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Background Macrophage phagocytosis constitutes an essential part of the host defence against microbes and the resolution of inflammation. Hyperglycaemia during sepsis is reported to reduce macrophage function, and thus, potentiate inflammatory deterioration. We investigated whether high-glucose concentrations augment lipopolysaccharide-induced reduction in macrophage phagocytosis via the endoplasmic stress-C/EBP homologous protein (CHOP) pathway using animal and laboratory investigations. Methods Peritoneal macrophages of artificially ventilated male Wistar rats, divided into four groups based on target blood glucose concentrations achieved by glucose administration with or without lipopolysaccharide, were obtained after 24 h. Human macrophages were also cultured in normal or high glucose with or without lipopolysaccharide exposure for 72 h. Changes in the phagocytic activity, intranuclear CHOP expression, and intracellular Akt phosphorylation status of macrophages were evaluated. These changes were also evaluated in human macrophages after genetic knock-down of CHOP by specific siRNA transfection or resolvin D2 treatment. Results Lipopolysaccharide impaired phagocytosis, increased intranuclear expression of CHOP, and inhibited Akt phosphorylation in both rat peritoneal and human macrophages. Hyperglycaemic glucose concentrations augmented these changes. Genetic knock-down of CHOP restored phagocytic ability and Akt phosphorylation in human macrophages. Furthermore, resolvin D2 co-incubation restored the inhibited phagocytosis and Akt phosphorylation along with the inhibition of intranuclear CHOP expression in human macrophages. Conclusions These findings imply that controlling endoplasmic reticulum stress might provide new strategies for restoring reduced macrophage phagocytosis in sepsis-induced hyperglycaemia.

Aim To investigate the effects of the c-Jun N-terminal kinase (JNK1/2) on the inflammation cytokine tumour necrosis factor-alpha (TNF-α)-enhanced production of matrix metalloproteinase-3 (MMP-3) in human dental pulp fibroblast-like cells (HPFs). Methodology HPFs were grown from pulp explants from healthy donors. Primary cultures were established by culturing the cells for 20 to 30 days. The experiments with HPFs were performed between passages 3 and 10. The HPFs were incubated in serum-free medium containing TNF-α for 24 h. The medium in each well was prepared in SDS sample buffer and was analysed for MMP-3 by Western blotting. Results JNK inhibitor SP601245 markedly inhibited the production of MMP-3 in TNF-α-stimulated human dental pulp fibroblasts. MMP-3 production was enhanced by TNF-α in HPFs; silencing JNK1 and JNK2 expression inhibited this activation. cAMP response element-binding protein (CREB) was activated by TNF-α in HPFs; silencing JNK1 and JNK2 expression inhibited this activation. Conclusion The activation of CREB via JNK pathways in the presence of TNF-α occurred with enhancement of MMP-3 production in dental pulp fibroblasts.

Background Adenosine, a metabolite of adenosine triphosphate degradation during ischemia, is reported to attenuate ischemia and reperfusion injury in several tissues. Dipyridamole is a nucleoside transport inhibitor that augments endogenous adenosine. In this study, we tested whether dipyridamole would attenuate hepatic I/R injury. For this purpose, dipyridamole was applied to a 2-hour total hepatic vascular exclusion model in dogs. Study design Dipyridamole (DYP) was given by continuous intravenous infusion for 1 hour before ischemia at a dose of 0.25 mg/kg (high-DYP, n=6), 0.1 mg/kg (medium-DYP, n=6), or 0.05 mg/kg (low-DYP, n=6). Nontreated animals were used as ischemic controls (CT, n=12). Two-week survival, systemic and hepatic hemodynamics, liver function tests, energy metabolism, adenosine 3′, 5′-cyclic monophosphate (cyclic AMP) levels, platelet numbers, arachidonic acid metabolites, and histopathology were analyzed. Results Two-week animal survival was 25% in CT, 17% in high-DYP, 100% in medium-DYP, and 17% in low-DYP. Dipyridamole significantly improved postreperfusion hepatic blood flow and energy metabolism, attenuated liver enzyme release and purine catabolite production, and augmented cyclic AMP levels. The medium dose of dipyridamole lessened platelet aggregation, thromboxane B2 production, and polymorphonuclear neutrophil infiltration, and improved survival. Conclusions We demonstrated marked hepatoprotective effects of dipyridamole against severe ischemia and reperfusion injury in canine livers. Dipyridamole is a promising agent for liver surgery and transplantation.

