Granulocyte-macrophage colony-stimulating factor elicits bone marrow-derived cells that promote efficient colonic mucosal healing.

BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy is effective in treating some Crohn's disease (CD) patients and protects mice from colitis induced by dextran sulfate sodium (DSS) administration. However, its mechanisms of action remain elusive. We hypothesized that GM-CSF affects intestinal mucosal repair. METHODS: DSS colitic mice were treated with daily pegylated GM-CSF or saline and clinical, histological, and inflammatory parameters were kinetically evaluated. Further, the role of bone marrow-derived cells in the impact of GM-CSF therapy on DSS colitis was addressed using cell transfers. RESULTS: GM-CSF therapy reduced clinical signs of colitis and the release of inflammatory mediators. GM-CSF therapy improved mucosal repair, with faster ulcer reepithelialization, accelerated hyperproliferative response of epithelial cells in ulcer-adjacent crypts, and lower colonoscopic ulceration scores in GM-CSF-administered mice relative to untreated mice. We observed that GM-CSF-induced promotion of mucosal repair is timely associated with a reduction in neutrophil numbers and increased accumulation of CD11b(+) monocytic cells in colon tissues. Importantly, transfer of splenic GM-CSF-induced CD11b(+) myeloid cells into DSS-exposed mice improved colitis, and lethally irradiated GM-CSF receptor-deficient mice reconstituted with wildtype bone marrow cells were protected from DSS-induced colitis upon GM-CSF therapy. Lastly, GM-CSF-induced CD11b(+) myeloid cells were shown to promote in vitro wound repair. CONCLUSIONS: Our study shows that GM-CSF-dependent stimulation of bone marrow-derived cells during DSS-induced colitis accelerates colonic tissue repair. These data provide a putative mechanism for the observed beneficial effects of GM-CSF therapy in Crohn's disease.

Induction of oxidative stress, lysosome activation and autophagy by nanoparticles in human brain-derived endothelial cells.

Different types of NPs (nanoparticles) are currently under development for diagnostic and therapeutic applications in the biomedical field, yet our knowledge about their possible effects and fate in living cells is still limited. In the present study, we examined the cellular response of human brain-derived endothelial cells to NPs of different size and structure: uncoated and oleic acid-coated iron oxide NPs (8-9 nm core), fluorescent 25 and 50 nm silica NPs, TiO2 NPs (21 nm mean core diameter) and PLGA [poly(lactic-co-glycolic acid)]-PEO [poly(ethylene oxide)] polymeric NPs (150 nm). We evaluated their uptake by the cells, and their localization, generation of oxidative stress and DNA-damaging effects in exposed cells. We show that NPs are internalized by human brain-derived endothelial cells; however, the extent of their intracellular uptake is dependent on the characteristics of the NPs. After their uptake by human brain-derived endothelial cells NPs are transported into the lysosomes of these cells, where they enhance the activation of lysosomal proteases. In brain-derived endothelial cells, NPs induce the production of an oxidative stress after exposure to iron oxide and TiO2 NPs, which is correlated with an increase in DNA strand breaks and defensive mechanisms that ultimately induce an autophagy process in the cells.

Auditing the management of vaccine-preventable disease outbreaks: the need for a tool

Public health activities, especially infectious disease control, depend on effective teamwork. We present the results of a pilot audit questionnaire aimed at assessing the quality of public health services in the management of VPD outbreaks. Audit questionnaire with three main areas indicators (structure, process and results) was developed. Guidelines were set and each indicator was assessed by three auditors. Differences in indicator scores according to median size of outbreaks were determined by ANOVA (significance at p (greater than or equal to) 0.05). Of 154 outbreaks; eighteen indicators had a satisfactory mean score, indicator "updated guidelines" and "timely reporting" had a poor mean score (2.84±106 and 2.44±1.67, respectively). Statistically significant differences were found according to outbreak size, in the indicators "availability of guidelines/protocol updated less than 3 years ago" (p = 0.03) and "days needed for outbreak control" (p = 0.04). Improving availability of updated guidelines, enhancing timely reporting and adequate recording of control procedures taken is needed to allow for management assessment and improvement.

