Habitual isomaltulose intake reduces arterial stiffness associated with postprandial hyperglycemia in middle-aged and elderly people: a randomized controlled trial.

Endothelin-1 (ET-1), produced by vascular endothelial cells, plays a pivotal role in the regulation of vascular tone. Isomaltulose, a naturally occurring sweetener and structural isomer of sucrose, reduces postprandial hyperglycemia, but its effect on arteriosclerosis due to hyperglycemia is unknown. The effects of 12 weeks of isomaltulose administration on ET-1 levels, a peptide that regulates arterial stiffness, blood pressure, and vascular tone, were tested before and after an oral glucose tolerance test. Fifty-four healthy middle-aged and older adults (30 men and 24 women) were divided into two groups: (1) a 25 g isomaltulose jelly drink intake group (Group I, 27 participants, mean age 55 ± 1 years) and (2) a sucrose jelly drink intake group (Group S, 27 participants, mean age 55 ± 1 years), each consuming isomaltulose or sucrose daily for 12 weeks, and a randomized, controlled study was conducted. Participants visited the laboratory before the intervention and 4, 8, and 12 weeks after the intervention to measure carotid-femoral (cf) and brachial-ankle (ba) pulse wave velocity (PWV), systolic blood pressure (BP), plasma glucose (PG), insulin, and ET-1 levels before and 60 and 120 min after a 75-g OGTT. baPWV, and ET-1 levels before intervention were significantly increased after 75-g OGTT compared to before 75-g OGTT in both groups (p < 0.05). The post-intervention baPWV, and ET-1 levels were significantly increased after 75-g OGTT in Group S compared to before 75-g OGTT (p < 0.05), whereas no significant changes were observed in Group I. These results suggest that consumption of isomaltulose, which has a lower GI than sucrose, is more effective in preventing the increases in systemic arterial stiffness associated with postprandial hyperglycemia in healthy middle-aged and older adults.

The relationship between Meckel's cartilage resorption and incisor tooth germ in mice.

Our understanding of the initiation and cellular mechanisms underlying endochondral resorption of Meckel's cartilage (MC) remains limited. Several studies have shown that the resorption site of MC and the mandibular incisor tooth germ are located close to each other. However, whether incisor tooth germ development is involved in MC resorption remains unclear. In this study, we aimed to elucidate the spatio-temporal interaction between the initiation site of MC resorption and the development of incisor tooth germs in an embryonic mouse model. To this effect, we developed a histology-based three-dimensional (3D) reconstruction technique using paraffin-embedded serial sections of various tissues in the jaw. The serial sections were cut in the frontal section and the tissue constituents (e.g., MC, incisor, and mineralized mandible) were studied using conventional and enzyme-based histochemistry. The outline of each component was marked on the frontal sectional images and 3D structures were constructed. To assess the vascular architecture at the site of MC resorption, immunohistochemical staining using anti-laminin, anti-factor VIII, and anti-VEGF antibodies was performed. MC resorption was first observed on the lateral incisor-facing side of the cartilage rods at sites anterior to the mental foramen on E16.0. The 3D analysis suggested that: (a) the posterior region of the clastic cartilage resorption corresponds to the cervical loop of the incisor; (b) the cervical portion of the tooth germ inflates probably due to temporal cellular congestion prior to differentiation into matrix-producing cells; (c) the incisor tooth germ tissue is present in close proximity to MC even in mouse with continuously growing tooth and determines the disappearance of MC as the tooth development.

Painless thyroiditis mimicking relapse of hyperthyroidism during or after potassium iodide or thionamide therapy for Graves' disease resulting in remission.

