Drug-induced Hypersensitivity Syndrome by EGFR-TKI in a Patient with Lung Cancer

An 83-years-old woman diagnosed with advanced Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma was administered afatinib as a first-line treatment. On Day 17, the patient presented with grade 3 diarrhea and a blood test analysis showed an increased inflammatory response. Afatinib treatment was discontinued on the same day. On Day 26, the patient displayed blepharedema and multiple irregular erythema covering her entire body. Drug-induced hypersensitivity syndrome (DIHS) was suspected, and the systemic administration of 30 mg/day prednisolone was administered. The symptoms subsided thereafter. A blood test analysis 3 weeks after onset revealed a reactivation of Human herpesvirus 6 (HHV-6) and a diagnosis of DIHS due to afatinib therapy was confirmed.     

On-pump versus off-pump coronary artery bypass using quadruple arterial grafts

The optimal combination of arterial grafts for quadruple coronary artery bypass is the bilateral internal mammary artery, the radial artery, and the gastroepiploic artery. Patients who underwent quadruple bypass in our hospital group between December 1995 and March 2001 were retrospectively analyzed to determine whether off-pump surgery (n = 27) provides better outcomes than conventional on-pump surgery (n = 51). Preoperative risk factors as well as the mean number of distal anastomoses (4.5 in the off-pump versus 4.8 in the on-pump patients) were not significantly different between the 2 groups. Postoperative recovery was significantly faster in the off-pump group than in the on-pump group (intubation time, 6.4 versus 16 hours; stay in intensive care unit, 2 versus 3 days; and postoperative hospital stay, 12.3 versus 15.8 days). Early stenosis-free graft patency rates did not differ significantly (90.3% versus 89.3%). No late cardiac events were observed in the off-pump group, while 4 occurred in the on-pump group. Quadruple arterial bypass without cardiopulmonary bypass is safe, and it allows faster recovery. The follow-up results of off-pump patients so far have been satisfactory.     

Alanine aminotransferase and HCV-RNA responses following interferon therapy of HCV-RNA positive chronic hepatitis

Interferon (IFN) has been shown to be effective for chronic hepatitis C. This study investigated changes of alanine aminotransferase (ALT) and HCV-RNA in chronic hepatitis C patients treated withα-IFN. IFN was given to 73 patients with HCV-RNA positive chronic hepatitis C. The pattern of changes in ALT activity after IFN aministration was classified into five types. Type 1 was characterized by normalization of ALT (≤25 K.U) during IFN administration and sustained normalization after the IFN therapy. Type 2 involved a rebound of ALT after termination of IFN therapy and subsequent normalization. Type 3 had no ALT normalization during IFN administration, with normalization after the completion of the therapy. Type 4 involved transient normalization of ALT level during IFN therapy, with a subsequent reversion to abnormal levels after the termination of IFN therapy. Type 5 showed sustained abnormally high levels of ALT activity both during and after treatment. Twenty four patients (32.9%) had sustained normalization ALT (≤25 K.U) after the termination of IFN treatment. The HCV-RNA negative rate at 6 months after IFN therapy in patients with sustained normalization of ALT was 87.5% (21/24).     

Skeletonized Radial Artery: New Technique for Graft Harvest with Improved Angiographic Results

To improve the patency rate of radial artery grafts, we have been using a skeletonized harvesting technique since September 2000. Our early reports confirmed better graft patency of skeletonized radial graft compared to conventional pedicled grafts. We present the angiographic and clinical follow-up data on skeletonized radial artery grafting. Between 09/01/2000 and 7/31/2002, a total of 268 patients underwent isolated coronary artery bypass using skeletonized radial artery graft, excluding T-grafting. Of these, 216 (80.6%) patients underwent postoperative angiography and their perioperative, early angiographic, and follow-up results were analyzed. There was 1 hospital death and 6 incidences of postoperative myocardial infarction. None were related to radial artery bypass. Early angiographic control revealed that the stenosis-free graft patency rate of radial artery anastomoses (318/331, 96.1%) was not significantly different from other conduits (the left internal mammary artery 93.5%, right internal mammary artery 90.8%, gastroepiploic artery 96.3%, and saphenous vein 97.6%). Follow-up was completed for all hospital survivors with a mean follow-up of 1.6 ± 0.4 years. There were no cardiac deaths, and 9 cardiac events, giving a cardiac event-free rate of 95.8%. The angiographical patency of the skeletonized radial artery was excellent. Although cardiac events were minimal, follow-up mid-term angiographics will be necessary to confirm our clinical outcome data.     

