Ischemic enteritis resulting from polycythemia vera.

Polycythemia vera is a chronic myeloproliferative disorder characterized by clonal proliferation of bone marrow progenitors. We report a case of ischemic enteritis and bowel obstruction resulting from polycythemia vera. A 76-year-old man was admitted to our hospital with abdominal distention. Contrast-enhanced computed tomography revealed portal vein thrombosis, superior mesenteric vein thrombosis, and dilated small intestinal loops with caliber changes at the end of the ileum. Laboratory data on admission revealed increased leukocyte, red blood cell, hemoglobin, and platelet levels. Polymerase chain reaction analysis for Janus kinase 2 V617F point mutation was positive. Intestinal obstruction due to either bowel adhesion or paralytic ileus secondary to the superior mesenteric artery and vein thrombosis caused by polycythemia vera was diagnosed. For decompression of the small intestinal obstruction, a transnasal ileus tube was placed. Despite conservative therapy, the small intestinal obstruction did not improve remarkably. Therefore, we decided to perform surgical treatment. Operative findings revealed extensive stricture in the ileum. Altogether, 30 cm of the ileum, including the known intestinal strictures, was resected. The pathological findings were consistent with ischemic enteritis. To the best of our knowledge, no case of ischemic enteritis caused by polycythemia vera has been previously reported in the literature.

Discovery of CYR715: A novel carboxylic acid-containing soluble guanylate cyclase stimulator.

Soluble guanylate cyclase (sGC) is a clinically validated therapeutic target in the treatment of pulmonary hypertension. Modulators of sGC have the potential to treat diseases that are affected by dysregulation of the NO-sGC-cGMP signal transduction pathway. This letter describes the SAR efforts that led to the discovery of CYR715, a novel carboxylic acid-containing sGC stimulator, with an improved metabolic profile relative to our previously described stimulator, IWP-051. CYR715 addressed potential idiosyncratic drug toxicity (IDT) liabilities associated with the formation of reactive, migrating acyl glucuronides (AG) found in related carboxylic acid-containing analogs and demonstrated high oral bioavailability in rat and dose-dependent hemodynamic pharmacology in normotensive Sprague-Dawley rats.

A rare case of plexiform neurofibroma of the liver in a patient without neurofibromatosis type 1.

Plexiform neurofibroma is mainly associated with neurofibromatosis type 1 and is seldom observed in the liver. Its occurrence in the liver without neurofibromatosis type 1 is even rarer. We report an extremely rare case of plexiform neurofibroma of the liver diagnosed by laparoscopic biopsy in a patient without neurofibromatosis type 1. The patient was a 35-year-old man who had neither clinical signs nor any family history of neurofibromatosis type 1. Abdominal ultrasonography, as part of a health screening, had detected a hepatic tumor. Subsequent contrast ultrasonography, computed tomography, and magnetic resonance imaging showed the tumor extending from the retroperitoneal space around the aorta to the hepatic hilum and distal portal branches in the right hepatic lobe, gallbladder, and left hepatic lobe. 18F-fluorodeoxyglucose positron emission tomography showed no abnormal accumulation. Histopathological examination of the tumor obtained laparoscopically led to a diagnosis of plexiform neurofibroma. Because the patient was asymptomatic with no features of malignancy, he was only monitored and managed. At follow-up 10 years later, computed tomography showed a decrease in tumor size. It is important to recognize that, while rare, plexiform neurofibroma can occur without neurofibromatosis type 1. We recommend follow-up instead of unreasonable surgery in such cases.

Photo-triggered large mass transport driven only by a photoresponsive surface skin layer.

