Inhibition from ventral tegmental area of nucleus accumbens neurons in the rat

The role of the ventral tegmental area (VTA), which is rich in dopamine-containing cell bodies, on nucleus accumbens (Acc) neurons was examined. In Acc neurons receiving input from parafascicular nucleus (Pf) of thalamus, VTA conditioning stimulation produced an inhibition of spike generation with Pf stimulation. In contrast, VTA conditioning stimulation did not affect Acc neurons receiving input from limbic structures such as the amygdala nucleus and hippocampus.     

c-Jun N-terminal kinase inhibition and alpha-tocopherol protect midbrain dopaminergic neurons from interferon-gamma/lipopolysaccharide-induced injury without affecting nitric oxide production

Interferon-gamma (IFN-gamma)/lipopolysaccharide (LPS) induces delayed dopaminergic neuron loss in midbrain slice cultures, because of nitric oxide production resulting from p38 mitogen-activated protein kinase (p38 MAPK)-dependent induction of inducible nitric oxide synthase (iNOS). In this study, we show that inhibition of c-Jun N-terminal kinase (JNK), but not of extracellular signal-regulated kinase, protects dopaminergic neurons from IFN-gamma/LPS-induced degeneration. In contrast to a p38 MAPK inhibitor, SB203580, however, a JNK inhibitor, anthra[1,9-cd]pyrazol-6(2H)-one (SP600125), did not suppress IFN-gamma/LPS-induced iNOS expression and nitric oxide production. Involvement of NADPH oxidase-derived superoxide production in dopaminergic neurodegeneration was not obvious, in that superoxide dismutase/catalase or manganese 3-methoxy-N,N'-bis(salicylidene)ethylenediamine chloride (EUK-134), a superoxide dismutase/catalase mimetic, did not afford neuroprotection. Moreover, the NADPH oxidase inhibitors apocynin and diphenylene iodonium were protective against IFN-gamma/LPS cytotoxicity only at concentrations that suppressed nitric oxide production. Notably, alpha-tocopherol effectively prevented IFN-gamma/LPS-induced dopaminergic neuron degeneration, without affecting iNOS induction and nitric oxide production. These results underscore the neuroprotective potential of JNK inhibitor and alpha-tocopherol, in the sense that both agents could rescue dopaminergic neurons under inflammatory conditions associated with robust increases in nitric oxide production.     

Cerebral bone subtraction CT angiography using 80 kVp and sinogram-affirmed iterative reconstruction: contrast medium and radiation dose reduction with improvement of image quality

Introduction

The purpose of this study was to evaluate the feasibility of a contrast medium (CM), radiation dose reduction protocol for cerebral bone-subtraction CT angiography (BSCTA) using 80-kVp and sinogram-affirmed iterative reconstruction (SAFIRE).

Methods

Seventy-five patients who had undergone BSCTA under the 120- (n = 37) or the 80-kVp protocol (n = 38) were included. CM was 370 mgI/kg for the 120-kVp and 296 mgI/kg for the 80-kVp protocol; the 120- and the 80-kVp images were reconstructed with filtered back-projection (FBP) and SAFIRE, respectively. We compared effective dose (ED), CT attenuation, image noise, and contrast-to-noise ratio (CNR) of two protocols. We also scored arterial contrast, sharpness, depiction of small arteries, visibility near skull base/clip, and overall image quality on a four-point scale.

Results

ED was 62% lower at 80- than 120-kVp (0.59 ± 0.06 vs 1.56 ± 0.13 mSv, p < 0.01). CT attenuation of the internal carotid artery (ICA) and middle cerebral artery (MCA) was significantly higher on 80- than 120-kVp (ICA: 557.4 ± 105.7 vs 370.0 ± 59.3 Hounsfield units (HU), p < 0.01; MCA: 551.9 ± 107.9 vs 364.6 ± 62.2 HU, p < 0.01). The CNR was also significantly higher on 80- than 120-kVp (ICA: 46.2 ± 10.2 vs 36.9 ± 7.6, p < 0.01; MCA: 45.7 ± 10.0 vs 35.7 ± 9.0, p < 0.01). Visibility near skull base and clip was not significantly different (p = 0.45). The other subjective scores were higher with the 80- than the 120-kVp protocol (p < 0.05).

Conclusion

The 80-kVp acquisition with SAFIRE yields better image quality for BSCTA and substantial reduction in the radiation and CM dose compared to the 120-kVp with FBP protocol.

