The aim of this study is to investigate the effects of internal organ motion on IMRT treatment planning of prostate patients using a spatial dose gradient and probability density function. Spatial dose distributions were generated from a Pinnacle3 planning system using a co-planar, five-field intensity modulated radiation therapy (IMRT) technique. Five plans were created for each patient using equally spaced beams but shifting the angular displacement of the beam by 15 degree increments. Dose profiles taken through the isocentre in anterior-posterior (A-P), right-left (R-L) and superior-inferior (S-I) directions for IMRT plans were analysed by exporting RTOG file data from Pinnacle. The convolution of the 'static' dose distribution D0(x, y, z) and probability density function (PDF), denoted as P(x, y, z), was used to analyse the combined effect of repositioning error and internal organ motion. Organ motion leads to an enlarged beam penumbra. The amount of percentage mean dose deviation (PMDD) depends on the dose gradient and organ motion probability density function. Organ motion dose sensitivity was defined by the rate of change in PMDD with standard deviation of motion PDF and was found to increase with the maximum dose gradient in anterior, posterior, left and right directions. Due to common inferior and superior field borders of the field segments, the sharpest dose gradient will occur in the inferior or both superior and inferior penumbrae. Thus, prostate motion in the S-I direction produces the highest dose difference. The PMDD is within 2.5% when standard deviation is less than 5 mm, but the PMDD is over 2.5% in the inferior direction when standard deviation is higher than 5 mm in the inferior direction. Verification of prostate organ motion in the inferior directions is essential. The margin of the planning target volume (PTV) significantly impacts on the confidence of tumour control probability (TCP) and level of normal tissue complication probability (NTCP). Smaller margins help to reduce the dose to normal tissues, but may compromise the dose coverage of the PTV. Lower rectal NTCP can be achieved by either a smaller margin or a steeper dose gradient between PTV and rectum. With the same DVH control points, the rectum has lower complication in the seven-beam technique used in this study because of the steeper dose gradient between the target volume and rectum. The relationship between dose gradient and rectal complication can be used to evaluate IMRT treatment planning. The dose gradient analysis is a powerful tool to improve IMRT treatment plans and can be used for QA checking of treatment plans for prostate patients.

Mutual-information maximization is one of the most popular algorithms for automatic image registration. However, many implementation issues have not been evaluated in a single, coherent context.

METHODS

Twenty-one registrations between MR and SPECT brain images (8 patients) were achieved by mutual-information maximization with different implementation strategies. The results of a popular strategy were chosen as the standard. All other results were compared with the standard, and the statistics of misregistrations were computed. The registration speed, accuracy, precision, and success rate were assessed.

RESULTS

Compared with trilinear interpolation, nearest-neighbor interpolation slightly sped the registration process, but with a lower success rate. The number of bins used to estimate the probability density function (pdf) affects the speed and robustness. Using fewer bins yielded a less robust registration. Adaptively changing the number of bins increased the registration speed and robustness. Simplex optimization increased the registration speed considerably, with a slightly degraded success rate. Simplex optimization with adaptive bin strategy improved the success rate and further decreased the registration time. Multiresolution optimization yielded a better success rate, with little effect on the accuracy and precision of registration. An increase in the number of resolution levels increased the success rate. Multisampling optimization also improved the success rate, but the results were less accurate and precise than those obtained with multiresolution optimization, with an increase in the number of levels decreasing the performance. Segmentation affected the registration speed and success rate. Because segmentation is problem specific, the effects were not conclusive.

CONCLUSIONS

Different implementation strategies considerably affect the performance of automatic image registration by mutual-information maximization. On the basis of the experimental findings, we suggest that the best implementation strategy would include trilinear interpolation, adaptive change of the number of bins when estimating pdf, and exploitation of a simplex optimization algorithm with a multiresolution scheme.

The current PDFPDFs) in theoretical predictions for LHC processes involves the combination of separate predictions computed using PDF sets from different groups, each of which comprises a relatively large number of either Hessian eigenvectors or Monte Carlo (MC) replicas. While many fixed-order and parton shower programs allow the evaluation of PDF uncertainties for a single PDF set at no additional CPU cost, this feature is not universal, and, moreover, the a posteriori combination of the predictions using at least three different PDF sets is still required. In this work, we present a strategy for the statistical combination of individual PDF sets, based on the MC representation of Hessian sets, followed by a compression algorithm for the reduction of the number of MC replicas. We illustrate our strategy with the combination and compression of the recent NNPDFPDF sets. The resulting compressed Monte Carlo PDF sets are validated at the level of parton luminosities and LHC inclusive cross sections and differential distributions. We determine that around 100 replicas provide an adequate representation of the probability distribution for the original combined PDF set, suitable for general applications to LHC phenomenology.