The diagnosis of painless thyroiditis (PT) during antithyroid drug (ATD) treatment of Graves' disease (GD) is difficult. We evaluated the thyroidal radioactive iodine uptake (RAIU) in 100 patients with relapsed thyrotoxicosis during or after careful ATD treatment. The RAIU was <5%/5 h in 35 patients (35%) (Group A - PT), 5%-15%/5 h in 6 patients (6%) (Group B - indefinite) and >15%/5 h in 59 patients (59%) (Group C - relapsed GD [rGD]). TSH receptor antibody (TBII) was positive in 4 (11.4%), 3 (50.0%) and 39 (only 66.1%) patients in Groups A, B and C, respectively. In Group A, the serum fT4 level spontaneously normalized after 35 (26-56) days, sometimes followed by transient hypothyroidism, confirming the diagnosis of PT. Nineteen (54.3%) had been treated with potassium iodide, and PT frequently occurred ironically when the ATD dosage was reduced. PT repeatedly occurred in nine patients. All went into remission smoothly or developed hypothyroidism, except one patient with strongly positive TBII who developed rGD after the resolution of PT (PT on GD). In 10 (50%) of 20 patients with negative TBII despite rGD in Group C, TBII became positive afterwards. In conclusion, it is important to recognize that PT can occur in the clinical course of GD, resulting in frequent remission despite relapse of PT. The thyroid function reflects the balance between the stimulating TBII activity and the responsiveness of the thyroid tissue (sometimes unresponsive and other times autostimulated). The RAIU is still a valuable tool in cases of ambiguous thyrotoxicosis.

A third-generation mouse model of Alzheimer's disease shows early and increased cored plaque pathology composed of wild-type human amyloid ß peptide.

We previously developed single App knock-in mouse models of Alzheimer's disease (AD) harboring the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (AppNL-G-F and AppNL-F mice, respectively). These models showed Aß pathology, neuroinflammation, and cognitive impairment in an age-dependent manner. The former model exhibits extensive pathology as early as 6 months, but is unsuitable for investigating Aß metabolism and clearance because the Arctic mutation renders Aß resistant to proteolytic degradation and prone to aggregation. In particular, it is inapplicable to preclinical immunotherapy studies due to its discrete affinity for anti-Aß antibodies. The latter model may take as long as 18 months for the pathology to become prominent, which leaves an unfulfilled need for an Alzheimer's disease animal model that is both swift to show pathology and useful for antibody therapy. We thus utilized mutant Psen1 knock-in mice into which a pathogenic mutation (P117L) had been introduced to generate a new model that exhibits early deposition of wild-type human Aß by crossbreeding the AppNL-F line with the Psen1P117L/WT line. We show that the effects of the pathogenic mutations in the App and Psen1 genes are additive or synergistic. This new third-generation mouse model showed more cored plaque pathology and neuroinflammation than AppNL-G-F mice and will help accelerate the development of disease-modifying therapies to treat preclinical AD.

Demonstration of aerosol profile measurement with a dual-wavelength high-spectral-resolution lidar using a scanning interferometer.

Simple dual-wavelength high-spectral-resolution lidar at 355 and 532 nm with a scanning interferometer was developed for continuous observations of aerosol profiles. Scanning the interferometer periodically over a range of one fringe at 532 nm (1.5 fringes at 355 nm) enabled recording of range-resolved interference signals at these two wavelengths. Reference signals taken from the transmitted laser were used to correct the interference phase shift due to laser frequency variation for every scan. Profiles of aerosol backscatter and extinction coefficients were retrieved from range-resolved interference data. One month of continuous measurements demonstrated the robustness of the system.

Iodide-sensitive Graves' hyperthyroidism and the strategy for resistant or escaped patients during potassium iodide treatment.

The effectiveness of potassium iodide (KI) (100 mg/day) was evaluated in 504 untreated patients with Graves' hyperthyroidism (GD). Initial response to KI within 180 days, the effect of additional methylmercaptoimidazole (MMI) or radioactive iodine (RI) in resistant or escaped patients, and long-term prognosis were evaluated. Serum fT4 levels became low or normal in 422 patients (83.7%, KI-sensitive group) without serious side effects. Among these patients, serum TSH levels became high (n = 92, hypothyroid) or normal (n = 78) in 170 patients (33.7%) (KI-sensitive with a recovered TSH response, Group A), but remained suppressed in 252 patients (50.0%) (KI-sensitive with TSH suppression, Group B). Serum fT4 levels decreased but remained high in 82 patients (16.3%) (KI-resistant, Group C). Older patients, or those with small goiter and mild GD were more KI-sensitive with a recovered TSH response than others. Escape from KI effect occurred in 0%, 36% and 82% in Group A, B and C, respectively. Patients in Group B and C were successfully treated with additional low-dosage MMI or RI. After 2-23 years' treatment (n = 429), remission (including possible remission) and spontaneous hypothyroidism were significantly more frequent in Group A (74.3% and 11.1%, respectively,) than in Groups B (46.3% and 2.8%, respectively) or C (53.6% and 1.5%, respectively) (p < 0.0001). In conclusion, a high KI sensitivity with a recovered TSH response was observed in about a third of the patients in GD associated with a better prognosis. Additional MMI or RI therapy was effective in escaped or KI-resistant patients with suppressed TSH level.

