Terminal differentiation of keratinocytes was damaged in type 2 diabetic mice.

AIMS: Although skin manifestations are common in diabetic patients, its characteristics are poorly identified. This study explored the differentiation process of keratinocytes in type 2 diabetes mellitus (T2DM) in vivo. METHODS: Back skin of T2DM model KKAy/TaJcl mice (KKAy) and C57BL/6JJcl mice (control) aged 8 and 12 weeks was used. The mRNA expression of differentiation markers of keratinocytes was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of each marker in situ was examined immunohistochemically. RESULTS: KKAy mice showed hyperglycemia versus control mice. The histological findings showed increased thickness and structural impairment of epidermal tissue in KKAy mice. The qRT-PCR revealed that the expression of integrin beta 1 and keratin 14 in KKAy and control mice was identical. However, the expression of involucrin at 8 weeks, keratin 10 at 12 weeks, and filaggrin and loricrin at 8 and 12 weeks was decreased in KKAy mice. Immunohistochemical findings showed that filaggrin was markedly decreased in KKAy mice, though Ki-67 remained unchanged. CONCLUSION: The terminal differentiation process was impaired in the diabetic skin, while keratinocyte proliferation was preserved. Damaged terminal differentiation of keratinocytes may contribute to impairment of the skin barrier function in diabetic dermatoses.

Vasopressin escape and memory impairment in a model of chronic syndrome of inappropriate secretion of antidiuretic hormone in mice.

Recently, chronic hyponatremia, even mild, has shown to be associated with poor quality of life and high mortality. The mechanism by which hyponatremia contributes to those symptoms, however, remains to be elucidated. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a primary cause of hyponatremia. Appropriate animal models are crucial for investigating the pathophysiology of SIADH. A rat model of SIADH has been generally used and mouse models have been rarely used. In this study, we developed a mouse model of chronic SIADH in which stable and sustained hyponatremia occurred after 3-week continuous infusion of the vasopressin V2 receptor agonist 1-desamino-8-D-arginine vasopressin (dDAVP) and liquid diet feeding to produce chronic water loading. Weight gain in chronic SIADH mice at week 2 and 3 after starting dDAVP injection was similar to that of control mice, suggesting that the animals adapted to chronic hyponatremia and grew up normally. AQP2 expression in the kidney, which reflects the renal action of vasopressin, was decreased in dDAVP-infused water-loaded mice as compared with control mice that received the same dDAVP infusion but were fed pelleted chow. These results suggest that "vasopressin escape" occurred, which is an important process for limiting potentially fatal severe hyponatremia. Behavioral analyses using the contextual and cued fear conditioning test and T-maze test demonstrated cognitive impairment, especially working memory impairment, in chronic SIADH mice, which was partially restored after correcting hyponatremia. Our results suggest that vasopressin escape occurred in chronic SIADH mice and that chronic hyponatremia contributed to their memory impairment.

Level of urinary liver-type fatty acid-binding protein is associated with cardiac markers and electrocardiographic abnormalities in type-2 diabetes with chronic kidney disease stage G1 and G2.

Urinary liver-type fatty acid-binding protein (L-FABP) reflects the degree of stress in proximal tubules of the kidney. We examined the level of L-FABP in type-2 diabetes mellitus (T2DM) patients with chronic kidney disease (CKD) stage G1 and G2, and its relationship with cardiac markers and electrocardiographic (ECG) abnormalities. T2DM patients whose estimated glomerular filtration rate (eGFR) was ≥60 mL/min/1.73 m(2) were recruited [n = 276 (165 males), mean age 64 years]. The median level of urinary L-FABP was 6.6 µg/gCr. Urinary L-FABP showed significant correlation with urinary albumin-to-creatinine ratio (ACR) (r = 0.51, p < 0.0001). Median (25th-75th percentile) eGFR was 82 (72-95) mL/min/1.73 m2. We divided patients into four subgroups (group 1, L-FABP ≤8.4 µg/gCr and ACR ≤30 mg/gCr; group 2, L-FABP ≤8.4 µg/gCr and ACR >30 mg/gCr; group 3, L-FABP >8.4 µg/gCr and ACR ≤30 mg/gCr; group 4, L-FABP >8.4 µg/gCr and ACR >30 mg/gCr). Compared with group 1, group 4 was significantly higher in systolic blood pressure, and eGFR using standardized serum cystatin C, high-sensitivity troponin T, and N-terminal pro-brain natriuretic peptide (NT-proBNP). Group 4 had significantly higher level of NT-proBNP than group 3. Groups 2, 3 and 4 showed more ECG abnormalities than group 1. These findings suggest that simultaneous measurement of urinary L-FABP and ACR should be useful to assess cardiovascular damage reflecting on the elevation of cardiac markers and ECG abnormalities in T2DM with CKD G1 and G2.