Background Thromboelastometric evaluation of coagulation might be useful for prediction and management of bleeding after paediatric cardiac surgery. We tested the hypothesis that the use of a thromboelastometry-guided algorithm for blood product management reduces blood loss and transfusion requirements. Methods We studied 78 patients undergoing paediatric cardiac surgery with cardiopulmonary bypass (CPB) for the initial 12 h after operation. Stepwise multiple linear regression was used to develop an algorithm to guide blood product transfusions. Thereafter, we randomly assigned 100 patients to conventional or algorithm-guided blood product management, and assessed bleeding and red cell transfusion requirements. Results CPB time, post-bypass rotational thromboelastometry (ROTEM ® ) EXTEM amplitude at 10 min (A10), and FIBTEM-A10 were independently associated with chest tube drainage volume during the initial 12 h after operation. Discriminative analysis determined cut-off values of 30 mm for EXTEM-A10 and 5 mm for FIBTEM-A10, and estimated optimal intraoperative fresh-frozen plasma and platelet concentrate transfusion volumes. Thromboelastometry-guided post-bypass blood product management significantly reduced postoperative bleeding (9 vs 16 ml kg −1 , P vs 23 ml kg −1 , P =0.005) at 12 h after surgery, and duration of critical care stay (60 vs 71 h, P =0.014). Conclusions Rotational thromboelastometry-guided early haemostatic intervention by rapid intraoperative correction of EXTEM-A10 and FIBTEM-A10 reduced blood loss and red cell transfusion requirements after CPB, and reduced critical care duration in paediatric cardiac surgical patients. Clinical trial registration UMIN Clinical Trials Registry UMIN000006832 (December 4, 2011).

As a member of the tetraspan family, it has been hypothesized that CD63 may be associated with signal transduction; however, its role in leukocyte function is unknown. To examine the potential ability of CD63 to activate neutrophils, the effects of five CD63 mAbs, AHN-16, -16.1, -16.2, -16.3, and -16.5, were examined for their ability to alter neutrophil adhesion to HUVEC monolayers. These CD63 Abs increased neutrophil adhesion to resting and TNF-stimulated HUVEC monolayers. This increase in neutrophil adhesion caused by CD63 Abs was blocked by a CD18 Ab and was associated with up-regulation of CD11/CD18 and down-regulation of CD62L on the neutrophil surface. CD11/CD18 was also found to be associated with CD63. This increase in neutrophil adhesion required physiologic extracellular calcium concentrations at or near the time of CD63 Ab binding. The incubation of CD63 Abs with cells in the absence of calcium for 10 min before repletion of calcium resulted in no increase in neutrophil adhesion. Protein kinase activity was detected in neutrophils associated with CD63. Most of the protein kinase activity associated with these Ags was tyrosine kinase activity, with a lesser amount of threonine and serine kinase activities. Src family kinases Lyn and Hck accounted for much of the associated tyrosine kinase activity. The data suggest that CD63 Ab binding to the neutrophil surface triggers a transient activation signal that requires extracellular calcium and regulates the adhesive activity of CD11/CD18. Associated protein kinase activity may play a role in signal transduction by CD63 to regulate other cell functions.