In the first paper in this series, we described the methods to synthesize an antibacterial polyurethane (PU) incorporating ciprofloxacin as the releasable antibiotic and poly(ethylene glycol) as the pore-forming agent. Here, we report that a thin, RF-plasma-deposited, n-butyl methacrylate (BMA) overlayer on this drug-loaded PU can act as a rate-limiting barrier to achieve a constant, sustained release of ciprofloxacin. Deposition power and deposition time during the coating process were optimized to give an appropriate crosslinked coating barrier that yielded desirable release rates, above the minimum required killing rate, N(kill). Electron spectroscopy for chemical analysis (ESCA), also known as X-ray photoelectron spectroscopy (XPS), was used to characterize the coating, and its crosslinking degree was indirectly related to the C/O ratio. Increasing either deposition power (10-60 W) or duration (5-25 min) resulted in increased C/O ratios and decreased ciprofloxacin release rates. The correlation between increased C/O ratios and reduced release rates is believed to be due to the increased crosslinking, increased hydrophobicity and increased thickness of the coating. The optimal plasma conditions to attain an appropriate crosslinked plasma-deposited film (PDF) required argon etching, pre-treatment of the matrices with an 80W-BMA plasma for 1 min, followed by immediate BMA plasma deposition at 40 W and 150 mT for 20 min. By using these plasma deposition protocols, we eliminated the initial burst effect, significantly reduced the release rates, and closely approached the zero order release kinetics for at least five days. In this study, we also showed that ESCA could be used as a powerful tool to explain the release behavior of molecules through the plasma-deposited films (PDFs).

It has become apparent in recent years that it is important, notably for a range of physics studies at the Large Hadron Collider, to have accurate knowledge on the distribution of photons in the proton. We show how the photon parton distribution function (PDF) can be determined in a model-independent manner, using electron-proton (ep) scattering data, in effect viewing the ep→e+X process as an electron scattering off the photon field of the proton. To this end, we consider an imaginary, beyond the Standard Model process with a flavor changing photon-lepton vertex. We write its cross section in two ways: one in terms of proton structure functions, the other in terms of a photon distribution. Requiring their equivalence yields the photon distribution as an integral over proton structure functions. As a result of the good precision of ep data, we constrain the photon PDF at the level of 1%-2% over a wide range of momentum fractions.

The prediction of the risks of cancer and other late effects from space radiation exposure carries large uncertainties mostly due to the lack of information on the risks from high charge and energy (HZE) particles and other high linear energy transfer (LET) radiation. In our recent work new methods were used to consider NASA's requirement to protect against the acceptable risk of no more than 3% probability of cancer fatality estimated at the 95% confidence level. Because it is not possible that a zero-level of uncertainty could be achieved, we suggest that an acceptable uncertainty level should be defined in relationship to a probability distribution function (PDF) that only suffers from modest skewness with higher uncertainty allowed for a normal PDF. In this paper, we evaluate PDFs and the number or "safe days" in space, which are defined as the mission length where risk limits are not exceeded, for several mission scenarios at different acceptable levels of uncertainty. In addition, we briefly discuss several important issues in risk assessment including non-cancer effects, the distinct tumor spectra and lethality found in animal experiments for HZE particles compared to background or low LET radiation associated tumors, and the possibility of non-targeted effects (NTE) modifying low dose responses and increasing relative biological effectiveness (RBE) factors for tumor induction. Each of these issues skew uncertainty distributions to higher fatality probabilities with the potential to increase central values of risk estimates in the future. Therefore they will require significant research efforts to support space exploration within acceptable levels of risk and uncertainty.

BACKGROUND

R is the statistical language commonly used by many life scientists in (omics) data analysis. At the same time, these complex analyses benefit from a workflow approach, such as used by the open source workflow management system Taverna. However, Taverna had limited support for R, because it supported just a few data types and only a single output. Also, there was no support for graphical output and persistent sessions. Altogether this made using R in Taverna impractical.