     

Gastric volvulus and giant Bochdalek hernia in an adult patient that were safely repaired by endoscopic reduction and elective laparoscopic surgery

A Bochdalek hernia (BH) is a congenital abnormality with incomplete closure of the diaphragm. It is usually manifested in infants but rarely in adults. Here, we report an adult patient with gastric volvulus and giant BH that were safely repaired by endoscopic reduction and elective laparoscopic surgery, respectively. A 79-year-old woman presented with left upper abdominal pain but no history of trauma. CT revealed a giant BH with gastric volvulus. After emergency endoscopic reduction of the volvulus, elective laparoscopic repair of the BH was performed. The 8 × 8-cm defect was repaired with interrupted nonabsorbable sutures and a mesh. The patient's postoperative course was uneventful, and no complications or recurrence were observed in the 6 months that followed.     

Healthy HTLV-I carriers in Japan: the haematological and immunological characteristics

The haematological and immunological characteristics of 34 healthy anti-HTLV-I antibody-positive individuals (HTLV-I carriers) in southwestern Japan were examined. No significant difference was noted between carriers and the controls in counts of RBC, WBC and the absolute number of lymphocytes. The serum IgG in the carriers was higher than that of the controls. The percentages of OKT4, OKT8, OKIa1 and B1-positive cells were found to be normal in the peripheral blood of the carriers, whereas the percentages of OKT11 and anti-Tac-positive cells were significantly higher in the carriers than in the controls. A correlation was observed between the percentages of anti-Tac-positive cells and the titres of anti-HTLV-I antibody in the carriers. After a 72 h incubation of peripheral blood lymphocytes with medium alone, the percentage of anti-Tac-positive cells tended to decrease in the controls, but to increase in carriers, with the appearance of large blastoid cells resembling blastic transformed lymphocytes cultured with mitogen. Tac and Ia antigens were markedly expressed on these large blastoid cells.     

Apoptosis and p53 expression in chondrocytes relate to degeneration in articular cartilage of immobilized knee joints

OBJECTIVE: We have reported that articular cartilage showed early stage degeneration at 7 and 14 days after immobilization, moderate degeneration at 28 days, and severe degeneration at 42 days in rabbits. To test whether apoptosis occurs in association with p53 expression in chondrocytes during the process of articular cartilage degeneration, we investigated the degree of cartilage degeneration, the frequency of apoptotic cells, and the levels of p53 mRNA in rabbits and mice after knee immobilization. METHODS: Right knees of male Japanese white rabbits were immobilized in full extension with fiberglass casts for up to 42 days. Similarly, right knees of male p53 wild-type [p53 (+/+)] and p53 null [p53 (-/-)] mice were immobilized in full extension with bandage tape for up to 84 days. Apoptotic cells were confirmed by TUNEL staining on the sections of knee joints. Total RNA of articular chondrocytes obtained from Day 0 or immobilized knees was analyzed semiquantitatively by RT-PCR using specific primers for p53. RESULTS: Articular cartilage degenerated after immobilization of p53 (+/+) mouse knees, but not after immobilization of p53 (-/-) knees. Apoptotic cells were observed in articular cartilage in the femur and tibia of rabbits and p53 (+/+) mice after immobilization. However, only a few apoptotic cells were observed at the same sites in p53 (-/-) mice. In RT-PCR analysis, the levels of p53 mRNA obtained from immobilized groups were significantly higher than those of Day 0 groups in rabbit and p53 (+/+) mouse knees. CONCLUSION: Apoptosis and p53 expression in chondrocytes relate to degeneration in articular cartilage of immobilized knee joints.     

The growth factor midkine regulates the renin-angiotensin system in mice

The renin-angiotensin system plays a pivotal role in regulating blood pressure and is involved in the pathogenesis of kidney disorders and other diseases. Here, we report that the growth factor midkine is what we believe to be a novel regulator of the renin-angiotensin system. The hypertension induced in mice by 5/6 nephrectomy was accompanied by renal damage and elevated plasma angiotensin II levels and was ameliorated by an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin receptor blocker. Notably, ACE activity in the lung, midkine expression in the lung, and midkine levels in the plasma were all increased after 5/6 nephrectomy. Exposure to midkine protein enhanced ACE expression in primary cultured human lung microvascular endothelial cells. Furthermore, hypertension was not induced and renal damage was less severe in midkine-deficient mice. Supplemental administration of midkine protein to midkine-deficient mice restored ACE expression in the lung and hypertension after 5/6 nephrectomy. Oxidative stress might be involved in midkine expression, since expression of NADH/NADPH oxidase–1, –2, and –4 was induced in the lung after 5/6 nephrectomy. Indeed, the antioxidative reagent tempol reduced midkine expression and plasma angiotensin II levels and consequently ameliorated hypertension. These results suggest that midkine regulates the renin-angiotensin system and mediates the kidney-lung interaction after 5/6 nephrectomy.     

