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Aim Methods Results Conclusion Coronavirus disease 2019 (COVID‐19) is a serious disease that has spread worldwide. In the absence of any effective treatment for mild‐to‐moderate‐stage COVID‐19, we report that treating patients with Kampo medicines could reduce or prevent disease progression. Herein, we report the current status of COVID‐19 treatment with a Kampo medicine, saikatsugekito.The clinical course of COVID‐19 in patients treated with saikatsugekito was retrospectively investigated from January 2020 to January 2021 at a hospital designated for infectious diseases in Akita City.Saikatsugekito was administered to 30 COVID‐19 patients, but the nine patients with infections caused by other pathogens or no symptoms and treated with steroids were excluded;finally, 21 patients were included in the study. Patients with symptoms such as fever and nasal discharge/obstruction were relieved about a week after hospitalization following treatment with saikatsugekito. However, hyposmia and ageusia persisted for a long time.Most patients recovered within a week without worsening. Our study suggests that saikatsugekito may be considered a treatment choice to relieve symptoms of mild‐to‐moderate‐stage COVID‐19. [ABSTRACT FROM AUTHOR] Copyright of Traditional & Kampo Medicine is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

We investigate historical regional climate changes in Japan from 1959 to 2020, analyzing a high-resolution dynamical downscaling forced by the Japanese 55-year Reanalysis (JRA-55). One-year continuous simulations are conducted by the non-hydrostatic regional climate model (NHRCM) with a land surface model that includes the snow accumulation process, which enables us to evaluate the seasonal variation of snow cover in all of Japan. Our simulation reproduces interannual variations of the annual mean surface air temperature and annual total precipitation, and it shows rapid warming since around 1980. The frequency of daily precipitation exceeding 100 mm/day and annual maximum daily precipitation are also well simulated; both show increasing trends as with the observations. The frequency of hourly precipitation of more than 50 mm/h significantly increased in most regions of Japan after 1981. On the other hand, the annual maximum snow depth and annual maximum daily snowfall show significant decreasing trends at lower elevations on the Japan Sea sides of eastern and western Japan. Areas at higher elevations in eastern Japan show no trend in the maximum snow depth and a significant increasing trend in the maximum daily snowfall. In northern Japan, altitudinal dependencies in snow depth and snowfall changes are smaller on the Japan Sea side than on the Pacific Ocean side: the Japan Sea side shows insignificant changes in snow depth at all elevations, while the Pacific Ocean side shows decreasing and significant increasing trends at lower and higher elevations, respectively. The total number of snow-covered days is decreasing at most elevations in all regions, while the rate of decrease is smaller at higher elevations and latitudes.

Cases We report cases of three patients infected with mild coronavirus disease 2019 (COVID‐19) treated only with Kampo medicine and discharged from the hospital without symptom exacerbation. Case 1 A 41‐year‐old healthy female suffering from headache, sore throat, and fever. Case 2: A 16‐year‐old healthy female sufferking from nasal congestion and taste disorder. Case 3: A 12‐year‐old healthy male suffering from nasal congestion and taste disorder. Outcome The three patients were prescribed saikatsugekito. Cases 1 and 3 initially presented with white and yellow tongue coating, which disappeared several days after the prescription of saikatsugekito. All three patients were discharged from the hospital without symptom exacerbation. Conclusion We believe that treatment with Kampo medicine, which is relatively safe clinically and has few side effects, should be taken at an early stage of COVID‐19 along with coping therapy. And we think that saikatsugekito may contribute to prevent the worsening of COVID‐19.

