Long-term effects of low-intensity training with slow movement on motor function of elderly patients: a prospective observational study.

BACKGROUND: Slow-motion training, which comprises exercising using extremely slow-movements, yields a training effect like that of high-intensity training, even when the applied load is small. We developed a slow-training exercise program that allows elderly people to safely use their own body weight without a machine. Previously, it was confirmed that functional gait and lower limb muscle strength were improved by low-intensity training using bodyweight training for 3 months. This study evaluated the long-term effects of low-intensity training using body weight with slow-movements on the motor function of frail, elderly patients. METHODS: Ninety-six elderly men and women aged 65 years or older whose level of nursing care was classified as either support required (1 and 2) or long-term care required (care levels 1 and 2) volunteered to participate. Two facilities were used. Participants at the first facility used low-intensity training using body weight with slow-movements (low-stress training [LST] group, n = 65), and participants at another facility used machine training (MT group, n = 31). Exercise interventions were conducted for 12 months, once or twice per week, depending on the required level of nursing care. Changes in motor function were examined. RESULTS: Post-intervention measurements based on the results of the chair-stand test after 12 months showed significant improvements from pre-intervention levels (P < 0.0001) in the LST group and MT group. Although the ability of performing the Timed Up & Go test and the ability to stand on one leg with eyes open improved in both groups, no significant change was observed. When changes after 12 months were compared between the two groups, no significant difference was observed for any variables. CONCLUSIONS: Slow body weight training for 12 months without a machine improved the lower limb muscle strength. Therefore, it could have the same effects as training using a machine. TRIAL REGISTRATION: UMIN000030853 . Registered 17 January 2018 (retrospectively registered).

Pharmacokinetic and Pharmacodynamic Profiles of Glyco-Modified Atrial Natriuretic Peptide Derivatives Synthesized Using Chemo-enzymatic Synthesis Approaches.

Atrial natriuretic peptide (ANP) exerts beneficial pharmacological effects in the treatment of various cardiovascular disorders, such as acute congestive heart failure (ADHF). However, the clinical use of ANP is limited to the continuous intravenous infusion owing to its short half-life (2.4 ± 0.7 min). In the present study, we conjugated the glyco-modified ANP with a monoclonal antibody (mAb) or an Fc via chemo-enzymatic glyco-engineering using EndoS D233Q/Q303L. The most potent derivative SG-ANP-Fc conjugate extended the half-life to 14.9 d and the duration of blood pressure lowering effect to over 28 d. This new biologic modality provides an opportunity to develop outpatient therapy after ADHF.

Effects of low-intensity bodyweight training with slow movement on motor function in frail elderly patients: a prospective observational study.

BACKGROUND: Slow-motion training, an exercise marked by extremely slow movements, yields a training effect like that of a highly intense training, even when the applied load is small. This study evaluated the effects of low-intensity bodyweight training with slow movement on motor function in frail, elderly patients. METHODS: Ninety-seven elderly men and women aged 65 years or older, whose level of nursing care was classified as either support required (1 and 2) or long-term care required (care level 1 and 2), volunteered to participate. Two facilities were used. Participants in the first facility used low-intensity bodyweight training with slow movement (the LST group, n = 65), and participants in another facility used machine training (the control group, n = 31). Exercises were conducted for 3 months, once or twice a week, depending on the required level of nursing care. Changes in motor function were examined. RESULTS: Post-exercise measurements showed significant improvements from the pre-exercise levels after 3 months, based on the results of the Timed Up and Go test (p = 0.0263) and chair-stand test (p = 0.0016) in the low-intensity exercise with slow movement and tonic force generation (LST) group. Although the ability to stand on one leg with eyes open tended to improve, no significant change was found (p = 0.0964). CONCLUSIONS: We confirmed that carrying out LST bodyweight training for 3 months led to improvements in ambulatory function and lower-limb muscle strength. In this way, it is possible that LST training performed by holding a bar or by staying seated on a chair contributes to improved motor function in elderly patients within a short time. TRIAL REGISTRATION: UMIN000030853 . Registered 17 January 2018. (retrospectively registered).

Single-pixel digital holography with phase-encoded illumination.

We demonstrate imaging of complex amplitude objects through digital holography with phase-structured illumination and bucket detection. The object is sampled with a set of micro-structured phase patterns implemented onto a liquid-crystal spatial light modulator while a bucket detector sequentially records the irradiance fluctuations corresponding to the interference between object and reference beams. Our reconstruction algorithm retrieves the unknown phase information from the full set of photocurrent measurements. Interestingly, the sampling functions can be codified onto the reference beam, so they can be nonlocal with respect to the object. Finally, we show that the system is well-fitted for transmission of the object information through scattering media.

