Morphological differentiation in giant salamanders, Andrias japonicus, A. davidianus, and their hybrids (Urodela, Cryptobranchidae), and its taxonomic implications.

For a long time, it has been debated whether the two giant salamanders, Andrias japonicus from Japan and A. davidianus from China, are conspecific or heterospecific. Morphological information about their diagnostic characteristics has been limited, without considering sexual dimorphism and/or body size variation. Recently, A. davidianus, which was introduced into Japan sometime in the past, has been found to hybridize with A. japonicus in situ. Taxonomic identification of individuals involved in this unusual breeding is made based on mitochondrial and nuclear DNA analyses. This identification method is time-consuming and costly. Thus, developing easier methods of identification, such as utilizing external morphological characteristics, is urgently needed. In this study, we verify previous descriptions showing that A. davidianus has a longer relative tail length than A. japonicus, and the tubercles on the lower jaw and throat were present in both sexes of A. davidianus. In addition, many head characteristics were found to be relatively larger in A. davidianus than in A. japonicus, which were new distinguishing characters. These morphological differences help support the idea that these are heterospecific lineages. In hybrids, relative values of head width and tail length were larger than those of A. japonicus, and the tubercles on their lower jaw and throat were present as in A. davidianus, suggesting that the hybrids and A. davidianus are distinguishable from A. japonicus.

[A case of HER2-positive breast cancer for which preoperative chemotherapy with pertuzumab resulted in a pathological complete response].

A right breast tumor was identified during screening in a 56-year-old woman, and she was then diagnosed with Stage II B breast cancer (T2N1M0) of Luminal -HER2 type. She was treated with preoperative chemotherapy with pertuzumab, trastuzumab, and docetaxel followed by epirubicin, cyclophosphamide, and fluorouracil. She was judged to have achieved a clinical complete response after 4 courses of pertuzumab, trastuzumab, and docetaxel, and she then underwent partial resection of the right breast and sentinel lymph node dissection. Pathological examination revealed that a pathological complete response was achieved. Combination therapy with pertuzumab, trastuzumab, and docetaxel seems to be a useful preoperative chemotherapy regimen for HER2-positive breast cancer.

The role of tissue plasminogen activator in methamphetamine-related reward and sensitization.

In the central nervous system, tissue plasminogen activator (tPA) plays a role in synaptic plasticity and remodeling. Our recent study has suggested that tPA participates in the rewarding effects of morphine by regulating dopamine release. In this study, we investigated the role of tPA in methamphetamine (METH)-related reward and sensitization. Repeated METH treatment dose-dependently induced tPA mRNA expression in the frontal cortex, nucleus accumbens, striatum and hippocampus, whereas single METH treatment did not affect tPA mRNA expression in these brain areas. The METH-induced increase in tPA mRNA expression in the nucleus accumbens was completely inhibited by pre-treatment with R(+)-SCH23390 and raclopride, dopamine D1 and D2 receptor antagonists, respectively. In addition, repeated METH treatment increased tPA activity in the nucleus accumbens. There was no difference in METH-induced hyperlocomotion between wild-type and tPA-deficient (tPA-/-) mice. On the other hand, METH-induced conditioned place preference and behavioral sensitization after repeated METH treatment were significantly reduced in tPA-/- mice compared with wild-type mice. The defect of behavioral sensitization in tPA-/- mice was reversed by microinjections of exogenous tPA into the nucleus accumbens. Our findings suggest that tPA is involved in the rewarding effects as well as the sensitization of the locomotor-stimulating effect of METH.

Role of tumor necrosis factor-alpha in methamphetamine-induced drug dependence and neurotoxicity.

Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, is now emerging as an important modulator of the function of the CNS. Methamphetamine (METH) is a widely abused psychostimulant that causes euphoria, hyperactivity, and drug dependence. High doses of METH cause long-term neurotoxicity in dopaminergic neurons. In this study, we investigated a role of TNF-alpha in METH-induced dependence and neurotoxicity. Repeated treatment with METH (2 mg/kg for 5 d) in rats induced a significant increase in TNF-alpha mRNA and protein expression in the brain. Exogenous TNF-alpha (1-4 microg) blocked locomotor-stimulating and rewarding effects of METH, as well as METH (4 mg/kg; four times at 2 hr intervals)-induced dopaminergic neurotoxicity in mice. To examine a role of endogenous TNF-alpha in behavioral and neurochemical effects of METH, we used mice with targeted deletions of the TNF-alpha gene. TNF-alpha-(-/-) mice showed enhanced responses to the locomotor-sensitizing, rewarding, and neurotoxic effects of METH compared with wild-type mice. We also examined the role of TNF-alpha in METH-induced dopamine (DA) release and uptake in vitro and in vivo in C57BL/6 mice. Exogenous TNF-alpha (4 microg) attenuated the METH-induced increase in extracellular striatal DA in vivo and potentiated striatal DA uptake into synaptosomes in vitro and in vivo. Furthermore, TNF-alpha activated vesicular DA uptake by itself and diminished the METH-induced decrease in vesicular DA uptake. Our findings suggest that TNF-alpha plays a neuroprotective role in METH-induced drug dependence and neurotoxicity by activating plasmalemmal and vesicular DA transporter as well as inhibiting METH-induced increase in extracellular DA levels.

The tissue plasminogen activator-plasmin system participates in the rewarding effect of morphine by regulating dopamine release.

Tissue plasminogen activator (tPA) is a serine protease that catalyzes the conversion of plasminogen (plg) to plasmin, which in turn functions to degrade extracellular matrix proteins in the central nervous system. The tPA-plasmin system plays a role in synaptic plasticity and remodeling. Here we show that this protease system participates in the rewarding effects of morphine by acutely regulating morphine-induced dopamine release in the nucleus accumbens (NAcc). A single morphine treatment induced tPA mRNA and protein expression in a naloxone-sensitive manner, which was associated with an increase in the enzyme activity in the NAcc. The acute effect of morphine in inducing tPA expression was diminished after repeated administration. Morphine-induced conditioned place preference and hyperlocomotion were significantly reduced in tPA(-/-) and plg(-/-) mice, being accompanied by a loss of morphine-induced dopamine release in the NAcc. The defect of morphine-induced dopamine release and hyperlocomotion in tPA(-/-) mice was reversed by microinjections of either exogenous tPA or plasmin into the NAcc. Our findings demonstrate a previously undescribed function of the tPA-plasmin system in regulating dopamine release, which is involved in the rewarding effects of morphine.