Optimizing the traversal time for gantry trajectories for proton arc therapy treatment plans.

Background.Proton arc therapy (PAT) is an emerging radiation therapy technique where either the gantry or the patient continuously rotates during the irradiation treatment. One of the perceived advantages of PAT is the reduced treatment time, but it is still unclear exactly how long these treatment times will be, given that no machine capable of its delivery is available on the market at the time of writing.Objective.We introduce the algorithm arc trajectory optimization method (ATOM), which aims to determine an efficient velocity profile for the gantry for rapid delivery of a given proton arc treatment plan. This algorithm could be used to minimize the delivery time of a proton arc plan without changing the plan or updating the machine.Approach.ATOM computes the trajectory with the shortest delivery time while ensuring there is enough time to deliver all spots in each energy layer and switch energy between layers. The feasibility of the dynamic gantry movement was assured by enforcing maximum and minimum limits for velocity, acceleration, and jerk. This was achieved by discretizing the gantry velocity and combining theA* algorithm with the open-source motion generation library Ruckig. The algorithm was tested on a synthetic data set as well as a liver case, a prostate case and a head and neck case.Main results.Arc trajectories for plans with 360 energy layers were calculated in under a second using 256 discrete velocities. The delivery time of the liver case, the prostate case and the head and neck case were 284 s, 288 s and 309 s respectively, for 180 energy layers.Significance.ATOM is an open-source C++ library with a Python interface that rapidly generates velocity profiles, making it a highly efficient tool for determining proton arc delivery times, which could be integrated into the treatment planning process.

Dose mimicking based strategies for online adaptive proton therapy of head and neck cancer.

Objective.To compare a not adapted (NA) robust planning strategy with three fully automated online adaptive proton therapy (OAPT) workflows based on the same optimization method: dose mimicking (DM). The added clinical value and limitations of the OAPT methods are investigated for head and neck cancer (HNC) patients.Approach.The three OAPT strategies aimed at compensating for inter-fractional anatomical changes by mimiking different dose distributions on corrected cone beam CT images (corrCBCTs). Order by complexity, the OAPTs were: (1) online adaptive dose restoration (OADR) where the approved clinical dose on the planning-CT (pCT) was mimicked, (2) online adaptation using DM of the deformed clinical dose from the pCT to corrCBCTs (OADEF), and (3) online adaptation applying DM to a predicted dose on corrCBCTs (OAML). Adaptation was only applied in fractions where the target coverage criteria were not met (D98% < 95% of the prescribed dose). For 10 HNC patients, the accumulated dose distributions over the 35 fractions were calculated for NA, OADR, OADEF, and OAML.Main results.Higher target coverage was observed for all OAPT strategies compared to no adaptation. OADEF and OAML outperformed both NA and OADR and were comparable in terms of target coverage to initial clinical plans. However, only OAML provided comparable NTCP values to those from the clinical dose without statistically significant differences. When the NA initial plan was evaluated on corrCBCTs, 51% of fractions needed adaptation. The adaptation rate decreased significantly to 25% when the last adapted plan with OADR was selected for delivery, to 16% with OADEF, and to 21% with OAML. The reduction was even greater when the best plan among previously generated adapted plans (instead of the last one) was selected.Significance. The implemented OAPT strategies provided superior target coverage compared to no adaptation, higher OAR sparing, and fewer required adaptations.

Gonadotrophin stimulation and risk of relapse in breast cancer.