The population dynamics of mosquitoes in temperate regions are not as well understood as those in tropical and subtropical regions, despite concerns that vector-borne diseases may be prevalent in future climates. Aedes albopictus, a vector mosquito in temperate regions, undergoes egg diapause while overwintering. To assess the prevalence of mosquito-borne diseases in the future, this study aimed to simulate and predict mosquito population dynamics under estimated future climatic conditions. In this study, we tailored the physiology-based climate-driven mosquito population (PCMP) model for temperate mosquitoes to incorporate egg diapauses for overwintering. We also investigated how the incorporation of the effect of rainfall on larval carrying capacity (into a model) changes the population dynamics of this species under future climate conditions. The PCMP model was constructed to simulate mosquito population dynamics, and the parameters of egg diapause and rainfall effects were estimated for each model to fit the observed data in Tokyo. We applied the global climate model data to the PCMP model and observed an increase in the mosquito population under future climate conditions. By applying the PCMP models (with or without the rainfall effect on the carrying capacity of the A. albopictus), our projections indicated that mosquito population dynamics in the future could experience changes in the patterns of their active season and population abundance. According to our results, the peak population number simulated using the highest CO2 emission scenario, while incorporating the rainfall effect on the carrying capacity, was approximately 1.35 times larger than that predicted using the model that did not consider the rainfall effect. This implies that the inclusion of rainfall effects on mosquito population dynamics has a major impact on the risk assessments of mosquito-borne diseases in the future.

Nowadays, people believe that not only the remote body operation by one direction control (Tele-existence) but also the remote body sharing by mutual control (Body-Sharing) will increase within few upcoming years. In the future, users -including elderly and disabled- can work and enjoy sightseeing using remote body sharing. Meanwhile, when many users deeply concentrate to act through remote bodies, their conscious is transferred to a remote place. As more users get immersed in the Body-Sharing, the number of unconscious users increases in arbitrary areas, leaving these areas unsafe. We aim to avoid the hazard resulting from high rates of unconscious users. In this research, the outcomes of five proposed rules that organize the unconscious users’ rate are revealed. These rules are (I) Time Limit Rule “limiting the Body-Sharing time of each user per day”, (II) Visitors Limit Rule “limiting the number of simultaneous remote Body-Sharing visitors into an area”, (III) Departures Limit Rule “limiting the number of allowed Body-Sharing users to depart from an area simultaneously”, (IV) Increase Charm Level Rule “granting larger budgets to the least attractive places”, and (V) Decrease Charm Level Rule “deducting budgets assigned to the most attractive places”. On the other hand, unconscious users rates are monitored when no rule (i.e. free Body-Sharing) is applied as a baseline for evaluation. In order to anticipate users’ popular Body-Sharing destinations, we use a sigmoid function for decision making whether or not he or she travels. The attractiveness levels of different areas are set using the statistical data provided by the Japanese government. With the sigmoid probability function for decision making, the attractiveness of probable destinations, the five proposed rules, and the organization of unconscious users rate are simulated. The inhabitants of the Japanese 47 prefectures are the study case; a total population of 126.9 million according to the announced statistics in 2016. Rules I and II were found, by simulation, effective to suppress depopulation/overpopulation areas compared to free Body-Sharing. We realized that like the widely adopted parental rule that limits the time spent online daily by children, applying the Time Limit Rule on the unconscious users’ rate organization outperformed other rules.

Cooperation in a public goods game has been studied extensively to find the conditions for sustaining the commons, yet the effect of asymmetry between agents has been explored very little. Here we study a game theoretic model of cooperation for pest control among farmers. In our simple model, each farmer has a paddy of the same size arranged adjacently on a line. A pest outbreak occurs at an abandoned paddy at one end of the line, directly threatening the frontier farmer adjacent to it. Each farmer pays a cost of his or her choice to an agricultural collective, and the total sum held by the collective is used for pest control, with success probability increasing with the sum. Because the farmers’ incentives depend on their distance from the pest outbreak, our model is an asymmetric public goods game. We derive each farmer’s cost strategy at the Nash equilibrium. We find that asymmetry among farmers leads to a few unexpected outcomes. The individual costs at the equilibrium do not necessarily increase with how much the future is valued but rather show threshold behavior. Moreover, an increase in the number of farmers can sometimes paradoxically undermine pest prevention. A comparison with a symmetric public goods game model reveals that the farmer at the greatest risk pays a disproportionate amount of cost in the asymmetric game, making the use of agricultural lands less sustainable.

