An Entropy-Based Tool to Help the Interpretation of Common-Factor Spaces in Factor Analysis.

This paper proposes a method for deriving interpretable common factors based on canonical correlation analysis applied to the vectors of common factors and manifest variables in the factor analysis model. First, an entropy-based method for measuring factor contributions is reviewed. Second, the entropy-based contribution measure of the common-factor vector is decomposed into those of canonical common factors, and it is also shown that the importance order of factors is that of their canonical correlation coefficients. Third, the method is applied to derive interpretable common factors. Numerical examples are provided to demonstrate the usefulness of the present approach.

Vasopressin secretion by hypertonic saline infusion during hemodialysis: effect of cardiopulmonary recirculation.

BACKGROUND: Intradialytic hypotension is the most common and severe acute complication of hemodialysis therapy. In our previous study, infusion of 20 mL of 10% saline into the venous line of a dialyzer increased blood pressure during dialysis hypotension by stimulating arginine vasopressin (AVP) secretion, independent of its effect on plasma volume (PV). This study examines the mechanism by which a small amount of hypertonic solution stimulates AVP secretion. METHODS: Hemodialysis patients were infused with 20 mL of 2.5 M saline (100 mOsm) over 5 (Protocol 1) or 2 min (Protocol 2) or with isotonic saline (Protocol 3) into the venous line. RESULTS: Arterial plasma osmolality (Posm) increased by 28.1 and 16.0 (P < 0.0001), while peripheral venous Posm increased by only 8.6 and 8.9 mOsm/kg H(2)O (P < 0.001) in Protocols 2 and 1, respectively. Plasma AVP (P(AVP)) increased significantly by 18.6 and 5.6 pg/mL, PV by 7.2 and 5.5% and mean arterial pressure (MAP) by 15.0 and 7.2 mmHg in Protocols 2 and 1, respectively. Thus, there were large differences in Posm between arterial and peripheral venous blood; osmolar gap, P(AVP) and MAP increased in proportion to the infusion rate. Isotonic saline (30.8 mOsm) infusion increased PV by 8.7% and MAP by 7.2 mmHg. CONCLUSION: Our results indicate that by a mechanism similar to cardiopulmonary recirculation, hypertonic saline infusion caused a striking increase in arterial Posm that enhanced AVP secretion and raised blood pressure. The effect of hypertonic saline on PV was less than one-third of isotonic saline under similar osmolar loads.

Cinacalcet effectively reduces parathyroid hormone secretion and gland volume regardless of pretreatment gland size in patients with secondary hyperparathyroidism.

BACKGROUND AND OBJECTIVES: Cinacalcet is effective in reducing serum parathyroid hormone (PTH) in patients with secondary hyperparathyroidism. However, it has not been proven whether parathyroid gland size predicts response to therapy and whether cinacalcet is capable of inducing a reduction in parathyroid volume. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This 52-week, multicenter, open-label study enrolled hemodialysis patients with moderate to severe secondary hyperparathyroidism (intact PTH >300 pg/ml). Doses of cinacalcet were adjusted between 25 and 100 mg to achieve intact PTH <180 pg/ml. Ultrasonography was performed to measure the parathyroid gland size at baseline, week 26, and week 52. Findings were also compared with those of historical controls. RESULTS: Of the 81 subjects enrolled, 56 had parathyroid glands smaller than 500 mm(3) (group S) and 25 had at least one enlarged gland larger than 500 mm(3) (group L). Treatment with cinacalcet effectively decreased intact PTH by 55% from baseline in group S and by 58% in group L. A slightly greater proportion of patients in group S versus group L achieved an intact PTH <180 pg/ml (46 versus 32%) and a >30% reduction from baseline (88 versus 78%), but this was not statistically significant. Cinacalcet therapy also resulted in a significant reduction in parathyroid gland volume regardless of pretreatment size, which was in sharp contrast to historical controls (n = 87) where parathyroid gland volume progressively increased with traditional therapy alone. CONCLUSIONS: Cinacalcet effectively decreases serum PTH levels and concomitantly reduces parathyroid gland volume, even in patients with marked parathyroid hyperplasia.

Effects of synthetic sphingosine-1-phosphate analogs on cytosolic phospholipase A2alpha-independent release of arachidonic acid and cell toxicity in L929 fibrosarcoma cells: the structure-activity relationship.