A case of Graves' disease presenting with internal ophthalmoplegia during methylmercaptoimidazole treatment.

A 28-year-old Japanese woman positive for TSH receptor antibody and anti-nuclear antibody complained of difficulty seeing nearby objects, severe throbbing retro-orbital pain, diplopia, blepharoptosis and upward gaze palsy when she became hypothyroid during treatment with 30 mg methylmercaptoimidazole for Graves' hyperthyroidism. Brain magnetic resonance imaging revealed slightly swollen bilateral inferior rectus muscles, suggesting the external ophthalmoplegia due to the muscle pathology commonly encountered in Graves' disease. The retro-orbital pain was associated with marked accommodation failure and the pupillary abnormalities. The left and/or right eye showed intermittent, asymmetric and fluctuating mydriasis, being unresponsive to ordinary light but slowly responsive to strong sunlight and slowly responsive in a dark room. During the 5-year period, mydriasis was observed 9 times on both sides, 11 times only on the right side and 4 times only on the left side. Internal ophthalmoplegia with tonic pupils and accommodation failure affecting both the pupillary sphincter muscle and ciliary muscle due to damage to the parasympathetic outflow to these muscles was suggested. Autoimmune mechanism and/or the mechanism underlying channelopathy affecting the ciliary ganglion or short ciliary nerves might be responsible for this fluctuating complication. This very rare panophthalmopathy affecting both external and internal muscles occurred when the patient was suffering from iatrogenic hypothyroidism during the 30 mg methylmercaptimidazole treatment for Graves' disease.

SARS-CoV-2 detection by fluorescence loop-mediated isothermal amplification with and without RNA extraction.

Rapid and simple point-of-care detection of SARS-CoV-2 is an urgent need to prevent pandemic. Reverse transcription loop-mediated isothermal amplification (RT-LAMP) can detect SARS-CoV-2 more rapidly than RT-PCR. Saliva is non-invasive specimen suitable for mass-screening, but data comparing utility of nasopharyngeal swab (NPS) and saliva in RT-LAMP test are lacking and it remains unclear whether SARS-CoV-2 could be detected by direct processing of samples without the need for prior RNA extraction saliva. In this study, we compared utility of saliva and NPS samples for the detection of SARS-CoV-2 by a novel RT-fluorescence LAMP (RT-fLAMP). The sensitivity and specificity of the RT-fLAMP with RNA extraction were 97% and 100%, respectively, with equivalent utility of NPS and saliva. However, sensitivity was decreased to 71% and 47% in NPS and saliva samples without RNA extraction, respectively, suggesting that RNA extraction process may be critical for the virus detection by RT-fLAMP.

Development of a 355-nm high-spectral-resolution lidar using a scanning Michelson interferometer for aerosol profile measurement.

A simple 355-nm high-spectral-resolution lidar (HSRL) is developed for continuous observation of aerosol profiles. A scanning Michelson interferometer is used to separate the Rayleigh and Mie scattering components. The interferometer is periodically scanned in the range of one fringe. Interference contrast, which contains aerosol backscatter information, is estimated at each height through fitting analysis of the scan data. The interference contrast and fringe position are calibrated with the reference signals taken from the transmitted laser. Furthermore, the 1-day continuous measurement of aerosol backscatter and extinction coefficients is demonstrated. Comparison with a nighttime Raman lidar indicates a good performance of the scanning method.

