The state of the art in beyond 5G distributed massive multiple-input multiple-output communication system solutions.

Beyond fifth generation (5G) communication systems aim towards data rates in the tera bits per second range, with improved and flexible coverage options, introducing many new technological challenges in the fields of network architecture, signal pro- cessing, and radio frequency front-ends. One option is to move towards cell-free, or distributed massive Multiple-Input Multiple-Output (MIMO) network architectures and highly integrated front-end solutions. This paper presents an outlook on be- yond 5G distributed massive MIMO communication systems, the signal processing, characterisation and simulation challenges, and an overview of the state of the art in millimetre wave antennas and electronics.

Nighttime pasture access: Comparing the effect of production pasture and exercise paddock on milk production and cow behavior in an automatic milking system.

With increasing intensification of the dairy sector in many countries and with the introduction of automatic milking, exercise paddocks combined with full indoor feeding, as an alternative to production pasture, are being used as a compromise between farm economics and cow welfare. This study examined whether there are production benefits for high-producing dairy cows in an alternative system that uses pasture at a level of approximately 50% of the total roughage intake in the diet. In an automatic milking system with 12-h night access to the outdoor environment, we compared milk production and behavior of cows in 2 systems: an exercise paddock combined with ad libitum grass silage indoor feeding and a production pasture combined with a restricted daytime grass silage ration. There were 20 cows in the former and 21 cows in the latter system, with the treatments running in parallel. The experiment started in late June with no complete darkness during the night, and lasted for 12 wk, with 5.6 h of darkness at the end. We therefore also explored the effect of night length on milk production and behavior parameters. All cows showed strong motivation for going outdoors and grazing when pasture access was given in early evening, but after a few hours both groups went to the barn and did not return to the pasture area during the remaining night. As the season progressed and nights became longer, cows on the exercise paddock treatment reduced time spent outdoors and grazing time, whereas they increased time spent resting outdoors. The group on exercise paddock had a greater milk yield (kg of milk) over the experimental period than the production pasture group. The latter group also showed a greater drop in milk yield over the duration of the trial. Thus, for cows milked in an automatic milking system and offered nighttime outdoor access, no milk production benefits were observed in offering production pasture with restricted indoor silage allowance instead of an exercise paddock with ad libitum silage. We therefore suggest that automatic milking farmers with similar production levels and automatic milking-management systems as in the present experiment, who wish to include grazed grass as part of the dairy cow diet, should ensure that cows have pasture access in the afternoon and evening.

The effects of high-sugar ryegrass/red clover silage diets on intake, production, digestibility, and N utilization in dairy cows, as measured in vivo and predicted by the NorFor model.

Grass silage-based diets often result in poor nitrogen utilization when fed to dairy cows. Perennial ryegrass cultivars with high concentrations of water-soluble carbohydrates (WSC) have proven potential for correcting this imbalance when fed fresh, and have also been shown to increase feed intake, milk production, and N utilization. The possibility of achieving corresponding effects with silage-based diets was investigated in change-over experiments in an incomplete block design with 16 (yr 1) or 12 (yr 2) Swedish Red dairy cows in mid lactation. Measurements on N excretion and rumen parameters were performed on subgroups of 8 and 4 cows, respectively. In yr 1, 2 ryegrass cultivars (standard = Fennema; high-WSC = Aberdart) and 2 cuts (first and second) were compared. In all treatments, ryegrass silage was mixed 75/25 on a dry matter (DM) basis, with red clover silage before feeding out. In yr 2, 1 basic mixture from the different cuts of these 2 cultivars was used and experimental factors were red clover silage inclusion (25 or 50%) and sucrose addition (0 or 10%) on a silage DM basis. Differences in WSC concentration in the silage mixtures in yr 1 were minor, whereas the differences between cuts were more substantial: 100 compared with 111 g/kg of DM for first-cut silage and 39 compared with 47 g/kg of DM for second-cut silage. The silages fed in yr 2 had a WSC concentration of 115 or 102 g/kg of DM (25 or 50% red clover, respectively), but when sucrose was added WSC concentration reached 198 and 189 g/kg of DM, respectively. Milk production (kg/d) did not differ between treatments in either year. Red clover inclusion to 50% of silage DM increased milk protein. Nitrogen efficiency (milk N/feed N) increased from 0.231 to 0.254 with sucrose inclusion in yr 2 (average for the 2 red clover levels). Overall rumen pH was 5.99 and increased sucrose level did not affect pH level or daily pH pattern. Sucrose addition reduced neutral detergent fiber digestibility, particularly at higher inclusion rates of clover. Rumen pool of total purines did not differ between treatments, nor did protein production assessed from urinary allantoin. The NorFor feed evaluation model overestimated digestibility of neutral detergent fiber and N, but underestimated N excretion in feces. We concluded that addition of WSC to dairy cow diets at levels up to 3 kg of WSC per day (>14% of DM) does not dramatically affect cow performance.

Experimental and simulation characterisation of flexural vibration modes in unimorph ultrasound transducers.

