Impairment of microglial responses to facial nerve axotomy in cathepsin S-deficient mice

Cathepsin S (CS) is a lysosomal/endosomal cysteine protease especially expressed in cells of a mononuclear lineage including microglia. To better understand the role of CS in microglia, we investigated microglial responses after a facial nerve axotomy in CS-deficient (CS-/-) and wild-type mice. Microglia in both groups accumulated in the facial motor nucleus following axotomy. However, the mean number of microglia in CS-/- mice on the axotomized side was significantly smaller than that in wild-type mice. Microglia were found to adhere to injured motoneurons in wild-type mice, whereas microglia abutted on injured motoneurons without spreading on their surface in CS-/- mice. At the same time, the axotomy-induced down-regulation of tenasin-R, an antiadhesive perineuronal net for microglia, was partially abrogated in CS-/- mice. Primary cultured microglia prepared from CS-/- mice showed that CS deficiency caused significant suppression of migration and transmigration of microglia. In CS-/- mice, impaired recruitments of circulating monocytes and T lymphocytes and reduced expression of the class II major compatibility complex on the axotomized side were observed. Interestingly, cathepsin B, a typical lysosomal cysteine protease, was markedly expressed on the axotomized side in CS-/- but not in wild-type microglia. Finally, we compared axotomy-induced neuronal death in the two groups and found that the percentage of motoneurons that survived in CS-/- mice was significantly smaller than that in wild-type mice. The present study strongly suggests that CS plays a role in the migration and activation of microglia to protect facial motoneurons against axotomy-induced injury.     

Specific acupuncture sensation correlates with EEGs and autonomic changes in human subjects

Sympathetic overactivation is suggested to be associated with chronic pain syndrome, and acupuncture is frequently applied in therapy for this syndrome. Furthermore, the forebrain including the various cerebral cortices has been implicated in inhibitory and facilitatory control of pain as well as autonomic functions. We investigated relationships among specific sensations induced by acupuncture manipulation, effects on sympathetic and parasympathetic autonomic functions, and EEG changes. An acupuncture needle was inserted into the right trapezius muscle of the subjects, and acupuncture manipulation was repeated to induce specific acupuncture sensation repeatedly while the needle was left in the muscle. Acupuncture manipulation significantly decreased heart rate (HR), and increased systolic blood pressure (SBP). Spectral analysis indicated that acupuncture manipulation significantly decreased low frequency components (LF) of both HR variability (HRV) and SBP variability (SBPV), and significantly reduced ratio of LF to high frequency component (HF) of HRV (LF/HF, index of sympathetic activity). Furthermore, there was a significant negative correlation between changes in LF/HF ratio of HRV and the number of specific acupuncture sensations reported, and a significant positive correlation between HF of HRV and the number of acupuncture sensations. Analyses of EEG data indicated that acupuncture manipulation non-specifically increased power of all spectral bands except the gamma band. Furthermore, changes in HF (index of parasympathetic activity) and total power (overall activity of the autonomic nervous system) of HRV were positively correlated with changes in theta, alpha, and gamma power, while changes in LF of SBPV and LF/HF of HRV were negatively correlated with changes in power of all spectral bands. These results are consistent with the suggestion that autonomic changes induced by manipulation inducing specific acupuncture sensations might be mediated through the central nervous system, especially through the forebrain as shown in EEG changes, and are beneficial to relieve chronic pain by inhibiting sympathetic nervous activity.     

Clinical significance of the serum IL-2R level and Ga-67 scan findings in making a differential diagnosis between sarcoidosis and non-Hodgkin's lymphoma

Objective To compare the serum-soluble interleukin-2 receptor (sIL-2R) levels of non-Hodgkin's lymphoma patients and active sarcoidosis patients in relation to the ⁶⁷Ga scan findings. Methods A total of 29 adenopathy patients suspected of having non-Hodgkin's lymphoma or sarcoidosis were enrolled in the study. All patients underwent a whole-body ⁶⁷Ga scan and single-photon emission computed tomography studies 48 h after intravenous injection of ⁶⁷Ga citrate. The sIL-2R levels were compared between the sarcoidosis patients and non-Hodgkin's lymphoma patients, the patients with and without the panda and/or lambda sign, the lymphoma patients with stage I/II disease and with stage III/IV disease, and the sarcoidosis patients and non-Hodgkin's lymphoma patients with stage III/IV disease. Results The range of the sIL-2R levels was 195–3750 U/ml in sarcoidosis and 240–62 300 U/ml in non-Hodgkin's lymphoma. The sIL-2R levels of the six non-Hodgkin's lymphoma patients with stage III/IV disease were significantly higher than those of the 15 sarcoidosis patients (P < 0.001). The sIL-2R levels of the sarcoidosis patients with the panda and/or lambda sign were significantly higher than those with neither sign (P < 0.005). The sIL-2R levels of the non-Hodgkin's lymphoma patients with stage III/IV disease were significantly higher than those of the patients with stage I/II disease (P < 0.005). Conclusions Measurement of sIL-2R levels was sometimes useful in differentiating between sarcoidosis and stage III/IV non-Hodgkin's lymphoma, staging non-Hodgkin's lymphoma, and predicting the presence of the panda and/or lambda sign in sarcoidosis patients.     

