Rationale, design and baseline characteristics of the effect of canagliflozin in patients with type 2 diabetes and microalbuminuria in the Japanese population: The CANPIONE study.

AIM: To evaluate the effect of canagliflozin, a sodium-glucose co-transporter-2 (SGLT2) inhibitor, on albuminuria and the decline of estimated glomerular filtration rate (eGFR) in participants with type 2 diabetes and microalbuminuria. METHODS: The CANPIONE study is a multicentre, randomized, parallel-group and open-labelled study consisting of a unique 24-week preintervention period, during which the rate of eGFR decline before intervention is estimated, followed by a 52-week intervention and a 4-week washout period. Participants with a geometric mean urinary albumin-to-creatinine ratio (UACR) of 50 and higher and less than 300 mg/g in two consecutive first-morning voids at two different time points, and an eGFR of 45 ml/min/1.73m2 or higher, are randomly assigned to receive canagliflozin 100 mg daily or to continue guideline-recommended treatment, except for SGLT2 inhibitors. The first primary outcome is the change in UACR, and the second primary outcome is the change in eGFR slope. RESULTS: A total of 258 participants were screened and 98 were randomized at 21 sites in Japan from August 2018 to May 2021. The mean baseline age was 61.4 years and 25.8% were female. The mean HbA1c was 7.9%, mean eGFR was 74.1 ml/min/1.73m2 and median UACR was 104.2 mg/g. CONCLUSIONS: The CANPIONE study will determine whether the SGLT2 inhibitor canagliflozin can reduce albuminuria and slow eGFR decline in participants with type 2 diabetes and microalbuminuria.

Effects of forest fires on mercury accumulation in soil at the artisanal small-scale gold mining.

In response to the Minamata Convention on Mercury, international organizations, governments, nonprofit organizations, and other institutions as well as individuals have worked to promote the development and implementation of safe and environmentally healthy practices, processes, and products. It is expected that the accumulation of mercury in the natural environment will decrease in volume each year. However, even after Hg ceases to be used, the Hg already accumulated in forests will continue to pose an ecological risk. Forest fires are serious events, partly because they release accumulated Hg from the environment. In this study, the effects of forest fires on the accumulation and chemical species of Hg in soil, related to the mobilization of Hg, were investigated. The research was conducted in secondary forests located near artisanal small-scale gold mining sites, where Hg is used for the amalgamation of gold in Camarines Norte, Philippines. The results showed that the original Hg accumulation level in the burned forest was not as high as that in the control forest, and that burn severity might have affected only the surface soil (0-5 cm). However, the proportion of water-soluble Hg, which was derived from ash, was increased by fire. Therefore, it is suggested that forest fires not only increase the release of Hg into the atmosphere but also increase the outflow risk to the aquatic system through rainfall.

Decrease in toe pinch force in male type 2 diabetic patients with diabetic nephropathy.

BACKGROUND: The purpose of this cross-sectional study was to investigate the toe pinch force (TPF) of type 2 diabetic patients with diabetic nephropathy by disease stage, and to clarify the factors affecting the TPF. METHODS: Seventy-four men with diabetic nephropathy (age: 62.7 ± 8.9 years, duration of diabetes: 14.2 ± 8.6 years) were enrolled. According to the staging of diabetic nephropathy, TPF and knee extension force (KEF) were compared among three groups: normoalbuminuria, microalbuminuria, and overt nephropathy. In addition, we investigated factors influencing TPF and KEF by performing multiple regression analysis. RESULTS: Normoalbuminuria group, microalbuminuria group, and overt nephropathy group included 26, 25, and 23 patients, respectively. The TPF of the overt nephropathy group (3.15 ± 0.75 kg) was significantly lower than that of the normoalbuminuria (4.2 ± 0.7 kg, p < 0.001) and microalbuminuria groups (3.65 ± 0.81 kg, p = 0.022). The KEF of the overt nephropathy group (37.1 ± 8.3 kgf) was significantly lower than that of the normoalbuminuria group (44.8 ± 8.3 kgf, p = 0.010). Multiple regression analysis revealed that diabetic polyneuropathy (DPN) and diabetic nephropathy were determinant factors of the TPF; and age, body mass index, and diabetic nephropathy were determinant factors of the KEF. CONCLUSION: We found in male patients with diabetic nephropathy, the TPF and KEF decreased with progression of diabetic nephropathy. Furthermore, our findings suggest diabetic nephropathy and DPN are critically involved in the reduction of TPF and KEF.

