Possible involvement of organic anion transporter 2 on the interaction of theophylline with erythromycin in the human liver.

Organic anion transporter 2 (Oat2 [SLC22A7]) is a multispecific organic anion transporter. Although several substrates of human Oat2 (hOat2) have been elucidated, a possible involvement of hOat2 in drug interaction is less defined. The purpose of this study was to investigate the interaction of theophylline with erythromycin mediated by hOat2 using a Xenopus laevis oocyte expression system. When expressed in Xenopus oocytes, hOat2 mediated the transport of theophylline and erythromycin. The finding indicates that the two compounds are novel substrates for hOat2. The apparent K(m) values for the uptake of hOat2 that mediated the transport of theophylline and erythromycin were 12.6 muM and 18.5 muM, respectively. The hOat2-mediated uptake of [(14)C]theophylline and [(14)C]erythromycin was cis-inhibited by adding erythromycin and theophylline, respectively. Our present findings suggest that hOat2 may, at least in part, be involved in the theophylline-erythromycin interaction in the human liver.     

Glucocorticoids modulate TGF-beta production

TGF- is thought to play a central role in pulmonary fibrosis inducing fibroblast differentiation and extracellular matrix synthesis. In human lung fibroblasts, it is still unclear how various TGB- isoforms affect TGF- production and whether glucocorticoids, commonly used agents to treat fibrotic lung disease, modulate these processes. To this end, human fetal lung fibroblasts (HFL-1) were cultured with various concentrations of glucocorticoids (budesonide, dexamethasone or hydrocortisone) with and without TFG-1, -2, and -3. TGF- mRNA was assessed by real time RT-PCR. Smad 2, 3, and 4 and AP-1 complex (c-fos and c-Jun) cellular localization were evaluated by immunostaining. TGF-2 and -3 stimulated TGF-1 production significantly (p < 0.01 relative to control). TGF-1 stimulated TGF-2 production (p < 0.01 relative to control). TGF-3 was undetectable. Glucocorticoids significantly inhibited TGF-1 and -2 production and reduced expression of the upregulated TGF-1 and -2 mRNA induced by exogenous TGF-1, -2 or -3 (p < 0.01 for each) but had no effect on Smads. Although c-jun-related nuclear staining was not intensified in TGF--stimulated cells, it was reduced by glucocorticoids. Thus, TGF- isoforms may stimulate production of various TGF- isoforms in the lung. Glucocorticoids then may block TGF- production by modulating mRNA levels and c-Jun.     

Proposed criteria for mixed-dust pneumoconiosis: definition, descriptions, and guidelines for pathologic diagnosis and clinical correlation

We defined mixed-dust pneumoconiosis (MDP) pathologically as a pneumoconiosis showing dust macules or mixed-dust fibrotic nodules (MDF), with or without silicotic nodules (SN), in an individual with a history of exposure to mixed dust. We defined the latter arbitrarily as a mixture of crystalline silica and nonfibrous silicates. According to our definition of MDP, therefore, MDF should outnumber SN in the lung to make a pathologic diagnosis of MDP. In the absence of confirmation of exposure, mineralogic analyses can be used to support the pathologic diagnosis. The clinical diagnosis of MDP requires the exclusion of other well-defined pneumoconioses, including asbestosis, coal workers’ pneumoconiosis, silicosis, hematite miners’ pneumoconiosis, welders’ pneumoconiosis, berylliosis, hard metal disease, silicate pneumoconiosis, diatomaceous earth pneumoconiosis, carborundum pneumoconiosis, and corundum pneumoconiosis. Typical occupations associated with the diagnosis of MDP include metal miners, quarry workers, foundry workers, pottery and ceramics workers, and stonemasons. Irregular opacities are the major radiographic findings in MDP (ILO 1980), in contrast to silicosis, in which small rounded opacities predominate. Clinical symptoms of MDP are nonspecific. MDP must be distinguished from a variety of nonoccupational interstitial pulmonary disorders.     

