To clarify the pathogenesis of altered bone metabolism in diabetic state and its underlying mechanisms, the bone mineral content and fasting levels of serum intact parathyroid hormone (i-PTH), intact osteocalcin (i-OC), tartrate-resistant acid phosphatase (TRAP) and osteoclastgenesis inhibitory factor/osteoprotegerin (OCIF/OPG) were measured in male type 2 diabetic patients and their age-matched controls. In addition, urine levels of osteoclastic markers, C-telopeptide of type I collagen (CTx), deoxypyridinoline (DPD), and N-telopeptide of type I collagen (NTx) were simultaneously determined. Serum levels of i-PTH and i-OC in diabetic patients were significantly lower than those in the controls. Conversely, serum concentrations of TRAP were significantly elevated in diabetic patients. However, no clear correlation was observed between serum i-OC and TRAP. It was also observed that urinary excretion of CTx, DPD, and NTx was significantly increased in the diabetics as compared with the controls. Unexpectedly, serum levels of OCIF/OPG tended to be higher in the diabetic group, and these values exhibited a significantly positive correlation with those of serum TRAP. There was found a significantly negative correlation between serum TRAP and bone mineral density (BMD) and also between serum OCIF/OPG and bone mineral density. It seems probable that OCIF/OPG has a suppressive role on the increased bone resorption to prevent further loss of the skeletal bone mass in type 2 diabetic patients.

Diabetes mellitus is, so called, the disease of the blood vessel. Indeed in many cases, atherosclerosis is already developed from the prediabetic state because of an existence of insulin resistance. Therefore, it is very important to elucidate the pathophysiological relationship between diabetes and cerebrovascular disease accompanied with intravascular calcium precipitation. Here we introduce the recent topics about the underlying relation between diabetes and cerebrovascular disease with atherosclerotic disorders.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) regulates several cellular functions, but its physiological role in pancreatic islet cells remains to be investigated. In this study, we confirmed the presence of PPAR-gamma in rat isolated islets and examined its role on insulin and glucagon secretion by using PPAR-gamma-overexpressed islets. PPAR-gamma overexpression significantly suppressed insulin secretion induced by stimulatory concentration of glucose (p<0.05). In addition, insulin secretion evoked by high potassium depolarization also was significantly decreased from PPAR-gamma-overexpressed islets (p<0.05). On the other hand, no significant change in glucagon release was observed after high potassium depolarization between PPAR-gamma-overexpressed and control islets. Insulin and glucagon content in islets was not statistically different between the two groups. In addition, the expression of uncoupling protein-2 (UCP-2) was found to be induced in PPAR-gamma-overexpressed islets. This result clearly indicates that the deteriorative effect of PPAR-gamma overexpression on the secretory machinery is selective for pancreatic beta-cells. And it is possible that its site of action can be located in the energy-consuming exocytotic process of insulin secretory granules, and that the reduction of ATP production through increased UCP-2 reduces insulin exocytosis.

In order to assess the beneficial effect of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist pioglitazone on reduction of mass and alteration of function of pancreatic beta cells under diabetic conditions, diabetic C57BL/KsJ db/db mice were treated with pioglitazone for 6 weeks, and insulin secretory capacity and insulin content of isolated pancreatic islets were evaluated. In addition, the expression of oxidative stress markers, 4-hydroxy-2-nonenal (HNE)-modified proteins and heme oxygenase-1, in endocrine pancreas was examined to measure reduction of oxidative stress in pancreatic beta cells. The capacity for glucose-induced insulin secretion from isolated islets and their insulin content were improved by pioglitazone treatment (P <.01). When beta cells were stained with anti-insulin antibodies, those of db/db mice treated with pioglitazone exhibited strong staining, as also observed in their lean littermates. The density of immunostaining for oxidative stress markers was significantly reduced in pancreatic islets of pioglitazone-treated db/db mice (P <.05). This study clearly demonstrates the benefit of long-term treatment with pioglitazone in decreasing hyperglycemia and improving glucose-induced insulin secretory capacity in diabetic db/db mice. The results of immunocytochemical examination suggest that this treatment reduces oxidative stress and thereby preserves beta-cell mass. Treatment with pioglitazone thus protects against beta-cell damage and would be useful for restoration of insulin secretory capacity in obese diabetes individuals.

