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Maintenance of the pluripotent state of mesenchymal stem cells (MSCs) during in vitro expansion is an important factor for the successful proliferation of MSCs possessing high differentiation capacity. However, the differentiation potential of MSCs can easily be lost during in vitro expansion, particularly at late passages. Reactive oxygen species (ROS) are signaling molecules that help to maintain MSC function; however, excessive ROS generation can induce senescence and impair both the differentiation capacity and proliferation of MSCs. In this study, we have designed an amphiphilic block copolymer (redox copolymer), which possesses ROS scavenging capacity in the hydrophobic site. When this redox copolymer was coated on cell culture dishes coupled with human E-cadherin chimeric antibody (hE-cad-Fc), it had an antioxidative effect on cultured MSCs. We also confirmed that the redox polymer construct poly(ethylene glycol) tethered chain on the surface prevented nonspecific cell binding, whereas the co-immobilized surface allowed high adhesion of E-cadherin-positive MSCs. Interestingly, the intracellular ROS level was significantly decreased by the prepared cell culture dish, despite ROS being scavenged only on the surface of the dish, on the cell exterior. Consequently, the cultured MSCs retained high expression levels of pluripotency-associated genes, including SOX2.

Acute inflammatory conditions such as sepsis lead to fatal conditions, including multiple organ failure. Several treatments such as steroidal anti-inflammatory drugs are currently being investigated in order to decrease the blood cytokine level, which increases remarkably. However, any of these therapeutic treatments are not always reliable and effective; none have drastically improved survival rates, and some have mostly ended with failure. Reactive oxygen species (ROS) are signaling molecules responsible for the production of cytokines and chemokines that can mediate hyperactivation of the immune response called cytokine storm. In addition to the above-mentioned agents, various antioxidants have been explored for the removal of excess ROS during inflammation. However, the development of low-molecular-weight (LMW) antioxidants as therapeutic agents has been hampered by several issues associated with toxicity, poor pharmacokinetics, low bioavailability, and rapid metabolism. In the present study, we aimed to overcome these limitations through the use of antioxidative nanoparticles possessing 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) which are covalently conjugated to polymer. Although treatment with antioxidative nanoparticles alone did not eliminate bacteria, combined treatment with an antibacterial agent was found to significantly improve survival rate of the treated mice as compared to the control group. More importantly, the antioxidative nanoparticles reduced oxidative tissue injury caused by the bacterial infection. Thus, our findings highlighted the effectiveness of combination treatment with antioxidative nanoparticles and an antibacterial agent to prevent severe inflammation caused by bacterial infection.

Background MicroRNAs (miRNAs) encapsulated in the exosomes of plasma is of interest as stable and minimally invasive biomarkers for recurrence and prognosis in cancer patients. The aim of this study was to clarify the predictive and prognostic value of plasma exosomal microRNA-451a (miR-451a) in patients with pancreatic ductal adenocarcinoma (PDAC). Methods Microarray-based expression profiling of miRNAs derived from exosomes in the plasma of six PDAC patients with UICC stage II was employed to identify a biomarker to distinguish between patients with and without recurrence. For validation analysis, plasma exosome samples of other 50 PDAC patients were measured by TaqMan MicroRNA assays. Results In the miRNA microarray analyses, miR-451a showed the highest upregulation in the stage II patients who showed recurrence after surgery. In the relationship to pathological factors, exosomal miR-451a showed a significant association with tumor size and stage. The overall survival (OS) and disease-free survival rates (DFS) of the high exosomal miR-451a patients were significantly worse than those of the low miR-451a patients. In Cox proportional hazards model analysis, exsomal miR-451a showed significance to OS and DFS. Conclusions Plasma exosomal miR-451a levels may be a useful minimally invasive biomarker for the prediction of recurrence and prognosis in PDAC patients.

This cross-sectional study aimed to examine the oral hygiene behaviors in the general population and identify factors affecting oral hygiene behaviors and plaque removal efficacy. A survey was distributed to patients through 11 dental practices in Japan, and each patient’s plaque index score (PIS) was recorded. In total, 1184 patients participated (521 women and 660 men), with 84.04% using manual toothbrushes (MTBs) and 15.96% using electric toothbrushes (ETBs). ETB users had a significantly lower PIS compared to MTB users (p = 0.0017). In addition, a statistically significant difference in the PIS was detected in relation to the frequency of brushing per day (≥2 times) and time spent on brushing (≥1 min). Some MTB users spent less than 1 min brushing, while all ETB users spent at least 1 min brushing, and extended brushing periods significantly improved the PIS for the MTB users. MTB users tend to replace brush heads more frequently than ETB users, and the frequency of replacement affected the PIS significantly (p < 0.01) for the MTB users. The status of dental treatment (first visit, in treatment versus recall) also significantly affected the PIS (p < 0.01). The ETB was more effective than the MTB in terms of better plaque removal and reduced frequency of brush head replacement.

