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Background:Boron is unusual to organic chemists, yet boron interacts greatly with organic biochemicals and has considerable bioactivity, especially as an antifungal and insecticide. The bestknown bioactive boron compounds are boric acid, its salt borax, and the closely related boronic acids. A newcomer is tavaborole (trade name Kerydin), recently developed and approved in 2014 for topical treatment of onychomycosis, a fungal infection of nails and the nail bed. It is timely to review the literature and explore the way in which these compounds may work.Methods:The focus of this review is to examine peer-reviewed literature relating to boric acid, boronic acid and tavaborole, the most bioactive boron-containing compounds, and the evidence for their proposed mechanism of antifungal action. In parallel with the literature, we have examined the fungistatic effects of boric acid on yeast.Results:All three compounds are reported to inhibit protein synthesis but their mechanism of action may differ. Chemistry studies indicate an interaction of boric acid with ribose and ribose-containing moieties such as NAD. In this review, we discuss the activity of boric acid and use both tavaborole and the boronic acids to exemplify the similar underlying mechanisms used. As there is a push to develop new antimicrobials, we demonstrate that boric acid’s fungistatic effect is alleviated with ribose, NAD and tryptophan.Conclusion:We speculate that boric acid inhibits yeast growth by disrupting tryptophan synthesis as well as downstream NAD, a rate limiting co-enzyme, essential for cellular function.

Aim: Pain is increasingly treated with opioids. Potential harms of opioid therapy disproportionally affect older patients. This study aims to provide information on trends, nature and duration of opioid prescribing to older adults, in primary care and to explore differences between older patients from different ages. Methods: Primary care data (2005–2017) were derived from routine electronic medical records of patients in Nivel Primary Care Database. All opioid prescriptions with Anatomical Therapeutic Chemical Classification (ATC) code N02A were selected (except for codeine). Diagnoses were recorded using the International Classification of Primary Care (ICPC). Patients were categorized in three age groups (65–74, 75–84, and ≥85 years). Descriptive analyses were used to describe the trend of opioid prescriptions for specific opioids, the duration of use and underlying diagnoses. Results: 283,600 patients were included of which 32,287 had at least one opioid prescription in 2017. An increase in the number of older adults who received at least one opioid was seen between 2005 and 2017. The oldest patients were more likely to be prescribed an opioid, especially when it comes to strong opioids, the increase in the volume of prescribing was highest in this group. Moreover, over 40% of the oldest patients used strong opioids chronically. Strong opioids were mostly prescribed for musculoskeletal diagnoses. Cancer was the second most common diagnosis for strong opioids in the younger subgroups, whereas less specified diagnoses were as second in the oldest subgroup. Conclusion: Opioid prescription changes with increasing age in frequency, nature, and duration, despite higher harm risks among older patients. Because of the high prevalence of chronic use, it is important to monitor the patient throughout the treatment and to critically evaluate the initiation and continuation of opioid prescriptions.

Background Patients with painful varicose veins and venous insufficiency can be treated by eliminating axial reflux only or by eliminating axial reflux plus phlebectomy with transilluminated powered phlebectomy. This study was undertaken with the aim of determining and improving signs and symptoms of venous disease (measured by venous clinical severity score) and complications (by routine surveillance ultrasound and long-term post-operative follow up) for each treatment strategy. Methods We performed a retrospective evaluation of prospectively collected data from 979 limbs undergoing procedures for significant varicose veins and venous insufficiency from March 2008 until June 2014 performed at a single tertiary referral hospital. Patient demographics, Clinical Etiology Anatomy and Pathophysiology classification, venous clinical severity scores pre- and post-procedure, treatment chosen, and peri-operative complications were collected; descriptive statistics were calculated and unadjusted surgical outcomes for patients stratified by the procedure performed. Multivariable logistic regression was used to evaluate the relationship between procedure type and thrombotic complications after adjusting for patient characteristics, severity of disease, pre-operative anticoagulation, and post-operative compression. Result Venous clinical severity scores improved more with radiofrequency ablation + transilluminated powered phlebectomy as compared to radiofrequency ablation alone (3.8 ± 3.4 vs. 3.2 ± 3.1, p = 0.018). Regarding deep venous thrombosis, there was no significant difference between radiofrequency ablation + transilluminated powered phlebectomy vs. radiofrequency ablation alone. There was no statistical difference in asymptomatic endovenous heat-induced thrombosis or infection, although there were slightly more hematomas and cases of asymptomatic superficial thrombophlebitis with combined therapy. On multivariable analysis, only procedure type predicted thrombotic complications. Conclusion Ablation of axial reflux plus transilluminated powered phlebectomy produces improved outcomes as measured by venous clinical severity score, with slight increases in minor post-operative complications and should be strongly considered as initial therapy when patients present with significant symptomatic varicose veins and superficial venous insufficiency. Implementation of a standardized thromboprophylaxis protocol with individual risk assessment results in few significant thrombotic complications amongst high-risk patients, thus potentially obviating the need for routine post-operative duplex.