A Randomized Controlled Trial of Short-term Toe Resistance Training to Improve Toe Pinch Force in Patients with Type 2 Diabetes.

Resistance training is effective against type 2 diabetes (T2DM), but the effect of resistance training on toe pinch force (TPF) is unknown. Here we investigated the effect of short-term toe resistance training on TPF in patients with T2DM, in a prospective, parallel-group, single-blind, randomized controlled trial. Twelve patients with T2DM who were hospitalized to improve glycemic control were enrolled. The patients were randomly allocated to the intervention (n=6) and control (n=6) groups. The intervention group performed traditional aerobic exercise and 4 newly developed toe-resistance training exercises. The control group performed aerobic exercise only. After 2 weeks of the exercise intervention program, we evaluated anthropometric parameters, clinical parameters, motor function, and muscle parameters in each patient. After the exercise intervention program, the TPF and toe muscle quality, isometric knee extension force, and knee muscle quality were significantly higher in the intervention group compared to the control group. Two weeks of toe-resistance training significantly increased the TPF in the T2DM patients. Toe resistance training is thus recommended in clinical practice for patients with T2DM.

Toe Pinch Force in Male Type 2 Diabetes Mellitus Patients.

We compared the toe pinch force in men with and without type 2 diabetes mellitus (T2DM). Sixty-eight male T2DM patients and 35 apparently healthy men matched for age, sex, and body mass index (BMI) were enrolled in this cross-sectional study. We compared the toe pinch force between the subjects with and without T2DM, and we evaluated the effect of diabetic polyneuropathy on toe pinch force in the patients. The toe pinch force of the T2DM patients was significantly lower than that of the subjects without diabetes (3.12±1.22 kg vs. 4.40±1.19 kg, p<0.001). Multiple regression analysis showed that T2DM was a determinant of reduced toe pinch force. In addition, the toe pinch force of patients with diabetic polyneuropathy was significantly lower than that of patients without diabetic polyneuropathy (2.31±0.93 kg vs. 3.70±1.07 kg, p<0.001). Multiple regression analysis showed that diabetic polyneuropathy was a determinant of the toe pinch force in men with T2DM, even after adjusting for age, BMI, HbA1c, and duration of diabetes. Reduced toe pinch force is a fundamental feature of motor dysfunction in men with T2DM, and diabetic polyneuropathy might be associated with toe pinch force in these patients.

Relationship of toe pinch force to other muscle strength parameters in men with type 2 diabetes.

OBJECTIVE: The aim of this study was to explore the relations between toe pinch force and other muscle strength parameters in male patients with type 2 diabetes mellitus. METHODS: A total of 40 men with type 2 diabetes (age: 53.4 ± 13.1 years, duration of diabetes: 8.5 ± 8.1 years) who needed exercise training were enrolled in this cross-sectional study. We evaluated the clinical parameters and 4 muscle strength parameters, which were toe pinch force, handgrip strength, isometric knee extension force, and isometric ankle dorsiflexion force. RESULTS: The HbA1c, toe pinch force, handgrip strength, isometric knee extension force, and isometric ankle dorsiflexion force were 10.1 ± 2.4 %, 3.2 ± 1.2 kg, 37.3 ± 7.0 kg, 39.6 ± 11.4 kgf, and 17.0 ± 6.3 kgf, respectively. Toe pinch force was significantly correlated with handgrip strength (r = 0.365, p = 0.0206), isometric knee extension force (r = 0.668, p < 0.0001), and isometric ankle dorsiflexion force (r = 0.514, p = 0.0007). All muscle strength parameters were significantly lower in patients with diabetic polyneuropathy than in those without polyneuropathy. CONCLUSION: Although toe pinch force was significantly correlated with the other muscle strength parameters, the correlation was not so strong. However, evaluation of toe pinch force might be recommended for assessment of distal limb muscle strength in patients with type 2 diabetes.

