Pigment-dispersing factor (PDF), an 18-amino acid neuropeptide, is a principal circadian neurotransmitter for the circadian rhythms of the locomotor activity in flies. Recently, two completely different types of PDF precursor were clarified; that of the cricket Gryllus bimaculatus and that of the last-summer cicada Meimuna opalifera. The G. bimaculatus PDF precursor is extraordinarily short and comprises a nuclear localization signal (NLS), while the M. opalifera PDF precursor is of ordinary length, comparable to that seen for the precursors of crustacean beta-PDH homologues. Although their PDF peptide regions were exactly the same, the regions containing a signal peptide combined with a PDF-associated peptide (PAP) were remarkably different from each other. Such a grouping suggested a fundamental role for the PAP peptide in the circadian clock, perhaps associated with PDF function. In the present study, the cDNA cloning of PDF from the adult brains of the housefly Musca domestica was carried out and it was found that an isolated clone (527 bp) encodes a PDF precursor protein of ordinary length. The PDF peptide shows a high sequence identity (78%-94%) and similarity (89%-100%) to insect PDFs and also to the crustacean beta-PDH peptides. In particular, there is only a single amino acid difference between the PDFs of Musca and Drosophila; at position 14 Ser for Musca PDF and Asn for Drosophila PDF. A characteristic Ser10 in Drosophila was retained in Musca, indicating the presence of a structural profile unique to these PDFs. The results of sequence analyses suggest that Musca and Drosophila PDFs are to be considered members of a single group that has evolved structurally. When the primary structure of the PAP regions was compared, the Musca PDF precursor also belonged to the same group as that to which the Drosophila PDF precursor belongs.

When rabbits are injected intravenously with a quantity of virulent streptococci or pneumococci sufficient to cause death within two to four days the septicemia takes a definite course with slight variations. The bacteria rapidly decrease in number from the time of the injection to from two to four hours, at which time the blood is sterile or contains only a few bacteria. Within five to six hours the bacteria reappear in the blood and steadily increase until the death of the animal. If the bacteria are less virulent, the same quantity of culture causes a chronic type of infection. The same initial decrease in the number of bacteria occurs. The reëntrance into the blood is somewhat delayed, the septicemia does not reach the height obtained in the acute cases, and a second fall occurs within the course of a few hours. These rabbits show a low blood invasion or a sterile blood culture for several days. During this time they become emaciated to a marked degree. Then the low septicemia rapidly rises or the rabbit with a sterile culture develops a severe septicemia within a few hours and death takes place from a few hours to two days thereafter. In this type of infection local lesions, pericarditis, pleurisy, peritonitis, etc., are usually found. In the infections which run an acute course no gross lesions are found. If the bacteria are still less virulent they never reënter the blood after the initial disappearance and the rabbits remain in good condition. In order to obtain uniform results, the quantity of bacteria injected must not be so large that the bacterial substances See PDF for Structure carried in are sufficient to cause an intoxication of the animal. If the quantity of bacteria injected is below this point the course of the infection depends largely upon the virulence of the infecting organisms. Yet variations in the natural resistance of individual animals may be sufficient to cause quite marked irregularities in the course of the infection. Pneumococci can be standardized so as to produce a particular type of infection more easily than streptococci. In general infections such as those produced by streptococci and pneumococci the number of the bacteria present in the circulating blood at a given time supplies accurate and delicate information regarding the severity of the disease. When the object is to determine the degree of virulence of bacteria, or of the efficiency of an experimental therapeutic method, the mere physical condition and mere death of the inoculated animals are not sufficient and satisfactory guides to the desired information. The death of the inoculated animal and the recovery of the infecting bacteria at autopsy do not give complete information concerning the intensity and course of the infection occurring during life. A large number of bacteria found in the blood and tissues at autopsy do not necessarily prove the existence of a heavy infection before the onset of the death agony, since it is a well known fact that bacteria multiply with enormous rapidity, once the natural resistance of the animal has been overcome. Therefore, if merely the life and death of the animal and autopsy findings must serve as our only guides, we shall lose much incidental information, perhaps of fundamental value. This may be especially true as regards the search for curative substances. Again, the individual animals of the same species, age, and apparently of identical physical condition react to the aggressive force of the infecting organisms variously. This fact is readily found out by the injection of a series of rabbits with lethal quantities of bacteria per body-weight, and by making tests at various periods before death results, which, in the case of streptococci, ranges from one to six days. Consequently a method which enables the determination of the degree and progress of the infection at any desired period is of obvious advantage.

