Balloon-occlusion Retrograde Transvenous Obliteration Using Gadoteridol As an Alternative Contrast Agent in a Patient with Iodine Allergy.

A 70-year-old woman with liver cirrhosis presented with gastric varices and recurrent hepatic encephalopathy. Magnetic resonance imaging (MRI) showed a splenorenal shunt, and balloon-occluded retrograde transvenous obliteration (B-RTO) was indicated but could not be performed due to iodine allergy. We then performed B-RTO using gadoteridol, an MRI contrast medium, instead of iodine contrast and successfully occluded the shunt vessel. After the procedure, hepatic encephalopathy did not recur, and the size of the gastric varices was reduced. This experience may aid in the management of iodine-allergic patients requiring interventional radiological treatment.

Improvement of Rectal Prolapse Using an Over-the-scope Clip System.

Rectal prolapse is typically treated surgically, and internal therapy has not been reported. We encountered a case of rectal prolapse that improved with an over-the-scope clip system (OTSC). An 81-year-old woman complaining of anorectal pain underwent colonoscopy, and rectal prolapse was observed prior to colonoscopy. Unfortunately, rectal perforation occurred while attempting endoscopic reversal. The OTSC system was used to close the rectal perforation and subsequently improved her rectal prolapse, probably because the rectal wall was anchored to the retroperitoneum. This is the first report to show that rectal prolapse can be endoscopically improved and that an OTSC system might be a viable alternative method for managing inoperable rectal prolapse.

Invasive Group G Streptococcal Infection Complicated by Posterior Reversible Encephalopathy Syndrome: A Case Report.

BACKGROUND Group G streptococcus (GGS) infection is reported to have invasive pathogenicity similar to that of group A streptococcus (GAS) infection, causing a strong systemic inflammatory response with bacteremia and various complications. Herein, we report a case of posterior reversible encephalopathy syndrome (PRES) as a rare complication of a GGS infection. CASE REPORT An 89-year-old Japanese man presented to our hospital with gastrointestinal bleeding and shoulder pain. Close examination revealed a refractory duodenal ulcer (DU) with disseminated intravascular coagulation and soft tissue infection of the right arm, which was found to be caused by GGS. A hemorrhagic tendency due to disseminated intravascular coagulation made it difficult to achieve hemostasis, leading to repeated blood transfusions. Although remission of both the DU and infection was achieved with treatment, impairment of swallowing function and vision subsequently appeared. Magnetic resonance imaging revealed hyperintense lesions with elevated apparent diffusion coefficient (ADC) values on T2-weighted imaging (T2WI), fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging (DWI). The patient was diagnosed with PRES, which did not improve even after discharge on day 118. CONCLUSIONS GGS infection developed with refractory duodenal ulcer bleeding, resulting in PRES with irreversible sequelae. The occurrence of PRES, which may be a rare complication of GGS infection, should be considered when central nervous system manifestations are observed in case of invasive streptococcal infection with a systemic inflammatory response.

Drainage of Afferent Limb Obstruction via the Trans-gastric-bile Duct Formed after Endoscopic Ultrasound-guided Hepaticogastrostomy in a Patient with Pancreatic Cancer.

A 63-year-old man with advanced pancreatic cancer and pyloric obstruction underwent surgical gastrojejunostomy. Malignant biliary obstruction appeared eight months after surgery and was managed with endoscopic ultrasound (EUS)-guided hepaticogastrostomy (HGS). Subsequently, afferent limb obstruction caused by cancer invasion occurred. Although an intestinal metal stent could not be placed, a biliary metal stent was deployed via the HGS route, which successfully decompressed the afferent limb; the abdominal symptoms subsequently disappeared. In future similar cases, decompression of the dilated intestine through the HGS and biliary stent might be a viable treatment option.

The Effects of Percutaneous Endoscopic Gastrostomy on Quality of Life in Patients With Dementia.

