Casual C peptide index: Predicting the subsequent need for insulin therapy in outpatients with type 2 diabetes under primary care

BackgroundEvaluation of residual beta cell function is indispensable in patients with type 2 diabetes as it informs not only diagnoses but also appropriate treatment modalities. However, there is a lack of convenient biomarkers for residual beta cell function. Therefore, we evaluated endogenous insulin level as a biomarker in outpatients who were being treated with insulin therapy and in patients who were introduced to insulin therapy after 4 years.MethodsData of 174 outpatients with type 2 diabetes (50% male) whose glycemia was moderately controlled (glycated A1c 7.3% [5.2%–14.8%]) were reviewed. Twenty patients whose estimated glomerular filtration rate was lower than 30 ml/min/1.73 m² were excluded from the evaluation of endogenous insulin level with both casual C‐peptide index (C‐CPI) and urinary C‐peptide/creatinine ratio (determined at any time, generally 1–2 h after breakfast). Patients were stratified based on the provision of insulin therapy.ResultsC‐CPI and UCPCR were significantly lower in the insulin‐treated patients than in the insulin‐untreated patients (0.9 vs. 2.2, p < 0.0001; 24.7 vs. 75.5, p = 0.0003, respectively). Moreover, C‐CPI were significantly lower in the insulin‐requiring patients for 4 years than in the insulin‐unrequiring patients (1.0 vs. 1.7, p = 0.0184). The multivariate logistic regression analysis revealed that both indicators of insulin secretion influenced the requirement for insulin therapy, but C‐CPI could serve as the most convenient and useful biomarker for not only current insulin therapy requirements (p = 0.0002) but also the subsequent requirement for insulin therapy (p = 0.0008).ConclusionsC‐CPI could be determined easily, and it was found to be a more practical marker for outpatients; therefore, our findings would have critical implications for primary care.     

IgG4-related Disease with a Cardiac Mass Causing Cerebral Infarction

Immunoglobulin G4-related disease (IgG4-RD) is a systemic inflammatory disease characterized by infiltration of extensive IgG4-positive plasma cells and lymphocytes. Although IgG4-RD has been observed in almost all organs, it rarely affects the myocardium. Cardiovascular lesions of IgG4-RD appear as aortic (aortic aneurysm and aortitis) and pericardial (constrictive pericarditis) lesions as well as pseudotumors around the coronary arteries. We herein report a case of IgG4-RD with a cardiac mass in the right atrium involving a sinus node. This condition caused arrhythmia and repeated strokes. We successfully treated the patient through resection of the cardiac mass, catheter ablation and immunosuppressive therapy.     

Glycine residues in potassium channel-like selectivity filters determine potassium selectivity in four-loop-per-subunit HKT transporters from plants

Plant HKT proteins comprise a family of cation transporters together with prokaryotic KtrB, TrkH, and KdpA transporter subunits and fungal Trk proteins. These transporters contain four loop domains in one polypeptide with a proposed distant homology to K(+) channel selectivity filters. Functional expression in yeast and Xenopus oocytes revealed that wheat HKT1 mediates Na(+)-coupled K(+) transport. Arabidopsis AtHKT1, however, transports only Na(+) in eukaryotic expression systems. To understand the molecular basis of this difference we constructed a series of AtHKT1/HKT1 chimeras and introduced point mutations to AtHKT1 and wheat HKT1 at positions predicted to be critical for K(+) selectivity. A single-point mutation, Ser-68 to glycine, was sufficient to restore K(+) permeability to AtHKT1. The reverse mutation in HKT1, Gly-91 to serine, abrogated K(+) permeability. This glycine in P-loop A of AtHKT1 and HKT1 can be modeled as the first glycine of the K(+) channel selectivity filter GYG motif. The importance of such filter glycines for K(+) selectivity was confirmed by interconversion of Ser-88 and Gly-88 in the rice paralogues OsHKT1 and OsHKT2. Surprisingly, all HKT homologues known from dicots have a serine at the filter position in P-loop A, suggesting that these proteins function mainly as Na(+) transporters in plants and that Na(+)/K(+) symport in HKT proteins is associated with a glycine in the filter residue. These data provide experimental evidence that the glycine residues in selectivity filters of HKT proteins are structurally related to those of K(+) channels.     

