Comparison of the antidiabetic effects of linagliptin among groups with a normal renal function and a mild or severe renal impairment – retrospective observation study of Japanese patients with type 2 diabetes mellitus

Objective: The clinical course > 6 months after the initiation of linagliptin in patients with type 2 diabetes was compared among the groups divided by their renal function.

Methods: Two hundred and sixteen Japanese patients with type 2 diabetes treated with 5 mg once daily linagliptin were studied as the treated set. One hundred and forty-five subjects whose medications were not changed during the observation period were investigated as the full analysis set to assess the effectiveness. The subjects were divided into three groups based on an eGFR: eGFR ≥ 60, 59 – 45 and < 45 ml/min/1.73 m². The parameters were analyzed separately in the patients receiving monotherapy and additional therapy of linagliptin.

Results: The HbA1c (NGSP) levels significantly improved in both the patients receiving monotherapy and additional therapy. The changes in the HbA1c levels at 6 months were not significantly different between the groups with an eGFR ≥ 60, 59 – 45 and < 45 ml/min/1.73 m² receiving monotherapy (?1.0, ?0.8 and ?0.8%, respectively). Similarly, those were not significantly different between the different groups receiving additional therapy (?0.6, ?0.5 and ?0.7%, respectively).

Conclusions: Linagliptin is considered to be effective for patients with type 2 diabetes and renal impairment in the present analysis performed at our institution.     

Role of Maternal Antibodies in Infants with Severe Diseases Related to Human Parechovirus Type 3

Human parechovirus type 3 (HPeV3) is an emerging pathogen that causes sepsis and meningoencephalitis in young infants. To test the hypothesis that maternal antibodies can protect this population, we measured neutralizing antibody titers (NATs) to HPeV3 and other genotypes (HPeV1 and HPeV6) in 175 cord blood samples in Japan. The seropositivity rate (>1:32) for HPeV3 was 61%, similar to that for the other genotypes, but decreased significantly as maternal age increased (p<0.001). Furthermore, during the 2014 HPeV3 epidemic, prospective measurement of NATs to HPeV3 in 45 patients with severe diseases caused by HPeV3 infection showed low NATs (<1:16) at onset and persistently high NATs (>1:512) until age 6 months. All intravenous immunoglobulin samples tested elicited high NATs to HPeV3. Our findings indicate that maternal antibodies to HPeV3 may help protect young infants from severe diseases related to HPeV3 and that antibody supplementation may benefit these patients.     

Estimated Daily Intake and Seasonal Food Sources of Quercetin in Japan

Quercetin is a promising food component, which can prevent lifestyle related diseases. To understand the dietary intake of quercetin in the subjects of a population-based cohort study and in the Japanese population, we first determined the quercetin content in foods available in the market during June and July in or near a town in Hokkaido, Japan. Red leaf lettuce, asparagus, and onions contained high amounts of quercetin derivatives. We then estimated the daily quercetin intake by 570 residents aged 20–92 years old in the town using a food frequency questionnaire (FFQ). The average and median quercetin intakes were 16.2 and 15.5 mg day⁻¹, respectively. The quercetin intakes by men were lower than those by women; the quercetin intakes showed a low correlation with age in both men and women. The estimated quercetin intake was similar during summer and winter. Quercetin was mainly ingested from onions and green tea, both in summer and in winter. Vegetables, such as asparagus, green pepper, tomatoes, and red leaf lettuce, were good sources of quercetin in summer. Our results will help to elucidate the association between quercetin intake and risks of lifestyle-related diseases by further prospective cohort study and establish healthy dietary requirements with the consumption of more physiologically useful components from foods.     

Disruption of autosomal recessive hypercholesterolemia gene shows different phenotype in vitro and in vivo

We previously characterized the patients with autosomal recessive hypercholesterolemia (ARH) as having severe hypercholesterolemia and retarded plasma low-density lipoprotein (LDL) clearance despite normal LDL receptor (LDLR) function in their cultured fibroblasts, and we identified a mutation in the ARH locus in these patients. ARH protein is an adaptor protein of the LDL and reportedly modulates its internalization. We developed ARH knockout mice (ARH-/-) to study the function of this protein. Plasma total cholesterol level was higher in ARH-/- mice than that in wild-type mice (ARH+/+), being attributed to a 6-fold increase of LDL, whereas plasma lipoprotein was normal in the heterozygotes (ARH+/-). Clearance of 125I-LDL from plasma was retarded in ARH-/- mice, as much as that found in LDLR-/- mice. Fluorescence activity of the intravenously injected 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-LDL was recovered in the cytosol of the hepatocytes of ARH+/+ mice, but not in those of ARH-/- or LDLR-/- mice. Also, less radioactivity was recovered in the liver of ARH-/- or LDLR-/- mice when [3H]cholesteryl oleyl ether (CE)-labeled LDL was injected. In contrast, uptakes of [3H]CE-labeled LDL, 125I-LDL, and DiI-LDL were all normal or slightly subnormal when the ARH-/- hepatocytes were cultured. We thus concluded that the function of the hepatic LDLR is impaired in the ARH-/- mice in vivo, despite its normal function in vitro. These findings were consistent with the observations with the ARH homozygous patients and suggested that certain cellular environmental factors modulate the requirement of ARH for the LDLR function.     

