Precise Measurement of Differential Cross Sections of the Σ

The differential cross sections of the Σ^{-}p→Λn reaction were measured accurately for the Σ^{-} momentum (p_{Σ}) ranging from 470 to 650 MeV/c at the J-PARC Hadron Experimental Facility. Precise angular information about the Σ^{-}p→Λn reaction was obtained for the first time by detecting approximately 100 reaction events at each angular step of Δcosθ=0.1. The obtained differential cross sections show a slightly forward-peaking structure in the measured momentum regions. The cross sections integrated for -0.7≤cosθ≤1.0 were obtained as 22.5±0.68 [statistical error(stat.)] ±0.65 [systematic error(syst.)] mb and 15.8±0.83(stat)±0.52(syst) mb for 470

Observation of Coulomb-Assisted Nuclear Bound State of Ξ

In an emulsion-counter hybrid experiment performed at J-PARC, a Ξ^{-} absorption event was observed which decayed into twin single-Λ hypernuclei. Kinematic calculations enabled a unique identification of the reaction process as Ξ^{-}+^{14}N→_{Λ}^{10}Be+_{Λ}^{5}He. For the binding energy of the Ξ^{-} hyperon in the Ξ^{-}-^{14}N system a value of 1.27±0.21 MeV was deduced. The energy level of Ξ^{-} is likely a nuclear 1p state which indicates a weak ΞN-ΛΛ coupling.

Addiction to the IGF2-ID1-IGF2 circuit for maintenance of the breast cancer stem-like cells.

The transcription factor nuclear factor-κB (NF-κB) has important roles for tumorigenesis, but how it regulates cancer stem cells (CSCs) remains largely unclear. We identified insulin-like growth factor 2 (IGF2) is a key target of NF-κB activated by HER2/HER3 signaling to form tumor spheres in breast cancer cells. The IGF2 receptor, IGF1 R, was expressed at high levels in CSC-enriched populations in primary breast cancer cells. Moreover, IGF2-PI3K (IGF2-phosphatidyl inositol 3 kinase) signaling induced expression of a stemness transcription factor, inhibitor of DNA-binding 1 (ID1), and IGF2 itself. ID1 knockdown greatly reduced IGF2 expression, and tumor sphere formation. Finally, treatment with anti-IGF1/2 antibodies blocked tumorigenesis derived from the IGF1Rhigh CSC-enriched population in a patient-derived xenograft model. Thus, NF-κB may trigger IGF2-ID1-IGF2-positive feedback circuits that allow cancer stem-like cells to appear. Then, they may become addicted to the circuits. As the circuits are the Achilles' heels of CSCs, it will be critical to break them for eradication of CSCs.

Characterization of cutaneous infiltrates in MRL/lpr mice monitored from onset to the full development of lupus erythematosus-like skin lesions.

The skin is a primary site injured in lupus erythematosus (LE), but it is still controversial whether the injury is due to cells of the mononuclear infiltrate and which immunocompetent cells play the major role in the development of cutaneous LE. To better characterize the role of immunocompetent cells, we performed an immunohistochemical examination of these cells in LE-like skin lesions in MRL/Mp-lpr/lpr (MRL/lpr) mice. Skin lesions in 60 female MRL/lpr mice were monitored from onset to full development. Skin specimens from each stage were stained for epidermal Ia+ Langerhans cells (Ia(+)-LC), for Thy-1+ dendritic epidermal cells (Thy-1+DEC), and for the phenotype of the mononuclear cell infiltrates. The numbers of Ia(+)-LC and Thy-1+DEC were decreased markedly in the skin lesions at the later stage. However, the numbers of Ia(+)-LC were increased significantly in the central portion of lesions at an early stage and in the peripheral portion of lesions later. L3T4+ cells were predominant, and the L3T4/Lyt-2 ratio was high in dermal infiltrates at an early stage. With advancing stage, the L3T4/Lyt-2 ratio gradually decreased in dermal infiltrates, whereas the Thy-1.2/Lyt-2 ratio in lymph nodes was reversed. L3T4+ cells were especially predominant in dermal infiltrates under the epidermis with increased numbers of Ia(+)-LC. This immunohistochemical analysis of a mouse model of cutaneous LE revealed changes in immunocompetent cell populations with the evolution of skin lesions, and we conclude that Ia(+)-LC and Thy-1+DEC, as well as L3T4+ and Lyt-2+ cells, may play pathogenic roles in the development of skin lesions.