Wavelength dependence of ice cloud backscatter properties for space-borne polarization lidar applications.

We investigated the use of backscatter properties of atmospheric ice particles for space-borne lidar applications. We estimated the average backscattering coefficient (ß), backscatter color ratio (χ), and depolarization ratio (δ) for ice particles with a wide range of effective radii for five randomly oriented three-dimensional (3D) and three quasi-horizontally oriented two-dimensional (2D) types of ice particle using physical optics and geometrical integral equation methods. This is the first study to estimate the lidar backscattering properties of quasi-horizontally oriented non-pristine ice crystals. We found that the χ-δ relationship was useful for discriminating particle types using Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observation (CALIPSO) Cloud-Aerosol Lidar with Orthogonal Polarization (CALIOP) data. The lidar ratio (S)-δ relationship, which is determined using space-borne high-spectral-resolution lidar products such as EarthCARE ATLID or future space-borne lidar missions, may also produce robust classification of ice particle types because it is complementary to the χ-δ relationship.

Plasmacytoid dendritic cells are crucial for the initiation of inflammation and T cell immunity in vivo.

Plasmacytoid dendritic cells (pDCs) are characterized as type I interferon-producing cells that engage endosomal toll-like receptors (TLRs) and exclusively express sialic acid binding Ig-like lectin (Siglec)-H. However, their role in vivo remains unclear. Here we report a critical role for pDCs in the regulation of inflammation and T cell immunity in vivo by using gene-targeted mice with a deficiency of Siglec-H and conditional ablation of pDCs. pDCs were required for inflammation triggered by a TLR ligand as well as by bacterial and viral infections. pDCs controlled homeostasis of effector and regulatory CD4(+) T cells. Upon antigenic stimulation and microbial infection, pDCs suppressed the induction of CD4(+) T cell responses and participated in the initiation of CD8(+) T cell responses. Furthermore, Siglec-H appeared to modulate the function of pDCs in vivo. Thus, our findings highlight previously unidentified roles of pDCs and the regulation of their function for the control of innate and adaptive immunity.

Clinical experience of treating Graves' hyperthyroidism complicated with malignancy-The possible role of potassium iodide for avoiding the risk of thionamide-associated neutropenia.

The treatment of Graves' hyperthyroidism (GD) complicated with malignancy is challenging, as anti-thyroid thionamide drugs (ATDs) and anti-cancer chemotherapy are both associated with a risk of neutropenia. Treatment with conventional ATDs, radioactive iodine (RAI) or potassium iodide (KI) was attempted in 8 patients with malignancy (34-80 years of age; 2 males and 6 females) in whom GD had been fortuitously diagnosed during a detailed systematic examination. Three patients requiring surgery were initially treated conventionally with methylmercaptoimidazole (MMI), MMI and KI or RAI (group A; one patient each). The patients became euthyroid on days 17-31 and underwent surgery on days 25-47. RAI therapy was administered to one patient after surgery. The patients were then treated with KI during chemotherapy. Five other patients who did not require surgery were initially treated with 100 mg KI monotherapy (group B). The serum free T4 level declined immediately in all of these patients, and they became euthyroid on days 7-18, remaining almost entirely euthyroid for more than 120 days. Anti-cancer chemotherapy was successfully completed for three of the patients while taking KI, despite the patients experiencing repeated episodes of anti-cancer chemotherapy-induced neutropenia. Our present findings suggest that, in patients with GD and malignancy, MMI + KI or RAI may be required if immediate surgery is scheduled, but KI monotherapy may be worth trying, if anti-cancer chemotherapy is scheduled, thus avoiding the possibility of thionamide-induced neutropenia.

Effects of a short-term increase in physical activity on arterial stiffness during hyperglycemia.

