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Large intramuscular triglyceride (IMTG) stores in sedentary, obese individuals have been linked to insulin resistance, yet well-trained athletes exhibit high IMTG levels whilst maintaining insulin sensitivity. Contrary to previous assumptions, it is now known that IMTG content per se does not result in insulin resistance. Rather, insulin resistance is caused, at least in part, by the presence of high concentrations of harmful lipid metabolites, such as diacylglycerols and ceramides in muscle. Several mechanistic differences between obese sedentary individuals and their highly trained counterparts have been identified, which determine the differential capacity for IMTG synthesis and breakdown in these populations. In this review, we first describe the most up-to-date mechanisms by which a low IMTG turnover rate (both breakdown and synthesis) leads to the accumulation of lipid metabolites and results in skeletal muscle insulin resistance. We then explore current and potential exercise and nutritional strategies that target IMTG turnover in sedentary obese individuals, to improve insulin sensitivity. Overall, improving IMTG turnover should be an important component of successful interventions that aim to prevent the development of insulin resistance in the ever-expanding sedentary, overweight and obese populations. Novelty: A description of the most up-to-date mechanisms regulating turnover of the IMTG pool. An exploration of current and potential exercise/nutritional strategies to target and enhance IMTG turnover in obese individuals. Overall, highlights the importance of improving IMTG turnover to prevent the development of insulin resistance.

A previous study of symmetric collisions of massive nuclei has shown that current models of multinucleon transfer (MNT) reactions do not adequately describe the transfer product yields. To gain further insight into this problem, we have measured the yields of MNT products in the interaction of 977 ($E/A=4.79$ MeV) and 1143 MeV ($E/A=5.60$ MeV) $^{204}\mathrm{Hg}$ with $^{208}\mathrm{Pb}$. We find that the yield of multinucleon transfer products are similar in these two reactions and are substantially lower than those observed in the reaction of 1257 MeV ($E/A=6.16$ MeV) $^{204}\mathrm{Hg}+^{198}\mathrm{Pt}$. We compare our measurements with the predictions of the GRAZING-F, dinuclear systems (DNS), and improved quantum molecular dynamics (ImQMD) models. For the observed isotopes of the elements Au, Hg, Tl, Pb, and Bi, the measured values of the MNT cross sections are orders of magnitude larger than the predicted values. Furthermore, the various models predict the formation of nuclides near the $N=126$ shell, which are not observed.

The Neutron Induced Fission Fragment Tracking Experiment (NIFFTE) collaboration has performed measurements with a fission time projection chamber (fissionTPC) to study the fission process by reconstructing full three-dimensional tracks of fission fragments and other ionizing radiation. The amount of linear momentum imparted to the fissioning nucleus by the incident neutron can be inferred by measuring the opening angle between the fission fragments. Using this measured linear momentum, fission fragment angular distributions can be converted to the center-of-mass frame for anisotropy measurements. Angular anisotropy is an important experimental observable for understanding the quantum mechanical state of the fissioning nucleus and vital to determining detection efficiency for cross section measurements. Neutron linear momentum transfer to fissioning $^{235}$U, $^{238}$U, and $^{239}$Pu and fission fragment angular anisotropy of $^{235}$U and $^{238}$U as a function of neutron energies in the range 130 keV--250 MeV are presented.

The total kinetic energy (TKE) release in the fast neutron induced fission of 235U was measured for neutron energies E n = 2 – 100 MeV . The TKE distributions are Gaussian in shape. The mean post neutron emission TKE release decreases non-linearly with increasing neutron energy and can be represented as TKE(MeV) = 170.92 − 3.73774 log 10 ⁡ E n − 0.65028 ( log 10 ⁡ E n ) 2 . Abrupt changes in the variances of the TKE distributions are observed at the onset of 2nd, 3rd, etc. chance fission. For E n = 20 – 100 MeV , the variances are approximately constant. These observations are compared to the predictions of the GEF model for neutron-induced fission. This model describes many of the features of the TKE release adequately.

Symmetric collisions of massive nuclei, such as 238U + 248Cm, have been proposed as ways to make new n-rich heavy nuclei via multi-nucleon transfer (MNT) reactions. We have measured the yields of several projectile-like and target-like fragments from the reaction of 1360 MeV 204Hg + 198Pt. We find that current models for this symmetric collision (GRAZING, DNS, ImQMD) significantly underestimate the yields of these transfer products, even for small transfers. Keywords: Multi-nucleon transfer, GRAZING predictions, DNS model, Improved Quantum Molecular Dynamics model, 204Hg + 198Pt

Fission fragment angular distributions can provide an important constraint on fission theory, improving predictive fission codes, and are a prerequisite for a precise ratio cross section measurement. Available anisotropy data is sparse, especially at neutron energies above 5 MeV. For the first time, a three-dimensional tracking detector is employed to study fragment emission angles and provide a direct measurement of angular anisotropy. The Neutron Induced Fission Fragment Tracking Experiment (NIFFTE) collaboration has deployed the fission time projection chamber (fissionTPC) to measure nuclear data with unprecedented precision. The fission fragment anisotropy of $^{235}$U has been measured over a wide range of incident neutron energies from 180 keV to 200 MeV; a careful study of the systematic uncertainties complement the data.