Pontine lesion in hyperglycemic crises: Relevance to osmotic demyelination syndrome and posterior reversible encephalopathy syndrome.

We herein describe a case of type 1 diabetes that presented with a pontine lesion during two hyperglycemic crises accompanied by marked fluctuations in serum osmotic pressure and blood pressure. Magnetic resonance imaging showed swollen pons with osmotic demyelination syndrome characteristics accompanying cytotoxic edema at the first crisis. The involvement of vasogenic edema was also assumed in the second crisis. Neurological symptoms were milder than magnetic resonance imaging findings. The patient recovered after 7 days without sequelae in both crises. Based on these findings, a pontine lesion needs to be considered in patients with poorly controlled diabetes showing rapid metabolic and blood pressure changes, as observed in hyperglycemic crises. Cytotoxic edema leading to osmotic demyelination syndrome and vasogenic edema caused by vascular endothelial cell damage might both be involved in the pathogenesis of a pontine lesion.

The dynamics of mercury around an artisanal and small-scale gold mining area, Camarines Norte, Philippines.

To elucidate the dynamics of mercury emitted and released by artisanal and small-scale gold mining (ASGM) activity and to estimate its impact on the ecosystems of the bay, the distribution of mercury in the atmosphere, soil, water, and sediment around Mambulao Bay, Camarines Norte, Philippines, was investigated. The ASGM operations use mercury to extract gold from ore and are located on the east shore side of the bay. Samplings were conducted in August 2017 and September 2018. The samples were used for determination of total mercury (T-Hg) and organic mercury (org-Hg) concentrations, total organic carbon (TOC) content, and chemical composition. The atmospheric mercury concentration on the east shore side, 6.1-25.8 ng m-3, was significantly higher than the value of 1.4-9.9 ng m-3 observed on the west shore side. The average concentrations of T-Hg in the forest soils of the west shore side and those of the east shore side were 0.081 ± 0.028 mg kg-1 and 0.496 ± 0.439 mg kg-1, respectively. In the vertical distribution of T-Hg in the soil of the east shore side, a higher concentration was observed near the surface. For the vertical variations in T-Hg in the marine sediment, higher values were observed near the estuary, and the vertical variations in core samples showed an increase in mercury concentration toward the surface. The highest concentration of T-Hg in sediment, 9.5 mg kg-1, which was 2 orders of magnitude higher than the background levels of this area, was found near the river mouth. The T-Hg, org-Hg, and TOC levels showed a positive correlation, suggesting that the rivers are the main sources of T-Hg and org-Hg in the bay. Although the fish sample containing a mercury content higher than the regulatory level for fish and shellfish of 0.4 mg kg-1 in Japan was only one of 42 samples, the percentage of org-Hg in fish samples was 91 ± 18%. Mercury released into the surroundings by the ASGM activities can be converted into methylmercury and affect the bay's ecosystem.

HbA1c of 5.8% or higher as the most useful indicator for recommendation of ultrasonography to detect nonalcoholic fatty liver disease.

Background and Aim: Nonalcoholic fatty liver disease (NAFLD) is closely associated with metabolic syndrome. This study was performed to examine the association between NAFLD and each factor of metabolic syndrome and to identify the factors that are most strongly associated with NAFLD in participants undergoing health checkups. Methods: We studied 6538 participants who underwent a health checkup from 2017 to 2018 in our institution. Participants with alcohol intake exceeding 20 g/day or with other chronic liver diseases were excluded. Fatty liver was detected by ultrasonography. Results: In total, 4310 participants were enrolled, and 28.4% had fatty liver (NAFLD). The prevalence of NAFLD was highest in the diabetes mellitus (DM)-only group than in the dyslipidemia-only or hypertension-only group. The DM-only group was the only group whose prevalence of NAFLD was >50% in the overall study and in males. The prevalence of NAFLD was higher in males than in females in the DM-only, hypertension-only, and dyslipidemia-only groups. The prevalence of NAFLD was >70% in the dyslipidemia and DM combined group. Multivariate analysis showed that gender and HbA1c were the independent factors most strongly associated with NAFLD. The cutoff value for HbA1c by receiver operating characteristic curve analysis was 5.8% (sensitivity, 57.9%; specificity, 72.6%; area under the curve, 0.70). Conclusion: NAFLD was most strongly associated with DM, among the various components of metabolic syndrome. We strongly recommend abdominal ultrasonography to detect NAFLD in patients with an HbA1c of ≥5.8% in general practice and during health checkups.

