Sexually dimorphic differences in angiogenesis markers predict brain aging trajectories.

Aberrant angiogenesis could contribute to cognitive impairment, representing a therapeutic target for preventing dementia. However, most angiogenesis studies focus on model organisms. To test the relevance of angiogenesis to human cognitive aging, we evaluated associations of circulating blood markers of angiogenesis with brain aging trajectories in two deeply phenotyped human cohorts (n=435, age 74 + 9) with longitudinal cognitive assessments, biospecimens, structural brain imaging, and clinical data. Machine learning and traditional statistics revealed sex dimorphic associations of plasma angiogenic growth factors with brain aging outcomes. Specifically, angiogenesis is associated with higher executive function and less brain atrophy in younger women (not men), a directionality of association that reverses around age 75. Higher levels of basic fibroblast growth factor, known for pleiotropic effects on multiple cell types, predicted favorable cognitive trajectories. This work demonstrates the relevance of angiogenesis to brain aging with important therapeutic implications for vascular cognitive impairment and dementia.

Antiviral RNA interference in mammalian cells.

In antiviral RNA interference (RNAi), the DICER enzyme processes virus-derived double-stranded RNA (dsRNA) into small interfering RNAs (siRNAs) that guide ARGONAUTE proteins to silence complementary viral RNA. As a counterdefense, viruses deploy viral suppressors of RNAi (VSRs). Well-established in plants and invertebrates, the existence of antiviral RNAi remains unknown in mammals. Here, we show that undifferentiated mouse cells infected with encephalomyocarditis virus (EMCV) or Nodamura virus (NoV) accumulate ~22-nucleotide RNAs with all the signature features of siRNAs. These derive from viral dsRNA replication intermediates, incorporate into AGO2, are eliminated in Dicer knockout cells, and decrease in abundance upon cell differentiation. Furthermore, genetically ablating a NoV-encoded VSR that antagonizes DICER during authentic infections reduces NoV accumulation, which is rescued in RNAi-deficient mouse cells. We conclude that antiviral RNAi operates in mammalian cells.

FLAIR and diffusion MRI signals are independent predictors of white matter hyperintensities.

BACKGROUND AND PURPOSE: WMH, associated with cognitive decline and cardiovascular risk factors, may represent only the extreme end of a more widespread continuous WM injury process that progresses during aging and is poorly understood. We investigated the ability of FLAIR and DTI to characterize the longitudinal course of WMH development. MATERIALS AND METHODS: One hundred nineteen participants (mean age, 74.5 ± 7.4), including cognitively healthy elders and subjects diagnosed with Alzheimer disease and mild cognitive impairment, received a comprehensive clinical evaluation and brain MR imaging, including FLAIR and DTI on 2 dates. The risk for each baseline normal-appearing WM voxel to convert into WMH was modeled as a function of baseline FA (model M1) and both baseline FA and standardized FLAIR (M2). Sensitivity, specificity, accuracy, and AUC for predicting conversion to WMH were compared between models. RESULTS: Independent of clinical diagnosis, lower baseline FA (P < .001, both models) and higher baseline FLAIR intensity (P < .001, M2) were independently associated with increased risk for conversion from normal WM to WMH. M1 exhibited higher sensitivity but lower specificity, accuracy, and AUC compared with M2. CONCLUSIONS: These findings provide further evidence that WMH result from a continuous process of WM degeneration with time. Stepwise decreases in WM integrity as measured by both DTI and FLAIR were independently associated with stepwise increases in WMH risk, emphasizing that these modalities may provide complementary information for understanding the time course of aging-associated WM degeneration.

[Interfacial behaviour of glycoconjugated tetraphenylporphyrins and their interaction with biomimetic models of the cell membrane]. / Comportement interfacial de tétraphénylporphyrines glycoconjuguées et leur interaction avec des modèles biomimétiques de la membrane cellulaire.