RESULTS

We have developed an R plugin for Taverna: RShell, which provides R functionality within workflows designed in Taverna. In order to fully support the R language, our RShell plugin directly uses the R interpreter. The RShell plugin consists of a Taverna processor for R scripts and an RShell Session Manager that communicates with the R server. We made the RShell processor highly configurable allowing the user to define multiple inputs and outputs. Also, various data types are supported, such as strings, numeric data and images. To limit data transport between multiple RShell processors, the RShell plugin also supports persistent sessions. Here, we will describe the architecture of RShell and the new features that are introduced in version 1.2, i.e.: i) Support for R up to and including R version 2.9; ii) Support for persistent sessions to limit data transfer; iii) Support for vector graphics output through PDF; iv)Syntax highlighting of the R code; v) Improved usability through fewer port types.Our new RShell processor is backwards compatible with workflows that use older versions of the RShell processor. We demonstrate the value of the RShell processor by a use-case workflow that maps oligonucleotide probes designed with DNA sequence information from Vega onto the Ensembl genome assembly.

CONCLUSIONS

Our RShell plugin enables Taverna users to employ R scripts within their workflows in a highly configurable way.

The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for hydroxyurea to cause adverse effects on reproduction and development in humans. Hydroxyurea is a drug used to treat cancer, sickle cell disease, and thalassemia. It is the only treatment for sickle cell disease in children, aside from blood transfusion and, in severe cases, hematopoietic stem cell transplantation. Hydroxyurea is FDA-approved for use in adults with sickle cell anemia to reduce the frequency of painful crises and the need for blood transfusions. Hydroxyurea may be given to children and adults with sickle cell disease for an extended period of time or for repeated cycles of therapy. Treatment with hydroxyurea is associated with known side effects such as cytotoxicity and myelosuppression, and hydroxyurea is genotoxic (can damage DNA). CERHR selected hydroxyurea for evaluation because of: its increasing use for treatment of sickle cell disease in children and adults, knowledge that it inhibits DNA synthesis and is cytotoxic, and published evidence of reproductive and developmental toxicity in rodents. The results of this evaluation are published in the NTP-CERHR Monograph on Hydroxyurea, which includes the NTP Brief and Expert Panel Report on the Reproductive and Developmental Toxicity of Hydroxyurea. Additional information related to the evaluation process, including public comments received on the draft NTP Brief and the final expert panel report, are available on the CERHR website (http:// cerhr.niehs.nih.gov/). See hydroxyurea under "CERHR Chemicals" on the homepage or go directly to http://cerhr.niehs.nih.gov/chemicals/hydroxyurea/hydroxyurea-eval.html). The NTP reached the following conclusions on the possible effects of exposure to hydroxyurea on human reproduction or development. The possible levels of concern, from lowest to highest, are negligible concern, minimal concern, some concern, concern, and serious concern. The NTP expresses serious concern that exposure of men to therapeutic doses of hydroxyurea may adversely affect sperm production. This level of concern is for all males who have reached puberty. The NTP concurs with the Expert Panel that there is concern that exposure of pregnant women to hydroxyurea may result in birth defects, abnormalities of fetal growth, or abnormal postnatal development in offspring. The NTP concurs with the Expert Panel that there is minimal concern that exposure of children to therapeutic doses of hydroxyurea at 5 -15 years of age will adversely affect growth. NTP will transmit the NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Hydroxyurea to federal and state agencies, interested parties, and the public and make it available in electronic PDF format on the CERHR web site (http://cerhr niehs nih gov) and in printed text or CD from CERHR.

OBJECTIVE

BB-81384, a novel peptide deformylase (PDF) inhibitor, was characterized in terms of enzyme inhibition profile, antibacterial activity, rodent pharmacokinetics and oral efficacy in murine infection models.

METHODS

MICs were determined by standard NCCLS broth microdilution. Selectivity of metalloenzyme inhibition was determined with a limited panel of enzymes via standard biochemical assays. Profiling of the pharmacokinetics and select tissue disposition in mice was determined and compared with that of the macrolide, azithromycin. In vivo murine efficacy studies using Streptococcus pneumoniae were conducted using a peritonitis model, as well as lung and thigh burden models of infection.

RESULTS

BB-81384 selectively inhibited PDF with an IC(50) approximately 10 nM and with MICs < 0.5 mg/L against most S. pneumoniae pathogens. Pharmacokinetic analysis revealed good oral bioavailability and moderate clearance and volume of distribution. BB-81384 partitioning to lung tissue was similar in terms of magnitude and kinetics to that of the plasma compartment. Single-administration oral efficacy in a mouse peritonitis model was evident with an ED(50) of 30 mg/kg. BB-81384 reduced the bacterial load by approximately 5 and 3 log units in organ-burden models of lung and thigh infection, respectively.