Since human health benefits are influenced by diets and lifestyle, the dietary intake and body–brain interactions of phytochemicals which are abundant in fruits, berries, vegetables, herbs, and in beverages are a promising avenue and resource that can provide dietary intervention and protection strategies against Alzheimer’s disease, Parkinson disease, Huntington disease, and Amyotrophic Lateral Sclerosis dementia diseases. The manipulation of the molecular mechanisms and metabolic processes of food consumption occurring in body and brain can direct, determine, and provide new strategies of how to optimize and select dietary constituents that may sustainably provide generic benefits for neurons to defend against insults and damage, and sustain mental fitness against all neurodegenerative diseases. This chapter provides a perspective of the molecular episodes of dietary phytochemicals including polyphenols, brain foods/beverages, and herbs that can be used and directed towards providing health-sustaining interventions against protein misfolding-neurodegenerative and dementia disorders.

Background Opioids like morphine and heroin induce mast cell degranulation in vitro. The release of mast cell mediators like histamine and tryptase may lead to allergic symptoms. In this study it was investigated whether mast cell mediator release also occurs in vivo in addicted patients who participated in a heroin on medical prescription trial, and were under treatment with large doses of heroin in combination with methadone. Method Plasma levels of tryptase, a specific marker for mast cell degranulation, were measured by immuno-assay at baseline and 60 min after heroin administration. Heroin was administered either by intravenous injection (11 subjects) or by inhalation (nine subjects). Single heroin doses varied from 200 to 450 mg. Besides tryptase, the plasma concentrations of heroin, its metabolite morphine and methadone were measured. Results After heroin injection, the mean tryptase plasma concentration increased dose dependently by on average 23.1% (95% CI 14.6–31.6%). After heroin inhalation, no tryptase release was observed. Heroin and morphine peak plasma concentrations were 3–5 times greater in heroin injectors than in inhalers. In heroin injectors, tryptase levels were related to morphine peak concentrations, but not to heroin concentrations. Tryptase plasma concentrations were not related to methadone levels. Mild allergic reactions were reported in five cases after intravenous heroin use, but not after inhalation. Conclusion This study revealed that mast cell mediator tryptase concentrations increase after intravenous heroin injection in chronic opioid users, but not after heroin inhalation. This may be explained by the higher C max levels of metabolite morphine that were achieved after injection than after inhalation. Although statistical significance was reached, the degree of mast cell degranulation after intravenous injection of heroin was mild, and did not lead to clinically relevant side effects in this group of opioid-tolerant subjects.

BACKGROUND: In several European countries and in Canada, clinical trials are being conducted in which heroin-addicted patients are treated with pharmaceutically prepared heroin in order to reduce the destructive behaviour that is so often associated with this drug. OBJECTIVE: To develop an integrated population pharmacokinetic model for heroin (diamorphine) and its pharmacodynamically active metabolites 6-acetylmorphine, morphine, morphine-3-glucuronide and morphine-6-glucuronide. Additionally, the influence on heroin pharmacokinetics of several covariates that are typical for this population was determined. METHOD: Plasma concentration data from 106 heroin-dependent patients in The Netherlands (74 heroin inhalers and 32 injectors) were obtained. The 'chasing the dragon' technique was used for inhalation, in which the fumes of heroin base, heated on aluminum foil, were inhaled. Heroin doses varied between 66 and 450 mg. Heroin, 6-acetylmorphine and morphine data were fitted simultaneously using sequential two-compartment models. Morphine-3-glucuronide and morphine-6-glucuronide data were fitted separately to one-compartment models. All data analysis was performed using nonlinear mixed-effect modelling. RESULTS: The bioavailability of inhaled heroin was estimated to be 53% (95% CI 43.7, 62.3). The terminal half-lives of heroin and 6-acetylmorphine were estimated to be 7.6 and 21.8 minutes, respectively. The clearances of morphine and the morphine-glucuronides were estimated to be 73.6 L/h (95% CI 62.8, 84.4) and between 6 and 10 L/h, respectively. The terminal half-life of 6-acetylmorphine was 13% lower in cocaine users (p < 0.05). No other significant relationships between covariates and pharmacokinetic parameters were discovered. CONCLUSIONS: Pharmacokinetic parameters of heroin and its five major metabolites were assessed simultaneously in one integrated model. Covariate analyses revealed that sex, bodyweight, benzodiazepine use and creatinine clearance (>60 mL/min) do not need to be taken into account in the medical prescription of pharmaceutically prepared heroin for the treatment of heroin dependency