The normalized $^{238}$U(n,f)/$^{235}$U(n,f) cross section ratio has been measured using the NIFFTE fission Time Projection Chamber from the reaction threshold to $30$~MeV. The fissionTPC is a two-volume MICROMEGAS time projection chamber that allows for full three-dimensional reconstruction of fission-fragment ionization profiles from neutron-induced fission. The measurement was performed at the Los Alamos Neutron Science Center, where the neutron energy is determined from neutron time-of-flight. The $^{238}$U(n,f)/$^{235}$U(n,f) ratio reported here is the first cross section measurement made with the fissionTPC, and will provide new experimental data for evaluation of the $^{238}$U(n,f) cross section, an important standard used in neutron-flux measurements. Use of a development target in this work prevented the determination of an absolute normalization, to be addressed in future measurements. Instead, the measured cross section ratio has been normalized to ENDF/B-VIII.$\beta$5 at 14.5 MeV.

States in $^{209}\mathrm{Tl}$ were populated using a multinucleon transfer reaction with a $^{136}\mathrm{Xe}$ beam impinging on a thick $^{208}\mathrm{Pb}$ target at $E=785$ MeV. The beam was pulsed at 825-ns intervals in order to perform isomer decay spectroscopy. The known ${J}^{\ensuremath{\pi}}=17/{2}^{+}$ isomer in $^{209}\mathrm{Tl}$ was located at 1228(4) keV and measured to have a half-life of ${T}_{1/2}=146(10)$ ns. A second isomer with ${J}^{\ensuremath{\pi}}=13/{2}^{+}$ was found to have ${T}_{1/2}=14(5)$ ns. The previously suggested low-energy X and Y transitions were found to have energies 57(2) and 47(2) keV respectively, while the measurement of conversion coefficients and a new decay path make the spin assignments below the isomers experimentally firm. Correlating the delayed $\ensuremath{\gamma}$ transitions with the prompt beam flash allowed the decay of states above the isomer to be found. The longer-lived isomer represents full alignment of the simplest two-particle, one-hole configuration and illuminates the remarkably weak coupling of the proton hole to the $^{210}\mathrm{Pb}$ core.

The yields of over 200 projectile-like fragments (PLFs) and target-like fragments (TLFs) from the interaction of (${E}_{\mathrm{c}.\mathrm{m}.}=450$ MeV) $^{136}\text{Xe}$ with a thick target of $^{208}\text{Pb}$ were measured using Gammasphere and off-line $\ensuremath{\gamma}$-ray spectroscopy, giving a comprehensive picture of the production cross sections in this reaction. The measured yields were compared to predictions of the grazing model and the predictions of Zagrebaev and Greiner using a quantitative metric, the theory evaluation factor $\mathit{t}ef$. The grazing model predictions are adequate for describing the yields of nuclei near the target or projectile but they grossly underestimate the yields of all other products. The predictions of Zagrebaev and Greiner correctly describe the magnitude and maxima of the observed TLF transfer cross sections for a wide range of transfers ($\mathrm{\ensuremath{\Delta}}Z=\ensuremath{-}8$ to $\mathrm{\ensuremath{\Delta}}Z=+2$). However, for $\mathrm{\ensuremath{\Delta}}Z=+4$, the observed position of the maximum in the distribution is four neutrons richer than the predicted maximum. The predicted yields of the neutron-rich $N=126$ nuclei exceed the measured values by two orders of magnitude. Correlations between TLF and PLF yields are discussed.

In this article I examine the theme of illness, health, and healing in the fourth-century Egyptian text, the Canons of Hippolytus. The study seeks to discover what may be distinctive in the Canons as a later reworking of the text known as the Apostolic Tradition. I explore the theme in the Canons under the headings of: (1) the general ministry to the sick by all members of the local church community; (2) the ministry to the sick by those with a charismatic gift of healing; and (3) the ministry to the sick by the bishop and other church leaders. I go on to argue in the light of this analysis that there is a stronger degree of emphasis on this theme in the community that produced the Canons than in other Christian communities outside Egypt for which we have evidence. And I suggest that when this evidence is coupled with evidence from an analysis of the theme in the Egyptian Sacramentary of Sarapion (or Prayers of Sarapion), it may indicate a feature of Christian life that is distinctive to Egypt in terms of the level of interest in, and concern for, this theme in that part of the Christian world in the third and particularly the fourth century

We have studied the fission-neutron emission competition in highly excited $^{274}$Hs (Z=108) (where the fission barrier is due to shell effects) formed by a hot fusion reaction. Matching cross bombardments ($^{26}$Mg + $^{248}$Cm and $^{25}$Mg + $^{248}$Cm) were used to identify the properties of first chance fission of $^{274}$Hs. A Harding-Farley analysis of the fission neutrons emitted in the $^{25,26}$Mg + $^{248}$Cm was performed to identify the pre- and post-scission components of the neutron multiplicities in each system. ($\Gamma$$_{n}$/$\Gamma$$_{t}$) for the first chance fission of $^{274}$Hs (E$^{\ast}$ = 63 MeV) is 0.89 $\pm$ 0.13, i.e., $\sim$ 90 $%$ of the highly excited nuclei survive.The high value of that survival probability is due to dissipative effects during de-excitation. A proper description of the survival probabilities of excited superheavy nuclei formed in hot fusion reactions requires consideration of both dynamic and static (shell-related) effects.

Background: The cross section for forming a heavy evaporation residue in fusion reactions depends on the capture cross section, the fusion probability, PCN, i.e., the probability that the projectile-target system will evolve inside the fission saddle point to form a completely fused system rather than reseparating (quasifission), and the survival of the completely fused system against fission. PCN is the least known of these quantities. Purpose: We want to determine PCN for the reactions of 101.2 MeV 18 O, 147.3 MeV 26 Mg, 170.9 MeV 30 Si, and 195.3 MeV 36 Sw ith 197 Au. Methods: We measured the fission fragment angular distributions for these reactions and used the formalism of Back to deduce the fusion-fission and quasifission cross sections. From these quantities we deduced PCN for each reaction. Results: The values of PCN for the reactions of 101.2 MeV 18 O, 147.3 MeV 26 Mg, 170.9 MeV 30 Si, and 195.3 MeV 36 S with 197 Au are 0.66, 1.00, 0.06, and 0.13, respectively. Conclusions: The new measured values of PCN agree roughly with the semiempirical systematic dependence of PCN upon fissility for excited nuclei.