As surface warming threatens rice production in temperate climates, the importance of cool regions is increasing. Cultivar choice is an important adaptation option for coping with cli- mate change but is generally evaluated with a single metric for a few hypothetical cultivars. Here, we evaluate adaptation to climate change based on multiple metrics and cultivars in presently cool climates in Japan. We applied the outputs of a global climate model (MIROC5) with a Repre- sentative Concentration Pathways 4.5 scenario, dynamically downscaled to a 10 km mesh for the present (1981�2000) and future (2081�2099) climate conditions. The data were input into a rice- growth model, and the performances of 10 major cultivars were compared in each mesh. With the present-day leading cultivars, the model predicted reduced low-temperature stress, a regional average yield increase of 17%, and several occurrences of high-temperature stress. The most suit- able cultivars in each grid cell changed dramatically because of climate change when a single metric was used as a criterion, and the yield advantage increased to 26%. When yield, cold, and heat stress were taken into account, however, the currently leading cultivars maintained superi- ority in 64% of the grid cells, with an average regional yield gain of 22%, suggesting a require- ment for developing new cultivars by pyramiding useful traits. A trait such as low sensitivity to temperature for phenology helps in ensuring stable growth under variable temperatures. Increas- ing photoperiod sensitivity can be an option under future climates in relatively warmer regions.

In the extratropical regions, surface winds enhance upward heat release from the ocean to atmosphere, resulting in cold surface ocean: surface ocean temperature is negatively correlated with upward heat flux. However, in the western boundary currents and eddy-rich regions, the warmer surface waters compared to surrounding waters enhance upward heat release–a positive correlation between upward heat release and surface ocean temperature, implying that the ocean drives the atmosphere. The atmospheric response to warm mesoscale ocean eddies with a horizontal extent of a few hundred kilometers remains unclear because of a lack of observations. By conducting regional atmospheric model experiments, we show that, in the Kuroshio–Oyashio Confluence region, wintertime warm eddies heat the marine atmospheric boundary layer (MABL), and accelerate westerly winds in the near-surface atmosphere via the vertical mixing effect, leading to wind convergence around the eastern edge of eddies. The warm-eddy-induced convergence forms local ascending motion where convective precipitation is enhanced, providing diabatic heating to the atmosphere above MABL. Our results indicate that warm eddies affect not only near-surface atmosphere but also free atmosphere, and possibly synoptic atmospheric variability. A detailed understanding of warm eddy–atmosphere interaction is necessary to improve in weather and climate projections.

Symbiosis is one of the most fundamental relationships between or among organisms and includes parasitism (which has negative effects on the fitness of the interacting partner), commensalism (no effect), and mutualism (positive effects). The effects of these interactions are usually assumed to influence a single component of a species’ fitness, either survival or fecundity, even though in reality the interaction can simultaneously affect both of these components. I used a dual lattice model to investigate the process of evolution of mutualistic symbiosis in the presence of interactive effects on both survival and fecundity. I demonstrate that a positive effect on survival and a negative effect on fecundity are key to the establishment of mutualism. Furthermore, both the parasitic and the mutualistic behaviour must carry large costs for mutualism to evolve. This helps develop a new understanding of symbiosis as a function of resource allocation, in which resources are shifted from fecundity to survival. The simultaneous establishment of mutualism from parasitism never occurs in two species, but can do so in one of the species as long as the partner still behaves parasitically. This suggests that one of the altruistic behaviours in a mutualistic unit consisting of two species must originate as a parasitic behaviour. Electronic supplementary material The online version of this article (doi:10.1007/s00114-014-1175-1) contains supplementary material, which is available to authorized users.