The BALB/c-bm/bm mouse is characterized by short limbs and short tail attributed to undersulfated glycosaminoglycans. Anterior transverse crossbite sometimes spontaneously appears in BALB/c-bm/bm mice. The BALB/c-bm/bm mouse shows a short nose and cranium. The reason for hypo-growth of anterior craniofacial structures has not been clarified, although the nasal septal cartilage might be related to the growth of anterior craniofacial structures. Therefore, the purpose of this study was to evaluate histological findings of the nasal septal cartilage at the border region of the ethmoid and sphenoid bone in BALB/c-bm/bm mice.BALB/c mice (wild type) and BALB/c-bm/bm mice with normal occlusion (bm/bm) were used. Sagittal sections of female mice aged 2, 4, and 8 weeks were stained with hematoxylin and eosin for histological analysis.At the border region between the nasal septal cartilage and the ethmoid bone in bm/bm, the area of proliferative zone was significantly smaller than that in wild type. At the border regions between the nasal septal cartilage and both the ethmoid and sphenoid bones, the number of proliferative chondrocytes was significantly smaller. Normal endochondral ossification was not observed at the border region between the nasal septal cartilage and the sphenoid bone in bm/bm.The findings suggest that disorder of endochondral ossification in the nasal septal cartilage contributes to the hypo-growth of anterior craniofacial structures in bm/bm.

Close interaction of human hematopoietic progenitors with the bone marrow microenvironment is important for the ordered progression of human hematopoiesis. Progenitor cell adhesion to stroma has a complex molecular basis, involving various cell-extracellular matrix and cell- cell interactions. We have previously shown that adhesion of colony- forming cells (CFC) to fibronectin, present in stromal extracellular matrix, involves multiple sites, including two heparin-binding synthetic peptides (FN-C/H I and FN-C/H II) and the alpha 4 beta 1 integrin-binding peptide CS1. These synthetic peptides are located in close proximity in the type III repeat 14 and the immediately adjacent type IIIcs region of fibronectin. In the current study, we evaluate receptors expressed by CFC responsible for their adhesion to fibronectin. We show that the alpha 4 beta 1 integrin mediates adhesion to CFC to the peptides FN-C/H I and CS1. Adhesion of CFC to fibronectin is also mediated by proteoglycans, because removal of cell surface chondroitin-sulfate proteoglycans resulted in decreased adhesion of CFC to FN-C/ I and FN-C/H II. The core protein of this proteoglycan was identified by immunoprecipitation as a 90-kD member of the CD44 group of adhesion molecules. Interestingly, although the proteoglycan core protein failed to adhere to FN-C/H II affinity columns, anti-CD44 monoclonal antibodies blocked CFC adhesion to FN-C/H II, indicating that these monoclonal antibodies may interfere with core protein- mediated intracellular signalling. Finally, we show that CD44 and alpha 4 beta 1 may cooperate in establishing progenitor adhesion, because anti-CD44 antibodies potentiated the adhesion-inhibitory effects of suboptimal concentrations of anti-alpha 4 or anti-beta 1 monoclonal antibodies. These results provide a working model for progenitor cell recognition of fibronectin (and possibly the marrow micro-environment) in which the coordinated action of integrins and cell surface proteoglycans is necessary for cell adhesion. This model can now be used to study the complex relationship between progenitor cell adhesion and the regulation of their proliferation and differentiation.

The aim of this study was to determine whether significant cranial and maxillary deformity exists in BALB/c-bm/bm (brachymorphism) mouse with spontaneous malocclusion using three-dimensional (3D) images.Thirty female mice were divided into the following three groups: control group (BALB/c mice, n = 10), Norm group (BALB/c-bm/bm mice with normal occlusion, n = 10), and Mal group (BALB/c-bm/bm mice with malocclusion, n = 10). Nine points in the skull were selected, and transverse and antero-posterior distances were measured using three-dimensional images of micro-computed tomography (CT). Moreover, 3D images were superimposed at the median plane to visualize the skull shape asymmetry.The transverse distances at the posterior cranial and maxillary region and the antero-posterior distances in the Norm and Mal groups were significantly shorter than those in the control group. The nasal septum of the Mal group was significantly shorter than that of the Norm group. Morphological measurements and superimposed 3D images showed that lateral deviation occurred at the anterior cranial and maxillary region in the Mal group.The 3D micro-CT images revealed that the antero-posterior length and posterior transverse width at the cranium and maxilla in BALB/c-bm/bm mice were significantly smaller than those in BALB/c mice. It was quantitatively and morphologically clear that BALB/c-bm/bm mice show a spontaneous transverse crossbite owing to lateral deviation of the maxilla and nasal bone.

