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Patients with deficiency of interleukin-36 receptor antagonist (DITRA), due to mutation of IL36RN, exhibit psoriatic phenotypes, typically generalized pustular psoriasis (GPP). We report a paediatric patient with DITRA, whose cutaneous lesions varied from psoriasis vulgaris in infancy to annular pustular psoriasis with acute exacerbation to GPP at 13 years of age. Conventional systemic treatments for GPP, which include oral retinoids, ciclosporin and methotrexate, are controversial in paediatric cases, because of their adverse effects and uncertain long-term consequences. Granulocyte monocyte apheresis, a process associated with few adverse events, promptly controlled the GPP of our paediatric patient, and has potential as a suitable alternative treatment for paediatric patients with DITRA.

Poor medication adherence among patients with chronic diseases can result in complications and increased health care expenditures. An outpatient pharmacy clinical service (OPCS) program targeted nonadherent diabetes mellitus (DM) and/or coronary artery disease (CAD) patients with hemoglobin A1c (HbA1c) and/or low-density lipoprotein cholesterol (LDL-C) outside clinical goals. Pharmacists engaged identified patients with a face-to-face B-SMART consult, a consultation methodology to identify Barriers to medication adherence, work on Solutions to identified barriers, Motivate patients, recommend Adherence tools, reinforce the pharmacist-patient Relationship, and Triage if needed, to other services such as health education to improve outcomes. To (a) assess rates of medication adherence and clinical outcomes in the OPCS program compared with usual care in an integrated health care system and (b) estimate return-on-investment (ROI) from this intervention. This retrospective cohort study used data from the Kaiser Permanente Southern California region to identify patients who received OPCS consultations and usual care patients from March 2009 through December 2010, with 1 year of follow-up from the initial consult (index date). Four patients from usual care were matched to each patient in the OPCS program and were assigned the same index date as the matching OPCS patient. Additional selection criteria were applied after matching. All patients were required to have a medication possession ratio (MPR) of less than 0.80 for their diabetes or dyslipidemia oral medications 1 year prior to the index date, indicating lower adherence to the prescribed therapy. Diabetic patients or dyslipidemic patients had to have a HbA1c or LDL-C lab result outside of clinical goals prior to the index date to be included in the study, respectively. Adherence outcomes as well as clinical outcomes were measured 12 months after the index date using chi-square tests for differences in percentages and t-tests for differences in means. The ROI was based on a cost-avoidance model that compared the cost of the OPCS program with the cost savings gained through reduced hospitalizations and emergency department (ED) visits. The diabetes and dyslipidemia cohorts were combined for the ROI analysis.Demographic and clinical characteristics at baseline were similar between the OPCS group (n = 1,480) and usual care group (n = 1,477). Among patients with diabetes, a higher percentage in the OPCS group than in the usual care group were adherent with their diabetes medications (53.5% vs. 37.4%, P = 0.001). There was no significant difference in average MPR between groups. However, patients in the OPCS group had a greater increase in mean MPR (0.19 vs. 0.15, P = 0.024); were less likely to discontinue taking their diabetes medications (11.7% vs. 35.5%, P = 0.001); and were more likely to have a timely first fill after the index date (34.8% vs. 12.9%, P = 0.001). The average number of days to the first fill after the index date was significantly shorter for the OPCS group (79.3 vs. 156.3, P = 0.001). Regarding clinical outcomes, patients with diabetes in the OPCS group had a lower mean HbA1c (8.48 vs. 8.80, P = 0.024) and a greater reduction in HbA1c (-1.25 vs. -0.75, P = 0.001) than in the usual care group. They were also less likely to have an ED visit (1.67% vs. 4.21%, P = 0.040), but there was no significant difference in the percentage of patients with a hospital admission. Among patients with dyslipidemia, the mean MPR was significantly lower for the OPCS group than the usual care group (0.70 vs. 0.74, P = 0.003). There were no significant differences in the percentage of adherent patients or the change in mean MPR from baseline. However, the OPCS group was significantly less likely to discontinue dyslipidemia medications (21.1% vs. 35.4%, P less than 0.001) and more likely to have a timely fill (28.3% vs. 15.1%, P less than 0.001). The average days to first fill after the index date was 106.9 for the OPCS group, compared with 162.6 for the usual care group (P less than 0.001). The OPCS group had a lower mean LDL-C (105.1 vs. 110.4, P = 0.001) and a greater reduction in LDL-C (-30.5 vs. -22.4, P = 0.001) than the usual care group. There were no significant differences in the percentage of patients with an ED visit or a hospital admission. In terms of ROI, assuming that 58% of hospitalizations and 8.5% of ED visits incurred in the usual care group were avoidable, approximately $5.79 could be saved for every dollar spent on the OPCS program. By engaging nonadherent patients to restart their DM or lipid medications during a face-to-face consult, the OPCS pharmacist was able to influence and improve medication adherence and clinical outcomes, particularly among patients with diabetes. A positive ROI was demonstrated.