Repeated insulin injection without site rotation affects skin thickness - ultrasonographic and histological evaluation.

AIMS/INTRODUCTION: The influence of repeated insulin injection on subcutaneous tissue is known, but its impact on the skin is unclear. Therefore, this study aimed to elucidate the impact of repeated insulin injections on the skin. MATERIAL AND METHODS: The properties of the skin and the subcutaneous tissue were evaluated in 52 insulin-treated adult patients with diabetes with abnormal findings at the site of self-injection (36 with subcutaneous nodules, 16 with suspected subcutaneous tissue induration) by ultrasonography. In all subjects, both normal and abnormal areas were examined. In addition, skin biopsies were performed in four subjects. RESULTS: The skin thickness of the normal and abnormal skin sites was 1.95 (1.60, 2.50) and 2.80 (2.27, 3.30) mm, respectively (median (first quartile, third quartile)), (P < 0.001). The biopsy specimens revealed slightly thickened and tight bundles of collagen in the dermis. Three patients had amyloid deposits in the subcutaneous tissue, and one also showed these in the dermis. These were positively stained for insulin antibody. CONCLUSIONS: Repeated insulin injection procedures result in skin thickening. Increased collagen fibers and possibly amyloid deposition in the dermis may be involved. The results reaffirmed the importance of appropriate site rotation in insulin injection and revealed the usefulness of ultrasonographic skin examination in evaluating the self-injection procedure.

Multiple skin ulceration and itch-scratch cycle in a diabetic patient.

Diabetic patients sometimes present generalized pruritus. Severe itching can cause an itch-scratch cycle, resulting in distress and impaired quality of life, but skin ulceration is a rare manifestation.

Preparation and in vitro tumor growth inhibitory effect of oligo (L-lactate) nanoparticles.

Oligo L-lactates (oligolactates) that have low molecular weights less than 2000 have been reported to inhibit tumor growth and extend the survival of experimental animals. Because oligolactates are scarcely soluble in water, they require a solvent or a solubilizing agent, such as a surfactant, to be dissolved in water. However, these agents are generally cytotoxic, an in vitro assay appropriate to evaluate the inhibitory effect on tumor growth has not been developed yet. Here, we prepared a solid nanodispersion of oligolactates using an oil-in-water emulsion solvent evaporation method to evaluate its tumor inhibitory activity in vitro without a solvent or surfactant. Polyol solutions containing polyvinyl alcohol (PVA) were used as a continuous phase. The formation of nanoparticles depended on the concentrations of polyol and PVA in the continuous phase. The nanoparticles with a particle size of approximately 100 nm were obtained using 10-15% PVA and 60% propylene glycol. The obtained aqueous nanodispersion of oligolactates inhibited the growth of B16-BL6 melanoma cells in vitro, whereas the medium alone did not affect tumor cell growth. Therefore, oligo(L-lactate) nanoparticles may be useful in the research and development of oligolactates as a remedy for cancer.

An exploratory study of relationship between lower-limb muscle mass and diabetic polyneuropathy in patients with type 2 diabetes.

PURPOSE: This exploratory study compared the lower-limb muscle mass (thigh muscle mass [TMM] and lower-leg muscle mass [LLMM]) in type 2 diabetic patients with and without diabetic polyneuropathy (DPN). METHODS: A total of 130 patients with type 2 diabetes, hospitalized for glycemic control, were enrolled in this cross-sectional study. TMM and LLMM were measured using the bioelectrical impedance method. The muscle mass value was normalized by the bodyweight, and the total muscle mass was calculated by combining the muscle mass on the left and right (%TMM and %LLMM). DPN was evaluated according to the Japanese criteria. Anthropometric parameters, blood pressure, laboratory data, exercise habits, medication, related index of diabetes, and diabetic complications were analyzed. RESULTS: Sixty patients, comprising of 32 males (47.8%) and 28 females (44.4%) with type 2 diabetes (46.2%), had DPN. The %TTM and %LLMM were significantly lower in type 2 diabetic patients with DPN than in those without DPN. Multiple regression analysis identified DPN, age, and hemoglobin A1c (HbA1c) as the determinants of %TMM, and DPN and HbA1c were identified as the determinants of %LLMM in type 2 diabetic patients. DISCUSSION: The %TMM and %LLMM were significantly decreased in type 2 diabetic patients with DPN. DPN was found to be the strongest determinant of %TMM and %LLMM. Preventing and improving DPN, through active physical therapy, may increase the muscle mass of the lower limbs.

