Calorie restriction and resveratrol supplementation prevent age-related DNA and RNA oxidative damage in a non-human primate.

Oxidative stress is a key factor in the aging process and in the development of age-related diseases. Because nutritional interventions such as caloric restriction (CR) delay the onset of age-related diseases and increase the lifespan of many species, the impact of a moderate CR was tested on male grey mouse lemur (Microcebus murinus), which have a median survival time of 5.7 years in captivity. The effects of CR on these lemurs were compared with a potential mimetic, resveratrol (RSV), a polyphenol naturally found in grapes. We hypothesized that both CR and RSV impact oxidative DNA and RNA damage compared to standard-fed control (CTL) animals. Adult (3-4 years old) male mouse lemurs were assigned to three dietary groups: a CTL group, a CR group receiving 30% fewer calories than the CTL and a RSV group receiving the CTL diet supplemented with RSV (200 mg·day(-1)·kg(-1)). Oxidative stress was estimated after 3, 9, 15 and 21 months of treatment using the measurement of oxidized nucleosides in urine samples by mass spectrometry. The resting metabolic rate, adjusted for changes in body composition, was also measured to assess the potential relationship between oxygen consumption and oxidative damage markers. This study provides evidence for oxidative stress accumulation with age in grey mouse lemur. Dietary interventions resulted in a short-term increase in oxidative stress levels followed by reduced levels with increasing age. Moreover, in this photoperiod-dependent heterotherm primate, seasonal variations in oxidative stress were observed, which was likely due to a season-dependent, cost-benefit trade-off between torpor use and oxidative stress.

Hepatic mRNA expression of acid labile subunit and deiodinase 1 differs between cows selected for high versus low concentrations of insulin-like growth factor 1 in late pregnancy.

The somatotropic axis is a key metabolic pathway during transition from late pregnancy to early lactation in dairy cows. The first objective of this study was to determine the feasibility of selecting cows with persistent differences in total insulin-like growth factor 1 (IGF-1) concentration by taking only a single antepartum blood sample. The second objective was to elucidate the underlying causes of differences in peripheral IGF-1 concentrations throughout late pregnancy and whether hormonal axes also differed in dairy cows with low versus high IGF-1. Twenty clinically healthy Holstein Friesian cows were chosen based on their plasma IGF-1 concentration at 244 to 254 d after artificial insemination (AI) and other selection criteria (health status, body condition score, number of lactations). These cows were selected from a large-scale farm, transported to the clinic, and monitored daily from 261 to 275 d after AI. The concentrations of IGF-1, growth hormone, IGF binding proteins 2, 3, and 4, insulin, cortisol, thyroid hormones, progesterone, and estradiol were measured. Ultimately, 7 IGF-1-low and 7 IGF-1-high cows were statistically analyzed. Additionally, a liver biopsy was taken on d 270 ± 1 after AI for analysis of gene expression of somatotropic family members, liver deiodinase 1, and suppressor of cytokine signaling-2. It was possible to select cows with different IGF-1 concentrations based upon only 1 blood sample collected in late pregnancy. Concentrations of IGF-1 in IGF-1-low versus IGF-1-high animals (n=7 each) remained significantly different between groups from the day of selection of the animals until d 275 after AI. Second, the differences in total plasma IGF-1 concentration between experimental groups may be attributed to differences in hepatic production of acid labile subunit. The ability of IGFBP-3 to bind IGF-1 declined before calving in all cows. Furthermore, in addition to decreased mRNA expression of growth hormone receptor 1A and IGF-1 relative to calving, serum binding capacities for IGF-1 also decreased. Insulin-like growth factor binding protein 4 mRNA expression was higher in cows with low IGF-1 concentrations; this binding protein inhibits IGF-1 action at the tissue level and therefore may reduce IGF-1 bioavailability. Finally, other endocrine end points (e.g., insulin and thyroid hormones) differed between the 2 groups.

Early brain amyloidosis in APP/PS1 mice with serum insulin-like growth factor-I deficiency.

The influence of insulin-like growth factor I (IGF-I) on the progression of Alzheimer's disease (AD) is discussed controversially. To help clarify the role of this circulating neurotrophic factor in brain amyloidosis, the major pathological trait in AD, we analyzed plaque formation in a mouse model of AD transgenic for human APP and PS1 mutations with reduced serum IGF-I levels (LIDAD mice). We found that brain amyloidosis in LIDAD mice appeared earlier than in AD mice, at 2 months of age, while attained comparable levels at 6 months. In parallel, early microgliosis was observed in LIDAD mice also at 2 months and remained exacerbated at 6 months. Collectively, these observations suggest a role of serum IGF-I in delaying early brain amyloidosis.