INTRODUCTION: Porphyrins are photosensitizers usable in photodynamic therapy. Although these molecules are clinically effective, their low water solubility and their lack of specificity are major drawbacks to their development. Our study was aimed at analysing the interfacial behaviour of glycoconjugated tetraphenylporphyrins newly synthesized at the Curie Institute, and their interaction with model membranes bearing a specific lectin mimicking a mannose membrane receptor in retinoblastoma. MATERIAL AND METHODS: The interfacial behaviour of the porphyrins was analysed by surface pressure measurements, and their specific interaction with the lectin, by dynamic light scattering (liposomes) and the quartz crystal microbalance technique (supported bilayers). RESULTS: All porphyrin derivatives were able to organize at the air/liquid interface. The dendrimeric compounds formed more stable monolayers than the others, and generally showed good mixing properties with the phospholipid used for liposome preparation. In the presence of concanavalin A, the porphyrin bearing-liposomes behaved differently depending on the nature (mannosylated or not) of the porphyrins. DISCUSSION: The interfacial behaviour of the tetraphenylporphyrins is directly related to the orientation of the tetrapyrrolic macrocycle controlled by the grafted groups. Incorporated into a liposome bilayer, glycodendrimeric porphyrins expose their sugar moieties at the vesicle surface. The spacer length plays a crucial role by increasing sugars freedom and enhancing glycosylated liposomes interaction with the lectin. CONCLUSION: Compared to the other studied compounds, the glycodendrimeric porphyrins seem very promising compounds and are now evaluated on cell cultures.

The contributions of MRI-based measures of gray matter, white matter hyperintensity, and white matter integrity to late-life cognition.

BACKGROUND AND PURPOSE: GM volume, WMH volume, and FA are each associated with cognition; however, few studies have detected whether these 3 different types of MR imaging measurements exert independent or additive effects on cognitive performance. To detect their extent of contribution to cognitive performance, we explored the independent and additive contributions of GM atrophy, white matter injury, and white matter integrity to cognition in elderly patients. MATERIALS AND METHODS: Two hundred and 9 elderly patients participated in the study: 97 were CN adults, 65 had MCI, and 47 had dementia. We measured GM on T1-weighted MR imaging, WMH on FLAIR, and FA on DTI, along with psychometrically matched measures of 4 domains of cognitive performance, including semantic memory, episodic memory, executive function, and spatial abilities. RESULTS: As expected, patients with dementia performed significantly more poorly in all 4 cognitive domains, whereas patients with MCI performed generally less poorly than dementia patients, though considerable overlap in performance was present across groups. GM, FA, and WMH each differed significantly between diagnostic groups and were associated with cognitive measures. In multivariate models that included all 3 MR imaging measures (GM, WMH, and FA), GM volume was the strongest determinant of cognitive performance. CONCLUSIONS: These results strongly suggest that MR imaging measures of GM are more closely associated with cognitive function than WM measures across a broad range of cognitive and functional impairment.

Reaction of the m-THPC triplet state with the antioxidant Trolox and the anesthetic Propofol: modulation of photosensitization mechanisms relevant to photodynamic therapy?

Antioxidants may affect the outcome of photodynamic therapy (PDT) through the inactivation of reactive oxygen species. Their direct interaction with photosensitizers excited at the triplet state is also worthy of interest. This process is investigated by laser flash photolysis of m-THPC (meso-tetra(3-hydroxyphenyl)chlorin, Foscan) hydroalcoholic solutions added with Trolox (TrOH), a standard antioxidant or Propofol (PfOH, Diprivan(®)), a common anesthetic agent also characterized for its antioxidant properties. Transient UV-visible absorption spectra, kinetics at selected wavelengths and final spectra after extensive laser irradiation show that both compounds react with the m-THPC triplet state, (3)m-THPC, to ultimately restore the photosensitizer in its ground state. For PfOH, this process mainly appears as a single step obeying pseudo-first order kinetics. The bimolecular rate constant for the quenching of (3)m-THPC by PfOH is around 2 × 10(6) M(-1) s(-1), a value increased to some extent by the water content of the solution. A bimolecular reaction between (3)m-THPC and TrOH is observed with a rate constant of similar magnitude and dependence upon water. However, the reaction leads, at least partly, to intermediate species assigned to the TrO˙ radical and the m-THPC anion radical. Within a few ms, these species back react to yield m-THPC in its ground state. A general mechanism involving an intermediate activated complex with some charge transfer character is proposed. Depending on the redox potentials for the oxidation of the antioxidant, this complex evolves predominantly either toward the formation of radicals (TrOH) or back to the photosensitizer ground state (PfOH). Notably, the kinetics data suggest that Propofol may quench (3)m-THPC at concentrations relevant of clinical situation in PDT involving anesthesia.

Nitrogen sources for current-year shoot growth in 50-year-old sessile oak trees: an in situ (15)N labeling approach.