Background Surgical results of patients with resected distal cholangiocarcinoma (DCC) were evaluated to elucidate prognostic impact of the type of preoperative biliary drainage (PBD). Methods Eighty-eight patients with resected DCC were stratified into two groups according to the type of PBD: the percutaneous transhepatic biliary drainage (PTBD) group (n = 25) and the endoscopic biliary drainage (EBD) group (n = 63). Results Overall 5-year survival rate of the patients in the PTBD group was poorer than in the EBD group (24% vs. 52%, P = 0.020). On univariate analysis, PTBD, pancreatic invasion, perineural invasion, and lymph node involvement were significant prognostic factors for poor overall survival. On multivariate analysis, PTBD was the only significantly independent prognostic factor for poor overall survival. The incidence of liver metastasis was significantly higher in the PTBD group than in the EBD group (32.0% vs. 13.3%, P = 0.034). Conclusions PTBD should be avoided as much as possible in patients with DCC since the patients who underwent PTBD had poorer overall survival and higher incidence of liver metastasis than those who underwent EBD.

During cell cultivation, excessively generated reactive oxygen species (ROS) affect cellular properties and functions. Although cell cultivation media contain several types of low-molecular-weight antioxidants, these small antioxidants are internalized into the mitochondria and they disrupt regulated redox balance. Here, we developed a novel biointerface that effectively eliminates ROS on a cell culture surface. Poly(ethylene glycol)-b-poly[4-(2,2,6,6-tetramethylpiperidine-1-oxyl)aminomethylstyrene] (PEG-b-PMNT) was synthesized and covalently coated on a carboxyl group-activated culture dish using sec-amino groups on a PMNT segment followed by immobilization of anti-CD34 antibodies. CD34-positive hematopoietic stem progenitor cells (HSPCs) were separated from mice fetal liver cells using our polymer-coated cell culture dish. The separated HSPCs possessed intact mitochondrial membrane potential compared with those in the conventional cell cultivation system. In addition, the expression level of CD34 was maintained for an extended period on our culture dish with the antioxidative biointerface. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2080-2085, 2016.

Transdermal vaccination with cancer antigens is expected to become a useful anti-cancer therapy. However, it is difficult to accumulate enough antigen in the epidermis for effective exposure to Langerhans cells because of diffusion into the skin and muscle. Carriers, such as liposomes and nanoparticles, may be useful for the prevention of antigen diffusion. Iontophoresis, via application of a small electric current, is a noninvasive and efficient technology for transdermal drug delivery. Previously, we succeeded in the iontophoretic transdermal delivery of liposomes encapsulating insulin, and accumulation of polymer-based nanoparticle nanogels in the stratum corneum of the skin. Therefore, in the present study, we examined the use of iontophoresis with cancer antigen gp-100 peptide KVPRNQDWL-loaded nanogels for anti-cancer vaccination. Iontophoresis resulted in the accumulation of gp-100 peptide and nanogels in the epidermis, and subsequent increase in the number of Langerhans cells in the epidermis. Moreover, tumor growth was significantly suppressed by iontophoresis of the antigen peptide-loaded nanogels. Thus, iontophoresis of the antigen peptide-loaded nanogels may serve as an effective transdermal delivery system for anti-cancer vaccination.

