Integration of repulsive guidance cues generates avascular zones that shape mammalian blood vessels

RATIONALE: Positive signals, such as vascular endothelial growth factor, direct endothelial cells (ECs) to specific locations during blood vessel formation. Less is known about repulsive signal contribution to shaping vessels. Recently, "neuronal guidance cues" have been shown to influence EC behavior, particularly in directing sprouting angiogenesis by repelling ECs. However, their role during de novo blood vessel formation remains unexplored. Objective: To identify signals that guide and pattern the first mammalian blood vessels. MethODS AND RESULTS: Using genetic mouse models, we show that blood vessels are sculpted through the generation of stereotyped avascular zones by EC-repulsive cues. We demonstrate that Semaphorin3E (Sema3E) is a key factor that shapes the paired dorsal aortae in mouse, as sema3E(-/-) embryos develop an abnormally branched aortic plexus with a markedly narrowed avascular midline. In vitro cultures and avian grafting experiments show strong repulsion of ECs by Sema3E-expressing cells. We further identify the mouse notochord as a rich source of multiple redundant neuronal guidance cues. Mouse embryos that lack notochords fail to form cohesive aortic vessels because of loss of the avascular midline, yet maintain lateral avascular zones. We demonstrate that lateral avascular zones are directly generated by the lateral plate mesoderm, a critical source of Sema3E. CONCLUSIONS: These findings demonstrate that Sema3E-generated avascular zones are critical regulators of mammalian cardiovascular patterning and are the first to identify a repulsive role for the lateral plate mesoderm. Integration of multiple, and in some cases redundant, repulsive cues from various tissues is critical to patterning the first embryonic blood vessels.     

Carotenoid oxidation products are stress signals that mediate gene responses to singlet oxygen in plants

(1)O(2) (singlet oxygen) is a reactive O(2) species produced from triplet excited chlorophylls in the chloroplasts, especially when plants are exposed to excess light energy. Similarly to other active O(2) species, (1)O(2) has a dual effect: It is toxic, causing oxidation of biomolecules, and it can act as a signal molecule that leads to cell death or to acclimation. Carotenoids are considered to be the main (1)O(2) quenchers in chloroplasts, and we show here that light stress induces the oxidation of the carotenoid β-carotene in Arabidopsis plants, leading to the accumulation of different volatile derivatives. One such compound, β-cyclocitral, was found to induce changes in the expression of a large set of genes that have been identified as (1)O(2) responsive genes. In contrast, β-cyclocitral had little effect on the expression of H(2)O(2) gene markers. β-Cyclocitral-induced reprogramming of gene expression was associated with an increased tolerance to photooxidative stress. The results indicate that β-cyclocitral is a stress signal produced in high light that is able to induce defense mechanisms and represents a likely messenger involved in the (1)O(2) signaling pathway in plants.     

Serum Aspergillus galactomannan for the management of disseminated histoplasmosis in AIDS

Abstract. Disseminated histoplasmosis is an emerging infection in patients with cellular immune deficiency in non-endemic countries, caused by the migration from endemic regions and the development of travels. Diagnosis can be challenging in this context because rapid diagnostic tools such as Histoplasma antigen detection or appropriate molecular tools are generally unavailable, serology is often negative in immunosuppressed patients, and isolation of the fungus from cultures often takes several weeks. Here, we report the contribution of galactomannan serum detection for the management of an HIV-infected patient with disseminated histoplasmosis.     

Prognostic impact of high ABC transporter activity in 111 adult acute myeloid leukemia patients with normal cytogenetics when compared to FLT3, NPM1, CEBPA and BAALC

ATP-binding cassette transporter (and specially P-glycoprotein) activity is a well known prognostic factor in acute myeloid leukemia, but when compared to other molecular markers its prognostic value has not been well studied. Here we study relationships between this activity, fms-like tyro-sine kinase 3(FLT3/ITD), nucleophosmin(NPM1), CAAT-enhancer binding protein alpha(CEBPα), and brain and acute leukemia cytoplasmic protein (BAALC), in 111 patients with normal cytogenetics who underwent the same treatment, and evaluate its prognostic impact. Independent factors for survival were age (P=0.0126), ATP-binding cassette transporter activity (P=0.018) and duplications in the fms-like tyrosine kinase 3 (P=0.0273). In the 66 patients without fms-like tyrosine kinase 3 duplication and without nucleophosmin mutation, independent prognostic factors for complete remission achievement and survival were age and ATP-binding cassette transporter activity. In conclusion, ATP-binding cassette transporter activity remains an independent prognostic factor, and could assist treatment decisions in patients with no nucleophosmin mutation and no fms-like tyrosine kinase 3 duplication.     

Hollow screws: a diagnostic tool for intracranial empyema

Background

Subdural (SDE) and epidural empyema (EDE) are life-threatening intracranial infections. They require immediate diagnosis and treatment. However, in some cases, magnet resonance imaging (MRI) is not able to contribute to diagnosis; therefore, surgical exploration is indicated. Hollow screws used for decompression of chronic subdural haematoma (cSDH) are valuable tools for minimally invasive biopsy in awake patients when SDE and EDE are suspected.

Methods

Between 2006 and 2010, eight patients in our department underwent biopsy of a suspected SDE or EDE using hollow screws. In these cases, MRI or computed tomography (CT) were not able to provide sufficient diagnostic security to indicate primary craniotomy. Diagnostic and therapeutic efficacy was evaluated on preoperative and postoperative imaging. The focus was on qualitative parameters, such as contrast enhancement or impaired diffusion on diffusion-weighted images (DWI).

