Complex Tracheocarinal Reconstructions Using Extrathoracic Muscle Flaps as Airway Substitutes

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Erythropoietin promotes Schwann cell migration and assembly of the provisional extracellular matrix by recruiting β1 integrin to the cell surface

In peripheral nerve injury, Schwann cells undergo profound phenotypic modulation, adopting a migratory phenotype and remodeling the extracellular matrix so that it is permissive for axonal regrowth. Erythropoietin (Epo) and its receptor (EpoR) are expressed by Schwann cells after nerve injury, regulating inflammatory cytokine expression and minimizing the duration of neuropathic pain. The mechanism of Epo activity in the injured peripheral nerve remains incompletely understood. Herein, we demonstrate that Epo promotes Schwann cell migration in vitro on fibronectin (FN)‐coated surfaces. Epo also rapidly recruits β1 integrin subunit to the Schwann cell surface by a JAK‐2‐dependent pathway. Although β1 integrin subunit‐containing integrins were not principally responsible for Schwann cell adhesion or migration on FN under basal conditions, β1 gene‐silencing blocked the ability of Epo to promote cell migration. Epo also induced Schwann cell FN expression in vitro and in vivo. The FN was organized into insoluble fibrils by Epo‐treated Schwann cells in vitro and into an extensive matrix surrounding Schwann cells in vivo. Our results support a model in which Epo promotes Schwann cell migration and assembly of the provisional extracellular matrix in the injured peripheral nerve by its effects on integrin recruitment to the cell surface and local FN production. © 2009 Wiley‐Liss, Inc.     

The 14C, 13C,and 15N syntheses of a potent VEGFR‐2 kinase inhibitor,Brivanib, and its prodrug,Brivanib Alaninate

The interruption of tyrosine kinase vascular endothelial growth factor receptor‐2 (VEGFR‐2) signaling by the binding of a small molecule inhibitor, for example, Brivanib, to VEGFR‐2 kinase domain has been shown as an effective method of slowing angiogenesis and tumor progression. [¹⁴C]Brivanib, 13 and its prodrug [¹⁴C]Brivanib Alaninate, 15 were prepared to support preclinical and clinical studies. Their respective stable isotope‐labeled versions, [¹³CN₂]Brivanib, 21 and [¹³CN₂]Brivanib Alaninate, 28, were also prepared to support bioanalytical LC‐MS analyses of clinical samples. All of the four title compounds were synthetically derived from the respective isotopically labeled common pyrrolotriazinone intermediate, 6 or 16. This labeled central core pyrrolotriazinone was also conveniently used to synthesize other structurally related drug discovery candidates. Copyright © 2011 John wiley & Sons, Ltd.     

GEMSP: A New Therapeutic Approach to Multiple Sclerosis

A new therapeutic approach called Endotherapia (GEMSP) for the treatment of Multiple Sclerosis (MS) is suggested. Endotherapia is the result of an immunopathological strategy addressing chronic incurable diseases with a multifactorial etiology. This approach combines a biomedical evaluation of circulating immunoglobulins directed against specific self-antigens and self-antigens modified by free radicals. GEMSP is a "tailor-made" combination of small molecules (fatty acids, antioxidants, radical scavengers, amino acids) linked to a non-immunogenic linear chain of poly-L.lysine (PLL). Each individual linkage or PLL derivative offers great advantages, such as an increase in the half-life of the active small molecules. GEMSP inhibits brain leukocyte infiltration and abolishes episodes of experimental autoimmune encephalomyelitis. In a clinical trial with 102 MS patients treated with GEMSP Endotherapia, 28% of them showed a worsening of their state; 20% showed a decrease in the progression of the disease; 17% showed disease stabilization; and 35% showed a reversal of the evolution of disease; i.e., an improvement in their disease state. In 72% of the cases, a positive evolution of the state of the MS patients treated with Endotherapia was observed (a decrease or stabilization of disease evolution or an improvement). Endotherapia is very safe and no side-effects were reported for GEMSP. Moreover, GEMSP showed no toxicity either in experimental animals or in humans. It seems that Endotherapia is a promising therapy for MS, with no side-effects, which should be considered in the management of long-term pathologies.     