In this paper, we propose the method to analyze the magnetization distribution in magnetoanisotropic materials by using the finite-element method considering the improved variable magnetization and Stoner-Wohlfarth model. By using this method, furthermore, the effect of the eddy currents induced in permanent magnets was analyzed. From the analyzed result, it is clarified how the magnetization distribution affects the performance of the surface permanent magnet-type motors.

To reduce the cost of a DVD player, we have integrated peripheral functions to the audio and video decoder LSI. The peripheral functions are controlled by the I/O processing tasks on single I/O control processor. I/O processing tasks are switched in constant cycle without overhead, to achieve real-time performance and flexibility of software control. In the case of video output handling, software can control each line parameter. Therefore software with line level support of hardware can perform many kinds of functions; image resizing, copy guard and dynamic blending of the image and graphics.

Background and Objectives Hepatitis A virus (HAV) transmission via contaminated blood products has been reported. Cell-adapted HAV strains are generally used to confirm virus inactivation in manufacturing blood products, but the strains may differ in their sensitivity to inactivation treatment. To select an appropriate cell-adapted HAV strain for virus validation, we compared the inactivation efficiency among four strains under two different physical inactivation treatments: heat and high hydrostatic pressure. Materials and Methods The cell-adapted HAV strains used here were KRM238, KRM003 (subgenotype IIIB), KRM031 (IA), and TKM005 (IB). The strains were treated at 60°C for up to 10 h or under high hydrostatic pressure (up to 420 MPa). The reduction in HAV infectivity was measured by an immunofocus-staining method. Results The heat treatment at 60°C for 10 h reduced HAV infectivity in the range of 3 to 5 log10 among the strains; KRM238 and TKM005 were harder to inactivate than the other two. The high hydrostatic pressure treatment at 420 MPa also reduced infectivity in the range of 3 to 5 log10 among the strains, and KRM031 was easier to inactivate than the other strains. Conclusion Heat treatment and high hydrostatic pressure treatment revealed differences in inactivation efficiencies among cell-adapted HAV strains, and each strain reacted differently depending on the treatment. KRM238 may be the best candidate for virus validation to ensure the safety of blood products against viral contamination, as it is harder to inactivate and it replicates better in cell culture than the other strains.

This paper presents an integrated platform for digital AV products. By applying all the parallelisms of pixel level processes, we developed a parallel processing architecture, which is a core component of the platform. This architecture can execute pixel level processes for MPEG2, MPEG4, JPEG, and H.264 codecs.

Introduces an architectural extension to the media core processor (MCP), which targets a system solution for consumer multimedia products. This extension implements HDTV video decoding (1080i, 720p, 480p and 480i), video resizing, 2-D graphics rendering, and conversion between various video formats for data broadcasting. For pixel-level operations in HDTV applications, a SIMD-style processor has been introduced. However, image resizing causes a difference in data structure between source and result dynamically. Therefore, an advanced inter-PE (processing element) communication mechanism is necessary as an extension to the common SIMD-style architecture. This processor achieves the flexibility of pixel-level operation and the efficiency of high bandwidth. Adopting this new MCP architecture enabled us to improve image quality to fulfill the requirements for consumer products.