We examined the effects of increasing physical activity on arterial stiffness during hyperglycemia. Nineteen glucose-intolerant elderly participated in the study. We randomly assigned 10 participants to increase their daily activity in everyday life, regardless of the time or intensity, for 1 month (PAI group) (age, 74.6 ± 1.3 years; mean ± SE) and nine participants to maintain their level of activity (CON group) (age, 79.2 ± 2.1 years; mean ± SE). The 75-g oral glucose tolerance test was conducted in each participant in both groups before and after the start of the intervention to confirm glucose intolerance. Brachial-ankle pulse wave velocity and cardio-ankle vascular index significantly increased from baseline at 30, 60, and 90 min after the 75-g glucose ingestion after the intervention in the CON group (p<0.05), but not in the PAI group. Heart-brachial pulse wave velocity did not change compared to baseline after the 75-g glucose ingestion in either group and did not change from baseline at 30, 60, and 90 min after the 75-g glucose ingestion before and after the intervention in both groups. The present findings indicate that a short-term increase in physical activity suppresses the increase in arterial stiffness after glucose intake.

Effects of different intensities and durations of aerobic exercise training on arterial stiffness.

[Purpose] In the present study, we investigated the effects of regular aerobic training with different intensities and durations on new indices of arterial stiffness measured via an upper-arm oscillometric device. [Participants and Methods] We gathered data from 41 middle-aged and older people (age 65.0 ± 11.7 years). Participants were randomly divided into five groups: (1) 15 minutes of low intensity aerobic training (n=10); (2) 30 minutes of low intensity training (n=7); (3) 15 minutes of moderate-intensity training (n=9); (4) 30 minutes of moderate-intensity training (n=8); and (5) a non-training group (n=7). Training was conducted for 8 weeks, three times per week. Arterial pulse wave index, arterial pressure-volume index, brachial-ankle and heart-brachial pulse wave velocity, cardio-ankle vascular index, brachial and ankle blood pressure, heart rate, and peak oxygen uptake were measured before and after the intervention. [Results] All indicators of arterial stiffness and brachial and ankle blood pressure in the exercise groups were significantly lower after versus before the intervention. Peak oxygen uptake did not differ before versus after the intervention. [Conclusion] The present findings indicate that regular aerobic exercise may be important in reducing arterial stiffness regardless of the intensity or duration of aerobic exercise.

Modeling the depolarization of space-borne lidar signals.

A physical model was extended with a polarization function to create a vectorized physical model (VPM) to analyze the vertical profile of the observed depolarization ratio due to multiple scattering from water clouds by space-borne lidar. The depolarization ratios due to single scattering, on-beam multiple scattering, and pulse stretching mechanisms are treated separately in the VPM. The VPM also includes a high-order scattering matrix and accommodates mechanisms that modify the polarization state during multiple scattering processes. The estimated profile of the depolarization ratio from the VPM showed good agreement with Monte Carlo simulations, with a mean relative error of about 2% ± 3%.

Interpretation of lidar ratio and depolarization ratio of ice clouds using spaceborne high-spectral-resolution polarization lidar.

The backscattering coefficient (ß), lidar ratio (S), and depolarization ratio (δ) of ice particles were estimated over a wide range of effective radii to interpret spaceborne 355-nm high-spectral-resolution lidar data from the ATLID sensor onboard the EarthCARE satellite. Five randomly oriented ice particle shapes (3D ice) and two quasi-horizontally oriented particle types (2D ice) were analyzed using five effective angles. The size dependence of ß, S, and δ was examined using physical optics and geometrical optics integral equation methods. Differences in ß for the same effective radius and ice water content among particle types exceeded one order of magnitude. S-δ relations are useful for inferring ice particle habit and orientation using ATLID data from EarthCARE.

Measurement of water mist particle size generated by rocket launch using a two-wavelength multi-static lidar.

Water mist generated during a rocket launch is thought to protect the rocket and payloads from acoustic noise. The size of mist particles is essential to understanding the effect on noise reduction. A two-wavelength multi-static lidar was developed for measuring water mist size at the launch site. The lidar determines particle size from signals at three scattering angles at two wavelengths. The method was tested with artificial mist and applied to the Japan Aerospace Exploration Agency's H-IIA/B large-scale rocket launches. The measured particle size near the outside edge of the mist cloud was 3.5-5 µm in diameter. The extinction coefficient at 532 nm derived using the Klett backward inversion method was 100-200 km-1. The estimated liquid water content (LWC) was ∼0.3 g/m3. The extinction coefficient was high, but the LWC was comparable to that of the water clouds.

