Metformin-associated Lactic Acidosis Induced by Excessive Alcohol Consumption.

A 65-year-old man with type 2 diabetes who was being treated with metformin developed lactic acidosis following excessive alcohol consumption. While an impaired renal function is a major risk factor for metformin-associated lactic acidosis (MALA), the patient's basal renal function was normal. Alcohol misuse reduces lactate clearance by utilizing nicotinamide adenine dinucleotides for ethanol oxidation, thereby promoting vulnerability to MALA. Nevertheless, as MALA in individuals with a normal renal function is extremely rare, the clinical picture of alcohol-induced MALA is unclear. We delineate the clinical picture and discuss the pathogenesis of alcohol-induced MALA based on our experience and previous case reports.

Potential Ketoacidosis Linked to Imeglimin and Metformin Co-administration in a Patient With Type 2 Diabetes.

A 74-year-old woman with type 2 diabetes mellitus developed ketoacidosis within six days of adding metformin to imeglimin treatment. The patient was insulin-sensitive and showed preserved insulin secretion; therefore, insulin insufficiency alone was unlikely to contribute to the development of ketoacidosis. Both imeglimin and metformin partially inhibit complex I in the mitochondrial respiratory chain. Inhibition of mitochondrial respiration can lead to tricarboxylic acid (TCA) cycle suppression. Thus, the entry of acetyl-coenzyme A into TCA cycle is restricted, and it is eventually used in ketogenesis. Therefore, the combination of imeglimin and metformin might have precipitated the development of ketoacidosis.

A Prospective, Open-Label Short-Term Pilot Study on Modification of the Skin Hydration Status During Treatment With a Sodium-Glucose Cotransporter-2 Inhibitor.

INTRODUCTION: Various types of skin lesions with pruritus have been reported in participants of Asian clinical trials on sodium-glucose cotransporter-2 (SGLT2) inhibitors. The aim of this study was to determine whether the diuretic effect of a SGLT2 inhibitor could modify skin hydration status in patients with type 2 diabetes mellitus. METHODS: A prospective, short-term, open-label, two-parallel-arm, pilot study was conducted. Eligible patients were assigned to either a SGLT2 inhibitor (50 mg ipragliflozin once daily) group or to a dipeptidyl peptidase-4 inhibitor (50 mg sitagliptin once daily) group (control). The biophysical characteristics of the skin were measured and blood chemistry tests were run in all participants 1 day prior to medication initiation (pre-treatment values) and 14 days thereafter (post-treatment values). RESULTS: Fourteen patients were enrolled in the study, of whom eight were in the ipragliflozin group and six in the sitagliptin group. Compared to the pre-treatment values, the glycated hemoglobin (HbA1c) levels were slightly but significantly reduced in the ipragliflozin group (p = 0.02), but the changes in HbA1c from the pre-treatment to post-treatment time points did not significantly differ between the two treatment groups. Serum 3-hydroxy butyrate levels were significantly higher in the ipragliflozin group than in the sitagliptin group (p < 0.02). Neither electrical capacitance nor electrical conductance of the stratum corneum (SC), parameters that reflect skin water content, was reduced by 14 days of ipragliflozin treatment; similarly, no changes in these parameters were found in the sitagliptin control group. There was also no difference in the changes in water barrier function of the SC between the two treatment groups. There was a significant linear correlation (p < 0.01) in skin water content at pre-treatment and that 14 days after treatment with each drug, respectively. CONCLUSION: Ipragliflozin treatment for 14 days did not significantly affect the skin hydration status in patients with well-controlled type 2 diabetes mellitus.

Antioxidant Artemisia princeps Extract Enhances the Expression of Filaggrin and Loricrin via the AHR/OVOL1 Pathway.