A pharmacokinetic-pharmacodynamic study was performed in opioid-dependent patients in the Netherlands, who were currently treated with high doses of pharmaceutically prepared heroin on medical prescription. Besides intravenous heroin, heroin was prescribed for inhalation by "chasing the dragon" method. In this technique, heroin base is heated on aluminium foil, and heroin vapours are inhaled into the lungs. Not much is known about the pharmacokinetics profile and bioavailability of this specific administration method. Therefore, a study was performed on pharmacokinetics and pharmacodynamics of heroin inhalation and intravenous use. Eleven patients who injected heroin and 9 patients who inhaled heroin entered the study. They were on steady-state heroin treatment for at least 12 months. For safety reasons, there was no crossing-over between heroin injection or inhalation. In a double-blind randomised study, 67-100-150% of the regular heroin maintenance dose was administered to each patient. Maximal single heroin dose was 450 mg. Plasma concentrations of heroin and its metabolites 6-monoacetylmorphine, morphine and morphine-glucuronides were analysed using LC-MS-MS. Blood pressure, heart rate, skin temperature and reaction time were assessed. Furthermore, visual analogue scales regarding craving and appreciation of heroin effect were scored by the subjects. Both in inhaling and injecting patients, the areas under curve of heroin and all measured metabolites were linearly related to heroin dose. Mean C(max) of heroin and its metabolites were 2-6 times lower after inhalation, than after intravenous injection. Bioavailability (F) of heroin inhalation was estimated as 52% (95% CI 44-61%). Heroin was rapidly cleared from plasma. Cl/F was 930 l/hr (95% CI 799-1061 l/hr) after intravenous administration, and 1939 l/hr (95% CI 1661-2217 l/hr) after inhalation. Heroin Cl and Vd were correlated to body weight (R(2) 15-19%). Morphine-glucuronides levels were inversely related to creatinine clearance. After heroin administration, the reaction time was significantly prolonged with 28+/-5.3 msec. in injecting and 13+/-4.9 msec. in inhaling patients. Cardiovascular changes were only mild after heroin administration. Craving-scores declined immediately after heroin administration in both administration groups. Subjective heroin effect was rated more positively in heroin inhaling than in injecting patients, despite the lower C(max) levels following heroin inhalation. In both groups, in this blinded study heroin dose increments were more appreciated than dose reductions. Increments of 50% of the regular heroin dose did not cause any serious side effect.

For a pharmacokinetic-pharmacodynamic study in opioid tolerant patients, who were treated with heroin in combination with methadone, a liquid chromatographic assay with tandem mass spectrometry detection (LC-MS/MS) was developed for the simultaneous determination of heroin, methadone, heroin metabolites 6-monoacetylmorphine, morphine, and morphine-6 and 3-glucuronide and methadone metabolite EMDP. To detect any abuse of substances besides the prescribed opioids the assay was extended with the detection of cocaine, its metabolites benzoylecgonine and norcocaine and illicit heroin adulterants acetylcodeine and codeine. Heroin-d6, morphine-d3, morphine-3-glucuronide-d3 and methadone-d9 were used as internal standards. The sample pre-treatment consisted of solid phase extraction using mixed mode sorbent columns (MCX Oasis). Chromatographic separation was performed at 25 degrees C on a reversed phase Zorbax column with a gradient mobile phase consisting of ammonium formate (pH 4.0) and acetonitrile. The run time was 15 min. MS with relatively mild electrospray ionisation under atmospheric pressure was applied. The triple quadrupole MS was operating in the positive ion mode and multiple reaction monitoring (MRM) was used for drug quantification. The method was validated over a concentration range of 5-500 ng/mL for all analytes. The total recovery of heroin varied between 86 and 96% and of the heroin metabolites between 76 and 101%. Intra-assay and inter-assay accuracy and precision of all analytes were always within the designated limits (< or =20% at lower limit of quantification (LLQ) and < or =15% for other samples). This specific and sensitive assay was successfully applied in pharmacokinetic studies with medically prescribed heroin and toxicological cases.

In preparation for a treatment program concerning the medical coprescription of heroin and methadone to treatment-resistant addicts in the Netherlands, we studied a novel strategy for monitoring co-use of illicit (nonprescribed) heroin. A deuterated analogue of heroin was added (1:20) to pharmaceutical, smokable heroin (a powder mixture of 75% w/w diacetylmorphine base and 25% w/w caffeine anhydrate), to be used by inhalation after volatilization ("chasing the dragon"). Plasma and urine samples were collected from nine male patients who had used pharmaceutical, smokable heroin during a four-day stay in a closed clinical research unit, and these samples were analyzed by liquid chromatography coupled with tandem mass spectrometry. Ratios of deuterated and undeuterated diacetylmorphine and 6-acetylmorphine (MAM/MAM-d3) in plasma and urine were calculated from peak areas of these substances in the respective chromatograms. The MAM/MAM-d3 ratios in plasma and urine were normally distributed (with small standard deviations) and independent from concentrations of 6-acetylmorphine and from time after use of pharmaceutical heroin. A MAM/MAM-d3 ratio in urine above 32.8 was considered indicative of co-use of illicit heroin, and this value was associated with a false-positive rate of only 1% (95% confidence interval: -1 to 3%). The MAM/MAM-d3 ratio was detectable in urine for 4-9.5 h after use of pharmaceutical, smokable heroin. Addition of stable, isotopically labelled heroin to pharmaceutical, smokable heroin is considered to be a feasible strategy for the detection of co-use of illicit heroin by patients in heroin-assisted treatment.