The long-term follow-up of patients with thionamide-treated Graves' hyperthyroidism.

Since there have been few reports on the long-term prognosis of Graves' hyperthyroidism, the prognosis of 549 Graves' hyperthyroidism patients initially treated with thionamide and followed for >8 (range: 8.6-36.4) years was studied, evaluating the change in the TSH binding inhibitor immunoglobulin activity (TBII). The distribution of the time required for the first disappearance of TBII was normal after logarithmic conversion, and the mean ± 2 SD was 1.5 (0.3-8.1) years. TBII became negative once within 5 years in 78.9% of patients. However, TBII re-elevation was observed in 47.8% of this group (fluctuating type). Remission was observed in 88.9% of the non-fluctuating type (smooth remission) and 37.2% of the fluctuating type patients. TBII remained positive for >5 years in 21.1% (smoldering type) of patients, with remission observed in only 19.8% of patients. Final remission was observed in 301 (54.8%) patients; the median time to remission was 6.8 (interquartile range: 4.0-10.9) years. A longer time until normalization of TBII and higher final thyroid weight were associated with a poor prognosis. Spontaneous hypothyroidism was observed in 6.0% of patients, independent of the TBII change. Our findings suggest that remission of Graves' hyperthyroidism mostly occurred after 4-11 years treatment. While predicting the prognosis before therapy was difficult, the clinical course may suggest a better prognosis if TBII disappears within five years without TBII fluctuation or enlargement of the goiter. Patients may safely wait more than five years to undergo ablative therapy if they hope to avoid permanent hypothyroidism.

Arterial stiffness during hyperglycemia in older adults with high physical activity vs low physical activity.

We compared arterial stiffness after glucose intake in active and inactive elderly people with impaired glucose tolerance and clarified whether physical activity was associated with arterial stiffness after ingestion of glucose. Twenty older adults with impaired glucose tolerance were analyzed in a cross-sectional design. Based on the international physical activity questionnaire, participants were divided into the active group (daily step count: 10,175.9 ± 837.8 steps/day, n = 10) or the inactive group (daily step count: 4,125.6 ± 485.9 steps/day, n = 10). Brachial-ankle (systemic) and heart-brachial (aortic) pulse wave velocity and cardio-ankle vascular index (systemic) were increased at 30, 60, and 90 min compared to baseline after a 75-g oral glucose tolerance test in the inactive but not the active group. Heart-brachial pulse wave velocity did not change compared to baseline after a 75-g oral glucose tolerance test in either group. The area under the curve for brachial-ankle pulse wave velocity was associated with daily living activity (r = -0.577, p = 0.008), daily step activity (r = -0.546, p = 0.013), and the daily step count (r = -0.797, p = 0.0001). The present findings indicate that physical activity or inactivity is associated with arterial stiffness following glucose ingestion.

Impact of heart failure on functional recovery after hip fracture.

[Purpose] Heart failure has been identified as a risk factor for reduced physical function and falls; however, the impact of heart failure on functional recovery after a hip fracture is unclear. This study aimed to examine how heart failure and pre-fracture physical function affect recovery after a hip fracture. [Participants and Methods] The study population consisted of 122 patients with sub-acute hip fracture (mean age 81.7 ± 9.7 years, 18.9% male) who were divided into two groups: heart failure and non-heart failure. The outcome measurement was the functional independence measure effectiveness. A two-way analysis of variance was performed to investigate how heart failure and ambulatory ability prior to hip fracture were related to the functional independence measure effectiveness. [Results] Seventeen patients (13.9%) had a history of heart failure. The two-way analysis of variance showed the two independent variables (heart failure and ambulatory ability before fracture) had significant main effects; however, their interaction effect was not significant. [Conclusion] Heart failure affects functional recovery after hip fracture independent of the pre-fracture physical function, and vice versa. Further research on rehabilitation in hip fracture patients with heart failure is required to develop strategies to overcome poor functional recovery in such patients.