A multithreaded processor is a good approach to increase the performance by utilizing coarse grain parallelism. The execution of multiple threads in parallel makes a performance prediction difficult because of a complicated behavior. Thus instruction-level simulation is necessary for a performance evaluation. In practice, it is very difficult to select optimum configuration of microarchitecture through a simulation of wide variety of candidates because of a long simulation time. The paper presents an evaluation method of microarchitecture for multithreaded processors. The method consists of three steps; first, the characteristics of the application are analysed, secondly, the candidates of microarchitecture are selected in consideration of the characteristics, lastly, the selected architectures are evaluated through the instruction-level simulation using practical application program. The experimental results using computer graphics application show that the proposed evaluation method of microarchitecture are very effective in order to increase the performance of multithreaded processors. >

The uninterruptible power supply (UPS) system at the NHK broadcasting center, Japan, has been restructured. The restructured system has been designed with emphasis on the following aspects: (1) parallel operation of several UPS units; (2) the system control configuration; and (3) the distribution system feeding power to the broadcasting equipment. A brief overview of this system is presented. The redundancy system was structured to provide for exchange switching with a bypass power source so as to allow the continued supply of power under any circumstances. Hence, the system was designed to permit backup in the event of malfunctions as well as separate system power supply during the execution of maintenance work, thus enhancing both reliability and maintenance characteristics. >

Volar melanotic macules are asymptomatic light-brown or tannish-grey macules usually found on the palms and/or soles of blacks, although they have also been reported on the volar surfaces of whites. Similar lesions have not been reported before in Japanese people. Since the cause is as yet unknown, it remains to be discussed whether they are a distinct entity.In this report, a 52-year-old Japanese man with volar melanotic macules is reported with the clinical and histopathological findings.A 52-year-old Japanese man presented with many light-brown macules on his bilateral soles. He had a 20-year history of tinea pedis. Histopathological examination revealed melanophages and inflammatory infiltrates in the superficial dermis. There was a slight increase in melanin granules around the acrosyringium. Fontana-Masson stain revealed a slight increase in melanin granules in the basal layer including the acrosyringium and superficial dermis. These changes corresponded with postinflammatory pigmentation.This is the first report of volar melanotic macules in Japanese people. We suggest that volar melanotic macules is not an independent entity but a clinicopathological one that includes postinflammatory pigmentation, and that the condition is the volar counterpart of mucosal melanotic macules.

Pigmentation is a characteristic clinical feature of basal cell carcinomas (BCCs) in Japanese patients. The pathogenesis of melanin pigment in pigmented BCCs is poorly understood.We have combined the techniques of morphometric analysis and electron microscopy to assess accurately the morphologic aspects of melanocytes that occurred in pigmented and non-pigmented areas of pigmented BCCs.In the pigmented areas melanocytes were not only located along the basal membrane but also interspersed between tumor cells in the central parts of the tumor nest, and had large and numerous dendrites. Those in a supra-basal location displayed some degree of degeneration due to mitochondrion and melanosome swelling. In the non-pigmented areas melanocytes were only basally located, showed fewer dendrites, and frequently showed abortive melanosomes. However, melanocytes in these two different portions were in the active state of melanogenesis and proliferation. Ultrastructural cytomorphometric analysis also showed significant differences in most of the nuclear and cell parameters including nuclear and cell area, the nuclear/cell area ratio, cell perimeter and cell form factor between these two types of melanocytes. Particularly melanocytes in the pigmented areas were twice the cell size of the latter. In addition, the melanosomes remained almost completely in the apoptotic tumor cells, and the phagocytosis of the melanosome-containing apoptotic cells by the neighboring tumor cells appeared to be followed by the formation of the melanosome complexes.These findings suggest that different populations of melanocytes are probably present in pigmented BCCs, and repeated cycles of phagocytosis of melanosome-containing apoptotic cells may represent the predominant way of forming large melanosome complexes. The present morphological observation and quantitative analysis provide a morphological basis for further studies to interpret other pathologic changes in pigmented BCCs.

