Lidocaine treatment during synapse reformation periods permanently inhibits NGF-induced excitation in an identified reconstructed synapse of Lymnaea stagnalis

Purpose  

Nerve growth factor (NGF) has been reported to affect synaptic transmission and cause neuropathic pain. In contrast, lidocaine has been used to reduce neuropathic pain; however, the effect of NGF and lidocaine on spontaneous transmitter release and synapse excitation has not been fully defined. Therefore, the effect of NGF and lidocaine on nerve regeneration, synapse reformation, and subsequent spontaneous transmitter release was investigated. We used Lymnaea stagnalis soma–soma-identified synaptic reconstruction to demonstrate that a transient increase in both frequency and amplitude of spontaneous events of miniature endplate potentials (MEPPs) occurs following NGF treatment and a short burst of action potentials in the presynaptic cell; in addition, the effect of lidocaine on NGF-induced synapse reformation was investigated.     

Reactive oxygen species involved cancer cellular specific 5-aminolevulinic acid uptake in gastric epithelial cells

Photodynamic therapy and photodynamic diagnosis using 5-aminolevulinic acid (ALA) are clinically useful for cancer treatments. Cancer cells have been reported that 5-aminolevulinic acid is incorporated via peptide transporter 1, which is one of the membrane transport proteins, and has been reported to be significantly expressed in various gastrointestinal cancer cells such as Caco-2. However, the mechanism of this protein expression has not been elucidated. Concentration of reactive oxygen species (ROS) is higher in cancer cells in comparison with that of normal cells. We have previously reported that ROS derived from mitochondria is likely related to invasions and proliferations of cancer cells. Since 5-aminolevulinic acid is the most important precursor of heme which is necessary protein for cellular proliferations, mitochondrial ROS (mitROS) may be also related to peptide transporter 1 expressions. In this study, we used a rat gastric mucosal cell line RGM1 and its cancer-like mutated cell line RGK1, and we clarified the ALA uptake mechanism and its relations between mitROS and peptide transporter 1 expression in RGK1. We also used our self-established stable clone of cell which over-expresses manganese superoxide dismutase, a mitROS scavenger. We studied differences of the photodynamic therapy effects in these cells after ALA administrations to clear the influence of mitROS.     

The three-year efficacy of iguratimod in clinical daily practice in patients with rheumatoid arthritis

Abstract

Objectives: To assess the middle-term outcome of iguratimod (IGU) in rheumatoid arthritis (RA) patients.

Methods: Sixty-nine RA patients (14 males and 55 females, mean age of 64.0 years) receiving IGU-containing therapies were enrolled. We divided these patients into three groups based on the treatment at the baseline: an IGU group, a methotrexate (MTX) plus IGU group, and a biologics plus IGU group. The baseline characteristics and clinical course were evaluated over three years. Predictive factors associated with the achievement of low disease activity (LDA) were statistically analyzed.

Results: The survival rate of IGU therapy at 3 years was 40.6%. The disease activity was significantly decreased in the IGU group and MTX plus IGU group compared with the baseline. Furthermore, 38 patients (55.1%) were in remission or had LDA at 3 years. The patient gender, use of prednisolone (PSL) and DAS28-CRP at baseline were the factors associated with the achievement of remission or LDA at three years.

Conclusion: IGU was effective without MTX or bDMARDs as well as in combination with MTX. A female gender, no use of PSL and a low DAS28-CRP at the initiation of IGU were associated with clinical remission or LDA achievement at three years.     

Hepatocellular carcinoma metastasis to the brain mimicking primary pituitary tumor around the sella turcica

We report on two cases of hepatocellular carcinoma (HCC) with metastasis to the cavernous sinus and sphenoid sinus. Both cases presented with diplopia and retro-orbital headache and both underwent surgery for a primary pituitary gland tumor. After surgery, both cases were diagnosed with metastases from HCC. Case 1 was a 67-year-old male with a history of HCC who was referred to our hospital for pituitary tumor surgery. The tumor appeared to be in the sella turcica and to invade the sphenoid sinus and right cavernous sinus. Transnasal transsphenoidal surgery (TSS) was performed. The tumor was postoperatively diagnosed by histology to be a metastatic pituitary tumor from HCC. Radiotherapy was administered to the metastatic site. Case 2 was a 58-year-old male with a history of TSS for a pituitary tumor 16 years previously. He was referred to our hospital for TSS for a recurrent pituitary adenoma. TSS was performed twice in 3 months. During a preoperative general examination, HCC and chronic hepatitis B were revealed. TSS was performed initially, followed by arterial infusion chemotherapy. After TSS, the pituitary tumor was diagnosed by histology to be a metastasis from HCC. As with Case 1, radiotherapy was administered to the metastasis. Most tumors in the sella turcica are pituitary adenomas, although some cases of metastatic pituitary tumors and skull base metastases have been reported. Distant metastases generally have a poor prognosis; however, surgery to the metastatic site can effectively control symptoms caused by the metastatic tumor.     

