Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism

Inorganic phosphate is essential for ECM mineralization and also as a constituent of important molecules in cellular metabolism. Investigations of several hypophosphatemic diseases indicated that a hormone-like molecule probably regulates serum phosphate concentration. FGF23 has recently been recognized as playing important pathophysiological roles in several hypophosphatemic diseases. We present here the evidence that FGF23 is a physiological regulator of serum phosphate and 1,25-dihydroxyvitamin D (1,25[OH]2D) by generating FGF23-null mice. Disruption of the Fgf23 gene did not result in embryonic lethality, although homozygous mice showed severe growth retardation with abnormal bone phenotype and markedly short life span. The Fgf23(-/-) mice displayed significantly high serum phosphate with increased renal phosphate reabsorption. They also showed an elevation in serum 1,25(OH)2D that was due to the enhanced expression of renal 25-hydroxyvitamin D-1alpha-hydroxylase (1alpha-OHase) from 10 days of age. These phenotypes could not be explained by currently known regulators of mineral homeostasis, indicating that FGF23 is essential for normal phosphate and vitamin D metabolism.     

Role of Dok-1 and Dok-2 in myeloid homeostasis and suppression of leukemia

Dok-1 and Dok-2 are closely related rasGAP-associated docking proteins expressed preferentially in hematopoietic cells. Although they are phosphorylated upon activation of many protein tyrosine kinases (PTKs), including those coupled with cytokine receptors and oncogenic PTKs like Bcr-Abl, their physiological roles are largely unidentified. Here, we generated mice lacking Dok-1 and/or Dok-2, which included the double-deficient mice succumbed to myeloproliferative disease resembling human chronic myelogenous leukemia (CML) and chronic myelomonocytic leukemia. The double-deficient mice displayed medullary and extramedullary hyperplasia of granulocyte/macrophage progenitors with leukemic potential, and their myeloid cells showed hyperproliferation and hypo-apoptosis upon treatment and deprivation of cytokines, respectively. Consistently, the mutant myeloid cells showed enhanced Erk and Akt activation upon cytokine stimulation. Moreover, loss of Dok-1 and/or Dok-2 induced blastic transformation of chronic phase CML-like disease in mice carrying the bcr-abl gene, a cause of CML. These findings demonstrate that Dok-1 and Dok-2 are key negative regulators of cytokine responses and are essential for myeloid homeostasis and suppression of leukemia.     

Oral ADSORBENT AST-120 decreases carotid intima-media thickness and arterial stiffness in patients with chronic renal failure

BACKGROUND/AIM: Intima media thickness (IMT) and stiffness of the carotid arteries is related to coronary artery disease, and chronic renal failure patients are at high risk for such diseases. An oral adsorbent, AST-120 (Kremezin; Kureha Chemical Industry, Tokyo, Japan), can delay the progression of chronic renal failure in undialyzed uremic patients. The aim of the present study was to determine whether AST-120 affects carotid artery IMT and pulse wave velocity (PWV) in patients with chronic renal failure not undergoing dialysis. METHODS: Fifty patients with non-diabetic chronic renal failure were randomly divided into two groups: 30 patients (18 men and 12 women; mean age 53.5 years; mean serum creatinine 3.2 mg/dl) who were given AST-120 (6.0 g/day) and 20 patients (12 men and 8 women; mean age 52.0 years; mean serum creatinine 3.5 mg/dl) who were not given AST-120. Thirty healthy age-matched subjects (18 men and 12 women; mean age 51.5 years; mean serum creatinine 0.9 mg/dl) were also included. The treatment period was 24 months. IMT and arterial stiffness were measured before and after treatment. RESULTS: The slope of the reciprocal serum creatinine concentration over time became significantly less steep in the AST-120 group than in the non-AST-120 group (p < 0.001). Before treatment, carotid artery IMT differed little between the AST-120 group (0.90 +/- 0.22 mm) and the non-AST-120 group (0.88 +/- 0.20 mm). IMT in these two groups was significantly greater than IMT in the control group (0.64 +/- 0.14 mm) (p < 0.01). Carotid IMT in the AST-120 group decreased slightly but not significantly to 0.84 +/- 0.20 mm after 12 months and then significantly after 24 months to 0.78 +/- 0.18 mm (p < 0.05). Carotid IMT in the non-AST group showed little change throughout the experimental period. PWV differed little between the AST-120 group (1,980 +/- 330 cm/s) and the non-AST group (1,940 +/- 360 cm/s) before treatment. PWV values in these two groups were significantly greater than PWV in the control group (1,280 +/- 240 cm/s) (p < 0.01). After 12 and 24 months, PWV in the AST-120 group decreased significantly to 1,840 +/- 280 cm/s (p < 0.05) and to 1,780 +/- 260 cm/s (p < 0.05), respectively; however, PWV in the non-AST group showed a slight increase during the experimental period. CONCLUSION: The data suggest that AST-120 may reduce arterial stiffness and IMT in non-diabetic chronic renal failure patients before dialysis.     

Graciloplasty for internal and external sphincteric resection of lower rectal cancer

Anal sphincteric resection for rectal cancer is most commonly followed by colostomy in the lower abdominal wall, which enforces quite a poor quality of life due to a permanent stoma. For surgeons treating lower rectal cancer, the goal is to achieve defecation via the anus without placing a stoma. Internal sphincteric resection, partial external sphincteric resection and coloanal anastomosis have been reported for the treatment of lower rectal cancer with avoiding a colostoma. Extended resection of the external sphincter, however, limits patient's daily activities because of poor functional results and necessitates reconstruction of damaged anal function. This paper describes a case of graciloplasty for postoperative anal dysfunction that yielded a good clinical outcome in a 65-year-old female who had undergone very low anterior resection with complete internal and partial external sphincteric resection for lower rectal cancer.     