OBJECTIVE

To present the implementation of a probability-based, four-dimensional (4D) intensity-modulated radiotherapy (IMRT) planning approach that explicitly optimizes the accumulated dose to moving tissue, estimated using the patient's probability density function (pdf) of respiratory motion. This is termed "optimization in tissue's-eye-view".

METHODS

The method incorporates 4D Monte Carlo dose calculation in multiple geometries of a respiratory-correlated CT dataset. The instance doses are weighted according to the breathing pdf and accumulated in a common reference geometry, which involves dose warping based on deformable registration. The algorithm produces deliverable multileaf collimator segments and was tested on a sample lung cancer patient dataset with large target excursion. Accumulated doses of the moving target and organs at risk of this plan were compared with those of corresponding margin-based static IMRT plans for free-breathing and gated treatment, as well as target tracking.

RESULTS

Target tracking provided best target coverage. Both the presented 4D IMRT approach for free-breathing treatment and gated treatment gave similar results for target coverage and lung dose, with significantly better target coverage than the margin-based static IMRT plan for free-breathing treatment.

CONCLUSIONS

The presented 4D planning concept offers an alternative to gating by providing the optimal dose for free-breathing IMRT treatment. Although the focus of this study was 4D lung planning, the approach can be generally applied for IMRT optimization in randomly deforming patient models.

NVP-PDFPDF-713 using guidelines of the National Committee for Clinical Laboratory Standards and the standardized disk diffusion method. A total of 420 NVP-PDF 713 zone diameter values were generated for each QC organism. The proposed zone diameter ranges contained 97.6-99.8% of the reported participant results and were: Staphylococcus aureus ATCC 25923 (25-35 mm), Streptococcus pneumoniae ATCC 49619 (30-37 mm), and Haemophilus influenzae ATCC 49247 (24-32 mm). These QC criteria for the disk diffusion method should be applied during the NVP-PDF 713 clinical trials to maximize test accuracy.

The release of guest species from within a nanoporous metal-organic framework (MOF) has been inhibited by amorphization of the guest-loaded framework structure under applied pressure. Thermogravimetric analyses have shown that by amorphizing ZIF-8 following sorption of molecular I(2), a hazardous radiological byproduct of nuclear energy production, the pore apertures in the framework are sufficiently distorted to kinetically trap I(2) and improve I(2) retention. Pair distribution function (PDF) analysis indicates that the local structure of the captive I(2) remains essentially unchanged upon amorphization of the framework, with the amorphization occurring under the same conditions for the vacant and guest-loaded framework. The low, accessible pressure range needed to effect this change in desorption is much lower than in tradition sorbents such as zeolites, opening the possibility for new molecular capture, interim storage, or controlled release applications.

Many biological and behavioural processes of animals are governed by an endogenous circadian clock, which is dependent on transcriptional regulation. Here we address post-transcriptional regulation and the role of miRNAs in Drosophila circadian rhythms. At least six miRNAs show cycling expression levels within the pigment dispersing factor (PDF) cell-pacemaker neurons; only mir-92a peaks during the night. In vivo calcium monitoring, dynamics of PDF projections, ArcLight, GCaMP6 imaging and sleep assays indicate that mir-92a suppresses neuronal excitability. In addition, mir-92a levels within PDF cells respond to light pulses and also affect the phase shift response. Translating ribosome affinity purification (TRAP) and in vitro luciferase reporter assay indicate that mir-92a suppresses expression of sirt2, which is homologous to human sir2 and sirt3. sirt2 RNAi also phenocopies mir-92a overexpression. These experiments indicate that sirt2 is a functional mir-92a target and that mir-92a modulates PDF neuronal excitability via suppressing SIRT2 levels in a rhythmic manner.