During cell cultivation on conventional culture dishes, various events results in strong stresses that lead to the production of bioactive species such as reactive oxygen species (ROS) and nitric oxide. These reactive species cause variable damage to cells and stimulate cellular responses. Here, we report the design of a novel biocompatible surface that decreases stress by not only morphologically modifying the dish surface by using poly(ethylene glycol) tethered chains, but also actively scavenging oxidative stress by using our novel nitroxide radical-containing polymer. A block copolymer, poly(ethylene glycol)-b-poly[(2,2,6,6-tetramethylpiperidine-N-oxyl)aminomethylstyrene] (PEG-b-PMNT) was used to coat the surface of a dish. Differentiation of undifferentiated human leukemia (HL-60) cells was found to be suppressed on the polymer-coated dish. Notably, HL-60 cell cultivation caused apoptosis under high-density conditions, while spontaneous apoptosis was suppressed in cells plated on the PEG-b-PMNT-modified surface, because a healthy mitochondrial membrane potential was maintained. In contrast, low molecular weight antioxidants did not have apparent effects on the maintenance of mitochondria. We attribute this to the lack of cellular internalization of our immobilized polymer and selective scavenging of excessive ROS generated outside of cells. These results demonstrate the utility of our novel biocompatible material for actively scavenging ROS and thus maintaining cellular morphology.

The prevention of encapsulating peritoneal sclerosis (EPS) and the enhancement of dialysis efficiency are two important strategies that can improve the quality of life of patients undergoing peritoneal dialysis. We have thus far developed bionanoparticles that effectively scavenge reactive oxygen species (redox nanoparticles; RNPs). The objective of this study was to apply RNPs as a component of dialysate to reduce oxidative stress. Porous silica nanoparticles were combined with RNPs to enhance the effective adsorption capacity of low-molecular weight (LMW) compounds. The silica-containing RNPs (siRNPs) were confirmed to statistically decrease the level of creatinine and blood urea nitrogen in vivo. EPS model rats that underwent an intraperitoneal injection of chlorhexidine gluconate exhibited dysfunction of the peritoneal membrane. siRNP administration did not result in dysfunction of the peritoneal membrane. An LMW nitroxide compound, TEMPOL, also showed a weak peritoneal protective effect, although its efficiency was limited. No blood uptake of siRNPs was observed when they were administered into the peritoneal cavity. However, LMW-TEMPOL diffused into the blood stream, which might have decreased its effective concentration in the peritoneal cavity and led to adverse effects across the entire body. Considering these results, siRNPs are expected to be a new multi-functional nanomaterial for high performance peritoneal dialysis.

Oxidative stress caused by reactive oxygen species (ROS) occurs as events in which living tissues contact certain materials. These events include cell cultures and implantation of materials. Because of the high reactivity of ROS, they damage cells by oxidizing DNA, lipids, and proteins. Conversely, ROS also act as signaling molecules regulating cellular morphology. In particular, mitochondrial ROS are involved in the regulation of cellular physiology, including differentiation, autophagy, metabolic adaptation, apoptosis, and immunity. The balance between generation and elimination of ROS is essential for signaling pathways and proper cell function, and redox imbalance leads to cellular dysfunction and disturbs cellular homeostasis. To reduce oxidative stress, versatile antioxidants, including natural compounds, have been used; however, their poor bioavailability and pro-oxidant effects have limited the versatility of these antioxidants. Recent developments of antioxidative biointerfaces may represent a potent solution to this issue. Designed biointerfaces composed of polymer antioxidants eliminate excessive ROS at the interface between living tissues and materials, and do not disturb regulated redox balance inside cells, thus eliminating unexpected cell responses, such as inflammation and dysfunction.

Enteric coatings that deliver drugs to specific regions of the small intestine were examined. Hypromellose acetate succinate (HPMCAS) with different values of succinoyl group contents was used. Decreasing the succinoyl group content resulted in an increase in the pH at which HPMCAS started to dissolve. Drug-containing granules with or without enteric coating were prepared and their in vitro dissolution in a simulated intestinal fluid of pH 6.8 was examined. Granules coated with HPMCAS having the succinoyl group content of 6.2% showed a lag time of about 30 min, although drug release from granules without coating was completed within 20 min. The time lag and dissolution rate were extended and reduced, respectively, as the succinoyl group content was decreased. Rat experiments indicated that enteric-coated granules disintegrated and the bulk of the drugs was immediately released when the granules reached a specific site of the small intestine where the pH corresponded to the pH at which the enteric coating agent started to dissolve. Similar results were observed in monkey experiments. It was suggested that HPMCAS with the succinoyl group content of about 5% was suitable as an enteric coating agent for delivering drugs to the middle-to-lower region of the small intestine.