Pairs of ewes or heifers were allowed to graze for short periods from previously prepared ‘homogeneous’ areas of ryegrass, in order to study their bite dimensions and movement patterns and to investigate the role of different species in initiating spatial heterogeneity. Apparent bite area was calculated from number of bites and total bitten area when ewes or heifers took 10–15 bites from an 80 cm ×80 cm area in a homogeneous Lolium perenne sward. Apparent bite depth was calculated from sward surface height (SSH) within and adjacent to bitten areas. Apparent bite mass was calculated from grazed stratum bulk density. Incisor arcade breadth was measured. Animals also grazed 20 m ×40 m plots for 45 min. Position and activity were recorded and distance travelled calculated. Number of bites and steps, number and duration of grazing bouts, feeding station dimensions and horizontal head sweep were recorded. Bites per bout, per feeding station and per m forward movement, bite rate, inter-bout interval, and distance travelled, speed of movement, number of steps, step length and step rate within and between bouts were calculated. Distribution of grazing bout and inter-bout durations and the animals’ foraging paths were tested for randomness. Apparent bite area for heifers was 2.2 times that for ewes and incisor arcade breadth 1.8 times that for ewes. Apparent bite depths were similar at 0.35 of SSH. SSH distribution within bitten areas was non-normal and differed between animal species. Heifers’ bite mass was 2.1 times that for ewes. Heifers had longer grazing bouts, more feeding stations per bout, moved farther per bout but had similar movement speed while grazing. Distance between feeding stations was similar between species but heifers’ feeding station residence time was twice as long. Heifers’ biting rate was lower but they took more bites per bout, per feeding station and per metre of forward movement. Mean head sweep distance was greater for heifers. Both species moved a similar distance between grazing bouts but ewes moved more slowly with more, shorter steps. For both species, grazing bout and inter-bout durations were not randomly distributed. At a 1 m 2 scale for both species and a 5 m 2 scale for heifers, movement was non-random with a strong propensity to walk in a straight line but at a 5 m 2 scale sheep movement was uniformly distributed on the circle.

Highly filled polypropylene (PP) composites have been produced by extrusion of polypropylenes with surface treated fillers. The aim is to include the highest proportion of filler that can provide hardness and high density, without undue brittleness. Modification of the filler surface provided significant enhancement of the processing properties that have been studied with parallel plate rheometry. The experimental results indicated that the viscoelastic behavior of melt flow of highly filled polypropylene composites significantly depended on the following properties of the fillers: aspect ratio, specific surface area and particle size in talc, calcium carbonate and barium sulfate filled polypropylene composites. Traditional surface modifiers such as stearic acid are useful, but titanates and in particular small amounts of silicones have provided the greatest rheological modification.

Highly filled polypropylene composites have been prepared with filler contents up to 43.8 vol.% (70 wt.%) after surface treatment of the fillers with titanate or silicone. The fillers used were calcium carbonate, talc and barium sulfate. Surface modification of the fillers facilitated extrusion and reduced brittleness while providing hard composites with high density. The high density and hardness provide a texture which is not characteristic of polypropylenes, but more like thermoset composites or ceramics; yet the composites can be extruded using typical thermoplastic processing equipment. The composition has been measured by thermogravimetry, and morphology observed with scanning electron microscopy. The tensile properties were measured and related to the composition, filler type and surface treatment.

Retirees who exhaust their savings while still alive are said to experience financial ruin. These savings are typically grown during the accumulation phase then spent during the retirement decumulation phase. Extensive research into invest-and-harvest decumulation strategies has been conducted, but recommendations differ markedly. This has likely been a source of concern and confusion for the retiree. Our goal is to find what has heretofore been elusive, namely an optimal decumulation strategy. Optimality implies that no alternate strategy exists or can be constructed that delivers a lower probability of ruin, given a fixed inflation-adjusted withdrawal rate., Proofs appendix with full C++ implementation is included

Meal patterns and rates of feed intake by grazing herbivores may be markedly different from those found in housed ruminants and monogastrics. Cumulative intakes over the evening meal (satiety curves) were measured using groups of sheep ( Ovis aries L.) grazing monocultures of white clover ( Trifolium repens L., cv. Kent Wild White) and ryegrass ( Lolium perenne L., cv. Parcour). Intake was measured by weighing ewes before and after grazing, with an allowance for insensible weight loss, for each of six groups in sequence; when grazing clover after 15, 30, 45, 60, 75 or >90 min and when grazing grass after 20, 40, 60, 80, 100 and >120 min. In each case, the sixth group was allowed to graze until a break of at least 6 min had occurred, which was taken to be an inter-meal as opposed to an intra-meal interval. Measurements were made on both herbage species using non-fasted control animals and animals that had been fasted for 24 h prior to measuring intake. Regressions of cumulative fresh and dry matter (DM) intakes against minutes of eating (excluding intra-meal intervals), constrained to pass through the origin, were best described by linear rather than curvilinear relationships. This showed that intake rates were constant within a meal. However, as the meal progressed, the number of intra-meal intervals increased and if these intervals were included in eating time, then the relationships were curvilinear with intake rate decreasing with time since the onset of the meal. The non-fasted animals had shorter meals than fasted animals and animals grazing clover had shorter meals than those grazing grass. The application of these results to intake control mechanisms is discussed.