BACKGROUND: To examine the effects of percutaneous endoscopic gastrostomy (PEG) on quality of life (QOL) in patients with dementia. METHODS: We retrospectively included 53 Japanese community and tertiary hospitals to investigate the relationship between the newly developed PEG and consecutive dementia patients with swallowing difficulty between Jan 1st 2006 and Dec 31st 2008. We set improvements in 1) the level of independent living, 2) pneumonia, 3) peroral intake as outcome measures of QOL and explored the factors associated with these improvements. RESULTS: Till October 31st 2010, 1,353 patients with Alzheimer's dementia (33.1%), vascular dementia (61.7%), dementia with Lewy body disease (2.0%), Pick disease (0.6%) and others were followed-up for a median of 847 days (mean 805 ± 542 days). A total of 509 deaths were observed (mortality 59%) in full-followed patients. After multivariate adjustments, improvement in the level of independent living was observed in milder dementia, or those who can live independently with someone, compared with advanced dementia, characterized by those who need care by someone: Odds Ratio (OR), 3.90, 95% confidence interval (95%CI), 1.59 - 9.39, P = 0.003. Similarly, improvement of peroral intake was noticed in milder dementia: OR, 2.69, 95%CI, 1.17 - 6.17, P = 0.02. Such significant associations were not observed in improvement of pneumonia. CONCLUSIONS: These results suggest that improvement of QOL after PEG insertion may be expected more in milder dementia than in advanced dementia.

Survival of geriatric patients after percutaneous endoscopic gastrostomy in Japan.

AIM: To examine the long term survival of geriatric patients treated with percutaneous endoscopic gastrostomy (PEG) in Japan. METHODS: We retrospectively included 46 Japanese community and tertiary hospitals to investigate 931 consecutive geriatric patients (≥ 65 years old) with swallowing difficulty and newly performed PEG between Jan 1st 2005 and Dec 31st 2008. We set death as an outcome and explored the associations among patient's characteristics at PEG using log-rank tests and Cox proportional hazard models. RESULTS: Nine hundred and thirty one patients were followed up for a median of 468 d. A total of 502 deaths were observed (mortality 53%). However, 99%, 95%, 88%, 75% and 66% of 931 patients survived more than 7, 30, 60 d, a half year and one year, respectively. In addition, 50% and 25% of the patients survived 753 and 1647 d, respectively. Eight deaths were considered as PEG-related, and were associated with lower serum albumin levels (P = 0.002). On the other hand, among 28 surviving patients (6.5%), PEG was removed. In a multivariate hazard model, older age [hazard ratio (HR), 1.02; 95% confidence interval (CI), 1.00-1.03; P = 0.009], higher C-reactive protein (HR, 1.04; 95% CI: 1.01-1.07; P = 0.005), and higher blood urea nitrogen (HR, 1.01; 95% CI: 1.00-1.02; P = 0.003) were significant poor prognostic factors, whereas higher albumin (HR, 0.67; 95% CI: 0.52-0.85; P = 0.001), female gender (HR, 0.60; 95% CI: 0.48-0.75; P < 0.001) and no previous history of ischemic heart disease (HR, 0.69; 95% CI: 0.54-0.88, P = 0.003) were markedly better prognostic factors. CONCLUSION: These results suggest that more than half of geriatric patients with PEG may survive longer than 2 years. The analysis elucidated prognostic factors.

The sky blue method as a screening test to detect misplacement of percutaneous endoscopic gastrostomy tube at exchange.

