New concepts in antimalarial use and mode of action in dermatology

Although chloroquine, hydroxychloroquine and quinacrine were originally developed for the treatment of malaria, these medications have been used to treat skin disease for over 50 years. Recent clinical data have confirmed the usefulness of these medications for the treatment of lupus erythematosus. Current research has further enhanced our understanding of the pharmacologic mechanisms of action of these drugs involving inhibition of endosomal toll-like receptor (TLR) signaling limiting B cell and dendritic cell activation. With this understanding, the use of these medications in dermatology is broadening. This article highlights the different antimalarials used within dermatology through their pharmacologic properties and mechanism of action, as well as indicating their clinical uses. In addition, contraindications, adverse effects, and possible drug interactions of antimalarials are reviewed.     

The Electrical Characteristics of Human Skin in Vivo

Purpose. The objectives of this study were to investigate the impedance properties of human skin in vivo and to examine the effect of iontophoresis upon them. Methods. Having established the intra- and inter-individual variation in basal values of skin impedance, the effect of varying iontophoretic current density, ionic strength and counter-ion on the rate of recovery of skin impedance after iontophoresis was investigated. Results. Passage of an iontophoretic current caused a significant reduction in the magnitude of the skin impedance. Increasing the current density caused an even greater reduction in the value of the skin impedance and slowed the rate of recovery. Reduction of the ionic strength resulted in an increase in the rate of recovery following iontophoresis. A significant increase in the rate of recovery was observed when CaCl₂ replaced NaCl as the electrolyte. Although visual inspection revealed the presence of greater erythema when CaCl₂ was used, there was an absence of the mild sensation experienced by volunteers when using NaCl. The last part of the study established a correlation between transepidermal water loss and impedance analysis as complementary methods for probing skin barrier function in vivo. The data were fitted to an equivalent circuit consisting of a resistor in parallel with a constant-phase element and a mechanistic model proposed to explain the electrical properties of the skin. Conclusions. The first comprehensive investigation of the effect of iontophoresis on the electrical properties of human skin in vivo has been described. It would appear from the results, and from their interpretation, that impedance spectroscopy may be an effective method to quantify the impact of iontophoresis on the skin, and to determine the extent to which proposed drug delivery regimens will perturb skin barrier function.     

DL-111-1T对雌鼠肝脏及人羊膜细胞混合功能氧化酶活性的选择性诱导

以抗早孕药3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole(DL-111-1T)20 mg/(kg.d)预处理♀大鼠2 d,即可使动物肝微粒体。     

Anesthesia considerations for patients with an implanted deep brain stimulator undergoing surgery: a review and update

Purpose

Deep brain stimulation (DBS) can be an effective treatment option for patients with essential tremor and Parkinson’s disease. This review provides an overview on the functioning of neurostimulators and recent advances in this technology and presents an updated guide on the anesthetic management of patients with an implanted neurostimulator undergoing surgery or medical intervention.

Source

A search was conducted on MEDLINE®, EMBASE?, and Cochrane Database of Systematic Reviews databases to identify studies published in English from 1974 to December 2015. Our search also included relevant and available incident reports from the manufacturers, Health Canada, the United States Food and Drug Administration, and the European Medicines Agency. Thirty of 232 articles identified were found to be relevant to this review.

Principal findings

Deep brain stimulation systems now offer a range of options, including pulse generators with dual-channel capabilities, rechargeable batteries, and current-control modes. Preoperatively, the anesthesiologist should ascertain the indications for DBS therapy, identify the type of device implanted, and consult a DBS specialist for specific precautions and device management. The major perioperative concern is the potential for interactions with the medical device resulting in patient morbidity. Neurostimulators should be turned off intraoperatively to minimize electromagnetic interference, and precautions should be taken when using electrosurgical equipment. Following surgery, the device should be turned on and checked by a DBS specialist.

Conclusion

The anesthesiologist plays an important role to ensure a safe operating environment for patients with an implanted DBS device. Pertinent issues include identifying the type of device, involving a DBS-trained physician, turning off the device intraoperatively, implementing precautions when using electrosurgical equipment, and checking the device postoperatively.