Impact of osteoporosis liaison services on the expected lifetime osteoporosis-related medical expenses of patients with fragility fracture in a private hospital in Japan.

We report the efficacy of a Japanese fracture liaison service (FLS), the osteoporosis liaison service (OLS), in suppressing osteoporosis-related expenses from the public insurance by preventing secondary fracture in spite of higher medication costs during expected life spans. OLS could reduce medical expenses for osteoporosis in all age groups. PURPOSE: Osteoporosis liaison services (OLS), which are based on fracture liaison services (FLS), are used in Japan to prevent both primary and secondary fractures in older people. We aimed to clarify the effects of OLS on the medical expenses. PATIENTS AND METHODS: We compared patients with fragile fractures hospitalized to Saitama Jikei Hospital before and after implementing OLS. These were labeled a non-OLS group and an OLS group, and they were further organized by age (< 75, 75-84, and ≥ 85 years). The expected osteoporosis-related medical expenses during life were calculated by the occurrence, fracture site, medication, and life expectancy and compared between the non-OLS and OLS groups by the age group. RESULTS: The non-OLS group included 400 people (100 males and 300 females, mean age 81.7 ± 9.7 years), comprising 154 with vertebral fractures and 246 with hip fractures. The OLS group included 406 patients (101 males and 305 females, mean age 82.4 ± 9.3 years), of whom 161 had vertebral fractures and 245 had hip fractures. The suppressive secondary fracture effects of OLS were previously reported. The expected expense of osteoporosis treatment in the OLS group was found to be greater than that in the non-OLS group for all age groups. In contrast, expected expenses for treating secondary fractures were shown to increase more in the non-OLS group. However, total expenses were lower in the OLS group across all age groups. CONCLUSION: The implementation of OLS can reduce overall healthcare costs despite the increased expenses required to provide medical therapy and periodic examinations.

Effectiveness of a Japanese multi-professional cooperative osteoporosis liaison service at a private hospital for decreasing secondary fractures in osteoporosis patients with fragility fractures.

PURPOSE: A fracture liaison service (FLS) was established in England to support patients with fragility fractures, and it was introduced in Japan as the osteoporosis liaison service (OLS). The study aim was to determine if the Japanese OLS/FLS prevents secondary fractures in patients with fragility fractures and assess the value of the OLS/FLS. Our OLS/FLS evaluated the status of osteoporosis in patients and their life circumstances. Additionally, it introduced osteoporosis therapies during the patients' hospitalization period and then continued periodical examinations and prescription of drug after discharge. PATIENTS AND METHODS: This study was conducted in consecutive patients: 400 were assigned to the non-OLS group and 406 to the OLS group. The mean age of the patients was 81.7 ± 9.7 years in the non-OLS group (154 patients with vertebral fractures and 246 with hip fractures; 100 males, 300 females) and 82.4 ± 9.3 years in the OLS group (245 patients with hip fractures and 161 with vertebral fractures; 101 males, 305 females). RESULTS: During hospitalization, 74.9% of the OLS group patients started medications and 63.9% of patients continued after discharge, while 35.8% and 53.5% of non-OLS group. The incidence rate of secondary fractures was 89.8/1000 person-years in the non-OLS group, and 55.2/1000 person-years in the OLS group. The multivariate Cox hazards test showed that secondary fractures after vertebral or hip fractures increased with age, and the risk was 0.58-fold in patients in the OLS group. CONCLUSION: OLS was effective in reducing secondary fractures in patients with osteoporosis with fragility fractures.

Risedronate Attenuates Podocyte Injury in Phosphate Transporter-Overexpressing Rats.

Osteoporosis patients with chronic kidney disease (CKD) are becoming common in our superaging society. Renal dysfunction causes phosphorus accumulation in the circulating plasma and leads to the development of CKD-mineral bone disorder (MBD). We have previously reported that type III Pi transporter-overexpressing transgenic (Pit-1 TG) rats manifest phosphate (Pi)-dependent podocyte injury. In the present study, we explored the effect of risedronate on Pi-induced podocyte injury in vivo. Pit-1 TG rats and wild-type rats at 5 weeks old were divided into a risedronate-treated group and an untreated group. We subcutaneously administered 5 µg/kg body weight of risedronate or saline twice a week during the experimental period. Risedronate did not alter serum creatinine levels at 5, 8, and 12 weeks of age. However, electron microscopy images showed that thickening of the glomerular basement membrane was improved in the risedronate treatment group. Furthermore, immunostaining for podocyte injury markers revealed that both desmin- and connexin43-positive areas were smaller in the risedronate-treated group than in the untreated group, suggesting that bisphosphonates could rescue Pi-induced podocyte injury. In conclusion, our findings suggest that risedronate could maintain glomerular barrier function by rescuing Pi-induced podocyte injury.