Ca(2+) binding proteins (CaBPs), calbindin-D(28k) (calbindin) and calretinin, are thought to contribute to the regulation of intracellular Ca(2+) in many neuronal populations and perhaps more importantly, signal functional modulation in neuronal activity. In the present experiments, light microscopic immunohistochemistry revealed that the immunoreactivity of calbindin and calretinin was contained in varicose axons in the posterior pituitary. The dual labeling study with confocal microscopy demonstrated that calbindin immunoreactivity was present in the terminals of both oxytocin (OXT) and arginine-vasopressin (AVP) neurons. However, calretinin immunoreactivity was exclusively seen in the OXT terminals. Moreover, the dual labeling study showed that most calretinin-positive terminals contained calbindin immunoreactivity, demonstrating the colocalization of calbindin and calretinin in the same OXT nerve terminals. By electron microscopy, calbindin and calretinin immunoreactivities were seen in the neurosecretory axons and nerve terminals. These immunoreactive nerve terminals were seen to contain more clear microvesicles than dense-core neurosecretory granules. This immunoelectron microscopic observation suggests that both calbindin and calretinin localize preferentially in the active zone of the nerve terminals, which usually face the perivascular space around fenestrated capillaries. In spite of similar localization of calbindin and calretinin within the posterior pituitary, Western blot analysis showed some differences between the two CaBPs. Calbindin was present mostly in the soluble fraction with little in the insoluble fraction, but a substantial portion of calretinin was present in both the insoluble and soluble fractions. Moreover, dehydration induced by drinking 2% NaCl solution and deprivation of drinking water increased calretinin levels in the posterior pituitary as compared with control, but the calbindin level was not changed. The present findings demonstrate that calbindin and calretinin colocalize in the active zones of OXT nerve terminals, but only calretinin is upregulated with dehydration, suggesting different physiological role of calbindin and calretinin in the nerve terminals.

The Bcl-2 homologue Bak is a potent inducer of apoptosis. We performed PCR-based single-strand conformational polymorphism and sequencing analysis of the entire coding region of the bak gene (exons 2-6) in 24 primary gastric cancers (6 early-stage and 18 advanced-stage cancers) and 20 primary colorectal cancers (6 early-stage and 14 advanced-stage cancers). The data herein demonstrate, for the first time, the mutation of the bak gene in gastric and colorectal cancers. Missense bak gene mutations were observed in 3 of 24 (12.5%) gastric cancers and 2 of 20 (10.0%) colorectal cancers. Sequence alterations without amino acid alteration were observed 1 of 24 (4.2%) gastric cancers and 2 of 20 (10.0%) colorectal cancers. Mutations in the bak gene were observed only in advanced-stage gastrointestinal cancers but not in early-stage cancers. Our observations suggest that mutations in this gene predispose bearers to the development of gastrointestinal malignancies in at least a subset of the cases.

The oncogenic ras mutation is a common and critical step in gastrointestinal carcinogenesis. In a previous study, we demonstrated that oncogenic ras activated the EGF-related peptide autocrine loop and that the apoptosis resistance observed in the oncogenic ras-stimulated cell (IEC-ras cell) was dependent on this activated EGF-related peptide autocrine loop. STATs (signal transducers and activators of transcription), first identified as intracellular signal transducers stimulated by cytokines, are known to also be activated by EGF. However, the role of STATs in the survival signal of IEC-ras cells is not clear. In the present study, we demonstrate that STAT3 is constitutively activated in ras-stimulated cells and that STAT3 activation is considerably suppressed by the EGF-specific receptor kinase inhibitor AG 1478. We also show that disruption of the STAT3 pathway by introduction of a dominant-negative STAT3 mutant abolishes the apoptosis resistance against UVC and MMC treatment observed in IEC-ras cells without affecting proliferation. Moreover, the expression of Bcl-2 and Bcl-xL, apoptosis-suppressive proteins, is reduced in dominant-negative STAT3-transfected cells. Thus, STAT3 appears to be an important mediator of the antiapoptotic signal in IEC-ras cells.

