Effectiveness of insulin degludec/liraglutide versus insulin degludec/insulin aspart in Japanese patients with type 2 diabetes.

Aims: To evaluate and compare the effectiveness of once-daily insulin degludec/liraglutide (IDegLira) to that of once-daily insulin degludec/insulin aspart (IDegAsp) after switching from basal insulin therapy at 6 months by assessing changes in hemoglobin A1c (HbA1c), body weight, and insulin doses in patients with type 2 diabetes (T2D). Materials and methods: A total of 91 patients with T2D with HbA1c levels exceeding 7.0% were included in this study. Adjusted least square mean changes in HbA1c, body weight, and total insulin doses were compared between the IDegLira group and IDegAsp group. Subgroup analyses were performed, stratified by median values of HbA1c (< 8.5 and ≥ 8.5%), obesity (body mass index < 25 and ≥ 25 kg/m2), and basal insulin doses (< 14 and ≥ 14 units) at baseline to assess treatment interaction by subgroup. Results: The IDegLira group showed a greater reduction in HbA1c levels than the IDegAsp group (- 0.17 vs - 0.79%, p = 0.003) with comparable body weight changes. The analyses of adjusted mean changes of total insulin doses showed that the IDegAsp group had a larger increase than the IDegLira group (3.64 vs 1.30 unis, p = 0.016). The effect of IDegLira on HbA1c levels was superior to that of IDegAsp in patients with high HbA1c. There were no inter-group differences in the rate of hypoglycemic episodes. Conclusions: Once-daily IDegLira had greater effects on HbA1c and a lesser increase in insulin doses than IDegAsp when patients are switched from basal insulin therapy. Moreover, the effect on HbA1c was enhanced in patients with high HbA1c levels at baseline.

Carbon and nitrogen stable isotopic offsets between diet and hair/feces in captive orangutans.

Estimating stable isotopic offset values is crucial for dietary reconstructions. Although research into stable isotope ecology of wild nonhuman primates is increasing overall, only a minority of studies involve laboratory experiments. This study is the first to report the carbon and nitrogen stable isotopic offset values in hair and feces of orangutans. During an experiment lasting 1 week, the weight of each consumed food item was recorded for each of six captive Bornean orangutan (Pongo pygmaeus) individuals. The food, hair, and fecal samples were collected for a few days, and their stable carbon and nitrogen isotope ratios were measured using an elemental analyzer/isotope ratio mass spectrometer. Subsamples of feces were treated with ethanol during the preservation process. Monte Carlo analyses showed that the 95% confidence intervals (CIs) of the carbon and nitrogen offset values between hair and diet were +0.9‰ to +3.9‰ and +2.3‰ to +4.5‰, respectively. The 95% CIs of the carbon and nitrogen offset values between feces and diet were -3.7‰ to -0.9‰ and +0.3‰ to +2.7‰, respectively. The effect of ethanol treatment on the stable isotope ratios of feces was unclear and inconclusive. The computed offset values of hair in captive orangutans are similar to those reported in other nonhuman primates, although those of feces showed greater interspecies variations. The offset values estimated in this study contribute to isotopic studies into the feeding ecology of free-ranging orangutans who are critically endangered in most wild settings.

Differential effects of sodium-glucose cotransporter 2 inhibitor and low-carbohydrate diet on body composition and metabolic profile in obese diabetic db/db mice.

INTRODUCTION: Treatment using sodium-glucose cotransporter (SGLT) 2 inhibitor and low-carbohydrate diet (LCD) for obesity and type 2 diabetes are similar in terms of carbohydrate limitation. However, their mechanisms of action differ, and the effects on the body remain unclear. We investigated the effects of SGLT2 inhibitor and LCD on body composition and metabolic profile using the db/db mouse model for obesity and type 2 diabetes. RESEARCH DESIGN AND METHODS: Eight-week-old male db/db mice were divided into four groups: mice receiving normal diet and vehicle or canagliflozin (Cana) administration and mice receiving LCD and vehicle or Cana administration for 8 weeks. Consumed calories were adjusted to be equal among the groups. RESULTS: Both Cana administration and LCD feeding resulted in significant weight gain. Cana administration significantly decreased plasma glucose levels and increased plasma insulin levels with preservation of pancreatic ß cells. However, LCD feeding did not improve plasma glucose levels but deteriorated insulin sensitivity. LCD feeding significantly reduced liver weight and hepatic triglyceride content; these effects were not observed with Cana administration. Combined treatment with LCD did not lead to an additive increase in blood ß-ketone levels. CONCLUSIONS: SGLT2 inhibitors and LCD exert differential effects on the body. Their combined use may achieve better metabolic improvements in obesity and type 2 diabetes.