The Japanese mugwort, Artemisia princeps (yomogi in Japanese), has anti-inflammatory and antioxidant effects. Skin care products containing Artemisia princeps extract (APE) are known to improve dry skin symptoms in atopic dermatitis. Atopic dry skin is associated with a marked reduction of skin barrier proteins, such as filaggrin (FLG) and loricrin (LOR). Recently, aryl hydrocarbon receptor (AHR), and its downstream transcription factor OVO-like 1 (OVOL1), have been shown to regulate the gene expression of FLG and LOR. The focus of this paper is to evaluate the effects of APE on the AHR/OVOL1/FLG or LOR pathway since they have remained unknown to this point. We first demonstrated that non-cytotoxic concentrations of APE significantly upregulated antioxidant enzymes, NAD(P)H dehydrogenase quinone 1 and heme oxygenase 1, in human keratinocytes. Even at these low concentrations, APE induced nuclear translocation of AHR and significantly upregulated CYP1A1 (a specific target gene for AHR activation), FLG, and LOR expression. AHR knockdown downregulated OVOL1 expression. The APE-induced upregulation of FLG and LOR was canceled in keratinocytes with AHR or OVOL1 knockdown. In conclusion, antioxidant APE is a potent phytoextract that upregulates FLG and LOR expression in an AHR/OVOL1-dependent manner and this may underpin the barrier-repairing effects of APE in treating atopic dry skin.

[Utilization of CAP Survey, Based on Questionnaire Results from Survey Participants].

The survey provided by the College of American Pathologists (CAP) is chosen as one of the proficiency testing programs in Japan, and, recently, the numbers of participating facilities have increased. CAP provides 754 programs, and more than 1,000 tests were provided in 2014. Materials are translated as the "CAP global inter-laboratory comparison program" under the instruction of the Japanese Society of Laboratory Medicine (JSLM) selected from CAP surveys in Japan, and 68 programs and 261 items are provided. The total number of participating facilities was 174. CAP itself and the other services CAP provides are not well-known, while recognition of "the CAP survey as the proficiency test" has increased. The question "What is CAP and the CAP survey" was analyzed as a result of the questionnaire surveys conducted in 2014, and the advantage of the CAP survey and how to utilize it were considered. A questionnaire survey was conducted about the CAP survey for Japanese participants in 2014. Fifty-three questions were asked about their satisfaction level, intended use, and improvement. Eighty replies were analyzed. As a result, most CAP survey participants are satisfied. They intend to mainly use the CAP survey for their quality control. Furthermore, they can continuously monitor their systems throughout all testing phases as the survey has numbers of shipments a year and several specimens per each mailing. This helps in laboratory performance improvement. The Evaluation and Participant Summary (PSR) also effectively improves the laboratories' performance. CAP-accredited laboratories are required to participate in all survey programs concerning the test menu which they provide. Therefore, they have become accustomed to reviewing the evaluation and performing self-evaluation with a high usage rate of the Evaluation and PSR of the CAP survey. The questionnaire proved that performing the CAP survey properly enhanced the laboratories' quality control, and this meets the participants' needs.

Molecular characterization and gene disruption of a novel zinc-finger protein, HIT-4, expressed in rodent brain.

To identify a novel regulatory factor involved in brain development or synaptic plasticity, we applied the differential display PCR method to mRNA samples from NMDA-stimulated and un-stimulated neocortical cultures. Among 64 cDNA clones isolated, eight clones were novel genes and one of them encodes a novel zinc-finger protein, HIT-4, which is 317 amino acid residues (36-38 kDa) in length and contains seven C2H2 zinc-finger motifs. Rat HIT-4 cDNA exhibits strong homology to human ZNF597 (57% amino acid identity and 72% homology) and identity to rat ZNF597 at the carboxyl region. Furthermore, genomic alignment of HIT-4 cDNA indicates that the alternative use of distinct promoters and exons produces HIT-4 and ZNF597 mRNAs. Northern blotting revealed that HIT-4 mRNA (approximately 6 kb) is expressed in various tissues such as the lung, heart, and liver, but enriched in the brain, while ZNF597 mRNA (approximately 1.5 kb) is found only in the testis. To evaluate biological roles of HIT-4/ZNF597, targeted mutagenesis of this gene was performed in mice. Homozygous (-/-) mutation was embryonic lethal, ceasing embryonic organization before cardiogenesis at embryonic day 7.5. Heterozygous (+/-) mice were able to survive but showing cell degeneration and vacuolization of the striatum, cingulate cortex, and their surrounding white matter. These results reveal novel biological and pathological roles of HIT-4 in brain development and/or maintenance.

Diurnal variation of biopyrrin excretion in random urine specimens is not corrected by creatinine.