The ras mutation is a common and critical step in carcinogenesis. Autocrine growth factors are also known to play an important role in cancer cell growth and transformation. However, the contribution of autocrine growth factors in regulation of proliferation and apoptosis of activated ras-stimulated intestinal epithelium is not fully understood. Therefore, we constructed activated ras-transfected intestinal epithelial cell clones (IEC-ras) to examine the role of epidermal growth factor (EGF)-related peptides in the behavior of IEC-ras. Overexpression of EGF family growth factors (transforming growth factor alpha, heparin-binding EGF-like growth factor, amphiregulin and betacellulin) and stronger phosphorylation of the EGF receptor was observed in IEC-ras compared with control cells. IEC-ras proliferated more rapidly than control cells, and a specific EGF receptor kinase inhibitor, AG 1478, abolished the increased proliferation of IEC-ras. Heparitinase and chlorate also prevented increased proliferation of IEC-ras. Additionally, IEC-ras expressed more bcl-2 and was more resistant to apoptosis induction by UV radiation and mitomycin C. AG 1478 suppressed bcl-2 expression and inhibited resistance to apoptosis of IEC-ras. Heparitinase and chlorate had effects similar to those of AG 1478. Our data indicate that heparin-binding EGF family growth factors play an important role in both increased proliferation and resistance to apoptosis of ras-stimulated intestinal epithelial cells.

The present study was designed to clarify whether bcl-xL is involved in the development of carcinoma in the stomach. Levels of bcl-xL and bcl-2 mRNA were determined by a reverse-transcription/polymerase-chain reaction in endoscopic gastric biopsy specimens from 10 control subjects, 11 patients with adenomas and 14 patients with carcinomas. In 6 of 11 adenomas, 5 of 8 early carcinomas and 3 of 6 advanced carcinomas, the bcl-xL gene was over-expressed. In carcinomas, over-expression of the bcl-xL gene was observed in 6 of 9 intestinal-type carcinomas and 2 of 5 diffuse-type carcinomas. No correlation was observed between bcl-xL and bcl-2 gene expression. In cases in which the bcl-xL gene was over-expressed, an apparent increase in the protein level of Bcl-xL was observed by immunoblot analysis and intense Bcl-x immunoreactivity was detected immunohistochemically within the tumor cells. In conclusion, we showed that bcl-xL is over-expressed in gastric carcinomas at both the RNA and protein levels, suggesting that over-expression of bcl-xL may play a role in gastric carcinogenesis.

An 8-year-old girl suffering from precocious puberty and pustular psoriasis with moyamoya disease is described. The possibilities of a causal relationship between precocious puberty and moyamoya disease are discussed. The relevance of the patient's earlier upper respiratory tract infections to the pustular psoriasis and moyamoya disease is also considered.

This paper reviews some of our findings which have shown the usefulness of in vitro methods in the study of hypothalamic neurones. (1) Membrane current analyses of dispersed neurones of the rat preoptic and anterior hypothalamus (POA) during thermal stimulation have revealed that warm-sensitive neurones are endowed with a non-inactivating Na+ channel having a high Q10 in the hyperthermic range (35-41 degrees C). (2) A brain slice study has shown that neurones in the organum vasculosum lamina terminalis (OVLT) region have much higher sensitivity to PGE2 than POA neurones. This provides further evidence of a critical role of the OVLT in translation of blood-borne cytokine signals into brain signals for fever induction. (3) Local application of IL-1 beta and IFN alpha altered the activity of thermosensitive (TS) neurones and glucose responsive (GR) neurones in vitro in an appropriate way to produce fever and anorexia. While the responses to IL-1 beta required the local release of prostaglandins, the responses to IFN alpha were found to be mediated by opioid receptor mechanisms. (4) The responses of POA TS neurones and VMH GR neurones to IL-1 beta but not those to IFN alpha, were reversibly blocked by alpha MSH, an endogenous antipyretic peptide. Thus, immune cytokines and their related neuroactive substances may affect hypothalamic TS and GR neurones thereby producing elaborately regulated changes in homeostatic functions such as thermoregulation (fever) and feeding (anorexia), which are considered as host defence responses.