     

Rapidly adapting pulmonary receptor afferents: II. Fine structure and synaptic organization of central terminal processes in the nucleus of the tractus solitarius

The nucleus of the tractus solitarius (nTS) is a site for termination of primary afferents originating from a variety of different visceral sensory endings (Kalia and Mesulam: J. Comp. Neurol. 193:523-553, '80). The light and electron microscopic evaluation of bouton terminals of slowly adapting lung stretch (SAR) afferent fibers originating from the tracheobronchial tree has been described previously (Kalia and Richter: J. Comp. Neurol. 241:503-520, 521-535, '85). The companion article (Kalia and Richter: J. Comp. Neurol. 273:000-000, '88) describes details of the light microscopic organization of a second group of pulmonary afferents, the rapidly adapting receptors (RARs), that are known to signal transient volume changes in airways (Sellick and Widdicombe: J. Physiol. (Lond.) 203: 359-381, '69; Q.J. Exp. Physiol. 55:153-163, '70). Terminals from RAR afferents are concentrated within two specific subnuclear groups of the nTS (dnTS and nI) and are distributed over 4 mm of the medulla oblongata rostrocaudally. Within the nTS, axon collaterals of RAR afferents remain myelinated up to a diameter of 0.4-1.0 microns. Preterminal processes are always unmyelinated and range in diameter from 0.15 to 0.3 microns. Bouton terminals (1.0-2.0 microns) are of both the en passant and end terminal varieties. The synaptic profiles formed by 143 bouton terminals of RAR afferents, were examined in uninterrupted sequential sections and are described in this paper. All the bouton terminals examined under the electron microscope were found to contain clear, round synaptic vesicles. Boutons made synaptic contact with different profiles in each of the two subnuclei (dnTS and nI) examined. Contacts were usually asymmetrical (type I) containing clear, round synaptic vesicles 35-50 nm in diameter. In the dorsal subnucleus of the nTS (dnTS), the synaptic arrangement of RAR boutons did not appear to be complex. The RAR bouton terminal was usually located in juxtaposition to unlabeled axon terminals of similar morphological characteristics. Typically, the RAR bouton terminal made synaptic contact with a medium-sized spiny dendrite. No axosomatic contacts involving RAR afferents were observed in this subnucleus. In the intermediate subnucleus of the nTS (nI), the most common synaptic arrangement of RAR bouton terminals was in the form of a "glomerulus," which was formed by five to seven different types of neuronal profiles surrounding the labeled RAR bouton terminal.(ABSTRACT TRUNCATED AT 400 WORDS)     

Piroxicam delivery into human stratum corneum in vivo: iontophoresis versus passive diffusion.

A nonsteroidal anti-inflammatory drug, piroxicam, was administered from a commercially available gel to human volunteers both passively and under the application of an iontophoretic current. The effect of occlusion on the passive delivery of piroxicam was also examined in a separate series of experiments. After treatment, the stratum corneum (SC) at the site of application was progressively tape-stripped and piroxicam transport into the membrane was assessed by UV-analysis of drug extracted from the tape-strips. Analysis of variance did not show any significant difference between passive piroxicam delivery after 30, 60 or 125 min. However, current application enhanced drug uptake into the SC, as indicated by both increased piroxicam concentrations in the horny layer and detectable concentrations at greater depths into the membrane. The total amount of drug recovered in the SC post-iontophoresis was significantly higher than that found following passive diffusion for each application time. The amounts of drug recovered from the tapes after 60 and 125 min of current application were significantly higher than that after 30 min treatment. Finally, the in vivo SC concentration profiles following passive delivery were fitted to the appropriate solution of Fick's second law of diffusion to determine skin partitioning and diffusivity parameters.     