Effect of ultraviolet irradiation on the activity of rat skin prostaglandin D synthetase.

The effect of ultraviolet light-B (UVB) irradiation on the activity of prostaglandin (PG) D synthetase was investigated in adult rat skin. Rats were irradiated with 500 mJ/cm2 of UVB, and PGD synthetase activity was determined in 100,000 g supernatant of the homogenate of rat skin in the presence of glutathione (GSH) before and 3, 6, 12, and 24 h after irradiation. The PGD synthetase activity was decreased time dependently, and within 24 h after UVB irradiation it had dropped to 50% of the control level before irradiation. In contrast, the synthesizing activities of PGE2 and PGF2 alpha were unaffected by UVB irradiation. The reduction of PGD synthetase activity after UVB irradiation was much more prominent in the epidermis than in the dermis, which was separated by heat treatment (55 degrees C, 30 sec). Immunohistochemical studies, using anti-(rat spleen PGD synthetase) antibody, revealed that the number of immunopositive cells, which were identified as Langerhans cells, decreased in the basal layer of the epidermis 24 h after UVB irradiation. These results, together with the reduction of ATPase positive cells in the epidermis after UVB irradiation, suggest that the decrease of PGD synthetase activity in rat skin by UVB irradiation is, at least in part, due to the reduced Langerhans cell population in the basal layer of the epidermis.

Spontaneous autoimmune skin lesions of MRL/n mice: autoimmune disease-prone genetic background in relation to Fas-defect MRL/1pr mice.

The autoimmune-prone MRL/Mp-lpr/lpr (MRL/lpr) mouse is characterized by the lpr mutation, which is a defect in the Fas antigen. Since Fas mediates apoptosis, this defect results in CD4-CD8- double negative T-cell proliferation, lupus nephritis, and macroscopic lupus erythematosus-like skin lesions. The control counterpart of MRL/lpr mouse is the MRL/Mp-+/+ (MRL/n) mouse, which lacks the lpr mutation and is almost normal during the first 6 mo of life. The lpr mutation, however, accelerates autoimmune phenomena in MRL/lpr mice. Thus, it is important to investigate autoimmune diseases like systemic lupus erythematosis in relation to the autoimmune disease-prone genetic background of MRL/n mice. We found that skin lesions in aged MRL/n mice had unique characteristics. The first characteristic is spontaneous occurrence, and the second is epidermal cell nuclear immunostaining with IgGs by direct immunofluorescence. The skin lesions in aged MRL/n mice showed milder inflammation than in MRL/lpr mice. A homogeneous pattern of epidermal cell nuclear staining was always associated with nuclear staining in kidney cells and also correlated with the in vitro binding of sera to keratinocytes cultured from newborn MRL/n mice. These results suggest that the skin lesions of aged MRL/n mice are a good model for certain types of cutaneous lupus erythematosus and also can provide new insights into the long-standing controversy whether epidermal cell nuclear staining occurs in vivo.

Telomerase activity and telomere length in benign and malignant human thyroid tissues.

Several studies have demonstrated that telomerase is activated and telomere length is altered in various types of tumors. In this study, we investigated telomerase activities and telomere length in 21 thyroid tumors. Telomerase activity was detected in 11 of 12 thyroid cancers and three of nine follicular adenomas. The mean telomere lengths in the cancers tissue and follicular adenomas were lower than in the respective background tissues, the differences being significant (P=0.0055 and P<0.006), respectively. Our findings suggest that change in telomerase activity and telomere length may be important for development of thyroid tumors.

Immunohistochemical prognostic indicators of gastrointestinal carcinoid tumours.