It is well recognised that ingestion of food is a trigger for functional bowel symptoms, particularly those associated with irritable bowel syndrome (IBS). Patients often use manipulation of diet as a means of controlling symptoms. Despite description of multiple dietary methods, few have scientific backing or quality evidence of efficacy. One approach is to define how specific food components influence the pathophysiology of IBS and then rationally design dietary approaches. For example, short-chain poorly absorbed carbohydrates (fermentable oligo-, di- and mono-saccharides and polyols (FODMAP)) cause luminal distension, which is a major stimulus for the development of symptoms in patients with visceral hypersensitivity. By determining food content of FODMAP, a diet in which foods low in FODMAP are favoured over those high in FODMAP can be designed. Observational, comparative and randomised controlled treatment and rechallenge studies have shown that such an approach is efficacious in the majority of patients with IBS. The low FODMAP diet is now the primary dietary therapy for such patients. Similar approaches can be applied to other food components, including proteins (such as gluten), fats and natural bioactive food chemicals. Such approaches have suggestions of efficacy, but the evidence base remains underdeveloped. An additional and important consideration for any dietary therapy is its nutritional adequacy and potential adverse health effects. Dietary manipulation is now a key management strategy in patients with functional bowel symptoms. Future well-designed interventional studies will lead to refinement of dietary approaches taken and to a better understanding of their long-term safety.

Although it is recognized that diarrhoea commonly complicates enteral nutrition, the causes remain unknown.To identify factors associated with diarrhoea in patients receiving enteral nutrition with specific attention to formula composition.Medical histories of in-patients receiving enteral nutrition were identified by ICD-10-AM coding and randomly selected from the year 2003 to 2008. Clinical and demographic data were extracted. Formulas were classified according to osmolality, fibre and FODMAP (fermentable oligo-, di- and mono-saccharides and polyols) content.Formula FODMAP levels ranged from 10.6 to 36.5 g/day. Of 160 patients receiving enteral nutrition, 61% had diarrhoea. Univariate analysis showed diarrhoea was associated with length of stay21 days (OR 4.2), enteral nutrition duration11 days (OR 4.0) and antibiotic use (OR 2.1). After adjusting for influencing variables through a logistic regression model, a greater than five-fold reduction in risk of developing diarrhoea was seen in patients initiated on Isosource 1.5 (P = 0.029; estimated OR 0.18). The only characteristic unique to this formula was its FODMAP content, being 47-71% lower than any other formula.Length of stay and enteral nutrition duration independently predicted diarrhoea development, while being initiated on a lower FODMAP formula reduced the likelihood of diarrhoea. As retrospective evaluation does not support a cause-effect relationship, an interventional study investigating FODMAPs in enteral formula is indicated.

The efficacy of recombinant vampire bat salivary plasminogen activator (bat-PA) as a thrombolytic agent was compared with that of human tissue-type plasminogen activator (t-PA) in a canine model of arterial thrombosis. An occlusive thrombus was formed in the femoral artery by insertion of a thrombogenic copper coil; femoral arterial blood flow was monitored with a Doppler flow meter. Bat-PA and t-PA, when administered by 5-minute intravenous infusion (14 nmol/kg), reperfused seven out of eight and four out of eight dogs, respectively. The median reperfusion times in the bat-PA and t-PA groups were 24 and greater than or equal to 131 minutes, respectively. The mean reperfusion times (+/- SEM) in the recanalized bat-PA- and t-PA-treated dogs were similar (20 +/- 5 and 11 +/- 2 minutes, respectively, p = NS). Maximal blood flow after reperfusion was greater with bat-PA than with t-PA (80 +/- 10% and 41 +/- 15% of control flow, respectively, p less than 0.05). Furthermore, the median reocclusion time was markedly delayed in the bat-PA group relative to the t-PA group (131 versus 34 minutes, respectively, p less than 0.05). Plasma fibrinogen and plasminogen were not significantly depleted by the administration of t-PA or bat-PA. However, plasma alpha 2-antiplasmin activity was moderately depressed in the t-PA group relative to the bat-PA group (p less than 0.05). The clearance profile for t-PA was monoexponential, with a half-life (t1/2) of 2.4 +/- 0.3 minutes and a mean residence time of 3.5 +/- 0.4 minutes. The clearance profile for bat-PA was biexponential, with a t1/2 alpha of 0.9 +/- 0.2 minutes, a t1/2 beta of 20.2 +/- 2.7 minutes, and a mean residence time of 21.3 +/- 4.3 minutes. The steady-state volume of distribution displayed by bat-PA was 16-fold greater than that of t-PA. Zymography of serial plasma samples from the bat-PA-treated dogs failed to demonstrate the apparent generation of a complex between bat-PA and plasminogen activator inhibitor-1; the corresponding complex with t-PA was observed in plasma samples from the t-PA-treated dogs. The sustained recanalization and improved blood flow in the bat-PA group relative to the t-PA group and the avoidance of fibrinogenolysis by bat-PA, despite its prolonged mean residence time, suggest that bat-PA may be superior to t-PA as a thrombolytic agent.

