Comparative pulmonary absorption, distribution, and toxicity of copper gallium diselenide, copper indium diselenide, and cadmium telluride in Sprague-Dawley rats

Copper gallium diselenide (CGS), copper indium diselenide (CIS), and cadmium telluride (CdTe) are novel compounds used in the photovoltaic and semiconductor industries. This study was conducted to characterize the relative toxicities of these compounds and to evaluate the pulmonary absorption and distribution after intratracheal instillation. Female Sprague-Dawley rats were administered a single equimolar dose (70 mM) of CGS (21 mg/kg), CIS (24 mg/kg), CdTe (17 mg/kg), or saline by intratracheal instillation. Bronchoalveolar lavage fluid (BALF) protein, fibronectin, inflammatory cells, lung hydroxyproline, and tissue distribution were measured 1, 3, 7, 14, and 28 days after instillation. Relative lung weights were significantly increased in CIS- and CdTe-treated rats at most time points. Inflammatory lesions in the lungs consisting of an influx of macrophages, lymphocytes, and PMNs were most severe in CdTe-treated rats, intermediate in CIS-treated rats, and minimal in rats receiving CGS. Hyperplasia of alveolar type 2 cells was present in CIS- and CdTe-treated rats and was greatest in CdTe-treated rats. Pulmonary interstitial fibrosis was observed in CdTe-treated rats at all time points. All three compounds caused marked increases in total BALF cell numbers, with the greatest increase observed in CIS-treated rats. BALF protein, fibronectin, and lung hydroxyproline were significantly increased in all treated animals and were highest in CdTe-treated animals. There was no apparent pulmonary absorption or tissue distribution of CGS. Indium levels increased in extrapulmonary tissues of CIS-treated rats, although Cu and Se levels remained unchanged. CdTe was absorbed from the lung to a greater extent than CGS and CIS. Cd and Te levels decreased in the lung and increased in extrapulmonary tissues. Of these compounds CdTe presents the greatest potential health risk because it causes severe pulmonary inflammation and fibrosis and because it is readily absorbed from the lung may potentially cause extrapulmonary toxicity.     

The call of the sirens: ethically navigating the sea of nonvalidated therapies

SHP-2 is an ubiquitously expressed cytosolic protein tyrosine phosphatase composed of two amino-terminal SH2 domains, a central phosphatase domain and a carboxy-terminal tail. Upon activation of cells with different stimuli, SHP-2 is recruited to the plasma membrane where it can associate with a number of tyrosine phosphorylated molecules, including receptor tyrosine kinases (e.g. growth factor receptors), multisite adapter proteins and cell adhesion molecules. SHP-2 is thought to function as a positive mediator of signals generated by activated membrane receptor complexes although the number and diversity of binding partners and substrates identified thus far suggests that it may have other functions. It is likely that several negative regulatory influences exist but that these are obscured by its positive function making the investigation of the inhibitory effects of this phosphatase difficult. The positive regulatory role of SHP-2 in signal cascades leading to cell growth suggests involvement in tumorigenesis, raising the possibility that SHP-2 may be a target in the treatment of some forms of cancer.     

Enhanced lipolysis in normal mice expressing liver-derived human lipoprotein lipase after adenoviral gene transfer

The authors previously demonstrated that the gene for human lipoprotein lipase (hLPL), an enzyme crucial to the breakdown of triglyceride (TG)-rich dietary fats, corrects the hypertriglyceridemia in lipoprotein lipase (LPL)-deficient knockout mice after adenoviral (Ad)-mediated LPL gene transfer. They have now extended their observations to primary cultured mouse hepatocytes and intact animals of normal LPL genotype, and confirm effective overexpression of hLPL from the liver and a sustained TG-lowering effect in plasma over 60 days. A typical first-generation Ad-vector containing the hLPL cDNA (Ad-LPL) resulted in efficient gene transfer into isolated mouse hepatocytes and significant de novo synthesis of active hLPL protein. In this experiment, 5 x 10(9) viral particles (5 x 10(7) pfu) of either Ad-LPL or an Ad-LacZ control vector were injected into CD1 mice of normal LPL genotype. Hepatic expression of hLPL was confirmed at Day 7 postinjection by in situ hybridization and direct measurement of LPL in the liver. This correlated with a total LPL activity (human + mouse) in postheparin plasma (PHP) of 1020.5 standard deviation [SD] 93.6 mU/mL, versus 479.5 SD 129.7 mU/mL (p < 0.001) in Ad-LacZ controls at Day 7. Respective hLPL activity comprised 49% of the total. Significantly raised levels of hLPL protein mass persisted until Day 60. Corresponding plasma TGs decreased to 39% of Ad-LacZ controls at Day 7, and, despite absent hLPL activity from Day 28 on, serum TGs remained significantly lower in Ad-LPL mice up to Day 42. Fast phase liquid chromatography analysis showed a dramatic depletion in TG-rich lipoproteins, mainly very low density lipoproteins (VLDL) and chylomicron fractions. Therefore, Ad-mediated overexpression of hepatic LPL was found to significantly decrease plasma TG levels unrelated to primary LPL deficiency.     

Establishment of a hybrid SalI-HgiDII type II restriction-modification system

In the SalI system, endonuclease activity can be only achieved in the presence of a functional modification gene. Thus, the DNA methyltransferase is involved in the control of restriction. By fusion of the restriction gene of the SalI system to the modification gene of the isospecific HgiDII system a hybrid type II restriction-modification system was created. Although in the hybrid situation the level of endonuclease activity was significantly lower than in the natural system, the HgiDII modification enzyme clearly supports SalI restriction. The mechanism by which the two isospecific methyltransferases control restriction is currently under study.     