AIMS: The aim of this study was to determine whether expression of the oncoproteins p21, p53, E-cadherin (EC), cyclin D1, bcl-2 and Rb and the proliferation marker Ki-67 is predictive of malignant behaviour in gastrointestinal carcinoid tumours. METHODS: Immunohistochemical (IHC) staining was performed on carcinoid tumours from 41 patients (31 rectal, eight gastrointestinal, two appendiceal lesions). The six tumours that had invaded deeply into the muscularis propria or beyond, had metastasized to regional lymph nodes or had metastasized to a distant site were classified as the malignant group, and the other 35 tumours formed the benign group. IHC expression was compared between the two groups, and the prognostic value of each marker was assessed. RESULTS: Of the six tumours in the malignant group, 66.7% were p21 positive, 0% were p53 positive, 33.3% were EC positive, 100% were cyclin D1 positive, 33.3% were Rb positive, 16.7% were bcl-2 positive and 50% were Ki-67 positive. Of the 35 tumours in the benign group, 17.1% were p21 positive, 0% were p53 positive, 100% were EC positive, 94.3% were cyclin D1 positive, 8.6% were Rb positive, 17.1% were bcl-2 positive and 0% were Ki-67 positive. CONCLUSIONS: These data show that p53, cyclin D1, Rb, bcl-2 and Ki-67 staining does not correlate with malignant behaviour but that overexpression of p21 (P=0.02) and reduced staining of EC (P=0.005) do correlate with malignant behaviour. These two parameters may therefore be useful as prognostic indicators for gastrointestinal carcinoid tumours.

Effect of glutamine on acute lung injury in rats with endotoxemia.

We administered endotoxin to rats to produce an acute lung injury model, and assessed the effect on respiratory function when glutamine was added to the solution for total parenteral nutrition. Rats given total parenteral nutrition with glutamine as 33% of the amino acid content were compared with rats given no glutamine. Endotoxin (500 microg/kg) was administered intravenously after 72 h of total parenteral nutrition. The survival rate and the nitrogen balance were significantly improved (P < 0.05) at 48 h after endotoxin administration as a result of glutamine treatment. In addition, the arterial oxygen partial pressure was significantly increased (P < 0.01) and the wet: dry lung weight ratio was decreased (P < 0.05) by glutamine. These results suggested that glutamine improved endotoxin-induced acute lung injury in rats.

Evaluation of ATPase-positive Langerhans' cells in skin lesions of lupus erythematosus and experimentally induced inflammations.

We examined the time-dependent dynamics of epidermal Langerhans' cells (LC) in human systemic lupus erythematosus (SLE), in MRL/Mp-lpr/lpr(MRL/lpr) mice, and in various experimental cutaneous inflammations, such as the Arthus reaction, dinitrochlorobenzene allergic dermatitis, and croton oil primary irritant dermatitis, in order to clarify the pathomechanisms of lupus skin lesions. The numbers of LC in untreated SLE patients with newly developed skin lesions decreased in the central lesional sites and increased significantly in the peripheral lesional sites. In MRL/lpr mice, the number of LC increased significantly in the central lesional sites during the initial stage and increased in the peripheral lesional sites and decreased in the central lesional sites 2-4 weeks after the onset of skin lesions. In contrast, with experimental cutaneous inflammations of guinea pigs, the increase in numbers of LC in the peripheral lesional sites was not significant during the time course of the reaction. These results suggest that the increased numbers of LC during the active and early stages of skin lesions in human SLE and MRL/lpr mice are closely related to the specific spontaneous development of skin lesions, unlike the dynamics of LC in experimental cutaneous inflammations.

Catecholamine and cytokine response to laparoscopic adrenalectomy in patients with pheochromocytoma.

This study assesses the surgical stress of laparoscopic adrenalectomy (LA) in patients with pheochromocytoma using catecholamine and cytokine. The study was conducted on one patient who had laparoscopic adrenalectomy performed for pheochromocytoma, and three patients as controls who had undergone laparoscopic cholecystectomy (LC) for cholecystolithiasis. Catecholamines, tumor necrosis factor alpha (TNFalpha) and interleukin 6 (IL-6) were measured at 30-minute intervals intraoperatively, and on the first, third and fifth postoperative days (POD) respectively. Plasma TNFalpha and IL-6 were measured by a commercially available sandwich enzyme-linked immunosorbent assay test. During the operation. changes of catecholamine concentration in LA were far larger than those in LC. The changes of TNFalpha concentration in LA were also larger than those in LC. TNFalpha returned to basal value at the end of the operation in LC, but it did not in LA. TNFalpha concentration in LC changed a little after the surgery, whereas that in LA sharply increased and was maintained at a high level from 1 POD until 5 POD. Enhanced cytokine responses were observed in LA compared to LC during and after the surgery. We concluded that laparoscopic adrenalectomy may give those patients with pheochromocytoma more surgical stress than laparoscopic cholecystectomy for cholecystolithiasis, during and after the operation.