The effect of physiological state lactating vs. non-lactating (dry) on grazing behaviour and herbage intake by Holstein-Friesian cows was examined on grass pastures maintained at 5, 7 or 9 cm sward surface height (SSH), typical of those provided under continuous variable stocking management. Intake rates were estimated over periods of 1 h by weighing the animals before and after grazing, retaining the faeces and urine excreted, and applying a correction for insensible weight loss. Grazing behaviour during these periods and over 24 h was recorded automatically using sensors to measure jaw movements. Bite mass (BM) did not differ significantly between lactating and dry cows but decreased ( P −1 as overall mean SSH decreased from 9 to 5 cm. An increase ( P =0.040) in grazing jaw movement (GJM) rate, from 75.3 to 80.3 GJM min −1 , as SSH decreased, did not compensate for reductions in bite mass, and intake rate declined linearly ( P =0.006) from 24.6 to 18.9 g OM min −1 . Lactating and dry cows compensated for the reduction in intake rate, by increasing total grazing time and total number of bites per day. As SSH decreased from 9 to 5 cm, lactating and dry cows increased total eating time (528 to 607 and 419 to 510 min), total GJM (40 400 to 49 300 and 31 300 to 40 600 GJM) and total bites (31 100 to 37 900 and 24 600 to 31 200 bites, respectively). As a result, there was no significant effect of SSH on daily intake of OM, although lactating cows had greater intakes than dry cows; 12.9 vs. 9.3 kg day −1 , ( P P P =0.060), allowing them 120 to 160 min more idling (i.e., non-grazing, non-ruminating) behaviour ( P =0.001).

Objective: Alterations in the vascular endothelial release of nitric oxide (NO) may contribute to the vasodilatory adaptation to normal pregnancy and to the vasoconstriction associated with preeclampsia. The aim of this study was to investigate these hypotheses by measuring plasma levels of the stable metabolites of NO, nitrite and nitrate, during normal human pregnancy and those complicated by preeclampsia.Methods: Plasma samples were obtained from women in the following groups: nonpregnant; normal first-, second-, and third-trimester pregnant; and preeclamptic. Nitrite concentrations in the samples were determined using a colorimetric assay. Nitrate concentrations were determined using anion-exchange chromatography with UV detection.Results: The plasma nitrite and nitrate concentrations of normal pregnant women (9.45 ± 0.58 u.M. n = 59. and 85 ± 8 µM, n = 29, respectively) were not significantly different from those of nonpregnant women (10.04 ± 1.47 µM, n = 10, and 95 ± 15 µM, n = 9, respectively), and...

Forty-eight, lactating, spring-calving, multiparous, Holstein-Friesian cows, continuously stocked on mixed grass-clover swards, were blocked by calving date, parity and milk yields in week 2 of lactation and randomly allocated to six treatments: 0 (U) or 4 (S) kg concentrate supplementation at sward heights of 40, 60 or 80 mm as measured by a rising plate meter. Jaw movements were recorded automatically for 24 h for a different cow on each treatment on each of 6 days during two periods (15–25 June (P1) and 25 July–6 August (P2)). Swards of 40 mm height were not used in P2. Total time grazing, ruminating or idling, and the number and duration of bouts of these activities, biting rate while grazing and chewing rate, number of boluses and chews per bolus while ruminating were recorded. Data were smoothed to give a minimum bout duration of 5 min. Herbage intakes were estimated using n -alkanes. Grazing time was greater at 40 mm than at 60 or 80 mm when unsupplemented but less when supplemented. Proportionately 0.88 of grazing time and 0.67 of ruminating time by dairy cows occurred during daylight with a large evening meal particularly evident. On the 40 mm sward unsupplemented animals grazed for longer with a higher biting rate but lower bite mass and less mastication and rumination. When supplement was offered at the 40 mm sward height animals appeared to ‘give up’ harvesting the sward more readily. Durations of ruminating and idling bouts were similar across all treatments with low variability.

We investigated the effect of an inhibitor of acetylcholine (ACh) synthesis, (2-benzoylethyl)trimethylammonium iodide (BETA), on prostaglandin (PG)E2 and PGF2 alpha release from incubated placental explants in the presence or absence of ACh or arachidonic acid (AA). BETA alone (100 microM) significantly reduced both PGE2 and PGF2 alpha release. However, this inhibitory effect of BETA was not reversed in the presence of ACh (10 microM to 1 mM). The addition of AA (10 to 100 microM) increased both PGE2 and PGF2 alpha release, and simultaneously overcame the inhibition of PGE2 but not PGF2 alpha release by BETA. These results are compatible with the hypothesis that BETA may be inhibiting the phospholipase A2 (PLA2) step rather than prostaglandin H synthase (PGHS) step in the enzymatic pathway of PG generation. This hypothesis was supported by evidence showing a lack of effect of BETA (10 and 100 microM) on ovine placental microsome PGHS activity. Moreover, human placental homogenate PLA2 activity was reversibly inhibited by BETA (100 microM). In the presence of BETA (100 microM), addition of exogenous ACh (100 microM) had no significant effect on placental PLA2 activity. These results indicate that the inhibitory effect of BETA on placental PG release was unlikely to be via an action on ACh synthesis, but rather via a reversible effect on PLA2 activity.