STUDY QUESTION: Is gonadotrophin stimulation as part of IVF associated with an increased risk of relapse in breast cancer? SUMMARY ANSWER: Controlled ovarian stimulation (COS) in connection with IVF in women with previous breast cancer was not associated with an increased risk of breast cancer relapse. WHAT IS KNOWN ALREADY: Breast cancer is the most common malignancy among women worldwide and the leading cause of cancer death among females. The use of COS with gonadotrophins with subsequent cryopreservation of oocytes or embryos in order to enhance the chances of pregnancy after cancer treatment is the current most established fertility preservation method for women with breast cancer. To date, there are only a few small retrospective hospital-based controlled studies evaluating the risk of breast cancer relapse in patients undergoing fertility preservation with or without COS, showing no evident risk of relapse in breast cancer after the use of gonadotoxic agents. STUDY DESIGN SIZE DURATION: This was a retrospective, population-based cohort study comprising 5857 women with previous breast cancer of whom 337 were exposed to COS. Exposure (COS) and outcomes (relapse and death) were identified for all patients from 2005 to 2014 by assessing the National Quality Register for Assisted Reproduction, the Swedish Medical Birth Register, the National Patient Register, the Swedish Prescribed Drug Register, the Swedish Cause of Death Register, the National Breast Cancer Register and the Swedish Cancer Register. Matching according to set criteria was possible for 334 women, who constituted the control group. A total of 274 women had undergone IVF after completing breast cancer treatment and 63 women had undergone COS for fertility preservation at the time of breast cancer diagnosis. PARTICIPANTS/MATERIALS SETTING METHODS: Women aged 20-44 years previously diagnosed with breast cancer and exposed to COS were matched for age at breast cancer diagnosis ±5 years, tumour size and lymph node involvement with a non-exposed control group, including women with known T- and N-stages. In a subsequent analysis, the matched cohort was assessed by also including women with unknown T- and N-stages. A secondary analysis comprised the entire non-matched cohort, including all women with known T- and N-stages. Also here, a subsequent analysis included women with missing data for T- and N-stages. The risk of relapse in breast cancer was estimated as crude hazard ratios (HRs) and 95% CI using Cox proportional hazards models in the primary and secondary analyses where T- and N-stages were known: otherwise the risks of relapse were only given descriptively. MAIN RESULTS AND THE ROLE OF CHANCE: In the primary matched analysis, relapse occurred in 20 of 126 women exposed to COS (15.9%) compared with 39 of 126 (31.0%) in the control cohort (HR = 0.70; 95% CI 0.39-1.45; P = 0.22). In the subsequent analysis, also including women with unknown T- and N-stages, relapse occurred in 27 of 337 (8.0%) women having undergone COS compared with 71/334 (21.3%) among the non-exposed. In the secondary adjusted analysis, relapse occurred in 20 of 126 (15.9%) exposed women and in 918 of 3729 (24.6%) non-exposed women (HR = 0.81; 95% CI 0.49-1.33; P = 0.70). In the subsequent analysis, including unknown T- and N-stages, relapse occurred in 27 of 337 (8.0%) women in the exposed group and 1176 of 5520 (21.3%) in the non-exposed cohort. LIMITATIONS REASONS FOR CAUTION: A substantial degree of missing data on important prognostic variables was a limitation, particularly when analysing the total cohort. Furthermore, data on confounding factors, such as BMI, were not completely covered. Another limitation was that a pre-specified variable for relapse was not in use for the majority of the National Breast Cancer Register. Furthermore, the follow-up time from available register data (2005-2014) is rather short. Finally, we cannot be sure whether the prognostic information from receptor status, showing a lower incidence in the exposed group, is representative. Information on T- and N-stages was missing in more than half of the patients. WIDER IMPLICATIONS OF THE FINDINGS: In this large, retrospective, matched cohort study, we found no increased risk of relapse in breast cancer among women who had been exposed to gonadotrophins as part of IVF. This is reassuring but might be confounded by the selection of a group of women with a more favourable prognosis than those not undergoing IVF. The present study strengthens previous findings by being large, national and register based. Its results are applicable to women undergoing fertility preservation as well as to those undergoing regular IVF treatment. STUDY FUNDING/COMPETING INTERESTS: Supported in part by grants from the Swedish state under the agreement between the Swedish government and the county councils the ALF-agreement (ALFGBG-720291), The Assar Gabrielsson Fund (FB 15-20), The Breast Cancer Fund and the Swedish Association of Local authorities and Regions, SKR. There are no conflicts of interest to declare. TRIAL REGISTRATION: N/A.

