A case report of olmesartan-associated sprue-like enteropathy: Diagnosis and healing confirmed by capsule endoscopy.

Herein, we describe a case of olmesartan-related sprue-like enteropathy in which improvement in villous atrophy was confirmed by small-bowel capsule endoscopy (CE). We successfully treated a 66-year-old man with a chief complaint of loose diarrhea. The patient had persistent watery diarrhea 10 times a day and experienced a weight loss of 9 kg in 3 months. An abdominal computed tomography scan showed fluid retention in the small intestine. Blood test results revealed no inflammatory reaction. Esophagogastroduodenoscopy detected villous atrophy in the stomach and duodenum. Moreover, small-bowel CE showed villous atrophy in about two-thirds of the small intestine. Based on other examinations, hyperthyroidism, intestinal tuberculosis, intestinal amyloidosis, and intestinal malignant lymphoma were ruled out. Therefore, the patient was suspected of having an olmesartan-related sprue-like disease. Early after discontinuation of medication, diarrhea symptoms improved, and a repeat CE indicated improvements in small intestinal villous atrophy. Since the patient had been administered olmesartan for a long time and CE showed villous atrophy throughout the small bowel, we suspected him of having the olmesartan-associated sprue-like disease. The findings of gastric mucosa atrophy on esophagogastroduodenoscopy may lead to an early diagnosis of this disease. Olmesartan-related sprue-like enteropathy should be considered as a differential diagnosis in patients with chronic severe watery diarrhea.

Aging in magma rheology.

Aging, change in property depending on the elapsed time from preparation, is known to affect the rheological behavior of various materials. Therefore, whether magma ages must be examined to characterize potentially widespread volcanic phenomena related to the transition from rest to flow. To achieve this, we performed rheological measurements and microstructural analyses on basaltic andesite lava from the 1986 Izu-Oshima eruption. The rheology shows an initial overshoot of shear stress during start-up flow that correlates with the duration and the shear rate of a pre-rest time. This indicates that the yield stress of magma and lava increases with aging. The microstructure shows that original aggregates of crystals, which may grow during crystallization, coalesce during the pre-rest period to form clusters without changing the crystal volume fraction. We conclude that the clusters are broken by shear in the start-up flow, which induces the stress overshoot. Thus, aging in magma rheology will impact the understanding of dynamic flow.

Nasal absorption enhancement of protein drugs independent to their chemical properties in the presence of hyaluronic acid modified with tetraglycine-L-octaarginine.

Our previous mouse studies demonstrated that mean bioavailability of exendin-4, which is an injectable glucagon-like peptide-1 (GLP-1) analogue whose molecular weight (Mw) and isoelectric point (pI) are ca. 4.2 kDa and 4.5, respectively, administered nasally with poly(N-vinylacetamide-co-acrylic acid) (PNVA-co-AA) bearing D-octaarginine, which is a typical cell-penetrating peptide, was 20% relative to subcutaneous administration even though it was less than 1% when exendin-4 alone was given nasally. The studies also revealed that the absorption-enhancing ability of D-octaarginine-linked PNVA-co-AA for exendin-4 was statistically equivalent to that of sodium salcaprozate (SNAC), which is an absorption enhancer formulated in tablets of semaglutide approved recently as an orally available GLP-1 analogue. From a perspective of clinical application of our technology, we have separately developed hyaluronic acid modified with L-octaarginine via a tetraglycine spacer which would be degraded in biological conditions. The present study revealed that tetraglycine-L-octaarginine-linked hyaluronic acid enhanced nasal absorption of exendin-4 in mice, as did D-octaarginine-linked PNVA-co-AA. There was no significant difference in absorption-enhancing abilities between the hyaluronic acid derivative and SNAC when octreotide (Mw: ca. 1.0 kDa, pI: 8.3) and lixisenatide (Mw: ca. 4.9 kDa, pI: 9.5) were used as a model protein drug. On the other hand, SNAC did not significantly enhance nasal absorption of somatropin (Mw: ca. 22.1 kDa, pI: 5.3) when compared with absorption enhancer-free conditions. Substitution of SNAC with tetraglycine-L-octaarginine-linked hyaluronic acid resulted in a 5-fold increase in absolute bioavailability of somatropin with statistical significance. It appeared that pI hardly ever influenced absorption-enhancing abilities of both enhancers. Results indicated that our polysaccharide derivative would be a promising absorption enhancer which delivers biologics applied on the nasal mucosa into systemic circulation and was of greater advantage than SNAC for enhancing nasal absorption of protein drugs with a larger Mw.