A pilot study suggests that the G/G genotype of resistin single nucleotide polymorphism at -420 may be an independent predictor of a reduction in fasting plasma glucose and insulin resistance by pioglitazone in type 2 diabetes.

The aim of this study was to determine the relation between the G/G genotype of a resistin gene promoter single nucleotide polymorphism (SNP) at -420 (rs1862513) and glycemic control by pioglitazone in type 2 diabetes. In Study 1, 121 type 2 diabetic patients were treated with pioglitazone (15 or 30 mg/day) for 12 weeks, in addition to previous medication. In Study 2, 63 patients who had been treated with pioglitazone for 12 weeks were examined retrospectively. In Study 1, multiple regression analysis revealed that the G/G but not C/G genotype was correlated with a reduction in fasting plasma glucose (FPG) and homeostasis model assessment of insulin resistance (HOMA-IR) compared to C/C. When adjusted for age, gender, and BMI, the G/G genotype was an independent factor for the reduction of FPG (P=0.020) and HOMA-IR (P =0.012). When studies 1 and 2 were combined by adjusting the studies, age, gender, and BMI, the reduction of HbA1c was correlated with the G/G genotype (beta=-0.511, P=0.044). Therefore, this pilot study suggests that the G/G genotype of resistin SNP -420 may be an independent predictor of the reduction of fasting plasma glucose and HOMA-IR by pioglitazone.

Immunohistochemical and electron microscopy studies of a case of hyalinizing trabecular tumor of the thyroid gland, with special consideration of the hyalinizing mass associated with it.

Hyalinizing trabecular tumor (HTT) of the thyroid gland is rare and benign, and it neither recurs nor metastasizes. In this lesion, tumor cells are arranged in trabeculae, in association with hyalinizing mass in the stroma. The origin and nature of the hyalinizing mass are still controversial. We report here a case of HTT with cytological, immunohistochemical, and ultrastructural findings, focused in particular on the hyalinizing mass. Cytologically, tumor cells exhibiting many intranuclear cytoplasmic inclusions and nuclear grooves were found in association with light green-positive, irregular, fluffy membranous structures on touch smear. Staining with antibody to collagen type IV was positive in these membranous structures. Histopathologically, tumor cells exhibited many intranuclear cytoplasmic inclusions, and were positive for staining with antibodies to S100 protein, neuron-specific enolase, thyroglobulin, and vimentin. The hyalinizing eosinophilic mass, which was positive for PAS reaction, and for staining by antibody to collagen type IV, gradually increased in the areas surrounding tumor cells. This mass then appeared to replace the tumor cells, and exhibited a peculiar filiform pattern. We demonstrated ultrastructurally that this pattern was composed of long, irregular, fine cytoplasmic processes of tumor cells and basal lamina-like substance in the hyalinizing mass. In fact, the homogeneous hyalinizing mass, similar to basal lamina-like substance, contained many degenerated cytoplasmic processes at the ultrastructural level. These results suggested that the key cytological finding in differentiating HTT from papillary carcinoma is the fluffy membranous structure, although nuclear pseudoinclusions are important as well. The filiform pattern noted at light microscopic level consisted of long cytoplasmic processes of tumor cells and hyalinized mass at the ultrastructural level.

Microparticles for sustained release of water-soluble drug based on a containment, dry coating technology.