No increased risk of relapse of breast cancer for women who give birth after assisted conception.

STUDY QUESTION: Is childbirth after IVF associated with a risk of relapse in breast cancer? SUMMARY ANSWER: Women who had been diagnosed with breast cancer and completed treatment had no increased risk of relapse if they gave birth after conceiving with IVF. WHAT IS KNOWN ALREADY: Pregnancy and childbirth have not been shown to increase the risk of relapse in breast cancer. Ovarian stimulation during IVF increases the oestrogen levels and could theoretically increase the risk of relapse in breast cancer. STUDY DESIGN SIZE DURATION: This is a retrospective register study, using national Swedish register data from the National Patient Register, the Medical Birth Register, the Swedish National Cancer Register, the National Breast Cancer Register, the National Quality Registry of Assisted Reproduction (Q-IVF), the National IVF Dataset, the Swedish Prescribed Drug Register and the Cause of Death Register. All women diagnosed with breast cancer who were between 20 and 44 years of age during the years 1982 to 2014 and identified in the cancer registries were assessed. PARTICIPANTS/MATERIALS SETTING METHODS: Women, previously diagnosed with breast cancer, who had given birth after IVF (29 after completed breast cancer treatment and 8 after fertility preservation) were compared with a matched control group who had given birth after spontaneous conception. Matching was done in a ratio 1:4, based on T-stage (size of the tumour) and year of diagnosis +/-5 years. MAIN RESULTS AND THE ROLE OF CHANCE: We found 26 114 women that had been diagnosed with breast cancer when 20-44 years old and of those 860 had subsequently given birth, 823 after spontaneous and 37 after IVF conception. Follow-up time was similar between the groups, ranging from 2.6 to 24.0 years, with a mean follow-up time of 10.3 (SD 4.2) years in the IVF group and 10.7 (SD 4.4) years in the control group. There were no relapses (0/37) in the IVF group. The relapse rate for the matched controls was 36/148 (24.8%). Ten women who suffered relapse died due to breast cancer. LIMITATIONS REASONS FOR CAUTION: This is reassuring data; however, the result is based on a few cases. The poor coverage of important prognostic variables in the register resulted in uncertain comparability of the groups. The main limitation in this study is the extent of missing data on tumour-related variables, due to poor coverage from the early years of the National Breast Cancer Register. It is possible that the women accepted for IVF had a less aggressive breast cancer and were generally healthier than women delivering after conceiving spontaneously and therefore had a lower risk of relapse. Other limitations are the lack of information on the anticancer therapies used and type of disease relapse, plus the older of the two IVF registers did not hold information on unsuccessful IVF cycles, leaving only cycles leading to birth, to be analysed. WIDER IMPLICATIONS OF THE FINDINGS: We found no indication that women who had been diagnosed with breast cancer had an increased risk of relapse if they gave birth after conceiving with IVF. Based on our findings, there is no evidence to advise against IVF treatment in this group of women. More detailed registry data would be valuable for future studies, enabling proper matching of tumour characteristics between groups. STUDY FUNDING/COMPETING INTERESTS: The study was financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-720291), The Assar Gabrielsson Fund (FB 15-20), The Breast Cancer Fund and the Swedish Association of Local Authorities and Regions, SKL. There are no conflicts of interest to declare.

Effects on adult cognitive function after neonatal exposure to clinically relevant doses of ionising radiation and ketamine in mice.