Emdogain has been used clinically for periodontal regeneration, although the underlying molecular mechanisms are not clear at present. In this study, we hypothesized that Emdogain stimulated degradation of type I collagen via osteoblasts. We showed that Emdogain enhanced cell-mediated degradation of type I collagen in an MMP-dependent manner. Although MG-63 cells spontaneously produced a zymogen form of MMP-1, treatment with Emdogain significantly induced the generation of the active form of this enzyme. We demonstrated that MMP-3 was produced from MG63 cells in response to Emdogain in a MEK1/2-dependent manner. Concomitantly, blocking of MEK1/2 activation by U0126 significantly inhibited the generation of the active form of MMP-1 without affecting the total production of this collagenase. These results suggest that Emdogain facilitates tissue regeneration through the activation of the collagenase, MMP-1, that degrades matrix proteins in bone tissue microenvironments.

The complication rate after emergency tracheostomy is two to five times greater than after elective procedures. One of the main causes of the high risk of complications in emergency tracheostomy appears to be the amount of time required to open the trachea. Therefore, simple and fast procedures are mandatory. We have developed a new procedure as follows: A horizontal skin incision is performed. Strap muscles are dissected and retracted laterally. A transverse cut between tracheal rings below the thyroid isthmus is performed up to membranous portion of the trachea. The cut ends of the trachea remain open naturally because of the elasticity of the trachea. Skin and tracheal cut-ends are then joined by interrupted sutures.We have used this procedure during the past three years and have not experienced any major complications. This demonstrates the clear advantage and the more physiological nature of the procedure over various other incisions of the tracheal wall.

K. Kamisaka 1, D. Sakui 1, Y. Hagiwara 1, K. Kamiya 2, T. Adachi 2, J. Iida 3, M. Morishima3, K. Ueyama3, S. Yamada4 1 Kitano Hospital, Tazuke Kofukai Medical Research Institute, Rehabilitation Center, Osaka, Japan; 2 Nagoya University Graduate School of Medicine, Program in Physical and Occupational Therapy, Nagoya, Japan; 3 Kitano Hospital, Tazuke Kofukai Medical Research Institute, Cardiovascular Center, Osaka, Japan; 4 Nagoya University Graduate School of Medicine, Rehabilitation Science, Aichi, Japan

The primary purpose of this study was to investigate the association between morphological abnormalities of brain and minor physical anomalies (MPAs) in childhood and adolescent onset schizophrenia.Twenty-seven patients who had been diagnosed with schizophrenia according to DSM-IV criteria before 18 years of age were included in the study. MPAs were evaluated with the modified version of Waldrop scale (WS) by Green et al. Morphological abnormalities of brain was evaluated with ventricular-brain ratio (VBR) by using cerebral magnetic resonance imaging (MRI) examination.A significant positive correlation was observed between WS scores and VBRs.This result indicates a relationship between MPAs and lateral ventricular enlargement, and supports neurodevelopmental etiology in childhood or adolescent onset schizophrenia.

A 19-year-old male had a traffic accident while driving his motorbike and suffered an injury to the left frontotemporal part of the head. He remained conscious, had no focal neurological signs, and brain-computed tomography was unremarkable at the prefectural hospital, department of neurosurgery. Six months later he demonstrated a personality change, which was marked by irritability, aggression, labile moods, childishness, irresponsibility, and a lack of motivation. He sometimes made trouble for those around him, and he consulted our hospital 2 years and 9 months after the accident. He was diagnosed as having posttraumatic personality disorder and was treated with clonazepam, a dosage of up to 1.5 mg/day. Although his symptoms were moderately improved, he complained of sleepiness as an adverse effect. Carbamazepine (100 mg/day) was added in expectation of further improvement. Within a few days he improved to his preaccident personality. After the administration of clonazepam was discontinued, he maintained his good mental status. Now about two years after the initiation of therapy, he works in social welfare facilities and has no relapses. Even if a head injury is mild without definite organic signs in brain, it may have a possibility of causing personality change, which may be treatable.