BACKGROUND: During tube exchange for percutaneous endoscopic gastrostomy (PEG), a misplaced tube can cause peritonitis and death. Thus, endoscopic or radiologic observation is required at tube exchange to make sure the tube is placed correctly. However, these procedures cost extensive time and money to perform in all patients at the time of tube exchange. Therefore, we developed the "sky blue method" as a screening test to detect misplacement of the PEG tube during tube exchange. METHODS: First, sky blue solution consisting of indigocarmine diluted with saline was injected into the gastric space via the old PEG tube just before the tube exchange. Next, the tube was exchanged using a standard method. Then, we checked whether the sky blue solution could be collected through the new tube or not. Finally, we confirmed correct placement of the tube by endoscopic or radiologic observation for all patients. RESULTS: A total of 961 patients were enrolled. Each tube exchange took 1 to 3 minutes, and there were no adverse effects. Four patients experienced a misplaced tube, all of which were detectable with the sky blue method. Diagnostic parameters of the sky blue method were as follows: sensitivity, 94% (95%CI: 92-95%); specificity, 100% (95%CI: 40-100%); positive predictive value, 100% (95%CI: 100-100%); negative predictive value, 6% (95%CI: 2-16%). CONCLUSION: These results suggest that the number of endoscopic or radiologic observations to confirm correct replacement of the PEG tube may be reduced to one fifteenth using the sky blue method.

The metabolic syndrome as a predictor of nonalcoholic fatty liver disease.

BACKGROUND: The frequent association of nonalcoholic fatty liver disease with components of the metabolic syndrome such as obesity, hyperglycemia, dyslipidemia, and hypertension is well known. However, no prospective study has examined the role of the metabolic syndrome in the development of this disease. OBJECTIVE: To characterize the longitudinal relationship between the metabolic syndrome and nonalcoholic fatty liver disease. DESIGN: A prospective observational study. SETTING: A medical health checkup program in a general hospital. PARTICIPANTS: 4401 apparently healthy Japanese men and women, 21 to 80 years of age, with a mean body mass index (BMI) of 22.6 kg/m2 (SD, 3.0). MEASUREMENTS: Alcohol intake was assessed by using a questionnaire. Biochemical tests for liver and metabolic function and abdominal ultrasonography were done. Modified criteria of the National Cholesterol Education Program Adult Treatment Panel III were used to characterize the metabolic syndrome. RESULTS: At baseline, 812 of 4401 (18%) participants had nonalcoholic fatty liver disease. During the mean follow-up period of 414 days (SD, 128), the authors observed 308 new cases (10%) of nonalcoholic fatty liver disease among 3147 participants who were disease-free at baseline and who completed a second examination. Regression of nonalcoholic fatty liver disease was found in 113 (16%) of 704 participants who had the disease at baseline and who completed a second examination. Men and women who met the criteria for the metabolic syndrome at baseline were more likely to develop the disease during follow-up (adjusted odds ratio, 4.00 [95% CI, 2.63 to 6.08] and 11.20 [CI, 4.85 to 25.87], respectively). Nonalcoholic fatty liver disease was less likely to regress in those participants with the metabolic syndrome at baseline. LIMITATIONS: Ultrasonography may lead to an incorrect diagnosis of nonalcoholic fatty liver disease in 10% to 30% of cases and cannot distinguish steatohepatitis from simple steatosis. Self-reported alcohol intake may cause bias. Because all of the participants were Japanese, generalizability to non-Japanese populations is uncertain. CONCLUSIONS: The metabolic syndrome is a strong predictor of nonalcoholic fatty liver disease.

Erectile dysfunction in patients with chronic viral liver disease: its relevance to protein malnutrition.

BACKGROUND: In patients with chronic liver disease (CLD), quality of life is generally accepted as poor, especially for physical function. However, sufficient data regarding erectile function has not been shown in patients with CLD. The international index of erectile function (IIEF) is widely used to assess erectile function, and a short form of the IIEF was recently developed (IIEF-5). Using this questionnaire, we evaluated erectile dysfunction (ED) in patients with CLD. METHODS: A total of 117 Japanese patients (64 with chronic hepatitis [CH] and 53 with liver cirrhosis [LC]) were analyzed. The etiologies were hepatitis B virus (HBV) in 21, HCV in 94, and non-B non-C in 2. The IIEF-5 and Medical Outcomes Study Short Form 36 (SF-36) were administered to the patients, and biochemical analyses for items serum albumin, prothrombin time, bilirubin, and ammonia were also performed. RESULTS: The incidence of ED was 85% in the total cohort with CLD, 78% in those with CH, and 92% in those with LC (P < 0.05 between CH and LC). ED was found in 50% of CLD patients under age 50 years, in 79% aged 50-59, and in 100% aged over 60 (P, overall <0.001). The scores for ED severity correlated with increasing grades of a modified Child-Pugh classification (P < 0.05). Simple regression analysis showed age (P < 0.01), physical function (P < 0.001), role physical (P < 0.001), and social functioning (P < 0.05) on the SF-36, and serum albumin (P < 0.001) as significant determinants of ED. Multiple regression analysis identified age (P < 0.001) and serum albumin (P < 0.001) as independent significant factors that determined ED. CONCLUSIONS: These data clearly demonstrate that liver disease is the cause of ED in patients with CLD, and serum protein status could be relevant to this condition in these patients.

