Objective:
Novel recombinant human lysosomal β‐hexosaminidase A (HexA) was developed for enzyme replacement therapy (ERT) for Tay‐Sachs and Sandhoff diseases, ie, autosomal recessive GM2 ...gangliosidoses, caused by HexA deficiency.
Methods:
A recombinant human HexA (Om4HexA) with a high mannose 6‐phosphate (M6P)‐type‐N‐glycan content, which was produced by a methylotrophic yeast strain, Ogataea minuta, overexpressing the OmMNN4 gene, was intracerebroventricularly (ICV) administered to Sandhoff disease model mice (Hexb−/− mice) at different doses (0.5–2.5mg/kg), and then the replacement and therapeutic effects were examined.
Results:
The Om4HexA was widely distributed across the ependymal cell layer, dose‐dependently restored the enzyme activity due to uptake via cell surface cation‐independent M6P receptor (CI‐M6PR) on neural cells, and reduced substrates, including GM2 ganglioside (GM2), asialo GM2 (GA2), and oligosaccharides with terminal N‐acetylglucosamine residues (GlcNAc‐oligosaccharides), accumulated in brain parenchyma. A significant inhibition of chemokine macrophage inflammatory protein‐1 α (MIP‐1α) induction was also revealed, especially in the hindbrain (<63%). The decrease in central neural storage correlated with an improvement of motor dysfunction as well as prolongation of the lifespan.
Interpretation:
This lysosome‐directed recombinant human enzyme drug derived from methylotrophic yeast has the high therapeutic potential to improve the motor dysfunction and quality of life of the lysosomal storage diseases (LSDs) patients with neurological manifestations. We emphasize the importance of neural cell surface M6P receptor as a delivery target of neural cell‐directed enzyme replacement therapy (NCDERT) for neurodegenerative metabolic diseases. ANN NEUROL 2010
Background: Colestimide has been reported to lower blood glucose levels in patients with type 2 diabetes complicated by hypercholesterolemia. Aim: To examine the mechanism by which colestimide ...decreases plasma glucose levels in the above patients. Methods: A total of 16 inpatients with type 2 diabetes complicated by hypercholesterolemia received colestimide for 1 week after their plasma glucose levels stabilized. We measured plasma glucose, serum immunoreactive insulin (IRI), serum lipid, plasma glucagon, and plasma glucagon-like peptide-1 (GLP-1) levels. These variables at baseline and 1 week of colestimide administration were compared. Results: Preprandial plasma glucose levels (baseline: 132 ± 33 mg/dL vs. completion: 118 ± 43 mg/dL, P=0.073) tended to decrease after colestimide administration, while 1-hr postprandial plasma glucose levels (baseline: 208 ± 49 mg/dL vs. completion: 166 ± 30 mg/dL, P<0.001) and 2-hr postprandial plasma glucose levels (baseline: 209 ± 56 mg/dL vs. completion: 178 ± 39 mg/dL, P=0.015) decreased significantly at 1 week of colestimide administration. The 2-hr postprandial plasma GLP-1 level was significantly (P=0.015) higher at 1 week of colestimide administration as compared with the baseline level, while there were no significant changes in preprandial and 1-hr postprandial plasma GLP-1 levels. Conclusions: The GLP-1-increasing activity of colestimide may explain, at least in part, the mechanism of its blood glucose-lowering activity in patients with type 2 diabetes complicated by hypercholesterolemia.
Aim: The aim of this study was to evaluate the difference in daily blood glucose profiles between once‐ and twice‐daily regimens of a moderate daily dose of glibenclamide or gliclazide in elderly ...patients with type 2 diabetes.
Methods: Daily blood glucose profile data were evaluated in 18 elderly type 2 diabetic patients treated with 80 mg/day gliclazide or 5 mg/day glibenclamide as monotherapy. The first daily blood glucose profile of the twice‐daily regimen was performed approximately 1 week before hospital discharge, and the second was performed after taking a once‐daily regimen for 4–7 days. Plasma glucose and plasma immunoreactive insulin (IRI) concentrations were measured daily at 12 time points: 08.00 (before breakfast); 10.00; 12.00 (before lunch); 14.00; 18.00 (before dinner); 20.00; 0.00; 02.00; 03.00; 04.00; 06.00; and 08.00 hours the next morning.
Results: Daily blood glucose profiles and plasma IRI profiles did not differ between the once‐ and twice‐daily regimen groups in either the gliclazide group or the glibenclamide group. Plasma glucose values between midnight and early morning tended to be lower than the 08.00 hours plasma glucose value in the glibenclamide group, but not in the gliclazide group.
