Therapeutics potentiating microglial p21-Nrf2 axis can rescue neurodegeneration caused by neuroinflammation.

Neurodegenerative disorders are caused by progressive neuronal loss, and there is no complete treatment available yet. Neuroinflammation is a common feature across neurodegenerative disorders and implicated in the progression of neurodegeneration. Dysregulated activation of microglia causes neuroinflammation and has been highlighted as a treatment target in therapeutic strategies. Here, we identified novel therapeutic candidate ALGERNON2 (altered generation of neurons 2) and demonstrate that ALGERNON2 suppressed the production of proinflammatory cytokines and rescued neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease model. ALGERNON2 stabilized cyclinD1/p21 complex, leading to up-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2), which contributes to antioxidative and anti-inflammatory responses. Notably, ALGERNON2 enhanced neuronal survival in other neuroinflammatory conditions such as the transplantation of induced pluripotent stem cell-derived dopaminergic neurons into murine brains. In conclusion, we present that the microglial potentiation of the p21-Nrf2 pathway can contribute to neuronal survival and provide novel therapeutic potential for neuroinflammation-triggered neurodegeneration.

Heterogeneous response of nasal and lung fibroblasts to transforming growth factor-beta 1.

BACKGROUND: Nasal polyposis is characterized by marked oedema, sparse extracellular matrix (ECM) and proliferating blood vessels. Pulmonary fibrosis is characterized by inflammatory cells accumulation, considerable ECM deposition and vascular abnormalities. Although lung fibrosis is not only and necessarily an inflammatory disorder, we hypothesized that the difference between nasal polyposis and pulmonary fibrosis may, in part, be due to the heterogeneity between nasal and lung fibroblasts. Fibroblasts participate in the inflammatory response by releasing ECM proteins and cytokines. TGF-beta is thought to participate in chronic inflammation and fibrosis. Myofibroblasts are the activated form of fibroblasts. A phenotypic hallmark of myofibroblasts is the expression of smooth muscle alpha-actin (SMA). OBJECTIVE: We examined whether there is any heterogeneity between nasal and lung fibroblasts upon stimulation with TGF-beta(1) with regard to the synthesis of SMA, pro-collagen type I and vascular endothelial growth factor (VEGF) as well as translocation of Smad proteins. METHODS: Fibroblasts lines were established from human biopsy tissue. The expression of SMA, pro-collagen type I, VEGF mRNA was evaluated by reverse transciptase RT-PCR. The amount of pro-collagen type I and VEGF was measured by ELISA. By immunocytochemistry, we analysed the expression of SMA and Smad2, 3, 4 in cultured fibroblasts. RESULTS: TGF-beta(1) induced SMA and pro-collagen type I synthesis in lung, but not in nasal fibroblasts. By contrast, TGF-beta(1) induced VEGF synthesis in both lung and nasal fibroblasts. After stimulation with TGF-beta(1), Smad2, 3, 4 were translocated from the cytoplasm to the nucleus in lung fibroblasts, whereas only Smad3 was translocated in nasal fibroblasts. CONCLUSION: These results establish the heterogeneous responsiveness of fibroblast populations in the airways to TGF-beta(1) and that such a heterogeneity may contribute, at least in part, to the different pathological outcomes of inflammation in the upper and lower airways.

Famotidine prevents canine gastric blood flow reduction by NSAIDs.

AIM: To investigate the effect of famotidine on gastric blood flow reduction induced by diclofenac sodium, a common non-steroidal anti-inflammatory drug in Japan, using laser Doppler flowmetry in the canine stomach. METHODS: The gastric mucosal blood flow was measured by laser Doppler flowmetry in 15 healthy male beagles before and 60 min after the administration of diclofenac suppository (1.0 mg/kg) into the rectum. The examination was done in a crossover, single-blinded fashion. All dogs underwent both famotidine (0.5 mg/kg) and placebo (saline) injection simultaneously with the administration of diclofenac. In addition, the tissue concentration of prostaglandin E2 was measured. RESULTS: The blood flow decreased by 18.3 +/- 9.1% in the gastric body, by 26.3 +/- 8.1% in the antrum in the placebo group after the administration of diclofenac sodium, while the decreases seen were significantly smaller in the famotidine group: 3.2 +/- 12.6% in the gastric body and 7.9 +/- 16.5% in the antrum (P = 0.001 for the gastric body, P = 0.0034 for the antrum). Conversely, the percentage of mucosal prostaglandin E2 concentration decrease in each group did not show a significant difference. CONCLUSION: Famotidine alleviates the reduction of gastric blood flow induced by diclofenac sodium. Further, not only mucosal prostaglandins but also gastric acid may play an important role in non-steroidal anti-inflammatory drugs-induced gastric microcirculatory disturbance.