Sphingolipid metabolites including ceramide, sphingosine, and their phosphorylated products [sphingosine-1-phosphate (S1P) and ceramide-1-phosphate] regulate cell functions including arachidonic acid (AA) metabolism and cell death. The development of analogs of S1P may be useful for regulating these mediator-induced cellular responses. We synthesized new analogs of S1P and examined their effects on the release of AA and cell death in L929 mouse fibrosarcoma cells. Among the analogs tested, several compounds including DMB-mC11S [dimethyl (2S,3R)-2-tert-butoxycarbonylamino-3-hydroxy-3-(3'-undecyl)phenylpropyl phosphate] and DMB-mC9S [dimethyl (2S,3R)-2-tert-butoxycarbonylamino-3-hydroxy-3-(3'-nonyl)phenylpropyl phosphate] released AA within 1 h and caused cell death 6 h after treatment. The release of AA was observed in C12 cells [a L929 variant lacking a type alpha cytosolic phospholipase A(2) (cPLA(2)alpha)] and L929-cPLAalpha-siRNA cells (L929 cells treated with small interference RNA for cPLA(2)alpha). Treatment with pharmacological inhibitors of secretory and Ca(2+)-independent PLA(2)s decreased the DMB-mC11S-induced release of AA. The effect of the S1P analogs tested on the release of AA was comparable to that on cell death in L929 cells, and a high correlation coefficient was observed. Two analogs lacking a butoxycarbonyl moiety [DMAc-mC11S (dimethyl (2S,3R)-2-acetamino-3-hydroxy-3-(3'-undecyl)phenylpropyl phosphate] and DMAm-mC11S [dimethyl (2S,3R)-2-amino-3-hydroxy-3-(3'-undecyl)phenylpropyl phosphate)] had inhibitory effects on the release of AA and cell toxicity induced by DMB-mC11S. Synthetic phosphorylated lipid analogs may be useful for studying PLA(2) activity and its toxicity in cells. [Supplementary Fig. 1: available only at http://dx.doi.org/10.1254/jphs.08284FP].

Cytotoxicity induced by inhibition of thioredoxin reductases via multiple signaling pathways: role of cytosolic phospholipase A(2)alpha-dependent and -independent release of arachidonic acid.

The thioredoxin (Trx) system, comprising Trx, the selenoprotein thioredoxin reductase (TrxR), and NADPH, functions as an antioxidant system. Trx has various biological activities including growth control and anti-apoptotic properties, and the Trx system offers a target for the development of drugs to treat and/or prevent cancer. We evaluated the role of TrxR inhibition in the release of arachidonic acid (AA), cell toxicity, and intracellular signaling pathways in L929 mouse fibrosarcoma cells. Treatment with 1-chloro-2,4-dinitrobenzene (DNCB, an inhibitor of TrxR) under conditions involving limited inhibition of TrxR activity in cells, released AA before causing cytotoxicity. Treatment with an inhibitor of p38 kinase, a downstream enzyme of the apoptosis signal-regulating kinase 1 pathway, and pyrrophenone (an inhibitor of alpha-type cytosolic phospholipase A(2), cPLA(2)alpha) partially but significantly decreased the DNCB-induced release of AA and cell death. The responses were much weaker in cPLA(2)alpha knockdown L929 cells. Exogenously added AA showed cytotoxicity. DNCB increased intracellular reactive oxygen species (ROS) levels, and butylated hydroxyanisole (an antioxidant) reduced DNCB-induced ROS formation and cell toxicity but not the phosphorylation of p38 kinase and release of AA. Auranofin, another inhibitor of TrxR having a different formula, released AA resulting in toxicity in L929 cells. DNCB caused the release of AA and cytotoxicity in A549 human lung carcinoma cells, and caused p38 kinase-dependent toxicity in PC12 rat pheochromocytoma cells. Our data suggest that a dysfunctional Trx system triggers multiple signaling pathways, and that the AA released by cPLA(2)alpha-dependent and -independent pathways is important to cytotoxicity. J. Cell. Physiol. 219: 606-616, 2009. (c) 2009 Wiley-Liss, Inc.

Effect of hyperosmolality on vasopressin secretion in intradialytic hypotension: a mechanistic study.

BACKGROUND: Administration of a small volume of hypertonic solution has been used as an effective treatment for patients with intradialytic hypotension. Hypertonic solutions have been considered to act as plasma volume expanders. This clinical study examines whether arginine vasopressin (AVP) is involved in this mechanism of blood pressure control. STUDY DESIGN: Nonrandomized trial. SETTING & PARTICIPANTS: 42 patients on long-term hemodialysis therapy at a single hospital. INTERVENTION: Effects of intravenous infusions of 20 mL of 10% saline, 20 mL of 50% glucose, 200 mL of 0.9% saline, or physiological doses of AVP were examined during intradialytic hypotension. OUTCOMES & MEASUREMENTS: Changes in plasma AVP levels, osmolality, plasma volume, and blood pressure were analyzed. RESULTS: Hypertonic saline infusion increased plasma osmolality (mean, 292.7 to 302.3 mOsm/kg H(2)O; P < 0.001), plasma AVP levels (3.9 to 7.8 pg/mL; P = 0.03), and mean arterial pressure (66.6 to 71.8 mm Hg; P = 0.01). The increase in plasma volume (2.3%; P = 0.03) was too small to increase blood pressure because of volume alone. Hypertonic glucose infusion yielded similar results. Isotonic saline infusion increased blood pressure with an abrupt increase in plasma volume (12.7%; P < 0.001). AVP infusion increased blood pressure and plasma AVP to levels similar to those induced by the hypertonic solutions. LIMITATIONS: There are limitations in accurately measuring changes in plasma volume during hemodialysis. CONCLUSIONS: Results strongly suggest that the osmotic stimulation of AVP secretion by hypertonic solutions has an important role in increasing blood pressure in patients with intradialytic hypotension. Manipulating plasma AVP appropriately may help correct and prevent intradialytic hypotension.