We used long-term in situ (15)N labeling of the soil to investigate the contribution of the two main nitrogen (N) sources (N uptake versus N reserves) to sun shoot growth from bud burst to full leaf expansion in 50-year-old sessile oaks. Recovery of (15)N by growing compartments (leaves, twigs and buds) and presence of (15)N in phloem sap were checked weekly. During the first 2 weeks following bud burst, remobilized N contributed ~90% of total N in growing leaves and twigs. Nitrogen uptake from the soil started concomitantly with N remobilization but contributed only slightly to bud burst. However, the fraction of total N due to N uptake increased markedly once bud burst had occurred, reaching 27% in fully expanded leaves and 18% in developed twigs. In phloem sap, the (15)N label appeared a few days after the beginning of labeling and increased until the end of bud burst, and then decreased at full leaf expansion in June. Of all the shoot compartments, leaves attracted most of the absorbed N, which accounted for 68% of new N in shoots, whereas twigs and new buds accounted for only 28 and 3%, respectively. New N allocated to leaves increased from unfolding to full expansion as total N concentration in the leaves decreased. Our results underline the crucial role played by stored N in rapid leaf growth and in the sustained growth of oak trees. Any factors that reduce N storage in autumn may therefore impair spring shoot growth.

Seasonal changes of C and N non-structural compounds in the stem sapwood of adult sessile oak and beech trees.

We assessed the pools of non-structural nitrogen compounds (NSNC) through a year, thereby addressing the question of whether mature sessile oak [Quercus petraea (Matt.) Liebl.] and beech (Fagus sylvatica L.), which differ in wood anatomy and growth patterns, exhibit contrasting seasonal dynamics of NSNC pools as previously shown for non-structural carbohydrate (NSC) pools. Seasonal fluctuations of NSNC (amino acids and soluble proteins) and NSC (starch and soluble sugars) pools were analyzed in the inner and the outer stem sapwood. In oak, NSC showed marked seasonal variation within the stem sapwood (accumulation during winter and decrease during bud burst and early wood growth), whereas in beech seasonal fluctuations in NSC were of minor amplitude. Even if the distribution and intensity of the NSNC pools differed between the two species, NSNC of the stem sapwood did not show seasonal variation. The most significant change in NSNC pools was the seasonal fluctuation of protein composition. In both species, two polypeptides of 13 kDa (PP13) and 26 kDa (PP26) accumulated during the coldest period in parallel with starch to sugar conversion and disappeared with the onset of spring growth. The absence of seasonal changes in total soluble protein concentration suggests that the polypeptides are involved in the internal nitrogen (N) cycling of the stem rather than in N storage and remobilization to the other growing organs of the tree.

[Towards a new treatment of retinoblastoma?]. / Vers un nouveau traitement du rétinoblastome ?

Photodynamic therapy (PDT) is a recent approach for the treatment of small cancerous tumours, on-surface or accessible by endoscopy in which a dye (usually a tetrapyrrolic macrocycle) absorbs light and generates cytotoxic reactive oxygen species leading to cellular damage. Retinoblastoma (Rb) is a rare intraocular tumour of childhood. All the multifocal forms are hereditary and constitute a syndrome of genetic predisposition in the cancer. The current treatments with etoposide or carboplatine expose the patient to the late risk of second cancer. The use of PDT as cancer therapy is particularly attractive due to the use of few mutagenic and non-toxic photosensitizers (PS) prior light excitation and to the localized tumour illumination. The photoefficiency towards Rb of a glycoconjugated porphyrin is discussed and compared with the results obtained with a second-generation photosensitizer, the Foscan. Some in vivo results on an animal model of Rb are presented by a point of view of photoefficiency, biodistribution, pharmacokinetic and longitudinal follow-up of the PDT effect using a new non-invasive method of magnetic resonance imaging of real-time. Photodynamic treatments in association with non-invasive sodium imaging open ways for new treatment tailoring or treatment individualization of retinoblastoma in clinic.

[Photosensitizing anticancer tetrapyrroles: or how photophysics becomes a mechanism of action]. / Tétrapyrroles anticancéreux photosensibilisants : ou comment la photophysique devient mécanisme d'action.

The macrocyclic tetrapyrrole derivatives used for the treatment of certain solid tumors include porphyrins and their chlorine and bacteriochlorin derivatives. These are highly conjugated, rigid molecules characterized by a strong absorbance in the spectral domain from near ultra-violet to far red (350-750 nm). The combination of tetrapyrroles plus light is called dynamic phototherapy (DPT). This combination transforms the molecule to its triplet form which by deactivation generates free radicals and a singlet oxygen from molecular oxygen, causing tumor destruction. Tetrapyrroles are thus, with psoralens, used for the treatment of psoriasis. They are the only drugs whose mechanism of action results exclusively from their electronic and photophysical spectroscopic characteristics. This class of anticancer agents is usually free of any specific cytotoxic effect. We describe here the current elements linking structure and spectroscopy and observations leading to the design of compounds with strong tumor selectivity and optimal cytotoxic properties.