Induction of eotaxin production by interleukin-4, interleukin-13 and lipopolysaccharide by nasal fibroblasts.

BACKGROUND: There is growing evidence that eotaxin is a key mediator in the development of tissue eosinophilia. Fibroblasts are a major source of eotaxin. The severity of diseases with eosinophilic inflammation like nasal polyposis, atopic dermatitis and asthma, where Th2-type cytokines (IL-4 and IL-13) and TGF-beta are expressed locally, was shown to correlate with bacterial factors such as lipopolysaccharide (LPS) rather than allergen. OBJECTIVE: We examined eotaxin production by nasal fibroblasts stimulated with IL-4 or IL-13 alone or in combination with LPS, and the effect of TGF-beta(1) on it. Moreover, we compared the magnitude of eotaxin produced by nasal fibroblasts with that produced by lung or skin fibroblasts. METHODS: Fibroblast lines were established from human biopsy tissue. The expression of eotaxin mRNA was evaluated by RT-PCR. The amount of eotaxin in the supernatants was measured by ELISA. RESULTS: IL-4, but not IL-13, synergized with LPS to produce eotaxin in a dose- and time-dependent manner. Sequential treatment of nasal fibroblasts with IL-4 and LPS did not have any effect. But when IL-4 and LPS were added together, synergy for eotaxin production was observed. Moreover, this synergy was observed in nasal and skin fibroblasts, but not in lung fibroblasts. The production of eotaxin by IL-4 and LPS was modulated by TGF-beta(1). CONCLUSION: These results suggest that a co-stimulus like LPS is necessary for IL-4 to make a strong induction of eotaxin in eosinophilic inflammations such as nasal polyposis. Modulation by TGF-beta(1) may have important implications for the development of eosinophilic inflammation.

[Off-pump coronary artery bypass grafting; its impact on renal function].

PURPOSE: We evaluated the impact of off-pump coronary artery bypass grafting (off-pump CABG: OPCAB) on the perioperative renal function. METHODS: Isolated CABG was performed on 359 patients during the period from January 1999 to September 2002. Nine patients on dialysis were excluded from this study and 350 patients were divided into 2 groups: OPCAB Group (n = 214) and on-pump Group (n = 136). Perioperative serum CRE levels of the 2 groups were compared. RESULTS: The ratio of patients with renal impairment (CRE > 1.5 mg/dl) in the OPCAB Group was 8%, which did not differ statistically from that of the on-pump Group (4%). Patients who had renal impairment postoperatively accounted for 20% of the OPCAB Group, which did not differ from that of the on-pump Group (18%). The postoperative CRE/preoperative CRE ratio was lower in the OPCAB Group (1.28) than that of the on-pump Group (1.44). CONCLUSION: The renal function was preserved in the OPCAB Group compared to the on-pump Group.

[A high aged case of herpes simplex viral encephalitis associated with progressive cerebral white matter lesion].

An 80-year-old male without abnormal past medical history presented with coma, general seizures, and fever subsequent to abnormal behavior. The pressure of the cerebrospinal fluid(CSF) elevated(13.5-20.5 cm H2O), and CSF examination revealed pleocytosis with predominant mononuclear cells(80-879/mm3) and elevated protein level(32-130 mg/dl). DNAs of herpes simplex virus(HSV) type 1 and 2 in CSF were not confirmed by polymerase chain reaction method in the acute phase. The HSV(type 1) antibody(HSV-1 Ab) ratio of serum to CSF(= [serum HSV-1 Ab]/[CSF HSV-1 Ab]) was 0.98 and HSV-1 Ab index(= [CSF HSV-1 Ab]/[serum HSV-1 Ab] divided by [CSF albumin]/[serum albumin]) was 62.4. Initial fluid attenuated inversion recovery(FLAIR) (TR/TE/TI = 6,882/110/1,700 msec) axial magnetic resonance(MR) imaging showed hyperintensity in the subfrontal area, inferomedial portions of the temporal lobes, cingulate gyri, and insular cortices bilaterally. Meningoencephalitis caused by HSV-1 was diagnosed based on the values of HSV-1 Ab ratio of serum to CSF(less than 20), of HSV-1 Ab index(larger than 1.91), and the findings of MR imaging. Diffuse white matter lesions manifesting hyperintensity on FLAIR imaging in the bilateral frontal and temporal lobes close to the affected cortices developed approximately six weeks after the onset despite administration of antiviral agent and steroid. The lesion extensively involved the white matter of the bilateral frontal and temporal lobes finally. The initial value of myelin basic protein(MBP) in CSF was 0.9 ng/ml (normal value: less than 4 ng/ml). Subsequent measurement of MBP in CSF about two, six weeks, two, three, and six months after the onset showed a marked increase of 233.9 ng/ml followed by a gradual decrease of 25.4 ng/ml, 18.4 ng/ml, 7.4 ng/ml and 4.3 ng/ml, respectively. Therefore, demyelination of the lesion in the cerebral white matter was suggested by the chronological change in FLAIR imaging and MBP in CSF.