New-onset diabetes mellitus developing in Asian adult living donor liver transplant recipients: a single-center experience

Background

New-onset diabetes mellitus (NODM) after liver transplantation is a common complication with a potentially negative impact on patient outcome.

Methods

To evaluate the incidence of NODM and its impact on Asian adult living donor liver transplant (LDLT) recipients, we investigated 369 adult LDLT cases in our institute.

Results

Preoperative diabetes mellitus (DM) was diagnosed in 38 (9 %) patients. NODM was observed in 128/331 (38 %) patients, 56 (44 %) with persistent NODM and 72 (56 %) with transient NODM. The mean interval between LDLT and the development of NODM was 0.6 ± 1.8 (range 0–1.4) months. Multivariate analyssis revealed that older age, being male and having a higher body mass index were independent risk factors among recipients for developing NODM, while hepatitis C virus infection was not a significant risk factor, and DM had no impact on patient outcome.

Conclusions

Although the long-term effect of DM on outcome remains to be investigated, the presence of DM after liver transplant, whether it was NODM or preexisting DM, had no impact on LDLT recipients’ outcomes in mid-term.     

Living donor liver transplantation for patients immunized against human leukocyte antigen

Background/purpose

The clinical features and perioperative management of liver transplant recipients who are already sensitized against human leukocyte antigen (HLA) prior to transplantation are not yet clear.

Materials and methods

Medical records of living donor liver transplant recipients were reviewed and clinical features of the patients possessing anti-HLA antibodies were studied.

Results

Among the 470 consecutive living donor liver transplant recipients, 6 patients (1.3%) had preformed anti-HLA antibodies. A review of the postoperative courses of these patients revealed that the problems included platelet transfusion refractoriness (PTR) due to immune-mediated destruction of platelet and thrombotic microangiopathy (TMA). PTR was observed in patients with anti-HLA class I antibodies and only HLA-matched platelet concentrate (HLA-matched PC) relieved thrombocytopenia. Intravenous gammaglobulin had an additive effect to HLA-matched PC in some cases, and platelet transfusion from close relatives might be a substitute for HLA-matched PC in life-threatening situations. Although the etiology of TMA is unremarkable, the incidence was high (67%, 4/6) compared with that in patients who were not sensitized against HLA (5.6%, 26/464; p < 0.01). Of the four patients, three were complicated with late-onset TMA.

Conclusions

Considering these clinical features, careful preparation and postoperative management are needed for liver transplant candidates with anti-HLA antibodies.     

Pheromone responsiveness threshold depends on temporal integration by antennal lobe projection neurons