Childhood- and adolescence-onset schizophrenic patients with obsessive-compulsive symptoms (OCS) constitute a specific subgroup of schizophrenia. We performed magnetic resonance imaging in this group seeking evidence of neurodevelopmental insults.Thirty-two schizophrenic patients were compared with 19 controls. Schizophrenic subjects were divided into 15 patients with OCS (SOCS+ group; onset at 15.5 +/- 1.6 years) and 17 without OCS (SOCS- group; onset at 15.3 +/- 1.3 years). Areas of the hippocampus, frontal lobe, corpus callosum and putamen were analysed morphometrically.The left hippocampus was significantly smaller in the SOCS+ group than in the SOCS- and control groups.Reduced size of the left hippocampus in the SOCS+ group supports a neurodevelopmental etiology in this subgroup.

The reactions of periodontal tissues to the mechanical stimulation of teeth seem to be different in patients of different ages. Although the effects of aging on other structures of the periodontal tissues, i.e., collagen fibre, bone, and cementum, have been reported, there is very little information available concerning the effects of aging on periodontal oxytalan fibre, which is reportedly the only elastic element in the human periodontal ligament. The purpose of this research was to clarify the aging related changes in the distribution of oxytalan fibres in the periodontal ligament of mice. Histological sections of the periodontal ligament of the lower first molar of 10-week-old (control group) and 1-year-old (aged group) ICR mice were specifically stained for oxytalan fibres with aldehyde fuchsin after preoxidization, and observed by light microscopy and confocal laser scanning microscopy (CLSM). In the aged group, oxytalan fibres seemed to be more prevalent around blood vessels in comparison with the control group. Furthermore, CLSM clearly showed that oxytalan fibres in the aged group were relatively more tortuous and complex than those in the control group. This tortuosity and complexity might imply that the oxytalan fibres in aged mice have lost a considerable amount of their original elasticity. While further study of these changes is required, these results may help orthodontists to establish better treatment strategies and methods for adult orthodontic patients.

A case of primary and malignant melanoma of the esophagus was reported. A 64-year-old male complaining of discomfort of anterior chest pain was admitted to our hospital for operation. Findings of upper G-1 X-ray and endoscopic examination revealed suspiciously malignant melanoma. Subtotal thoracic esophagectomy with R III dissection was performed. Operative findings included A0 N2 Pl0 M0 Stage III. Macroscopically it showed black-grayish colored polypoid tumors, 7 cm in size. The typical finding of junctional activity adjacent to the tumor mass and melanocytes were microscopically found. The patient received postoperative systemic chemotherapy, but was died of multiple liver and bone metastases 125 days after surgery. Malignant melanoma of the esophagus has extremely poor prognosis and none of effective therapies has been reported.

Unilateral recurrent laryngeal nerve paralysis causes the vocal cord to atrophy, leading to glottic incompetence. The voice is characterized by hoarseness, breathlessness, rapid air escape, ineffective cough and aspiration. Traditional treatments of unilateral vocal cord paralysis include intracordal injection, laryngeal framework surgery, and laryngeal reinnervation for medialization of the vocal cord. In this paper we report on a new technique of transcutaneous intracordal silicon injection in which the injection is made through the thyroid lamina under local anesthesia monitoring fiberscopy. We performed this procedure on 30 patients with unilateral vocal cord paralysis and later evaluated their post-operative voice. The silicon injection resulted in improvement of vocal quality, favorable clearance of sputum, and aspiration control. We found that, since it can be performed under local anesthesia without hospitalization, transcutaneous intracordal silicon injection should be performed as a therapy for treating unilateral vocal cord paralysis.

A 19-year-old male underwent an emergent operation for a massive brain tumor in the right cerebral basal ganglia. However, brain herniation had already developed and he subsequently died. Histological examination showed the tumor consisted of immature epithelial arrangements and glandular structures, considered as immature teratoma containing choriocarcinomatous components. Such an immature teratoma arising in the cerebral basal ganglia in an adult is very rare.