CONCLUSIONS

BB-81384, a novel PDF inhibitor with good activity against S. pneumoniae in vitro, was the first compound of this class to be profiled for oral pharmacokinetics and tissue disposition and to demonstrate oral anti-pneumococcal efficacy in mice.

Placental calcification commonly increases with gestational age. The mechanism of apatite mineralization probably involves one of three known mechanisms of tissue calcification: physiological (like bone), dystrophic (ischaemia-related) or metastatic (mineralization in a supersaturated environment). This study was designed to determine the mechanism of calcification by examining (1) the mineral content of placental calcifications in comparison to other physiological and pathological apatites, and (2) the expression of bone morphogenetic proteins (BMPs), which are important in physiological calcification, across gestational age. By energy-dispersive x-ray analysis (EDXA), the Ca/P weight ratio for apatitic mineral from mature calcifications was 2.00+/-0.05 (s.e.), which is similar to that for stones formed in a metastatic, supersaturated environment and lower than that observed in physiological calcification. Biologically active BMP, which was determined by bioassay, was demonstrated in mature and postmature placentae. The BMPs PLAB, PDF and related protein INSL-4 were identified by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR), but their mRNA expression was independent of gestational age (7-41 weeks of gestation). We conclude that (1) the identified BMPs were not related directly to placental calcification, which argues against physiological calcification, and (2) the chemical composition of the apatitic mineral was suggestive of rapid formation in a supersaturated environment, which is consistent with a metastatic mechanism of calcification.

In the present study we examined profiles of nerve fiber varicosities containing dense core vesicles (DCVs) in the distal medulla of the housefly's optic lobe using electron microscopic methods. These profiles are infrequent among other neuronal profiles and do not contain presynaptic specializations for the release of DCVs. Presynaptic elements surrounded by electron-translucent vesicles were only occasionally detected, whereas synaptic input sites to the profiles containing DCVs were never observed. Among the varicosities in the distal medulla, those immunoreactive to pigment-dispersing hormone (PDH) are most numerous. The DCVs of PDH-immunoreactive (PDH-ir) varicosities differ by size from DCVs of other profiles. Moreover, in the day/night cycle PDH-ir varicosities show differences in structure revealing the rhythmic accumulation and release of PDF. There were fewer PDH-ir DCV per varicosity profile in flies fixed 1 hour after lights-on than in flies fixed 1 hour after lights-off. Moreover, at the beginning of the day all DCVs harbored an electron-dense matrix, while at the beginning of the night numerous electron-lucent DCVs were observed. By applying a bath stimulation with a high potassium concentration we also showed that depolarizing events are involved in peptide release in the medulla. After potassium treatment immunolabeling with anti-PDH serum was weaker and PDH-ir varicosities were smaller and more distant from each other than in control animals.

BACKGROUND

Ischemia/reperfusion injury after liver transplantation (LT) may be associated with primary graft dysfunction (PDF) or non-function. Prostaglandins were demonstrated to be beneficial in reducing ischemic injury by improving microcirculation and protecting endothelial cells. The aim of this study was to analyze the effect of the continuously administered prostaglandin I(2) analog iloprost on allograft function after LT.

METHODS

Eighty patients were prospectively randomized and assigned to two groups. Patients in the treatment group received iloprost for seven d after transplantation, and those in the control group did not. The primary end point was graft dysfunction.

RESULTS

The incidence of PDF was 20% (n = 8) in the control group and 5% (n = 2) in the treatment group, respectively (p = 0.087). Four patients in the control group underwent re-transplantation for initial non-function (INF). There was no evidence for INF in the treatment group. Iloprost was associated with improved allograft function. Clinical course and outcome were comparable.

CONCLUSIONS

We suggest iloprost to be beneficial for early post-transplant liver function. If the rate of PDF can be significantly reduced with this treatment concept, it should be analyzed in a larger number of patients (ISRCTN95672167).

The circadian system of hemimetabolous insects is reviewed in respect to the locus of the circadian clock and multioscillatory organization. Because of relatively easy access to the nervous system, the neuronal organization of the clock system in hemimetabolous insects has been studied, yielding identification of the compound eye as the major photoreceptor for entrainment and the optic lobe for the circadian clock locus. The clock site within the optic lobe is inconsistent among reported species; in cockroaches the lobula was previously thought to be a most likely clock locus but accessory medulla is recently stressed to be a clock center, while more distal part of the optic lobe including the lamina and the outer medulla area for the cricket. Identification of the clock cells needs further critical studies. Although each optic lobe clock seems functionally identical, in respect to photic entrainment and generation of the rhythm, the bilaterally paired clocks form a functional unit. They interact to produce a stable time structure within individual insects by exchanging photic and temporal information through neural pathways, in which serotonin and pigment-dispersing factor (PDF) are involved as chemical messengers. The mutual interaction also plays an important role in seasonal adaptation of the rhythm.

