Syphilis. Therapie

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Discharge patterns of bulbar respiratory neurons in response to the morphinomimetic agent, fentanyl, in chloralosed dogs

In anaesthetized, paralysed and artificially ventilated dogs, activities were recorded from the phrenic nerve and from respiratory units within the nucleus tractus solitarii (nTS), the nucleus ambiguus (nA) and the nucleus retroambigualis (nRA). The respiratory neurons were classified according to their discharge pattern and their response to lung inflation. Fentanyl injected into the vertebral artery (0.5-2 micrograms/kg) or intravenously (10 micrograms/kg) produced a depressant effect on the phrenic nerve motoneurons, on inspiratory cells (I alpha and I beta) and on phase-spanning expiratory-inspiratory neurons of the nTS and the nA. The duration of the inspiratory burst increased and the number of spikes and the peak activity were reduced. This pattern of inhibition was followed by complete blockade of spike genesis. Fentanyl also altered expiratory neurons: the duration of the expiratory discharge was enhanced. An increase followed by a decrease in the number of spikes per burst and a reduction in the peak activity were observed. When the phrenic nerve was silent, continuous discharges appeared. High doses of fentanyl were needed to inhibit these tonic discharges. This pattern of inhibition concerns late peak expiratory units, expiratory units with a constant discharge pattern and the phase-spanning inspiratory-expiratory neurons. Naloxone antagonized these effects but induced the appearance of tonic discharges in fentanyl-treated phase-spanning expiratory-inspiratory neurons. Stimulation of peripheral chemoreceptors with almitrine (0.2 mg/kg i.v.) antagonized the effects of fentanyl. In addition, fentanyl facilitated the lung inflation reflex on respiratory neurons.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prolongation of culture-isolated neonatal islet xenografts without immunosuppression

Xenogeneic transplantation of 300-400 neonatal rat islets (Fischer 344) to the kidney subcapsular site of streptozotocin-induced nonimmunosuppressed diabetic adult mice (C57BL/6ByJ) resulted in a return to normoglycemia in 87% of the recipients. Of the 13 successfully reversed recipients, 5 exhibited graft rejection (hyperglycemia of +250 mg/dl) within 2 weeks posttransplantation, and 2 mice had rejected their rat islets by 3 weeks. The 6 remaining recipients exhibited significantly prolonged survival of the cultured islets: 1 remained reversed until 4 weeks posttransplantation, 2 remained normoglycemic for 5 weeks, in 3 diabetes remained reversed for more than 7 weeks--in one of these animals the disease was reversed for 17 weeks. Transplanted islets were isolated from neonatal rat pancreas during a period in culture that varied from 8 to 17 days. Although morphological integrity of the endocrine cells was confirmed by ultrastructural study, nonendocrine cells were not identifiable within the islets after 8 days of culture. Xenografted islets examined morphologically prior to obtaining physiological evidence of rejection were associated with extensive peripheral lymphocytic accumulation. Modification of islet immunogenicity leading to prolonged xenograft survival may reflect the degree to which the in vitro environment permits the differential survival of endocrine cells while purging the islet of cells initiating the immune response.     

Targeting angiogenesis in ovarian cancer

Results of standard chemotherapy in ovarian cancer are hampered by the development of drug resistance leading to disease recurrence. This prompted interest in the development of therapies targeting critical pathways responsible for tumor progression. Angiogenesis is a key process that enables ovarian cancer growth and metastasis in the peritoneal space. Its regulation relies on signaling mechanisms initiated by the vascular endothelial growth factor, the platelet-derived growth factor, the fibroblast growth factor, angiopoietins, and others. These pathways are not only important to the modulation of the tumor microenvironment and vasculature, but also control cancer cell proliferation and survival. In this review, we discuss preclinical evidence supporting the rationale for inhibiting these pathways and provide an overview for the clinical development of agents targeting them. Clinical trials evaluating such agents alone and in combination with chemotherapy are ongoing. Early clinical results position antiangiogenic therapy at the forefront of change to the standard treatment of difficult to treat ovarian cancer.     

Vécu subjectif de la maladie et de la guérison chez 13 adolescents et jeunes adultes traités pour une hémopathie maligne dans l’enfance

The authors report the results of a study conducted in 2010, which consisted meeting, through a semi-structured interview, 13 adolescents or young adults medically cured of childhood haematological malignancies, treated in the department of haematology at the Children’s Hospital of Nancy. The objective is to explore the experience of illness and treatment, especially the experience of recovery. Some of them present significant distress in various subjects. Thus, body image and self-esteem are often altered among these young patients. Concerns about possible infertility or severe sexual dysfunction are found. Ambivalence about their future parenting emerges from their speech. These elements are obstacles to the recovery process. A follow-up psychological consultation could be provided in a systematic way by a professional trained in these specific problems.     

The role of histone demethylases in cancer therapy

Reversible histone methylation has emerged in the last few years as an important mechanism of epigenetic regulation. Histone methyltransferases and demethylases have been identified as contributing factors in the development of several diseases, especially cancer. Therefore, they have been postulated to be new drug targets with high therapeutic potential. Here, we review histone demethylases with a special focus on their potential role in oncology drug discovery. We present an overview over the different classes of enzymes, their biochemistry, selected data on their role in physiology and already available inhibitors.     

Structure of the processive rubber oxygenase RoxA from Xanthomonas sp

Rubber oxygenase A (RoxA) is one of only two known enzymes able to catalyze the oxidative cleavage of latex for biodegradation. RoxA acts as a processive dioxygenase to yield the predominant product 12-oxo-4,8-dimethyl-trideca-4,8-diene-1-al (ODTD), a tri-isoprene unit. Here we present a structural analysis of RoxA from Xanthomonas sp. strain 35Y at a resolution of 1.8 Å. The enzyme is a 75-kDa diheme c-type cytochrome with an unusually low degree of secondary structure. Analysis of the heme group arrangement and peptide chain topology of RoxA confirmed a distant kinship with diheme peroxidases of the CcpA family, but the proteins are functionally distinct, and the extracellular RoxA has evolved to have twice the molecular mass by successively accumulating extensions of peripheral loops. RoxA incorporates both oxygen atoms of its cosubstrate dioxygen into the rubber cleavage product ODTD, and we show that RoxA is isolated with O₂ stably bound to the active site heme iron. Activation and cleavage of O₂ require binding of polyisoprene, and thus the substrate needs to use hydrophobic access channels to reach the deeply buried active site of RoxA. The location and nature of these channels support a processive mechanism of latex cleavage.