Cell adhesion to extracellular matrices is fundamental for maintaining normal tissue architecture and function. Many diseases are characterized, in part, by molecular changes in cell adhesion. These changes can occur as a result of modifications of the composition or integrity of the extracellular matrix or as a result of disease associated changes in the expression and/or function of adhesion receptors. Such alterations in cell adhesion can have profound effects on the phenotypic traits of cells, and as a result, these changes in cell adhesion can be of primary importance in facilitating disease-associated breakdown of normal tissue function. This is most apparent in a disease such as cancer, where neoplastic transformation can lead to alterations in tumor cell growth, changes in the composition or integrity of tissue proteins, tumor cell migration, invasion, and ultimately metastasis formation. Understanding the molecular basis of cell adhesion could lead to new insights into the molecular basis of many diseases, leading to better therapies. The purpose of this review is to highlight the role that collagens play in mediating cell adhesion, with an emphasis on the structural features of collagen important for cellular recognition and adhesion. Additionally, we briefly review the major receptors and intracellular signals that are important for cellular recognition of, and adhesion to, collagens.

The authors report a rare case of intracranial aspergillosis presenting marked granulomatous pachymeningitis. A 58-year-old male who had a three-year history of diabetes and chronic bronchitis was referred to us because of progressive left hemiparesis and dysarthria. Postcontrast CT scan showed a ring-enhancing lesion with marked perifocal edema in the right parietal lobe, and right subdural enhancing mass. MR image revealed hypertrophic dura mater in the right convexity. On June 9, 1992, partial removal of the intra-axial cystic mass and granulomatous dura mater was performed. A number of characteristic aspergillus hyphae were recognized in the resected cyst and granulomatous dura mater. Postoperatively, the patient was treated with amphotericin-B and fluconazole. But granulomatous pachymeningitis became progressively enlarged and eventually created a large mass effect again. On January 23, 1993, the patient died of pneumonia. Cerebral aspergillosis is getting common but preoperative diagnosis is still difficult because of its causing several clinical features such as brain abscess, granuloma, intracerebral hemorrhage, cerebral infarction, meningitis, and encephalitis. Several comments were made about the pathogenesis of these features, and the necessity of early diagnosis and treatment was emphasized.

Despite recent advances in the diagnosis and therapy of many forms of cancer, metastasis remains the major cause of death in cancer patients. As tumors progress they become increasingly heterogeneous, giving rise to aggressive subpopulations of tumor cells that subsequently invade local tissues, the lymphatics, and the circulatory system. This invasive behavior can ultimately lead to the widespread dissemination and metastasis of the primary tumor. In hematogenous metastasis, emboli consisting of tumor cells, host cells, platelets, and fibrin are transported to distant sites where they arrest in the microvasculature prior to extravasation. It is well accepted that tumor cell adhesion plays a fundamental role in many of the stages of the metastatic process. Tumor cell interactions with extracellular matrix components of tissue, tissue boundaries (basement membranes), or cell adhesion-promoting components of plasma; influence tumor cell motility, invasiveness, and many other important aspects of the metastatic tumor cell phenotype. Tumor cell adhesion also has a rate-limiting influence at various stages within the metastatic process, such as tumor cell arrest and extravasation. In addition, the ability of the immune system to recognize and successfully eradicated tumors is also highly dependent on the adhesion of activated lymphocytes to target tumor cells. Despite the rapid accumulation of information on the molecular basis of cell adhesion, our understanding of the relationship between tumor cell adhesion and hematogenous metastasis per se is fragmented and incomplete. Nevertheless, clear progress has been made, both in understanding the molecular basis of tumor cell adhesion and its relationship to the biology of tumor metastasis. New and exciting directions have been identified that are likely to yield direct benefits in developing new therapeutic or diagnostic approaches for malignant neoplasms. Our purpose is to briefly review the molecular basis of tumor cell adhesion from the standpoint of many of the receptors involved as well as their putative ligands. The relationship between specific tumor cell adhesion events and the formation of metastatic lesions is also addressed.