Expression of p57/Kip2 protein in extrahepatic bile duct carcinoma and intrahepatic cholangiocellular carcinoma

BACKGROUND: Evaluation of the biological character of carcinomas requires understanding of cell cycle regulators. P57 (Kip2) belongs to the Cip/Kip family and is known to be one of the universal negative regulators of cell cycle. METHODS: In the present study, therefore, we investigated p57 expression in 37 extrahepatic bile duct carcinomas (BDC) and 28 intrahepatic cholangiocellular carcinomas (CCC). RESULTS: The average p57 labeling index (LI) in BDC and CCC were 60.8 +/- 7.9 and 58.6 +/- 18.6, respectively, which were significantly lower (p = 0.0008 and p = 0.0408, respectively) than those in normal duct epithelia (73.1 +/- 7.9, 70.4 +/- 8.2). p57 LI was significantly lower in BDC and CCC cases with biological aggressive phenotypes such as poor differentiation (p = 0.0260 and p = 0.0069), lymph node metastasis (p = 0.0274 and p = 0.0214), high Ki-67 LI (p = 0.0164 and p = 0.0343) and cyclin D1 overexpression (p = 0.0359 and p = 0.0255). CONCLUSION: These findings suggest that decreased p57 expression is related to the increased activity of cell proliferation and also the progression of these carcinomas.     

Ivabradine as an Adjuvant Agent for Severe Heart Failure Occurring in the Early Phase after Allogeneic Hematopoietic Cell Transplantation

Cardiotoxicity is a critical complication of allogeneic hematopoietic cell transplantation (allo-HCT). In particular, management of severe cardiotoxicity occurring in the early phases of allo-HCT is challenging. We encountered a case of severe cardiotoxicity resulting from AHF six days after allo-HCT, which resisted catecholamines and diuretics. The patient was treated with anthracycline-containing regimens and underwent myeloablative conditioning, including high-dose cyclophosphamide. As invasive circulatory assisting devices were contraindicated because of his immunocompromised status and bleeding tendency, we successfully treated the patient with ivabradine-containing medications. Ivabradine may therefore be considered an alternative drug for the treatment of severe cardiotoxicity induced by cytotoxic agents.     

Case of Mycobacterium haemophilum misdiagnosed as Mycobacterium intracellulare due to one base insertion in the bacterial genome

Mycobacterium haemophilum is a slow‐growing, non‐tuberculous mycobacteria that causes cutaneous infection. We describe a case of cutaneous infection in a 68‐year‐old Japanese man with polymyositis. This was caused by M. haemophilum harboring one base insertion in gene sequence. At first, the causal microorganism was misidentified as M. intracellulare by COBAS^® TaqMan^® MAI test. However, poor growth on Ogawa media and growth enhancement on 7H11C agar around a hemin‐containing disk prompted us to reinvestigate the causal microorganisms, which were revealed to be M. haemophilum. Amplified polymerase chain reaction products were sequenced, and the 16S rRNA gene, rpoB, hsp65 and internal transcribed spacer region sequences showed a 100%, 100%, 99.66% and 99.7% match, respectively, with the corresponding regions of M. haemophilum, but it harbored a novel gene sequence in hsp65. The sequences determined by gene analysis of the M. haemophilum strain were deposited into the International Nucleotide Sequence Database. Although numerous cases of M. haemophilum infection have been reported in other countries, only six cases have been reported in Japan to date. It could be possible that this novel mutation lead to misdiagnosis. As M. haemophilum prefers a lower growth temperature (30–32°C) and it requires iron in the culture medium, M. haemophilum could be misidentified or overlooked. Accordingly, a M. haemophilum infection should be considered in cases of cutaneous infection of the body sites, of which surface temperature is low.     