There is increasing interest in the impacts of pulsed resource inputs (e.g., seasonal fluctuations in primary production) on ecosystem properties. However, theoretical models have focused on the ecosystem role of consumers only in stable environments. We investigated how the consumption rate affects ecosystem properties when resource supplies are pulsed using a simple model with numerical simulations. We initially investigated how primary production responds to resource supply shortages under various consumption rates and found that a vigorous consumer attenuates a rapid reduction in primary production. We next examined ecosystem properties under pulsed resource supplies. Intermediate consumption enhances primary production. The consumption rate that maximizes productivity differs for producers and consumers in a given resource supply environment, irrespective of the pattern of pulsation. The enhancement of primary production and the maximization of secondary production occur simultaneously in a stable environment but are not always the same when the resource supply is pulsed. We also investigated the variability of primary production and found that intermediate consumption rates reduce its coefficient of variation. In addition, we found that consumers with either very low or very high consumption rates are vulnerable to extinction when resource supplies are pulsed. Therefore, consumers with intermediate consumption rates contribute not only to the enhancement and stabilization of primary production but also to the stability of the consumer population itself.

To discover the evolutionary logic of intracellular endosymbiosis, we investigated a theoretical model (simultaneous ordinary differential equations) of a material-cycling system inside a host cell. In the model, we introduced a recently developed cell biology concept called "autophagy", which is a decomposing-recycle process of self-compiled materials found universally among eukaryote cells. Our model is based on traditional simultaneous ODE for natural ecosystems that involve producing, grazing, and decomposing processes in material cycling. In the basic intracellular metabolic system, several enzymes regulate metabolism by synthesizing and converting metabolites into biomolecules that are precursors for enzymes involved in the producing process. Symbionts are involved in grazing processes and autophagosomes that degrade materials are involved in decomposing recycles. We compared and analyzed the local stability of ODE systems in three cases: (1) the independent, free-living cell (the basal state of a cell), (2) the case where symbionts invade and exploit macrobiomaterials as parasites inside a host cell, and (3) the combination where symbionts assist the host's metabolism. We conclude that: (i) as consumers, symbionts are required to have a growth rate that is higher than the rate of autophagosome decomposition, (ii) the host cell with a biomass larger than the threshold size would realize the mutualistic relationship with its symbiont, and (iii) this partnership accelerates the biomaterial turnover flow on the basis of biomaterials.

Both monocyte-granulocytapheresis (M-GCAP) and leukocytapheresis (LCAP) are categorized as extracorporeal leukocyte removal therapies (ECCTs). These therapies have been recognized as efficient adjuncts for patients of steroid-resistant ulcerative colitis (UC). This study aimed to consider the adaptation and the limitation of these new therapies from the clinical standpoint based on a case of UC showing strong resistance to high-dose continuous steroid injection therapy. The patient successfully underwent a scheduled colectomy while maintaining remission after applying M-GCAP and LCAP independently. Surgical therapy was chosen because of a deep ulcer in the patient's sigmoid colon, which was assumed to constitute a future risk for perforation. This case suggests that combining ECCT with steroid therapy can maintain such poorly controlled and high-risk UC patients safely for the scheduled colectomy while improving the prognosis by reducing the dosage of steroid efficiently prior to operation.

We report an erythema nodosum (EN) patient whose condition became apparent during the clinical course of ulcerative colitis (UC). The patient relapsed frequently in spite of taking a high dose adrenocortical steroid during his morbidity period of UC. Monocyte-granulocytapheresis (M-GCAP) was combined with 5-aminosalicylic acid 2250 mg/day peroral and once a day of steroid enema. Monocyte-granulocytapheresis was performed once a week for 5 weeks, and succeeded in inducing clinical remission for both UC and EN. The immunological and clinical connections between UC and EN have never been fully elucidated. In this case, because the symptoms of UC and EN revealed parallel improvement after his inflammatory reaction had been brought under control by combining M-GCAP therapy, we hypothesize that the onset of EN appeared as a result of the patient's long-term, treatment-resistant immuno-disturbance, which first appeared as symptoms of UC. Immunomodulative effects induced by M-GCAP might help to control other chronic non-specific inflammations not concerned with targeted organ(s).