BACKGROUND: Radiological methods for screening, diagnostics and therapy are frequently used in healthcare. In infants and children, anaesthesia/sedation is often used in these situations to relieve the patients' perception of stress or pain. Both ionising radiation (IR) and ketamine have been shown to induce developmental neurotoxic effects and this study aimed to identify the combined effects of these in a murine model. METHODS: Male mice were exposed to a single dose of ketamine (7.5 mg kg-1 body weight) s.c. on postnatal day 10. One hour after ketamine exposure, mice were whole body irradiated with 50-200 mGy gamma radiation (137Cs). Behavioural observations were performed at 2, 4 and 5 months of age. At 6 months of age, cerebral cortex and hippocampus tissue were analysed for neuroprotein levels. RESULTS: Animals co-exposed to IR and ketamine displayed significant (P≤0.01) lack of habituation in the spontaneous behaviour test, when compared with controls and single agent exposed mice. In the Morris Water Maze test, co-exposed animals showed significant (P≤0.05) impaired learning and memory capacity in both the spatial acquisition task and the relearning test compared with controls and single agent exposed mice. Furthermore, in co-exposed mice a significantly (P≤0.05) elevated level of tau protein in cerebral cortex was observed. Single agent exposure did not cause any significant effects on the investigated endpoints. CONCLUSION: Co-exposure to IR and ketamine can aggravate developmental neurotoxic effects at doses where the single agent exposure does not impact on the measured variables. These findings show that estimation of risk after paediatric low-dose IR exposure, based upon radiation dose alone, may underestimate the consequences for this vulnerable population.

Etomidate exposure in early infant mice (P10) does not induce apoptosis or affect behaviour.

BACKGROUND: Numerous animal studies have shown that all commonly used intravenous anaesthetic drugs and volatile agents may cause neuronal apoptosis following exposure in early life. Most studies have focussed on detecting increased apoptosis but their methods are not always readily transferrable to humans. The lipid formulation of etomidate represents an alternative to the currently established intravenous anaesthetic agents but there is no animal or human data on apoptosis or long-term behavioural changes. The aim of our study was to investigate the effects of etomidate on cerebral neuronal apoptosis and long-term behavioural effects using an established mouse model that represents the clinically relevant period of anaesthesia during early infancy in humans. METHODS: Six groups of 10 day old mice (P10) were injected with either etomidate 0.3, 3 or 10 mg/kg, propofol 60 mg/kg, ketamine 50 mg/kg or placebo only. Apoptosis in the cerebral cortex and hippocampus was assessed 24 h after treatment (activated caspase-3). Late behavioural effects were tested at 2 months of age (spontaneous activity in a new environment). RESULTS: No evidence was found of differences in activated caspase 3-concentrations among the study groups. Significant late behavioural changes were only observed in the ketamine group. CONCLUSION: A single dose of etomidate in early infant mice at P10 did not produce evidence of cerebral apoptosis or impaired adult motor behaviour.

Guided Internet-delivered cognitive behavioural therapy for chronic pain patients who have residual symptoms after rehabilitation treatment: randomized controlled trial.

BACKGROUND: Chronic pain can be treated with cognitive behavioural therapy delivered in multidisciplinary settings. However, relapse is likely, and there is a need for cost-effective secondary interventions for persons with residual problems after rehabilitation. The aim of the present study was to investigate the effects of a guided Internet-delivered cognitive behavioural intervention for patients who had completed multidisciplinary treatment at a pain management unit. METHODS: A total of 72 persons with residual pain problems were included in the study and were randomized to either treatment for 8 weeks or to a control group who were invited to participate in a moderated online discussion forum. The participants had different chronic pain conditions, and a majority were women (72%). Twenty-two percent of the participants dropped out of the study before the post-treatment assessment. RESULTS: Intent-to-treat analyses demonstrated differences on the catastrophizing subscale of the Coping Strategies Questionnaire (Cohen's d = 0.70), in favour of the treatment group but a small within-group effect. Differences were also found on other measures of pain-related distress, anxiety and depressive symptoms. A 6-month follow-up exhibited maintenance of improvements. CONCLUSIONS: We conclude that Internet-delivered treatment can be partly effective for persons with residual problems after completed pain rehabilitation.

Clonidine abolishes the adverse effects on apoptosis and behaviour after neonatal ketamine exposure in mice.