Activation of extracellular signal-regulated kinases in the sciatic nerves of rats with experimental autoimmune neuritis

To investigate whether the phosphorylation of extracellular signal-regulated kinase (ERK) is involved in autoimmune injury of the peripheral nervous system (PNS), the expression of phosphorylated ERK (p-ERK) was analyzed in experimental autoimmune neuritis (EAN) in rats. Western blot analysis showed that the level of p-ERK was increased significantly in the sciatic nerves of rats on days 14 (p<0.05) and 24 (p<0.01) post-immunization, compared with controls, and its reaction declined at day 30 post-immunization. Immunohistochemistry showed that p-ERK protein was weakly expressed in Schwann cells and vascular endothelial cells in the sciatic nerves of CFA-immunized control rats. In EAN-affected sciatic nerves, p-ERK immunoreactivity was found mainly in ED1-positive macrophages on days 14 and 24 post-immunization. Moreover, on days 24 and 30 post-immunization, p-ERK immunoreactivity increased gradually in the Schwann cells of rat sciatic nerves with EAN. Based on these results, we postulated that the phosphorylation of ERK has an important role in the differentiation and survival of cells, including inflammatory cells and Schwann cells, in the rat sciatic nerve in EAN. Specifically, the activation of ERK in the recovery phase of EAN paralysis seems to be related in the survival of Schwann cells.     

Synaptic mechanisms acting on lumbar motoneurons during postural augmentation induced by serotonin injection into the rostral pontine reticular formation in decerebrate cats

Intrapontine microinjections of serotonin in acutely decerebrated cats resulted in the bilateral augmentation of the postural muscle tone of the hindlimbs. Optimal injection sites were located in the dorsomedial part of the rostral pontine reticular formation corresponding to the nucleus reticularis ponds oralis (NRPo). In this study, attempts were made to elucidate the cellular basis for the serotoninergically induced augmentation of postural muscle tone by recording the electromyographic (EMG) activity of hindlimb extensor muscles, the monosynaptic reflex responses evoked by electrical stimulation of group Ia muscle afferent fibres and the membrane potentials of hindlimb alpha-motoneurons (MNs). Serotonin injections resulted not only in the augmentation of the EMG activity of gastrocnemius soleus muscles, but also in the restoration of EMG suppression, which was induced by previous injection of carbachol into the NRPo. Extensor and flexor monosynaptic reflex responses were facilitated by serotonin injections into the NRPo. Such reflex facilitation was not induced by serotonin injections into the mesencephalic or the medullary reticular formation. Intrapontine serotonin injections resulted in membrane depolarization of extensor and flexor MNs with decreases in input resistance and rheobase. Spontaneous depolarizing synaptic potentials (EPSPs) increased in both frequency and amplitude. Peak voltage of Ia monosynaptic EPSPs also increased. Serotonin injections which followed carbachol injections resulted in membrane depolarization of MNs along with an increase in the frequency of spontaneous EPSPs and a decrease in carbachol-induced inhibitory postsynaptic potentials. Following pontine carbachol injections, antidromic and orthodromic responses in MNs were suppressed. Discharges of MNs evoked by intracellular current injections were also suppressed, but were restored following serotonin injections. These results indicate that postsynaptic excitation, presynaptic facilitation and disinhibition (withdrawal of postsynaptic inhibition) simultaneously act on the hindlimb MNs during serotonin-induced postural augmentation and restoration.     

Longitudinal assessment of anti-Müllerian hormone after cesarean section and influence of bilateral salpingectomy on ovarian reserve

ObjectiveThis study aimed to compare longitudinal changes in ovarian reserve markers after cesarean section (CS) with and without bilateral salpingectomy (BS).Study designWe prospectively enrolled women >35 weeks’ gestation scheduled for CS alone or CS + BS and obtained blood samples for anti-Müllerian hormone prior to surgery and at 3 and 6 months after surgery. At the 3-month visit, we similarly performed transvaginal ultrasound for antral follicle count.ResultsWe enrolled 50 women; 30 underwent CS only and 20 underwent CS + BS. Although anti-Müllerian hormone level increased over 6 months of follow-up in both groups, no clinically important differences in the geometric mean (interquartile range) (ng/mL) were observed at any timepoint (baseline [0.69 {0.36?1.21} {CS only} vs 0.49 {0.32?2.10} {CS + BS}, p = 0.64]; 3 months [1.35 {0.58?3.13} vs 1.45 {1.04?2.25}, p = 0.79]; and 6 months [1.74 {0.93?4.45} vs 2.60 {1.41?5.10}, p =0.27]). Similarly, we detected no difference in antral follicle count.ConclusionBS at the time of CS does not have a negative impact on ovarian reserve 6 months after surgery.ImplicationWhile our results provide reassuring data that bilateral salpingectomy for permanent contraception at the time of cesarean section does not impact ovarian reserve, longer adequately powered studies are needed.