Incidence of hepatocellular carcinoma in HCV-infected patients with normal alanine aminotransferase levels categorized by Japanese treatment guidelines

Background

This study was conducted to evaluate Japanese treatment guidelines for patients with chronic hepatitis C virus (HCV) infection and normal alanine aminotransferase (N-ALT) levels from the viewpoint of the incidence of hepatocellular carcinoma (HCC).

Methods

Four groups of patients with chronic HCV infection treated with pegylated interferon (Peg-IFN) plus ribavirin, and classified according to the N-ALT guidelines, were examined for HCC incidence: group A (n = 353), ALT ≤30 IU/L and platelet (PLT) ≥15 × 10⁴/mm³; group B (n = 123), ALT ≤30 IU/L and PLT <15 × 10⁴/mm³; group C (n = 233), 30 < ALT ≤ 40 IU/L and PLT ≥15 × 10⁴/mm³; and group D (n = 100), 30 < ALT ≤ 40 IU/L and PLT <15 × 10⁴/mm³. The mean observation period was 36.2 ± 16.5 months

Results

In groups A and C, the HCC incidence was low even in patients with non-response (NR) (cumulative rates at 3 years, 0.0 and 2.9 %, respectively). In groups B and D, 14.5 and 5.3 % of NR patients had developed HCC at 3 years, but none of the patients with sustained virologic response (SVR) or relapse had developed HCC. In group B, no patients with mild fibrosis developed HCC irrespective of the antiviral effect of the treatment. Among patients with PLT <15 × 10⁴/mm³ (group B plus group D), the HCC incidence was significantly lower in patients with SVR and relapse than in NR patients (p < 0.001, p = 0.021, respectively).

Conclusion

These results suggest that N-ALT patients with PLT <15 × 10⁴/mm³ could be candidates for early antiviral therapy.     

Protein kinase A activates protein phosphatase 2A by phosphorylation of the B56delta subunit

Our previous studies of DARPP-32 in striatal slices have shown that activation of D1 receptors leads to cAMP-dependent dephosphorylation of Thr-75, the Cdk5 site in DARPP-32. In the current study, we have elucidated a mechanism whereby protein phosphatase 2A (PP2A) is activated by a cAMP/PKA-dependent pathway, leading to dephosphorylation of Thr-75. PP2A consists of a catalytic C subunit that associates with the scaffolding A subunit and a variety of B subunits. We have found that the A/C subunits of PP2A, in association with the B56delta (or PPP2R5D) regulatory subunit, is an active DARPP-32 phosphatase. The B56delta subunit expressed in HEK293 cells forms a heterotrimeric assembly that catalyzes PKA-mediated dephosphorylation at Thr-75 in DARPP-32 (also cotransfected into HEK293 cells). The B56delta subunit is phosphorylated by PKA, and this increases the overall activity of PP2A in vitro and in vivo. Among four PKA-phosphorylation sites identified in B56delta in vitro, Ser-566 was found to be critical for the regulation of PP2A activity. Moreover, Ser-566 was phosphorylated by PKA in response to activation of D1 receptors in striatal slices. Based on these studies, we propose that the B56delta/A/C PP2A complex regulates the dephosphorylation of DARPP-32 at Thr-75, thereby helping coordinate the efficacy of dopaminergic neurotransmission in striatal neurons. Moreover, stimulation of protein phosphatase activity by this mechanism may represent an important signaling pathway regulated by cAMP in neurons and other types of cell.     

A case of scirrhous gastric cancer with peritonitis carcinomatosa controlled by TS-1(R) + paclitaxel for 36 mo after diagnosis

A 34-year-old female complaining of abdominal fullness was diagnosed as scirrhous gastric cancer (type 4')with peritonitis carcinomatosa in July 2002. A combined chemotherapy regimen was selected to control massive ascites; TS-1(R) 80 mg/m2 was given orally on d 1-14,22-35, and paclitaxel 50 mg/m2 was administered intravenously on d 1, 8, 22 and 29. After 2 courses of this regimen, the primary tumor was markedly reduced,and ascites completely vanished. Alopecia (grade 1,since d 30), leukocytopenia (grade 2, on d 34) and anemia (grade 2, on d 34) were the only adverse events throughout the following courses. The chemotherapy was effective for 28 mo, and then it was discontinued upon the patient's own request, and she survived for 36mo after diagnosis.