BACKGROUND: An increasing amount of both experimental and epidemiological data indicates that neonatal anaesthesia causes disruption of normal brain development in rodents and primates, as manifested by acute increased apoptosis and long-lasting altered behaviour and learning. It is necessary to seek strategies that avoid the possible adverse effects after anaesthesia. Our purpose is to show that increased apoptosis and behavioural alterations after ketamine exposure during this period may be prevented by clonidine, a compound already used by paediatric anaesthetists for sedation. METHODS: To investigate the protective properties of clonidine pre-treatment, five groups of 10-day-old mice were injected with either ketamine 50 mg/kg, clonidine 40 µg/kg, ketamine 50 mg/kg 30 min after 10 µg/kg clonidine, ketamine 50 mg/kg 30 min after 40 µg/kg clonidine or saline (control). Apoptosis was measured 24 h after treatment using Flouro-Jade staining. Spontaneous activity in a novel environment was tested at an age of 55 days. RESULTS: Pre-treatment with 40 µg/kg clonidine, but not 10 µg/kg clonidine, 30 min before ketamine exposure abolished ketamine-induced apoptosis and the behavioural changes observed in the young adult mice. The mice exposed to clonidine alone showed no differences from the saline-treated (control) mice. CONCLUSION: The administration of clonidine eliminated the adverse effects of ketamine in this mouse model, suggesting a possible strategy for protection. Alone, clonidine did not cause any adverse effects in these tests.

Exercise alleviates Parkinsonism: clinical and laboratory evidence.

The present review examines the putative benefits for individuals afflicted with Parkinsonism, whether in the clinical setting or in the animal laboratory, accruing from different exercise regimes. The tendency for patients with Parkinson's disease (PD) to express either normal or reduced exercise capacity appears regulated by factors such as fatigue, quality-of-life and disorder severity. The associations between physical exercise and risk for PD, the effects of exercise on idiopathic Parkinsonism and quality-of-life, the effects of exercise on animal laboratory models of Parkinsonism and dopamine (DA) loss following neurotoxic insults, and the effects of exercise on the DA precursor, L-Dopa, efficacy are examined. It would appear to be case that in view of the particular responsiveness of the dopaminergic neurons to exercise, the principle of 'use it or lose' may be of special applicability among PD patients.

Neonatal exposure to deca-brominated diphenyl ether (PBDE 209) causes dose-response changes in spontaneous behaviour and cholinergic susceptibility in adult mice.

Polybrominated diphenyl ethers (PBDEs), used as additive flame-retardants, are increasing in the environment and are present in human mother's milk, newborns and toddlers. We reported earlier that several PBDEs, highly brominated PBDEs, caused developmental neurotoxic effects in mice, manifested as persistent aberrations in spontaneous behaviour, habituation capability, learning and memory, and changes in the cholinergic system. The present study was undertaken to explore the dose-response effects of PBDE 209 on spontaneous behaviour, habituation and its effects on the murine cholinergic system. Neonatal male NMRI mice were given 1.4, 2.3, 14 or 21micromol PBDE 209/kg body weight, when 3 days old. The agent was administered as a single oral dose via a metal gastric tube. Spontaneous behaviour and response to the cholinergic agonist nicotine were observed in adult mice at 2 and 4 months of age. Mice were also observed for anxiety-like behaviour in an elevated plus-maze. Adult mice, 2 and 4 months old, showed a dose-response related change in spontaneous behaviour, viz. were hyperactive and showed reduced or lack of habituation, effects that worsen with age. At the adult age of 4 months the susceptibility of the cholinergic system was also affected in a dose-response related manner, viz. reduced and/or hypoactive response to nicotine. This shows that PBDE 209 can be as potent as the lower brominated PBDEs in causing developmental neurotoxic defects.

Neonatal exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) causes neurobehavioural defects in adult mice.