Stereoselective synthesis of Gly-Gly-type (E)-methylalkene and (Z)-chloroalkene dipeptide isosteres and their application to 14-mer RGG peptidomimetics

Stereoselective and efficient synthesis of Gly-Gly-type (E)-methylalkene and (Z)-chloroalkene dipeptide isosteres is realized by organocuprate-mediated single electron transfer reduction. The synthetic isosteres can be used in Fmoc-based solid phase peptide synthesis, resulting in the preparation of the 14-mer RGG peptidomimetics containing an (E)-methylalkene or a (Z)-chloroalkene unit.

An efficient synthesis of Gly-Gly-type (E)-methylalkene and (Z)-chloroalkene dipeptide isosteres is realized by organocuprate-mediated single electron transfer reduction.

Glycylglycine (Gly-Gly) is the smallest dipeptide and has been synthesized by many approaches in the last 100 years.¹ Due to its versatile nature and ready availability, glycylglycine has been used as a chemical probe² and buffer³ in biochemical studies and also as a reagent which can enhance the solubility of overexpressed proteins.⁴ In addition to the utility of Gly-Gly itself, oligoglycine (oligo-Gly) motifs are notable for being more flexible and less-functionalized than any combination of other amino acids. These features are useful in bioconjugation strategies which link multiple biomolecules without interfering with the function of each biomolecule, allowing synthesis of bioconjugated artificial molecules including dimeric, multi-domain, and fusion proteins.⁵ The flexibility of oligo-Gly enables the formation of unusual secondary structures of peptides and proteins.⁶ Thus, the oligo-Gly motif can be found in the biologically important peptides and proteins such as Met/Leu-enkephalin ( and ), the C-terminus of ubiquitin , ctenidin,⁷ shepherin I,⁸ and DNA/RNA-binding proteins with repeated sequences related to the various physiological processes via protein–protein and protein–nucleic acids interactions.⁹ These proteins relate with gene expression, DNA damage signal and apoptosis, however, the detail effects of Gly-Gly with steric and electronic factors to these functions are unknown. Given the importance of oligo-Gly in various fields, non-hydrolyzable peptidomimetics of oligo-Gly could be attractive building blocks for the synthesis of novel bioconjugated molecules and complex peptidomimetics with improved chemical stability and functionality. For example, even the Gly-Gly dipeptide mimic with the tetra-substituted alkene unit replacing the Gly-Gly peptide bond has been shown to promote the β-hairpin formation, and is thus the smallest peptidomimetic that is known to control a peptide structure.¹⁰ There are two reports of the synthesis of Gly-Gly-type fluoroalkene dipeptide isosteres.¹¹ However, the poor synthetic access to such molecules has hindered their application to the peptidomimetics. Our long-standing interest in the drug discovery with amide-to-alkene isosteric switching prompted this investigation into the stereoselective synthesis of Gly-Gly-type (E)-methylalkene and (Z)-chloroalkene dipeptide isosteres.In this report, we describe the beginning of our oligo-Gly-based peptidomimetic study with the stereoselective synthesis of Gly-Gly-type (E)-methylalkene and (Z)-chloroalkene dipeptide isosteres and their use in Fmoc-based solid phase peptide synthesis (SPPS). In the first application of isosteres of this type to access complex peptidomimetics, we synthesize 14-mer RGG peptidomimetics containing (E)-methylalkene or (Z)-chloroalkene unit as surrogates for a Gly-Gly peptide bond. These two isosteres were selected because the potentials of both isosteres have not been fully uncovered, though there are several promising examples.^12,13 Since the carbonyl oxygen equivalents of those isosteres are similar in their size¹⁴ but differ in their electronic properties,¹⁵ comparative studies of these isosteres would have the advantage of exploring the role of peptide bonds in terms of their steric and electronic natures. This work also uncovered the unique ability of the Gly-Gly-type (Z)-chloroalkene isostere to induce β-turn structures in the almost unfoled peptides (Fig. 1).Open in a separate windowFig. 1Gly-Gly peptide and its alkene-type peptidomimetics.The main challenges in this study include the stereoselective formation of the (E)-methylalkene and (Z)-chloroalkene moieties as the surrogates of the Gly-Gly trans-peptide bond, together with the control of the olefine isomerization under the condition of the isostere synthesis and Fmoc-based SPPS. There are several synthetic approaches toward tri-substituted alkene-type isosteres, including the Overman rearrangement,¹³ the S_N2′-type opening of alkenylaziridines,^12a Cu-mediated CF₃-coupling of vinyl iodide,¹⁶ and cross-couplings of vinyl stannane.¹⁷ Organocuprate-mediated reactions of α,β-unsaturated carbonyl compounds with γ-leaving group(s) are also powerful methods to produce tri-substituted alkene-type isosteres, and are particularly suitable for the stereoselective synthesis of (Z)-fluoroalkene¹⁸ and (Z)-chloroalkene isosteres.¹⁹The preparation of Gly-Gly-type alkene dipeptide isosteres was facilitated by the organocuprate-mediated SET reduction that was used in the stereoselective formation of the (E)-methylalkene and (Z)-chloroalkene moieties. Scheme 1 shows the synthesis of (E)-methylalkene isosteres (5). A Witting reaction of methacrolein (1) with ethyl (triphenylphosphoranylidene)acetate followed by epoxidation with m-CPBA afforded the alkenyl oxirane (2) which, treated with Gillman reagent (n-Bu₂CuLi), produced the allylic alcohol (3) with high E-selectivity. A Mitsunobu reaction of 3 with Ns(Boc)NH and deprotection provided the Gly-Gly-type (E)-methylalkene dipeptide isostere 5 that can be applied to the Fmoc-based SPPS. All reactions leading to the synthesis of 5 were performed on a gram scale.Open in a separate windowScheme 1Synthesis of Gly-Gly-type (E)-methylalkene dipeptide isosteres (5).Synthesis of chloroalkene isostere (14) is shown in Scheme 2. Based on previous results for the successful, efficient synthesis of Val-Xaa-type chloroalkene isosteres,^19c we assumed that a similar protocol would allow for the synthesis of 14. However, our attempts revealed that the Gly substrate used has different reactivity and selectivity compared to the other substrates, particularly in the SET reduction step. Consequently, Gly-specific reaction conditions are necessary. The nucleophilic addition of the lithium enolate of methyl dichloroacetate to the N-sulfinylaldimine (7), prepared from (±)-tert-butylsulfinamide (6) and paraformaldehyde and m-CPBA oxidation of 6 gave the N-tert-butylsulfonyl (Bus)-protected α,α-dichloro-β-amino ester (8). Precise control of the amount of DIBAL-H at low temperatures enables the partial reduction of 8, and this is followed by a Horner–Wadsworth–Emmons reaction to produce the corresponding (E)-enoate (9). Initial efforts to apply our established conditions for SET reduction with Me₂CuLi identified the poor Z-selectivity of the reaction and also its propensity to form the α-methylated side products 11 and 12 (Open in a separate windowScheme 2Synthesis of Gly-Gly-type (Z)-chloroalkene dipeptide isosteres (14).Reactivity of (E)-enoate (9) with organocuprates^a