α-Glucosidase inhibitor miglitol attenuates glucose fluctuation, heart rate variability and sympathetic activity in patients with type 2 diabetes and acute coronary syndrome: a multicenter randomized controlled (MACS) study.

BACKGROUND: Little is known about clinical associations between glucose fluctuations including hypoglycemia, heart rate variability (HRV), and the activity of the sympathetic nervous system (SNS) in patients with acute phase of acute coronary syndrome (ACS). This pilot study aimed to evaluate the short-term effects of glucose fluctuations on HRV and SNS activity in type 2 diabetes mellitus (T2DM) patients with recent ACS. We also examined the effect of suppressing glucose fluctuations with miglitol on these variables. METHODS: This prospective, randomized, open-label, blinded-endpoint, multicenter, parallel-group comparative study included 39 T2DM patients with recent ACS, who were randomly assigned to either a miglitol group (n = 19) or a control group (n = 20). After initial 24-h Holter electrocardiogram (ECG) (Day 1), miglitol was commenced and another 24-h Holter ECG (Day 2) was recorded. In addition, continuous glucose monitoring (CGM) was performed throughout the Holter ECG. RESULTS: Although frequent episodes of subclinical hypoglycemia (≤4.44 mmo/L) during CGM were observed on Day 1 in the both groups (35% of patients in the control group and 31% in the miglitol group), glucose fluctuations were decreased and the minimum glucose level was increased with substantial reduction in the episodes of subclinical hypoglycemia to 7.7% in the miglitol group on Day 2. Holter ECG showed that the mean and maximum heart rate and mean LF/HF were increased on Day 2 in the control group, and these increases were attenuated by miglitol. When divided 24-h time periods into day-time (0700-1800 h), night-time (1800-0000 h), and bed-time (0000-0700 h), we found increased SNS activity during day-time, increased maximum heart rate during night-time, and glucose fluctuations during bed-time, which were attenuated by miglitol treatment. CONCLUSIONS: In T2DM patients with recent ACS, glucose fluctuations with subclinical hypoglycemia were associated with alterations of HRV and SNS activity, which were mitigated by miglitol, suggesting that these pathological relationships may be a residual therapeutic target in such patients. Trial registration Unique Trial Number, UMIN000005874 ( https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000006929 ).

Fast computer hologram generation by flexible-ratio adaptive point-spread spherical wave synthesis.

We propose a flexible-ratio adaptive point-spread spherical wave synthesis method for fast computer-generated hologram calculation. The conventional adaptive point-spread algorithm uses a fixed ratio between the major and minor axes of the point source, whereas the proposed method uses flexible-ratio sources, i.e., ellipses, for more effective calculation. Numerical simulation was conducted to validate the proposed method. The results show that the proposed method has the potential to achieve faster calculation, compared to the calculation in conventional methods, without significant image degradation.

Single-shot three-dimensional shape measurement by low-coherent optical path difference digital holography.

A single-shot three-dimensional (3D) shape measurement by low-coherent optical path difference digital holography with small energy consumption is proposed. The use of a superluminescent diode makes it possible. Weighting of the single hologram and numerical reconstruction give the 3D shape of an object. Experimental results using a simple object (the surface of a button cell battery) are given. By comparison with experimental results using a vertical scanning method, the proposed method is confirmed. The effects of a shift interval of the hologram and a zero-order component on a measurement result are also discussed.

Speckle reduction in holographic projection by random pixel separation with time multiplexing.

A speckle-reduction method with random locations of sparse object points is proposed for image quality improvement based on a time-multiplexing approach in holographic reconstruction. The object points of a reconstructed image are divided into groups of sparse object points. Pixel separation of the periodic location, in general, is used for the sparse object points. However, an unwanted periodic fringe pattern is caused, and it dominantly degrades the reconstructed image quality. The proposed random pixel separation enables the reconstructed image quality to improve more effectively. The numerical simulation and the optical experiment are presented to confirm the performance of the proposed method.

Application of polyimide films as a nuclear track detector (2): A latent track structure study with Fourier transform infrared spectroscopy.