The olfactory system of male moths has an extreme sensitivity with the capability to detect and recognize conspecific pheromones dispersed and greatly diluted in the air. Just 170 molecules of the silkmoth (Bombyx mori) sex pheromone bombykol are sufficient to induce sexual behavior in the male. However, it is still unclear how the sensitivity of olfactory receptor neurons (ORNs) is relayed through the brain to generate high behavioral responsiveness. Here, we show that ORN activity that is subthreshold in terms of behavior can be amplified to suprathreshold levels by temporal integration in antennal lobe projection neurons (PNs) if occurring within a specific time window. To control ORN inputs with high temporal resolution, channelrhodopsin-2 was genetically introduced into bombykol-responsive ORNs. Temporal integration in PNs was only observed for weak inputs, but not for strong inputs. Pharmacological dissection revealed that GABAergic mechanisms inhibit temporal integration of strong inputs, showing that GABA signaling regulates PN responses in a stimulus-dependent fashion. Our results show that boosting of the PNs’ responses by temporal integration of olfactory information occurs specifically near the behavioral threshold, effectively defining the lower bound for behavioral responsiveness.Olfaction is a key element in many aspects of animal behavior, such as foraging, oviposition, and mate recognition. In many moth species, a special class of odorants called sex pheromones plays a critical role for identification of and orientation to potential mates. Because sex pheromones emitted by females are greatly diluted and dispersed in the air, sophisticated olfactory systems to detect minute amounts of sex pheromones and processing systems to translate subtle peripheral sensory responses into appropriate behavioral responses have evolved in male moths. Theoretical calculations have shown that the detection of 170 molecules of the sex pheromone bombykol [(E,Z)-10,12-hexadecadienol] can trigger sexual behavioral responses in males of the silkmoth Bombyx mori (1). The physical and chemical mechanisms in the antennae, the sensilla, and the olfactory receptor neurons (ORNs) responsible for this remarkably high sensitivity, which can detect even a single molecule, are well understood (2, 3). However, it is unclear how a small number of spikes from a small number of ORNs is processed centrally to allow for high behavioral responsiveness.In moths, pheromone molecules are detected by specialized antennal ORNs that express particular pheromone receptor genes (4–10). The axons of ORNs convey pheromone information to the first olfactory center, the antennal lobe (AL; an analog of the vertebrate olfactory bulb). The AL is composed of a number of glomeruli where ORNs establish connections with two types of neurons: projection neurons (PNs), which relay olfactory information to higher brain regions, and local interneurons (LNs), which are involved in processing olfactory information within the deutocerebrum (11). In particular, male ALs have a specialized pheromone-processing unit called the macroglomerular complex (MGC), which comprises several glomeruli (12). In the silkmoth, the toroid glomerulus in the MGC is known to exclusively process bombykol information (13).Previous reports have shown that the sensitivity of pheromone-responsive ORNs is ∼1,000-fold lower than that of PNs tuned to the same pheromone compound (14, 15), suggesting that the AL network amplifies ORN inputs. One possible source of amplification is the high convergence ratio between ORNs and PNs (16). Considering the small size of most antennae, spatial integration would be likely to occur; however, the fact that weak stimuli activate a few ORNs at best calls for additional mechanisms to explain the high behavioral sensitivity.One candidate explanation is temporal integration, which is a fundamental mechanism for contributing to the amplification of synaptic inputs (17–19). In the olfactory system, the temporal integration properties of AL neurons and their relevance for the initiation of behavior are unknown. Temporal integration in the olfactory system has been challenging to investigate in detail because of the difficulty of accurately controlling olfactory stimuli within a given time period. Under natural conditions, odor molecules are distributed in odor plumes with intermittent local dynamics of odor exposure lasting >100 ms, followed by odor-free air lasting several hundreds of milliseconds (20–24). However, another study showed that “bursts” of odor within a plume structure can be as little 10–20 ms (25, 26). Therefore, the stimulation of pheromone-responsive ORNs must be controlled in the millisecond range.To examine the role of temporal integration in the generation of low thresholds for pheromone-induced behavioral responses, we generated GAL4/UAS transgenic silkmoths expressing channelrhodopsin-2 (ChR2), a light-gated ion channel from green algae, in bombykol-responsive ORNs. The transgenic silkmoths showed light-activated pheromone orientation behavior, and we succeeded in controlling the activity of bombykol-responsive ORNs with single-spike resolution. Using paired-pulse photostimulation at various interstimulus intervals (ISIs), we tested whether temporal integration in the AL network could be the basis of the high behavioral sensitivity.     

Activation of natural cytotoxic activity and concomitant reduction of triglyceride content of murine spleen, treated with an antitumor antibiotic, ascofuranone

Ascofuranone (AF) elevated natural cytotoxic activity of spleen when it was administered intraperitoneally to male mice. The elevation was observed both in low and high responder mice. AF-activated splenocytes lysed NK-resistant tumor cells, FM3A, P388 and sarcoma 180 cells as well as NK-sensitive YAC-1 cells. However, AF suppressed other lymphatic functions such as mitogenic responses and interleukin 2 production. Because AF did not activate splenic NK activity in vitro, the activation is assumed to be caused by a host-mediated process. One of the possibilities is modulation of the lipid metabolism of splenocytes. Thus, we examined splenic lipid contents and revealed that AF decreased splenic triglycerides without affecting other lipids. In contrast, the antibiotic significantly increased triglyceride in muscle.