This monograph describes the history, findings and international context of heroin-assisted treatment (HAT) in the Netherlands. The monograph consists of (1) a short introduction and seven paragraphs describing the following aspects of HAT in the Netherlands: (2) history of HAT studies and implementation of routine HAT in the Netherlands; (3) main findings on efficacy, safety and cost-effectiveness from the two randomized controlled HAT trials in the Netherland; (4) new findings from a large cohort study on the effectiveness of HAT in routine clinical practice in the Netherlands; (5) unique data on the patients perspective of HAT; (6) data on the pharmacological and pharmaceutical basis for HAT in the Netherlands; (7) description of the registration process; and (8) account of the international context of HAT. Together, these data show that HAT can now be considered a safe and proven-effective intervention for the treatment of chronic, treatment-resistant heroin dependent patients. (C) 2010 Elsevier B.V. and ECNP. All rights reserved

Many infectious diseases that cause significant morbidity and mortality, especially in the developing world, could be preventable through vaccination. The effort to produce safe, thermally stable, and needle-free mucosal vaccines has become increasingly important for global health considerations. We have previously demonstrated that a thermally stable nanoemulsion, a mucosal adjuvant for needle-free nasal immunization, is safe and induces protective immunity with a variety of antigens, including recombinant protein. The successful use of nanoemulsion-based vaccines, however, poses numerous challenges. Among the challenges is optimization of the formulation to maintain thermal stability and potency and another is accuracy and efficiency of dispensing the vaccines to the nasal mucosa in the anterior and turbinate region of the nasal cavity or potentially to the nasopharynx-associated lymphoid tissue.We have examined the effects of different diluents [phosphate-buffered saline (PBS) and 0.9% NaCl] on the stability and potency of nanoemulsion-based vaccines. In addition, we have determined the efficiency of delivering them using commercially available nasal spray devices (Pfeiffer SAP-62602 multidose pump and the BD Hypak SCF 0.5 ml unit dose Accuspray(TM)).We report the stability and potency of PBS-diluted ovalbumin-nanomeulsion mixtures for up to 8 months and NaCl-diluted mixtures up to 6 months when stored at room temperature. Significant differences in spray characteristics including droplet size, spray angle, plume width, and ovality ratios were observed between the two pumps. Further, we have demonstrated that the nanoemulsion-based vaccines are not physically or chemically altered and retain potency following actuation with nasal spray devices. Using either device, the measured spray characteristics suggest deposition of nanoemulsion-based vaccines in inductive tissues located in the anterior region of the nasal cavity.The results of this study suggest that nanoemulsion-based vaccines do not require specially engineered delivery devices and support their potential use as nasopharyngeal vaccine adjuvants.

SUMMARYDuring weeks 3–23 of lactation, 63 multiparous and 28 primiparous Friesian cows were offered ad libitum access to grass silage of either average (A)(ME 10·6 MJ/kg DM; CP 158 g/kg DM) or low (L)(ME 9·9 MJ/kg DM; CP 154 g/kg DM) energy value, either alone or in mixtures consisting of one of these grass silages with 25, 50 or 75% of the forage DM as maize silage. In addition, all cows received 7·2 kg DM/day of concentrate (ME 12·9 MJ/kg DM; CP 202 g/kg DM). There was a significant (P < 0·001) linear relationship between silage DM intake and percentage maize inclusion with grass silage. For grass silage A, DM intake of the mixture of grass and maize in a 1:1 DM ratio was significantly (P < 0·001) higher that at other inclusion levels. There was a significant (P < 0·05) overall linear effect of proportion of maize on milk yield, with a regression coefficient of 0·022 ± 0·009 kg/day per percentage maize proportion. Although milk composition was unaffected by treatment, there was a significant (P < 0·01) linear effect of maize proportion on protein yield for grass silage L, the regression coefficient being 0·8±0·03 g/day/percentage maize proportion. The mixture of grass silage A and maize silage in a 1:1 DM ratio produced the highest yield of milk protein.

The ingestive behaviour of non-lactating ewes ( Ovis aries L.) continuously stocked on monocultures of white clover ( Trifolium repens L. cv. ‘Huia') or perennial ryegrass ( Lolium perenne L. cv. ‘S23') maintained at a sward height of 6 cm was recorded. Animals on the clover sward spent significantly less time grazing and ruminating and longer idling than those on grass. Prehension biting rate, masticating rate and ruminating rate were not significantly different between treatments. Bite weight and intake rate were significantly higher on the clover sward but total intake was similar on both treatments. Animals grazing clover ate more, shorter, meals than those grazing grass but the intermeal interval was similar. There was a distinct pattern of grazing over the day on both swards with 70–99% of grazing occurring during daylight hours and 25–48% during the 4 h prior to sunset. Bite weight was positively related to animal liveweight but not to dental arcade width.

Data for individually recorded silage dry-matter intake (SDMI), concentrate dry-matter intake (CDMI), live weight, milk yield and milk composition of lactating dairy cows offered silage ad libitum and concentrates on a flat-rate basis, together with data for silage composition from experiments conducted at four sites, were used to obtain simple and multiple regressions of SDMI on other variables.Simple regressions showed that the most important variables affecting SDMI were, in order of importance: silage ammonia nitrogen, fat yield, CDMI, silage digestible organic matter concentration (DOMD) and live weight. The best multiple regression for the mean SDMI over weeks 4 to 13 of lactation accounted for proportionately 0·649 of the variation. Examination of week by week data for weeks 3 to 20 of lactation showed that two models for early and mid lactation were required to give a reasonable pattern of residual variances. These models accounted for 0·627 and 0·581 of the variation respectively. It was necessary to fit time effects explicitly in early lactation. Live weight was best represented by fitting post-calving live weight and deviations from post-calving live weight separately. A number of models requiring fewer input variables were also obtained to allow for use in situations where the full range of measurements is not made.The new models were tested using independent data from three sites. They performed better than a number of previously published models but the best model still gave a prediction error of proportionately 0·17 about the mean actual silage intake in early lactation and 015 in late lactation.The results suggest that there is little to be gained from further refinement of the functional form of the models and that the construction of a number of models for specific food and management situations is preferable to the use of global models.