This paper reports the relation between latent track structure and the detection threshold of etch pits formation in UPILEX-S® and Kapton. At the similar stopping power value, effective track core radii and G values for heavier ions are lower than those of lighter ions. These results would be due to the difference of the radial dose distribution for low- and high-velocity ions. The G value starts more rapidly rising above 600 and 1000 keV/µm for Kapton and UPILEX-S®, respectively. The detection threshold of UPILEX-S is 4000 keV/µm for Ar ions, at which effective track core radii of all functional groups are larger than 2 nm. Since the length of a molecule unit of UPILEX-S® is about 1.4 nm, at least more than two molecule units have to be damaged for the etch pit formation. A similar discussion is applicable to Kapton, whose detection threshold is significantly lower than UPILEX-S®.

Application of polyimide films as a nuclear track detector (1): A systematic study of track registration sensitivity.

This paper reports the variation of track registration sensitivity as a function of the stopping power of heavy ions in UPILEX-S® films, which is known as the most radiation tolerant polyimide (PI). The detection thresholds in the stopping power for etch pit formation are determined as 4,000, 4,100, 4,800, and 5600 keV/µm for 40Ar, 84Kr, 132Xe and 238U ions, respectively. Furthermore, we investigate the latent track structure in two kinds of PI films (UPILEX-S® and Kapton) by means of FT-IR spectroscopy. At the similar stopping power value, the radiation chemical yields (G value) for heavier ions are lower than those of lighter ions. This is due to the difference of the radial dose distribution for low and high velocity ions.

Synthesis and optimization of novel (3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as orally active renin inhibitors.

We report synthesis and optimization of a series of (3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as renin inhibitors. Chemical modification of P1', P2' and P3 portions led to a promising 3,5-disubstituted piperidine 32o showing high renin inhibitory activity and favorable oral exposure in both rats and cynomolgus monkeys with acceptable CYP and hERG current inhibition. Compound 32o exhibited a significant blood pressure lowering effect by oral administration in two hypertensive animal models, double transgenic rats and furosemide pretreated cynomolgus monkeys.

Synthesis method from low-coherence digital holograms for improvement of image quality in holographic display.

In holographic displays, it is undesirable to observe the speckle noises with the reconstructed images. A method for improvement of reconstructed image quality by synthesizing low-coherence digital holograms is proposed. It is possible to obtain speckleless reconstruction of holograms due to low-coherence digital holography. An image sensor records low-coherence digital holograms, and the holograms are synthesized by computational calculation. Two approaches, the threshold-processing and the picking-a-peak methods, are proposed in order to reduce random noise of low-coherence digital holograms. The reconstructed image quality by the proposed methods is compared with the case of high-coherence digital holography. Quantitative evaluation is given to confirm the proposed methods. In addition, the visual evaluation by 15 people is also shown.

Cellulosibacter alkalithermophilus gen. nov., sp. nov., an anaerobic alkalithermophilic, cellulolytic-xylanolytic bacterium isolated from soil of a coconut garden.

An obligately anaerobic, cellulolytic-xylanolytic bacterium, designated strain A6(T), was isolated from soil of a coconut garden in the Bangkuntien district of Bangkok, Thailand. The strain was Gram-stain positive, catalase-negative, endospore-forming, motile and rod-shaped with a cell size of 0.2-0.3×2.0-3.0 µm. Optimal growth of strain A6(T) occurred at pH(55 °C) 9.5, 55 °C. Strain A6(T) fermented various carbohydrates, and the end products from the fermentation of cellobiose were acetate, ethanol, propionate and a small amount of butyrate. The major cellular fatty acids were iso-C(14:0) 3-OH, iso-C(15:0), iso-C(16:0) and C(16:0). The cell-wall peptidoglycan contained meso-diaminopimelic acid. No respiratory quinones were detected. The DNA G+C content was 30.0 mol%. Phylogenetic analysis based on 16S rRNA gene sequences revealed that the strain represented a new phyletic sublineage within the family Clostridiaceae, with <93.0% 16S rRNA gene sequence similarity to recognized species of this family. On the basis of phenotypic, genotypic and physiological evidence, strain A6(T) represents a novel species of a new genus, for which the name Cellulosibacter alkalithermophilus gen. nov., sp. nov. is proposed. The type strain of the type species is A6(T) ( = TISTR 1915(T) = KCTC 5874(T)).

Design and discovery of new (3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]piperidine-3-carboxamides as potent renin inhibitors.