Establishment of synchronization in carrot cell suspension culture and studies on stage specific activation of glyoxalase I

The present report summarizes and compares the effects of three cell cycle inhibitors, viz. aphidicolin, hydroxyurea and mimosine, in inducing synchronization of a rapidly proliferating suspension culture of carrot. These treatments efficiently synchronized the cell cycle as the doubling time of the cell population was roughly equal to the total length of one cell cycle. Protoplasts derived from mimosine treated cell suspension culture were resolved via flow cytometry to get an idea of the temporal organization of the cell cycle events. The biochemical analysis showed a rise in stage specific activity of glyoxalase I, an auxin inducible marker enzyme activated at G₂-M. This activity peak could be shifted to an early phase of interphase in response to auxin treatment.     

Toxigenic Helicobacter pylori induces changes in the gastric mucosal microcirculation in rats

BACKGROUND AND AIMS: One of the key components of inflammation is changes in vascular structure and function. This suggests that the microcirculation may be a key target of Helicobacter pylori released factors. It has previously been shown in vivo that pooled H pylori extracts from duodenal ulcer/gastritis patients induce platelet aggregation but no leucocyte activation within rat gastric mucosal microcirculation (GMMC). However, infection with strains associated with ulcer disease as compared with gastritis may exert greater effects on the microcirculation. This study used fluorescent in vivo microscopy to determine the acute effects of extracts of genotypically different H pylori strains on the GMMC. METHODS: Three H pylori extracts, with different cagA and VacA toxigenic status, were individually administered to the gastric mucosa of anaesthetised Wistar rats. The mucosal surface was visualised via an incision made in the exteriorised stomach. Fluoroscein isothiocyanate conjugated to bovine serum albumin (FITC-BSA) or acridine orange was used to quantify macromolecular leak (MML) and leucocyte/platelet activity respectively for 120 minutes. Changes in capillary and post-capillary venule (PCV) diameters were also monitored. RESULTS: The cagA(+) VacA toxigenic strain 60190 induced significant and sustained MML by five minutes (p<0.01). Transient and less leakage was observed with its isogenic VacA(-) mutant and other non-toxigenic strains regardless of cagA status. Significant increases in leucocyte adhesion (p<0.05), platelet aggregation (p<0.05), and PCV vasoconstriction (p<0.05) were only observed with the cag A(+) and toxigenic strain. CONCLUSION: Extracts of H pylori are capable of inducing marked disturbances within the rat GMMC. These disturbances seem to be dependent on the production of an active vacuolating cytotoxin. Varying effects on the GMMC may explain the clinically diverse outcomes associated with genotypically different strains.     

Mechanisms of Helicobacter pylori-Induced Rat Gastric Mucosal Microcirculatory Disturbances In Vivo

The exact mechanisms by which Helicobacter pylori infection results in gastric mucosal injury are unclear. However, it has been demonstrated that surface protein extracts of the bacterium can induce a number of disturbances within the rat gastric mucosal microcirculation, including platelet aggregation and macromolecular leakage (MML) of labeled albumin. This study aimed to determine the mechanisms involved in inducing these events using the technique of fluorescent in vivo microscopy. Male Wistar rats were pretreated with either ketotifen, a mast cell stabilizer (1 mg/kg), pyrilamine, an H₁-receptor antagonist (30 mg/kg), hexanolamine-PAF, a PAF-receptor antagonist (10 g/kg), l-arginine, the nitric oxide precursor (300 mg/kg) or vehicle, saline. Then 0.5 ml of H. pylori extract was administered to the exteriorized gastric mucosa of the anesthetized rat. Alterations in fluorescein-labeled albumin leak, vessel diameters, and acridine red-labeled leukocyte and platelet activity were determined over a 2-hr period. Saline pretreated animals demonstrated significant MML with a peak at 5 min (11%, P < 0.02). This was prevented with ketotifen and pyrilamine, but not with hexanolamine-PAF (17.5%, P < 0.05) and l-arginine (13%, P < 0.05). Significant numbers of platelet emboli and thrombi were observed within mucosal capillaries and postcapillary venules with vehicle pretreatment; this was prevented with hexanolamine-PAF and l-arginine, but not with ketotifen and pyrilamine. In conclusion, these studies demonstrate that more than one mediator is involved in inducing the rat gastric mucosal microcirculatory disturbances associated with H. pylori administration. Mast cells and histamine are linked to MML, with PAF, probably not derived from mast cells, involved in platelet activation.