Gas flux cyclic regime at an open vent magmatic column inferred from seismic and acoustic records.

On August 7, 2014, a new effusive vent opened on the northern flank of Stromboli. A characteristic pattern was observed in both seismic and infrasonic signal amplitudes prior to this effusive eruption. The pattern consisted of the repeating cycle: (1) quiet phase, (2) puffing phase, and (3) explosion phase. Correlation between seismic and infrasound signal suggests that pulses in the puffing phase were caused by repetitive bursts of small gas pockets at the central crater, while the explosion phase coincided with an explosion at the central crater. We show that degassing of the magma column occurred in cycles of increasing gas flux, which controlled the transition from a bubbly flow (puffing phase), to a slug flow (explosion phase) gas regime. The quiet phase was characterized by a constant time length of 150 s, indicating that the gas rose in the magma column as well-organized waves of gas layers. These cycles represent cyclic changes of the gas flux regime in the shallow magma column, associated with increases in the magma-gas supply input rate before the effusive eruption.

FGF2-responsive genes in human dental pulp cells assessed using a rat spinal cord injury model.

The central nervous system in adult mammals does not heal spontaneously after spinal cord injury (SCI). However, SCI treatment has been improved recently following the development of cell transplantation therapy. We recently reported that fibroblast growth factor (FGF) 2-pretreated human dental pulp cells (hDPCs) can improve recovery in a rat model of SCI. This study aimed to investigate mechanisms underlying the curative effect of SCI enhanced via FGF2 pretreatment; we selected three hDPC lines upon screening for the presence of mesenchymal stem cell markers and of their functionality in a rat model of SCI, as assessed using the Basso, Beattie, and Bresnahan score of locomotor functional scale, electrophysiological tests, and morphological analyses. We identified FGF2-responsive genes via gene expression analyses in these lines. FGF2 treatment upregulated GABRB1, MMP1, and DRD2, which suggested to contribute to SCI or central the nervous system. In an expanded screening of additional lines, GABRB1 displayed rather unique and interesting behavior; two lines with the lowest sensitivity of GABRB1 to FGF2 treatment displayed an extremely minor effect in the SCI model. These findings provide insights into the role of FGF2-responsive genes, especially GABRB1, in recovery from SCI, using hDPCs treated with FGF2.

Priming with FGF2 stimulates human dental pulp cells to promote axonal regeneration and locomotor function recovery after spinal cord injury.

Human dental pulp cells (DPCs), adherent cells derived from dental pulp tissues, are potential tools for cell transplantation therapy. However, little work has been done to optimize such transplantation. In this study, DPCs were treated with fibroblast growth factor-2 (FGF2) for 5-6 consecutive serial passages and were transplanted into the injury site immediately after complete transection of the rat spinal cord. FGF2 priming facilitated the DPCs to promote axonal regeneration and to improve locomotor function in the rat with spinal cord injury (SCI). Additional analyses revealed that FGF2 priming protected cultured DPCs from hydrogen-peroxide-induced cell death and increased the number of DPCs in the SCI rat spinal cord even 7 weeks after transplantation. The production of major neurotrophic factors was equivalent in FGF2-treated and untreated DPCs. These observations suggest that FGF2 priming might protect DPCs from the post-trauma microenvironment in which DPCs infiltrate and resident immune cells generate cytotoxic reactive oxygen species. Surviving DPCs could increase the availability of neurotrophic factors in the lesion site, thereby promoting axonal regeneration and locomotor function recovery.

Relationship between shoulder roll and hand propulsion in the front crawl stroke.