Since the discovery 25 years ago, many investigations have reported light-induced macroscopic mass migration of azobenzene-containing polymer films. Various mechanisms have been proposed to account for these motions. This study explores light-inert side chain liquid crystalline polymer (SCLCP) films with a photoresponsive polymer only at the free surface and reports the key effects of the topmost surface to generate surface relief gratings (SRGs) for SCLCP films. The top-coating with an azobenzene-containing SCLCP is achieved by the Langmuir-Schaefer (LS) method or surface segregation. A negligible amount of the photoresponsive skin layer can induce large SRGs upon patterned UV light irradiation. Conversely, the motion of the SRG-forming azobenzene SCLCP is impeded by the existence of a LS monolayer of the octadecyl side chain polymer on the top. These results are well understood by considering the Marangoni flow driven by the surface tension instability. This approach should pave the way toward in-situ inscription of the surface topography for light-inert materials and eliminate the strong light absorption of azobenzene, which is a drawback in optical device applications.

The Administration of Tenofovir Disoproxil Fumarate for Pregnant Japanese Women with Chronic Hepatitis B.

The appropriate management of hepatitis B virus (HBV) infection during pregnancy has not been established in Japan. We herein report five HBV-infected pregnant Japanese women who received tenofovir disoproxil fumarate (TDF). Two of them had been born after the introduction of nationwide immunoprophylaxis and were vertically infected with HBV, highlighting the need to address mother-to-child transmission further. In both entecavir-experienced and nucleoside/nucleotide analog-naïve mothers, TDF suppressed HBV replication without serious adverse events. All five children were free from congenital disorders, growth impairment, and HBV infection. TDF showed safety and efficacy for pregnant woman with chronic hepatitis B and might have helped prevent mother-to-child transmission.

Discovery of stimulator binding to a conserved pocket in the heme domain of soluble guanylyl cyclase.

Soluble guanylyl cyclase (sGC) is the receptor for nitric oxide and a highly sought-after therapeutic target for the management of cardiovascular diseases. New compounds that stimulate sGC show clinical promise, but where these stimulator compounds bind and how they function remains unknown. Here, using a photolyzable diazirine derivative of a novel stimulator compound, IWP-051, and MS analysis, we localized drug binding to the ß1 heme domain of sGC proteins from the hawkmoth Manduca sexta and from human. Covalent attachments to the stimulator were also identified in bacterial homologs of the sGC heme domain, referred to as H-NOX domains, including those from Nostoc sp. PCC 7120, Shewanella oneidensis, Shewanella woodyi, and Clostridium botulinum, indicating that the binding site is highly conserved. The identification of photoaffinity-labeled peptides was aided by a signature MS fragmentation pattern of general applicability for unequivocal identification of covalently attached compounds. Using NMR, we also examined stimulator binding to sGC from M. sexta and bacterial H-NOX homologs. These data indicated that stimulators bind to a conserved cleft between two subdomains in the sGC heme domain. L12W/T48W substitutions within the binding pocket resulted in a 9-fold decrease in drug response, suggesting that the bulkier tryptophan residues directly block stimulator binding. The localization of stimulator binding to the sGC heme domain reported here resolves the longstanding question of where stimulators bind and provides a path forward for drug discovery.

Rapid profiling method for mammalian feces short chain fatty acids by GC-MS.

Short chain fatty acids (SCFAs) are key feces metabolites generated by gut bacteria fermentation. Despite the importance of profiling feces SCFAs, technical difficulties in analysis remain due to their volatility and hydrophilicity. We improve previous protocols to profile SCFAs and optimize the metabolite profiling platform for mammalian feces samples. In this study, we investigated feces as biological samples using gas chromatography-mass spectrometry (GC-MS). Isobutyl chloroformate was used for a derivatization in aqueous solution without drying out the samples. Ultimately, we envisage being able to determine the way in which gut bacteria fermentation influences host gut condition by using our rapid metabolite profiling methods.

Discovery of IWP-051, a Novel Orally Bioavailable sGC Stimulator with Once-Daily Dosing Potential in Humans.

In recent years, soluble guanylate cyclase (sGC, EC 4.6.1.2) has emerged as an attractive therapeutic target for treating cardiovascular diseases and diseases associated with fibrosis and end-organ failure. Herein, we describe our design and synthesis of a series of 4-hydroxypyrimidine sGC stimulators starting with an internally discovered lead. Our efforts have led to the discovery of IWP-051, a molecule that achieves good alignment of potency, stability, selectivity, and pharmacodynamic effects while maintaining favorable pharmacokinetic properties with once-daily dosing potential in humans.