Perfluorinated compounds (PFCs) are found in applications such oil/water repellents for clothing fabrics, carpets, food packaging, lubricants, surfactants and fire extinguishers. PFCs are persistent in the environment. They have been found in humans and in wildlife. We reported earlier that persistent organic pollutants (POPs), such as DDT, PCBs and BFRs, caused developmental neurotoxic defects in mice, manifested as persistent aberrations in spontaneous behaviour, habituation capability, learning and memory, and changes in the cholinergic system in adults, when mice were exposed during a critical period of neonatal brain development. The present study was conducted to see whether PFCs can cause similar developmental neurotoxic effects as earlier observed for POPs as PCBs and PBDEs. NMRI male mice were exposed to a single-oral dose, either 1.4 or 21 micromol/kg body weight of PFOS (0.75 or 11.3 mg), PFOA (0.58 or 8.70 mg), or PFDA (0.72 or 10.8 mg), via a metal gastric-tube at the age of 10 days. The control animals received in the same manner 10 ml/kg body weight of the 20% fat emulsion vehicle. Spontaneous behaviour (locomotion, rearing, and total activity), and habituation were observed in 2- and 4-month-old mice. The susceptibility of the cholinergic system was explored in a nicotine-induced spontaneous behaviour test in 4-month-old mice. Deranged spontaneous behaviour was observed in mice exposed to PFOS and PFOA, manifested as reduced and/or lack of habituation and hyperactivity in adult mice. These effects were also seen to worse with age. Neonatal exposure to PFOS and PFOA affected the cholinergic system, manifested as a hypoactive response to nicotine, compared to a hyperactive response to nicotine in controls. These developmental neurotoxic effects are similar to those we reported earlier for PCBs and PBDEs. This suggests that PFOS and PFOA be included in the group of POPs known to be developmental neurotoxicants.

Postnatal iron overload destroys NA-DA functional interactions.

C57/BL6 mice were administered either postnatal iron (Fe(2+) 7.5 mg/kg, on postnatal days 10-12) or vehicle, followed by administration of either DSP4 (50 mg/kg, s.c., 30 min after injection of zimeldine, 20 mg/kg, s.c.) or vehicle (saline) at 63 days of age. Three weeks later, iron/vehicle treated, DSP4/vehicle treated mice were injected with either a low dose of MPTP (2 x 20 mg/kg, with a 24-hr interval between injections) or vehicle. Behaviour testing took place a further three weeks (spontaneous behaviour and L-Dopa induced) and two weeks (clonidine-L-Dopa induced) later. Postnatal iron administration exacerbated the bradykinesia induced by MPTP and virtually abolished all spontaneous motor activity in NA-denervated mice that were MPTP-treated. Postnatal iron administration reduced markedly the restoration of motor activity by suprathreshold L-Dopa (20 mg/kg) following a 60-min habituation to the test chambers. Pretreatment with DSP4 effectively eliminated the restorative effect of L-Dopa in the MPTP mice. The synergistic effects of co-administration of clinidine (1 mg/kg) with a subthreshold dose of L-Dopa (5 mg/kg) in elevating the motor activity of MPTP mice were reduced markedly by postnatal iron administration, as well as by pretreatment with DSP4. NA-denervation by DSP4, after postnatal iron treatment, totally abolished the activity-elevating effects of the alpha-adrenoceptor agonist + DA-precursor combination in MPTP mice, and virtually eliminated these effects in saline (non-MPTP) mice. Postnatal iron administration caused enduring higher levels of total iron content in all the groups with an increased level in mice treated with DSP4 followed by MPTP. These divergent findings confirm the direct influence of NA innervation upon dopaminergic functional expression and indicate a permanent vulnerability both in the noradrenergic and dopaminergic pathways following the postnatal infliction of an iron overload.

Microwaving in F-18 chemistry: quirks and tweaks.