The importance of tumor necrosis factor (TNF)-alpha and the TNF receptor gene polymorphisms in the etipathogenesis of inflammatory bowel disease (IBD) has not been elucidated. DNA from peripheral blood samples was obtained from 124 patients with Crohn's disease (CD), 106 patients with ulcerative colitis (UC), and 111 unrelated healthy controls. We examined two single nucleotide polymorphisms (SNPs) of the TNF-alpha gene, TNF (–308 G/A and –238 G/A), an SNP of the TNF receptor superfamily member 1A gene, TNFRSF1A(also known as TNFR1), at codon 12 in exon 1 (CCA/CCG), and two SNPs of the 1B gene, TNFRSF1B (also known as TNFR2), (1466 A/G and 1493 C/T). There was a difference in the carrier frequency for haplotype AG (–308 A, –238 G) between UC patients and the controls (OR=4.76, 95% CI=1.53–14.74, P

Heparanase activity is correlated with the metastatic potential of several cancer cells and is a key enzyme in the breakdown of tissue barriers. It is also involved in the regulation of growth factor and cytokine activity. However, little is known about the factors that induce heparanase in cancer cells. We investigated the effect of three growth factors, platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF), on heparanase mRNA induction in lung cancer cells in vitro. In addition, we examined the effect of erythromycin (EM) and clarithromycin (CAM), which are 14-membered ring macrolide antibiotics that act as biological response modifiers, on the expression of heparanase mRNA induced by growth factors. PDGF, HGF and bFGF stimulated cell migration activity and enhanced the expression of heparanase mRNA in the human lung adenocarcinoma cell line A549. Via different mechanisms, EM and CAM modulate the induction by these factors of heparanase mRNA expression on A549 cells. EM also significantly suppressed A549 cell migration induced by PDGF and HGF, and CAM significantly suppressed A549cell migration induced by bFGF. The results suggest that the growth factors PDGF, HGF and bFGF are important inducers of heparanase in potentially invasive and metastatic cancer cells. The suppressive effect of heparanase mRNA expression by EM and CAM may have interestingtherapeutic applications in the prevention of metastasis.

Intracellular adhesion molecule-1 (ICAM-1)-mediated cell-cell adhesion is thought to play an important role at sites of inflammation. Recent evidence suggests that ICAM-1 surface expression on alveolar macrophages is increased in pulmonary sarcoidosis and that inflammatory granuloma formation is characterized by the aggregation of macrophages. The present study shows that ICAM-1 expression is significantly elevated on alveolar macrophages from patients with sarcoidosis in response to tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (INF-gamma) compared with healthy controls. Aggregation and adhesion were significantly increased in alveolar macrophages treated with TNF-alpha and INF-gamma, and significantly inhibited in those pretreated with a monoclonal antibody to ICAM-1. Similarly, aggregation and adhesion were inhibited in macrophages treated with heparin, which then exhibited a wide range of biological activities relevant to inflammation. These results suggested that the surface expression of ICAM-1 on alveolar macrophages in response to TNF-alpha and INF-gamma is important in mediating aggregation and adhesion. Additionally, heparin may be useful for developing novel therapeutic agents for fibrotic lung disease.

As we consider succinic acid to be an exacerbating factor in ulcerative colitis, we investigated its influence on rat colonic mucosa in terms of mucosal blood flow and superoxide generation. We measured mucosal blood flow by the hydrogen gas clearance method and superoxide generation by the chemiluminescence method, and observed histopathological findings to determine the effects of succinic acid. After the instillation of succinic acid of any concentration tested to the colon, mucosal blood flow decreased. Histopathologically, the higher the concentration of succinic acid, the greater was the erosion formation in the colonic mucosa, while significant polymorpho-nuclear cell infiltration and superoxide generation from colon tissue were observed with 0.01% succinic acid compared with higher or lower concentrations. Succinic acid, at fecal concentrations found in active stage ulcerative colitis, appears to be implicated in mucosal injury, mediated by a decrease in colonic mucosal blood flow and infiltration of superoxide-generating polymorpho-nuclear cells into the mucosa.