Impaired sleep patterns are common symptoms of Alzheimer's disease (AD). Cellular mechanisms underlying sleep disturbance in AD remain largely unknown. Here, using a Drosophila Aβ42 AD model, we show that Aβ42 markedly decreases sleep in a large population, which is accompanied with postdevelopmental axonal arborization of wake-promoting pigment-dispersing factor (PDF) neurons. The arborization is mediated in part via JNK activation and can be reversed by decreasing JNK signaling activity. Axonal arborization and impaired sleep are correlated in Aβ42 and JNK kinase hemipterous mutant flies. Image reconstruction revealed that these aberrant fibers preferentially project to pars intercerebralis (PI), a fly brain region analogous to the mammalian hypothalamus. Moreover, PDF signaling in PI neurons was found to modulate sleep/wake activities, suggesting that excessive release of PDF by these aberrant fibers may lead to the impaired sleep in Aβ42 flies. Finally, inhibition of JNK activation in Aβ42 flies restores nighttime sleep loss, decreases Aβ42 accumulation, and attenuates neurodegeneration. These data provide a new mechanism by which sleep disturbance could be induced by Aβ42 burden, a key initiator of a complex pathogenic cascade in AD.

The behavior of a compound metacentric fourth chromosome (see <em>PDF</em>) has been examined to determine whether arm length or total length is the basis for recognition in distributive pairing. Recognition was judged by the frequency with which the (see <em>PDF</em>) nondisjoined from a series of X duplications (Dp), ranging in size from </= 0.3 to>> 4 times the size of a single fourth chromosome. Dp, (see <em>PDF</em>) nondisjunction was measured in the absence and in the presence of a competitor, a compound metacentric X. In both situations, total length and not arm length, was found to confer the characteristic recognition property to the (see <em>PDF</em>). A comparison of Dp, (see <em>PDF</em>) nondisjunction curves for both the noncompetitive and competitive situations with analogous Dp, 4 curves previously obtained, show the Dp, (see <em>PDF</em>) curves to be similar in shape to those obtained earlier but displaced one unit to the right, corresponding precisely to the difference in size between the (see <em>PDF</em>) and the 4. Rules governing chromosome recognition for acrocentrics were found completely applicable to metacentrics; disjunctive behavior of metacentrics differed from that of acrocentrics in that two arms conferred on a chromosome the capacity to act as the intermediate of a trivalent when size no longer warranted this attribute. This capacity, itself, is size-dependent.

The ventilatory response curve (VRC) as a function of alveolar and arterial pCO2 was recorded in 6 high-performance athletes and 6 nonathletes. The best fit to the data points could be found for an equation of the form (see article) showing that the results are strongly related to a Gaussian probability density function (PDF). After normalizing the equation to a form (see article) (M = mean value of PDF), sigma, A and M could be determined for both groups. Sigma and A are smaller in the athletic group, whereas M did not show any systematic difference. Regarding the respiratory center consisting of functional "elements" responding indirectly to variable pCO2 it can be concluded that the frequency distribution of the different active elements is greater and spread over a wider pCO2 range in the nonathletes with the same mean value in both groups. Using Loeschcke's model (1960), the open loop gain factor for different V CO2 as a function of p(A)CO2 was computed; the gain factor showed a maximum in the physiological range of pCO2.

(i) The effects of daily oral administration of 125 mg of DL-ethionine upon the serum lipides and lipoproteins of dogs were studied. (ii) The feeding of the ethionine resulted in a prompt reduction in the levels of serum fatty acids, phospholipides, and cholesterol. See PDF for Figure At the end of 25 days, negligible amounts of these lipides remained in serum. (iii) A reduction in the levels of low- and high-density lipoproteins also resulted from the feeding of ethionine. In general, the extent of reduction in all lipoprotein fractions paralleled that observed in lipides. (iv) The removal of ethionine from the diet led to a prompt restoration of the concentrations of all lipide and lipoprotein constituents to normal.

A program is presented which will return the most probable sequence location for a short connected set of residues in a protein given just (13)C(alpha) chemical shifts (delta((13)C(alpha))) and data restricting the phi and psi backbone angles. Data taken from both the BioMagResBank and the Protein Data Bank were used to create a probability density function (PDF) using a multivariate normal distribution in delta((13)C(alpha)), phi, and psi space for each amino acid residue. Extracting and combining probabilities for particular amino acid residues in a short proposed sequence yields a score indicative of the correctness of the proposed assignment. The program is illustrated using several proteins for which structure and (13)C(alpha) chemical shift data are available.