Conclusion: These results suggest that the blood glucose‐lowering effects of a once‐ and twice‐daily moderate daily dose of glibenclamide or gliclazide do not differ in elderly type 2 diabetic patients. However, glibenclamide, regardless of the dosage schedule, tends to lower the plasma glucose values between midnight and early morning.
Background: The present study sought to investigate the relationship between asymptomatic leukocyturia (ASL) and autonomic nervous function by power spectral analysis of the R‐R intervals in women.
...Methods: One hundred and forty‐two female outpatients aged 23–91 years were studied. We regarded ASL to be present if two consecutive samples were found to have 10 or more leukocytes/high‐power field at ×400 magnification in a centrifuged midstream urine sample. The R‐R intervals of all subjects were measured by the wavelet transform analysis system. This system detected R‐R variation data distributed in two bands: low‐frequency power (LF) (0.04–0.15 Hz) and high‐frequency power (HF) (0.15–0.40 Hz). The ratio of LF to HF (LF/HF) was also determined. Post‐void residual urine volume was measured using an automated, compact 3‐D ultrasound device.
Results: The patients with ASL had diabetes mellitus more frequently than those without ASL. Residual urine volume was significantly higher in the former than in the latter, while the HF values in both a recumbent position and a standing position were significantly lower in the former than in the latter (P = 0.003, P = 0.001, respectively). However, there were no significant differences in LF or LF/HF values in either a recumbent or a standing position between the two groups. The HF values in both a recumbent position and in a standing position were independent indicators of ASL, even after adjustment for age, diabetes mellitus and residual urine volume.
Conclusion: The present study reveals the relationship between ASL and impairment of the parasympathetic nervous system in women.
Background: Colestimide has been reported to lower blood glucose levels in patients with type 2 diabetes complicated by hypercholesterolemia. Aim: To examine the mechanism by which colestimide ...decreases plasma glucose levels in the above patients. Methods: A total of 16 inpatients with type 2 diabetes complicated by hypercholesterolemia received colestimide for 1 week after their plasma glucose levels stabilized. We measured plasma glucose, serum immunoreactive insulin (IRI), serum lipid, plasma glucagon, and plasma glucagon-like peptide-1 (GLP-1) levels. These variables at baseline and 1 week of colestimide administration were compared. Results: Preprandial plasma glucose levels (baseline:132±33mg/dL vs. completion:118±43mg/dL, P=0.073) tended to decrease after colestimide administration, while 1-hr postprandial plasma glucose levels (baseline:208±49mg/dL vs. completion:166±30mg/dL, P<0.001) and 2-hr postprandial plasma glucose levels (baseline:209±56mg/dL vs. completion:178±39mg/dL, P=0.015) decreased significantly at 1 week of colestimide administration. The 2-hr postprandial plasma GLP-1 level was significantly (P=0.015) higher at 1 week of colestimide administration as compared with the baseline level, while there were no significant changes in preprandial and 1-hr postprandial plasma GLP-1 levels. Conclusions: The GLP-1-increasing activity of colestimide may explain, at least in part, the mechanism of its blood glucose-lowering activity in patients with type 2 diabetes complicated by hypercholesterolemia.
Abstract: Purpose: The purpose of this study is to clarify the needs of nursing students for mutual support in their academic activities, and to examine the feasibility of mutual support by ...implementing and evaluating the "Consultation on practical training by senior students".Method: An anonymous online survey was conducted with first- to fourth-year students majoring in nursing at University A. The survey asked students whether they were experiencing difficulties in five categories of learning activity, namely, preparing for the National Nurse Licensure Examination, job-seeking, on-site training, preparing for examinations, and course registration. Students were also surveyed regarding their need for mutual supports in relation to these learning activities and whether they wanted to become a learning advisor to provide such support. In addition, we analyzed the evaluations and impressions of students who participated in the "Consultation on practical training by senior students".Results: Responses from 115 students were analyzed (valid response rate: 36.0%). A high percentage of students (89.6%) responded that they needed support from other students in relation to preparing for the national examination and job seeking. In contrast, low percentages of students expressed a desire to become a learning advisor to support with either of these categories of activity (48.7% and 47.8%, respectively).Discussion: The results suggest that it is important to provide support among students involved in career development from the first grade. In addition to support from seniors, it was also indicated that it is necessary to utilize mutual support among classmates.
Background
We recently demonstrated that cascade stomach detected by barium studies was correlated with upper gastrointestinal symptoms. We developed a new endoscopic classification of cascade ...stomach and examined its relationship with reflux esophagitis.
Methods
Study 1: the classification (grades 0–3) was based on detecting a ridge that runs from the cardia toward the anterior wall crossing the greater curvature. Inter-observer variation was evaluated by kappa statistics when ten experienced endoscopists used this classification three times each. Study 2: in 710 consecutive subjects (500 men and 210 women) undergoing endoscopic screening, the grade of cascade stomach and incidence of reflux esophagitis were compared.