Circulating bilirubin is thought to function as a physiological antioxidant. One of the decomposition products of this process is the biopyrrins, which include two regioisomers: biotripyrrin-a (1,14,15,17-tetrahydro-2,7,13-trimethyl-1,14-deoxy-3-vinyl-16H-tripyrrin-8,12-dipropionic acid) and biotripyrrin-b (1,14,15,17-tetrahydro-3,7,13-trimethyl-1,14-deoxy-3-vinyl-16H-tripyrrin-8,12-dipropionic acid). We measured biopyrrins in random urine specimens and investigated whether the biopyrrin values obtained were valid when expressed as a ratio of the creatinine (Cr) concentrations. All of the random urine specimens collected over 48 hr were from presumably healthy adults. We measured the biopyrrins by means of an enzyme-linked immunosorbent assay (ELISA) using an anti-bilirubin monoclonal antibody. When the values were expressed in terms of the ratio to Cr, the within-day coefficient of variation (%CV) of the excretion of biopyrrins was reduced to 27%+/-10% (P<0.05) from 59%+/-27%. However, assay values on random or spot urine specimens were unreliable because of the large %CV. The biopyrrin concentrations only in the first-morning-urine specimens in terms of both absolute amounts and ratios to Cr significantly reflected those in a 24-hr urine specimen (P<0.001). Concentrations in a random urine specimen voided at the second collection or later did not correlate with the concentration in a 24-hr urine specimen (P>0.05), even if their values were corrected by Cr. The amounts of biopyrrins excreted in 24-hr urine specimens were significantly correlated with the 24-hr cortisol excretion (P<0.001) but not to uropepsin (P>0.05).

The assay of ascorbic acid in serum is not affected by physiological concentrations of transferrin and hemoglobin.

Transferrin and hemoglobin have been reported to oxidize L-ascorbic acid (AA) in vitro. The aim of this study was to determine whether or not physiological concentrations of serum transferrin (reference range 22-45 micromol/L) and hemoglobin (reference range 0-3.0 micromol/L) interfer with the measurement of AA in the serum. Transferrin (33 to 41 micromol/L) and hemoglobin (1.9 micromol/L) added to freshly pooled serum significantly decreased measured AA in the serum (p < 0.05). However, we found that the magnitude of the decrease in AA due to transferrin at concentrations within the reference range or up to 80 micromol/L was inconsequential, and had no clinical importance in diagnosing a low AA concentration. Hemoglobin at concentrations within the reference range had little affect on the serum AA measurement. However, when serum specimens were stored at 4 degrees C for more than 1.5 h, the magnitude of the decrease in AA due to hemoglobin at physiological concentrations may cause a misleading clinical diagnostic evaluation of low AA concentration.

Ligation of human CD46 with purified complement C3b or F(ab')(2) of monoclonal antibodies enhances isoform-specific interferon gamma-dependent nitric oxide production in macrophages.

CD46, a complement regulatory protein widely expressed on human cells, serves as an entry receptor for measles virus (MV). We have previously shown that the expression of human CD46 in mouse macrophages restricts MV replication in these cells and enhances the production of nitric oxide (NO) in the presence of gamma interferon (IFN-gamma). In this study, we show that crosslinking human CD46 expressed on the mouse macrophage-like cell line RAW264.7 with purified C3b multimer but not monomer enhances NO production. The enhanced production of NO in response to IFN-gamma was observed again with C3b multimer but not monomer. The augmentation of NO production is human CD46-dependent with a CYT1>CYT2 profile. Thus, the reported MV-mediated NO production, irrespective of whether it is IFN-gamma-dependent or -independent, should be largely attributable to CD46 signaling but not to MV replication. Similar CYT1-dependent augmentation of NO production was reproducible with two CD46 ligating reagents, CD46-specific monoclonal antibodies (mAb) or their F(ab')(2) and MV hemagglutinin (H) and fusion (F) glycoproteins. Co-cultivation of mouse macrophages bearing human CD46 with Chinese hamster ovary (CHO) cells expressing MV H and F enhanced IFN-gamma-induced NO production. Yet, the NO levels induced by F(ab')(2) against CD46 or MV H/F on CHO cells were much lower than those induced by CD46-crosslinking mAb with Fc or MV infection. Removing the cytoplasmic tails of CD46 abrogated the augmentation of NO production triggered by all three stimulators. Thus, the CD46 CYT1 and CYT2 isoforms functionally diverge to elicit innate immune responses, which can be modulated by purified C3b multimer or anti-CD46 mAbs.