Fructose malabsorption, lactose malabsorption and an early rise in breath hydrogen after lactulose (ERBHAL) may play roles in induction of symptoms in gastrointestinal conditions.To compare prevalence and interactions of fructose malabsorption, lactose malabsorption and ERBHAL among healthy subjects and those with chronic intestinal disorders using consistent breath hydrogen testing methodologies.Consecutive series of Caucasian patients with Crohn's disease (n = 91), ulcerative colitis (56), functional gastrointestinal disorders (FGID) (201), coeliac disease (136) and 71 healthy volunteers underwent breath hydrogen testing using lactulose, fructose and lactose.Early rise in breath hydrogen after lactulose occurred more commonly in healthy controls (39%) than in Crohn's disease (20%) and untreated coeliac disease (14%; P0.008), but not FGID (27%), ulcerative colitis (26%) or treated coeliac disease (29%). Fructose malabsorption was more frequent in Crohn's disease (61%) than other groups (33-44%, P0.05). Lactose malabsorption was most common in Crohn's disease (42%) and ulcerative colitis (40%) and uncommon (10%) in 79 patients with newly diagnosed coeliac disease. In Crohn's disease, concurrent Fructose malabsorption and lactose malabsorption was most common (29%), and the association of fructose malabsorption with ERBHAL seen overall (62%) was not observed (36%, P0.0001).Carbohydrate malabsorption and ERBHAL are normal physiological phenomena. The abnormal patterns observed in Crohn's disease may have pathogenic importance.

Fluconazole is being increasingly used to prevent and treat invasive candidiasis in neonates, yet dosing is largely empirical due to the lack of adequate pharmacokinetic (PK) data. We performed a multicenter population PK study of fluconazole in 23- to 40-week-gestation infants less than 120 days of age. We developed a population PK model using nonlinear mixed effect modeling (NONMEM) with the NONMEM algorithm. Covariate effects were predefined and evaluated based on estimation precision and clinical significance. We studied fluconazole PK in 55 infants who at enrollment had a median (range) weight of 1.02 (0.440 to 7.125) kg, a gestational age at birth (BGA) of 26 (23 to 40) weeks, and a postnatal age (PNA) of 2.3 (0.14 to 12.6) weeks. The final data set contained 357 samples; 217/357 (61%) were collected prospectively at prespecified time intervals, and 140/357 (39%) were scavenged from discarded clinical specimens. Fluconazole population PK was best described by a one-compartment model with covariates normalized to median values. The population mean clearance (CL) can be derived for this population by the equation CL (liter/h) equals 0.015 · (weight/1) 0.75 · (BGA/26) 1.739 · (PNA/2) 0.237 · serum creatinine (SCRT) −4.896 (when SCRT is >1.0 mg/dl), and using a volume of distribution ( V ) (liter) of 1.024 · (weight/1). The relative standard error around the fixed effects point estimates ranged from 3 to 24%. CL doubles between birth and 28 days of age from 0.008 to 0.016 and from 0.010 to 0.022 liter/kg/h for typical 24- and 32-week-gestation infants, respectively. This population PK model of fluconazole discriminated the impact of BGA, PNA, and creatinine on drug CL. Our data suggest that dosing in young infants will require adjustment for BGA and PNA to achieve targeted systemic drug exposures.

Fructose is found widely in the diet as a free hexose, as the disaccharide, sucrose and in a polymerized form (fructans). Free fructose has limited absorption in the small intestine, with up to one half of the population unable to completely absorb a load of 25 g. Average daily intake of fructose varies from 11 to 54 g around the world. Fructans are not hydrolysed or absorbed in the small intestine. The physiological consequences of their malabsorption include increasing osmotic load, providing substrate for rapid bacterial fermentation, changing gastrointestinal motility, promoting mucosal biofilm and altering the profile of bacteria. These effects are additive with other short-chain poorly absorbed carbohydrates such as sorbitol. The clinical significance of these events depends upon the response of the bowel to such changes; they have a higher chance of inducing symptoms in patients with functional gut disorders than asymptomatic subjects. Restricting dietary intake of free fructose and/or fructans may have durable symptomatic benefits in a high proportion of patients with functional gut disorders, but high quality evidence is lacking. It is proposed that confusion over the clinical relevance of fructose malabsorption may be reduced by regarding it not as an abnormality but as a physiological process offering an opportunity to improve functional gastrointestinal symptoms by dietary change.

We have created a data warehouse for human pharmacokinetic (PK) and pharmacodynamic (PD) data generated primarily within the Clinical PK Group of the Drug Metabolism and Pharmacokinetics (DMPK) Department of DuPont Pharmaceuticals.Data which enters an Oracle-based LIMS directly from chromatography systems or through files from contract research organizations are accessed via SAS/PH.Kinetics, GLP-compliant data analysis software residing on individual users' workstations. Upon completion of the final PK or PD analysis, data are pushed to a predefined location. Data analyzed/created with other software (i.e., WinNonlin, NONMEM, Adapt, etc.) are added to this file repository as well. The warehouse creates views to these data and accumulates metadata on all data sources defined in the warehouse. The warehouse is managed via the SAS/Warehouse Administrator product that defines the environment, creates summarized data structures, and schedules data refresh.The clinical PK/PD warehouse encompasses laboratory, biometric, PK and PD data streams. Detailed logical tables for each compound are created/updated as the clinical PK/PD data warehouse is populated. The data model defined to the warehouse is based on a star schema. Summarized data structures such as multidimensional data bases (MDDB), infomarts, and datamarts are created from detail tables. Data mining and querying of highly summarized data as well as drill-down to detail data is possible via the creation of exploitation tools which front-end the warehouse data. Based on periodic refreshing of the warehouse data, these applications are able to access the most current data available and do not require a manual interface to update/populate the data store. Prototype applications have been web-enabled to facilitate their usage to varied data customers across platform and location. The warehouse also contains automated mechanisms for the construction of study data listings and SAS transport files for eventual incorporation into an electronic submission.This environment permits the management of online analytical processing via a single administrator once the data model and warehouse configuration have been designed. The expansion of the current environment will eventually connect data from all phases of research and development ensuring the return on investment and hopefully efficiencies in data processing unforeseen with earlier legacy systems.