Gene therapy, a potential solution to hereditary and nonhereditary diseases, faces the challenges of safe and specific gene delivery. Cationic carrier molecules (e.g., liposome and polymers) that form noncovalent complexes with negatively charged DNA have been in use as nonviral gene delivery vectors. Although they tend to be relatively less efficient than viral systems, they have inherent advantages of flexibility and safety. Their derivatives, in conjugation with functional molecules such as peptides, proteins, growth factors, and antibodies, have been focused on to generate nanocarriers with low toxicity, high stability, high efficiency, and cell-specific targeting features. Here we describe internalizing polyclonal and monoclonal antibodies against a stress chaperone, mortalin/mtHsp70. We demonstrate that these internalizing anti-mortalin antibodies (i-mot Ab) could be employed for (1) internalization of nanoparticles (quantum dots, Qdots) and the generation of illuminating cells and (2) gene delivery. By using cancer and normal human cells in parallel, we further demonstrate that gene delivery can be specifically enhanced in human cancer cells if cationic polymer polyethylenimine (PEI) and i-mot Ab complex are used and may provide a novel cancer-targeting nanocarrier.

Background Chemotherapy for unresectable pancreatic cancer should not only prolong survival but maintain quality of life, considering its limited life expectancy. To achieve these goals, biweekly gemcitabine plus S-1 was assessed in the clinical practice setting. Methods Fifty-two patients with either locally advanced or metastatic pancreatic cancer who received biweekly gemcitabine plus S-1 as a first-line anti-cancer treatment were included in this study. Treatment delivery, toxicity, response, and survival were reviewed to assess the feasibility and efficacy. Results The completion rate of treatment delivery was 95.1%, with relative dose intensity of 97.1% for gemcitabine and 97.3% for S-1. Overall, grade 3 or worse adverse events were rare, with hematologic toxicities occurring in 5.8%. The objective response rate was 30.8%, and more than a 50% reduction of CA19-9 was observed in 77.1%. Surgical conversion was completed with a margin-negative resection in four patients whose tumor had shrunk for at least 6 months. The median progression-free and overall survivals were 10.4 and 18.2 months, respectively. Reduction of CA19-9 was associated with longer survival. Conclusions Biweekly gemcitabine plus S-1 may be a good alternative to current standard chemotherapies for unresectable pancreatic cancer with less toxicity and less treatment burden without losing efficacy.

We report a straightforward method for the site-specific modification of long double-stranded DNA by using a maleimide adduct of deoxycytidine. This novel nucleoside analogue was efficiently incorporated at the 3'-termini of DNA by terminal deoxynucleotidyl transferase (TdT). Thiol-containing compounds can be covalently linked to the maleimide moieties. We added a nuclear localization signal peptide to the 3'-terminal of a 350 bp-long DNA that encoded short-hairpin RNA, and these modifications resulted in the enhancement of silencing activity by RNA interference. This enhancement is mainly attributed to increased stability of the template DNA.

Proteins containing unnatural amino acids have immense potential in biotechnology and medicine. We prepared several histidine analogues including a novel histidine analogue, beta-(1,2,3-triazol-4-yl)-DL-alanine. These histidine analogues were assayed for translational activity in histidine-auxotrophic Escherichia coli strain UTH780. We observed that several histidine analogues, including our novel histidine analogue, were efficiently incorporated into the protein in vivo; however, other analogues were rejected. These results suggest that the hydrogen atom at a specific position seriously affects incorporation.

Reactive oxygen species (ROS) play important roles in regulating cellular morphology. In particular, mitochondrial ROS are involved in the regulation of cellular physiology. The balance between generation and elimination of ROS is essential for signaling pathway maintenance. However, excessive ROS are generated during cell culture in response to high oxygen concentration, cell contact with cell culture instruments and pro-oxidants in culture medium also generate ROS. Redox balance disruptions lead to changes in cellular morphology and disturb cellular homeostasis. Therefore, suppression of excessively generated ROS during cell subculture and treatments is very important issue, especially in the field of cellular therapeutics where cellular morphology should be strictly controlled. Though addition of low molecular weight (LMW) antioxidants to culture media suppresses such effect to some extent, they cause unwanted morphological changes of cultivating cells after internalization into the cells. In this work, we constructed a new biocompatible instrument based on ROS scavenging character and demonstrated the utility of a ROS-scavenging polymer as a novel biocompatible material. A polymer (PEG-b-PMNT) composed of poly(ethylene glycol) (PEG) and polystyrene segment with a nitroxide radicals (TEMPO) as a side chain, which catalytically scavenges ROS, was coated onto the surface of a dish via covalent linkage. Differentiation and spontaneous apoptosis of several kinds of cells including hematopoietic stem cells were suppressed on the polymer-coated dish. In contrast, LMW antioxidants showed disruption of mitochondrial membrane potential and induction of cellular differentiations. These adverse effects were likely due to the internalization of LMW antioxidants into mitochondria, resulting in a disrupted redox balance. In contrast, ROS-scavenging polymer could not internalize in cells and, therefore, could not have any adverse effects within the cell or mitochondria. These results demonstrate the utility of our novel biocompatible material for actively scavenging ROS and thus maintaining cellular properties.