Review of 41 patients operated on for primary hyperparathyroidism.

We reviewed 41 cases of operation for primary hyperparathyroidism (PHPT) in our institution between 1987 and 1999. The objective of this study was 1) to evaluate the sensitivity and positive predictive value of several localization studies for an enlarged parathyroid gland; 2) to determine whether a selective. unilateral-exploration operation is safe; and 3) to investigate rates of coexisting malignancies of other organs. A total of 61 enlarged parathyroid glands (701 +/- 131 mg wt) were removed, and the lesions consisted of 32 adenomas, two cancers, and seven hyperplasias. MIBI scintigraphy had both a high sensitivity (88.9%) and positive predictive value (88.9%) for localization of abnormal parathyroid glands and yielded better performance than the other techniques, including ultrasonography, CT scanning, and Tl-Tc scintigraphy. However, all of the localization techniques failed to detect enlarged glands (18/32 glands = 62.5%) in patients with multi-glandular parathyroid lesions. Initial operations with selective unilateral exploration of the neck were successful in 23 of 24 patients (95.8%). Operative failure was due to missing the second adenoma of a double adenoma. Malignant tumors were found in 11 patients (26.8%) previously treated or concurrently managed at the time of parathyroidectomy. There was a significant increase in serum-intact PTH level in patients with concurrent malignant tumors compared to patients who had no association of malignancies. In conclusion, 1) at least two preoperative localization tests, an MIBI scan and ultrasonography, are helpful in accurately localizing an abnormal parathyroid gland; 2) selective unilateral exploration is safe and desirable if the second ipsilateral gland is normal macroscopically; and 3) systematic examination for malignant tumors is necessary in PHPT patients before and after parathyroidectomy.

Coexistence of pemphigus and bullous pemphigoid.

Widespread tense blisters developed on a 60-year-old Japanese man who had been diagnosed with pemphigus 11 years earlier, because of a history of pruritic erythema and erosions on his face, chest, and back, mild supra-basal layer blister formation found in a biopsy specimen, and a positive direct immunofluorescence test showing IgG deposition in the intercellular space. The histological findings showed subepidermal blister, and the immunoblot study detected 180kD bullous pemphigoid antigen. Direct immunofluorescence test revealed intercellular staining for IgG, and indirect immunofluorescence tests repeatedly demonstrated the presence of circulating antibodies to the intercellular space. From these observations, this case suggests the coexistence of pemphigus and bullous pemphigoid.

Evaluation of the Japanese-Chinese herbal medicine, kampo, for the treatment of lupus dermatoses in autoimmune prone MRL/Mp-lpr/lpr mice.

Kampo, a Japanese-Chinese traditional herbal medicine, has been used for the treatment of various diseases for about 3,000 years in China. Among herbal medicines, Sairei-to is well known for improving the symptoms of rheumatoid arthritis (RA) and other collagen diseases. However, its immunosuppressive effects on autoimmune cutaneous phenomena are not completely understood. We investigated the effects of Sairei-to on the development of lupus dermatoses in autoimmune-prone MRL/Mp-lpr/lpr (MRL/lpr) mice, an animal model which spontaneously develops skin lesions similar to those seen in human lupus erythematosus. Virgin female MRL/lpr mice at 1 month of age, which were treated orally with Sairei-to, had reduced amounts of IgG deposition at the dermoepidermal junction, titers of anti-DNA antibodies and rheumatoid factor, and lymphoproliferation. These results support the use of traditional herbal medicines in patients with human RA and systemic lupus erythematosus.

Giant metastatic malignant melanoma with an unknown primary site.