We show that the information gained in spectroscopic experiments regarding the number and distribution of atomic environments can be used as a valuable constraint in the refinement of the atomic-scale structures of nanostructured or amorphous materials from pair distribution function (PDF) data. We illustrate the effectiveness of this approach for three paradigmatic disordered systems: molecular C60, a-Si, and a-SiO2. Much improved atomistic models are attained in each case without any a priori assumptions regarding coordination number or local geometry. We propose that this approach may form the basis for a generalized methodology for structure "solution" from PDF data applicable to network, nanostructured and molecular systems alike.

Pulsion cold system (PCS, COLD) is a haemodynamic monitoring system that allows measurement of cardiac output (CO), partial blood volumes, lung water, and liver function. The aim of the study was to evaluate this monitoring system during human orthotopic liver transplantation (OLT) for the following: (a) to determine agreement between CO measurements via pulmonary artery thermodilution (CO TDpa), and aortic transpulmonary thermodilution (CO TDa); (b) to compare the preload dates obtained with the COLD with central venous pressure (CVP) and pulmonary capillary wedge (PCWP); and (c) to assess the use of the plasma disappearance rate (PDR) of indocyanine green (ICG) as a measure of graft function. Fifteen consecutive patients undergoing OLT were studied. Each patient received a pulmonary artery catheter and a 5F aortic catheter with an integrated thermistor. The thermistor of the aortic catheter were connected to one computer system (COLD-Z201, Pulsion Medical Systems, Munich, Germany). Haemodynamic data were registered an all the phases of OLT. PDR was measured during surgery in 12 patients. Correlations between PDR and the other markers of graft function (transaminases, protrombine time, and bile production) were sought. The correlation coefficient between CO TDa (COLD) and CO TDpa was r = 0.766 (p < 0.001), and an additional analysis according to Bland-Altman was also performed. There was a better correlation between the cardiac index (determined by two monitoring systems) and the volume measurements than the correlation observed with pressure preload parameters. The best correlations were found between the cardiac index in the femoral artery and intrathoracic blood volume index (ITBVI) and pulmonary blood volume index (PBVI) (r = 0.79 and r = 0.72, respectively; p < 0.01). PDR measured in the group patients with bad early graft function were lower (13.6 +/- 2.7) than those in the group with a good graft function (21.6 +/- 9) (p < 0.05). The degree of discrepancy between femoral and pulmonary thermodilution cardiac output measures is very wide during OLT so as to make the techniques using the COLD machine clinically useless. On the other hand, the volumes measured by COLD, specially ITBVI and PBVI, are more useful to asses the pre-load than pressure measurements. In OLT, the PDR measured within the first few hours after liver reperfusion may become a useful tool for early diagnosis of primary graft dysfunction (PDF).

Peptide deformylase (PDF) inhibitors represent a potential new class of antibiotics targeting a large number of bacterial species. We studied the pharmacokinetics and safety of LBM415, a novel PDF inhibitor, administered as a single oral dose at 100-3,000 mg in the fasted state and at 1,000 mg in the fed state in healthy volunteers. LBM415 was then administered at dosages ranging from 100 mg q.d. to 1,000 mg t.i.d. for 11 days. Dose-proportional pharmacokinetics was observed, with a peak plasma concentration (C(max)) of 17.85 ± 5.96 µg/ml at 1,000 mg b.i.d. (the projected therapeutic dose) and an area under the concentration-time curve (AUC)(0-24h) of 36.83 ± 10.36 µg/ml·h. The half-life, as determined after a 1,000-mg single dose, was 2.18 ± 0.61 h. The compound was well tolerated at low doses, but at the highest dose, 1,000 mg t.i.d., reversible cyanosis and low oxygen saturation, attributable to methemoglobinemia, were detected on day 11. Oxygen saturation was as low as 88% in one subject on day 11.