Benzimidazoles as non-peptide luteinizing hormone-releasing hormone (LHRH) antagonists. Part 3: Discovery of 1-(1H-benzimidazol-5-yl)-3-tert-butylurea derivatives.

1-(1H-Benzimidazol-5-yl)-3-tert-butylurea derivatives have been identified as a novel class of non-peptide luteinizing hormone-releasing hormone (LHRH) antagonists. Herein, we disclose the synthesis and structure-activity relationships (SAR) of this class resulting in the identification of compound 12c, with dual functional activity on human and rat receptors (rat LHRH: IC50=120 nM; human LHRH: IC50=18 nM). These SAR studies suggest that 1-(1H-benzimidazol-5-yl)-3-tert-butylurea is a new pharmacophore for small molecule LHRH antagonists.

Benzimidazole derivatives as novel nonpeptide luteinizing hormone-releasing hormone (LHRH) antagonists. Part 1: Benzimidazole-5-sulfonamides.

A new class of benzimidazole-5-sulfonamides has been identified as nonpeptide luteinizing hormone-releasing hormone (LHRH) antagonists. Initial structure-activity relationships are presented resulting in compounds 19 and 28 with submicromolar dual functional activity on human and rat receptors.

Synthesis and structure-activity relationships of novel IKK-beta inhibitors. Part 2: Improvement of in vitro activity.

A series of 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl)pyridine derivatives was synthesized and evaluated as IkappaB kinase beta (IKK-beta) inhibitors. Substitution of an aminoalkyl group for the aromatic group at the 4-position on the core pyridine ring resulted in a marked increase in both kinase enzyme and cellular potencies, and provided potent IKK-beta inhibitors with IC(50) values of below 100 nM.

Development of a simple homogeneous assay to screen for inhibitors of N-acetylglucosamine-6-sulfotransferases.

L-selectin, a leukocyte adhesion molecule, plays a central role in lymphocyte homing to secondary lymphoid tissue and to certain sites of inflammation. Carbohydrate sulfation was implicated in this process, when it was demonstrated that carbohydrate sulfotransferase-mediated sulfation of N-acetylglucosamine (GlcNAc) within sialyl Lewis X of cognate endothelial ligands for L-selectin was an essential modification for L-selectin binding. The recently identified GlcNAc-6-sulfotransferases GlcNAc6ST-1 and -2, which facilitate GlcNAc sulfation by catalyzing the transfer of a sulfonyl group from 3(')-phosphoadenosine 5(')-phosphosulfate (PAPS) to the 6-hydroxy group of the acceptor GlcNAc moiety, contribute to the biosynthesis of the 6-sulfosialyl Lewis X motif. Due to their pivotal role in L-selectin ligand biosynthesis, this enzyme class has recently emerged as an important and relatively unexplored class of potential targets for anti-inflammatory therapy. However, no inhibitors have been reported to date and screening for lead inhibitors has been hampered by the lack of simple assay formats suitable for high-throughput screening. Here, we report the development of a simple homogeneous in vitro sulfotransferase assay using a newly synthesized biotinylated glycoside as a substrate. The assay is based on GlcNAc6ST-2-mediated [35S]sulfate transfer from [35S]PAPS to the biotinylated glycoside and subsequent detection using streptavidin-coated SPA beads. K(m) values with partially purified GlcNAc6ST-2 for PAPS and the biotinylated glycoside were estimated to be 8.4 and 34.5 microM, respectively. The sulfotransferase reaction could be inhibited by 3('),5(')-ADP with an IC(50) of 2.1 microM. The assay can be operated in 384-well format; is characterized by a high signal-to-noise ratio, low variation, and excellent Z factors; and is highly suitable for high-throughput screening.