The evolutionary origins and advantages of clonal reproduction relative to sexual reproduction have been discussed for several taxonomic groups. In particular, organisms with a sessile lifestyle are often exposed to spatial and temporal environmental fluctuations. Thus, clonal propagation may be advantageous in such fluctuating environments, for sessile species that can reproduce both sexually and clonally. Here we introduce the concept of niche to a lattice space that changes spatially and temporally, by incorporating the compatibility between the characteristics of a sessile clonal plant with its habitat into a spatially explicit individual-based model. We evaluate the impact of spatially and temporally heterogeneous environments on the evolution of reproductive strategies: the optimal balance between seed and clonal reproduction of a clonal plant. The spatial niche case with local habitats led to avoidance of specialization in reproductive strategy, whereas stable environments or intensive environmental change tended to result in specialization in either clonal or seed reproduction under neutral conditions. Furthermore, an increase in spatial niches made clonal reproduction advantageous, as a consequence of competition among several genets under disturbed conditions, because a ramet reached a favorable habitat through a rare long-distance dispersal event via seed production. Thus, the existence of spatial niches could explain the advantages of clonal propagation.

Chronic cough is the only symptom of eosinophilic bronchitis (EB). There is considerable overlap between EB and atopic cough. To investigate the antitussive effects of a histamine H1-recetor antagonist, epinastine hydrochloride (epinastine, CAS 80012-43-7, Alesion; 20 mg/day, once daily), cough scores, pulmonary function, capsaicin cough threshold, and bronchial hyperresonsiveness (BHR) to methacholine (MCh) were evaluated before and after a 4-week treatment with epinastine in patients with EB. In the epinastine group, the cough scores were decreased significantly (18.3 +/- 6.1 in week 1, 17.4 +/- 6.7 in week 2, 15.1 +/- 6.2 in week 3, 14.0 +/- 4.8 in week 4) in comparison with the value of 35.3 +/- 8.7 in week -2). The cough threshold for capsaicin improved from 1.70 +/- 3.04 micromol/l to 12.7 +/- 17.6 micromol/l in the epinastine group (p0.05; baseline vs. week 4) The bronchial hyperresponsiveness to MCh (Dmin) did not change significantly either in the epinastine or the placebo groups. The morning and evening peak expiratory flow rate (PEFR, L/min) did not change from the baseline period in either the epinastine or the placebo groups. These results suggested that epinastine may be useful for treating patients with EB and that histamine H1-receptor is related to the pathophysiology of coughing in EB.

Background. The etiology of inflammatory bowel disease, which includes ulcerative colitis and Crohn’s disease, has not yet been made clear. However, inflammatory bowel disease is recognized as a multifactorial disease, and innate genetic factors might contribute to the pathogenesis. Cytokine genes are thought to be important in inflammatory bowel disease. Recently, interleukin 18, cloned as a novel proinflammatory cytokine, has been implicated in inflammatory bowel disease, especially Crohn’s disease. Methods. To identify germline mutations in patients with inflammatory bowel disease, the entire coding region of IL18 was examined using a DNA sequencing procedure. Results. No functional mutations were found, but a novel single nucleotide polymorphism (SNP) was identified as TCA/ TCC at codon 35. In patients with Crohn’s disease, the frequency of TCC allele carriers was significantly higher than in healthy controls (χ2 = 9.35, P = 0.002229, OR = 2.58, 95% CI = 1.39–4.80). Also, the magnitude of the association was more remarkable in females (χ 2 = 16.36, P = 0.000052, OR = 8.17, 95% CI = 2.73–24.41). The TCC allele at codon 35 of IL18 may increase the risk for Crohn’s disease, especially in females. Conclusions. IL18 is probably one of several genes that determine susceptibility to Crohn’s disease.