Free Surface Command Layer for Photoswitchable Out-of-Plane Alignment Control in Liquid Crystalline Polymer Films.

To date, reversible alignment controls of liquid crystalline materials have widely been achieved by photoreactive layers on solid substrates. In contrast, this work demonstrates the reversible out-of-plane photocontrols of liquid crystalline polymer films by using a photoresponsive skin layer existing at the free surface. A polymethacrylate containing a cyanobiphenyl side-chain mesogen adopts the planar orientation. Upon blending a small amount of azobenzene-containing side-chain polymer followed by successive annealing, segregation of the azobenzene polymer at the free surface occurs and induces a planar to homeotropic orientation transition of cyanobiphenyl mesogens underneath. By irradiation with UV light, the mesogen orientation turns into the planar orientation. The orientation reverts to the homeotropic state upon visible light irradiation or thermally, and such cyclic processes can be repeated many times. On the basis of this principle, erasable optical patterning is performed by irradiating UV light through a photomask.

[Combination Chemotherapy Using Sorafenib and Hepatic Arterial Infusion with a Fine-Powder Formulation of Cisplatin for Advanced Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis--A Case Report].

Sorafenib has been a standard therapy for advanced hepatocellular carcinoma (HCC) with portal vein thrombosis. Hepatic arterial infusion chemotherapy (HAIC) is still preferably performed in Japan because of its relatively good tumor-shrinking effect. We report a case of advanced multiple HCC with portal thrombus that responded to combination chemotherapy with sorafenib and repeat hepatic arterial infusion with a fine-powder formulation of cisplatin (IA-call®). A 57-year-old man presented for the treatment of HCC with alcoholic cirrhosis. Multiple HCC were found to be rapidly progressing with portal thrombosis. HAIC with IA-call® was performed, but the tumors progressed. TAE was performed 3 times thereafter and the main tumor shrunk to some extent. A month after the last TAE, the HCC was found to progress again, and oral sorafenib was administered. A reservoir and catheter were placed and HAIC with low-dose 5-fluorouracil and cisplatin was performed for 3 cycles following 1 HAIC cycle with epirubicin and mitomycin C, which was not effective. For 10 months after initial therapy, HAIC using IA-call® has been performed once for 6 weeks. After performing HAIC with IA-call® 5 times, the serum levels of HCC tumor markers AFP and PIVKA-Ⅱdecreased, and the tumors continued to shrink and were not stained on enhanced CT scan. The patient has been alive for 23 months after the initial therapy and has maintained stable disease.

[A case of paralytic ileus associated with varicella zoster virus infection].

A 79-year-old woman with a history of pyothorax was admitted with a 4-day history of abdominal distension. Physical examination revealed marked abdominal distention, absent bowel sounds, and a vesicular rash over the left Th8-10 dermatome. Abdominal radiography showed gaseous distension of the colon and ileum. Colonoscopy excluded any obstructive process of the colon. Laboratory findings yielded positive results for serum IgM and IgG against the varicella zoster virus (VZV) . Paralytic ileus associated with the VZV was therefore diagnosed. The ileus improved after conservative treatment with intravenous acyclovir. Although shingles is frequently encountered, it is a rare cause of paralytic ileus. In the future, the VZV should be considered as one of the causes of paralytic ileus, and complete resolution can be achieved with conservative management.

[Three cases of recurrent hepatocellular carcinoma treated with laparoscopic hepatectomy after oral administration of sorafenib].