Low-carbohydrate diet by staple change attenuates postprandial GIP and CPR levels in type 2 diabetes patients.

AIMS: The aim of this study is to investigate the effects of a low-carbohydrate staple food (i.e., low-carbohydrate bread) on glucose and lipid metabolism and pancreatic and enteroendocrine hormone secretion in comparison with meals containing normal-carbohydrate bread, without consideration of the carbohydrate content of the side dishes. METHODS: T2DM patients (n = 41) were provided meals containing low-carbohydrate bread (LB) together with side dishes or normal-carbohydrate bread (NB) together with side dishes every other day as a breakfast. Blood glucose levels were evaluated by using a continuous glucose monitoring system; blood samples were collected before and 1 and 2 h after the breakfast. RESULTS: Postprandial blood glucose levels, plasma insulin, plasma glucose-dependent insulinotropic polypeptide (GIP) and plasma triglyceride were significantly lower and plasma glucagon levels were significantly higher in LB compared with those in NB. Plasma glucagon-like peptide-1 (GLP-1) levels did not differ in the LB and NB groups. CONCLUSIONS: These results indicate that changing only the carbohydrate content of the staple food has benefits on glucose and lipid metabolism in T2DM patients concomitant with the decrease of insulin and GIP secretion, which ameliorate body weight gain and insulin resistance.

[Papillary adenocarcinoma in a seminal vesicle cyst associated with contralateral renal agenesis: a case report].

We report a case of papillary adenocarcinoma inside a seminal vesicle cyst associated with contralateral renal agenesis in a 30-year-old man. Coexistence of a seminal vesicle cyst and tumors is rare. Surgical excision was performed but he died due to liver metastases one year later.

Nutritional status of calcium and other bone-related nutrients in Japanese type 2 diabetes patients.

OBJECTIVES: Traditional Japanese food appears to be healthy but contains a small amount of milk products. Type 2 diabetes (T2DM) patients commonly reduce their energy intake to control their blood glucose levels. However, nutritional guidance for diabetes does not emphasize calcium (Ca) consumption. The aim of this study is to estimate the nutritional status of Ca and other nutrients, which affect bone and Ca metabolism, in T2DM patients. METHODS: This observational study was conducted with Japanese T2DM patients (n = 96; M/F = 50/46; age: 61.6 ± 10.1 years). We estimated nutrient intake using a simple food frequency questionnaire. RESULTS: Median total energy intake was 1750 kcal/day (1440-1970). Their median daily intake of Ca, vitamin D, and vitamin K was 451 mg (336-560), 10.2 µg (8.5-12), and 206 µg (84-261), respectively. Only 17.7% of the study subjects were found to take more than 600 mg/day of Ca. Protein and salt intake was 78 (64-90) and 10.6 (9.3-12.2) g/day, respectively. Male subjects had more salt, less Ca and vitamin K than female. Daily Ca intake was positively associated with total energy, protein, and lipid intake but not with carbohydrates. Vitamin D intake correlated only with protein intake. CONCLUSIONS: The daily Ca intake of Japanese T2DM patients appears to be insufficient and could depend on protein and lipid intake. Additionally, these patients should have specific recommendations to ensure sufficient intake of Ca with protein and lipid during energy restriction.

Synthetic peptides of actin-tropomyosin binding region of troponin I and heat shock protein 20 modulate the relaxation process of skinned preparations of taenia caeci from guinea pig.

To explore the possible role of the thin filament-linked regulation of cross-bridge cycling in living smooth muscle contraction, we studied the effects of TnIp and HSP20p, a synthetic peptide originating from an actin tropomyosin binding region of rabbit cardiac troponin I (residues 136-147; GKFKRPTLRRVR), and that of human heat shock protein 20 (residues 110-121; GFVAREFHRRYR) on the relaxation of skinned (cell membrane ilized) preparations from guinea pig taenia caeci. An active stress of the skinned preparations, resulting from actin-myosin interaction, rapidly decayed following Ca(2+) removal (relaxation). TnIp accelerated the initial rapid phase and slowed the following slow phase of the relaxation. On the other hand, HSP20p only slowed the whole process of the relaxation. The relaxation time courses were well fitted in a double exponential manner, and the double exponential decay of the stress could be explained as a portion of fast-detaching cross bridges not to dissociate rapidly by Ca(2+) removal, but to transfer to latch bridges dissociating very slowly. Our present results suggested that (i) TnIp and HSP20p accelerated transferring from fast-detaching cross bridges to slow-detaching (latch) bridges, and (ii) TnIp accelerated dissociation of the fast-detaching cross bridges and the latch bridges, while HSP20p slowed dissociation the fast-detaching cross bridges. Since TnIp and HSP20p are thought to bind to actin and tropomyosin, but not to myosin, we concluded that through thin-filament-dependent mechanisms these peptides regulated the formation and/or deformation of latch bridges in smooth muscle. The thin-filament-dependent regulation might physiologically control the stress maintenance and relaxation in smooth muscle cells.