In order to investigate the underlying mechanism of alterations in bone mineral metabolism in patients with type 2 diabetes, we determined circulating levels of bone functional markers along with urinary excretion of sorbitol (SOR) and bone mineral density (BMD), and also examined their mutual interrelationship. A total of 151 male type 2 diabetic patients were examined in this study. Forty-eight age-matched male healthy subjects were also studied as the controls. A significant reduction of serum intact osteocalcin (i-OC) was found in the diabetic groups (p<0.01). On the other hand, circulating levels of tartrate resistant acid phosphatase (TRAP) in the diabetic patients were significantly higher than those in the controls (p<0.01). Interestingly, a significantly negative relationship was observed between BMD and serum TRAP (p<0.01), although no significant relationship was noted between BMD and serum i-OC in diabetic patients. Urinary excretion of SOR was significantly elevated in the diabetic patients when compared with the controls (p<0.01). In addition, a significantly positive correlation was observed between serum TRAP and urinary SOR (p<0.01), but not between serum i-OC and urinary SOR. Elevated serum TRAP in diabetes was reduced after the administration of aldose reductase inhibitor (p<0.05). It seems most likely that the increase in osteoclastic function probably due to accelerated polyol pathway plays a crucial role in the pathogenesis of decreased bone mineral content in male patients with type 2 diabetes.

Diverse age-associated neurodegenerative disorders are featured at a molecular level by depositions of self-aggregating molecules, as represented by amyloid beta peptides (Abeta) and tau proteins in Alzheimer's disease, and cascade-type chain reactions are supposedly commenced with biochemical aberrancies of these amyloidogenic components. Mutagenesis and multiplication of the genes encoding Abeta, tau and other pathogenic initiators may accelerate the incipient process at the cascade top, rationalizing generations of transgenic and knock-in animal models of these illnesses. Meanwhile, these genetic manipulations do not necessarily compress the timelines of crucial intermediate events linking amyloidogenesis and neuronal lethality, resulting in an incomplete recapitulation of the diseases. Requirements for modeling the entire cascade can be illustrated by a side-by-side comparison of humans and animal models with the aid of imaging-based biomarkers commonly applicable to different species. Notably, key components in a highly reactive state are assayable by probe-assisted neuroimaging techniques exemplified by positron emission tomography (PET), providing critical information on the in-vivo accessibility of these target molecules. In fact, multispecies PET studies in conjunction with biochemical, electrophysiological and neuropathological tests have revealed putative neurotoxic subspecies of Abeta assemblies, translocator proteins accumulating in aggressive but not neuroprotective microglia, and functionally active neuroreceptors available to endogenous neurotransmitters and exogenous agonistic ligands. Bidirectional translational studies between human cases and model strains based on this experimental paradigm are presently aimed at clarifying the tau pathogenesis, and would be expanded to analyses of disrupted calcium homeostasis and mitochondrial impairments. Since reciprocal causalities among the key processes have indicated an architectural interchangeability between cascade and network connections as an etiological representation, longitudinal imaging assays with manifold probes covering the cascade from top to bottom virtually delineate the network dynamics continuously altering in the course of the disease and its treatment, and therefore expedite the evaluation and optimization of therapeutic strategies intended for suppressing the neurodegenerative pathway over its full length.

We reevaluate the absolute fluorescence and phosphorescence quantum yields of standard solutions by using a novel instrument developed for measuring the absolute emission quantum yields of solutions. The instrument consists of an integrating sphere equipped with a monochromatized Xe arc lamp as the light source and a multichannel spectrometer. By using a back-thinned CCD (BT-CCD) as the detector, the sensitivity for spectral detection in both the short and long wavelength regions is greatly improved compared with that of an optical detection system that uses a conventional photodetector. Using this instrument, we reevaluate the absolute fluorescence quantum yields (Phi(f)) of some commonly used fluorescence standard solutions by taking into account the effect of reabsorption/reemission. The value of Phi(f) for 5 x 10(-3) M quinine bisulfate in 1 N H(2)SO(4) is measured to be 0.52, which is in good agreement with the value (0.508) obtained by Melhuish by using a modified Vavilov method. In contrast, the value of Phi(f) for 1.0 x 10(-5) M quinine bisulfate in 1 N H(2)SO(4), which is one of the most commonly used standards in quantum yield measurements based on the relative method, is measured to be 0.60. This value is significantly larger than Melhuish's value (0.546), which was estimated by extrapolating the value of Phi(f) for 5 x 10(-3) M quinine bisulfate solution to infinite dilution using the self-quenching constant. The fluorescence quantum yield of 9,10-diphenylanthracene in cyclohexane is measured to be 0.97. This system can also be used to determine the phosphorescence quantum yields (Phi(p)) of metal complexes that emit phosphorescence in the near-infrared region: the values of Phi(p) for [Ru(bpy)(3)](2+)(bpy = 2,2'-bipyridine) are estimated to be 0.063 in water and 0.095 in acetonitrile under deaerated conditions at 298 K, while that in aerated water, which is frequently used as a luminescent reference in biological studies, is reevaluated to be 0.040.