[Voyage en Italie : 1824-1830]. , [Voie des Tombeaux : tombeau dit "des Guirlandes"] : [détails d'élévation, élèvation principale] : [dessin] / h. L. [Henri Labrouste]

Référence bibliographique : Weigert, 441

Structure and kinematics of the Jungfrau syncline, Faflertal (Valais, Alps), and its regional significance

The formation and structural evolution of the jungrau syncline is described, based on excellent outcrops occurring in the lotschental, in the central alps of switzerland. the quality of the outcrops allows us to demonstrate that the external massifs of the swiss alps have developed due to internal folding. The jungfrau suncline, which separates the autochtonous gastern dome from the aar massif basement gneiss folds, is composed of slivers of basement rocks with their mesozoic sedimentary cover. in the inner faflertal, a side valley of the lotschental, the 200 m thick syncline cp, roses fpir imots, the gastern massif with a reduced mesozoic sedimentary cover in a normal stratigraphic succession, two units of overturned basement rocks with their mesozoic sedimentary cover, and the overturned lower limn of the tschingelhorn gneiss fold of the aar massif with lenses of its sedimentary cover. stratigraphy shows that the lower units, related to the gastern massis, are condensed and that the upper units, deposited farther away from a gastern paleo-high, form a more complete sequence, linked to the doldenhorn meso-cneozoic basin fill. the integration of these local observations with published regional data leads to the following model. on the northern margin of the doldenhorn hbasin, at the northern fringe of the alpine tethuys, the pre-triassic crystalline basement and its mesozoic sedimentary cover were folded by ductile deformation at temperatures above 300 degrees C and in the presence of high fluid pressures, as the helveti c and penninic nappes were overthrusted towards the northwest during the main alpine deformation phase, the visosity contrast between the basement gneisses and the sediments caused the formation of large basement anticlines and tight sedimentary sunclines (mullion-type structures). The edges of basement blocks bounded buy pre-cursor se-dipping normal faults at the northwestern border of the doldenhorn basin were deformed bu simple shear, creating overturned slices of crystalline rocks with their sedimentary cover in what now forms the hungfrau syncline. the localisation of ductile deformation in the vicinity of pre-existing se-dipping faults is thought to have been helped by the circulation of fluids along the faults; these fluids would have been released from the mesozoic sediments by metamorphic dehydration reactions accompanied by creep and dynamic recrystallisation of quartz at temperatures above 300 degrees C. Quantification of the deformation suggests an strain ellipsoid with a ratio (1 + e(1)/+ e(3)) of approximately 1000. The jungfrau suncline was deformed bu more brittle nw-directed shear creating well-developed shear band cleavages at a late stage, after cooling by uplift and erosion. It is suggested that the external massifs of the apls are basement gneiss folds created at temperatures of 300 degrees C by detachment through ductile deformation of the upper crust of the european plate as it was underthrusted below the adriatic plate.

A multicentre, retrospective case-control study assessing the role of trabecular bone score (TBS) in menopausal Caucasian women with low areal bone mineral density (BMDa): Analysing the odds of vertebral fracture.

INTRODUCTION: The trabecular bone score (TBS) is a new parameter that is determined from grey level analysis of DXA images. It relies on the mean thickness and volume fraction of trabecular bone microarchitecture. This was a preliminary case-control study to evaluate the potential diagnostic value of TBS, both alone and combined with bone mineral density (BMDa), in the assessment of vertebral fracture. METHODS: Out of a subject pool of 441 Caucasian, postmenopausal women between the ages of 50 and 80 years, we identified 42 women with osteoporosis-related vertebral fractures, and compared them with 126 age-matched women without any fractures (1 case: 3 controls). Primary outcomes were BMDa and TBS. Inter-group comparisons were undertaken using Student's t-tests and Wilcoxon signed ranks tests for parametric and non-parametric data, respectively. Odds ratios for vertebral fracture were calculated for each incremental one standard deviation decrease in BMDa and TBS, and areas under the receiver operating curve (AUC) calculated and sensitivity analysis were conducted to compare BMDa alone, TBS alone, and the combination of BMDa and TBS. Subgroup analyses were performed specifically for women with osteopenia, and for women with T-score-defined osteoporosis. RESULTS: Across all subjects (n=42, 126) weight and body mass index were greater and BMDa and TBS both less in women with fractures. The odds of vertebral fracture were 3.20 (95% CI, 2.01-5.08) for each incremental decrease in TBS, 1.95 (1.34-2.84) for BMDa, and 3.62 (2.32-5.65) for BMDa + TBS combined. The AUC was greater for TBS than for BMDa (0.746 vs. 0.662, p=0.011). At iso-specificity (61.9%) or iso-sensitivity (61.9%) for both BMDa and TBS, TBS + BMDa sensitivity or specificity was 19.1% or 16.7% greater than for either BMDa or TBS alone. Among subjects with osteoporosis (n=11, 40) both BMDa (p=0.0008) and TBS (p=0.0001) were lower in subjects with fractures, and both OR and AUC (p=0.013) for BMDa + TBS were greater than for BMDa alone (OR=4.04 [2.35-6.92] vs. 2.43 [1.49-3.95]; AUC=0.835 [0.755-0.897] vs. 0.718 [0.627-0.797], p=0.013). Among subjects with osteopenia, TBS was lower in women with fractures (p=0.0296), but BMDa was not (p=0.75). Similarly, the OR for TBS was statistically greater than 1.00 (2.82, 1.27-6.26), but not for BMDa (1.12, 0.56-2.22), as was the AUC (p=0.035), but there was no statistical difference in specificity (p=0.357) or sensitivity (p=0.678). CONCLUSIONS: The trabecular bone score warrants further study as to whether it has any clinical application in osteoporosis detection and the evaluation of fracture risk.