The highly competitive pharmaceutical industry has seen many external changes to its landscape as companies consume each other increasing their pipelines while removing redundant functions and processes. Internally, companies have sought to streamline the discovery and development phases in an attempt to improve candidate selection and reduce the time to regulatory filing. In conjunction with efforts to screen and develop more compounds faster and more efficiently, database management systems (DBMS) have been developed for numerous groups supporting various RD efforts. An outgrowth of DBMS evolution has been the birth of data warehousing. Often confused with DBMS, data warehousing provides a conduit for data residing across platforms, networks, and in different data structures. Through the use of metadata, the warehouse establishes connectivity of varied data stores (operational detail data, ODD) and permits identification of data ownership, location and transaction history. This evolution has closely mirrored and in some ways been driven by the electronic submission (formerly CANDA). The integration of the electronic submissions and document management with RD data warehousing initiatives should provide a platform by which companies can address compliance with 21 CFR Part 11. Now more than ever "corporate memory" is being extended to the data itself. The when, why and how of successes and failures are constantly being probed by RD management teams. The volume of information being generated by today's pharmaceutical companies requires mining of historical data on a routine basis. Data warehousing represents a core technology to assist in this endeavor. New initiatives in this field address the necessity of data portals through which warehouse data can be web-enabled and exploited by diverse data customers both internal and external to the company. The epiphany of data warehousing technologies within the pharmaceutical industry has begun and promises to change the way in which companies process and provide data to regulatory agencies. The improvements in drug discovery and reduction in development timelines remain to be seen but would seem to be rational if such technology is fully exploited.

The disposition of XV459, a potent, selective GP IIb/IIIa antagonist, has been examined following intravenous administration of XP280, the benzenesulphonate salt, and 3H-SA202, the trifluroacetic acid salt, to male guinea pigs. A liquid chromatography-mass spectrometry (LC-MS) method was developed and validated for XV459 quantitation in guinea pig plasma with an LLOQ of 0.1 ng/mL. Intravenous infusions (30 min) of XP280 at doses of 0.5 and 2.0 microg/kg were administered to guinea pigs which were sequentially sacrificed at 0.5, 1, 1.5, 4, 8, 12, 24, 48 and 72 h postinitiation of infusion. Maximum total (unbound and GP IIb/IIIa displaced) XV459 plasma concentration of approximately 3.5 microg/mL was obtained at the 2.0 microg/kg dose. Pooling individual concentration-time data yielded a systemic clearance of 1.42 mL/min/kg, Vss of 0.24 L/kg, and a terminal half-life of 2.8 h in the guinea pig at the 0.5 microg/kg dose. The 2.0 microg/kg dose yielded XV459 exposure that was less than proportional to the previous dose. Similar behaviour has been observed in human trials. Cumulative (up to 72 h) urinary and faecal recovery of total radioactivity was 66.4 and 11.2%, respectively. The time course of spleen, marrow and whole blood radioactivity profiles was similar, suggesting that XV459 was not preferentially sequestered on non-plasma GP IIb/IIIa binding sites. Tissue to blood ratios of 20.7 and 8.3 for the spleen and bone marrow, respectively, indicate that increased (relative to blood) exposure was evident for sites containing the GP IIb/IIIa receptor. In vitro studies confirmed the similarity of XV459 binding to both resting and activated platelets in the guinea pig and humans. Given the comparability of dissociation rate constants and IC50s based on in vitro platelet aggregation, human dosimetry estimates should assume similar partitioning of radiolabelled XV459 as in the guinea pig. These results suggest that the guinea pig may indeed be an appropriate animal model for pharmacokinetic and distribution studies with DMP754; in conjunction with recent pharmacological findings with GP IIb/IIIa antagonists, our results suggest that the guinea pig may be the rodent species of choice for preclinical studies with some other GP IIb/IIIa antagonists.

Selegiline is a selective, irreversible inhibitor of MAO-B, used in the treatment of Parkinson's disease, either alone or as an adjunct to L-DOPA. The sole recommended dosing regimen is 5 mg given in the morning and at noon with breakfast and lunch. A pulsatile oral dosage form was developed to mimic the conventional tablet release from two oral administrations separated by 4 h, to permit once-daily dosing and increase compliance. The pharmacokinetics of the pulsatile delivery system was studied in six healthy male volunteers. The plasma concentration-time profile from the pulsatile system of selegiline and metabolites is dissimilar to that obtained from the 5 mg bid administration of the conventional tablet and cannot be considered to be bioequivalent. The initial pulse of the delivery system is rapidly absorbed but to a lesser extent than the conventional regimen; the second pulse exhibits absorption which is delayed and prolonged. The decrease in the selegiline concentration may be due to the less absorptive surface of the lower GI tract which is available to the second pulse. Another reason could be the disparity between the in vitro and in vivo release profiles from the second pulse. Compartmental analysis indicates that the ratio of formation-absorption rate constant for the selegiline to N-desmethylselegiline pathway decreases from 1.57 +/- 1.04 for the first pulse to 0.61 +/- 0.54 for the second pulse of the pulsatile delivery system, suggesting that the upper portion of the GI tract has a greater capacity to convert selegiline to N-desmethylselegiline than the lower GI tract. The lack of in vivo and in vitro correlation is most likely due to site specific absorption/metabolism. Regimen has been previously shown to be a significant factor in estimating the extent of selegiline and metabolite exposure following oral administration. The inequivalence of dosing regimens of the same total daily dose may ultimately be linked to the saturability of gut wall metabolism. This phenomenon may preclude the development of novel delivery systems designed to mimic the recommended dosing regimen of the conventional Eldepryl tablet.