Kaposi's sarcoma (KS) (Kaposi, 1872) is classified into at least three forms: 1) the classic form; in elderly men of southern European, Jewish, and Italian origin, 2) the endemic form; among native populations in equatorial Africa and 3) the epidemic form; as a complication of AIDS. As one additional form could be posttransplantation KS in organ transplant recipients. Histologically, KS is composed of two characteristic features; a proliferation of angiomatous lesion and of spindle-shaped cells. The pathological entity of the disease is still controversial. As a cause of the disease, human cytomegalovirus (HCMV) has been the subject based on epidemiologic, serologic, geopathologic and histopathologic observations. About half of KS cases with AIDS has shown evidence of HCMV infection as cytomegalic viral inclusions of the cells. In contrast, about 30% of AIDS cases without KS showed histological HCMV infection. A connection between HCMV and KS was suggested by the detection of herpes-type virus particles in several KS tissue culture lines and in a tumor specimen. DNA and RNA homologous with HCMV sequences have been detected in tumor tissue of both endemic and epidemic KS by electrophoretic methods. HCMV sequences was detected in extracted DNA of 30% of classic KS, using Southern blot technique. In situ hybridization technique using specific DNA probes for HCMV has been developed to reveal endogenous nucleic acid sequences in fixed tissue sections. However, some reports showed that by the in situ technique only a small number of KS cells in the AIDS cases and no case of the classic KS were positive for HCMV within KS lesions. HCMV infections are ubiquitous. There is a very high seropositivity of HCMV in African inhabitants as well as in Africans with endemic KS. A strong association between HCMV and KS was not known. As for HIV itself in AIDS with KS, previous studies have showed the presence of chromosomal abnormalities of KS cells, but not revealed the presence of HIV DNA sequences in KS. Vascular tumors were produced by NIH/3T3 cells transfected with KS DNA of AIDS. An oncogene isolated by transfection of KS DNA encodes a growth factor; FGF. Isolation of rearranged human transforming gene following transfection of KS DNA was performed. DNA having transforming genetic elements which have been repetitively transmitted into phenotypically normal NIH/3T3 cells through cycles of transfection was isolated from tissues of KS with AIDS.(ABSTRACT TRUNCATED AT 400 WORDS)

Glycosidic enzymes were used as probes to analyze the mechanism of NK cell-mediated cytotoxicity. Pretreatment of nylon wool-enriched CBA/J spleen cells, a murine NK clone, or human peripheral blood lymphocytes (PBL) with alpha-mannosidase, an exoglycosidase, led to a marked dose-dependent inhibition of NK lytic activity against YAC-1.2 or K562 tumor cells. Maximal inhibition occurred after a 60-min pretreatment of murine effectors at 37 degrees C, and the kinetics of NK inhibition by alpha-mannosidase was similar to the reported kinetics for enzymatic activity. Released hexose was detected chemically in the supernatant of mouse spleen cells treated with NK inhibitory dose of alpha-mannosidase, and inactivation of enzymatic function with EDTA reversed the NK inhibitory effect. These results suggest that alpha-mannosidase inhibited NK function by virtue of its enzymatic action. Culture of human PBL for 20-hr after treatment with this enzyme led to a greater than 70% recovery in NK lytic function. Recovery was blocked by incorporating tunicamycin, a glycosylation inhibitor of asparagine-linked glycoproteins, into the culture medium. These results suggest that the alpha-mannosidase-sensitive site may be de novo synthesized glycoprotein. Neuraminidase, beta-galactosidase, endo-beta-N-acetylglucosaminidase-D and H, and peptide-N-glycosidase treatments did not inhibit human NK cell lysis of K562 cells. Pretreatment of nylon wool-enriched CBA/J spleen cells or Percoll-enriched human LGL with alpha-mannosidase did not influence their capacity to bind YAC 1.2 target cells or K562 target cells, respectively, Ca++ pulse experiments revealed that the alpha-mannosidase-sensitive site on the NK cells was involved after target-effector binding but before the Ca++ influx. Pretreatment of effector cells with this enzyme which normally occurs after effector-target cell interaction. These results suggest that the phospholipid methylation reaction is coupled to the alpha-mannosidase-sensitive site on the NK cells. By analogy to other physiologic systems, such as histamine release in mast cells, the triggering of phospholipid methylation in the NK cells may serve as a mechanism for signal transduction across the plasma membrane.