An index of filling efficiency incorporating stiffness and relaxation (S&R) parameters has not been derived or validated, although numerous studies have focused on the effects of altered relaxation or stiffness on early rapid filling and diastolic function. Previous studies show that S&R parameters can be obtained from early rapid filling (Doppler E-wave) via kinematic modeling. E-wave contours are governed by harmonic oscillatory motion modeled via the parameterized diastolic filling (PDF) formalism. The previously validated model determines three (unique) oscillator parameters from each E-wave having established physiological analogues: x(o) (load), c (relaxation/viscoelasticity) and k (chamber stiffness). We define the dimensionless, filling-volume-based kinematic filling efficiency index (KFEI) as the ratio of the velocity-time integral (VTI) of the actual clinical E-wave contour fit via PDF to the VTI of the PDF model-predicted ideal E-wave contour having the same x(o) and k, but with no resistance to filling (c = 0). To validate the new index, Doppler E-waves from 36 patients with normal ventricular function, 17 diabetic and 19 well-matched non-diabetic controls, were analyzed. E-wave parameters x(o), c and k and KFEI were computed for each patient and compared. In concordance with prior human and animal studies in which c differentiated between normal and diabetic hearts, KFEI differentiated (p < 0.001) between nondiabetics (55.8% +/- 3.3%) and diabetics (49.1% +/- 3.3%). Thus, the new index introduces and validates the concept of filling efficiency, and, using diabetes as a working example, provides quantitative and mechanistic insight into how S&R affect ventricular filling efficiency.

Information on the fraction of total hand surface area touching a contaminated object is necessary in accurately estimating contaminant (e.g., pesticides, pathogens) loadings onto the hands during hand-to-object contacts. While several existing physical-stochastic human exposure models require such surface area data to estimate dermal and non-dietary ingestion exposure, there are very limited data sets. This paper provides statistical distributions of fractional surface areas (FSAs) for children's outdoor hand contacts. These distributions were constructed by combining information collected from two distinct studies exploring children's activity patterns and quantifying hand contact surface area. Results show that for outdoor contacts with "All Objects", a range of 0.13-0.27 captured median FSAs, while a range of 0.12-0.24 captured time-weighted FSAs. Overall, an FSA of 0.31 captured 80-100% of FSAs involved in each child's outdoor hand contacts, depending upon the object of interest. These values are much lower than the often conservative assumptions of up to 1 (i.e., the entire hand) that researchers currently make regarding FSAs involved in indoor and outdoor contacts [USEPA, 1997. Standard operating procedures (SOPs) for residential exposure assessments. Contract no. 68-W6-0030. http://www.epa.gov/pesticides/trac/science/trac6a05.pdf].

<AbstractText>This article has been corrected. The original version (<em>PDF</em>) is appended to this article as a Supplement.</AbstractText><AbstractText>Atrial fibrillation (AF) and heart failure (HF) frequently coexist and are associated with increased morbidity and mortality risk.</AbstractText><AbstractText>To compare benefits and harms between catheter ablation and drug therapy in adult patients with AF and HF.</AbstractText><AbstractText>ClinicalTrials.gov, PubMed, Web of Science (Clarivate Analytics), EBSCO Information Services, Cochrane Central Register of Controlled Trials, Google Scholar, and various scientific conference sessions from 1 January 2005 to 1 October 2018.</AbstractText><AbstractText>Randomized controlled trials (RCTs) published in English that had at least 6 months of follow-up and compared clinical outcomes of catheter ablation versus drug therapy in adults with AF and HF.</AbstractText><AbstractText>2 investigators independently extracted data and assessed study quality.</AbstractText><AbstractText>6 RCTs involving 775 patients met inclusion criteria. Compared with drug therapy, AF ablation reduced all-cause mortality (9.0% vs. 17.6%; risk ratio [RR], 0.52 [95% CI, 0.33 to 0.81]) and HF hospitalizations (16.4% vs. 27.6%; RR, 0.60 [CI, 0.39 to 0.93]). Ablation improved left ventricular ejection fraction (LVEF) (mean difference, 6.95% [CI, 3.0% to 10.9%]), 6-minute walk test distance (mean difference, 20.93 m [CI, 5.91 to 35.95 m]), peak oxygen consumption (Vo2max) (mean difference, 3.17 mL/kg per minute [CI, 1.26 to 5.07 mL/kg per minute]), and quality of life (mean difference in Minnesota Living with Heart Failure Questionnaire score, -9.02 points [CI, -19.75 to 1.71 points]). Serious adverse events were more common in the ablation groups, although differences between the ablation and drug therapy groups were not statistically significant (7.2% vs. 3.8%; RR, 1.68 [CI, 0.58 to 4.85]).</AbstractText><AbstractText>Results driven primarily by 1 clinical trial, possible patient selection bias in the ablation group, lack of patient-level data, open-label trial designs, and heterogeneous follow-up length among trials.</AbstractText><AbstractText>Catheter ablation was superior to conventional drug therapy in improving all-cause mortality, HF hospitalizations, LVEF, 6-minute walk test distance, Vo2max, and quality of life, with no statistically significant increase in serious adverse events.</AbstractText><AbstractText>None.</AbstractText>

