ABA levels in imbibed dormant seeds requires the permanent expression of the DELLA gene RGL2, where it remains insensitive to gibberellins (GA) unlike in nondormant seeds. These findings present the seed coat as an organ actively controlling germination upon seed imbibition and provide a framework to investigate how environmental factors break seed dormancy.     

Treatment of experimental renal osteodystrophy with pamidronate

We evaluated the effects of the bisphosphonate pamidronate on bone histomorphometry, structure and strength in male rats with uninephrectomy or with chronic renal disease induced by 5/6 nephrectomy. In rats with chronic renal disease the plasma urea, phosphate and parathyroid hormone levels were significantly increased compared to rats with a uninephroctomy and none of these parameters was affected by pamidronate treatment. In the femoral midshaft, chronic renal disease reduced cortical bone mineral density and content. No difference was observed in the breaking load of the femoral midshaft. In the distal femur, a high-turnover renal osteodystrophy was found but pamidronate suppressed this bone turnover and increased bone mineral content. Treatment had no effect on chronic disease-induced augmentation of osteoid volume or fibroblast surface. These studies show that in this model of stage 3 renal disease, pamidronate increased mineral content in the femoral midshaft and distal metaphysis primarily by adding bone to endocortical and trabecular surfaces but did not reduce osteitis fibrosa.     

Epidermal growth factor receptor signaling is required for microadenoma formation in the mouse azoxymethane model of colonic carcinogenesis

Colonic carcinogenesis involves the progressive dysregulation of homeostatic mechanisms that control growth. The epidermal growth factor (EGF) receptor (EGFR) regulates colonocyte growth and differentiation and is overexpressed in many human colon cancers. A requirement for EGFR in colonic premalignancy, however, has not been shown. In the current study, we used a specific EGFR antagonist, gefitinib, to investigate this role of the receptor in azoxymethane colonic premalignancy. The azoxymethane model shares many clinical, histologic, and molecular features of human colon cancer. Mice received azoxymethane i.p. (5 mg/kg/wk) or saline for 6 weeks. Animals were also gavaged with gefitinib (10 mg/kg body weight) or vehicle (DMSO) thrice weekly for 18 weeks, a dose schedule that inhibited normal receptor activation by exogenous EGF. Compared with control colonocytes [bromodeoxyuridine (BrdUrd), 2.2+/-1.2%], azoxymethane significantly increased proliferation (BrdUrd, 12.6+/-2.8%), whereas gefitinib inhibited this hyperproliferation (BrdUrd, 6.2+/-4.0%; <0.005). Azoxymethane significantly induced pro-transforming growth factor-alpha (6.4+/-1.3-fold) and increased phospho-(active) EGFR (5.9+/-1.1-fold), phospho-(active) ErbB2 (2.3+/-0.2-fold), and phospho-(active) extracellular signal-regulated kinase (3.3+/-0.4-fold) in premalignant colonocytes. Gefitinib inhibited activations of these kinases by >75% (P<0.05). Gefitinib also significantly reduced the number of large aberrant crypt foci and decreased the incidence of colonic microadenomas from 75% to 33% (P<0.05). Gefitinib concomitantly decreased cell cycle-regulating cyclin D1 and prostanoid biosynthetic enzyme cyclooxygenase-2 in microadenomas, suggesting that these regulators are key targets of EGFR in colonic carcinogenesis. These results show for the first time that EGFR signaling is required for early stages of colonic carcinogenesis. Our findings suggest, moreover, that inhibitors of EGFR might be useful in chemopreventive strategies in individuals at increased risk for colonic malignancies.     

Primary pigmented nodular adrenocortical disease (PPNAD) as an underlying cause of symptoms in a patient presenting with hirsutism and secondary amenorrhea: case report and literature review

Abstract

Hypercortisolemia in females may lead to menstrual cycle disturbances, infertility, hirsutism and acne. Herewith, we present a 18-year-old patient, who was diagnosed due to weight gain, secondary amenorrhea, slowly progressing hirsutism, acne and hot flashes. Thorough diagnostics lead to a conclusion, that the symptoms was the first manifestation of primary pigmented nodular adrenocortical disease (PPNAD). All symptoms of Cushing syndrome including hirsutism and menstrual disturbances resolved after bilateral adrenalectomy. Our report indicates that oligo- or amenorrhea, hirsutism, acne in combination with weight gain, growth failure, hypertension and slightly expressed cushingoid features in a young woman requires diagnostics towards hypercortisolemia. Despite PPNAD is a very rare cause of ACTH-independent Cushing syndrome, it has to be taken into consideration, especially when adrenal glands appear to be normal on imaging and paradoxical rise in cortisol level in high-dose dexamethasone test is observed. Unlike in our patient, in vast majority of patients, PPNAD is associated with Carney complex (CC). Therefore, these patients and their first-degree relatives should be always carefully screened for symptoms of PPNAD, CC and genetic mutations of PRKAR1A, PDE11A, and PDE8B genes.     

Dietary calcium and obesity in men

Increased calcium intake has been associated with lower body weight, BMI and adiposity, mostly in children, youth and women. In men results are inconclusive. In this study the relation between calcium intake and body weight and body fat in obese men was investigated. 200 men, the mean age 45.1 +/- 9.4 y, the mean BMI 33.2 +/- 4.8 kg/m2, were divided into 4 groups on the basis of their calcium/protein index. No significant differences in body weight, BMI, fat mass, percentage of body fat were found across subgroups and no significant correlations between calcium intake and body variables were stated. This study did not confirm the association between calcium intake and body weight and adiposity in men.