Case 1 involved a 63-year-old woman who had multiple hepatocellular carcinomas (HCC) associated with hepatitis C virus infection. She was treated with hepatic arterial infusion chemotherapy (HAIC) and transcatheter arterial chemoembolization (TACE), followed by oral administration of sorafenib (200 mg/day). However, a lesion on the left lateral segment of the liver enlarged rapidly. Laparoscopic left lateral sectionectomy was performed. Histopathological examination revealed combined hepatocellular and cholangiocellular carcinoma. Case 2 involved a 54-year-old man who had multiple recurrent HCCs associated with hepatitis C virus infection after undergoing hepatectomy twice. Oral administration of sorafenib (200 mg/day) was initiated. The intrahepatic lesions decreased in size, but metastasis in an enlarged lymph node behind the portal vein was suspected. Laparoscopic partial hepatectomy and lymph node dissection were performed. HCC metastasis in the lymph node and partial necrosis in the intrahepatic lesions were identified histopathologically. Case 3 involved a 56- year-old man who had multiple recurrent HCCs associated with hepatitis C virus infection. TACE was performed thrice, and oral administration of sorafenib( 400-600 mg/day) was initiated. The lesion in the right lateral segment of the liver decreased in size but lesions in the left lateral segment were enlarged. Therefore, laparoscopic left hemihepatectomy was performed.

[A case of primary biliary cirrhosis with systemic lymph node enlargement].

A 40's woman was hospitalized with cervical lymph node enlargement. Laboratory examinations showed elevated serum bile duct enzymes and the presence of anti-mitochondrial antibody. Abdominal ultrasonography and computed tomography showed enlargement of not only perihepatic lymph nodes, but also axillary and cervical lymph nodes. FDG-PET showed intense uptake concordant with these lymph nodes. We performed endoscopic ultrasonographic fine-needle aspiration biopsy of a perihepatic lymph node, but detected no malignant cells. We then performed liver biopsy, and obtained a histological diagnosed primary biliary cirrhosis. Systemic lymph nodes decreased together with serum bile duct enzyme levels during treatment with ursodeoxycholic acid.

Injectable hydrogel for sustained protein release by salt-induced association of hyaluronic acid nanogel.

A hyaluronic acid-based anionic nanogel formed by self-assembly of cholesteryl-group-bearing HA is designed for protein delivery. The HA nanogel spontaneously binds various types of proteins without denaturation, such as recombinant human growth hormone, erythropoietin, exendin-4, and lysozyme. The HA nanogel shows unique colloidal properties, in particular that an injectable hydrogel is formed by salt-induced association of the HA nanogel. A pharmacokinetic study in rats shows that an in situ gel formulation, prepared by simply mixing rhGH and HA nanogel in phosphate buffer, maintains plasma rhGH levels within a narrow range over one week. Therefore, HA nanogels offer a simple method for easy formulation of therapeutic proteins and are effective for sustained protein release systems.

[Effectiveness of preoperative panretinal photocoagulation in severe proliferative diabetic retinopathy].

PURPOSE: To evaluate correlations between the surgical outcomes, either presence or absence of preoperative panretinal photocoagulation and types of retinal detachment in patients undergoing vitrectomy for severe proliferative diabetic retinopathy. MATERIALS AND METHODS: We reviewed 67 eyes that underwent vitrectomy for severe proliferative diabetic retinopathy accompanied by either macular tractinal retinal detachment or combined tractinal and rhegmatogenous retinal detachment. RESULTS: The postoperative visual acuity (p < 0.05) of eyes with preoperative panretinal photocoagulation (PRPC) showed significant improvement. There was a higher success rate of retinal attachment (p < 0.05) than in those without PRPC. There was no significant difference in surgical outcome amang the types of retinal detachment. CONCLUSION: Preoperative panretinal photocoagulation for severe proliferative diabetic retinopathy improves surgical success.

The 2b protein of cucumber mosaic virus is essential for viral infection of the shoot apical meristem and for efficient invasion of leaf primordia in infected tobacco plants.