This study investigated the effects of nanoencapsulated curcumin (NEC) and praziquantel (PZQ) treatment on the resolution of periductal fibrosis (PDF) and bile canalicular (BC) abnormalities in Opisthorchis viverrini infected hamsters. Chronic O. viverrini infection (OV) was initially treated with either PZQ (OP) and subsequently treated with NEC (OP+NEC), curcumin (OP+Cur) or unloaded carriers (OP+carrier) daily for one month. OP+NEC treatment reduced the PDF by suppression of fibrotic markers (hydroxyproline content, α-SMA, CTGF, fibronectin, collagen I and III), cytokines (TGF-β and TNF-α) and TIMP-1, 2, 3 expression and upregulation of MMP-7, 13 genes. Higher activity of NEC in reducing fibrosis compared to curcumin was also demonstrated in in vitro studies. Moreover, OP+NEC also prevented BC abnormalities and upregulated several genes involved in bile acid metabolism. These results demonstrate that NEC and PZQ treatment reduces PDF and attenuates BC defect in experimental opisthorchiasis. From the Clinical Editor: Infection by Opisthorchis viverrini leads to liver fibrosis and affects population in SE Asia. Currently, praziquantel (PZQ) is the drug of choice but this drug has significant side effects. In this study, the authors combined curcumin (NEC) and praziquantel in a nanocarrier to test the anti-oxidative effect of curcumin in an animal model. The encouraging results may pave a way for better treatment in the future.

The adoption of simulation tools to predict surgical outcomes is increasingly leading to questions about the variability of these predictions in the presence of uncertainty associated with the input clinical data. In the present study, we propose a methodology for full propagation of uncertainty from clinical data to model results that, unlike deterministic simulation, enables estimation of the confidence associated with model predictions. We illustrate this problem in a virtual stage II single ventricle palliation surgery example. First, probability density functions (PDFs) of right pulmonary artery (PA) flow split ratio and average pulmonary pressure are determined from clinical measurements, complemented by literature data. Starting from a zero-dimensional semi-empirical approximation, Bayesian parameter estimation is used to find the distributions of boundary conditions that produce the expected PA flow split and average pressure PDFs as pre-operative model results. To reduce computational cost, this inverse problem is solved using a Kriging approximant. Second, uncertainties in the boundary conditions are propagated to simulation predictions. Sparse grid stochastic collocation is employed to statistically characterize model predictions of post-operative hemodynamics in models with and without PA stenosis. The results quantify the statistical variability in virtual surgery predictions, allowing for placement of confidence intervals on simulation outputs.

Peptide deformylase (PDF) is considered an excellent target to develop antibiotics. We have performed an extensive characterization of a new PDF from the pathogen Streptococcus agalactiae, showing properties similar to other known PDFs. S. agalactiae PDF could be used as PDF prototype as it allowed to get complete sets of 3-dimensional, biophysical and kinetic data with virtually any inhibitor compound. Structure-activity relationship analysis with this single reference system allowed us to reveal distinct binding modes for different PDF inhibitors and the key role of a hydrogen bond in potentiating the interaction between ligand and target. We propose this protein as an irreplaceable tool, allowing easy and relevant fine comparisons between series, to design, challenge and validate novel series of inhibitors. As proof-of-concept, we report here the design and synthesis of effective specific bacterial PDF inhibitors of an oxadiazole series with potent antimicrobial activity against a multidrug resistant clinical isolate.