In the development of pine wilting disease caused by Bursaphelenchus lignicolus, water status in pines plays an important role in the pinenematode relationship. Levelling off in transpiration causes a population growth of nematodes in the wood. Such pines invariably wilt several weeks after the reduction of transpiration. The paper contains details of oleoresin exudation, transpiration and xylem water potential as well as the nematode population in the wood in connection with disease development.

The pine wilting disease prevalent in western Japan was studied with respect to the pine wood nematode, Bursaphelenchus lignicolus, as a causal agent. The relationship between the behavior of nematode populations within pines and disease development is discussed.

The effect of oxygen- and Ar-plasma treatment on glassy polysulfone and polyimide films upon the gas diffusion process was investigated in the permeation of CO2 and H2. The plasma treatment apparently induced a reduction of only the diffusivity of Henry's law population, while the diffusion coefficient of the Langmuir population was not altered by plasma treatment. The oxygen- and Ar-plasma treatment on polysulfone films is favorable for permselectivity of H2 relative to CO2. Such a surface modification of polyimide films appears to be ineffective for improvement of permselectivity of H2.

The effect of cerebellar lesions upon the pupillary light reflex was examined in anesthetized cats. The pupillary response elicited by a step and sinusoidally modulated light stimulus was used. In acute cerebellectomized cats, the high frequency cutoff of the frequency response of the pupillary reflex was moved to a lower level after cerebellar lesions. Selective lesions were made in the deep cerebellar nuclei and the frequency responses of the pupillary reflex were compared. The fastigial lesions produced the most prominent change in the frequency responses. Electrical stimulation of the deep cerebellar nuclei, especially the fastigial nuclei, induced pupillary dilatation. Thus the cerebellum appears to participate in the control of the pupillary light reflex by improving the frequency responses of the pupil so that it can follow changing light stimuli better, and this control is exerted via the bilateral fastigial nuclei.

Normal mouse spleen cells exhibited nonspecific cytotoxicity against MM2 and other NK-insensitive mouse ascites tumor cells after culture for 3 or 4 days in vitro in the presence of heat-inactivated foetal calf serum and 5 X 10(-5) M 2-mercapthoethanol. The cytotoxicity was assayed by 51Cr-release during 18 hr incubation. Culture of spleen cells from C3H/He or C57BL/6 mice resulted in strong cytotoxicity, while cytotoxicity did not appear or appeared only weakly during culture of spleen cells from Balb/c, DDD, DBA/2 or athymic mice. High activity was observed when spleen cells from aged mice were used. The effector cells which lysed MM2 cells seemed glass dish non-adherent, Sephadex G-10 adherent, nylon wool adherent, and Thy 1.2 positive cells. The induction of cytotoxicity was inhibited by adding cytosine arabinoside to the culture medium. Mouse serum was also inhibitory. Restriction specificity between the effector and the targets was not observed for the lytic reaction. By cold target competition experiments, it was shown that the effector cells recognize cell surface structures commonly present on the surface of wide range of tumor cells which are unrelated with respect to tumor specific antigenicity.

In synthetic studies on the chemical modification of the nucleoside antibiotic bredinin, two new derivatives, 5-carbamoyl-1H-imidazol-4-yl 1-adamantanecarboxylate and 5-carbamoyl-1H-imidazol-4-yl piperonylate, were found to possess a potent antitumor activity in several experimental tumor systems, even though bredinin itself shows only in vitro cytotoxicity and thus lacks therapeutic effectiveness. These two derivatives of bredinin exhibited antitumor activity against a wide variety of tumors, including leukemias L1210 and P388, Lewis lung carcinoma, B16 melanoma, Colon 26 and 38 adenocarcinomas. Ehrlich carcinoma, and Sarcoma 180. It is noteworthy that these agents showed good therapeutic effects not only against ascitic types of tumors but also against a number of slow-growing solid tumor lines, particularly the ascitic and solid forms of Ehrlich carcinoma. At their optimal doses, both compounds effected a complete cure of all or most of the mice treated. Although the mechanisms of action of these compounds remain unknown, they are able to suppress in vivo tumor growth, presumably by being slowly anabolized in vivo to an active form and inhibiting purine de novo synthesis as bredinin does.