Gynaecological diagnosis by ultrasound and the measurement of urinary sex steroid hormones in female orangutans.

Gynaecological diagnoses were carried in three adult female orangutans (Pongo spp.) using ultrasound, and their estrous states were estimated by measuring urinary sex steroid hormone concentrations using enzyme immunoassay. Ultrasound diagnosis revealed that the endometrial thickness and follicle size were correlated with the oestrogen-3-glucuronide concentrations in the follicular phase. In addition, administration of the ovulation inducer human chorionic gonadotropin (hCG) had the strongest effect on the pregnanediol-3-glucuronide (PdG) concentration when the follicle size was 22.3 mm, suggesting that the follicle reaches this size before ovulation. The similarity between this and the maximum ovarian follicle size in humans (approximately 20 mm) indicates that the ancestral reproductive characteristics may have been retained in these species.

The Effects of the Environment on the Drawings of an Extraordinarily Productive Orangutan (Pongo pygmaeus) Artist.

We report on the case of an extraordinary orangutan who spontaneously produced over a thousand drawings in 5 years. This female orangutan, Molly, started drawing when she was estimated to be 50 years old. Although it has been established that great apes spontaneously draw without training, she produced an enormous number of paintings in her old age, and the numbers of lines and colors in her drawings varied from day to day. As her drawings seemed to be affected by her surroundings, we attempted to analyze quantitatively relationships between her drawings and potentially influential factors during a specific period in which no ostensibly major events were observed. According to our results, her drawings were affected by the identity of her keeper, implying that her drawing behavior may have been affected by environmental factors. Thus, drawings may serve as windows to the internal states of non-human primates.

Orangutans (Pongo pygmaeus) recognize their own past actions.

The ability to recognize oneself in a mirror is known as self-recognition, whereas delayed self-recognition is the ability to recognize the relationship between current self and past actions. While 3-year-old human children have self-recognition without the ability for delayed self-recognition, 4-year-old human children demonstrate the capability for both. Chimpanzees, the most closely related species to humans, have displayed the ability for delayed self-recognition. However, little is known about whether this ability is shared among all hominid species. In this study, we examined whether orangutans, the most distantly related species to humans within the hominid group, could recognize their own past actions using the preferential-looking paradigm. Our results demonstrated that orangutans were able to discriminate between a delayed video of themselves presented after a 2-s delay and a recorded video of the day prior. This suggests that orangutans have the ability to relate their own past actions to current actions, although we found no evidence of self-directed behaviour. We believe these findings will contribute to our growing understanding of hominid self-recognition.

Urinary sex steroid hormone and placental leucine aminopeptidase concentration differences between live births and stillbirth of Bornean orangutans (Pongo pygmaeus).

BACKGROUND: Under the environment of pregnancy, the placenta assumes an important steroidogenic role in the maintenance of pregnancy. METHODS: Urinary placental leucine aminopeptidase (PLAP), estrone-3-glucuronide (E1 G), and pregnanediol-3-glucuronide (PdG) concentrations were compared among five pregnancies (four live births and one stillbirth) in four orangutans. RESULTS: The gestation period of the stillbirth (223 days) was shorter than that of the live births (239-254 days). In females who gave a live birth, average PLAP and E1 G concentrations increased until the delivery. Conversely, in the female who gave a stillbirth, PLAP concentration failed to increase, and E1 G concentration was significantly low in late pregnancy period. Regarding PdG concentrations, there was no significant difference among all pregnancies. CONCLUSIONS: This is the first study reporting a change in urinary PLAP, E1 G, and PdG concentrations during orangutan stillbirth and live birth pregnancies. The findings will assist in developing pregnancy screening tests.