Time Window for the Contribution of the δ-opioid Receptor to Cardioprotection by Ischemic Preconditioning in the Rat Heart

The present study aimed to examine (1) whether the role of the opioid receptor in ischemic preconditioning (PC) is consistent regardless of the duration of ischemic insult and (2) which opioid receptor subtype contributes to PC. In the first series of experiments, the effects of PC, a nonselective opioid receptor antagonist (naloxone), and their combination on the infarct size after various durations of ischemia were assessed. In anesthetized, open-chest rats, the coronary artery was occluded for 20, 30, or 40 minutes to induce infarction and was reperfused for 3 hours, PC was performed with two cycles of 5-minute ischemia followed by 5-minute reperfusion before the sustained ischemia. At 25 minutes before the ischemia, naloxone was injected alone or in combination with subsequent PC. Infarct size was determined by tetrazolium staining and was expressed as a percentage of the risk area size (%IS/RA). In the second series of experiments, the effects of a -receptor selective antagonist, naltrindole (NTI), and a -receptor selective antagonist, nor-binaltrophimine (nor-BNI), on PC before 30-minute coronary occlusion were assessed. In untreated controls, %IS/RA was 53.1 ± 3.2 after 20 minutes, 67.9 ± 3.9 after 30 minutes, and 87.8 ± 2.0 after 40 minutes of ischemia, respectively. PC significantly reduced %IS/RA after 20, 30, and 40 minutes of ischemia to 3.1 ± 0.8, 12.8 ± 1.1, and 42.1 ± 4.3, respectively (P < 0.05 vs. each control). Naloxone (6 mg/kg) partially attenuated the protection afforded by PC when the sustained ischemia was 30 minutes (%IS/RA = 27.4 ± 4.5; P < 0.05 vs. PC), but this inhibitory effect of naloxone was not detected when the duration of the ischemia was 20 or 40 minutes. NTI (10 mg/kg) also attenuated infarct size limitation by PC after 30 minutes of ischemia (%IS/RA = 25.6 ± 3.7), but nor-BNI (10 mg/kg) failed to modify infarct size limitation by PC (%IS/RA = 13.3 ± 3.2). The present results suggest that activation of the opioid -receptor partly contributes to preconditioning against infarction in the rat and that there may be a time window (at around 30 minutes after the onset of ischemia) for this opioid receptor–mediated protective mechanism.     