PEGylation enhances the therapeutic potential for insulin-like growth factor I in central nervous system disorders.

OBJECTIVE: Due to its potent neurotrophic activity, insulin-like growth factor I (IGF-I) has been proposed many times for therapeutic application in disorders of the central nervous system (CNS). However, insufficient brain delivery to yield beneficial central without peripheral side effects have prevented clinical development in most instances. DESIGN: We recently reported the generation of a polyethylene-glycol modified IGF-I variant (PEG-IGF-I) with prolonged half-life and less acute side effects, but with fully maintained slow anabolic activity. Here we investigated if these beneficial properties result in improved brain availability of the drug, thereby reaching therapeutically relevant steady-state concentrations to elicit beneficial effects on neuronal function. RESULTS: After a single subcutaneous injection, PEG-IGF-I reached much higher steady-state levels in brain tissue and cerebrospinal fluid compared with IGF-I. Two weeks treatment with PEG-IGF-I was sufficient to modulate brain plasticity processes, as judged by changes in synaptic proteins and related animal behavior. Furthermore, chronic treatment of a mouse model of brain amyloidosis with PEG-IGF-I reverted deficits in insulin/IGF-I signaling, synaptic proteins and cognitive performance. CONCLUSIONS: Our data generate the therapeutic potential for PEG-IGF-I to treat CNS disorders by systemic drug application, and in addition scientifically support its application in disorders of synaptic function and neuronal development.

[Bevacizumab and lung cancer: eligible patients in daily practice]. / Bévacizumab et cancer bronchique: population cible en pratique quotidienne.

BACKGROUND: Combining bevacizumab with platinum-based chemotherapy significantly improves survival for patients with advanced non-squamous non-small cell lung cancer. The objective of this study was to assess the proportion of patients who could receive this combined therapy. METHODS: This was a retrospective single centre analysis of patients treated between 2007 and 2008. Exclusion criteria for bevacizumab included: squamous cell carcinoma, contraindication to platinum-based chemotherapy, uncontrolled hypertension, haemoptysis superior to 2.5 mL, recent surgery, and/or tomodensitometric criteria after independent review by two radiologists (contact with a proximal vessel, tracheobronchial involvement, cavitation). Cardiovascular diseases and central tumour location were not systematically considered as contraindications. RESULTS: Among 194 patients analysed, 21 (10.8%) to 35 (18%) patients were eligible for bevacizumab, whether or not cardiovascular diseases and central tumour location were considered as contraindications. The kappa coefficient was 0.49. CONCLUSION: Even though the proportion of patients who can receive chemotherapy plus bevacizumab may vary according to the eligibility criteria chosen and the interpretation of the CT scan, it is unlikely to exceed 25% of patients in daily practice.

The contribution of CT-guided transthoracic lung biopsy to the diagnosis of organising pneumonia.

BACKGROUND: Organising pneumonia is a pulmonary disease with variable clinical and radiological features and with many differential diagnoses. Diagnosis is based on histology obtained by either transbronchial or surgical lung biopsy but these techniques have several disadvantages. The aim of this study was to evaluate the diagnostic yield of CT-guided transthoracic lung biopsy in organising pneumonia and to compare it to the usual diagnostic tools. METHODS: Six cases of organising pneumonia diagnosed with CT-guided lung biopsy are reported and discussed. The role of CT-guided lung biopsy in the diagnosis of organising pneumonia was also reviewed in the literature. RESULTS: CT-guided transthoracic lung biopsies provided a higher rate of adequate samples than transbronchial biopsies (92-100% versus 77-86%). The samples were larger, which reduced the risks of misdiagnosis and increased the diagnostic yield (88-97% versus 26-55% in pulmonary nodules and 42-100% versus 66-75% in diffuse pulmonary disease). Complications were rare and generally not serious. CONCLUSION: CT-guided transthoracic lung biopsy may be considered in place of transbronchial biopsy in the diagnosis of organising pneumonia. Surgical lung biopsy remains the gold standard method for diagnosis.

[The contribution of CT-guided transthoracic lung biopsy to the diagnosis of organizing pneumonia]. / Apport de la biopsie pulmonaire transthoracique dans le diagnostic de pneumonie organisée.