The blood glucose level increased in parallel with the heart rate following cilostazol administration in three diabetic patients.

Cilostazol, a phosphodiesterase III inhibitor, is known to increase the heart rate; however, its effects on glucose metabolism remain unclear. We observed that the blood glucose level varied in parallel with the heart rate immediately after starting or stopping cilostazol therapy in three patients with type 2 diabetes. This finding indicates that cilostazol induces hyperglycemia and tachycardia in a portion of diabetic patients, presumably via similar pharmacological effects on different organs. Much more attention should be paid to the possible effects of cilostazol on glycemic control, including taking into consideration the risk-benefit ratio of cilostazol use and individual circumstances.

Human RGM249-derived small RNAs potentially regulate tumor malignancy.

The human noncoding RNA gene RGM249 has been shown to regulate the degree of cancer cell differentiation. In this study, we investigated the effects of 3 microRNA-like molecules digested from RGM249 on the loss of malignant properties in cancer cells in immunodeficient KSN/Slc mice. We utilized small interfering RNAs (siRNAs) alone or in combination with a cationized drug delivery system (DDS) consisting of atelocollagen or gelatin hydrogel microspheres. The results demonstrated growth inhibition and apoptosis and the inhibition of both neovascularization and metastasis, indicating that the DDSs effectively infiltrated the majority of tumor cells in vivo. Systemic administration of the 3 siRNAs inhibited the metastatic ability of malignant cells. Cotransfection of these siRNAs exerted a regulatory effect upon the genes involved in differentiation, pluripotency, and proliferation in cancer cells. These results suggest that RGM249-derived oligonucleotides may be involved in the regulation of metastasis, proliferation, and differentiation in vivo, and that the tested siRNAs may therefore represent a new anticancer therapeutic approach.

[Diagnosis of mild hemophilia A made by massive intraabdominal bleeding in a 13-year-old boy].

We report a 13-year-old boy who had massive intra-abdominal bleeding without a history of bleeding episodes or traumatic cause of bleeding. The patient underwent surgical treatment because bleeding was not controlled after treatment with tranexamic acid and transfusions including fresh-frozen plasma. Bleeding was traced to the lower left lobe of the liver. The mother's side of the family had a history of bleeding episodes in the boy's grandfather, great uncle, and son of a great aunt. A low level of plasma factor VIII coagulant activity (22%) led to a diagnosis of mild hemophilia A. Compared with severe hemophilia, mild hemophilia is more difficult to diagnose because bleeding episodes are less frequent. Most cases are found after incidental trauma or uncontrolled surgery-related bleeding, there is rarely a family history of hemophilia and activated partial thromboplastin time is normal or slightly prolonged. However, bleeding episodes in mild hemophilia may result in excessive, sometimes life-threatening hemorrhage and require early diagnosis and replacement treatment with adequate amounts of factor VIII, as in severe hemophilia.

Visual discrimination in an orangutan (Pongo pygmaeus): measuring visual preference.

Although previous studies have confirmed that trained orangutans visually discriminate between mammals and artificial objects, whether orangutans without operant conditioning can discriminate remains unknown. The visual discrimination ability in an orangutan (Pongo pygmaeus) with no experience in operant learning was examined using measures of visual preference. Sixteen color photographs of inanimate objects and of mammals with four legs were randomly presented to an orangutan. The results showed that the mean looking time at photographs of mammals with four legs was longer than that for inanimate objects, suggesting that the orangutan discriminated mammals with four legs from inanimate objects. The results implied that orangutans who have not experienced operant conditioning may possess the ability to discriminate visually.

Retinoic acid receptor antagonist LE540 attenuates wakefulness via the dopamine D1 receptor in mice.