In this paper, a new statistical model for representing the amplitude statistics of ultrasonic images is presented. The model is called the Rician inverse Gaussian (RiIG) distribution, due to the fact that it is constructed as a mixture of the Rice distribution and the Inverse Gaussian distribution. The probability density function (pdf) of the RiIG model is given in closed form as a function of three parameters. Some theoretical background on this new model is discussed, and an iterative algorithm for estimating its parameters from data is given. Then, the appropriateness of the RiIG distribution as a model for the amplitude statistics of medical ultrasound images is experimentally studied. It is shown that the new distribution can fit to the various shapes of local histograms of linearly scaled ultrasound data better than existing models. A log-likelihood cross-validation comparison of the predictive performance of the RiIG, the K, and the generalized Nakagami models turns out in favor of the new model. Furthermore, a maximum a posteriori (MAP) filter is developed based on the RiIG distribution. Experimental studies show that the RiIG MAP filter has excellent filtering performance in the sense that it smooths homogeneous regions, and at the same time preserves details.

BACKGROUND

Post-dialysis fatigue (PDF) is a common, debilitating symptom that remains poorly understood. Cardiac wall motion abnormalities (WMAs) may worsen during dialysis, but it is unknown whether WMA are associated with PDF.

METHODS

Forty patients were recruited from University of California San Francisco-affiliated dialysis units between January 2010 and February 2011. Participants underwent echocardiograms before and during the last hour of 79 dialysis sessions. Myocardial segments were graded 1-4 by a blinded reviewer, with four representing the worst WMA, and the segmental scores were summed for each echocardiogram. Patients completed questionnaires about their symptoms. Severe PDF (defined as lasting >2 h after dialysis) was analysed using a generalized linear model with candidate predictors including anemia, intradialytic hemodynamics and cardiac function.

RESULTS

Forty-four percent of patients with worsened WMA (n=9) had severe PDF, compared with 13% of patients with improved or unchanged WMA (P = 0.04). A one-point increase in the WMA score during dialysis was associated with a 10% higher RR of severe PDF [RR: 1.1, 95% CI (1.1, 1.2), P < 0.001]. After multivariable adjustment, every point increase in the WMA score was associated with a 2-fold higher risk of severe PDF [RR: 1.9, 95% CI (1.4, 2.6), P < 0.001]. History of depression was associated with severe PDF after adjustment for demographics and comorbidities [RR: 3.4, 95% CI (1.3, 9), P = 0.01], but anemia, hemodynamics and other parameters of cardiac function were not.

CONCLUSIONS

Although cross-sectional, these results suggest that some patients may experience severe PDF as a symptom of cardiac ischemia occurring during dialysis.

The beet cyst nematode Heterodera schachtii induces a feeding site, called syncytium, in roots of host plants. In Arabidopsis, one of the genes whose expression is strongly induced in these structures is <em>Pdf</em>2.1 which codes for an antimicrobial plant defensin. Arabidopsis has 13 plant defensin genes. Besides <em>Pdf</em>2.1, the <em>Pdf</em>2.2 and <em>Pdf</em>2.3 genes were strongly expressed in syncytia and therefore the expression of all three <em>Pdf</em> genes was studied in detail. The promoter of the <em>Pdf</em>2.1 gene turned out to be an interesting candidate to drive a syncytium-specific expression of foreign genes as RT-PCR showed that apart from the feeding site it was only expressed in siliques (seeds). The <em>Pdf</em>2.2 and <em>Pdf</em>2.3 genes were in addition expressed in seedlings, roots, leaves, stems, and flowers. These results were supported by the analysis of promoter::GUS lines. After infection with H. schachtii all GUS lines showed a strong staining in syncytia at 5 and 15 dpi. This expression pattern was confirmed by in situ RT-PCR.