Results
In study 1, the kappa values at the third assessment were 0.85, 0.58, 0.50, and 0.78 for each grade, respectively, while overall agreement was 0.68. In study 2, the incidence of reflux esophagitis in men was 20 % in grade 0, 17 % in grade 1, 25 % in grade 2, and 30 % in grade 3, showing significant differences. Among women, the incidence of reflux esophagitis in each grade was 9, 3, 6, and 35 %, respectively, also showing significant differences. Multivariate analysis showed that independent risk factors for reflux esophagitis were cascade stomach (odds ratio = 2.20), body mass index, and hiatus hernia in men, as well as cascade stomach (odds ratio = 9.01) and smoking tobacco in women.
Conclusions
This endoscopic classification of cascade stomach showed acceptable inter-observer variation. Cascade stomach is a risk factor for reflux esophagitis.
Amazake is a traditional Japanese beverage. Its main ingredients are sake cake and rice malt. In this study, we examined the effect of sake cake and rice malt on the intestinal barrier function and ...gut microbiota. BALB/c mice were fed a control diet or a diet containing a mixture of sake cake and rice malt powder (SRP) for four weeks. Fecal IgA values did not change between groups, but the fecal mucin level was significantly greater in the SRP-fed group. Gene expression analysis in the ileum by real-time PCR demonstrated
expression did not change, while the
expression was upregulated in the SRP-fed group. Furthermore, microbiota analysis demonstrated a change by SRP intake at the family level, and the proportion of
significantly increased in the SRP-fed group. At the genus level, the proportion of
also significantly increased in the SRP-fed group. These results suggest that the intake of a mixture of sake cake and rice malt improves intestinal barrier function by increasing mucin levels and inducing changes in intestinal microbiota.
The present study aims to understand the effects of interindividual differences in thermal comfort on the relationship between the preferred temperature and the thermoregulatory responses to ambient ...cooling. Thirteen young women subjects chose the preferred ambient temperature (preferred
T
a) in a climate chamber and were categorized into the H group (preferring ≥29
°C;
n=6) and the M group (preferring <29
°C;
n=7). The H group preferred warmer sensations than the M group (
P<0.05) and the average of preferred
T
a was 27.6
°C and 30.2
°C in the M group and H group, respectively. Then all subjects were exposed to temperature variations in the climate chamber. During
T
a variations from 33
°C to 25
°C, the H group felt colder than the M group, although no difference was noted in the
T
sk (mean skin temperature) and
T
s-hand between the 2 groups. From the view of the relationship between the
T
sk and thermal sensation, although the thermal sensitivity to the
T
sk was almost similar in the H and M groups, the H group might have lower threshold to decreasing
T
a than the M group.
► We measured the thermoregulatory responses to ambient cooling. ► Subjects were the young females who preferred high (H group) and medium (M group) temperature. ► During decreasing temperature, no difference was noted in the mean skin temperature. ► However, the H group felt colder than the M group. ► Sensory threshold to temperature variations differ in M and H groups.
N-terminal truncation of the Escherichia coli ethanolamine ammonia-lyase β-subunit does not affect the catalytic properties of the enzyme (Akita, K., Hieda, N., Baba, N., Kawaguchi, S., Sakamoto, H., ...Nakanishi, Y., Yamanishi, M., Mori, K., and Toraya, T. (2010) J. Biochem. 147, 83–93). The binary complex of the truncated enzyme with cyanocobalamin and the ternary complex with cyanocobalamin or adeninylpentylcobalamin and substrates were crystallized, and their x-ray structures were analyzed. The enzyme exists as a trimer of the (αβ)2 dimer. The active site is in the (β/α)8 barrel of the α-subunit; the β-subunit covers the lower part of the cobalamin that is bound in the interface of the α- and β-subunits. The structure complexed with adeninylpentylcobalamin revealed the presence of an adenine ring-binding pocket in the enzyme that accommodates the adenine moiety through a hydrogen bond network. The substrate is bound by six hydrogen bonds with active-site residues. Argα160 contributes to substrate binding most likely by hydrogen bonding with the O1 atom. The modeling study implies that marked angular strains and tensile forces induced by tight enzyme-coenzyme interactions are responsible for breaking the coenzyme Co–C bond. The coenzyme adenosyl radical in the productive conformation was modeled by superimposing its adenine ring on the adenine ring-binding site followed by ribosyl rotation around the N-glycosidic bond. A major structural change upon substrate binding was not observed with this particular enzyme. Gluα287, one of the substrate-binding residues, has a direct contact with the ribose group of the modeled adenosylcobalamin, which may contribute to the substrate-induced additional labilization of the Co–C bond.
PDF