Vitamin A is a common lipophilic vitamin, and its function is mainly mediated by the binding of its metabolite retinoic acid to retinoic acid receptors (RARs) and retinoid X receptors. Recently, it was reported that the expression of the RARb (an RAR subtype) gene determines the contribution of the delta oscillation in the sleep electroencephalogram (EEG) patterns in mice. We also reported that 4-week dietary deficiency of vitamin A (VAD) causes the attenuation of delta power in sleep and spontaneous activity in mice. However, our previous study could not clarify whether the attenuation of delta power by VAD is attributed to the suppression of RARs. To address this problem, we investigated whether the chronic administration of LE540 (30mg/kg/day), an antagonist of RARs, for 1 or 4weeks attenuated EEG delta power during sleep in mice. Consequently, 4-week LE540 administration induced a significant attenuation of wakefulness and delta power in non-rapid eye movement sleep. Western blot analysis revealed a significant decrease in the expression of dopamine D1 receptor (D1DR) in the striatum and tyrosine hydroxylase in the midbrain of mice that were administered LE540 for 4weeks. High-performance liquid chromatography analysis of striatal tissue revealed a significant decrease in the homovanillic acid/dopamine ratio. Meanwhile, dopamine levels did not change in these mice. Our results suggest that the 4-week antagonism of RARs induces the attenuation of delta power. However, the attenuation of delta power may be elicited indirectly by the decrease of wakefulness followed by the hypo-expression of dopamine receptors especially D1DR.

A noncoding RNA gene on chromosome 10p15.3 may function upstream of hTERT.

BACKGROUND: We attempted to clone candidate genes on 10p 14-15 which may regulate hTERT expression, through exon trapping using 3 BAC clones covering the region. After obtaining 20 exons, we examined the function of RGM249 (RGM: RNA gene for miRNAs) we cloned from primary cultured human hepatocytes and hepatoma cell lines. We confirmed approximately 20 bp products digested by Dicer, and investigated the function of this cloned gene and its involvement in hTERT expression by transfecting the hepatoma cell lines with full-length dsRNA, gene-specific designed siRNA, and shRNA-generating plasmid. RESULTS: RGM249 showed cancer-dominant intense expression similar to hTERT in cancer cell lines, whereas very weak expression was evident in human primary hepatocytes without telomerase activity. This gene was predicted to be a noncoding precursor RNA gene. Interestingly, RGM249 dsRNA, siRNA, and shRNA inhibited more than 80% of hTERT mRNA expression. In contrast, primary cultured cells overexpressing the gene showed no significant change in hTERT mRNA expression; the overexpression of the gene strongly suppressed hTERT mRNA in poorly differentiated cells. CONCLUSION: These findings indicate that RGM249 might be a microRNA precursor gene involved in the differentiation and function upstream of hTERT.

Clinical impact of serum transforming growth factor-alpha mRNA as a predictive biomarker for the prognosis of fulminant hepatitis.

PURPOSE: We previously reported that measuring serum telomerase reverse transcriptase (hTERT) mRNA with a quantitative, one-step, real-time RT-PCR was superior to conventional tumor markers for hepatocellular carcinoma and lung cancer. Here, we examined serum regeneration-related mRNA detection as a biomarker for fulminant hepatitis (FH). METHODS: In 53 patients, including 17 patients with acute hepatitis (AH), seven with severe hepatitis (SH), four with late-onset hepatic failure (LOHF), and 25 with FH, we measured serum mRNA levels of hTERT, hepatocyte growth factor (HGF), hepatocyte growth factor receptor (c-met), epidermal growth factor receptor (EGFR), and transforming growth factor-alpha (TGF-alpha). We examined the sensitivity and specificity of the technique in FH diagnosis as well as its clinical and prognostic significance compared with other clinical and prognostic tests. RESULTS: Serum copy number of TGF-alpha mRNA in FH on admission was significantly smaller than in AH and SH. In FH, TGF-alpha mRNA level was 10(6)-fold higher in survivors than in patients who died or received liver transplants (P = 0.034), although these patients were not discriminated by other clinical parameters. The sensitivity/specificity for prognosis in FH was 74.3/65.5% for TGF-alpha mRNA. Of four prognostic scoring systems, only logit-lambda was useful for prognosis assessment. CONCLUSIONS: TGF-alpha mRNA is an early predictor of FH outcome and a sensitive biomarker of lower regenerative liver capacity. This assay could help facilitate early therapy choice, such as liver transplantation.