An autopsy case of granulocyte-colony-stimulating-factor-producing extrahepatic bile duct carcinoma

A 79-year-old man was referred to this department due to the presence of extrahepatic bile duct carcinoma with a tumor at the left chest wall. The lesion was suspected to be a metastasis of bile duct carcinoma to the left wall, however, computed tomography （CT） revealed no regional lymph node or liver metastases. In addition, cytological and pathological examinations did not show malignancy. At the time of admission, the white blood cell count was 21 460 cells/μL （neutrophils, 18 240 cells/μL） and this elevated to 106 040 before death. In addition, serum granulocyte colony-stimulating factor （G-CSF） was elevated. At 28 d after admission, the patient died. An autopsy showed a poorly differentiated adenocarcinoma with sarcomatous change, which had slightly invaded into the pancreas around the bile duct, and was found in the distal bile duct with multiple metastases to the chest wall, lung, kidney, adrenal body, liver, mesentery, vertebra and mediastinal and para-aortic lymph nodes, without locoregional lymph node and liver metastasis. The cancer cells showed positive immunohistochemical staining for anti-G-CSF antibody. This is believed to be the first report of an extrahepatic bile duct carcinoma that produces G-CSF. Since G-CSF-producing carcinoma and sarcomatous change of the biliary tract leads to poor prognosis, early diagnosis and treatment are needed. When infection is ruled out, the G-CSF in serum should be examined. In addition, examinations such as bonescintigraphy and chest CT should also be considered for distant metastasis.     

Intraperitoneal administration of the biological response modifier OK-432 and peritoneal recurrence following gastrectomy

In patients with gastric cancer invading the serosa, there is often peritoneal dissemination. In an attempt to control such peritoneal recurrences, OK-432, a compound composed of penicillin G-treated, attenuated Streptococcus pyogens of human origin, was administered intraperitoneally at the time of gastrectomy. The non-specific antitumor activity of the peritoneal macrophages was investigated for its cytostatic activity against the cultured human lung cancer cell line, QG-90. OK-432 given intraperitoneally significantly increased the number of the peritoneal macrophages (p less than 0.05), and also enhanced the cytostatic activity (p less than 0.01). On the basis of these findings, OK-432 IP after gastrectomy was given to 13 of 68 patients with gastric cancer invading the serosa and who underwent curative resection. The five-year survival rate of patients given the drug was 63.5%, while the rate was 52.9% in those not given the drug. OK-432 IP seemed to be effective when lymph node involvement was nil or limited to around the area of the stomach. The peritoneal recurrence rate was, however, not affected by OK-432 IP. Elevation of body temperature and some dehydration were the only observed side effects of OK-432. In attempts to control peritoneal recurrences in patients with gastric cancer invading the serosa, randomized controlled trials on OK-432 IP are now being designed.     

Prediction of Treatment Efficacy and Telaprevir-Resistant Variants after Triple Therapy in Patients Infected with Hepatitis C Virus Genotype 1

It is often difficult to predict the response to telaprevir-pegylated interferon (PEG-IFN)-ribavirin triple therapy and the appearance of telaprevir-resistant variants. The present study determined the predictive factors of a sustained virological response (SVR) to 12- or 24-week triple therapy (T12PR12 or T12PR24, respectively) in 194 Japanese patients infected with hepatitis C virus genotype 1b (HCV-1b). The study also evaluated whether ultradeep sequencing technology can predict at baseline the emergence of resistant variants after the start of therapy. Analysis of the data of the entire group indicated that an SVR was achieved in 78% of the patients. Multivariate analysis identified IL28B rs8099917 (genotype TT), the substitution of amino acid (aa) 70 (Arg70), response to prior treatment (naive or relapse), PEG-IFN dose (≥1.3 μg/kg of body weight), and treatment regimen (T12PR24) as significant determinants of SVR. Among patients of the T12PR24 group, 92% with genotype TT achieved an SVR, irrespective of a substitution at aa 70. In patients with the non-TT genotype, an SVR was achieved in 76% of those with Arg70, while only 14% of patients with the non-TT genotype, Gln70(His70), and nonresponse to ribavirin combination therapy achieved an SVR. Ultradeep sequencing was conducted for 17 patients who did not achieve an SVR to determine the emergence of resistant variants during therapy. De novo resistant variants were detected in 16 of 17 patients (94%), regardless of the variant frequencies detected at baseline. In conclusion, the results indicate that the response to triple therapy can be predicted by the combination of host, viral, and treatment factors and that it is difficult to predict at baseline the telaprevir-resistant variants that emerge during triple therapy, even with the use of ultradeep sequencing.