Utilizing X-ray crystal structure analysis, (3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]piperidine-3-carboxamides were designed and identified as renin inhibitors. The most potent compound 15 demonstrated favorable pharmacokinetic and pharmacodynamic profiles in rat.

Isolation and characterization of a new cellulosome-producing Clostridium thermocellum strain.

The anaerobic thermophilic bacterium, Clostridium thermocellum, is a potent cellulolytic microorganism that produces large extracellular multienzyme complexes called cellulosomes. To isolate C. thermocellum organisms that possess effective cellulose-degrading ability, new thermophilic cellulolytic strains were screened from more than 800 samples obtained mainly from agriculture residues in Thailand using microcrystalline cellulose as a carbon source. A new strain, C. thermocellum S14, having high cellulose-degrading ability was isolated from bagasse paper sludge. Cellulosomes prepared from S14 demonstrated faster degradation of microcrystalline cellulose, and 3.4- and 5.6-fold greater Avicelase activity than those from C. thermocellum ATCC27405 and JW20 (ATCC31449), respectively. Scanning electron microscopic analysis showed that S14 had unique cell surface features with few protuberances in contrast to the type strains. In addition, the cellulosome of S14 was resistant to inhibition by cellobiose that is a major end product of cellulose hydrolysis. Saccharification tests conducted using rice straw soaked with sodium hydroxide indicated the cellulosome of S14 released approximately 1.5-fold more total sugars compared to that of ATCC27405. This newly isolated S14 strain has the potential as an enzyme resource for effective lignocellulose degradation.

Unique "delta lock" structure of telmisartan is involved in its strongest binding affinity to angiotensin II type 1 receptor.

Angiotensin II type 1 receptor (AT1 receptor) blockers (ARBs) are one of the most popular anti-hypertensive agents. Control of blood pressure (BP) by ARBs is now a therapeutic target for the organ protection in patients with hypertension. Recent meta-analysis demonstrated the possibility that telmisartan was the strongest ARB for the reduction of BP in patients with essential hypertension. However, which molecular interactions of telmisartan with the AT1 receptor could explain its strongest BP lowering activity remains unclear. To address the issue, we constructed models for the interaction between commonly used ARBs and AT1 receptor and compared the docking model of telmisartan with that of other ARBs. Telmisartan has a unique binding mode to the AT1 receptor due to its distal benzimidazole portion. This unique portion could explain the highest molecular lipophilicity, the greatest volume distribution and the strongest binding affinity of telmisartan to AT1 receptor. Furthermore, telmisartan was found to firmly bind to the AT1 receptor through the unique "delta lock" structure. Our present study suggests that due to its "delta lock" structure, telmisartan may be superior to other ARBs in halting cardiovascular disease in patients with hypertension.

Direct ethanol production from cassava pulp using a surface-engineered yeast strain co-displaying two amylases, two cellulases, and ß-glucosidase.

In order to develop a method for producing fuel ethanol from cassava pulp using cell surface engineering (arming) technology, an arming yeast co-displaying α-amylase (α-AM), glucoamylase, endoglucanase, cellobiohydrase, and ß-glucosidase on the surface of the yeast cells was constructed. The novel yeast strain, possessing the activities of all enzymes, was able to produce ethanol directly from soluble starch, barley ß-glucan, and acid-treated Avicel. Cassava is a major crop in Southeast Asia and used mainly for starch production. In the starch manufacturing process, large amounts of solid wastes, called cassava pulp, are produced. The major components of cassava pulp are starch (approximately 60%) and cellulose fiber (approximately 30%). We attempted simultaneous saccharification and ethanol fermentation of cassava pulp with this arming yeast. During fermentation, ethanol concentration increased as the starch and cellulose fiber substrates contained in the cassava pulp decreased. The results clearly showed that the arming yeast was able to produce ethanol directly from cassava pulp without addition of any hydrolytic enzymes.

[Efficacy of a DPP-4 inhibitor as assessed by continuous glucose monitoring (CGM)].