An orally bioavailable small molecule antagonist of CRTH2, ramatroban (BAY u3405), inhibits prostaglandin D2-induced eosinophil migration in vitro.

Ramatroban (Baynas, BAY u3405), a thromboxane A(2) (TxA(2)) antagonist marketed for allergic rhinitis, has been shown to partially attenuate prostaglandin (PG)D(2)-induced bronchial hyperresponsiveness in humans, as well as reduce antigen-induced early- and late-phase inflammatory responses in mice, guinea pigs, and rats. PGD(2) is known to induce eosinophilia following intranasal administration, and to induce eosinophil activation in vitro. In addition to the TxA(2) receptor, PGD(2) is known as a ligand for the PGD(2) receptor, and the newly identified G-protein-coupled chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). To fully characterize PGD(2)-mediated inflammatory responses relevant to eosinophil activation, further analysis of the mechanism of action of ramatroban has now been performed. PGD(2)-stimulated human eosinophil migration was shown to be mediated exclusively through activation of CRTH2, and surprisingly, these effects were completely inhibited by ramatroban. This is also the first report detailing an orally bioavailable small molecule CRTH2 antagonist. Our findings suggest that clinical efficacy of ramatroban may be in part mediated through its action on this Th2-, eosinophil-, and basophil-specific chemoattractant receptor.

Discovery of novel and selective IKK-beta serine-threonine protein kinase inhibitors. Part 1.

IkappaB kinase beta (IKK-beta) is a serine-threonine protein kinase critically involved in the activation of the transcription factor Nuclear Factor kappa B (NF-kappaB) in response to various inflammatory stimuli. We have identified a small molecule inhibitor of IKK-beta. Optimization of the lead compound resulted in improvements in both in vitro and in vivo potency, and provided IKK-beta inhibitors exhibiting potent activity in an acute cytokine release model (LPS-induced TNFalpha).

Therapeutic effect of intraarterial prednisolone injection in severe intestinal Behçet's disease.

A 64-year-old woman with severe intestinal Behçet's disease who was unresponsive to conventional therapies, including intensive intravenous steroid injections, underwent intraarterial steroid injection therapy. After the infusion of prednisolone into the mesenteric arteries, her colon ulcers improved markedly, and the frequency of bloody stools decreased immediately. The present case suggests that intraarterial steroid injection therapy may be potentially useful in severe intestinal Behçet's disease.

Staphylococcal scalded-skin syndrome in an adult due to methicillin-resistant Staphylococcus aureus.

We report a case of a 71-year-old man with staphylococcal scalded-skin syndrome (SSSS). The patient, with a chronic history of diabetes mellitus, was admitted to our hospital with lumbago, and a diagnosis of renal-cell carcinoma with bone metastasis was made. In hospital he had sudden onset of high fever and erythema, followed by the formation of flaccid bullae and exfoliation, with a positive Nikolsky sign. Methicillin-resistant Staphylococcus aureus (MRSA), producing exfoliative toxin B, was isolated from blood and bile cultures, and Aeromonas hydrophila was isolated from bile culture. Skin biopsy specimen showed a cleavage of the epidermis at the level of the granular layer. The patient was diagnosed as having SSSS and cholecystitis, and was treated with intravenous antibiotics and percutaneous transhepatic gallbladder drainage, which led to recovery. SSSS in adults is usually associated with immunosuppression. A. hydrophila is recognized as an opportunistic pathogen. SSSS should be considered in the differential diagnosis of immunocompromised adult patients with sudden onset of high fever and erythema.