De Quervain disease is caused by a stenosing tenosynovitis in the first dorsal compartment, and the main aetiology is extensor pollicis brevis (EPB) tenosynovitis. We encountered three cases in which EPB tenosynovitis was absent and abductor pollicis longus (APL) tenosynovitis was confirmed during operation. In the treatment of de Quervain disease, APL tenosynovitis should be paid as much attention as EPB tenosynovitis.

A procedure was developed for the quantitative determination of chafuroside A, a flavone C-glycoside with potent anti-inflammatory activity, and its regioisomer chafuroside B, as well as isovitexin and vitexin, by selected reaction monitoring liquid chromatography-tandem mass spectrometry (SRM LC-MS/MS) analysis. This method was successfully applied to commercial leaves of green tea, houji tea, oolong tea, and black tea. High levels of chafurosides A and B were found in oolong tea leaves that had been heated at >140 degrees C. Next, their precursors, prechafurosides A and B, were isolated from methanol extract of oolong tea leaves prepared from Shizu 7132, Camellia sinensis (L.) O. Kuntze, by partition with n-butanol and H(2)O and chromatography on Diaion SP-825, Sephadex LH-20, and ODS C-18, guided by assay of chafuroside formation. Prechafurosides A and B gave chafurosides A and B, respectively, in good yields when heated at 160 degrees C for 0.5 h. Solvolysis of prechafurosides A and B with pyridine and dioxane quantitatively afforded isovitexin and vitexin, respectively. On the basis of these results and physicochemical data (MS, UV, and NMR), prechafurosides A and B were concluded to be new flavone C-glycoside sulfates, isovitexin-2''-sulfate and vitexin-2''-sulfate, respectively.

The review deals with the analysis of osteodensitometry data from the cosmonauts flown on Russian space station MIR and the International space station and suppositions about involvement of different levels of metabolism regulation in bone loss triggered by insufficient mechanic loading in microgravity attendant by redistribution of body liquids. It is surmised that the initial reactions are associated with the biomechanical factor and recruitment of local mechanisms, i.e. osteocyte osteolysis and inhibition of osteoblast histogenesis. Regulation on the level of tissues and organs is responsible for destabilization of calcium homeostasis (low calcium absorption in the intestine and readsorption in the kidney). Changes in the hierarchy of ion and volume regulation may provoke osteoclast resorption which further increases osteopenia.

Hyperglycemia and increase in advanced glycation end products in patients with diabetes are known to cause impaired calcium homeostasis such as reduction in parathyroid hormone secretion, decrease in calcium (Ca) absorption resulting from impaired vitamin D action, increase in urinary Ca excretion, impaired osteoblastic function, and deterioration of bone quality. On the other hand, fat deposition accompanied by the metabolic syndrome are positively linked to increased bone mineral density (BMD) and reduced fracture risk through increased body weight. However, body fat has a detrimental effect on BMD after adjustment for weight, and gives less mechanical stress on bone than muscle tissue that is firmly attached to bone via the tendon. Thus, converting fat into muscle tissue by regular exercise and healthy diet helps not only prevent hyperglycemia but also osteoporosis.