BACKGROUND: Organizing pneumonia is a pulmonary disease with variable clinical and radiological features and with many differential diagnoses. Diagnosis is based on histology obtained by either transbronchial or surgical lung biopsy but these techniques have several disadvantages. The aim of this study was to evaluate the diagnostic yield of CT-guided transthoracic lung biopsy in organizing pneumonia and to compare it to the usual diagnostic tools. METHODS: Six cases of organizing pneumonia diagnosed with CT-guided lung biopsy are reported and discussed. A review of literature concerning the role of CT-guided lung biopsy in the diagnosis of organizing pneumonia was performed. RESULTS: CT-guided transthoracic lung biopsies provided a higher rate of adequate samples than transbronchial biopsies (92-100% versus 77-86%). The samples were larger, which reduced the risks of misdiagnosis and increased the diagnostic yield (88-97% versus 26-55% in pulmonary nodules and 42-100% versus 66-75% in diffuse pulmonary disease). Complications were rare and generally not serious. CONCLUSION: CT-guided transthoracic lung biopsy may be considered in place of transbronchial biopsy in the diagnosis of organizing pneumonia. Surgical lung biopsy remains the reference method for diagnosis.

Therapeutic actions of insulin-like growth factor I on APP/PS2 mice with severe brain amyloidosis.

Transgenic mice expressing mutant forms of both amyloid-beta (Abeta) precursor protein (APP) and presenilin (PS) 2 develop severe brain amyloidosis and cognitive deficits, two pathological hallmarks of Alzheimer's disease (AD). One-year-old APP/PS2 mice with high brain levels of Abeta and abundant Abeta plaques show disturbances in spatial learning and memory. Treatment of these deteriorated mice with a systemic slow-release formulation of insulin-like growth factor I (IGF-I) significantly ameliorated AD-like disturbances. Thus, IGF-I enhanced cognitive performance, decreased brain Abeta load, increased the levels of synaptic proteins, and reduced astrogliosis associated to Abeta plaques. The beneficial effects of IGF-I were associated to a significant increase in brain Abeta complexed to protein carriers such as albumin, apolipoprotein J or transthyretin. Since levels of APP were not modified after IGF-I therapy, and in vitro data showed that IGF-I increases the transport of Abeta/carrier protein complexes through the choroid plexus barrier, it seems that IGF-I favors elimination of Abeta from the brain, supporting a therapeutic use of this growth factor in AD.

Protein kinase C activity modulates dendritic differentiation of rat Purkinje cells in cerebellar slice cultures.

The molecular mechanisms underlying dendritic differentiation in neurons are currently poorly understood. We used slice cultures from rat cerebellum of postnatal day 8 to investigate the effect of protein kinase C (PKC) activity on dendritic development of Purkinje cells. After 12 days in culture under control conditions, Purkinje cells had developed a typical dendritic tree consisting of a few long primary dendrites with shorter side branches. Following treatment with the PKC agonist, phorbol-12-myristate-13-acetate (PMA), the dendritic tree area was strongly reduced to 32% of control and primary dendrites were short with only a few side branches. Delayed addition of PMA after 6 days resulted in a retraction of existing dendrites, whereas discontinuation of PMA treatment after 6 days resulted in a recovery of the dendritic tree to almost control values. In the presence of the PKC inhibitor, 2-[1-(3-dimethylaminopropyl)indol-3-yl]-3-(indol-3-yl)maleimide (GF109203X), the dendritic tree area was increased to 158% of control with much more ramified branches after 12 days. The overall morphology of the cultures and the survival of Purkinje cells were unaffected by PKC modulators. Our data show that increased activity of PKC inhibits, and reduced activity of PKC promotes dendritic growth. This suggests that PKC activity is a critical regulator of dendritic growth and differentiation in cerebellar Purkinje cells.

Sulphonylurea binding in rat isolated glomeruli: pharmacological characterization and dependence on cell metabolism and cytoskeleton.

The kidney is endowed with ATP-sensitive K+ channels (KATP channels) both at the vascular and at the epithelial level. In this study we have characterized the binding of the sulphonylurea glibenclamide, the most widely used blocker of KATP channels, in rat isolated glomeruli. In metabolically intact glomeruli, 3H-glibenclamide labelled two different binding components with affinities of 47 +/- 12 nM and 10 +/- 1 microM and estimated binding capacities of 1.2 +/- 0.1 and 501 +/- 11 pmol/mg protein, respectively. 3H-glibenclamide binding was inhibited differentially by other sulphonylureas (tolbutamide, glibornuride, gliquidone and glipizide) and benzoic acid analogues such as meglitinide, AZ-DF 265 and UL-DF 9. Sulphonylureas interacted with the high affinity component and, in some cases, also with the low affinity component whereas the benzoic acid derivatives inhibited exclusively low affinity glibenclamide binding. Severe metabolic stress affected both components of glibenclamide binding by shifting high affinity binding to the right and reducing the capacity of the low affinity component. Disruption of the cytoskeletal actin filaments by cytochalasin B and D mimicked the effect of metabolic stress on the high affinity component but left the low affinity component unchanged. In crude membranes, the affinity of the first component was again reduced and a major loss of the low affinity sites was observed. The data show that the two binding components of glibenclamide binding in rat isolated glomeruli have very different properties. The high affinity component is not recognized by the benzoic acid derivatives; its affinity is modulated by cell metabolism and the actin component of the cytoskeleton. The low affinity sites are, in their majority, cytosolic. The function and cellular localization of the high affinity sites are under further study.