The glucose transporter 4 FQQI motif is necessary for Akt Substrate of 160-Kilodalton-dependent plasma membrane translocation but not Golgi-localized g-ear-containing Arf-binding protein-dependent entry into the insulin-responsive storage compartment.

Newly synthesized glucose transporter 4 (GLUT4) enters into the insulin-responsive storage compartment in a process that is Golgi-localized γ-ear-containing Arf-binding protein (GGA) dependent, whereas insulin-stimulated translocation is regulated by Akt substrate of 160 kDa (AS160). In the present study, using a variety of GLUT4/GLUT1 chimeras, we have analyzed the specific motifs of GLUT4 that are important for GGA and AS160 regulation of GLUT4 trafficking. Substitution of the amino terminus and the large intracellular loop of GLUT4 into GLUT1 (chimera 1-441) fully recapitulated the basal state retention, insulin-stimulated translocation, and GGA and AS160 sensitivity of wild-type GLUT4 (GLUT4-WT). GLUT4 point mutation (GLUT4-F5A) resulted in loss of GLUT4 intracellular retention in the basal state when coexpressed with both wild-type GGA and AS160. Nevertheless, similar to GLUT4-WT, the insulin-stimulated plasma membrane localization of GLUT4-F5A was significantly inhibited by coexpression of dominant-interfering GGA. In addition, coexpression with a dominant-interfering AS160 (AS160-4P) abolished insulin-stimulated GLUT4-WT but not GLUT4-F5A translocation. GLUT4 endocytosis and intracellular sequestration also required both the amino terminus and large cytoplasmic loop of GLUT4. Furthermore, both the FQQI and the SLL motifs participate in the initial endocytosis from the plasma membrane; however, once internalized, unlike the FQQI motif, the SLL motif is not responsible for intracellular recycling of GLUT4 back to the specialized compartment. Together, we have demonstrated that the FQQI motif within the amino terminus of GLUT4 is essential for GLUT4 endocytosis and AS160-dependent intracellular retention but not for the GGA-dependent sorting of GLUT4 into the insulin-responsive storage compartment.

Isolated disturbance of written language-acquisition as an initial symptom of epileptic aphasia in a 7-year-old child - a 3-year follow-up-study

A 7-year-old right-handed girl developed partial complex seizures with a left-sided onset. A brief period of post-ictal aphasia of the conduction type was documented before seizure control and complete normalization of oral language were obtained. We also found that she had a history of previous unexplained difficulty with written language acquisition that had occurred prior to the clinically recognized epilepsy and a subsequent loss of this ability. This rapidly improved with control of the epilepsy. The evolution of written language were been followed for 3 years, and continued improvement has occurred with fluctuations related to her epilepsy. This observation adds support to the growing body of data indicating that specific cognitive disturbances can be due to epilepsy in young children. It shows the vulnerability of skills which are in a period of active development, and the possibility that oral/written language can be differentially involved by cerebral dysfunction in the young child.

Incidência de viroses e enfezamentos e estimativa de perdas causadas por molicutes em milho no Paraná

O objetivo deste trabalho foi avaliar a incidência de viroses e enfezamentos e estimar as perdas causadas por enfezamentos na cultura do milho safrinha. Os diagnósticos baseados em sintomas foram confirmados por PCR ou RTPCR. Em todas as lavouras, foram identificadas plantas com sintomas de enfezamentos, em incidência de 6,2% a 49,9% (média de 20,7%). Na identificação de insetos vetores desses patógenos, a cigarrinha Dalbulus maidis foi detectada em 20 lavouras das 24 amostradas, constituindo 66,6% do total de espécimens de cigarrinhas coletadas. A perda potencial causada pelos enfezamentos no período foi estimada em cerca de 16,5 milhões de dólares. A ocorrência de plantas com sintomas de "Maize rayado fino virus" e "Maize dwarf mosaic virus" foi baixa e o diagnóstico confirmado por RTPCR. A análise de 441 amostras suspeitas de infecção por "Mal de Río Cuarto virus", por DASELISA, mostrou ausência desse vírus. Resultados de PCR indicaram a presença de um possível fitoplasma distinto de "Maize bushy stunt phytoplasma" em duas plantas apresentando nanismo acentuado, folhas estreitas, enrijecidas, com deformações, e grãos na inflorescência, havendo necessidade de mais estudos para a confirmação da identidade desse possível novo fitoplasma.