Controlled release microparticles in a sub-gram-scale batch were fabricated using a ball mill, dry coating technique, to coat the water-soluble core material. This process also guaranteed the maintenance of the containment's integrity during the dry coating process. Quinine (average diameter, ca. 10 µm) and carnauba wax were used as the core and coating material, respectively. We evaluated the influence of process time, milling speed, and quinine-to-carnauba wax ratio on the particle size of the coated particles and their in vitro drug release profiles. Scanning electron microscopic observations suggested that the small wax particles attached to the core (quinine) particles resulted in a smooth film during the dry coating process. The size distribution of the coated particles agreed with the theoretically estimated size distribution. The in vitro release test demonstrated that the coated particles released quinine over 2 h in a biphasic mode. These results suggest that dry coating of microparticles less than 50 µm (D99) is feasible on a several-grams-batch scale. This new ball mill-coating technique also enables a guaranteed containment, a prerequisite for the manufacturing of highly bioactive or biohazard substances.

The Influence of Sodium and Potassium Intake and Insulin Resistance on Blood Pressure in Normotensive Individuals Is More Evident in Women.

BACKGROUND: Considering sex differences, salt sensitivity, and insulin resistance (IR), the effect of sodium restriction and increased potassium intake on blood pressure remains unclear in normotensive Asian individuals, compared to that in hypertensive patients. METHODS: To assess the influence of sodium and potassium intake in normotensive individuals, we evaluated the estimated 24-hour urinary sodium and potassium excretion rate in 3,392 drug-naïve normotensive Japanese individuals (average age: 48.4 years) and analyzed its relation to blood pressure using multivariate regression analysis. RESULTS: Multivariate regression analysis revealed that a 10-mmol/day increment in urinary sodium excretion related to an elevation in systolic blood pressure of 0.16 mm Hg in men and 0.37 mm Hg in women, after adjusting for known risk factors to salt sensitivity, including age, body mass index, serum creatinine, homeostasis model assessment of IR, and urinary potassium excretion. For urinary potassium excretion, a 10-mmol/day increment was associated with a decrease in systolic blood pressure, -0.54 mm Hg in men and -1.49 mm Hg in women, respectively. Furthermore, involvement of IR on blood pressure was observed only in women. CONCLUSIONS: In drug-naïve normotensive individuals, the effects of a lower-salt and higher-potassium diet, and IR on blood pressure, were more evident in women. These results suggest that to prevent the new onset of hypertension and its complications, the balances of a sodium restriction and an increased potassium intake are important even in normotensive individuals, independent of known risk factors for salt sensitivity, especially in women.

Synthesis of phosphorothioate oligonucleotide-peptide conjugates by solid phase fragment condensation.

Phosphorothioate oligonucleotide-peptide conjugates were synthesized by solid phase fragment condensation (SPFC). Arginine rich peptides could be successfully conjugated in 2.8-13.4% isolated yields. All the products were fully characterized by reversed phase HPLC and MALDI-TOF-MS to give satisfactory results.

A pilot study of short-term toe resistance training in patients with type 2 diabetes mellitus.

OBJECTIVE: The purpose of this pilot study was to investigate the effect of short-term toe resistance training on toe pinch force and toe muscle quality in patients with type 2 diabetes mellitus. METHODS: A total of 12 patients with type 2 diabetes mellitus who were hospitalized to improve glycemic control (8 men and 4 women, duration of diabetes 12.2 ± 9.5 years) were enrolled in this pilot study. Exercise therapy was performed with conventional aerobic exercise and four newly developed toe resistance training exercises for 2 weeks. Changes in anthropometric parameters, blood pressure (BP), heart rate, and muscle parameters, i.e. muscle mass, toe pinch force and toe muscle quality were evaluated after the exercise program. RESULTS: There were no significant differences of body weight, body mass index, BP, heart rate, and upper/lower muscle mass after exercise performance. However, toe pinch force was significantly increased (pre: 2.92 ± 1.19 kg, post: 3.65 ± 1.58 kg, p = 0.007). Toe muscle quality (toe pinch force/lower leg muscle mass) were also significantly increased (pre: 2.15 ± 0.86 kg/kg, post: 2.72 ± 1.26 kg/kg, p = 0.009). CONCLUSIONS: Two weeks of toe resistance training significantly increased toe pinch force and toe muscle quality in patients with type 2 diabetes mellitus. Toe resistance training is might be essential for treating patients with diabetes mellitus in clinical practice.