Peptide deformylase (PDF) is an essential enzyme in both gram-negative and gram-positive bacteria. It hydrolyzes formylated N-terminal peptides to generate free N-terminal peptides during the process of protein maturation. Inhibition of this enzyme results in cessation of bacterial growth. We have examined the effect of a potent PDF inhibitor, LBM-415 (also known as VIC-104959), on the proteomes of Staphylococcus aureus and Streptococcus pneumoniae using two-dimensional electrophoresis. Both S. aureus and S. pneumoniae showed accumulation of many N-terminal formylated peptides/proteins upon PDF inhibition. In S. pneumoniae, formylated peptide/protein accumulation was time dependent. Following inhibition, subsequent removal of the inhibitor resulted in deformylation of formylated peptides/proteins; this recovery process was also time dependent. If instead the inhibited cells were maintained in the presence of sub-MIC levels of the PDF inhibitor, the formylated peptides/proteins remained for a much longer time, which correlated with a prolonged postantibiotic effect in vitro. These observations may have broader implications for the application of this class of antibiotics in vivo.

Bacterial peptide deformylases (PDF, EC 3.5.1.27) are metalloenzymes that cleave the N-formyl groups from N-blocked methionine polypeptides. Peptide aldehydes containing a methional or norleucinal inhibited recombinant peptide deformylase from gram-negative Escherichia coli and gram-positive Bacillus subtilis. The most potent inhibitor was calpeptin, N-CBZ-Leu-norleucinal, which was a competitive inhibitor of the zinc-containing metalloenzymes, E. coli and B. subtilis PDF with Ki values of 26.0 and 55.6 microM, respectively. Cobalt-substituted E. coli and B. subtilis deformylases were also inhibited by these aldehydes with Ki values for calpeptin of 9.5 and 12.4 microM, respectively. Distinct spectral changes were observed upon binding of calpeptin to the Co(II)-deformylases, consistent with the noncovalent binding of the inhibitor rather than the formation of a covalent complex. In contrast, the chelator 1,10-phenanthroline caused the time-dependent inhibition of B. subtilis Co(II)-PDF activity with the loss of the active site metal. The fact that calpeptin was nearly equipotent against deformylases from both gram-negative and gram-positive bacterial sources lends further support to the idea that a single deformylase inhibitor might have broad-spectrum antibacterial activity.

