Suppression by adrenoceptor beta-agonists of vascular permeability increase and edema formation induced by arachidonate metabolites, platelet-activating factor, and tumor-promoting phorbol ester TPA

Air-pouch-type inflammation was induced by injecting sodium carboxymethyl cellulose solution containing leukotriene C4 (LTC4, 3.20 x 10(-7) M, 0.2 micrograms/ml) and prostaglandin E2 (PGE2, 5.68 x 10(-6) M, 2.0 micrograms/ml), platelet-activating factor (PAF, 1 x 10(-6) M, 0.52 micrograms/ml), or 12-O-tetradecanoyl phorbol 13-acetate (TPA, 1.62 x 10(-6) M, 1.0 micrograms/ml) into an air pouch made on the dorsum of rats. Vascular permeability and tissue edema formation were significantly increased by injecting the phlogogen solution. The histamine level in the pouch fluid was dramatically increased by injecting TPA but not by LTC4 and PGE2, or PAF. Injection of isoproterenol or procaterol with the phlogogen solution produced dose-dependent suppression of both vascular permeability increase and tissue edema formation. However, the TPA-induced increase in the histamine level was not suppressed in parallel with the decrease of vascular permeability or tissue edema formation. These results indicate that beta-agonists suppress vascular permeability response and local tissue edema formation not by inhibiting mast cell degranulation, but by inhibiting the reactivity of the local vasculature to chemical mediators such as arachidonate metabolites, PAF, and histamine and serotonin released from mast cells.     

Membranous lipodystrophy

Summary The case is described of a 35-year-old housewife diagnosed as having membranous lipodystrophy (as described by Nasu et al. in 1970 and called lipomembranous polycystic osteodysplasia by Hakola in 1972). The main symptom of this patient was a slowly progressive dementia. Skeletal symptoms were not seen. The computerized tomogram of the brain showed calcification of bilateral basal ganglia and the plain roentgenograms of the bones revealed cystic radiolucent areas at the distal end of the bones of the patient's extremities. Histological examination of the curetted material from the right talus revealed a membranocystic pattern. The fatty tissue curetted from the cyst of the talus and the lysosomal enzymes of the white blood cells were biochemically normal. A possible relationship between this disease entity and connective disorders is considered.     

The effect of posterior-neck-muscle vibration on apparent straight-ahead and visual localization of targets

We examined the time course of apparent motion and apparent displacement of a visual target, and also the horizontal deviation of apparent straight-ahead related to left-posterior neck-muscle vibration. In Experiment 1, eight observers verbally judged the apparent motion and displacement of a visual target for 60 s from prior to the vibration to after its offset. We found that rightward apparent motion was an almost identical in magnitude during the vibration and disappeared within 20 s after the vibration offset. In contrast, rightward apparent displacement gradually increased during the vibration, and was sustained over 40 s after the vibration offset. In Experiment 2, five observers manually pointed to the position of a visual point in the median plane; the mean pointed position in the vibration condition was found to deviate maximally 3 degrees to the right of the mean pointed position in the control condition. In Experiment 3, the same observers closed their eyes and pointed to the apparent straight-ahead; the mean pointed positions did not differ between the vibration and control conditions.     

Protective effects of ketotifen on allergen-induced bronchoconstriction and skin weal

A single-blind cross-over method was used to investigate the effects of ketotifen on the total respiratory resistance response curve to inhalation of a high concentration of allergen (1:5 w/v house dust or 1:10 w/v Japanese cedar pollen) and the weal response to intradermal injection of serially diluted allergen (1:10(3)-1:10(6) w/v). Five subjects received 2 mg of ketotifen every 12 hr for the first week and an inactive placebo in the same manner for the second week. The remaining five subjects received the placebo for the first week and ketotifen for the second week. Ketotifen did not alter base-line pulmonary function, but significantly delayed the time from the start of allergen exposure to the beginning of elevation of total respiratory resistance (P less than 0.02), and the time from the start of allergen exposure to the point at which total respiratory conductance decreased by 35% from the base-line value (P less than 0.01). Ketotifen also decreased skin test sensitivity significantly (P less than 0.01).     

Crystal structure of human DAAM1 formin homology 2 domain

Reorganization of the actin filament is an essential process for cell motility, cell-cell attachment and intracellular transport. Formin proteins promote nucleation and elongation of the actin filament, and thus are key regulators for this process. The formin homology 2 (FH2) domain forms a head-to-tail ring-shaped dimer, and processively moves towards the barbed end. Dishevelled-associated activator of morphogenesis (DAAM) is a Rho-regulated formin implicated in neuronal development. Here, we present the crystal structure of human DAAM1 FH2 dimer at 2.8 A resolution. This is the first dimeric structure of the mammalian formin. The core structure of human DAAM1 is similar to those of mouse mDia1 and yeast Bni1p, whereas the orientations of the FH2 dimeric rings are different between human DAAM1 and yeast Bni1p, despite their similar dimer interactions. This difference supports the previous prediction that the dimer architecture of the formin is highly flexible in the actin-free state. The results of the actin assembly assays using the DAAM1 mutants demonstrated that the length of the linker connecting the N-terminal domain and the core region is crucial for the activity.     