Is benzoyl peroxide 3% topical gel effective and safe in the treatment of acne vulgaris in Japanese patients? A multicenter,randomized, double‐blind,vehicle‐controlled,parallel‐group study

Benzoyl peroxide (BPO) as an anti‐acne medication is not yet approved in Japan. This study evaluated the efficacy and safety of a once‐daily topical application of BPO 3% gel versus an inert vehicle gel in Japanese acne patients. Three hundred and sixty patients were randomized to receive BPO 3% or vehicle for 12 weeks. The primary efficacy end‐point was absolute change in number of total lesions (TL) from baseline to week 12 to demonstrate the superiority of BPO 3% versus vehicle. Secondary efficacy end‐points were absolute and percent change in TL, inflammatory lesions (IL), non‐inflammatory lesions (non‐IL) and Investigator's Static Global Assessment (ISGA). Change in TL counts from baseline to week 12 for BPO 3% was superior to vehicle (difference, ?21.0; P < 0.001). Absolute and percent reductions in TL, IL and non‐IL counts were greater for BPO 3% at all study visits. The proportion of patients with improvement in ISGA scores was significantly higher with BPO 3% than with vehicle from week 2. All adverse events were mild or moderate. Adverse drug‐related reactions were higher for BPO 3% (30%) than with vehicle (5%). Local tolerability scores of grade 1 or more (slight to moderate) were more frequent with BPO 3% than vehicle with the most significant differences observed in dryness (56% vs 27% at week 1–4), peeling (19% vs 9% at week 1–2) and burning/stinging (58% vs 15% at week 1–12). These results indicate that BPO 3% is effective while maintaining a favorable safety and tolerability profile in Japanese acne patients.     

Synthesis of methyl methacrylate/styrene copolymer bearing a carbomethoxyallyl end group with limited molecular weight by addition-fragmentation reaction of methyl α-(bromomethyl)-acrylate

The synthesis of methyl methacrylate/styrene copolymer bearing overwhelmingly bromine and the 2-carbomethoxyallyl group (CH₂?C(COOCH₃)CH₂? ) at the α- and ω-termini instead of the fragment of the initiator with reduced molecular weight was investigated by using methyl α-(bromomethyl)acrylate as chain transfer agent through the addition-fragmentation mechanism. The molecular weight of the copolymer was effectively decreased with bromomethylacrylate, and the unsaturated end groups quantitatively bound to two types of the monomeric units were differentiated by means of ¹H NMR spectroscopy. Equations estimating the reactivities of methyl α-(bromomethyl)acrylate towards polystyrene and poly(methyl methacrylate) radicals were derived. Methyl α-(bromomethyl)acrylate was found to be more reactive toward the poly(methyl methacrylate) radical than the polystyrene radical by a factor of 0,62.     

The effects of nucleotides and potassium channel openers on the SUR2A/Kir6.2 complex K+ channel expressed in a mammalian cell line, HEK293T cells

 The effects of potassium channel opening drugs and intracellular nucleotides on the ATP-sensitive K+ (K_ATP) channel composed of SUR2A and Kir6.2 in HEK293T cells were examined using the patch-clamp technique. The SUR2A/Kir6.2 channel was activated effectively by pinacidil, marginally by nicorandil but not by diazoxide. The pinacidil-activated channel currents were inhibited by glibenclamide with a K _i value of 160 nM. Upon formation of inside-out (I-O) patches, spontaneous openings of the channels appeared, which were inhibited by intracellular ATP (ATP_i) equipotently in the presence and in the absence of intracellular Mg²⁺ (Mg²⁺ _i). The channel activity ran-down gradually in I-O patches. The run-down channels could be reactivated by ATP_i only in the presence of Mg²⁺ _i. Uridine 5’-diphosphate (UDP) antagonized the ATP_i-mediated inhibition of the channel activity before run-down. After run-down, UDP activated the channel without antagonizing ATP_i-mediated channel inhibition. Thus, the SUR2A/Kir6.2 reproduced the major properties of the native cardiac K_ATP channel well in terms of nucleotide regulation and pharmacology, and therefore can be a useful tool with which to elucidate the molecular mechanisms characterizing the K_ATP channel. Received: 24 October 1997 / Received after revision and accepted: 4 December 1997