TAK-778, a novel synthetic 3-benzothiepin derivative, promotes chondrogenesis in vitro and in vivo.

TAK-778, a novel synthetic 3-benzothiepin derivative, stimulates the formation of cartilaginous nodules in mouse chondroprogenitor-like ATDC5 cells in vitro in association with upregulation of the gene expression of transforming growth factor-beta(2), but not bone morphogenetic protein-4 and insulin-like growth factor-I. One-shot injection of the TAK-778-containing sustained-release microcapsules accelerated the repair process of the full thickness defects of articular cartilage in rabbit knees. Our in vitro and in vivo results indicate that TAK-778 may be a therapeutically useful synthetic agent for articular cartilage repair.

[A case report of a coronary fistula from left coronary artery to left ventricle].

The patient is a 44-year-old man. He has had chest pain on effort since 1994, diagnosed as unstable angina in 1996. He was found to have three vessel disease on coronary angiography and was sent to TWMC for operation. CABG was performed for the right and left anterior descending arteries, and TMLR for the posteroinferior region because the left circumflex artery was fine and ungraftable. Both the grafts were patent and there was improved LV function. Interestingly, we found a coronary fistula running from the left coronary artery to the left ventricle. As far as we can tell from our literature searches, this is the first time that a coronary fistula has been found after TMLR.

Bioactive bone cement: comparison of apatite and wollastonite containing glass-ceramic, hydroxyapatite, and beta-tricalcium phosphate fillers on bone-bonding strength.

A study was conducted to compare the bone-bonding strengths of three types of bioactive bone cement, consisting of either apatite- and wollastonite-containing glass-ceramic (AW-GC) powder, hydroxyapatite (HA) powder, or beta-tricalcium phosphate (beta-TCP) powder as an inorganic filler and bisphenol-a-glycidyl methacrylate (Bis-GMA) based resin as an organic matrix. Seventy percent (w/w) filler was added to the cement. Rectangular plates (10 x 15 x 2 mm) of each cement were made and abraded with #2000 alumina powder. After soaking in simulated body fluid for 2 days, the AW cement (AWC) and HA cement (HAC) formed bonelike apatite over their entire surfaces, but the TCP cement (TCPC) did not. Plates of each type of cement were implanted into the tibial metaphyses of male Japanese white rabbits, and the failure loads were measured by a detaching test at 10 and 25 weeks after implantation. The failure loads of AWC, HAC, and TCPC were 3.95, 2.04, and 2.03 kgf at 10 weeks and 4.36, 3.45, and 3.10 kgf at 25 weeks, respectively. The failure loads of the AWC were significantly higher than those of the HAC and TCPC at 10 and 25 weeks. Histological examination by contact microradiogram and Giemsa surface staining of the bone-cement interface revealed that all the bioactive bone cements were in direct contact with bone. However, scanning electron microscopy and energy-dispersive X-ray microanalysis showed that only AWC had contacted to the bone via a Ca-P rich layer formed at the interface between the AW-GC powder and the bone, which might explain its high bone-bonding strength. Neither the HAC nor the TCPC contacted the bone through such a layer between each powder and the bone, although the HAC and TCPC directly contacted with bone. Our results indicate that all three types of abraded and prefabricated cement have bonding strength to bone, but AWC has superior bone-bonding strength compared to HAC and TCPC.

Photoablation and lens damage from fractional Talbot images of Dammann gratings.

UV photoablation of materials is recorded for both the near and far fields after transmission through a Dammann grating. The fused silica Fourier lens used for far-field imaging was damaged by a near-field intensity pattern with the same periodicity as the Dammann grating. The lens was located inadvertently at one eighth of the Talbot distance Z (T) behind the Dammann grating. Patterns recorded in copper film at the even-fractional Talbot planes compare qualitatively with calculated intensities. On the basis of these findings, a near-field intensity pattern was used to ablate vias in copper and polyimide films. The pattern at a distance of Z(T)/8 was used for via ablation because it is the pattern with the most fluence per spot.

Useful laser source criteria for optical storage employing extended eye-diagram jitter theory.

In view of the recent progress in visible lasers for next-generation optical disks, we describe the influence of source wavelength, aberration, and noise on eye-diagram jitter, which determines the ultimate disk density. The analysis indicates that the sources used in a readout of a 6× areal density, (4,22) run-length-limited code with a minimum mark length of 0.4 µm must have a wavelength that satisfies the Nyquist condition of relationship between the spot size and the minimum mark length, a wave-front aberration of less than 0.035 rms λ, and relative intensity noise of less than -125 dB/Hz.