Hypoxia is a feature of solid tumors and tumor hypoxia is known to promote mutagenesis, invasiveness. A strategy for targeting the hypoxic region of tumors is highly required; however, several issues such as adverse effects and poor penetration property of drugs have hampered developments. In this study, we developed a novel system in which antitumor prodrug is inactivated by the modification with the functional group and reduces the adverse effect to normal tissues which are generally present under normoxia condition but releases active anticancer drug under hypoxic condition. We have applied this technology to several anticancer drugs. In vivo experiments, doxorubicin prodrug (pro-Dox) was evaluated using tumor bearing mice and significant anti-tumor effect of pro-Dox was observed. Importantly, administration of pro-Dox did not show any apparent adverse effect and drastically improved survival rate of mice. Immunofluorescence analyses confirmed that the designed prodrug localized at the hypoxic region, in contrast to conventional anticancer drugs, which localized only at the normoxic region. These results indicate that the developed prodrug drastically improved the therapeutic effect by reducing adverse effects, improving drug penetration, and specifically activating the drug at hypoxic regions

Thirty-one patients with chronic sinusitis were treated with 150 mg of roxithromycin (RXM) per day for 12 weeks.The percentages of patients with an excellent or a good subjective response after 12 weeks of therapy were: 37.9% with reduced frequency of nose blowing, 37.9% with increased ease of nose blowing, 36.0% with reduced frequency of postnasal drip, 36.0% with easier removal of postnasal drip, 45.9% with less nasal obstruction, 40.0% with less headache, 45.5% with improved sense of smell.Objective findings were reduced as follows: redness of the nasal mucosa in 31.8%, edema of the nasal mucosa in 34.4%, quantity of the nasal discharge in 48.3%. The quality of the nasal discharge was improved in 48.3%, and the X-ray findings in the maxillary sinus (36 sides) were improved in 11.1%, and in the ethmoid sinus (38 sides) in 10.5%.The percentages of patients improved after 4, 8, and 12 weeks of therapy were not significantly different.No side effects of RXM were noted during this investigation.

This paper describes a case of dietetic ileus due to “mochi” capable of being confirmed by preoperative CT examination of the abdomen. A 53-year-old man was seen at the hospital because of abdominal pain and vomiting. Simple abdominal X-ray examination revealed a remarkable dilatation of the small intestine. Abdominal CT showed shadows of foreign body in the terminal ileum and stomach. The patient was diagnosed as intestinal obstruction due to some foreign body and underwent emergency operation. On laparotomy a great number of pieces of “mochi” was found in the terminal ileum and stomach. It was dietetic ileus caused by “mochi”. These mochi pieces were removed by incision of the intestine and stomach. This paper also presents a review of the literature.

Food–drug interactions may reduce the bioavailability of drugs taken after meals (negative food effects). We designed enteric-coated tablets that start to disintegrate when they reach the middle-to-lower region of the small intestine, and examined whether they could reduce negative food effects in dogs. Tablets containing trientine as a model drug were coated with hypromellose acetate succinate (HPMCAS) with various values of succinoyl group content. The time lag of drug dissolution from these enteric-coated tablets in simulated intestinal fluid of pH 6.8 increased as the succinoyl group content was decreased. The AUC of trientine after oral administration of its aqueous solution to fed dogs was one-eighth of that in fasted dogs. The low drug absorption in fed dogs was improved when trientine was administered as enteric-coated tablets. The average ratio of AUC in the fed state to that in the fasted state increased with decreasing succinoyl group content of HPMCAS. Negative food effects completely disappeared after oral administration of tablets coated with HPMCAS having a succinoyl group content of 6.2% or less, which probably disintegrated in the middle-to-lower small intestine. Our results indicated that food–drug interactions were avoided by separating the main absorption site of drugs from that of food components. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:5341–5353, 2008

