Clipping by ring-closing metathesis freezes rotation of a C-C bond to result in forming axial chirality. Treatment of bisbenzimidazole bearing an N-(3-butenyl) substituent with a Grubbs' catalyst undergoes ring-closing metathesis, in which the stereochemistry of the thus formed olefin was exclusively E-form. Analysis by HPLC with a chiral stationary column confirmed clear baseline separation of each enantiomer.

BACKGROUND: Autosomal dominant polycystic kidney disease is a lifelong progressive disorder. However, how age, blood pressure, and stage of chronic kidney disease (CKD) affect the rate of kidney function deterioration is not clearly understood. METHODS: In this long-term observational case study up to 13.9 years (median observation period for slope was 3.3 years), serum creatinine was serially measured in 255 mostly adult patients. The glomerular filtration rate was estimated (eGFR) using a modified Modification of Diet in Renal Disease Study method. The total kidney volume (TKV) has been measured in 86 patients at one center since 2006. RESULTS: As age increased, eGFR declined significantly (P < 0.0001), but the annual rate of decline of eGFR did not correlate with age or initially measured eGFR. In patients with CKD stage 1, eGFR declined at a rate which was not significantly different from other advanced CKD stages. Hypertensive patients had lower eGFR and larger TKV than normotensive patients at a young adult age. The slopes of regression lines of eGFR and TKV in relation to age were not different between high and normal blood pressure groups. CONCLUSION: The declining rate of eGFR was relatively constant and did not correlate with age or eGFR after adolescence. eGFR was already low in young adult patients with hypertension. As age increased after adolescence, eGFR declined and TKV increased similarly between normal and high blood pressure groups. eGFR starts to decline in patients with normal eGFR, suggesting that the decline starts earlier than previously thought.

BACKGROUND: The purpose of this study was to evaluate the long-term safety of the Igaki-Tamai stent, the first-in-man fully biodegradable coronary stent made of poly-l-lactic acid. METHODS AND RESULTS: Between September 1998 and April 2000, 50 patients with 63 lesions were treated electively with 84 Igaki-Tamai stents. Overall clinical follow-up (>10 years) of major adverse cardiac events (MACE) and rates of scaffold thrombosis were analyzed together with the results of angiography and intravascular ultrasound (IVUS). MACE included all-cause death, nonfatal myocardial infarction (MI) and target lesion revascularization / target vessel revascularization (TLR/TVR). During the overall clinical follow-up period (121±17 months), 2 patients were lost to follow-up. There was 1 cardiac death, 6 non-cardiac deaths and 4 MIs. Survival rates free of all-cause death, cardiac death and MACE at 10 years were 87%, 98% and 50%, respectively. The cumulative rates of TLR (TVR) were 16%(16%) at 1 year, 18%(22%) at 5 years and 28%(38%) at 10 years. Two definite scaffold thromboses (1 subacute, 1 very late) were recorded. The latter case was related to a sirolimus-eluting stent, which was implanted for a lesion proximal to an Igaki-Tamai stent. From the analysis of IVUS data, the stent struts mostly disappeared within 3 years. The external elastic membrane area and the stent area did not change. CONCLUSIONS: Acceptable MACE and scaffold thrombosis rates without stent recoil and vessel remodeling suggested the long-term safety of the Igaki-Tamai stent.

Aims: To further elucidate the clinical relevance of T-cell abnormalities in minimal change nephrotic syndrome (MCNS), and to predict the consequences of MCNS, we studied T-cell receptor (TCR) diversity by analyzing CDR3 size distribution and the frequency of Vβ repertoire usage. Methods: Participants comprised 36 pediatric patients with MCNS. 18 were frequent relapsers (FRs) and/or steroid-dependent (SD) and 18 were non-frequent relapsers (NFRs). Serial changes in TCR Vβ repertoires were analyzed for these two groups of patients. Frequencies of Vβ repertoire usage were determined by flow cytometry, and TCR CDR3 length distribution was analyzed by GeneScan. Results: In NFRs, abnormalities in the distribution of Vβ repertoires were few in both CD4+ and CD8+ T cells. In FRs/ SD patients, patterns were normal in CD4+ T cells, while selected Vβ repertoires were significantly increased in CD8+ T cells in some patients. Furthermore, TCR diversity was significantly reduced in CD8+ T cells in FRs/SD patients, as shown by marked skewing of CDR3 size distributions. Of note was the finding that some FRs/SD patients showed improvements in the initially abnormal TCR diversity with improvement in clinical symptoms, eventually becoming NFRs. Conclusion: Analysis of TCR diversity may delineate the subgroup of FRs/SD patients and provide a rationale for early intervention with immunosuppressive therapy for these patients.