Immunohistochemical analysis of steroidogenic enzymes in ovarian‐type stroma of pancreatic mucinous cystic neoplasms: Comparative study of subepithelial stromal cells in intraductal papillary mucinous neoplasms of the pancreas

Mucinous cystic neoplasms (MCNs) are generally defined as cyst‐forming epithelial neoplasms that arise in the pancreas and harbor characteristic ovarian‐type stroma beneath the epithelium. In this study, we compared the immunoreactivity of steroid‐related factors in these subepithelial stromal cells in MCNs to those in intraductal papillary mucinous neoplasms (IPMNs) to further characterize this unique MCN ovarian‐type stroma through evaluation of sex steroid biosynthesis. Twenty MCNs and twenty IPMNs were examined. Immunoreactivity of steroid hormone receptors, including estrogen receptor (ERα and ERβ), progesterone receptor (PR, PR‐A, and PR‐B), and androgen receptor (AR), was more frequently detected in MCN ovarian‐type stromal cells than in IPMN stromal cells (P < 0.01). The H‐scores (mean ± SD) of steroidogenic factor (SF)‐1 were also significantly higher in MCNs (112.3 ± 33.1) than in IPMNs (0.9 ± 1.2) (P < 0.01). The steroidogenic enzymes cytochrome P450 cholesterol side‐chain cleavage enzyme (P450scc), cytochrome P450 17 alpha‐hydroxylase (P450c17) and 3β‐hydroxysteroid dehydrogenase (3β‐HSD) showed immunoreactivity in 9/20 (45.0 %), 15/20 (75.0 %) and 13/20 (65.0 %), respectively, of ovarian‐type stroma from MCN cases. These results demonstrate that the ovarian‐type stroma of MCNs can express steroidogenic enzymes. Thus, the ovarian‐type stroma of MCNs can produce sex steroids that may also act on these cells.     

Detection of bone marrow and extramedullary involvement in patients with non-Hodgkin’s lymphoma by whole-body MRI: comparison with bone and <Superscript>67</Superscript>Ga scintigraphies

The aim of this study was to evaluate the diagnostic potential of whole-body MRI (WB-MRI) for the detection of bone marrow and extramedullary involvement in patients with non-Hodgkins lymphoma. WB-MRI, which was performed on 34 patients, consisted of the recording of T1-weighted spin-echo images and a fast STIR sequence covering the entire skeleton. The WB-MRI findings for bone marrow and extramedullary involvement were compared with those from ⁶⁷Ga and bone scintigraphies and bone marrow biopsy results. Two MRI specialists reviewed the WB-MRI results and two expert radiologists in the field of nuclear medicine reviewed the bone and ⁶⁷Ga scintigraphy findings. Bone marrow and extramedullary involvement of non-Hodgkins lymphoma were confirmed by follow-up radiographs and CT and/or a histological biopsy. The detection rate of WB-MRI was high. More bone marrow involvement was detected by biopsy, and more lesions were detected by scintigraphies. In total, 89 lesions were detected by WB-MRI, whereas 15 were found by biopsy, 5 by ⁶⁷Ga scintigraphy, and 14 by bone scintigraphy. WB-MRI could also detect more extramedullary lesions than ⁶⁷Ga scintigraphy; i.e., 72 lesions were detected by WB-MRI, whereas 54 were discovered by ⁶⁷Ga scintigraphy. WB-MRI is useful for evaluating the involvement of bone marrow and extramedullary lesions throughout the skeleton in patients with non-Hodgkins lymphoma.     

Rac-WAVE2 signaling is involved in the invasive and metastatic phenotypes of murine melanoma cells

WAVEs (WASP-family verprolin-homologous proteins) regulate the actin cytoskeleton through activation of Arp2/3 complex. As cell motility is regulated by actin cytoskeleton rearrangement and is required for tumor invasion and metastasis, blocking actin polymerization may be an effective strategy to prevent tumor dissemination. We show that WAVEs, especially WAVE2, are essential for invasion and metastasis of melanoma cells. Malignant B16F10 mouse melanoma cells expressed more WAVE1 and WAVE2 proteins and showed higher Rac activity than B16 parental cells, which are neither invasive nor metastatic. The effect of WAVE2 silencing by RNA interference (RNAi) on the highly invasive nature of B16F10 cells was more dramatic than that of WAVE1 RNAi. Membrane ruffling, cell motility, invasion into the extracellular matrix, and pulmonary metastasis of B16F10 cells were suppressed by WAVE2 RNAi. WAVE2 RNAi also had a profound effect on invasion induced by a constitutively active form of Rac (RacCA). In addition, ectopic expression of both RacCA and WAVE2 in B16 cells resulted in further increase in the invasiveness than that observed in B16 cells expressing only RacCA. Thus, WAVE2 acts as the primary effector downstream of Rac to achieve invasion and metastasis, suggesting that suppression of WAVE2 activity holds a promise for preventing cancer invasion and metastasis.     

Multiple myeloma complicated by autoimmune hemolytic anemia

A 57-year-old man was admitted with severe anemia and hypergamma globulinemia. After a diagnosis of multiple myeloma and autoimmune hemolytic anemia was made, chemotherapy rapidly decreased the M-protein level and improved his anemia with normalization of the direct Coombs test. The immunoglobulin binding to the patient's red cells was immunoglobulin G kappa chain like the myeloma M-protein. However, monoclonal immunoglobulin G derived from short-term culture of the patient's bone marrow mononuclear cells did not bind to a panel of red cells. Therefore, the relationship between the M protein produced by his myeloma cells and hemolysis remained unclear.