This article reviews the pharmacokinetics of heroin after intravenous, oral, intranasal, intramuscular and rectal application and after inhalation in humans, with a special focus on heroin maintenance therapy in heroin dependent patients. In heroin maintenance therapy high doses pharmaceutically prepared heroin (up to 1000 mg/day) are prescribed to chronic heroin dependents, who do not respond to conventional interventions such as methadone maintenance treatment. Possible drug-drug interactions with the hydrolysis of heroin into 6-monoacetylmorphine and morphine, the glucuronidation of morphine and interactions with drug transporting proteins are described. Since renal and hepatic impairment is common in the special population of heroin dependent patients, specific attention was paid on the impact of renal and hepatic impairment. Hepatic impairment did not seem to have a clinically relevant effect on the pharmacokinetics of heroin and its metabolites. However, some modest effects of renal impairment have been noted, and therefore control of the creatinine clearance during heroin-assisted treatment seems recommendable.

Six sheep were trained, over a period of 11 weeks, to work for a reward of freshly cut clover by walking along a variable length, U-shaped race. Training included habituation to the presence of an observer and to isolation from conspecifics. Following training, motivation to eat clover was tested by varying the work (distance walked) required to access a 5 g (dry matter) clover reward. Each sheep was tested using three different race lengths (3, 8 or 20 m) in random order on three different days. In each test, the sheep were allowed up to 1 h to access the reward 25 times. The sheep could only obtain clover in the reward area but could graze grass at all other times. There was a linear decline in the number of visits to the reward area within 1 h (P = 0.05) as the distance walked increased. Distance walked did not significantly affect walking speed in the race (P = 0.10). The latency between visits showed a linear decline as number of visits increased (P = 0.01). The total amount of clover consumed and the time spent in race transit and reward area residency were used to calculate effective clover intake rates for each treatment (5.1, 4.4 and 3.7 g DM min−1). Theoretical calculations indicated that there would be a net energy benefit from obtaining the clover reward at the two shorter distance treatments, but that using the system at the longest distance would only yield a very small energy benefit.

The aim of this study was to investigate the use of illicit heroin among patients in a heroin-assisted treatment program. In this program, pharmaceutical-grade heroin was administered to heroin-addicted patients. Monitoring of illicit heroin use was considered important for the evaluation of this treatment program. Acetylcodeine and codeine, common adulterants of "street" heroin, were used as markers for illicit heroin. A liquid chromatography method with tandem mass spectrometric detection (LC-MS-MS) was developed, for quantitative analysis of heroin and methadone, their metabolites, and the simultaneous detection of acetylcodeine. One-hundred patients in a heroin-assisted treatment program were screened for acetylcodeine in plasma. Furthermore, patients were interviewed about illicit heroin use, and they were tested for alcohol and cocaine use. In plasma samples of 16% of the patients, acetylcodeine was detected. Overall agreement between self-report and plasma samples was 95% (kappa: 0.81). Patients who tested positive for acetylcodeine had visited the outpatients' clinics significantly less frequently than the patients who tested negative. Alcohol and cocaine use was more common in patients who tested positive for acetylcodeine. Illicit heroin use was observed in a limited percentage of patients. Overall agreement between self-report and markers of illicit heroin use was good.

In preparation for a trial on co-prescription of inhalable heroin and methadone, two methods for inhalation of heroin/caffeine tablets were compared: the commonly used method of 'chasing the dragon' and a standardised procedure for inhalation of volatilised heroin, using a heating device. Five male addicts inhaled a tablet of smokable heroin daily for 5 days, alternating the inhalation method. Plasma concentrations of heroin, 6-acetylmorphine, morphine and morphine-3- and -6-glucuronide were determined using a liquid chromatography method with tandem mass spectrometric detection. The exposure to heroin and its metabolites (expressed as areas under the concentrationtime curve) was significantly lower after smoking via the heating device than after 'chasing the dragon': heroin 80% and 6-acetylmorphine 73% lower (p

Parasitic nematodes, even in the absence of any clinical disease, can cause a reduction in voluntary feed intake in housed ruminants. This trial examined these effects on young cattle grazing pastures. Twenty dairy heifer calves, born in the previous autumn, were blocked according to liveweight and allocated to one of two groups: either untreated or dosed with an IVOMEC((R)) (ivermectin) SR Bolus 10 days prior to turnout on 1 May 1998. The groups grazed separately on two paddocks on predominately ryegrass swards. Liveweights were recorded every 28 days and faecal samples taken for worm egg counts at the same time. In mid-May and mid-July, for two 14-day periods, animals were paired within treatment groups and transferred to one of 10 replicate paddocks of similar sward height and herbage mass. Grazing behaviour and herbage intake were measured during these periods. In mid-May, 2 weeks after turnout, treated and untreated animals showed no difference in grazing behaviour or daily intake of grass. By mid-July, 10 weeks after turnout, the untreated heifers spent on average 105min less per day in grazing time and their daily herbage intake was 0.78kg dry matter (DM) per day lower than that of the treated animals. Residual sward height, mass and composition in the trial paddocks reflected these differences. There were no clinical signs of gastrointestinal parasitism in the untreated group up to this time; in July, the mean worm egg count in this group was 120 eggs per gram (e.p.g.) of faeces. Faecal samples from several untreated animals were positive for lungworm larvae by July, mild clinical signs of bronchitis were observed in two of these animals in mid-July. Over the period from turnout until mid-July, the untreated heifers showed a reduction in mean daily liveweight gain of 150g, compared to the treated animals.