The results of thirteen control experiments, designed to show the number of glomeruli in the rabbit's kidney open to the circulation under the chosen experimental conditions without intentional interference, indicate the "normal" range to be from 42 to 100 per cent. Since ten of the thirteen results fall within the figures 56 and 89 per cent, we may take these figures as the chief basis for our discussion. Three experiments only were made in which renal vasodilatation was produced by caffeine and salt. The percentage of open glomeruli found was in every case higher than any control except one. The results show without ambiguity that in rabbits, as in frogs, renal vasodilatation by caffeine is accompanied by increase in number of patent glomeruli. Our prime interest lay in the general question rather than in the action of individual substances in the group of vasodilators; hence this series was not extended further. Among the experiments designed to test the effects of renal vasoconstriction are to be found nine in which adrenalin was injected, two in which CO(2) was inhaled, two in which the splanchnic nerve was stimulated, and four in which hemorrhage was induced. Not all are of equal value for our present purpose, inasmuch as the degree of certainty with which we can assume that renal vasoconstriction was actually produced is not the same in all. Enough experience with the action of adrenalin on the kidney of the anesthetized rabbit is available to permit the assertion that the dosages used in the nine adrenalin experiments were sufficient to insure constriction of renal vessels. Similar certainty exists in the experiment in which high concentration of CO(2) was used; less in the case of 10 per cent CO(2). Stimulation of the splanchnic nerve in rabbits so frequently fails to produce results typical of direct constriction of renal vessels that we may regard the production of this effect in the two experiments in which this was done as doubtful. In the perfusion experiments by Richards and Plant (7) the reactions of the renal vessels to stimulation of the splanchnic nerve resembled those to intravenously injected adrenalin rather than to the direct excitation of constrictor fibers. In six rabbits in which Livingston subjected the nerve to varying degrees of electrical stimulation, in one only was distinct constriction of the renal vessels produced, and in this a latent period of 45 seconds occurred between the beginning of stimulation and the production of effect. In one of our experiments a rabbit was used in which the superior cervical sympathetic ganglion on the left side had been extirpated months before. During the stimulation of the splanchnic nerve the left pupil was observed to dilate, showing increased adrenalin secretion. Hence, we are inclined to regard the two attempts to produce vasoconstriction by this means as having been largely unsuccessful. In one experiment only of the four in which hemorrhage was induced was there unmistakable evidence of compensatory vasoconstriction which may have involved the renal vessels. The blood pressure curve of this animal showed rhythmically occurring waves of the Traube-Hering type and dyspnea was noted. In this the estimate of open glomeruli was 28 per cent. In the other three experiments no such change occurred and no dyspnea was seen. In pithed frogs, hemorrhage alone of moderate extent is less apt to lessen the number of patent glomeruli than are any of the other constrictor agencies tried by Richards and Schmidt. In this discussion, therefore, we lay little weight on the results obtained in the two experiments in which the splanchnic nerve was stimulated and on those of the first three hemorrhage experiments. The chief conclusion to be drawn from these experiments is that which was anticipated from the observations of Richards and Schmidt on frogs, and of Khanolkar on rabbits; viz., that in the rabbit, renal vasodilatation and renal vasoconstriction are usually associated with increase and decrease respectively in number of glomeruli through which blood flows (see Text-fig. 1). Analogous changes apparently occur in the capillary pathway in individual glomeruli. Hence renal function in mammals may be altered by changes in the extent of glomerular filtration surface to which the blood has access. Other conditions remaining the same, it is obvious that changes in extent of filtration surface must result in proportionate changes in urinary output. The figures for rate of urine elimination at the time of injection of the dye in these experiments are in substantial agreement with these statements (see Text-fig. 2). Exceptions to our chief conclusion as stated have been encountered. In Experiment 57,86 per cent of the glomeruli were open in a constricted kidney which was excreting no urine: in Experiment 30, 16 per cent were open in the kidney which was eliminating seven drops per minute: the outputs of the kidneys in the caffeine experiments were far higher than those of control kidneys in which comparable numbers of glomeruli were open. In considering these exceptions, account must be taken of the fact that other conditions do not commonly remain constant. When a renal vasodilator is introduced we conceive not only of possible increase in extent of accessible glomerular surface, but also of increase in glomerular pressure and increased rate of renewal of fluid in contact with glomerular membranes. Hence the response is greater than can be accounted for by any one factor alone. A basis of experiment exists in support of the belief that usually sufficient differences in physiological state exist among the small arteries and arterioles of the kidney so that a constrictor influence, exerted equally upon all, elicits various degrees of response (1). Closure of some, continuing patency of others, results. Blood flow and blood pressure in the glomeruli which are supplied by the vessels which remain open may be decreased, increased, or unchanged according See PDF for Structure. to the relation between the degree of reaction in those vessels and the height of arterial blood pressure. It is not to be expected that urinary outputs will uniformly vary with the number of glomeruli remaining open. Rapid blood flow and high glomerular pressure in relatively few glomeruli may result in more urine than slow flow and low pressure in many. This argument is implicit in Hermann's original statement and is completely in harmony with the result of direct observation in the frog. It is supported by the data of Experiment 30. In Experiment 57, however, urine was suppressed by adrenalin when 86 per cent of the glomeruli remained open. The kidney in this experiment was highly diuretic before the adrenalin injection. We may, therefore, assume that all or nearly all of the glomeruli were open and that intermittent contractions of the arterioles were minimal; hence, that the physiological state of the vessels concerned was more nearly uniform than is conceived to be the case when only a fraction of the glomeruli are open and in which intermittent contractions and relaxations must be pronounced. Thus a relatively uniform constriction was produced in all of such degree as to lessen materially glomerular pressure and blood flow, but insufficient to actually close more than a few afferent arterioles. In Experiment 33, the dosage of adrenalin was such as to permit the possibility that constrictor action may have been largely confined to efferent vessels (8). While the exceptional results have been discussed at greater length than has been devoted to the majority of experiments, we believe that they do not constitute adequate ground for criticism of the chief conclusion as stated.

OBJECTIVE

The influence of antepartal, intrapartal and early neonatal risk factors, are very important during the pregnancy and the pregnancy outcome, also for the early neonatal period and the forthcoming children development. Our aim is to detect the risks groups of pregnant women that later develop Pregnancy Induced Hypertension (PIH) and risk factors that precede its appearance.

METHODS

We examined 67 preeclamptic and 129 normotensive pregnancies. In research are included only single pregnancies and the following parameters: maternal age, parity and previous pregnancy history.

RESULTS

Average age is 25.73+/-5.77 years. After all, the largest number of primipara with preeclampsia is in category from 20 years (p<0.01). Considering the multipara we noticed that preeclampsia is most commonly developed in age between 31-35 years (p<0.01). Biggest number of pregnancies in normotensive group had previous normal pregnancies (59.15 %), while in hypertensive group only 30.77 % patients had normal pregnancies (p<0.05).