Neuroimaging correlates of subjective memory deficits in a community population.

BACKGROUND: Subjective memory deficit (SMD) is one of few potential presenting symptoms for people with early cognitive impairment. However, associations with underlying brain changes are unclear. METHODS: In a community sample of 1,779 people without dementia, and with neuroimaging (MRI) data, associations were investigated for SMD with white matter lesion volume and with the following volumetric measures: gray and white matter, CSF, hippocampal, parahippocampal, and amygdalar. Covariates included depressive symptoms (Center for Epidemiologic Studies Depression Scale), a battery of cognitive tests, physical health, and social activity. RESULTS: SMD was present in 26.4% of the sample. Of the neuroimaging measures analyzed, SMD was most strongly associated with temporal WML (OR for highest quintile compared to the remainder 1.44, 95% CI 1.12-1.85), and lower hippocampal volume (OR per decreasing quintile 1.22, 1.11-1.35). These associations were independent of all other covariates, including cognitive function. CONCLUSIONS: Subjective memory deficit (SMD) was associated with neuroimaging characteristics in the temporal and hippocampal regions, suggesting that SMD may, at least in some cases, represent a realistic appraisal of underlying brain function independent of measured cognition. However, further research is required for volumetric measures and SMD to establish whether the association reflects lifelong structure or neurodegenerative changes.

[Malignant tumors arising in extra-ovarian endometriosis: a case report]. / Endométriose extra-ovarienne dégénérée.

We report a case of degenerative extra-ovarian endometriosis. This is a rare complication of endometriosis, the frequency of which is estimated at 0.9%. In more than 50% of the cases, the diagnosis is made following investigation for abdominal pain. If the degeneration is of the same histological type as the endometriosis, it can be said to have arisen from the endometriosis. First-line treatment is surgery, removing as much endometriosis as possible, staging at this point is also necessary. Second-line treatment, with chemotherapy, radiotherapy and even hormonotherapy may be needed. Prognosis for this tumor is variable, from 10 to 100% five-year survival, depending on histological type and localization of the disease.

[Different methods for assessing quality in health sector]. / Les différents modes de reconnaissance de la qualité en santé.

AN OBLIGATION: The "management" of quality is an integral part of "medical" management today. The health centers and professionals have to prove their value and know-how through distinct signs of recognition. A METHOD FOR ASSESSING QUALITY: This paper defines the method of assessment of quality and specifies the typology of the persons, organisms, supervisors and clients of the French health system who have a personal or collective interest in judging the quality of health services. DIFFERENT POSSIBILITIES: Numerous existing methods for assessing quality are presented together with their use, implementation and the use made by the actors and consumers of the health system. Some of these assessment methods are formal, others informal, some are mandatory, others optional; some concern the general population, others the professionals. Although know-how is essential in health, making it known is strategic today.

Photobiological activity of exogenous and endogenous porphyrin derivatives in Escherichia coli and Enterococcus hirae cells.

Photodynamic treatment, the combined application of a photosensitiser and visible light, represents a new and promising approach for the inactivation of microorganisms. The photosensitising potentials of exogenous zinc-phthalocyanine-tetrasulphonate (ZnPsTS), tetraphenylporphyrins (TPPs) and endogenous porphyrin derivatives were tested and compared on Gram-negative and Gram-positive bacteria, Escherichia coli B. and Enterococcus hirae, respectively. The synthesis of endogenous porphyrins was induced by 5-aminolevulinic acid (delta-ALA). The porphyrin- or delta-ALA-treated cells were irradiated with white light. The photosensitising efficiency of endogenous derivatives on both types of bacteria is ZnPcTS < TP(4-OGluOH)3P < TP(4-OGluOH)4P. However, neither exogenous derivatives exhibit appreciable photosensitising activity for disinfection application. ALA-induced photodynamic treatment showed good potential for the inactivation of Escherichia coli cells, but not towards Enterococcus hirae cells. The failure of photosensitisation of the Enterococcus hirae strain selected indicates that apart from the Gram-positive character, other structural elements of the membrane can influence the result of photodynamic treatments.

Nonenveloped nucleocapsids of hepatitis C virus in the serum of infected patients.