Superficial granulomatous pyoderma

Superficial granulomatous pyoderma (SGP) is a form of pyoderma gangrenosum (PG) characterized by superficial ulceration and chronic course. To date it has been described as a condition with specific histopathological findings. We report a new case with clinical characteristics of SGP and describe why we believe that the histological changes previously described are not typical of this entity.     

Rapid effects of cytochalasin-D on contraction and intracellular calcium in single rat ventricular myocytes

Contraction and intracellular calcium ([Ca2+]i) transients were recorded using a video edge detector and fluorescence spectrophotometry, respectively, in rat ventricular myocytes at 22-24 degreesC stimulated at a frequency of 1 Hz. Application of the F-actin disrupter cytochalasin-D (Cyt-D) caused a large reduction in the amplitude of contraction and a small increase in the [Ca2+]i transient. These responses began within a few seconds of application and were complete after 2 min of exposure. Phase-plane relationships of contraction and [Ca2+]i were consistent with cytochalasin-D causing a decrease in myofilament responsiveness to Ca2+.     

Mind-body medicine. Practical applications in dermatology

It is only recently that Western physicians are rediscovering the link between thought and health. The spectrum of causative factors in inflammatory dermatoses are often multifactorial. Stress and negative thoughts are major factors in dermatologic conditions. This article begins with some basic information on the ways that thoughts affect health. Practical methods of intervention including meditation, journal writing, affirmations, prayer, biofeedback, and hypnosis are presented.     

Temporal synthesis of band 3 oligomers during terminal maturation of mouse erythroblasts. Dimers and tetramers exist in the membrane as preformed stable species

Band 3, the anion transport protein of the erythrocyte membrane, exists in the membrane as a mixture of dimers (B3D) and tetramers (B3T). The dimers are not linked to the skeleton and constitute the free mobile band 3 fraction. The tetramers are linked to the skeleton by their interaction with ankyrin. In this report we have examined the temporal synthesis and assembly of band 3 oligomers into the plasma membrane during red cell maturation. The oligomeric state of newly synthesized band 3 in early and late erythroblasts was analyzed by size-exclusion high-pressure liquid chromatography of band 3 extracts derived by mild extraction of plasma membranes with the nonionic detergent C12E8 (octaethylene glycol n-dodecyl monoether). This analysis revealed that at the early erythroblast stage, the newly synthesized band 3 is present predominantly as tetramers, whereas at the late stages of erythroid maturation, it is present exclusively as dimers. To examine whether the dimers and tetramers exist in the membrane as preformed stable species or whether they are interconvertible, the fate of band 3 species synthesized during erythroblast maturation was examined by pulse-chase analysis. We showed that the newly synthesized band 3 dimers and tetramers are stable and that there is no interconversion between these species in erythroblast membranes. Pulse-chase analysis followed by cellular fractionation showed that, in early erythroblasts, the newly synthesized band 3 tetramers are initially present in the microsomal fraction and later incorporated stably into the plasma membrane fraction. In contrast, in late erythroblasts the newly synthesized band 3 dimers move rapidly to the plasma membrane fraction but then recycle between the plasma membrane and microsomal fractions. Fluorescence photobleaching recovery studies showed that significant fractions of B3T and B3D are laterally mobile in early and late erythroblast plasma membranes, respectively, suggesting that many B3T-ankyrin complexes are unattached to the membrane skeleton in early erythroblasts and that the membrane skeleton has yet to become tightly organized in late erythroblasts. We postulate that in early erythroblasts, band 3 tetramers are transported through microsomes and stably incorporated into the plasma membrane. However, when ankyrin synthesis is downregulated in late erythroblasts, it appears that B3D are rapidly transported to the plasma membrane but then recycled between the plasma membrane and microsomal compartments. These observations may suggest novel roles for membrane skeletal proteins in stabilizing integral membrane protein oligomers at the plasma membrane and in regulating the endocytosis of such proteins.     

Spontaneous reinitiation of atrial fibrillation following transvenous atrial defibrillation

Spontaneous reinitiation of atrial fibrillation (AF) has not been systematically looked at in patients undergoing transvenous AF. This study involved 11 patients, the mean age 60 +/- 8 years, 3 male and 8 female, in whom transvenous atrial defibrillation successfully converted AF to sinus rhythm. Eight patients had paroxysmal AF and three patients had chronic persistent AF for 4 weeks or more. Four patients were taking antiarrhythmic medications at the time of testing. Multipolar transvenous catheters were positioned inside the coronary sinus, right atrium, and the right ventricle. Atrial defibrillation testing was performed using the METRIX atrial defibrillation system in nine patients and the Ventritex HVSO2 in the remaining two patients. A total of 64 therapeutic shocks (range 3-11) were delivered in the 11 patients, and 31 of these successfully converted AF to sinus rhythm. In four patients spontaneous AF was reinitiated following 12 successful transvenous atrial defibrillation episodes. The mean time to reinitiation of AF following shock delivery and restoration of sinus rhythm was 8.26 +/- 5.25 seconds, range 1.8-19.9 seconds. All 12 episodes of spontaneous AF were preceded by a spontaneous premature atrial complex. The coupling interval of the premature atrial complexes was 443 +/- 43 ms, range 390-510 ms. None of the patients taking antiarrhythmic medications or those demonstrating no premature atrial complexes had spontaneous reinitiation of AF. In conclusion, spontaneous reinitiation of AF can occur in a significant proportion of patients with AF undergoing transvenous atrial defibrillation. This phenomenon is preceded by the occurrence of atrial premature complex. Findings of this study may have significant clinical implications.