It has been reported previously that a 2b protein-defective mutant of the cucumber mosaic virus (CMV) Pepo strain (Delta 2b) induces only mild symptoms in systemically infected tobacco plants. To clarify further the role of the 2b protein as an RNA silencing suppressor in mosaic symptom expression during CMV infection, this study monitored the sequential distribution of Delta 2b in the shoot meristem and leaf primordia (LP) of inoculated tobacco. Time-course histochemical observations revealed that Delta 2b was distributed in the shoot meristem at 7 days post-inoculation (p.i.), but could not invade shoot apical meristem (SAM) and quickly disappeared from the shoot meristem, whereas wild-type (Pepo) transiently appeared in SAM from 4 to 10 days p.i. In LP, Delta 2b signals were detected only at 14 and 21 days p.i., whereas dense Pepo signals were observed in LP from 4 to 18 days p.i. Northern blot analysis showed that small interfering RNA (siRNA) derived from Delta 2b RNA accumulated earlier in the shoot meristem and LP than that of Pepo. However, a similar amount of siRNA was detected in both Pepo- and Delta 2b-infected plants at late time points. Tissue printing analysis of the inoculated leaves indicated that the areas infected by Pepo increased faster than those infected by Delta 2b, whereas accumulation of Delta 2b in protoplasts was similar to that of Pepo. These findings suggest that the 2b protein of the CMV Pepo strain determines virulence by facilitating the distribution of CMV in the shoot meristem and LP via prevention of RNA silencing and/or acceleration of cell-to-cell movement.

A case of mesenteric lymphadenitis with long-acting symptom, showing marked response to corticosteroid.

A 17-year-old girl who had right lower abdominal pain with multiple swelling of lymph nodes in the ileocecal region and she was admitted to a neighboring hospital. Since there was no improvement of condition with antibiotic resistance, we were consulted. Lymph node biopsy under laparoscopy demonstrated nonspecific findings. She then developed erythema nodosum, suggesting the presence of autoimmune etiology. Treatment with systemic corticosteroid resulted in symptomatic improvement. Mesenteric lymphadenitis like this case is rare.

Effective killing of the human pathogen Candida albicans by a specific inhibitor of non-essential mitotic kinesin Kip1p.

Kinesins from the bipolar (Kinesin-5) family are conserved in eukaryotic organisms and play critical roles during the earliest stages of mitosis to mediate spindle pole body separation and formation of a bipolar mitotic spindle. To date, genes encoding bipolar kinesins have been reported to be essential in all organisms studied. We report the characterization of CaKip1p, the sole member of this family in the human pathogenic yeast Candida albicans. C. albicans Kip1p appears to localize to the mitotic spindle and loss of CaKip1p function interferes with normal progression through mitosis. Inducible excision of CaKIP1 revealed phenotypes unique to C. albicans, including viable homozygous Cakip1 mutants and an aberrant spindle morphology in which multiple spindle poles accumulate in close proximity to each other. Expression of the C. albicans Kip1 motor domain in Escherichia coli produced a protein with microtubule-stimulated ATPase activity that was inhibited by an aminobenzothiazole (ABT) compound in an ATP-competitive fashion. This inhibition results in 'rigor-like', tight association with microtubules in vitro. Upon treatment of C. albicans cells with the ABT compound, cells were killed, and terminal phenotype analysis revealed an aberrant spindle morphology similar to that induced by loss of the CaKIP1 gene. The ABT compound discovered is the first example of a fungal spindle inhibitor targeted to a mitotic kinesin. Our results also show that the non-essential nature and implementation of the bipolar motor in C. albicans differs from that seen in other organisms, and suggest that inhibitors of a non-essential mitotic kinesin may offer promise as cidal agents for antifungal drug discovery.

A strategy to profile prime and non-prime proteolytic substrate specificity.

A strategy was developed to determine the prime and non-prime substrate specificity of serine, threonine and cysteine proteases. ACC positional scanning technology was employed to determine the P4-P1 non-prime site substrate specificity. The data was used to synthesize biased donor-quencher positional scanning libraries to profile the P1'-P4' prime site substrate specificity. Directed sorting using the Irori Nanokan system allowed for the archiving of multiple P1'-P4' positional scanning libraries. From these libraries focused donor-quencher libraries incorporating P4-P1 data for each protease under study could be rapidly prepared. The profiling of thrombin and caspase-3 P4-P4' substrate specificity, comparison of the library specificity data to single substrates, and the analysis of physiological cleavage sites are described.