Diabetes mellitus is a risk factor for heart failure. Increased reactive oxygen species (ROS) have been proposed as a possible mechanism of cardiac dysfunction in diabetic patients. However, the mechanisms of ROS increase are still elusive. We hypothesized that activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) induced by impaired intracellular Ca(2+)([Ca(2+)](i)) metabolism may stimulate ROS production in the diabetic heart. Cultured cardiomyocytes from neonatal rats were exposed to high glucose concentrations (25mmol/L) and ROS levels were analyzed in 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester (CM-H(2)DCFDA)-loaded cells by flow cytometry analysis. Exposure to high glucose concentrations for 24h significantly increased CM-H(2)DCFDA fluorescence, which was significantly inhibited by 1,2-bis (o-aminophenoxy) ethane- N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester (BAPTA-AM), a [Ca(2+)](i) chelator, and KB-R7943, an inhibitor of the Na(+)-Ca(2+) exchanger (NCX) in the reverse mode. These results indicate that [Ca(2+)](i) increase by NCX activation may induce ROS increase following exposure to high glucose concentrations. We confirmed that exposure to high glucose concentrations significantly increased [Ca(2+)](i), which was inhibited by KB-R7943. Na(+)-H(+) exchanger (NHE) is a key factor in [Ca(2+)](i) metabolism, and is known to activate NCX by increasing the intracellular Na(+)([Na(+)](i)) level. We showed that the expression of NHE isoform 1 and NHE activity increased following exposure to high glucose concentrations by evaluating protein expressions and intracellular pH recovery from acid loading. Exposure to high glucose concentrations up-regulated phosphorylated CaMKII expression in cardiomyocytes that was inhibited by KB-R7943. Further, autocamtide 2-related inhibitory peptide (AIP), a CaMKII inhibitor, significantly attenuated the ROS increase following exposure to high glucose concentrations. We confirmed these results obtained in in vitro experiments in an animal model of diabetes. ROS level and components of NADPH oxidase, p47phox and p67phox were up-regulated in streptozotocin-induced diabetic rat heart, which were attenuated by KN-93, a CaMKII inhibitor. Consistently, expression of phosphorylated CaMKII was increased in the diabetic heart. Activation of CaMKII by impaired [Ca(2+)](i) metabolism may be a mechanism of ROS increase in the heart with diabetes mellitus.

Human noggin (NOG) is a responsible gene for multiple synostosis syndrome (SYNS1) and proximal symphalangism (SYM1), two conditions that are recently known to be within a wider range of clinical manifestations of stapes ankylosis with symphalangism. This study was performed to determine the range of phenotype caused by NOG mutations, using Japanese patients with various phenotypes including sporadic inherited SYM1, dominantly inherited SYM1, stapes ankylosis with broad thumb and toes (Teunissen and Cremer syndrome). In addition, 33 patients with typical otosclerosis (without symphalangism) were studied. Direct sequencing analysis disclosed three novel mutations of the NOG gene in three SYM1 families. None of the otosclerosis patients without symphalangism had NOG mutations, indicating that NOG mutations may be restrictively found within patients with various skeletal abnormalities. These results together with the literature review indicated that there are no clear genotype-phenotype correlations for NOG mutations. With regard to surgical outcome, most of the patients in these three families with NOG mutations showed remarkable air-bone gap recovery after stapes surgery. Molecular genetic testing is useful to differentiate syndromic stapes ankylosis from otosclerosis, and even mild skeletal anomalies can be a diagnostic indicator of NOG-associated disease.