We report a case of malignant melanoma of unknown primary origin which presented with a giant metastatic tumor in his right inguinal region. A 94-year-old man noticed a small subcutaneous tumor in the right inguinal region 3 years earlier, which eventually became as larger as 9 cm in diameter without treatment. Although a histological examination of the lesion showed malignant melanoma, extensive examination did not reveal its primary lesion or any metastasis other than that to the right inguinal area. Our case took an interesting course in that this well-growing metastatic tumor was localized in only one region and supported a previous report indicating that malignant melanoma with unknown primary origin has a low tendency to metastasize and a relatively good prognosis.

Adrenalectomy overcomes the blunted natriuretic response to atrial natriuretic peptide during hypocapnia in rats.

1. Hypocapnia has been shown to blunt the natriuretic effect of atrial natriuretic peptide (ANP) independently of the renal nerves. In order to examine whether the adrenal glands are a limiting factor for the natriuretic effect of ANP, we evaluated the natriuretic responses of adrenalectomized rats to ANP infusion during hypocapnia. 2. Rats subjected to total adrenalectomy (ADX) or sham-operation (sham) were divided into hypocapnic and normocapnic groups depending on their arterial PCO2 levels. 3. In sham rats, ANP infusion at a rate of 12 micrograms/kg per h resulted in a smaller increase in the fractional excretion of sodium during hypocapnia (mean +/- SEM: 1.02 +/- 0.40%, n = 10) than normocapnia (3.95 +/- 0.64%, n = 9; P < 0.001). The level of fractional excretion of sodium with ANP infusion during hypocapnia was not significantly different from the level in saline-infused hypocapnic sham rats (0.93 +/- 0.62%, n = 10). In hypocapnic ADX rats (n = 11), ANP induced greater increases in the fractional excretion of sodium (5.59 +/- 1.35%) than did saline infusion (1.04 +/- 1.02%, n = 10; P < 0.002). In the absence of adrenal glands, the magnitude of natriuresis after ANP infusion during hypocapnia and normocapnia (3.32 +/- 1.07%, n = 9) were the same. 4. We conclude that the natriuretic effect of ANP is blunted during hypocapnia in the presence, but not in the absence, of adrenal glands. Our data suggest that the adrenal glands have an important role in limiting the natriuretic effect of ANP.

Inhibitory effect of aldosterone on the natriuretic response to atrial natriuretic peptide in hypocapnic rats.

UNLABELLED: 1. Previous studies have shown that acute hypocapnia blunts the natriuretic effect of atrial natriuretic peptide (ANP) independently of the renal nerves and that the effect of ANP is restored by total adrenalectomy. We investigated the natriuretic response to ANP in potassium canrenoate (aldosterone receptor antagonist)-treated rats to clarify whether aldosterone contributes to the attenuated natriuretic response to ANP during hypocapnia. 2. Wistar rats, challenged with either canrenoate or saline vehicle, were infused with 10 micrograms/kg per h ANP during acute hypocapnia achieved by mechanical ventilation. 3. In saline-treated hypocapnic rats, ANP infusion failed to increase the fractional excretion of sodium (FENa) (from 3.49 +/- 0.26 to 5.03 +/- 0.42%, respectively; n = 6) which was similar to values for time control rats (from 3.00 +/- 0.61 to 4.41 +/- 0.68%; n = 6). The hyporesponsiveness to ANP during hypocapnia was also evident when the FENa was compared with that of normocapnic rats (from 3.92 +/- 0.69 to 7.87 +/- 0.45%; P < 0.05; n = 6). In canrenoate-treated rats, ANP infusion caused greater increases in sodium excretion (FENA from 3.05 +/- 0.71 to 7.21 +/- 0.45%; P < 0.05; n = 8) than saline infusion (FENA from 4.16 +/- 1.11 to 5.47 +/- 0.66%; n = 6), despite the hypocapnia. The increase in FENA after ANP infusion during hypocapnia (4.16 +/- 0.86%) was similar to the increase seen during normocapnia (3.89 +/- 0.86%; n = 9). 4. IN CONCLUSION: (i) acute hypocapnia blunts the natriuretic effects of ANP; and (ii) this attenuation is restored by potassium canrenoate treatment. The data suggest that aldosterone plays an important role by limiting the renal actions of ANP during acute hypocapnia.