Multiscale responses of microbial life to spatial distance and environmental heterogeneity in a patchy ecosystem

Spatial distance (SD) and environmental heterogeneity (EH) are currently thought to represent major factors shaping genetic variation and population abundance, but their relative importance is still poorly understood. Because EH varies at multiple spatial scales, so too are microbial variables expected to vary. The determination of SD x EH interactions at multiple scales is, however, not a trivial exercise, especially when one examines their effects on microbial abundance and genomic similarities. Here we assessed those interactions at all scales perceptible in a patchy environment composed of known plant species and of heterogeneous soil physical and chemical parameters. For free-living, soil-borne Burkholderia ambifaria, genomic similarities responded to most of the spatial scales that the experimental sampling scheme could reveal, despite limited dispersal of the individuals. Species abundance and community composition were, however, responding to much smaller scales more consistent with local responses to EH. Our results suggest that whole-genome similarities may reflect the simultaneous effects of both SD and EH in microbial populations, but the pure effects of each factor only contributed to < 2% of the total genetic variation. The large amount of unexplained variation that remains after considering most environmental, spatial, and biological interactions is then posited to be the result of noise introduced by unmeasured environmental and spatial variability, sampling effects, and neutral ecological drift.     

Decrease in the stroke case fatality rates in a French population-based twenty-year study. A comparison between men and women

BACKGROUND: The aim of the study was to estimate trends in stroke case fatality in a French population-based study over the last 20 years, and to compare trends in men and women. METHODS: We prospectively ascertained first-ever strokes in a well-defined population-based study, from 1985 to 2004, in Dijon (France) (150,000 inhabitants). The study was both specific and exhaustive. The follow-up made it possible to analyze case fatality, according to stroke subtypes and sex. RESULTS: From the ascertainment of 3,691 strokes divided in 1,920 cerebral infarcts from large artery atheroma, 725 cerebral infarcts from small perforating artery atheroma, 497 cardioembolic infarcts, 134 cerebral infarcts from undetermined mechanism, 341 primary cerebral hemorrhages and 74 subarachno?d hemorrhages, we observed a significant decrease in 28-day case fatality rates of almost 25% (p = 0.03). Case fatality rates decreased in men aged >75 years (p = 0.01) and in women aged >75 years (p = 0.02) and >65 years (p = 0.03). The magnitude of the decrease was smaller in women but not significantly so. According to stroke subtypes, case fatality rates significantly decreased for small perforating artery infarct (p = 0.04) and for primary cerebral hemorrhage (p = 0.03). In multivariate regression analyses, hemorrhagic stroke, the first period of the study (1985-1989), blood hypertension, previous myocardial infarction and age <85 years had a negative effect. CONCLUSION: This is the first population-based study using continuous ascertainment over a period of 20 years that has demonstrated a significant reduction in case fatality rates. We did not observe any significant differences between men and women.     

GCH1, BH4 and pain

Understanding and consequently treating neuropathic pain effectively is a challenge for modern medicine, as unlike inflammation, which can be controlled relatively well, chronic pain due to nerve injury is refractory to most current therapeutics. Here we define a target pathway for a new class of analgesics, tetrahydrobiopterin (BH4) synthesis and metabolism. BH4 is an essential co-factor in the synthesis of serotonin, dopamine, epinephrine, norepinephrine and nitric oxide and as a result, its availability influences many systems, including neurons. Following peripheral nerve damage, levels of BH4 are dramatically increased in sensory neurons, consequently this has a profound effect on the physiology of these cells, causing increased activity and pain hypersensitivity. These changes are principally due to the upregulation of the rate limiting enzyme for BH4 synthesis GTP Cyclohydrolase 1 (GCH1). A GCH1 pain-protective haplotype which decreases pain levels in a variety of settings, by reducing the levels of endogenous activation of this enzyme, has been characterized in humans. Here we define the control of BH4 homeostasis and discuss the consequences of large perturbations within this system, both negatively via genetic mutations and after pathological increases in the production of this cofactor that result in chronic pain. We explain the nature of the GCH1 reduced-function haplotype and set out the potential for a ' BH4 blocking' drug as a novel analgesic.