Selegiline (SEL) is a selective, irreversible inhibitor of MAO-B, used in the treatment of Parkinson's disease, either alone or as an adjunct to L-DOPA. Selegiline hydrochloride (HCl) undergoes significant first-pass metabolism following oral administration. Transdermal delivery avoids the first-pass effect and provides greater and more prolonged levels of unchanged SEL and reduced levels of metabolites (N-desmethylselegiline (DES), L-amphetamine (AMP), and L-methamphetamine (MET) compared to the oral regimen. An integrated pharmacokinetic-metabolic model which predicts plasma concentrations of SEL and metabolites following a single 24 h application of a selegiline transdermal system (STS) is proposed. The model is based on the metabolic conversion of SEL to DES and MET and subsequently to AMP. The input function is described by a zero-order constant for the delivery of SEL from the STS system based on in vitro studies of penetration of SEL across human skin. The elimination-non-metabolic constants for each analyte account for the urinary elimination. Plasma concentration data from a pilot pharmacokinetic study in which six healthy male volunteers were administered single 24 h applications of a 1.8 mg cm2, 10 cm2 STS were used to examine this model. The coefficient of determination was 0.98 and model selection criterion was 3.4 for mean data fits, supporting the goodness of fit of the model. The pharmacokinetic parameters obtained by non-compartmental analysis were comparable to those predicted by a compartmental model. The model also predicted urinary recoveries for AMP and MET and negligible recovery for SEL and DES consistent with recent studies with the STS in which urine was collected. The metabolic conversion constant from SEL to DES was significantly lower than the conversion constant from SEL to MET, indicating that metabolism of SEL is primarily driven towards MET following transdermal administration. The metabolic conversion from MET to AMP was less than the conversion from DES to AMP. This simultaneous prediction of the SEL and metabolites is essential as the metabolic ratios have been linked to the neuroprotective effects of SEL. These findings support the proposed regional delivery advantage attributed to the transdermal route compared to the conventional therapy with the oral tablet. Future model applications may also help identify significant covariates (i.e. age, gender, and disease state) in upcoming clinical trials.

Ipriflavone (IP) is a derivative of naturally occurring isoflavones and is marketed as Osteofix for the treatment of osteoporosis in Europe. IP has poor aqueous solubility, and the Osteofix compressed tablet has poor and variable bioavailability (F ). IP is incompletely absorbed after oral administration and is converted to five major metabolites (M1, M2, M3, M4, and M5). It is also further converted to metabolites M6 and M7 to a very small extent. The metabolites, especially M2 and M5, also have activity. A pilot study was conducted in healthy male volunteers that showed an 8- to 20-fold increase in the IP bioavailability after administration of Osteofix tablets in the fed state relative to the fasting state. A four-way crossover study was conducted in 16 healthy male volunteers, receiving Osteofix in fed state and 50, 100, and 200 mg of IP corn-oil suspension in fasted state. All IP administrations were safe and well tolerated. There was a reduction in the IP plasma level variability after 100-mg corn-oil administration as compared with that for the tablet. There was an increased relative F after the suspension, which was such that the 50-mg IP corn-oil suspension yielded similar levels as the 200-mg tablet. M5 was the major metabolite, consistent with earlier reports. The area under the curve to the last measured time point (AUC ( t ) ) levels were lower for M5, M3, and M2; higher for M1 and M2; and similar for IP after 50-mg corn-oil administration, as compared with the values for the tablet. This result may partially be explained by differences in the half-lives. Absorption/formation of M2 was delayed. The metabolite formation, except for M1 and M5, decreased with increased doses, which was accompanied by the prolonged half-life of IP and nonproportional increase in the IP AUC ( t ). This result may be due to autoinhibition of IP metabolism, because IP is an inhibitor of CYP3A4, and the metabolism of IP may be partly CYP3A4 mediated. Osteofix F may be improved by formulations that increase solubility, such as the corn-oil suspension. Although equivalent IP exposure from the tablet may be achieved at much lower overall doses because of the improved F by the corn-oil suspension, higher doses may require reconfirmation of safety and efficacy, given the differences in metabolic profiles obtained at higher doses.