Structural changes occurring in an Fe(72.5)Cu1Nb2Mo2Si(15.5)B7 alloy during a combination of constant rate heating (20 K min(-1)) and isothermal holding at 500 and 520 °C were investigated using in situ high-energy X-ray diffraction. We found that the ferromagnetic-to-paramagnetic transition of the amorphous phase is revealed as a change in the slope of the thermal expansion curve when heating a sample at a constant rate up to 520 °C. Real space analysis by means of the atomic pair distribution function (PDF) demonstrated that the rate and extent of the thermal expansion strongly depend on the interatomic separation. The PDF proved to be a reliable method for the description of crystallization kinetics. Further it allows determination of sizes of ultrafine nanocrystals with grain sizes well below 8 nm and thus makes observation of early stages of nanocrystallization possible. Following grain growth kinetics during isothermal annealing at 500 and 520 °C we found that the activation energy of the process is 357 ± 12 kJ mol(-1).

BACKGROUND

Glucose and glucose degradation products (GDPs) in peritoneal dialysis fluids (PDFs) are both thought to mediate progressive peritoneal worsening.

METHODS

In a multicenter, prospective, randomized crossover study, incident continuous ambulatory peritoneal dialysis patients were treated either with conventional lactate-buffered PDF (sPD regimen) or with a regimen low in glucose and GDPs: Nutrineal×1, Extraneal×1, and Physioneal×2 (NEPP regimen; all solutions: Baxter Healthcare, Utrecht, The Netherlands). After 6 months, patients were switched to the alternative regimen for another 6 months. After 6 weeks of run-in, before the switch, and at the end of the study, 4-hour peritoneal equilibration tests were performed, and overnight effluents were analyzed for cells and biomarkers. Differences between the regimens were assessed by multivariate analysis corrected for time and regimen sequence.

RESULTS

The 45 patients who completed the study were equally distributed over both groups. During NEPP treatment, D(4)/D(0) glucose was lower (p < 0.01) and D/P creatinine was higher (p = 0.04). In NEPP overnight effluent, mesothelial cells (p < 0.0001), cancer antigen 125 (p < 0.0001), hyaluronan (p < 0.0001), leukocytes (p < 0.001), interleukins 6 (p = 0.001) and 8 (p = 0.0001), and vascular endothelial growth factor (VEGF, p < 0.0001) were increased by a factor of 2-3 compared with levels in sPD effluent. The NEPP regimen was associated with higher transport parameters, but that association disappeared after the addition of VEGF to the model. The association between NEPP and higher effluent levels of VEGF could not be attributed to glucose and GDP loads.

CONCLUSIONS

Study results indicate preservation of the mesothelium and increased peritoneal activation during NEPP treatment. Whether the increase in VEGF reflects an increase in mesothelial cell mass or whether it points to another, undesirable mechanism cannot be determined from the present study. Longitudinal studies are needed to finally evaluate the usefulness of the NEPP regimen for further clinical use.

BACKGROUND

Bacterial peritonitis is a frequent complication in patients on peritoneal dialysis (PD). We previously reported that PD fluid (PDF) suppressed expression of monocyte chemoattractant protein 1 (MCP-1) in mesothelial cells in vitro and in vivo, which was ascribed to the suppression of nuclear factor-κB (NF-κB). To elucidate molecular mechanisms underlying this effect, we tested a role of endoplasmic reticulum (ER) stress.

METHODS

Mesothelial cells and other cell types were exposed to acidic stress, and induction of the unfolded protein response was examined. Peritoneal induction of ER stress was also tested in mice exposed to acidic and neutralized PDF. Activation of NF-κB and expression of MCP-1 by tumour necrosis factor-α were evaluated in mesothelial cells under acidic and ER stress conditions. Peritoneal expression of MCP-1 and infiltration of monocytes were compared in lipopolysaccharide (LPS)-treated mice between normal and ER stress conditions.

RESULTS

PDF, but not neutralized PDF, caused ER stress in the peritoneum. In vitro, acidic stress, but not metabolic and osmotic stress, induced ER stress in mesothelial cells and other cell types and suppressed activation of NF-κB and NF-κB-dependent MCP-1 induction. This effect was reproducible by other ER stress inducers, and attenuation of ER stress reversed the suppressive effect of low pH on NF-κB. Like PDF, ER stress inducers suppressed expression of MCP-1 and infiltration of mononuclear cells in the peritoneum of LPS-treated mice.

CONCLUSIONS

These results indicate a role for the acidic stress-ER stress pathway in blunted activation of NF-κB, which may cause perturbation of monocyte recruitment by mesothelial cells in PD patients.