During the course of treatment with a DPP-4 inhibitor, 24-hour glycemic variations were assessed by continuous glucose monitoring to evaluate the magnitude of postprandial glycemic excursions as well as nighttime/late-night glycemic variations. The DPP-4 inhibitor given alone or in combination with a sulfonylurea (SU) reduced not only the 24-hour mean glucose level as equivalent to the HbAlc value but also the SD of 288 glucose levels for 24 hour and the mean amplitude glucose excursions (MAGE). Particularly, the DPP-4 inhibitor, when given in addition to SU, produces not only additive reductions in mean glucose levels but also reductions in the magnitude of glycemic variations, while at the same time exhibiting the potential to serve as a glucose modulator in low glucose levels. Furthermore, while monotherapy with a DPP-4 inhibitor improves postprandial hyperglycemia, combination therapy with a DPP-4 inhibitor and an alphaglucosidase inhibitor leads to additive improvements in postprandial hyperglycemia, thus exhibiting the potential to flatten the 24-hour glycemic variations. In summary, when assessed for its effects on 24-hour glycemic variations, the DPP-4 inhibitor produces reductions not only in the 24-hour mean glucose level but also in the magnitude of glycemic excursions, thus likely representing a new type of anti-diabetic agent that combines the merits of an SU, which potently lowers HbAlc primarily by reducing fasting glucose levels, and an alpha-glucosidase inhibitor, which reduces the magnitude of glycemic variations primarily by lowering postprandial glucose levels.

[Exploring an optimal approach to the use of oral hypoglycemic agents based on CGM results: implications for combination therapy with oral hypoglycemic agents].

In the treatment of type 2 diabetes aimed at prevention of cardiovascular events impacting the prognosis of affected patients, it is critically important not only to lower HbAlc values but to find a way to improve postprandial hyperglycemia without causing hypoglycemia thus minimizing drastic glycemic variations or to maintain favorable glycemic control with daily glycemic variations in mind. In other words, it is no longer adequate to emphasize quantitative reductions in HbAlc as in conventional therapeutic approaches but qualitative glycemic control that takes daily glycemic variations into account is becoming of increasing importance to the management of type 2 diabetes. On the other hand, the 6 oral hypoglycemic agent (OHA) classes currently available for clinical use, i.e., biguanides (BGs), thiazolidinediones (TZDs), alpha-glucosidase inhibitors, sulfonylureas (SUs), fast-acting insulin secretagogues (glinides) and DPP-4 inhibitors, appear to vary from class to class or even from agent from agent within a class in regard to their impact on daily glycemic variations. In our CMG-based study of their impact on glycemic variations, it was demonstrated that BGs and TZDs improve hyperglycemia during nighttime and before breakfast more effectively than they do postprandial glycemic excursions; that, of the insulin secretagogues, glinides reduce daily glycemic variations as do alpha-glucosidase inhibitors, while SUs do not affect them very much; and that DPP-4 inhibitors lower not only mean glucose levels which are deemed equivalent to HbAlc values but also narrow the range of glycemic variations. Thus, OHAs can be broadly classified into those that primarily reduce 24-hour mean glucose levels as equivalent to HbAlc values and those that primarily narrow the range of glycemic variations. Therefore, with either of these agents as monotherapy, it is next to impossible to achieve reductions in HbAlc with a narrow range of glycemic variations, and combination therapy appears to be the only option available to fine-tune glycemic control. In other words, combining an agent that primarily reduces 24-hour mean glucose levels (HbAlc) with another that primarily narrows the range of daily glycemic variations appears to be an extremely useful option in achieving high-quality glycemic control (HbA1c reductions with a narrow range of glycemic variations).

Purification and characterization of a multienzyme complex produced by Paenibacillus curdlanolyticus B-6.

Paenibacillus curdlanolyticus B-6 showed effective degradation activities for xylan and cellulose and produced an extracellular multienzyme complex (approximately 1,450 kDa) containing several xylanases and cellulases. To characterize the multienzyme complex, we purified the complex from culture supernatants by four kind of chromatography. The purified multienzyme complex was composed of a 280-kDa protein with xylanase activity, a 260-kDa protein that was a truncated form on the C-terminal side of the 280-kDa protein, two xylanases of 40 and 48 kDa, and 60 and 65 kDa proteins having both xylanase and carboxymethyl cellulase activities. The 280-kDa protein resembled the scaffolding proteins of cellulosomes based on its migratory behavior in polyacrylamide gels and as a glycoprotein. Cloning of the 40-kDa major xylanase subunit named Xyn11A revealed that Xyn11A contained two functional domains which belonged to glycosyl hydrolase family-11 and to carbohydrate-binding module family-36, respectively, and a glycine- and asparagine-rich linker. However, an amino acid sequence similar to a dockerin domain, which is crucial to cellulosome assembly, was not found in Xyn11A. These results suggest that the multienzyme complex produced by P. curdlanolyticus B-6 should assemble by a mechanism distinct from the cohesin-dockerin interactions known in cellulosomes.