Release of arachidonic acid induced by tumor necrosis factor-alpha in the presence of caspase inhibition: evidence for a cytosolic phospholipase A2alpha-independent pathway.

Stimulation of L929 cells with tumor necrosis factor-alpha (TNFalpha) caused cell death accompanied by a release of arachidonic acid (AA). Although the inhibition of caspases has been shown to cause necrosis in TNFalpha-treated L929 cells, its role in the TNFalpha-induced release of AA has not been elucidated. The release of AA is tightly regulated by phospholipase A(2) (PLA(2)). To find out the mechanisms underlying the TNFalpha-induced release of AA, we investigated the relationship between TNFalpha stimulation and PLA(2) regulation with and without zVAD, an inhibitor of caspases. In the present study, we found that treatment with TNFalpha and zVAD stimulated release of AA and cell death in C12 cells (a variant of L929 cells lacking alpha type of cytosolic PLA(2) (cPLA(2)alpha)). Stimulation with TNFalpha/zVAD also caused the release of AA from L929-cPLA(2)alpha-siRNA cells. Treatment with pyrrophenone (a selective inhibitor of cPLA(2)alpha) completely inhibited the TNFalpha-induced release of AA, but only partially inhibited the TNFalpha/zVAD-induced response in L929 cells. The TNFalpha/zVAD-induced release of AA from C12 and L929-cPLA(2)alpha-siRNA cells was pyrrophenone-insensitive, but inhibited by treatment with butylated hydroxyanisole (BHA, an antioxidant). Treatment with dithiothreitol, which inactivates secretory PLA(2) activity, decreased the amount of AA released by TNFalpha/zVAD. TNFalpha/zVAD appears to stimulate release of AA from C12 cells in a cPLA(2)alpha-independent, BHA-sensitive manner. The possible roles of secretory PLA(2) and reactive oxygen species from different pools in the release of AA and cell death were discussed.

Prediction method for decreases in blood pressure during hemocatharsis therapy by arteriolar blood flow measurement.

In clinical practice, the prediction of changes in blood pressure during hemocatharsis therapy depends on invasive monitoring, the physician's experience, or blood pressure measurement when patients ask for it. It is extremely difficult to predict blood pressure variation in patients under general anesthesia or with disturbance of consciousness. Therefore, the prediction of blood pressure variation during hemocatharsis therapy is an important issue. To address this issue, we invented a new noninvasive continuous blood flow monitor using arteriolar blood flow measurement by laser Doppler flowmetry. Then we examined and determined some extremely important phenomena, including the relationship between rapid blood pressure change and arteriolar blood flow, and failures of the cerebral blood flow autoregulatory mechanism, through measurements in clinical practice of hemodialysis, specific hemocatharsis therapy, and drug monitoring. The results suggest that blood pressure variation during hemocatharsis therapy is highly predictable by arteriolar blood flow measurement. Therefore, this new method for arteriolar blood flow measurement might be widely useful for patients under anesthesia, anesthesia monitoring in neonatal infants and animals (no conversation ability), as well as for hemocatharsis therapy.

Analysis of hemodynamics during blood purification therapy using a newly developed noninvasive continuous monitoring method.

Advancement in blood purification therapy extends not only to consoles and dialyzers, but also to patient management during blood purification therapy. However, no monitor has been devised for hemodynamics during blood purification therapy that is carried out continuously and non-invasively. By studying the laser Doppler flowmeter (LDF), we have developed a probe that can continuously measure changes in blood flow in tissues of the head and lower extremities during blood purification therapy. By applying the improved LDF, we have developed a non-invasive continuous monitoring method (NICOMM). Hemodynamics in various types of blood purification therapies were also studied by simultaneously measuring with an automatic oscillometric sphygmomanometer.

Control of parathyroid function in patients with a short history of hemodialysis.