The toxicology and toxicokinetics of a selegiline transdermal system (STS) were evaluated in a 3 month dog study of daily 24 h applications of placebo 4, 8, or 12 STSs in 32 male and 32 female beagle dogs. Each STS delivered approximately 5 mg selegiline over 24 h. No drug-related signs of toxicity were noted in any group with respect to clinical observations, dermal effects, body weight, food consumption, hematology, urinalysis data, or ophthalmoscopic or electrocardiographic examinations. Clinical chemistry data revealed no consistent adverse effects except for an increase in alanine aminotransferase in dogs receiving 8 and 12 STSs. Histological evaluation of tissues revealed the presence of pigment in the Kupffer cells of dogs treated with 8 and 12 STSs. There were no pathology findings suggestive of hemolysis or cholestasis. The no-effect level (NOEL) was 4 STSs (2.9 mg kg-1 d-1). There were no degenerative or life-threatening toxic effects up to 12 STSs (8.5 mg kg-1 d-1). Gender-related differences in steady-state plasma levels were not observed. Steady-state plasma concentrations were similar to maximum plasma concentrations obtained in single-dose studies, suggesting that drug accumulation was not evident. Simulation of systemic exposure following oral administration of 16.8 mg kg-1 d-1 from previous toxicology studies indicated that selegiline exposure following 12 STSs is sixfold greater while N-desmethylselegiline, L-amphetamine, and L-methamphetamine exposure is 0.5, 0.15, and 0.14 times the exposure in the oral study. The threefold difference in NOEL between oral and transdermal studies in the dog (0.8 versus 2.9 mg kg-1 d-1) is probably related to greater L-amphetamine and L-methamphetamine exposure following oral administration. The reduction in metabolite formation, relative exposure of selegiline in the dog at the NOEL compared to oral toxicology studies, and margin of safety provided, given that the expected clinical dose is less than the dosage of oral Eldepryl (0.15 mg kg-1 d-1), documents the safety of the selegiline drug substance and indicates that additional toxicologic findings with the STS may not be expected.

A Selegiline Transdermal System (STS) is under development for indications which may not be optimally or safely treated with oral selegiline. Studies were conducted to evaluate the in vitro penetration and skin metabolism of selegiline in order to better understand the toxicological findings and the observed plasma levels of selegiline and its metabolites in animals and man.In vitro penetration studies were conducted in four different species (male hairless mice, male and female rats, female dog and male Micropig) and compared to human skin. In another study, viable human skin was used to estimate the extent of metabolism of selegiline by human skin using Franz diffusion cells.Results indicated that female dog and male Micropig skin were reasonable animal models for 24 hour in vitro selegiline penetration through human skin. Penetration of selegiline through rat skin and hairless mouse skin was 2-fold and 3-fold higher than through human skin, respectively. Metabolism was negligible in human skin. Selegiline metabolites (L-methamphetamine and N-desmethylselegiline but not L-amphetamine) were detected at all time points but the extent of selegiline metabolism was negligible. The cumulative 24 hour in vitro selegiline permeation from a 1.83 mg/cm2 STS through human skin was 5.0 mg. This was similar to the in vivo permeation in humans as assessed by residual patch analysis.The similarity of dog and human skin permeation results support the use of the dog as a species for evaluating the toxicology of transdermally-administered selegiline. Selegiline is not metabolized cutaneously and hence the metabolic profile following STS administration is likely due to hepatic metabolism only.

The absorption and disposition of selegiline (SEL) and its metabolites N-desmethylselegiline (DMS), L-methamphetamine (MET), and L-amphetamine (AMP) were assessed in 8 healthy male volunteers at proximal and distal regions of the intestine relative to oral administration (in the stomach) to determine if intestinal site dependence contributed to the erratic oral absorption of selegiline hydrochloride which is manifest as low and variable bioavailability.An open-label, four-way crossover, single dose pharmacokinetic study comparing the bioavailability of 10 mg selegiline hydrochloride administered to healthy young males as a solution by the oral route (in the stomach) and by a nasoenteric tube to the following three sites: duodenum, jejunum and terminal ileum was conducted. Infusions were administered over a 1 minute interval and a two week washout was observed between treatments. Samples were taken over 96 hours and analyzed by LC/MS/MS.Selegiline exposure was greatest following administration to the stomach (approximately 150%duodenum or jejunum) and least in the terminal ileum (approximately 33% less than duodenum or jejunum). Duodenal and jejunal sites were equivocal based on selegiline absorption and subsequent metabolism. While both AMP and MET exposure was equivalent at all dosing sites, DMS exposure was less (approximately 18%) at the terminal ileum.The oral absorption of selegiline is neither permeability-limited or intestinal site-dependent. Stomach absorption may bypass presystemic metabolism. The reduced DMS exposure at the terminal ileum is consistent with the theorized presystemic formation of DMS via luminal P450 enzymes and the density of these enzymes in the duodenum and jejunum relative to the ileum. AMP and MET metabolites were insensitive to dosing site consistent with their hepatic formation. The true magnitude of these effects would require multiple dosing as single dose pharmacokinetics do not predict the extent of multiple dose selegiline exposure.

Introduction Retrospective studies suggest that dietary restriction of fermentable carbohydrates (Fermentable Oligosaccharides, Disaccharides, Monosaccharides and Polyols, FODMAPs) improves irritable bowel syndrome (IBS) symptoms. Prebiotic fructo-oligosaccharides and galacto-oligosaccharides stimulate colonic bifidobacteria, however the effect of a fermentable carbohydrate restricted diet on the gut microbiota has never been examined. The aim of this randomised controlled trial was to investigate the impact of a fermentable carbohydrate restricted diet on luminal microbiota, fermentation and symptoms in IBS. Methods Adult patients with IBS were recruited from gastroenterology outpatient clinics. Eligible patients were randomised to the intervention diet or their habitual diet for 4 weeks. A fresh stool sample was collected and analysed for the major bacterial groups using fluorescent in situ hybridisation, short chain fatty acid (SCFA) concentration was analysed using gas liquid chromatography and pH was recorded. The incidence and severity of GI symptoms and stool output were recorded and dietary intake was assessed using food diaries. All outcome measures were recorded at baseline and 4 weeks. Continuous data were compared using an independent samples t-test and categorical data were compared using the χ 2 test. Results Of 41 patients randomised, six withdrew (five protocol violations, one lost to follow-up). In the intention-to-treat analysis, more patients in the intervention group reported adequate control of symptoms (68%) compared with controls (23%) (p=0.003). However, there were strikingly lower concentrations (7.4 vs 8.2 log 10 cells/g, p=0.001) and proportions (1.2% vs 5.5%, p=0.002) of bifidobacteria in the intervention group compared with controls at follow-up. This was not associated with any change in luminal markers of fermentation. There were no differences in energy, protein or fat intake at 4 weeks between groups but total carbohydrate intake was lower in the intervention group. Conclusion This is the first randomised controlled trial investigating the effect of a fermentable carbohydrate restricted diet, demonstrating significant improvements in symptoms but a dramatic reduction in luminal bifidobacteria, a species that have an important role in colonic health. Significant questions remain; is the shift in bifidobacteria permanent, how might it be prevented and what is the impact of reintroduction of fermentable carbohydrates on the microbiota? Competing interests None declared.