An 18-year-old woman was treated with leukocytapheresis (LCAP) for her combined ulcerative colitis (UC) and aortitis syndrome (AS). Because a close relationship between these two diseases has been suspected based on their etiological and/or pathological findings, we had hypothesized that LCAP, which has satisfactory effects on inflammatory bowel disease such as UC and Crohn's disease might be effective for both her UC and her AS. After informed consent, LCAP therapy was performed once a week for a total of 7 times. Endoscopic remission of the UC was observed. Even though there were no significant improvements in her subjective symptoms of AS such as side-neck pain and dizziness, objective evidence of improvement was obtained when the patient's condition was compared before and after LCAP by angiography, angio-magnetic resonance imaging, and the plethysmogram of her fingertips. These results suggest that LCAP may be valuable as a new adjunct therapy for AS.

In nature, we can find an organism plays a mutualistic role on its partner species in a particular situation even though it is parasite in essence. What condition realizes such a flexible symbiotic...

Leukocytapheresis (LCAP), performed with a leukocyte removal filter, was administered five times, at 1-week intervals, for 5 weeks of intensive therapy and five times, at approximately 1-month intervals, for approximately 5 months of maintenance therapy, to 13 patients with inflammatory bowel disease (IBD) diagnosed as ulcerative colitis (UC) in 8 and Crohn's disease (CD) in 5. Clinical and blood examinations showed no side effects in any of the patients. During the intensive therapy, excellent or moderate clinical response was recognized in 11 of the 13 patients (84.6%), of whom 6 had a dramatic response; the excellent or moderate clinical response continued throughout the maintenance therapy in 8 of the patients (61.5%). Flow cytometry showed that the patients who had improved generally had high values for percentages of HLADR+, HLADR+CD3+, and HLADR+CD8+ cells before the first LCAP, and that these values and the C-reactive protein levels and erythrocyte sedimentation rates had decreased to the normal range by the end of both intensive and maintenance therapy. In the patients who showed poor response, in contrast, all the above values had been at or near normal before the initial LCAP administration. The clinical improvement in the absence of any additional medical treatment suggests that LCAP has the capacity to influence the causal mechanism(s) of IBD and that IBD is strongly associated with the cell-mediated immune response.

Histochemical investigation of lectin-binding sites was carried out on basal cell epithelioma (BCE) and carcinoma (BCC) cells obtained from human skin lesions. The HRP-conjugated lectin technique was employed (Con A, for detecting glucose and mannose; RCA-1, for Gal; PNA and SBA, for Gal and GaiNAc; DBA, for GalNAc; UEA-1, for fucose; and WGA, for GlcNAc and NANA). Irrespective of histologic variation in BCE and BCC, the tumor cells exhibited rather weak binding to lectin conjugates, and the tumor cells adjacent to keratinizing epithelia in keratotic BCE displayed stronger lectin staining as compared to those in non-keratinized tumors. Some of the desquamated tumor cells found in cystic spaces of cystic BCE had the strongest reaction for the PNA conjugate. The cytochemical distribution of lectin conjugates in BCE and BCC was usually confined to intercellular materials and surface of the tumor cells, but the lectin staining was not strong. No major difference was found between tumor cells of BCE and BCC with respect to lectin-binding.

The binding of horseradish peroxidase (HRP)-conjugated lectin was studied in the oral mucosa of several mammals. The following lectins were used; Con A, PNA, SBA, DBA, RCA-1, UEA-1, and WGA. Con A staining was exhibited strongly in the connective tissue cells, moderately in germinal cells, and negatively in the keratinized layer. However, following periodate oxidation (PA/Con A) it revealed a different distribution patterns as compared to single Con A staining; i.e., PA/Con A was limited to the spinous cell epithelium. Lectin binding gave weak results in basal cells, strong in spinous cells, and showed no effect in keratinized layers. Using lectins-PNA, SBA, RCA-1, UEA-1, and WGA-, the effects in the oral squamous epithelium revealed zonal or regional distribution in their respective individual layers except for a few exceptions.