Secondary hyperparathyroidism (SHPT) is one of the serious complications in patients with chronic kidney disease. Parathyroid glands secrete parathyroid hormone (PTH), stimulated partly by hyperphosphatemia and hypocalcemia complicating chronic kidney disease (CKD). Use of a calcium-based phosphate binder might be sufficient to reduce serum PTH levels in mild SHPT, while the recent K/DOQI clinical guidelines recommended vitamin D therapy for dialysis patients with serum level of intact parathyroid hormone of 300 pg/mL or more. We conducted a 6-month prospective controlled trial of 50 patients initiating hemodialysis therapy who were randomized to receive oral calcium carbonate alone or the drug plus oral vitamin D sterol, calcitriol or alfacalcidol. The primary end point was the proportion of randomized patients who had a mean PTH level of 300 pg/mL or less at the end of this study. The secondary end point included the percent change in the values for corrected calcium, phosphorus, the calcium-phosphorus product, and PTH. Eighty percent of patients receiving calcium carbonate without vitamin D sterols (20 of 25) reached the primary end point-a mean PTH level of 300 pg/mL or less after the period-as compared with 84% of those receiving calcium carbonate and vitamin D sterol (21 of 25) (Mantel-Haenszel odds ratio 0.76, 95% confidence interval: 0.18-3.25, P = 0.71). The other effects of the two regimens on the secondary end points were not significantly different after 6 months. In SHPT of dialysis patients initiating hemodialysis, oral calcium carbonate use alone was not inferior to additional vitamin D sterol use with calcium carbonate in reducing serum PTH levels. Our result indicated that, if serum calcium and phosphorus levels are controlled primarily regardless of used agents, it will be followed by reduction of serum PTH level in these patients.

Preparation of ultrapure dialysate in Japan--clinical usefulness and short-term future.

In 1994, the water quality standard of dialysate and substitution fluid for on-line HDF was established by the Kyushu Society for HDF. On the other hand, with the widespread use of high-flux membrane, reverse filtration and reverse diffusion became evident, and purification of the dialysate has become essential even for usual hemodialysis. By using ultrapure dialysate, new blood purification methods can be performed, such as internal filtration-enhanced hemodialysis, on-line HDF, and on-line HF. As a result, various clinical effects have been reported, such as improvement in anemia and in chronic inflammatory reactions. Suppression of complications involving long-term dialysis is expected, and even the prolongation of life expectancy. By using ultrapure dialysate as substitution fluid for saline solution, a fully automated dialysis machine has been developed. Furthermore, if fully automated consoles can be made smaller in size, they will contribute to the widespread use of home hemodialysis.

Role of osteoclastic dysfunction in the development of renal bone disease.

A 47-year-old-man was referred for treatment for end-stage renal failure. He had been diagnosed with type II adult onset osteopetrosis before the deterioration of his renal function. He presented with anaemia, severe hypocalcaemia, secondary hyperparathyroidism and azotaemia. An iliac bone biopsy revealed increased bone volume, disturbed osteoid calcification, active osteoclastic bone resorption and fibrous transformation in the bone marrow space. Incomplete osteoclastic dysfunction strongly suggested hypocalcaemia and secondary hyperparathyroidism, and the osteoclastic bone resorption also indicated secondary hyperparathyroidism, even though bone resorption was potentially suppressed. The present case shows that evidence of the involvement of osteoclastic dysfunction in the development of renal bone disease can be found in bone histology.

Solute-free versus electrolyte-free water clearance in the analysis of osmoregulation.

BACKGROUND: Although attention has recently focused on electrolyte-free water clearance (E-CH2O) as a replacement for solute-free water clearance (CH2O), especially from the viewpoint of plasma sodium regulation, a thorough comparison of the two has yet to be conducted. METHODS: CH2O and E-CH2O were systematically compared in normal subjects in different diuretic stages, including furosemide-induced solute diuresis, and in patients with renal disease. RESULTS: The normal renal ability to conserve free water based on E-CH2O was only 41% of that based on CH2O. E-CH2O remained positive until the urinary osmolality exceeded 500 mosm/kg H2O, markedly different from the 300 mosm/kg H2O for CH2O. The difference between E-CH2O and CH2O could ultimately be attributed to urea osmolar clearance, i.e., urea excretion rate/plasma osmolality, which accounted for about 40% of the osmolar clearance. CH2O underestimated the free water clearance by about 1 ml/min on average at all diuretic stages. CONCLUSIONS: E-CH2O is a more correct parameter than CH2O with regard to the regulation of both plasma sodium and plasma osmolality. However, there is the opinion that the concept of E-CH2O is difficult to understand and that E-CH2O is still not a generally accepted parameter. It is expected that the results of the present study will lead to more general acceptance.