On a enregistre les potentiels electriques monoet poly-synaptiques (EPSPs) des cellules du nucleus reticularis tegmenti pontis en stimulant le nucleus interpositus (NI), le brachium conjunctivum (BC) et le pedoncule cerebelleux. Les experiences de collision ont montre que des axones des cellules NRTP activent leurs neurones via BC. Quelques potentiels postsynaptiques exitateurs induits par le nucleus interpositus ont ete inverses par un courant depolarisant applique au voisinage de la microelectrode de derivation, ce qui indique que les terminaisons synaptiques d'axones NI se trouvent pres du sommet des cellules NRTP.

Antidromically and synaptically activated spike and synaptic potentials in the nucleus reticularis tegmenti pontis (NRTP) of the cat were recorded intracellularly. The antidromic firing of the NRTP neurone is composed of IS-SD spikes with short duration and short spike-after-hyperpolarization. Membrane resistance and firing patterns were studied by applying depolarizing and hyperpolarizing current through the recording electrode. Findings indicate that the NRTP neurone has a relatively high membrane resistance and is capable of firing at a high frequency. Single shock stimulation of the interpositus (IP) and lateral nucleus (LN) of the cerebellum, brachium conjunctivum (BC), red nucleus (RN) and cerebral peduncle (CP) induced monosynaptic EPSPs in the NRTP neurones. Superior vestibular nucleus (SVN) stimulation induced monosynaptic IPSPs. Collision tests showed that (1) NRTP neurones are activated by the axons of IP and LN neurones which travel through BC, (2) these axons also send collaterals to RN, and (3) there is convergence of cerebellar, cerebral and brain stem inputs to a single NRTP neurone.

Three beta-N-acetylhexosaminidases [EC 3.2.1.52] and one beta-galactosidase [EC 3.2.1.23] were purified from the culture filtrate of streptococcus 6646 group K by a combination of column chromatographies on p-aminophenyl beta-D-thiogalactopyranoside-substituted Sepharose and N-(paminophenyl)oxamic acid-substituted Sepharose. These beta-N-acetylhexosaminidases showed optimal activities between pH 5.0 and 5.5 and could hydrolyze synthetic and glycopeptidic substrates. Glycolipids such as GM2, asialo-GM2, and globoside I were no susceptible to these beta-hexosaminidases. beta-Galactosidase, which was purified more than 11,000-fold, had a substrate specificity rather similar to that of beta-galactosidase from E. coli. This enzyme was inhibited by EDTA and activated by Mn2+, Ca2+, and Mg2+. Problems pertinent to the application of affinity chromatography to the purification of glycosidases are also discussed.

Proteinase inhibitor II' from adzuki beans was subjected to peptic digestion. One of the resulting fragments, which inhibited chymotrypsin but not trypsin, was composed of 27 amino acid residues. The fragment was confirmed to be derived from the chymotrypsin-inhibitory domain of the original inhibitor. Another fragment, which inhibited trypsin only, contained 38 amino acid residues and consisted of two peptide chains. One of them, consisting of 25 amino acid residues, corresponded to the original reactive site region for trypsin. These fragments were also obtained from inhibitor II by peptic digestion. These findings, confirm that these inhibitors, which do not inhibit chymotrypsin and trypsin simultaneously, have separate and independent domains for the inhibition of each enzyme. The active fragments are homologous in chemical structures with the two fragments from soybean Bowman-Birk proteinase inhibitor. However, unlike the fragments from Bowman-Birk inhibitor, our chymotrypsin-inhibitory fragment was a potent inhibitor of the enzyme and was as resistant as the intact inhibitor to the attack of excess chymotrypsin. The trypsin-inhibitory fragment had a lower anti-tryptic action than the original inhibitor and was gradually inactivated by trypsin. These differences between our fragments and those of the Bowman-Birk inhibitor are probably a result of the replacement of a few amino acid residues in the reactive site regions.