[1] Monitoring seawater CO2 for a full year with seasonal observations of community metabolism in Ishigaki Island, Japan, revealed seasonal variation and anomalous values owing to the bleaching event in 1998. The daily average pCO2 showed a seasonal pattern on an annual scale, 280 to 320 μatm in winter and 360 to 400 μatm in summer, which was determined primarily by the seasonal change in seawater temperature. By contrast, the range in the diel variation in pCO2, 400 to 500 μatm in summer 200 to 300 μatm in winter, was attributed to the seasonal variation in community metabolism: Gross primary production (Pg) and respiration (R) were high in summer and low in winter. During the 1998 bleaching event, although Pg and R increased, community excess organic production (E) decreased by three quarters compared with the same month in 1999, when the coral community showed high recovery. This change in metabolism led to large diel range and increased average value of pCO2 levels in the seawater on the reef flat. The decrease in the range and increase in the average value of pCO2 were observed by monitoring the Palau barrier reef flat, where overall mortality of corals occurred after the bleaching. All the metabolic parameters, Pg, R, E and calcification (G) were reduced by half after the bleaching, which increased the average pCO2 value by 10 μatm and decreased its diel range from 200–400 μatm to 100–200 μatm. Bleaching and resultant mortality of coral reefs led to degradation of their metabolic performance, and thus resulted in the loss of their active interaction with the carbon cycle.

The anti-inflammatory effect of flurbiprofen tape (FP-T) by topical application was investigated, and the findings were compared with the results of oral administration of flurbiprofen to adjuvant arthritic rats. The topical application of FP-T significantly suppressed both applied and non-applied hind paw edema, with a potency similar to that seen with the oral administration of flurbiprofen. Body weight also increased with these treatments. Plasma levels of flurbiprofen differed little between topical application of FP-T and oral administration of flurbiprofen. Gastric damage induced by topical application of FP-T was significantly less than that seen in case of oral administration of flurbiprofen. These results suggest that the anti-inflammatory effects of FP-T cannot be entirely explained by flurbiprofen permeating inflamed tissue below the application site; rather, flurbiprofen penetrating into the systemic circulation may explain these actions.

Our own and other previous studies demonstrate marked anti-proliferative activity of the tyrophostin adaphostin (NSC680410) in a variety of hematologic malignancies including chronic myelocytic leukemia (CML), chronic lymphcytic leukemia (CLL), acute myelocytic leukemia (AML), and Multiple Myeloma. Here we show that adaphostin (NSC680410), similar to bortezomib, additionally inhibits tumor angiogenesis within the MM bone marrow (BM) microenvironment. This effect is elicited both indirectly by inhibition of VEGF production and secretion in MM cells, as well as directly by abrogation of endothelial cell growth. Specifically, adaphostin triggers marked downregulation of nuclear c-Myc expression in MM cells. Both adaphostin, as well as specific downregulation of c-Myc using siRNA, lead to a decrease in cobalt chloride- induced Hif-1alpha- expression and Hif-1alpha activity, as evidenced by western blot analysis and expression of Hif-1alpha- driven luciferase, respectively. Indeed secretion of the Hif-1alpha target gene VEGF is markedly inhibited in a dose- and time- dependent manner. Importantly, neither knockdown of c-Abl expression nor exogenous overexpression of caspase- cleavage- induced c-Abl fragment abrogates drug- induced Hif-1alpha downregulation or inhibition of its activity. Taken together, these results indicate the existence of a c-Myc/ Hif-1alpha- dependent, but c-Abl- independent, pathway modulating MM cell production and secretion of VEGF. In contrast, we demonstrate a direct antiangiogenic effect of adaphostin on endothelial cells, similar to H2O2, is mediated via c-Jun upregulation, inhibition of cell proliferation, and the induction of cell apoptosis. Moreover, our data further demonstrate activity of adaphostin within the BM microenvironment. Adaphostin, similar to bortezomib, significantly inhibits VEGF secretion triggered by adhesion of MM cells to BMSCs and endothelial cells. Consequently, conditioned medium derived from adaphostin- treated co-cultures markedly inhibits endothelial cell growth and tubule formation in a dose- dependent manner. Finally, we confirmed these in vitro results using an in vivo xenograft mouse model of human MM. Specifically, western blot analysis, as well as immunohistochemistry, demonstrate marked downregulation of both Hif-1alpha and CD31 in tumors isolated from adaphostin- treated animals versus control animals, confirming the in vivo antiangiogenic effect of adaphostin. Similar effects were obtained using a SCIDhu mouse model as well as a significant decrease of MM- related bone disease, due to anti- VEGF activity of adaphostin. Taken together, these data provide the rationale for the clinical evaluation of adaphostin to target both MM cells and the BM milieu to improve patient outcome in Multiple Myeloma.