This study re-evaluated the magnitude of hand propulsion (HP) in the pull and push phases of the front crawl stroke and investigated the association between the angular velocity of shoulder roll (ωSR) and hand propulsive lift (HPL). ωSR was computed in the plane normal to a forward direction for 16 skilled swimmers performing the front crawl stroke at a maximal sprinting pace. HP, hand propulsive drag (HPD) and HPL were determined by a dynamic pressure approach. HP and HPD in the pull phase were greater than in the push phase (P < 0.05) while HPL in the pull phase was similar to that in the push phase. Eleven swimmers out of the 16 swimmers had a significant within-swimmers correlation between ωSR and HPL in the push phase (P < 0.05). That is, HPL increased in the push phase as the ωSR of rolling back to the neutral position became faster. A swimmer should use more drag for hand propulsion in the pull phase and propulsion from drag and lift equally in the push phase. Based on the relationship between ωSR and HPL in the push phase, a possible stroke technique to enhance HPL using ωSR is discussed.

Unsteady hydrodynamic forces acting on a hand and its flow field during sculling motion.

The goal of this research is to clarify the mechanism by which unsteady forces are generated during sculling by a skilled swimmer and thereby to contribute to improving propulsive techniques. We used particle image velocimetry (PIV) to acquire data on the kinematics of the hand during sculling, such as fluid forces and flow field. By investigating the correlations between these data, we expected to find a new propulsion mechanism. The experiment was performed in a flow-controlled water channel. The participant executed sculling motions to remain at a fixed position despite constant water flow. PIV was used to visualize the flow-field cross-section in the plane of hand motion. Moreover, the fluid forces acting on the hand were estimated from pressure distribution measurements performed on the hand and simultaneous three-dimensional motion analysis. By executing the sculling motion, a skilled swimmer produces large unsteady fluid forces when the leading-edge vortex occurs on the dorsal side of the hand and wake capture occurs on the palm side. By using a new approach, we observed interesting unsteady fluid phenomena similar to those of flying insects. The study indicates that it is essential for swimmers to fully exploit vortices. A better understanding of these phenomena might lead to an improvement in sculling techniques.

Soluble Lutheran/basal cell adhesion molecule is detectable in plasma of hepatocellular carcinoma patients and modulates cellular interaction with laminin-511 in vitro.

Lutheran (Lu), an immunoglobulin superfamily transmembrane receptor, is also known as basal cell adhesion molecule (B-CAM). Lu/B-CAM is a specific receptor for laminin α5, a subunit of laminin-511 (LM-511) that is a major component of basement membranes in various tissues. Our previous study showed that Lu/B-CAM was cleaved by MT1-MMP and released from cell surfaces. In this study we examined the soluble Lu/B-CAM in culture media and in plasma of mice bearing HuH-7 hepatocellular carcinoma (HCC) cells and patients with HCC. Two HCC cell lines, HepG2 and HuH-7, released Lu/B-CAM into the culture media. Although Lu/B-CAM was cleaved by MT1-MMP in HuH-7 cells, HepG2 cells released Lu/B-CAM in a MMP-independent manner. The concentration of Lu/B-CAM released into mouse plasma correlated with tumor size. Moreover the soluble Lu/B-CAM in plasma of HCC patients was significantly decreased after resection of the tumor. Immunohistochemical studies showed that although the expression of Lu/B-CAM was observed in most HCCs, MT1-MMP was not always expressed in tumor tissues, suggesting that a part of Lu/B-CAM in plasma of HCC patients was also released in a MMP-independent manner. In vitro studies showed that the soluble Lu/B-CAM released from HCC cells bound to LM-511. Moreover the soluble Lu/B-CAM influenced cell migration on LM-511. These results suggest that soluble Lu/B-CAM serves as not only a novel marker for HCC but also a modulator in tumor progression.

Maintenance of hepatic differentiation by hepatocyte attachment peptides derived from laminin chains.