Since the late 1980s, microwave dielectric heating has been used to speed up chemical transformations, also in radiolabeling tracers for positron emission tomography. In addition to shorter reaction times, higher yields, cleaner product mixtures and improved reproducibility have also been obtained for reactions involving polar components that require heating at elevated temperatures. The conditions used in microwave chemistry can differ considerably from those in conventional heating. Understanding the factors that influence the interaction of the electromagnetic field with the sample is critical for the successful implementation of microwave heating. These parameters are discussed here and exemplified with radiolabelings with fluorine-18.

Subchronic administration of haloperidol influences the functional deficits of postnatal iron administration in mice.

C57/BL6 mice were administered either 7.5 mg Fe(2+) (II)/ kg or vehicle (saline) postnatally on Days 10-12 after birth. From 64 days of age onwards for 24 days, groups of mice were administered either haloperidol (0.25 or 1 or 2 mg/kg, s.c.) or vehicle (Tween-80). Twenty-four hours after the final injection of either neuroleptic compound or vehicle, spontaneous motor activity was measured over a 60-min interval. Postnatal Fe(2+)-treatment (7.5 mg/kg, postnatally) reduced motor activity parameters during the initial 20-min periods (0-20 and 20-40 min) and then induced hyperactivity during the final 20-min period over all three parameters of activity, confirming previous observations. Subchronic administration of haloperidol, at the 1 and 2 mg/kg doses, and to a lesser extent the 0.25 mg/kg dose, increased the levels of activity in all three motor activity parameters in postnatal iron-treated mice: locomotion (1st and 2nd 20 min periods), rearing (1st and 2nd 20 min periods) and total activity (1st 20 min period). All three doses of haloperidol abolished the later hyperactivity in iron-treated mice, with the exception of the 0.25 mg/kg dose with regard to rearing behaviour. Apomorphine (1 mg/kg, s.c.)-induced activity was elevated by postnatal iron administration and by subchronic administration of apomorphine at the higher dose levels. In the context of these and other observations, it is suggested that subchronic administration of haloperidol interacting with postnatal iron induces different expressions of dopamine neuron comorbidity underlying movement disorder.

Norharman-induced motoric impairment in mice: neurodegeneration and glial activation in substantia nigra.

The beta-carboline norharman is present in cooked food and tobacco smoke and show structural resemblance to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. C57BL/6 mice were injected subcutaneously with norharman (3 and 10 mg/kg) twice per day for five consecutive days. Eighteen hours after the last dose an increased expression of glial fibrillary acidic protein and fluoro-jade staining were demonstrated whereas the number of tyrosine hydroxylase positive cells were unchanged in the substantia nigra. Two weeks after the last treatment a decreased motor activity was observed whereas cognitive functions remained intact. In cultured PC12 cells norharman treatment induced mitochondrial dysfunction and increased the number of caspase-3 and TUNEL-positive cells. The results demonstrate that norharman induced apoptosis in cultured cells as well as early neurodegeneration, glial activation and sustained motor deficits in mice and suggest that exposure to norharman may contribute to idiopathic Parkinson's disease.

Postnatal iron-induced motor behaviour alterations following chronic neuroleptic administration in mice.