Background and purpose.  Resveratrol is a polyphenol abundantly found in grape skins and red wine. In the present study, we investigated whether resveratrol exerts cardioprotective effects against ischemia/reperfusion and also explored its mechanisms. Experimental approach.  Infarct size and functional recovery in isolated perfused rat hearts subjected to no-flow global ischemia followed by reperfusion were measured. Cultured neonatal rat cardiomyocytes were exposed to H(2) O(2 )(100 µmol.L(-1)) to induce cell injury. Intracellular ion concentrations were measured using specific dyes. Western blotting was used to quantify protein expression levels. Key Results.  In isolated perfused rat hearts, treatment with resveratrol (20 and 100 µmol.L(-1)) 15 min before ischemia considerably improved left ventricular functional recovery and infarct size. In cultured neonatal rat cardiomyocytes, resveratrol significantly attenuated the increase in reactive oxygen species and loss of mitochondrial inner membrane potential. Resveratrol also suppressed the increase in intracellular concentrations of Na(+)([Na(+)](i)) and Ca(2+)([Ca(2+)](i)) after H(2) O(2) application; however, it did not suppress the ouabain-induced [Ca(2+)](i) increase. By measuring changes in intracellular pH recovery after acidification, we also confirmed that acid-induced activation of Na(+)-H(+) exchanger (NHE) was prevented by pre-treatment with resveratrol. Furthermore, resveratrol inhibited the H(2) O(2)-induced translocation of PKC-α from the cytosol to the cell membrane; this translocation is believed to activate NHE. Conclusions and Implications.  Resveratrol exerts cardioprotection by reducing ROS and preserving mitochondrial function. The PKC-α-dependent inhibition of NHE and subsequent attenuation of [Ca(2+)](i) overload may be a cardioprotective mechanism.

OBJECTIVES This study aimed to investigate a wide variety of factors that influence auditory, speech, and language development following pediatric cochlear implantation (CI). STUDY DESIGN Prospective collection of language tested data in profound hearing-impaired children. HYPOTHESIS Pediatric CI can potentially be effective to development of practical communication skills and early implantation is more effective. METHODS We proposed a set of language tests (assessment package of the language development for Japanese hearing-impaired children; ALADJIN) consisting of communication skills testing (test for question-answer interaction development; TQAID), comprehensive (Peabody Picture Vocabulary Test-Revised; PVT-R and Standardized Comprehension Test for Abstract Words; SCTAW) and productive vocabulary (Word Fluency Test; WFT), and comprehensive and productive syntax (Syntactic processing Test for Aphasia; STA). Of 638 hearing-impaired children recruited for this study, 282 (44.2%) with >70 dB hearing impairment had undergone CI. After excluding children with low birth weight (<1800 g), those with >11 points on the Pervasive Developmental Disorder ASJ Rating Scale for the test of autistic tendency, and those <2 SD on Raven's Colored Progressive Matrices for the test of non-verbal intelligence, 190 children were subjected to this set of language tests. RESULTS Sixty children (31.6%) were unilateral CI-only users, 128 (67.4%) were CI-hearing aid (HA) users, and 2 (1.1%) were bilateral CI users. Hearing loss level of CI users was significantly (p<0.01) worse than that of HA-only users. However, the threshold level, maximum speech discrimination score, and speech intelligibility rating in CI users were significantly (p<0.01) better than those in HA-only users. The scores for PVT-R (p<0.01), SCTAW, and WFT in CI users were better than those in HA-only users. STA and TQAID scores in CI-HA users were significantly (p<0.05) better than those in unilateral CI-only users. The high correlation (r=0.52) has been found between the age of CI and maximum speech discrimination score. The scores of speech and language tests in the implanted children before 24 months of age have been better than those in the implanted children after 24 months of age. CONCLUSIONS We could indicate that CI was effective for language development in Japanese hearing-impaired children and early CI was more effective for productive vocabulary and syntax.

Megacystis is frequently involved with chronic intestinal pseudoobstruction syndrome; however, isolated megacystis without intestinal obstruction is extremely rare. We present the case of a female patient with isolated congenital megacystis without severe intestinal obstruction. In this case, barium enema did not reveal any significant findings; however, histologic evaluation of her rectum showed hypoganglionosis of the submucous and myenteric plexuses. These findings indicate that this case may be a mild variant of chronic intestinal pseudoobstruction syndrome. The presence of megacystis should alert the physician to the possibility of chronic intestinal pseudoobstruction syndrome.

Abstract: Although rarely encountered, major vascular injury is a serious complication of total hip arthroplasty (THA). We report the case of an 85-year-old woman who sustained a deep femoral artery injury associated with a superficial femoral artery thrombosis during revision of a dislocated bipolar hemiarthroplasty to a THA. Altered anatomy due to migration of the femoral head was thought to be one of the factors leading to this complication. Following the revision procedure, no signs of vascular insufficiency were detected in the immediate postoperative period, but ischaemia was clinically evident 12 hours after surgery. The importance of careful preoperative and postoperative assessment is addressed.