Infection with hepatitis B virus genotype A in Tokyo, Japan during 1976 through 2001

Background Because genotype A of hepatitis B virus (HBV) is not indigenous, there have been only few data on infection with it in Japan.Methods We examined clinical and virological features of the 66 Japanese patients who admitted Toranomon Hospital in Tokyo, Japan, between 1976 and 2001, who were found to have HBV/A infection. HBV genotype A was classified into subtype A (European type) and A (South African type) by phylogenetic analysis of the preS1 and preS2 regions, and the S gene sequences.Results Of the 66 patients infected with HBV/A, 14 (21%) were asymptomatic carriers, 26 (39%) presented with acute hepatitis, 22 (33%) with chronic hepatitis, and 4 (6%) with liver cirrhosis. HBV/A infection persisted for more than 6 months in 5 of the 26 (19%) patients with acute hepatitis. The frequency of acute hepatitis in patients infected with HBV/A was higher after than before 1991 (2/22 [9%] vs 24/44 [55%]; P < 0.0001). The frequency of nucleotide 1858 of T was higher in asymptomatic carriers than in patients with acute hepatitis in whom infection was resolved (5/14 [36%] vs 0/21 [0%]; P = 0.008). Of the 57 patients for whom subtypes of genotype A were determined, subtype A was identified in 53 (93%) and subtype A in only 4 (7%). All patients infected with subtype A were persistently infected with HBV.Conclusions HBV/A infection has become more frequent during recent years, predominantly presenting as acute hepatitis, and subtype A is uncommon in the Tokyo metropolitan area.     

Metastatic renal cell carcinoma presenting as multiple pleural tumours

A 66-year-old man was admitted with dyspnoea. Chest X-ray and chest computed tomography (CT) demonstrated a left-sided pleural effusion and multiple tumours, suggesting malignant mesothelioma in the left pleural space, but there were no pulmonary lesions. However, abdominal CT revealed a right renal tumour. An ultrasonography-guided needle biopsy of the pleural mass provided evidence of metastatic renal cell carcinoma (RCC). The pleural lesions dramatically decreased in size following right radical nephrectomy and subsequent interferon-alpha treatment. While the thorax is a frequently affected site of RCC, sole pleural metastases are rare and are often secondary to lung involvement. Batson's plexus, a network of vertebral valve-less veins with multiple connections, is likely responsible for the contralateral pleural metastases of RCC.     

Factors associated with incomplete colonoscopy at a Japanese academic hospital

AIM:To evaluate significant risk factors for incomplete colonoscopy at a Japanese academic hospital.METHODS:A total of 11812 consecutive Japanese people were identified who underwent a colonoscopy at an academic hospital.A multiple logistic regression model was used to evaluate retrospectively the significant risk factors for incomplete colonoscopy.RESULTS:The cecal intubation rate was 95.0%.By univariate analysis,age,female sex,poor bowel cleansing,and a history of abdominal or pelvic surgery were significant risk factors for incomplete colonoscopy(P<0.001).Moreover,age-and sex-adjusted analysis showed that significant risk factors for incomplete colonoscopy were female sex(OR=1.38,95%CI:1.17-1.64,P=0.0002),age≥60 years old(OR=1.44,95%CI:1.22-1.71,P<0.0001),a history of prior abdominal or pelvic surgery(OR=1.55,95%CI:1.28-1.86,P<0.0001),poor bowel cleansing(OR=4.64,95%CI:3.69-5.84,P<0.0001),and inflammatory bowel disease(IBD)(OR=1.48,95%CI:1.13-1.95,P=0.0048).In Japanese men,by age-adjusted analysis,IBD(OR=1.69,95%CI:1.18-2.43,P=0.005)was an independent risk factor for incomplete colonoscopy.CONCLUSION:Several characteristics in the Japanese population were identified that could predict technical difficulty with colonoscopy.