C57/BL6 mice were administered either 7.5 mg Fe(2+)/kg or vehicle (saline) postnatally on days 10-12 after birth. From 61 days of age onwards for 21 days, groups of mice were administered either clozapine (1 or 5 mg/kg, s.c.) or haloperidol (1 mg/kg, s.c.) or vehicle (Tween-80). Twenty-four hours after the final injection of either neuroleptic compound or vehicle, spontaneous motor activity was measured over a 60-min interval. Following this, each animal was removed, injected apomorphine (1 mg/kg, s.c.) and replaced in the same test chamber. It was found that postnatal administration of Fe(2+) at the 7.5 mg/kg dose level reduced activity during the initial 20-min periods (0-20 and 20-40 min) and then induced hyperactivity during the final 20-min period over all three parameters of activity. Subchronic treatment with the higher, 5 mg/kg, dose of clozapine abolished or attenuated the hypoactivity in by postnatal Fe(2+) during the 1(st) two 20-min periods over all three parameters of activity. Subchronic treatment with the higher, 5 mg/kg, dose of clozapine abolished or attenuated the hyperactivity in by postnatal Fe(2+) during the 3(rd) and final 20-min period. Subchronic administration of haloperidol, without postnatal iron, increased the level of both locomotion (1(st) 20 min) and rearing (2(nd) 20 min) activity. Postnatal administration of Fe(2+) at the 7.5 mg/kg dose increased the levels of both locomotion and rearing, but not total activity, following administration of apomorphine (1 mg/kg). Subchronic administration of clozapine, at both the 1 and 5 mg/kg doses, reduced the increased locomotor activity caused by postnatal Fe(2+), whereas clozapine, 5 mg/kg, elevated further the postnatal Fe(2+)-induced increased in rearing. Subchronic administration of clozapine, at both the 1 and 5 mg/kg doses, and haloperidol, 1 mg/kg, increased the level of locomotor following administration of apomorphine (1 mg/kg) in mice treated postnatally with vehicle, whereas only clozapine increased the level of rearing. Correlational analyses indicated that both apomorphine-induced locomotion and rearing were highly correlated with the total iron content in the basal ganglia, thereby offering direct evidence of the linear relationship between iron content in the basal ganglia and the behavioural expression of DA D(2)-receptor supersensitivity in mice.

Influence of noradrenaline denervation on MPTP-induced deficits in mice.

C57/BL6 mice were administered either DSP4 (50 mg/kg, s.c., 30 min after injection of zimeldine, 20 mg/kg, s.c.) or vehicle (saline) at 63 days of age. Three weeks later, one group (n = 10) of DSP4-treated and one group of vehicle-treated mice were administered MPTP (2 x 40 mg/kg, s.c., 24 hours between injections; the High dose groups), one group (n = 10) of DSP4-treated and one group of vehicle-treated mice were administered MPTP (2 x 20 mg/kg, s.c., 24 hours between injections; the Low dose groups), and one group (n = 10) of DSP4-treated and one group of vehicle-treated mice were administered vehicle. Three weeks later, all six groups were tested in motor activity test chambers, followed by injections of L-Dopa (20 mg/kg, s.c.), and then tested over a further 360 min in the activity test chambers. It was found that pretreatment with the selective NA neurotoxin, DSP4, deteriorated markedly the dose-dependent motor activity deficits observed in the vehicle pretreated MPTP treated mice. These 'ultra-deficits' in the spontaneous motor behaviour of MPTP-treated mice were observed over all three parameters: locomotion, rearing and total activity, and were restricted to the 1(st) and 2(nd) 20-min periods. Administration of L-Dopa (20 mg/kg) following the 60-min testing of spontaneous behaviour restored the motor activity of Vehicle + MPTP treated mice (neither the Vehicle + MPTP-Low nor the Vehicle + MPTP-High groups differed from the Vehicle-Vehicle group, here) but failed to do so in the DSP4 pretreated mice. Here, a dose-dependent deficit of L-Dopa-induced motor activity (over all three parameters) was obtained thereby offering further evidence of an 'ultra-deficit' of function due to previous denervation of the NA terminals. The present findings support the notion that severe damage to the locus coeruleus noradrenergic system, through systemic DSP4, disrupts the facilitatory influence on the nigrostriatal DA system, and interferes with the ability of the nigrostriatal pathway to compensate for or recover from marked injury, MPTP treatment.

Direct observation of a self-assembled monolayer of heptyl xanthate at the germanium/water interface: a polarized FTIR study.

The adsorption of heptyl xanthate on germanium has been studied by the attenuated total reflection (ATR) technique. Polarized infrared light was used in situ to determine the average orientation of the alkyl chain in heptyl xanthate adsorbed at the germanium/solution interface. Spectra reveal the formation of closely packed xanthate ions with the alkyl chains in the all-trans conformation. The average tilt angle of the alkyl chains of heptyl xanthate was approximately 47 degrees from the surface normal.