Six cases of normal perssure hydrocephalus (NPH) were found among 160 surgical cases of intracranial hematoma due to severe head injury, in the past 10 years. Out of the 160 cases, 80 were followed up. The incidence of post-traumatic NPH was 3.7%, or 7.5% in the followed-up cases. After a little improvement following the removal of intracranial hematoma, these cases showed prolonged disturbance of consciousness or a delayed recovery rate and a progressive enlargement of the ventricle without cerebral atrophy on CT scan. Diagnosis of post-traumatic NPH was made by the plateau level of clinical improvement accompanied by absence of intracranial hypertension and a progressive ventricular dilatation shown by an increased bicaudate cerebroventricular index on CT scan. Radioisotope serum albumin cisternography revealed disturbance of cerebrospinal fluid (CSF) circulation in all these cases and was a reliable tool for determining the indication for a shunting operation, which brought a marked improvement in five patients. The authors believe that the shunting operation should be tried on post-traumatic NPH patients who do not show cerebral atrophy. Presence of a subarachnoidal and a contusional hemorrhage on brain surfaces, noted in the operation, suggests the need to pay attention not only to the disturbance of the conventional extracerebral CSF pathway, but to that of the intracerebral pathway as regards the pathogenesis of post-traumatic NPH.

The present studies were performed to investigate the metabolic role of the lungs in the renin-angiotensin system under hypothermia by measuring plasma renin activity, plasma angiotensin I (A I), plasma angiotensin II (A II), plasma aldosterone and plasma angiotensin converting enzyme activity on 14 patients who underwent open-heart surgery with surface-induced simple hypothermia. In addition, dog experiments were performed, in which changes of renal blood flow and angiotensin metabolism in lungs and kidneys under hypothermia were studied in vivo. The following results were obtained: 1) During and after open-heart surgery with surface-induced simple hypothermia, the homeostasis in the renin-angiotensin system is still maintained. 2) An increase of A II may play an important role in maintaining blood pressure under hypothermia. 3) Under hypothermia, the conversion of A I to A II in the kidneys may contribute to an increase of plasma A II.

濾過型人工腎の治療において, ある種のhemofilterでは濾過されず濾液中には出現してこない溶質が, 血中では明らかに低下する現象が観察されている. このことは血液濾過治療の操作中に, これらの溶質が一部はhemofilter膜により吸着除去されている可能性を示唆している.この仮説を確かめるために, 各種の膜材料を用いた吸着実験を試みた.多数の透析患者の血漿を集めてプールした. これに各種hemofilter膜の小切片を加えて, 室温下で3時間のインキュベーションを行った. この操作の前後で血漿中の各種溶質を測定し, その変動を検討した.膜切片を加えないコントロールの場合では, 各種溶質の操作前後での濃度比は0.9-1.5程度であった.PMMA膜の場合はグルカゴン0.2, β2ミクログロブリン0.1, リゾチーム0.5と著明な低下を認め, PAN膜ではβ2ミクログロブリン0.5, リゾチーム0.1と, 同様に高度の減少を確認した. クプロファン膜では軽度に低下する溶質も見られたが, 最も著しい場合でも0.75-0.8程度であった.このことから一部の溶質は, ある種の膜表面で吸着あるいは付着の現象により, 血中から除去されている可能性が確かめられた.

In order to clarify the inhibitory mechanism of insulin secretion associated with open-heart surgery, the influence of insulin antagonistic hormones on insulin secretion was studied in 20 patients with congenital heart diseases undergoing open-heart surgery, under simple deep hypothermia. Despite a hyperglycemia, plasma immunoreactive insulin and C-peptide showed no change during the cooling period, while with the exception of plasma human growth hormone, dopamine-beta-hydroxylase, immunoreactive glucagon, cortisol and cyclic AMP in plasma, either showed no change, or a decrease during the cooling period. It is assumed that catecholamine, glucocorticoid and glucagon do not play an important role in the inhibitory mechanism of insulin secretion during hypothermic open-heart surgery, and a transient hypofunction of the pancreas as well as the liver and the adrenal gland is probably involved.