Human placental explants were incubated in the presence of physostigmine (3.08 microM), and release of acetylcholine (ACh) and prostaglandin (PG) were measured in the fourth hour by bioassay and radioimmunoassay, respectively. The choline acetyltransferase inhibitor (2-benzoylethyl)trimethylammonium (100 microM, n = 6) significantly reduced ACh release by 36 +/- 6%, PGE2 release by 23 +/- 8% and PGF2 alpha release by 29 +/- 10%. The inhibitor of vesicular acetylcholine storage, vesamicol (100 microM, n = 7), significantly reduced ACh release by 22 +/- 4%, PGE2 release by 46 +/- 13% and PGF2 alpha release by 32 +/- 9%. In the absence of physostigmine, ACh release was reduced by 89 +/- 2%, whereas PG release did not change compared with that in the presence of physostigmine. The presence of atropine (14.4 microM) did not affect PG release. These results suggest that if there is a relationship between human placental production of ACh and PGs, it does not appear to depend on muscarinic receptor activation or the activity of placental cholinesterase.

Comparaison des couts du traitement des eaux usees par filtration sur du charbon actif granulaire et sur du sable. Modelisation de l'adsorption du carbone organique total sur le charbon actif, en vue de l'evaluation des performances de la methode

Images Figs. 1-4

The effect of sward surface height (SSH) on grazing behaviour and intake by lactating Holstein Friesian cows on continuously stocked grass pastures maintained at mean heights of 5, 7 and 9 cm was studied during the growing season. Intake rate was estimated over periods of 1 h by weighing animals before and after grazing, with a correction made for insensible weight loss. Grazing behaviour during that hour and over 24 h was recorded automatically using sensors to measure jaw movements. Although maintained at the overall mean SSH, swards had a patchy appearance with short, frequently grazed areas interspersed with taller, infrequently grazed areas, which is typical of pastures continuously stocked with cattle. Daily organic matter (OM) intake, calculated as the product of daily grazing time and intake rate, was greater at a SSH of 7 cm than at 5 or 9 cm (14.1 vs. 10.5 and 12.1 kg respectively). On the 5-cm sward, OM intake per grazing jaw movement (GJM) was reduced compared with that on the 7-cm sward (0.182 vs. 0.264 g respectively), and because cows were unable either to increase significantly GJM rate (95.8 vs. 90.1 GJM min(-1)) or the proportion of GJM that were bites (0.80 vs. 0.81) OM intake rate was reduced (16.9 vs. 23.5 g min(-1)). Cows were unable to increase their grazing time significantly (628 vs. 604 min d(-1)) to compensate for the reduction in intake rate, and as a result daily intakes were lower. Cows grazing the 9-cm sward also incurred a reduction in OM intake GJM(-1) compared with those on the 7-cm sward (0.237 vs. 0.264 g respectively) and therefore there was a reduction in OM intake rate (21.6 vs. 23.5 g min(-1)). These animals did not compensate by increasing the time spent grazing (581 min d(-1)), probably owing to an increased ruminating requirement per kg of herbage ingested compared with those on 7 cm SSH (2264 vs. 1780 ruminating jaw movements respectively). The results show that SSH can significantly influence intake rate, but, while the cow's only effective strategy to compensate for any reduction in intake rate is to increase grazing time, this may be limited by the requirement for ruminating and non-grazing, non-ruminating activities, which is influenced by qualitative and quantitative aspects of the herbage ingested, whereas the cows' only effective strategy to compensate for any reduction in intake rate is to increase grazing time.

The human placenta contains both acetylcholine (ACh) and choline acetyltransferase, and in vitro bilaterally perfused placental lobules release ACh. The function of this placental cholinergic system has not yet been clearly defined, although changes occur in it during parturition and it may be linked to placental prostaglandin generation at this time. It has also been suggested that ACh may regulate placental amino-acid transport and/or blood flow. It has been found that ACh release from fetal vessels of bilaterally perfused placental lobules is reduced during preeclampsia but is not necessarily correlated with any change in perfusion pressure or materno-fetal transfer of the nonmetabolizable amino acid alpha-aminoisobutyric acid. However, a correlation has been found between releases from human placental explants of ACh (when inhibited by (2-benzoylethyl)trimethylammonium or vesamicol) and of prostaglandins E2 and F2 alpha. Thus, although the evidence for a role of ACh in the control of placental amino-acid transfer or vascular tone is not conclusive, inhibition of the human placental cholinergic system has been shown to be associated with reduced output of prostaglandins from this tissue.