Binding of [3H]-P1075, an opener of ATP-sensitive K+ channels, to rat glomerular preparations.

ATP-sensitive K+ channels (KATP channels) in the kidney have been found in the tubular system and in the afferent arteriole. In this study we have examined the binding of [3H]-P1075 ([3H]-N-cyano-N'-(1, 1-dimethylpropyl)-N"-3-pyridylguanidine), a selective opener of KATP channels, in rat glomerular preparations. Equilibrium (saturation, competition) and kinetic experiments indicated that [3H]-P1075 binds to a single class of sites with a dissociation constant of about 3 nM and a maximum binding capacity of 10 fmol mg-1 glomerular protein. The association rate constant of the complex was 6,5 x 10(7) M-1 min-1; dissociation occurred with a half-time of 6.2 min. Specific [3H]-P1075 binding was strongly reduced when the metabolic state of the glomerular preparation was impaired during the preparation procedure or the binding assay or when the preparation was subjected to mild collagenase treatment. In different metabolically competent preparations, the amount of specific [3H]-P1075 binding correlated well with the number of vascular endings adherent to the glomeruli; no specific binding was found in mesangial cells in culture. Specific [3H]-P1075 binding was inhibited by representatives of the different classes of KATP channel openers and by sulphonylurea-type blockers with inhibition constants similar to those obtained in rat aortic rings. It is concluded that rat glomerular preparations possess specific binding sites for KATP channel openers with vascular characteristics. The sensitivity of binding to mild collagenase treatment suggests that these sites are located on a membrane protein; in addition, the data suggest that these sites are localized on smooth muscle and/or renin secreting cells of the afferent vascular endings attached to some of the glomeruli. Their estimated density (1,500 microns-2) is much higher than that of KATP channels in smooth muscle.

[Intraoperative diagnosis of the heart and great vessels--echocardiography]. / Intraoperative Diagnostik des Herzens und der herznahen grossen Gefässe--Echokardiographie.

Two-dimensional echocardiography including color Doppler techniques can be used for analysis of the morphology and function and of the blood flow of the heart and the great vessels. Epicardial echocardiography has the advantage of high resolution and multiple scan planes. The restriction to the intraoperative period is a clear disadvantage. In addition, the scan planes are difficult to standardize. Transesophageal echocardiography can be used for monitoring during the whole operative period but is restricted to horizontal and/or longitudinal scan planes. It is a non-contact procedure and thus, sterile conditions are not affected. For evaluation of surgical success, intraoperative echocardiography can be used for analysis in patients with congenital heart disease, mitral valve regurgitation, hypertrophic obstructive cardiomyopathy, and aortic dissection. Acute intraoperative revisions with a second extracorporal circulation period will avoid reoperation. In patients with coronary artery disease the flow within the bypass and also the status of the anastomosis can be scanned and may contribute to reduce the perioperative infarct rate. Intraoperative echocardiography needs additional costs and man power. Only after randomized comparative prospective studies have demonstrated that patients controlled by intraoperative echocardiography have a better outcome and prognosis than patients without intraoperative control this method will become routine in open-heart surgery.

[Manual labor and Dupuytren disease. The results of a computerized survey in the field of iron metallurgy]. / Travail manuel et maladie de Dupuytren. Résultat d'une enquête informatisée en milieu sidérurgique.

A survey was made among ironworkers to determine if manual work had a special influence on the onset of Dupuytren's disease. In 5,206 workmen examined, 196 were affected, and a careful study of their working conditions showed a definite correlation between hard manual work over many years and the occurrence of Dupuytren's disease, especially in the younger age group. We observed that familial arterial hypertension is a contributory factor. Although Dupuytren's disease cannot be considered as an occupational disease, its development, is favored by hard manual work for at least 10 years. The initiating role of trauma, especially a fracture of the wrist, is confirmed.