Antecedent hypertension interacts with adverse ventricular remodeling after myocardial infarction

BACKGROUND: Ventricular remodeling is an independent predictor of left ventricular function in patients with myocardial infarction (MI). Accelerated ventricular remodeling is a probable contributor to the increased mortality observed after MI in hypertensive patients. The purpose of this study is to assess the relationship of antecedent hypertension to ventricular remodeling after MI. METHODS: Seventy-nine patients presenting with a first acute MI (AMI) who were treated and attained Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 with re-perfusion therapy within 12 hours of their symptom onset were enrolled in this study. All of them underwent left ventriculography (LVG) immediately after re-perfusion therapy and again at 6 months after the occurrence of MI. Patients were divided into two groups; hypertensive group and normotensive group. End-diastolic volume index (EDVI), end-systolic volume index (ESVI), and EF were compared between acute phase and 6 months after AMI in each group. RESULTS: The hypertensive group showed a significant increase in both EDVI and ESVI after 6 months, whereas the normotensive group did not. In addition, there was no change in EF in the hypertensive group, whereas EF increased significantly after 6 months in the normotensive group. As a result, percent change in ESVI and EF showed significantly differences between the hypertensive group and normotensive group, whereas percent change in EDVI showed no significant difference between the two groups. CONCLUSIONS: Antecedent hypertension interacts with ventricular remodeling after MI.     

Some dietary fibers increase elimination of orally administered polychlorinated biphenyls but not that of retinol in mice

Dietary fiber supplementation can increase the size and nutrient absorption capacities of the small intestine in some mammals, but does this increase the risk of accumulating environmental contaminants? This study addressed this question by feeding mice diets containing various types of fiber at 0 or 100 g/kg (cellulose, lactosucrose, polydextrose, indigestible dextrin, soy polysaccharide, rice bran and chitosan) for 10 wk. During the final 2 wk, the mice were fed retinol and a dose of Arochlor 1254 [polychlorinated biphenyls (PCB)] estimated to be 5% of the median lethal dose. Accumulation was determined using whole blood samples collected on days 1, 3 and 7 as well as eight tissues (whole blood, small and large intestine, liver, gall bladder, mesentery, kidney and brain). Elimination of Arochlor 1254 and retinol was determined using daily collections of feces and urine. The patterns of accumulation and elimination differed between Arochlor 1254 and retinol, among tissues, and among mice fed diets with various amounts and types of fiber. Dietary fiber supplementation did not decrease accumulation of PCB. However, the diet with chitosan increased fecal excretion of Arochlor 1254 compared to the fiber-free diet (P<0.05). The diets with fermentable fiber (polydextrose, indigestible dextrin and soy polysaccharides) increased urinary excretion of PCB compared to the diets with water-insoluble fiber (cellulose, rice bran and chitosan; P<0.05). The most efficacious diets for minimizing accumulation of environmental contaminants and accelerating elimination likely include a combination of soluble and insoluble fiber, but the specific types, proportions and amounts remain to be determined.     

Effects of changing shift schedules from a full-day to a half-day shift before a night shift on physical activities and sleep patterns of single nurses and married nurses with children

To clarify the effects of changing shift schedules from a full-day to a half-day before a night shift, 12 single nurses and 18 married nurses with children that engaged in night shift work in a Japanese hospital were investigated. Subjects worked 2 different shift patterns consisting of a night shift after a half-day shift (HF-N) and a night shift after a day shift (D-N). Physical activity levels were recorded with a physical activity volume meter to measure sleep/wake time more precisely without restricting subjects' activities. The duration of sleep before a night shift of married nurses was significantly shorter than that of single nurses for both shift schedules. Changing shift from the D-N to the HF-N increased the duration of sleep before a night shift for both groups, and made wake-up time earlier for single nurses only. Repeated ANCOVA of the series of physical activities showed significant differences with shift (p < 0.01) and marriage (p < 0.01) for variances, and age (p < 0.05) for a covariance. The paired t-test to compare the effects of changing shift patterns in each subject group and ANCOVA for examining the hourly activity differences between single and married nurses showed that the effects of a change in shift schedules seemed to have less effect on married nurses than single nurses. These differences might due to the differences of their family/home responsibilities.     

FR227244, a novel antifungal antibiotic from Myrothecium cinctum No. 002 Taxonomy, fermentation, isolation and physico-chemical properties

A novel antifungal antibiotic, FR227244, was isolated from the culture broth of a fungal strain No. 002. The strain was identified as Myrothecium cinctum from morphological and physiological characteristics. This compound was isolated from the culture broth by solvent extraction, HP-20 and YMC ODS gel column chromatographies, and n-hexane precipitation. FR227244 is a white powder which melts at 210 to approximately 211 degrees C and possesses the molecular formula C38H58O11. FR227244 is a novel triterpene glycoside with antifungal activity against Aspergillus fumigatus. The effects of FR227244 on the morphology of A. fumigatus were shown to be similar to those of FR901379 which is a known 1,3-beta-glucan synthase inhibitor.     

New class of corticotropin-releasing factor (CRF) antagonists: small peptides having high binding affinity for CRF receptor

The discovery of small and potent peptide antagonists of the corticotropin-releasing factor (CRF) receptor is described. Through the structure-activity relationship studies of 12-amino acid peptide corresponding to the C-terminal residues of astressin, we assumed that a particular surface of the alpha-helix was important for binding to the receptor. The small peptide containing d-Ala31 and cyclohexylalanine38 on that surface was as potent as astressin in binding to the CRF receptor and showed significant ACTH suppression when administered to rats.