Results

The application of the hollow screw under local anaesthesia permitted an exact diagnosis in all cases. In one case, the suspected diagnosis of cSDH could be refuted by diagnostic puncture. In four cases of uncertain diagnosis, the application of the hollow screw revealed a cSDH. Seven of eight patients previously received neurosurgical treatment; three of those cases were SDE or EDE and four were cSDH. Cases of SDE and EDE needed further craniotomy after diagnostic puncture, whereas patients with cSDH were sufficiently treated by hollow screws.

Conclusions

Given their comparably wide diameter, hollow screws allow a sufficient sample size and, therefore, lead to precise diagnosis of SDE and EDE without significant operative risks or strains for the patient.     

Exercise Prevents Fructose-Induced Hypertriglyceridemia in Healthy Young Subjects

Excess fructose intake causes hypertriglyceridemia and hepatic insulin resistance in sedentary humans. Since exercise improves insulin sensitivity in insulin-resistant patients, we hypothesized that it would also prevent fructose-induced hypertriglyceridemia. This study was therefore designed to evaluate the effects of exercise on circulating lipids in healthy subjects fed a weight-maintenance, high-fructose diet. Eight healthy males were studied on three occasions after 4 days of 1) a diet low in fructose and no exercise (C), 2) a diet with 30% fructose and no exercise (HFr), or 3) a diet with 30% fructose and moderate aerobic exercise (HFrEx). On all three occasions, a 9-h oral [¹³C]-labeled fructose loading test was performed on the fifth day to measure [¹³C]palmitate in triglyceride-rich lipoprotein (TRL)-triglycerides (TG). Compared with C, HFr significantly increased fasting glucose, total TG, TRL-TG concentrations, and apolipoprotein (apo)B48 concentrations as well as postfructose glucose, total TG, TRL-TG, and [¹³C]palmitate in TRL-TG. HFrEx completely normalized fasting and postfructose TG, TRL-TG, and [¹³C]palmitate concentration in TRL-TG and apoB48 concentrations. In addition, it increased lipid oxidation and plasma nonesterified fatty acid concentrations compared with HFr. These data indicate that exercise prevents the dyslipidemia induced by high fructose intake independently of energy balance.It is currently suspected that overconsumption of fructose, in the form of either sugar or high-fructose corn syrup, may promote obesity and favor the development of metabolic diseases such as type 2 diabetes and dyslipidemia (1,2). This is supported by a large number of studies in rodents, which demonstrate that a high-sucrose diet causes obesity, diabetes, dyslipidemia, and hepatic steatosis (3) and that this effect is mainly due to the fructose component of sucrose (4,5). Consistent with this hypothesis, epidemiological studies have shown that high intakes of sugar, fructose, or sweetened beverages are associated with the development of obesity (6,7), diabetes (8), hypertriglyceridemia (9), an increase in small dense atherogenic LDL particles (10), high blood pressure (11), albuminuria (12), and nonalcoholic fatty liver diseases (13). Several short-term studies have further documented that hypercaloric, high-fructose diets can cause increases in a number of cardiometabolic risk factors in humans, such as fasting and postprandial hypertriglyceridemia (14–18), ectopic lipid deposition in liver cells (19,20), impaired postprandial glucose homeostasis (18), and hepatic insulin resistance (21,22). Some of these effects may be related, at least in part, to the fact that fructose can be converted into fatty acids, which has been demonstrated after both acute (23) and chronic (18) fructose feeding. Exercise is very efficient at reducing the metabolic dysfunctions associated with obesity (24,25), and although many of these effects appear to be related to enhanced energy expenditure and improved energy balance (26,27), there is growing evidence that such improvements are independent of the changes in energy balance or body composition (28,29). Exercise has also been shown to prevent the accumulation of triglyceride-rich lipoprotein (TRL)-triglycerides (TG) and improve the plasma atherogenic lipid profile in healthy subjects fed a high-carbohydrate diet (30). The purpose of this study was to investigate whether exercise would similarly prevent fructose-induced metabolic effects.     

Allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning regimen in children: a single-center experience

This single-center retrospective study reported the outcome of 19 children treated with a reduced-intensity conditioning (RIC) regimen prior to allogeneic stem cell transplantation (allo-SCT), for hematologic malignancies (n = 17), bone marrow failure (n = 1), and neuroblastoma (n = 1). Children were ineligible for standard myeloablative conditioning because of severe comorbidities (n = 9), a previous auto or allo-SCT (n = 7) or a prior history of extensive chemotherapy (n = 3). All patients underwent a fludarabine-based RIC regimen, and received grafts from matched-related donors (n = 5), match-unrelated donors (n = 6), or unrelated cord blood (UCB, n = 8). In this series, two patients treated with UCB failed to engraft and 63% achieved full donor chimerism at day 100 after allo-SCT. With a median follow-up of 537 d (range, 115-4136), treatment-related mortality was 16% and overall survival was 47%. The principal cause of death was disease relapse (n = 7). Acute graft versus host disease (GVHD) occurred in 53% of patients, while only 10% developed extensive chronic GVHD. Overall, results from this series suggest that RIC allo-SCT can be a valid alternative treatment option in unfit children with malignant hematological diseases. Prospective studies are needed to enlarge pediatric experience in this domain and better identify those children more suitable for a RIC allo-SCT approach.