CONCLUSIONS

PIH is most frequently appearing in young primiparas and adult multiparas. Pregnancies with PIH, really often there were negative ending of previous pregnancies (Tab. 5, Ref. 20). Full Text in free PDF www.bmj.sk.

The lead compound 5-bromoindolyl-3-acetohydroxamic acid (10) was recently identified as a potent inhibitor of bacterial peptide deformylases (<em>PDFs</em>). The synthesis and associated activities of new variants were investigated at position 5 to optimize the fit at the S1' subsite and at position 1 to improve both potency and antibacterial activity. A morphomimetic series, termed "reverse-indole" was synthesized. The indole derivatives remain selective in vitro inhibitors of <em>PDF</em>2 over <em>PDF</em>1. Bromide is the best group at position 5 and cannot be replaced by bulkier substituents. In this series, an N-benzyl group at position 1 in 19 e improves the potency relative to 10. In the case of <em>PDF</em>1, and unlike <em>PDF</em>2, potency is increased as the alkyl chain becomes longer and more ramified. These data support the results of NMR footprinting experiments that were performed with (15)N-labeled Ni-<em>PDF</em> and the corresponding 3-acetic acid derivatives. Most of the compounds have antibacterial activities toward B. subtilis, but are inefficient toward E. coli owing to active removal by the major efflux pumps. Among the reverse-indole derivatives, 23 c, which is the exact mirror image of 19 e, shows strong potency in vitro against <em>PDF</em>2, but little against <em>PDF</em>1, although this compound displays significant antibacterial activity toward an efflux-minus mutant of E. coli. All the compounds were assessed with major pathogenic bacteria, but most of them are inefficient antibacterial agents. The reverse-indole compounds 23 a and 23 c have potency against S. pneumoniae that is similar to that of actinonin.

It has recently been suggested that "standard" data distributions for key exposure variables should be developed wherever appropriate for use in probabilistic or "Monte Carlo" exposure analyses. Soil-on-skin adherence estimates represent an ideal candidate for development of a standard data distribution: There are several readily available studies which offer a consistent pattern of reported results, and more importantly, soil adherence to skin is likely to vary little from site-to-site. In this paper, we thoroughly review each of the published soil adherence studies with respect to study design, sampling, and analytical methods, and level of confidence in the reported results. Based on these studies, probability density functions (PDF) of soil adherence values were examined for different age groups and different sampling techniques. The soil adherence PDF developed from adult data was found to resemble closely the soil adherence PDF based on child data in terms of both central tendency (mean = 0.49 and 0.63 mg-soil/cm2-skin, respectively) and 95th percentile values (1.6 and 2.4 mg-soil/cm2-skin, respectively). Accordingly, a single, "standard" PDF is presented based on all data collected for all age groups. This standard PDF is lognormally distributed; the arithmetic mean and standard deviation are 0.52 +/- 0.9 mg-soil/cm2-skin. Since our review of the literature indicates that soil adherence under environmental conditions will be minimally influenced by age, sex, soil type, or particle size, this PDF should be considered applicable to all settings. The 50th and 95th percentile values of the standard PDF (0.25 and 1.7 mg-soil/cm2-skin, respectively) are very similar to recent U.S. EPA estimates of "average" and "upper-bound" soil adherence (0.2 and 1.0 mg-soil/cm2-skin, respectively).

OBJECTIVE

Bacterial drug resistance is a worrying public health problem and there is an urgent need for research and development to provide new antibacterial molecules. Peptide deformylase (PDF) is now a well-described intracellular target selected for the design of a new antibiotic group, PDF inhibitors (PDFIs). The initial bacterial susceptibility to an inhibitor of a cytoplasmic target is directly associated with the diffusion of the compound through the membrane barrier of Gram-negative bacteria and with its cytosolic accumulation at the required concentration.

METHODS

We have recently demonstrated that the activity of different PDFIs is strongly dependent on the accumulation of the active molecules by using permeabilizing agents, efflux inhibitors or efflux-mutated strains. In this work we assessed various combination protocols using different putative inhibitors (PDFIs, methionine aminopeptidase inhibitors etc.) to improve antibacterial activity against various resistant Gram-negative bacteria.

RESULTS

The maximum effect was observed when combining actinonin with a dual inhibitor of methionine aminopeptidase and PDF, this molecule being also able to interact with the target while actinonin is bound to the PDF active site.

CONCLUSIONS

Such a combination of inhibitors acting on two tightly associated metabolic steps results in a cooperative effect on bacterial cells and opens an original way to combat multidrug-resistant bacteria.