Keratin proteins were immunohistochemically demonstrated in different parts of the oral epithelium. Keratin staining in the squamous-cell epithelium was restricted to the spinous and granular cell layers, with a comparatively low reaction in the basal layer cells and none in the superficial cornified layer. In comparing the keratin staining levels, those in the buccal and sublingual epithelia were rather higher than those in the hard palatal epithelia. Staining intensities for keratin proteins were not the same in either different locations of the oral epithelium or in the same location in different animals.

Sugar residues in the epithelial cells of verruca vulgaris and seborrheic keratosis were demonstrated by the horseradish peroxidase-conjugated lectin methods. The lectins, Con A, RCA-1, UEA-1, DBA, PNA, SBA, and WGA were used to bind specifically to the sugars, Man, Glc, Gal, Fuc, GalNAc, GlcNAc and NANA. The cytochemical distribution of lectin bindings were limited to the cell surface, intercellular materials and basement membrane in the epithelial structures of the lesions. The lectin bindings in the basal layer cells were negative or weak, but increased gradually in upper spinous cells from moderate to strong levels. Vacuolated cells in verruca vulgaris showed positive lectin stainings. The intercellular materials of parakeratinized cells bound lectins differently, but orthokeratinized cells failed to bind lectins. The regional distribution of lectin bindings in stratified squamous epithelia may indicate an expression of keratinocytic stratification as well as in keratinized benign lesions.

Histochemical distribution of lectin binding sites and keratin protein was studied for epithelial components, stromal elements and giant cells in calcifying epithelioma of Malherbe as well as for normal hair follicles. The HRP (horseradish peroxidase) -conjugated lectin technique was employed; the lectins used were Con A, PNA, RCA-1, DBA, SBA, WGA and UEA-1. Immunocytochemical detection of keratin protein was made using the indirect PAP technique. Basophilic cells and shadow cells in the tumor epithelial components revealed histochemical properties similar to those of matrix cells and cortex cells in growing hair follicles, respectively. Most prominent lectin binding was observed in Con A staining. In the tumor stroma, many fibrillar elements which were distinguished as immature or mature hair were found by lectin and keratin staining. Tumor giant cells showed a stronger staining for Con A and keratin, which were enhanced following treatment with amylase. The staining intensity of lectins was usually decreased in both epithelial cells and connective tissue stroma following treatment with neuraminidase.

Quantitative analysis of epithelial components, immunohistochemical staining of MoAb to keratin proteins, and 3H-thymidine labeling were tested to evaluate the carcinogenic process in experimentally hyperkeratinized epithelia induced by topical application of DMBA in hamster cheek pouch. The epithelial lesions were classified histologically into 3 types; A type (acanthotic type), B type (mixed type), and C type (basal hyperplastic type). Initial change of hamster pouch epithelium (0-3 W) was begun from the A type (acanthotic epithelium) and in more advancing stages (5-7 W), lesions showed highei frequency of the C type, and they fi nally occurred similar frequencies for 3 types.Keratin staining in the B and C types was characterized by irregular distribution and disappearance for PKK 1 keratin in basal cells and KL 1 keratin in the epithelial layer, although PKK 1 in the normal epithelium was confined to basal cells.3H-thymidine labeling was correlated strongly to decrease or tractable staining for PKK 1 keratins in basal cells of the precancerous epithelium.

Paget cells from cases of mammary and extramammary Paget’s disease were examined for carcinoembryonic antigen (CEA) and CEA-related antigens by the immunoperoxidase method. Paget cells showed a conspicuous positive reaction with antiserum to CEA, but were negative when nonspecific cross-reacting-antigen (NCA)-absorbed antiserum to CEA, or a monoclonal antibody to CEA was used as the detecting agents. Paget cells may contain large amounts of NCA antigen or CEA-related substances.