A man suffering from persecutory delusions attempted to commit suicide by holding the head of a three-inch masonry nail against a wall and head-butting its point until he had driven it fully into his forehead.

A Microsoft Windows-based front-end, NM-Win, has been written to provide a more user-friendly environment to do nonlinear mixed effect modeling with the NONMEM program. NM-Win utilizes an object-oriented interface design which allows users to view and edit control, PRED, and/or data files using Windows Notepad. In addition, calls made to the Microsoft FORTRAN compiler and linker which generate the final NONMEN executable are performed simply by clicking the "Run NONMEN" button. During the executive step, interactions can be viewed in a window to check the progress of the run. Errors encountered while NONMEN or NM-TRAN is running are brought to a window for ease in debugging. Advanced options allow the user the flexibility of compiling user-written PRED files and creating linker response files. While the PC platform is not optimal for large data set or complex models, it does permit easier debugging and offers multitasking while Windows is running.

The pharmacokinetics and pharmacodynamics of L-703,014, a fibrinogen receptor antagonist, have been examined in the dog. An analytical method which utilizes methanol precipitation of dog plasma proteins followed by HPLC with an automated column switching technique using the chemical analogue L-704,326 as internal standard was developed for the determination of L-703,014 in dog plasma. The compound was not metabolized in the dog and was eliminated in the kidneys and into bile. Of the administered dose, 68.9 +/- 1.3% (i.v.) and 80.5 +/- 11.9% (p.o.) were recovered in the feces; 20.3 +/- 1.3% (i.v.) and 2.2 +/- 0.2% (p.o.) were recovered in the urine by 72 hr. L-703,014 was 23 +/- 3.4% bound in dog plasma protein and the mean ratio of plasma/whole blood was 1.22 +/- 0.05. The mean terminal half-life was 118 +/- 36 min, the mean steady-state volume of distribution was 0.61 +/- 0.22 L/kg, and the mean plasma clearance was 8 +/- 2 mL/min/kg. Ex vivo platelet aggregation measurements were made by inducing platelet aggregation with 10 micrograms/mL collagen in the presence of 1 microM epinephrine as an agonist. The mean C50 was 44.4 +/- 6.0 ng/mL, and the mean Hill coefficient was 1.5 +/- 0.3. The mean bioavailability was 4.9 +/- 1.4% in dogs administered 2.0 mg/kg (p.o.).

Based on the stress-strain and temperature elongation data obtained on ACSR conductors, a new method of sag calculation is presented to provide improved accuracy at higher temperatures and mechanical loads. Permanent elongation of steel cores at loads above 50 per cent of conductor UTS is found to be an important factor in calculating both the temporary high-temperature sags and permanent sags after heavy loading of steel cores.

An accurate new model for calculating AC resistance of ACSR conductors has been developed and verified for single, two and three layer conductor designs. Current redistribution was found to be far more important in determining the AC/DC resistance ratio than hysteresis losses in the steel core except in single layer conductors. The model suggests ways of reducing the AC resistance and promises to be a useful design tool.

A new sag-tension computer program, STESS has been developed for use in transmission line design and operation. The program is based on a conductor model which is more realistic and conceptually simpler than the traditional graphic method.

A motor load analyzer instrumented to a high intensity mixer was examined for its ability to monitor the granulation process with varying formulation and processing parameters. A lactose/microcrystalline cellulose blend with povidone as the binder was used as the test system.The motor load analyzer was able to note chopper operation and liquid addition methods. However, it could not differentiate between povidone addition as an aqueous solution or as part of the lactose microcrystalline cellulose blend, followed by massing with water. The compression characteristics of the granulations depended upon chopper usage, and povidone and liquid amounts, and their methods of addition.

A perturbed angular correlation study of 111Cd ions in frozen aqueous solutions of InCl3 and In(NO3)3 has demonstrated the variation in behavior of these systems with temperature from − 140 to − 20°C. At the lowest temperature a strong static quadrupole interaction (ωQ = 1.6 × 107rad/sec) was observed. Above − 80°C, a time‐dependent perturbation was found, and the temperature dependence of the correlation time was measured.

The temperature dependence of the magnetic field at 181Ta nuclei in a nickel lattice has been determined by time-differential perturbed angular correlations. Results consistent with nonmagnetic impurity behavior were obtained.

An electromagnet of inhomogeneous magneticfield has been used to measure the magnetic susceptibility of the frog's nerve. Specimen of frog sciatic nerve were attached to a thin tungsten wire hanging into the inhomogeneous magnetic field, and from the deviation of this pendulum from the perpendicular position the magnetic susceptibility of the nerve has been determined to be -0.8 . 10(-6) cm3g-1 in a good agreement with the known magnetic property of the constituents of the nerve.