One of the characteristics of hepatitis C virus (HCV) is the high incidence of persistent infection. HCV core protein, in addition to forming the viral nucleocapsid, has multiple regulatory functions in host-cell transcription, apoptosis, cell transformation, and lipid metabolism and may play a role in suppressing host immune response. This protein is thought to be present in the bloodstream of the infected host as the nucleocapsid of infectious, enveloped virions. This study provides evidence that viral particles with the physicochemical, morphological, and antigenic properties of nonenveloped HCV nucleocapsids are present in the plasma of HCV-infected individuals. These particles have a buoyant density of 1.32 to 1.34 g/ml in CsCl, are heterogeneous in size (with predominance of particles 38 to 43 or 54 to 62 nm in diameter on electron microscopy), and express on their surface epitopes located in amino acids 24 to 68 of the core protein. Similar nucleocapsid-like particles are also produced in insect cells infected with recombinant baculovirus bearing cDNA for structural HCV proteins. HCV core particles isolated from plasma were used to generate anti-core monoclonal antibodies (MAbs). These MAbs stained HCV core in the cytoplasm of hepatocytes from experimentally infected chimpanzees in the acute phase of the infection. These chimpanzees had concomitantly HCV core antigen in serum. These findings suggest that overproduction of nonenveloped nucleocapsids and their release into the bloodstream are properties of HCV morphogenesis. The presence of circulating cores in serum and accumulation of the core protein in liver cells during the early phase of infection may contribute to the persistence of HCV and its many immunopathological effects in the infected host.

Photoinduced inactivation of T7 phage sensitized by symmetrically and asymmetrically substituted tetraphenyl porphyrin: comparison of efficiency and mechanism of action.

We investigated the efficiency and the mechanism of action of two--one symmetrically and one asymmetrically substituted--glycoconjugated tetraphenyl porphyrins in their photoreaction with T7 phage as a model of nucleoprotein (NP) complexes. A correlation was found between the dark inactivation of T7 and the binding of porphyrins determined by fluorescence spectroscopy. Both types of porphyrin sensitized the photoinactivation of T7, but the slopes of inactivation kinetics were markedly different. There was no correlation between the dark binding and the photosensitizing efficacy of the two derivatives. Inactivation was moderated by 1,3-diphenylisobenzofuran and 1,3-dimethyl-2-thiourea; however, neither of them inhibited T7 inactivation completely. This result suggests that both Type-I and Type-II reactions play a role in the virus inactivation. Optical melting studies revealed structural changes in the protein part but not in the DNA of the photochemically treated NP complex. Polymerase chain reaction analysis of a 555 bp segment of gene 1 and a 3826 bp segment of genes 3 and 4 failed to demonstrate any DNA damage.

Interactive effects of elevated CO2 concentration and nitrogen supply on partitioning of newly fixed 13C and 15N between shoot and roots of pedunculate oak seedlings (Quercus robur).

Pedunculate oak (Quercus robur L.) seedlings were grown for 3 or 4 months (second- and third-flush stages) in greenhouses at two atmospheric CO2 concentrations ([CO2]) (350 or 700 micromol mol(-1)) and two nitrogen fertilization regimes (6.1 or 0.61 mmol N l(-1) nutrient solution). Combined effects of [CO2] and nitrogen fertilization on partitioning of newly acquired carbon (C) and nitrogen (N) were assessed by dual 13C and 15N short-term labeling of seedlings at the second- or third-flush stage of development. In the low-N treatment, root growth, but not shoot growth, was stimulated by elevated [CO2], with the result that shoot/root biomass ratio declined. At the second-flush stage, overall seedling biomass growth was increased (13%) by elevated [CO2] regardless of N fertilization. At the third-flush stage, elevated [CO2] increased growth sharply (139%) in the high-N but not the low-N treatment. Root/shoot biomass ratios were threefold higher in the low-N treatment relative to the high-N treatment. At the second-flush stage, leaf area was 45-51% greater in the high-N treatment than in the low-N treatment. At the-third flush stage, there was a positive interaction between the effects of N fertilization and [CO2] on leaf area, which was 93% greater in the high-N/elevated [CO2] treatment than in the low-N/ambient [CO2] treatment. Specific leaf area was reduced (17-25%) by elevated [CO2], whereas C and N concentrations of seedlings increased significantly in response to either elevated [CO2] or high-N fertilization. At the third-flush stage, acquisition of C and N per unit dry mass of leaf and fine root was 51 and 77% greater, respectively, in the elevated [CO2]/high-N fertilization treatment than in the ambient [CO2]/low-N fertilization treatment. However, there was dilution of leaf N in response to elevated [CO2]. Partitioning of newly acquired C and N between shoot and roots was altered by N fertilization but not [CO2]. More newly acquired C and N were partitioned to roots in the low-N treatment than in the high-N treatment.