Hepatocytes rapidly lose hepatic functions upon isolation from liver, perhaps due to disrupted cell/matrix interactions. The matrix macromolecule laminin-111 consists of three chains, α1, ß1, and γ1; it is a major component of Matrigel, which can maintain hepatic differentiation. We previously showed that the A13 peptide (RQVFQVAYIIIKA, α1 chain 121-133) derived from mouse laminin α1 exhibits hepatocyte attachment activity and maintains hepatic differentiation. Here, we sought to identify hepatocyte adhesive sequences from the mouse laminin ß1 and γ1 chains using 22 synthetic peptides that show biological activity for fibrosarcoma cells. Nine peptides showed hepatocyte attachment activity. Of these, B160 (VILQQSAADIAR, ß1 chain 1607-1618), and C16 (KAFDITYVRLKF γ1 chain 139-150) exhibited the most potent activity. Hepatocytes cultured on both peptides also maintained expression of albumin, tyrosine aminotransferase, tryptophan-2,3-dioxygenase, and cytochrome P450. The morphology of hepatocytes on both peptides was a rounded shape typical for hepatic differentiation. We also characterized the nature of adhesion to the peptides. Heparin and EDTA inhibited cell attachment to both peptides, suggesting that hepatocyte attachment to the peptides was mediated by multiple receptors. The identification of active sequences regulating hepatic functions may facilitate the design of hepatocyte culture substrata that can regulate specific cellular behaviors in the context of a bioartificial liver.

An antibody to the lutheran glycoprotein (Lu) recognizing the LU4 blood type variant inhibits cell adhesion to laminin α5.

BACKGROUND: The Lutheran blood group glycoprotein (Lu), an Ig superfamily (IgSF) transmembrane receptor, is also known as basal cell adhesion molecule (B-CAM). Lu/B-CAM is a specific receptor for laminin α5, a major component of basement membranes in various tissues. Previous reports have shown that Lu/B-CAM binding to laminin α5 contributes to sickle cell vaso-occlusion. However, as there are no useful tools such as function-blocking antibodies or drugs, it is unclear how epithelial and sickled red blood cells adhere to laminin α5 via Lu/B-CAM. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we discovered a function-blocking antibody that inhibits Lu binding to laminin α5 using a unique binding assay on tissue sections. To characterize the function-blocking antibody, we identified the site on Lu/B-CAM recognized by this antibody. The extracellular domain of Lu/B-CAM contains five IgSF domains, D1-D2-D3-D4-D5. The antibody epitope was localized to D2, but not to the D3 domain containing the major part of the laminin α5 binding site. Furthermore, mutagenesis studies showed that Arg(175), the LU4 blood group antigenic site, was crucial for forming the epitope and the antibody bound sufficiently close to sterically hinder the interaction with α5. Cell adhesion assay using the antibody also showed that Lu/B-CAM serves as a secondary receptor for the adhesion of carcinoma cells to laminin α5. CONCLUSION/SIGNIFICANCE: This function-blocking antibody against Lu/B-CAM should be useful for not only investigating cell adhesion to laminin α5 but also for developing drugs to inhibit sickle cell vaso-occlusion.

The influence of synthetic peptides derived from the laminin alpha1 chain on hepatocyte adhesion and gene expression.

Laminin-111, a heterotrimer composed of the laminin alpha1, beta1, and gamma1 chains, has been used as a biomaterial for primary cell culture to maintain cellular functions. Our previous studies have reported that synthetic peptides derived from laminin alpha1 exhibit biological functions such as influencing cell adhesion, migration, angiogenesis, and tumor metastasis. In this study we screened hepatocyte attachment peptides using twenty-five biologically active peptides from laminin alpha1 and examined the maintenance of hepatic function on the peptides using primary rat hepatocytes. Peptide A13 (RQVFQVAYIIIKA), mouse laminin alpha1 chain residues 121-133, exhibited the strongest activity. Furthermore, primary hepatocytes on A13 peptide maintained expression of hepatic differentiation markers such as tyrosine aminotransferase, tryptophan-2,3-dioxygenase, and cytochrome P450. We also determined the active core sequence of A13 using systematically truncated N- and C-terminal peptides. The results indicated that the nine-amino acid sequence RQVFQVAYI was critical for A13's hepatocyte adhesion activity. However, the truncated peptides could not interact with beta1-intgerin and maintain expression of hepatic differentiation markers. The amino acid sequence of A13 peptide was required for regulating hepatocyte behavior. The hepatocyte adhesive peptides can be utilized in tailoring synthetic biomaterials in order to achieve a specific cellular response.