Cine MR imaging of uterine peristalsis in patients with endometriosis

Endometriosis is one of the most important causes of infertility; however the precise mechanism by which it affects female fertility is unclear. The objective of this study was to study the functional aspects of the uterus by evaluating uterine contractility in patients with endometrial cysts of the ovary. The study population was recruited from two institutes and consisted of 26 women (periovulatory (10), luteal (13), and menstrual phase (3); age range: 19–51 years) with untreated endometriosis; the control group consisted of 12 healthy women (age range: 22–41 years). Cine MR imaging obtained by a 1.5T magnet was visually evaluated at 12× faster than real speed, focusing on the presence of uterine peristalsis, the direction and frequency of peristalsis, and the presence of sustained uterine contractions. Uterine peristalsis was identifiable in 3/10, 3/13, and 3/3 of the endometriosis patients in each menstrual cycle, respectively, and in 11/12, 3/12, and 5/12 of their control subjects. Peristaltic detection rate and frequency were significantly less for the endometriosis group than for the controls in the periovulatory phase only (p<0.05). Sustained contractions were recognized in 19/36 control subjects and in 13/26 endometriosis patients, but the difference was not significant. Uterine peristalsis appears to be suppressed during the periovulatory phase in patients with endometriosis, which may have an adverse effect on sperm transport. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users.     

Different epidermal growth factor receptor gene mutations in a patient with 2 synchronous lung cancers

Recently, the frequency of lung adenocarcinoma has been increasing among nonsmokers, though the etiology remains unclear. Mutations of the epidermal growth factor receptor (EGFR) gene are frequently detected in the lung adenocarcinomas seen in nonsmokers. Thus, EGFR mutations can be implicated in carcinogenesis of lung adenocarcinoma. Herein, we report a case of 2 synchronous lung adenocarcinomas composed of 2 distinct pathological subtypes with different EGFR mutations: homozygous deletion in exon 19 in the papillary subtype of adenocarcinoma and a point mutation of L858R in exon 21 in the tubular adenocarcinoma. These findings suggest that specific mutations can occur randomly in the EGFR hot spot, and that these EGFR mutations can contribute to the distinct carcinogenic process of each adenocarcinoma.     

Abstracts

We present the first case report of left ventricle muscular diverticulum which stands in front of the right ventricle in an asymptomatic 20-year-old male. The diverticulum has a connection with the left ventricular outflow truct, and contracts simultaneously with the left ventricle. The patient has been included in our congenital anomaly follow-up program.     

A new low-field extremity magnetic resonance imaging and proposed compact MRI score: evaluation of anti-tumor necrosis factor biologics on rheumatoid arthritis

Magnetic resonance imaging (MRI) is a useful tool for evaluating disease activity and therapeutic efficacy in rheumatoid arthritis (RA). However, conventional whole-body MRI is inconvenient on several levels. We have therefore developed a new low-field extremity MRI (compact MRI, cMRI) and examined its clinical utility. Thirteen RA patients treated with anti-tumor necrosis factor (TNF) biologics were included in the study. The MRI was performed twice using a 0.21-T extremity MRI system. The MRI images were scored using our proposed cMRI scoring system, which we devised with reference to the Outcome Measures in Rheumatology Clinical Trials RA MRI score (OMERACT RAMRIS). In our cMRI scoring system, synovitis, bone edema, and bone erosion are separately graded on a scale from 0 to 3 by imaging over the whole hand, including the proximal interphalangeal joint. The total cMRI score (cMRIS) is then obtained by calculating the total bone erosion score × 1.5 + total bone edema score × 1.25 + total synovitis score. In this study, one patient showed a progression of bone destruction even under low clinical activity, as assessed by the disease activity score on 28 joints (DAS28); however, another patient’s cMRIS decreased concurrently with the decrease in DAS28, with the positive correlation observed between ΔDAS28 and ΔcMRIS (R = 0.055, P < 0.05). We conclude that cMRI and cMRIS are useful for assessing total disease activity and as a method linking MRI image evaluation to clinical evaluation.     

Interferon-α-induced mTOR activation is an anti-hepatitis C virus signal via the phosphatidylinositol 3-kinase-Akt-independent pathway

Object  The interferon-induced Jak-STAT signal alone is not sufficient to explain all the biological effects of IFN. The PI3-K pathways have emerged as a critical additional component of IFN-induced signaling. This study attempted to clarify that relationship between IFN-induced PI3-K-Akt-mTOR activity and anti-viral action. Result  When the human normal hepatocyte derived cell line was treated with rapamycin (rapa) before accretion of IFN-α, tyrosine phosphorylation of STAT-1 was diminished. Pretreatment of rapa had an inhibitory effect on the IFN-α-induced expression of PKR and p48 in a dose dependent manner. Rapa inhibited the IFN-α inducible IFN-stimulated regulatory element luciferase activity in a dose-dependent manner. However, wortmannin, LY294002 and Akt inhibitor did not influence IFN-α inducible luciferase activity. To examine the effect of PI3-K-Akt-mTOR on the anti-HCV action of IFN-α, the full-length HCV replication system, OR6 cells were used. The pretreatment of rapa attenuated its anti-HCV replication effect in comparison to IFN-α alone, whereas the pretreatment with PI3-K inhibitors, wortmannin and LY294002 and Akt inhibitor did not influence IFN-induced anti-HCV replication. Conclusion  IFN-induced mTOR activity, independent of PI3K and Akt, is the critical factor for its anti-HCV activity. Jak independent mTOR activity involved STAT-1 phosphorylation and nuclear location, and then PKR is expressed in hepatocytes.