Stress sensitization induced by stressor and methamphetamine]

Repetitive or acute treatment of methamphetamine (MAP) or amphetamine (AMP) induces sensitization to both subsequent challenge treatment of the drugs, and exposure to emotional and physiological stress. In addition, chronic treatment of AMP enhanced DA utilization/release in striatum. Similarly, repetitive exposure to footshock or tail shock stress induces sensitization of noradrenaline or 3-methoxy-4-hydroxyphenylglycol (MHPG) to subsequent mild stress and to small amounts of AMP or MAP injection. Striatum, nucleus accumbens and prefrontal dopaminergic systems have an important role in the development of this sensitization. Immediate early gene (IEG) expression in the hypothalamus, nucleus accumbens and striatum may be involved in this process. Neurobiological vulnerability to schizophrenia may be induced by the interaction of multiple gene disposition and environmental insult, and schizophrenia onset and/or relapse in response to mild, non-specific stress. Stress-sensitive systems therefore are postulated in the pathophysiology of schizophrenia. In this regard, mesolimbic DA systems may be involved in the pathophysiology of schizophrenia. In contrast to MAP- or AMP- and stress-induced sensitization, haloperidol and clozapine induce IEG expression in the caudate-putamen and amygdala. Collectively, MAP- or AMP-induced sensitization may, in part, share an early functional process of neurobiological mechanisms.     

Receptor ligand-triggered resistance to alectinib and its circumvention by Hsp90 inhibition in EML4-ALK lung cancer cells

Alectinib is a new generation ALK inhibitor with activity against the gatekeeper L1196M mutation that showed remarkable activity in a phase I/II study with echinoderm microtubule associated protein-like 4 (EML4) - anaplastic lymphoma kinase (ALK) non-small cell lung cancer (NSCLC) patients. However, alectinib resistance may eventually develop. Here, we found that EGFR ligands and HGF, a ligand of the MET receptor, activate EGFR and MET, respectively, as alternative pathways, and thereby induce resistance to alectinib. Additionally, the heat shock protein 90 (Hsp90) inhibitor suppressed protein expression of ALK, MET, EGFR, and AKT, and thereby induced apoptosis in EML4-ALK NSCLC cells, even in the presence of EGFR ligands or HGF. These results suggest that Hsp90 inhibitors may overcome ligand-triggered resistance to new generation ALK inhibitors and may result in more successful treatment of NSCLC patients with EML4-ALK.     

Maintenance and characterization of an Epstein Barr virus-infected CD56-negative T cell lymphoma.

T cell lymphoma carrying Epstein Barr virus (EBV(+) TL) is very rare among Western countries while it is much more common among Japanese. Here we report an EBV(+) TL which has been maintained for years by the use of mice with severe combined immune deficiency (SCID) mice. Lymphoma was obtained from a 55-year-old male suffering from oculomotor nerve palsy and lymphadenopathy. A small piece of biopsied tumor was transplanted into SCID mice and the lymphoma has been maintained for over 3 years with passages every 2 - 3 weeks. The maintained lymphoma, termed as TMS24, and the original lymphoma cells showed identical phenotype and genotype, including diffuse medium-sized cell morphology lacking granules, suppressor / cytotoxic immunophenotype and identical T cell receptor beta-chain gene rearrangement mode. Further, both were shown to carry an identical EBV clone in terms of the number of terminal repeats and the latency II-type restricted gene expression profile. Cytogenetically, TMS24 retained two characteristic chromosomal translocations of t(1;18)(q32;q21) and t(6;12)(p21;q24). Since only one cell line with such characters has been reported previously, TMS24 should be useful for detailed analysis of EBV(+) TL.     