Therapeutic results of 130 primary cases of maxillary sinus carcinoma from1967 to 1969 and 80 primary cases in 1972 and 1973, were analysed in December 1975.The 2-year and the 5-year crude survival rates for the former were 42% and 30%, and the 2-year crude survival for the latter was 53%. The treatment policy over these periods consisted of combined irradiation and intraarterial infusion given as the first step and maxillectomy performed in only recurrent cases. Therefore, a numerical comparison could be made between survival rate in the initial combined therapy alone and that in the following maxillectomy.The survival rates of both groups from 1967 to 1969 were almost equal, but, in 1972 and 1973, the therapeutic weight of the initial combined therapy became much heavier than that of the following operation. A randomized study, carried out from 1967 to 1969, concerning 25 cases treated by intraarterial infusion of 5-FU alone, 35 cases by intraarterial infusion with other combined drugs and 45 cases by irradiation alone, resulted in the significantly better survival rate and the local nonrecurrence rate of the 5-FU intraarterial infusion group than that of the other groups.In a trial undertaken in 1972 and 1973, 63 cases, 70% of the total cases, were treated by the combination of intraarterial infusion of 5-FU and irradiation with a total irradiation dose of 5000 rads in 10 fractions during 5 weeks or 3500 rads in 7 fractions during 3.5 weeks.There was no significant difference of the rates concerned between the two groups. At the same time, therapeutic results of the group in which tumor tissue was removed from the maxillary sinus by curettage were compared with those of group treated without curettage and no significant difference crude survival rates was found between the two groups.However, the 2-year non-recurrence rate by initial treatment combined with curettage was significantly better than that without curettage.This could be evaluated as a worth treatment for preservation of both the figure and the function.On the other hand, this mode of treatment left us such problems as difficulty in following maxillectomy and increase in occurrence of distant metastases. The authors concluded that in the series of trials for the principle treatment policy of maxillary sinus carcinoma, the best results were obtained by initial treatment by 5000 rads irradiation of Co-60 gamma-ray in 25 fractions during 5 weeks combined with continuous intraarterial infusion of 5-FU in the amount of 2000mg during 4 weeks, and antrostomy in all cases and curettage, if necessary.The following treatment composed of maxillectomy as a rule and the intracavital or external irradiation additionally depending upon the situation

One hundred and seven patients with ventricular septal defect who survived one and a half to thirteen years after hypothermic open-heart surgery were reviewed with respect to somatic, intellectual, and psychomotor development. There were no negative effects associated with deep hypothermic arrest in any of these areas. Abnormal electroencephalograms were seen in one-half the number of patients examined, but there was no close relation between the circulatory arrest period and electroencephalographic findings. CT scanning of the brain indicated that the abnormality decreased with the lapse of the time after hypothermic open-heart surgery. It would appear that hypothermic open-heart surgery with limited circulatory arrest is a useful method, providing that the circulatory arrest is not allowed to exceed a limited period. However electroencephalographic assessment suggests that postoperative cerebral abnormalities may occur more frequently than previously suspected, despite the lack of preoperative abnormalities on the electroencephalograms.

The recovery of the Assyrian Empire from the time of confusion and hardship had begun, though slowly, as early as the end of the tenth century B.C. But Assyria's real expansion dates from the time of Assurnaṣirpal II (883–859 B.C.). He recovered Assyria's former settlements in the land Na'iri, which had been seized by the Aramaeans in the days of his predecessors, and founded new colonies in North Syria. Likewise, his son Shalmaneser III (858–824 B.C.) restored the old Assyrian bases on the Euphrates and added to the colonies that he had built in the same region, designating them as his “royal cities”.Yet the rising power of Assyria and its expansionist policy did not go unchallenged. The people whom the Neo-Assyrian kings attempted to subdue mustered their considerable strength to fight against the destructive might of the Assyrian army, and their strongly fortified cities were among the major sources of their power of resistance, as we are told in the Assyrian royal inscriptions. Kaprabi in the land of Bit-Adini, for example, is described as a well fortified city that had “hovered like a cloud in the sky”, while Pitura on the Tigris was, “exceedingly difficult; it was surrounded by two walls; its citadel had the form of mountain peak”. All these strong cities are designated as āl dannūti, “fortified city”, in the Neo-Assyrian royal inscriptions. When the ruler of a city is known, the city is designated as “his fortified city”, while a city of tribal people, whose country is only loosely organized, is usually called “their fortified city”, whether the name of the ruler of the city or land is known or not (see Table I).