Type I (T1) diabetes, also called insulin dependent diabetes mellitus (IDDM), is characterized by little or no insulin production and hyperglycemia. One of the less well known complications of T1-diabetes is bone loss which occurs in humans and animal models. This complication is receiving increased attention because T1-diabetics are living longer due to better therapeutics, and are faced with their existing health concerns being compounded by complications associated with aging, such as osteoporosis. Both male and female, endochondrial and intra-membranous, and axial and appendicular bones are susceptible to T1-diabetic bone loss. Exact mechanisms accounting for T1-diabetic bone loss are not known. Existing data indicate that the bone defect in T1-diabetes is anabolic rather than catabolic, suggesting that anabolic therapeutics may be more effective in preventing bone loss. Potential contributors to T1-diabetic suppression of bone formation are discussed in this review and include: increased marrow adiposity, hyperlipidemia, reduced insulin signaling, hyperglycemia, inflammation, altered adipokine and endocrine factors, increased cell death, and altered metabolism. Differences between T1-diabetic- and age-associated bone loss underlie the importance of condition specific, individualized treatments for osteoporosis. Optimizing therapies that prevent bone loss or restore bone density will allow T1-diabetic patients to live longer with strong healthy bones. J. Cell. Biochem.(c) 2007 Wiley-Liss, Inc.

AIMS: To elucidate bone mineral density (BMD) and bone turnover in an un-selected group of patients with Systemic Sclerosis (SSc) in national based registry. MATERIAL AND METHODS: All patients who have been diagnosed with SSc in Iceland were invited to participate in the study. Participants underwent standardized interview and delivered urine and blood samples for measurements of various bone metabolites (e.g. PTH, osteocalcin, Cross Laps, PINP, IGF-1, Cystatin-C and 25-OH-vitamin-D), before they underwent measurement of BMD with DEXA (QDR 4500 Elite). RESULTS: Twenty-four individuals, 20 female and four male, of 29 diagnosed patients with SSc in Iceland accepted to participate in the study (83%). The mean age was 60 +/- 15 years. Seventeen of 20 females were postmenopausal. Twelve patients had history of fractures. Only four patients were on treatment with bisphosphonate. All measured bone metabolites were in normal ranges, but U-calcium was in the lower ranges. According to DEXA, eight patients had osteopenia (T-value =-1.0 --2.5) and three osteoporosis (T-value <---2.5), while six patients had BMD more than one standard deviation below the mean of age matched controls. CONCLUSION: Although the majority of patients with SSc have normal bone turnover and BMD, every fourth patient may have low BMD. No single pathogenic factor was observed, however, several individuals are in calcium saving stages reflected in low urinary calcium excretion. This may be result of defects in intestinal absorption of calcium due to gastrointestinal involvement of the disease. This study does not give opportunity to evaluate effects of treatment on BMD in this group of patients. Thus, individual evaluation concerning osteoporosis is recommended in patients with SSc.

As for the factor in the diabetes in which it takes part in a bone abnormal metabolism, this is given the insulin lack state, a high blood glucose state, and the complications accompanying diabetes, such as arteriosclerosis, neuropathy, and a renal dysfunction. The absolute, and/or relative insulin lack state deteriorate the function and reduce the number of osteoblast, in addition, the osteoblast dysfunction is also caused by the sorbitol accumulation brought in the osteoblast as the result of the continuation of high blood glucose state. It also prompts the osteoclastic bone absorption, and suppresses the expression of transcription factor gene that regulates the osteoblast differentiation, and resultantly, the apoptosis of the osteoblast is promoted. By these mechanisms intertwining, the differentiation and the maturity of the osteoblast is thought to be decrease and the bone formation process is obstructed.

INTRODUCTION: The aim of this study was to point out some dilemmas about the existence and pathogenesis of primary diabetic osteopathy as a separate entity, based on currently available studies. Expert disagreements are present not only about the occurrence of generalized osteopathy with diabetic disease, but also about direct relationship between metabolic diabetes control and bone metabolism and influence of disease duration and sex on bone changes. PATHOGENESIS OF DIABETIC OSTEOPATHY: Decreased bone formation is the basic mechanism leading to decreased bone mass. Biochemical markers showed no clear connection with bone density measurement. Insulin and insulin-like growth facotr (IGF) affect bone metabolism. OSTEOPATHY IN PATIENTS WITH DIABETIC DISEASE-TYPE1: Some clinical studies have shown that patients with diabetic disease-type have a mild decrease in bone mass, while others have not presented such results. OSTEOPATHY IN PATIENTS WITH DIABETIC DISEASE-TYPE2: In patients with diabetic disease-type 2 the risk for osteopathy is even less defined. Patients treated with oral hypoglycemics present with higher decrease of bone mass has than patients treated with insulin therapy. This could partly be explained by anabolic effects of insulin on bones. BONE FRACTURES IN PATIENTS WITH DIABETIC DISEASE: Literature data are contradictory concerning the occurrence of bone fractures in diabetic patients. A survey of bone fracture occurrence in diabetic patients was performed in "Veljko Vlahović Medical Center" in Vrbas and it included a group of 100 patients with diabetic disease. The results show that 12 patients had some fractures: mostly females in postmenopause, aged and with secondary insulin-dependent diabetes and most frequently arm fractures. Considering contradictory literature data, further longitudinal studies are necessary.