ACh response in the isolated duodenum from SART stressed (repeated cold stressed) mice was remarkably decreased in comparison to normal mice 5 days after onset of loading SART stress, and maximal contraction in SART stress mice duodenum was about 37% of that in non-stressed mice. Pilocarpine and KCl responses were also considerably decreased, but BaCl2 response was much the same as in the controls. Thus, the contraction system of the muscle is apparently not damaged by SART stress. Though body weights decreased, the daily intake of food incressed in SART stressed mice. Length of small intestine from SART stressed mice was much the same as in controls, but wet weights of small intestines were larger than in controls. Autonomic agonists, antagonists, tranquilizers and other drugs were given intraperitoneally to mice once daily during SART stress, and the ACh responses in the isolated duodenum were investigated. Pretreatment with adrenergic and anticholinergic drugs inhibited the decrease of ACh response, but antiadrenergic and cholinergic drugs had no effects. Pretreatment with tranquilizers such as reserpine, chlorpromazine, carpipramine and imipramine inhibited the decrease of ACh response in the isolated duodenum, but diazepam, meprobamate and benadryl had no influence. Pretreatment of neurotropin, a neurosedative had good inhibitory effects. Our results suggest that SART stressed mice may be in a state of unbalance regarding sympathetic and parasympathetic nerves, particularly with regard to abnormal tension in the parasympathetic nervous system, in part of duodenum. Pretreatment with most of the above drugs had no influence on loss of body weight in SART stressed mice while pretreatment with neurotropin inhibited body weight to a considerable extent.

Mice that received N alpha-acetylmuramyl-L-alanyl-D-isoglutaminyl-N epsilon-stearoyl-L-lysine [MDP-Lys (L18)] were resistant to Sendai virus infection. In these protected mice, a significant growth inhibition of the virus was confirmed repeatedly at 10(0.2) to 10(0.4) of haemadsorbing units at an early non-specific phase but not at a late virus-eliminating phase of the infection. Virus growth was enhanced by treatment with silica but not by treatment with anti-asialo GM1 serum in MDP-Lys (L18)-treated mice. Peritoneal adherent cells activated by MDP-Lys(L18) showed an enhanced uptake and ability to inactivate Sendai virus in vitro. Excess interferon production in MDP-Lys (L18)-treated mice was seen on day 1 but not on days 2 to 7 of the infection. The possible role of macrophages and interferon in providing non-specific protection against Sendai virus in the MDP-Lys (L18)-treated mice is discussed.

Adjuvant activities of pantethine (PaSS) and pantetheine-4'-phosphate (PSH-4'-P) were investigated in mice. By the multiple intraperitoneal administration, both PaSS and PSH-4'-P activated the functions of mouse peritoneal adherent cells and splenic natural killer cells. PSH-4'-P was also effective for the activation of natural killer cells by single injection. In in vitro, PaSS induced interleukin-1 (IL-1) secretion at a low concentration but PSH-4'-P did not. Both PaSS and PSH-4'-P could neither induce interleukin-2 (IL-2) secretion, nor could enhance IL-2 secretion by Con A.

We investigated that the antimetastatic and antiadhesive activities of peptides based on Arg-Gly-Asp adhesive signal in fibronectin could be augmented by their polymerization. Poly(Arg-Gly-Asp), which consists of a repetitive sequence of Arg-Gly-Asp, inhibited lung metastases in C57BL/6 mice more effectively than Arg-Gly-Asp tripeptide was able to do, when coinjected or separately injected with B16-BL6 cells. The adhesion of tumor cells to fibronectin was specifically inhibited by adding poly(Arg-Gly-Asp) but not unrelated peptides. In contrast, poly(Arg, Gly, Asp), in which three amino acids are randomly arranged, showed neither inhibition of lung metastases nor any adhesive ability to attach to tumor cells. The inhibitory effect of polymeric peptides containing the Arg-Gly-Asp sequence on lung metastases decreased according to the decreasing repeat units of the Arg-Gly-Asp core sequence. Polymeric peptides with Arg-Gly-Asp entrapped within the liposome membranes also caused a remarkable reduction of metastatic colonies. In a spontaneous metastasis model, multiple i.v. administrations of poly(Arg-Gly-Asp) after tumor inoculation caused the significant reduction of metastatic colonies in the lung but did not affect the growth (size) of primary tumor. We found that the polymerization (multivalency) of the Arg-Gly-Asp core sequence was able to augment the inhibition of tumor lung metastases in experimental and spontaneous metastasis models as well as the cell-adhesive property more effectively than a monovalent unit of Arg-Gly-Asp peptide.