The importance of renal function in anemic patients treated with edoxaban after orthopedic surgery in a real-world clinical setting: A retrospective study

Edoxaban (Edx) has been approved to prevent venous thromboembolism after total knee and/or hip arthroplasty in Japan. However, the risk of anemia with Edx treatment remains elusive. No risk factors for Edx-associated anemia after orthopedic surgery have been reported. This study aimed to clarify the risk of anemia associated with Edx treatment and determine the risk factors for Edx-associated anemia after orthopedic surgery with a high risk for bleeding. First, the association between Edx treatment and the incidence of anemia-related events was retrospectively investigated by pharmacovigilance analyses using data from 5769,866 reports between the first quarters of 2016 and 2020 in the Food and Drug Administration Adverse Event Reporting System and 2752,050 reports between the fourth quarters of 2011 and 2019 in the Japanese Adverse Drug Event Report. Second, 221 patients who underwent Edx treatment after total knee and/or hip arthroplasty between July 2011 and June 2012 at a single center were included in a case−control study to clarify the risk factors for anemia. Edx treatment was associated with an increased risk of anemia-related events in orthopedic patients. Reduced renal function was identified as a critical risk factor for Edx-associated anemia after orthopedic surgery. The present study indicates that renal function should be considered in the risk management of increased Edx-associated anemia after orthopedic surgery.     

Association between maternal gestational diabetes mellitus and high‐sensitivity C‐reactive protein levels in 8‐year‐old children: The Yamanashi Adjunct Study of the Japan Environment and Children’s Study (JECS)

Gestational diabetes mellitus (GDM) is one of the most common pregnancy‐related complications; it is associated with adverse pregnancy outcomes and metabolic disorders in offspring, consistent with the concept of the developmental origins of health and disease. This cohort study of women without diabetes (n = 761), who were part of the Yamanashi Adjunct Study of the Japan Environment and Children’s Study, aimed to explore the associations between maternal GDM and their offspring’s level of high‐sensitivity C‐reactive protein (hsCRP), a biomarker of inflammatory and cardiovascular diseases. We analyzed the associations between GDM and the offspring’s hsCRP levels using a multiple logistic regression model. A mother with GDM significantly increased the risk for high hsCRP level by 4.07‐fold (≥2.0 mg/L) in the child. As such, maternal GDM was significantly associated with increased serum hsCRP levels in 8‐year‐old children.     

Device Landing Zone Calcification Predicts Significant Paravalvular Regurgitation after Transcatheter Aortic Valve Replacement: A Real Time Three‐Dimensional Transesophageal Echocardiography Study

Paravalvular regurgitation (PVR) after transcatheter aortic valve replacement (TAVR) is one of the major complications with negative clinical prognosis. Therefore, its prediction is important for further improvement of the outcome. We present a case with TAVR, in which we successfully evaluated aortic valve calcification protruding inward and into the left ventricular outflow tract by real time three‐dimensional transesophageal echocardiography, and predicted significant PVR after the procedure. In conclusion, device landing zone calcification protruding inward is a key for the prediction of significant PVR after TAVR.     

Comparison of the clinical courses of the opticospinal and conventional forms of multiple sclerosis in Japan

We evaluated the clinical courses of 216 patients with multiple sclerosis (MS) diagnosed according to the recommended diagnostic criteria of McDonald et al (10). Sixty-five patients clinically displaying selective involvement of the optic nerves and spinal cord were classified as opticospinal MS (OS-MS), while the other 151 showing disseminated involvement of the central nervous system were classified as conventional MS (C-MS). The disease duration did not differ significantly between the two subtypes (11.2 years vs. 11.5 years). In addition to a higher age of onset, female preponderance and higher Kurtzke's expanded disability status scale (EDSS) scores, the OS-MS patients showed a markedly lower frequency of secondary progressive MS than the C-MS patients (4.6% vs. 29.1%, p=0.0001). The EDSS scores of the C-MS patients were significantly correlated with the disease duration, while those of the OS-MS patients were not. Among the C-MS patients, the frequency of secondary progressive MS was significantly more common in patients with a disease duration of more than 10 years than in those with a shorter duration. These results suggest that the irreversible disability in OS-MS is determined by relapses, rather than by chronic progression, whereas C-MS has a similar clinical course to MS in Westerners.