Primary hypercalciuria (PH) is very often accompanied by some degree of bone demineralization. The most frequent clinical condition in which this association has been observed is calcium nephrolithiasis. In patients affected by this disorder, bone density is very frequently low, and increased susceptibility to fragility fractures is reported. The very poor definition of this bone disease from a histomorphometric point of view is a crucial aspect. At present, the most common finding seems to be a low bone turnover condition. Many factors are involved in the complex relationships between bone loss and PH. Since bone loss was mainly reported in patients with fasting hypercalciuria, a primary alteration in bone metabolism was proposed as a cause of both hypercalciuria and bone demineralization. This hypothesis was strengthened by the observation that some bone resorbing-cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor nechrosis factor-alpha (TNF-alpha), are high in hypercalciuric patients. An excessive response to the acid load induced by dietary protein intake seems to be an additional factor explaining a primitive alteration of bone. The intestine plays a major role in the clinical course of bone disease in PH. Patients with absorptive hypercalciuria less frequently show bone disease, and a reduction in dietary calcium greatly increases the probability of bone loss in PH subjects. It has recently been reported that greater bone loss is associated with a larger increase in intestinal calcium absorption in PH patients. Considering the absence of parathyroid hormone (PTH) alterations, it was proposed that this is not a compensatory phenomenon, but probably the marker of disturbed cell calcium transport, involving both intestinal and bone tissues. While renal hypercalciuria is rather uncommon, the kidney still seems to play a role in the pathogenesis of bone loss in PH patients, possibly via the effect of mild-to-moderate urinary phosphate loss with secondary hypophosphatemia. In conclusion, bone loss is very common in PH patients. Even if most of the factors involved in this process have been identified, many aspects of this intriguing clinical condition remain to be elucidated.

Recently it is understood that bone metabolic markers are useful for monitoring bone diseases. On the other hand, metabolic disorders of calcium occur in some organic dysfunction, especially in renal dysfunction, and recent reports suggest that some bone metabolic markers might be useful to detect these disorders. This report refers to bone metabolic markers about renal and the other organic dysfunction.

Although osteopenia has been associated with human diabetes mellitus, the pathogenesis of diabetic osteopenia is unclear. In the present study, we evaluated the effect of diabetes on histomorphometry, bone mineral density (BMD)-measured by dual-energy X-ray absorptiometry (DXA)-and biomarkers of bone metabolism in rats up to 120 days after the onset of experimental diabetes. Female Wistar rats with a regular estrous cycle were randomly divided into two groups: control rats (n = 15) and diabetic rats without insulin treatment (n = 25). Diabetes was induced by injection of alloxan and was confirmed by the determination of blood glucose concentration (>250 mg/dl). The results revealed an approximate threefold increase of femoral trabecular distance in diabetic rats compared to controls. Conversely, trabecular thickness and bone trabecular volume were reduced twofold and 77%, respectively. BMD in both the metadiaphyseal region and total area of the femur was found to be clearly reduced in diabetic animals, with no significant differences between the groups. Serum alkaline phosphatase (ALP) and tartarate-resistant acid phosphatase (TRAP) activities showed significant six- and twofold increases, respectively, in diabetic rats. There were significant decreases in serum calcium and albumin concentrations in diabetic rats, but no difference was observed in serum magnesium, phosphorus, or creatinine concentrations between the groups. Overall, our findings support the conclusion that the diabetic state is associated with alterations in bone turnover, resulting in the development of osteopenia, which is related to the time of evolution of the disorder.