Meédicaments: une cause sous-estimée d'hypertension artérielle [Drugs: an underestimated cause of arterial hypertension].

In Switzerland, as in other Occidental countries, the prevalence of arterial hypertension (AHT) in the adult population is around 30-40%. Among the causes of secondary AHT, drug induced hypertension is sometimes omitted. Many molecules can induce AHT or worsen it due to an interaction with anti hypertensive drugs. Among these, NSAIDs and anti depressants, widely prescribed, should be used with caution, particularly in patients at risk, namely: those with preexisting AHT, the elderly, or patients suffering from kidney disease, diabetes, and/or heart failure. Increases in blood pressure have also been described with anti-vascular endothelial growth factor (VEGF) drugs, used in the treatment of (metastatic) cancer. A thorough anamnesis of drugs, including over the counter ones, should be performed in every hypertensive patient, and can avoid cumbersome and unnecessary investigations and therapy.

Nouveaux aspects de la prise en charge de l'hypertension artérielle chez le patient insuffisant rénal chronique [New aspects of hypertension management in patients with chronic kidney disease].

Hypertension is a frequent finding in patients with chronic kidney disease. Whether primary or secondary to renal disease, hypertension remains an important risk factory for the progression of chronic kidney disease and the occurrence of cardiovascular events. The objective of this paper is to review different treatment strategies in hypertensive CKD patients, with the exclusion of patients with renal replacement therapy such as dialysis or renal transplantation.

Role of reactive hyperreninemia in blood pressure changes induced by sodium depletion in patients with refractory hypertension

Sixteen patients with refractory hypertension were submitted to vigorous sodium depletion while cardiovascular homeostasis was monitored with measurements of hormonal and hemodynamic parameters and repeat saralasin tests. This regimen resulted in a negative sodium balance by an average of 300 mEq. The loss of sodium closely correlated to the decrease of body weight (r = 0.70, p less than 0.005). Blood pressure (BP) decreased from 176/166 +/- 8/3 to 155/109 +/-6/3 mm Hg. There was a significant correlation between percent increments in plasma renin activity (PRA) and the rise in plasma norepinephrine (r = 0.68, p less than 0.05) and a close negative correlation between percent increase in PRA and the ratio of fall in mean blood pressure (MAP) per unit of weight loss (r = -0.73, p less than 0.005). Thus, patients with the least percent increase in PRA demonstrated the greatest fall in BP per unit of weight loss, indicating that relative rather than absolute elevation of renin may be the factor limiting antihypertensive efficacy of sodium depletion. Sodium depletion induced increase in peripheral resistance and decrease in cardiac output, both mostly attributable to relative hyperreninemia. Indeed, the adverse hemodynamic changes were reversed by angiotensin inhibition, during which BP normalized. It is concluded that vigorous sodium depletion complemented by angiotensin blockade or suppression with sympatholytic agents improves management of otherwise refractory hypertension.

Interruptions of cART limits CD4 T-cell recovery and increases the risk for opportunistic complications and death.

BACKGROUND: A major goal of antiretroviral therapy (ART) for HIV-1-infected persons is the recovery of CD4 T lymphocytes, resulting in thorough protection against opportunistic complications. Interruptions of ART are still frequent. The long-term effect on CD4 T-cell recovery and clinical events remains unknown. METHODS: Immunological and clinical endpoints were evaluated in 2491 participants of the Swiss HIV Cohort Study initiating ART during a mean follow-up of 7.1 years. Data were analysed in persons with treatment interruptions (n = 1271; group A), continuous ART, but intermittent HIV-1 RNA at least 1000 copies/ml (n = 469; group B) and continuous ART and HIV-1 RNA constantly less than 1000 copies/ml (n = 751; group C). Risk factors for low CD4 T-cell counts and clinical events were analysed using Cox proportional hazards models. RESULTS: In groups A-C, CD4 T lymphocytes increased to a median of 427, 525 and 645 cells/μl at 8 years. In group A, 63.0 and 37.2% reached above 350 and 500 CD4 T cells/μl, whereas in group B 76.3 and 55.8% and in group C 87.3 and 68.0% reached these thresholds (P < 0.001). CD4 T-cell recovery directly depended on the cumulative duration of treatment interruptions. In addition, participants of group A had more Centers for Disease Control and Prevention B/C events, resulting in an increased risk of death. Major risk factors for not reaching CD4 T cells above 500 cells/μl included lower baseline CD4 T-cell count, higher age and hepatitis C virus co-infection. CONCLUSION: In persons receiving continuous ART larger CD4 T-cell recovery and a reduced risk for opportunistic complications and death was observed. CD4 T-cell recovery was smaller in persons with treatment interruptions more than 6 months.