[A case demonstrating knot formation at the upper end of a ureteral stent].

A 37-year old man underwent extracorporeal shock wave lithotripsy for left renal stones after placing a ureteral stent (6 Fr multilength stent). Three months later the stent could not be extracted because of knot formation at the upper end. We performed ureterotomy and removed the stent.

[Schwannoma with purely cystic form originating from the adrenal area: a case report].

A 62-year-old woman was hospitalized with complaints of right upper abdominal discomfort. Various imaging studies showed an extremely large suprarenal mass with solitary cystic formation. Partial adrenalectomy was successfully performed through the transperitoneal approach. The resected mass measured 12 x 10 x 10 cm and weighed 600 g. A pathological examination showed an Antoni-B predominant-type benign schwannoma containing a large volume of degenerative fluid. Our search of literature yielded few reports of solitary cystic schwannomas in the retroperitoneal cavity or throughout the body. This unusual cystic manifestation is thought to be a terminal stage of degeneration of a long-standing schwannoma.

Relative levels of the inflammatory cytokine TNFα and the soluble CD40 ligand profile in serum correlate with the thyrotoxic activity of Graves' disease.

BACKGROUND: Interactions between CD40 and its ligand (CD40L) have important roles in T-cell-dependent activation of B cells, which may be related to the thyrotoxic activity of Graves' disease (GD). Soluble forms of CD40 ligand (sCD40L) are released from activated T cells and platelets, and several types of inflammatory cytokines are increased in patients with hyperthyroid GD. The aim of this study was to assess sCD40L and other cytokines as clinical indicators of disease activity or as possible markers of remission in GD. METHODS: Serum levels of sCD40L, interleukin 18 (IL-18), tumor necrosis factor-alpha (TNFα), and TNFα receptors 1 and 2 (TNFR1 and TNFR2) were investigated in patients with active GD (GD-A), intractable GD (GD-IT), inactive GD (GD-IA), GD in remission (GD-R), and Hashimoto's thyroiditis (HT), and in control subjects (CON). RESULTS: Serum concentrations of sCD40L were higher in the GD-A and GD-IT groups than in the HT and CON groups. Similarly, serum concentrations of IL-18, which induces Th1 cytokines, such as interferon-γ, were higher in the GD-A and GD-IT groups than in all other groups. Serum levels of TNFR1 and TNFR2 were also significantly higher in the GD-A than in all other groups. The mean serum concentration of TNFα was higher in the GD-R compared with the GD-A and GD-IT groups, although the difference was not significant. Serum sCD40L concentrations in the GD-R group were lower than in the GD-A and GD-IT groups. Finally, the ratio of serum TNFα to sCD40L was higher in the GD-R group than in the GD-A and GD-IT groups. This is the first report that serum sCD40L is increased in active GD, and that the serum TNFα:sCD40L ratio is a marker for remission in GD. CONCLUSIONS: Our results suggest that not only thyrotoxicosis, but also the activity of the immunoreaction presenting as anti-thyrotropin receptor antibodies (TRAb) titer in GD, affects inflammatory cytokine serum profiles. Serum profiles of cytokines vary in patients with GD depending on disease activity. An elevated serum TNFα:sCD40L ratio indicates declining disease activity and reflects a shift from Th2 to Th1 dominance, suggesting that suppression of sCD40L or increased production of TNFα is required to initiate or maintain remission of GD.

Troponin I inhibitory peptide suppresses the force generation in smooth muscle by directly interfering with cross-bridge formation.

To explore possible mechanisms involving the thin filament-linked regulation of contraction in living smooth muscles, we studied the effects of a synthetic peptide of rabbit cardiac troponin I [residues 136-147] (TnIp), which is a minimal sequence required to inhibit striated muscle acto-tropomyosin-myosin ATPase activity, on the mechanical properties of beta-escin skinned preparations of taenia caeci from guinea pig. TnIp reversibly suppressed the Ca(2+)-activated force without significant effects on the Ca(2+) sensitivity and on the phosphorylation level of myosin regulatory light chain (MLC(20)). TnIp also reversibly suppressed the Ca(2+)/calmodulin-independent contraction induced by 30mM Mg(2+). An analogue of TnIp, which lost inhibiting action on acto-tropomyosin-myosin ATPase activity, affected neither Ca(2+)-activated nor 30mM Mg(2+)-induced contraction. These results indicate that TnIp suppresses the force generation in smooth muscle by directly interfering with cross-bridge formation rather than inhibiting the Ca(2+)/calmodulin-dependent thick and thin filament activating processes.