Bupivacaine-induced cellular entry of QX-314 and its contribution to differential nerve block

Background and Purpose: Selective nociceptor fibre block is achieved by introducing the cell membrane impermeant sodium channel blocker lidocaine N-ethyl bromide (QX-314) through transient receptor potential V1 (TRPV1) channels into nociceptors. We screened local anaesthetics for their capacity to activate TRP channels, and characterized the nerve block obtained by combination with QX-314.Experimental Approach: We investigated TRP channel activation in dorsal root ganglion (DRG) neurons by calcium imaging and patch-clamp recordings, and cellular QX-314 uptake by MS. To characterize nerve block, compound action potential (CAP) recordings from isolated nerves and behavioural responses were analysed.Key Results: Of the 12 compounds tested, bupivacaine was the most potent activator of ruthenium red-sensitive calcium entry in DRG neurons and activated heterologously expressed TRPA1 channels. QX-314 permeated through TRPA1 channels and accumulated intracellularly after activation of these channels. Upon sciatic injections, QX-314 markedly prolonged bupivacaine''s nociceptive block and also extended (to a lesser degree) its motor block. Bupivacaine''s blockade of C-, but not A-fibre, CAPs in sciatic nerves was extended by co-application of QX-314. Surprisingly, however, this action was the same in wild-type, TRPA1-knockout and TRPV1/TRPA1-double knockout mice, suggesting a TRP-channel independent entry pathway. Consistent with this, high doses of bupivacaine promoted a non-selective, cellular uptake of QX-314.Conclusions and Implications: Bupivacaine, combined with QX-314, produced a long-lasting sensory nerve block. This did not require QX-314 permeation through TRPA1, although bupivacaine activated these channels. Regardless of entry pathway, the greatly extended duration of block produced by QX-314 and bupivacaine may be clinically useful.     

Bevacizumab with angiostatin-armed oHSV increases antiangiogenesis and decreases bevacizumab-induced invasion in U87 glioma

Bevacizumab (BEV) is an antiangiogenic drug approved for glioblastoma (GBM) treatment. However, it does not increase survival and is associated with glioma invasion. Angiostatin is an antiangiogenic polypeptide that also inhibits migration of cancer cells, but is difficult to deliver. Oncolytic viruses (OV) can potentially spread throughout the tumor, reach isolated infiltrating cells, kill them and deliver anticancer agents to uninfected cells. We have tested a combination treatment of BEV plus an OV expressing angiostatin (G47Δ-mAngio) in mice-bearing human GBM. Using a vascular intracranial human glioma model (U87) in athymic mice, we performed histopathological analysis of tumors treated with G47Δ-mAngio or BEV alone or in combination, followed tumor response by magnetic resonance imaging (MRI), and assessed animal survival. Our results indicate that injection of G47Δ-mAngio during BEV treatment allows increased virus spread, tumor lysis, and angiostatin-mediated inhibition of vascular endothelial growth factor (VEGF) expression and of BEV-induced invasion markers (matrix metalloproteinases-2 (MMP2), MMP9, and collagen). This leads to increased survival and antiangiogenesis and decreased invasive phenotypes. We show for the first time the possibility of improving the antiangiogenic effect of BEV while decreasing the tumor invasive-like phenotype induced by this drug, and demonstrate the therapeutic advantage of combining systemic and local antiangiogenic treatments with viral oncolytic therapy.     

Early window of diabetes determinism in NOD mice, dependent on the complement receptor CRIg, identified by noninvasive imaging

All juvenile mice of the nonobese diabetic (NOD) strain develop insulitis, but there is considerable variation in their progression to diabetes. Here we used a strategy based on magnetic resonance imaging (MRI) of magnetic nanoparticles to noninvasively visualize local effects of pancreatic-islet inflammation to predict the onset of diabetes in NOD mice. MRI signals acquired during a narrow early time window allowed us to sort mice into groups that would progress to clinical disease or not and to estimate the time to diabetes development. We exploited this approach to identify previously unknown molecular and cellular elements correlated with disease protection, including the complement receptor of the immunoglobulin superfamily (CRIg), which marked a subset of macrophages associated with diabetes resistance. Administration of a fusion of CRIg and the Fc portion of immunoglobulin resulted in lower MRI signals and diabetes incidence. In addition to identifying regulators of disease progression, we show here that diabetes is set at an early age in NOD mice.     

The distal femoral epiphyseal ossification center in the assessment of third-trimester menstrual age: sonographic identification and measurement

The distal femoral epiphyseal secondary ossification center (DFE), which can be reliably identified and measured sonographically, may assist the sonologist in predicting third-trimester menstrual age. Between 28 and 35 menstrual weeks, the percentage of fetuses with a DFE progressively increases. Although the mean age at DFE appearance is approximately 32-33 menstrual weeks, the DFE may be seen as early as 29 menstrual weeks. Nevertheless, the age of a fetus without an identifiable DFE is most likely less than or equal to 34 menstrual weeks. Measurements of the DFE show that its size increases linearly: the menstrual age of a fetus whose DFE measures greater than or equal to 7mm is most likely greater than or equal to 37 weeks.     

Expression of CDw29 and CD45R antigens on epithelial cells in oral lichen planus

The CD45R and CDw29 antigens are expressed on naive and primed helper T cell populations which serve suppressor-inducer or helper-inducer functions, respectively. These antigens may also be expressed on epithelial cell subpopulations. In the present study, monoclonal antibodies reacting with T lymphocytes and Langerhans cells (LC) were used to characterize the expression of CD45R and CDw29 antigens in oral lichen planus. CDw29 was expressed by LC and lymphocytic cells whereas keratinocyte reactivity varied from negative through to full thickness staining. Expression of CD45R was confined to intraepithelial cells with either lymphocytic or dendritic morphology. A relatively constant ratio of CD1a + LC to CD45R + cells (2:1) was seen. These results demonstrate the existence of intraepithelial cells expressing antigens which are functionally important in T cell responses and which may provide local immunoregulatory influences.     

Nonpalpable breast lesion localization: limited efficacy of sonography

We attempted to use hand-held, high-resolution breast sonography to localize for biopsy 11 solid, nonpalpable lesions detected by mammography. Using sonography, we identified and localized only one of four lesions presenting as poorly defined masses and only one of seven lesions presenting as clusters of tiny calcifications. This 18% rate of success is too low to justify the use of sonography for all patients undergoing needle localization. Mammography remains the procedure of choice for localizing solid, nonpalpable breast masses and clustered calcifications.     

金艾康合并化学药物治疗肿瘤临床疗效观察

目的：探讨金艾康（汉防己甲素片）合用化学药物治疗肿瘤的临床增效作用。方法：通过比较治疗组与对照组（金艾康合并化学药物者为治疗组,单用化学药物者为对照组,每组各为３０例）的总缓解率与毒副反应来评价金艾康对化疗药物的增效作用。结果：治疗组与对照组的总缓解率分别为８０％与６６．７％,其中部分毒副反应如消化道反应与肢端订木症状等治疗组明显低于对照组。结论：金艾康具有对化学药物治疗肿瘤增效作用,其作用机理可     

Amniotic sheets

Seventeen cases of an aberrant sheet of tissue in the amniotic cavity are described to expand and clarify previous observations of this entity. The sheet of tissue demonstrates a thickened base and a free edge that undulates. The fetus moves freely about the sheet of tissue. There are no associated fetal deformities, and infants have no manifestations of the amniotic-band syndrome. Evidence suggests that these sheets may originate from "wrapping" of the amniochorionic membrane over a uterine synechia. These benign sheets of tissue should not be confused with the amniotic-band syndrome.