A unimorph flexural transducer design is proposed and tested with regard to mode shapes and frequencies. The transducers consist of a passive metal cap structure, and a thin piezoelectric disc, rigidly bonded to the inside. Extensive finite element (FE) modelling, and experimental 2D, time-resolved displacement measurements were done to characterise the transducers flexural properties, and to compare them to the analytical solutions of thin vibrating plates. Emphasis was put on characterising the passive layer of the unimorph structure, before bonding the piezoelectric element, to understand how the active element affects the behaviour of the flexing plate. A high power Nd:YAG laser was used to actuate the metal plate (non-contact), and the frequency content of the resulting displacement signal was analysed to identify the flexural modes. The non-axisymmetric modes, which are conventionally disregarded because of their unfavourable acoustic properties, were also taken into account. There was excellent agreement between the experimental results and the FE simulation data. There was good agreement with the analytical edge clamped plate model, but with some notable deviations, which have not previously been identified or commented upon. Specifically, the second axisymmetric mode is split into three separate modes, which is not explained by the traditional theory of vibrating plates.

PET/CT-guided treatment planning for paediatric cancer patients: a simulation study of proton and conventional photon therapy.

OBJECTIVE: To investigate the impact of including fluorine-18 fludeoxyglucose ((18)F-FDG) positron emission tomography (PET) scanning in the planning of paediatric radiotherapy (RT). METHODS: Target volumes were first delineated without and subsequently re-delineated with access to (18)F-FDG PET scan information, on duplicate CT sets. RT plans were generated for three-dimensional conformal photon RT (3DCRT) and intensity-modulated proton therapy (IMPT). The results were evaluated by comparison of target volumes, target dose coverage parameters, normal tissue complication probability (NTCP) and estimated risk of secondary cancer (SC). RESULTS: Considerable deviations between CT- and PET/CT-guided target volumes were seen in 3 out of the 11 patients studied. However, averaging over the whole cohort, CT or PET/CT guidance introduced no significant difference in the shape or size of the target volumes, target dose coverage, irradiated volumes, estimated NTCP or SC risk, neither for IMPT nor 3DCRT. CONCLUSION: Our results imply that the inclusion of PET/CT scans in the RT planning process could have considerable impact for individual patients. There were no general trends of increasing or decreasing irradiated volumes, suggesting that the long-term morbidity of RT in childhood would on average remain largely unaffected. ADVANCES IN KNOWLEDGE: (18)F-FDG PET-based RT planning does not systematically change NTCP or SC risk for paediatric cancer patients compared with CT only. 3 out of 11 patients had a distinct change of target volumes when PET-guided planning was introduced. Dice and mismatch metrics are not sufficient to assess the consequences of target volume differences in the context of RT.

Effects on milk urea concentration, urine output, and drinking water intake from incremental doses of potassium bicarbonate fed to mid-lactation dairy cows.

Large variation exists in the potassium content of dairy cow feeds and also within a feed type due to soil type and fertilization. Increased ration K concentration causes a subsequent increase in urinary volume and could be expected to also lower milk urea concentration. Six multiparous mid-lactation Swedish Red dairy cows, all fitted with rumen cannulas, were subjected to 3 different levels of K intake in a Latin square experiment with three 2-wk periods to evaluate the effects on concentrations of milk urea and rumen ammonia, urinary output, and drinking water intake. The treatments were achieved by K supplementation on top of a low-K basal ration fed at individual allowances fixed throughout the experiment. The basal ration, consumed at 20.2 kg of dry matter (DM)/d, provided 165 g of crude protein/kg of DM and consisted of grass silage, concentrates, and urea in the proportions 39.3:60.0:0.7 on a DM basis. Potassium bicarbonate supplementation was 0, 616, and 1,142 g/d, respectively, to give total ration K concentrations that were low (LO; 12 g/kg of DM), medium (MED; 23 g/kg of DM), or high (HI; 32 g/kg of DM). Production and composition of milk was not affected by treatment. A linear effect on milk urea concentration was detected, being 4.48, 4.18, and 3.77 mM for LO, MED, and HI, respectively, and a linear tendency for rumen ammonia concentration with 6.65, 6.51, and 5.84 mg of NH3-N/dL for LO, MED, and HI, respectively. Milk urea concentration peaked about 3h after the rumen ammonia peak from the morning feeding, at a level 1.3mM over the baseline. Urinary urea excretion declined linearly (105, 103, and 98 g of urea-N/d for LO, MED, and HI, respectively). Linear increases occurred in urinary output (0.058 ± 0.001 kg of urine/g of K intake; no intercept; coefficient of determination=0.997) and drinking water intake (65.9 ± 2.02 + 0.069 ± 0.004 kg of water/g of K intake; coefficient of determination=0.95). Urinary K concentration leveled off at 12.4 g/L. Urinary creatinine excretion was not affected by K addition, but allantoin excretion increased linearly by 27% from LO to HI, suggesting increased rumen microbial growth. Rumen pH, acetate proportion of total volatile fatty acids, and digestibility of DM, organic matter, and neutral detergent fiber increased linearly with increasing potassium intake. We concluded that increased ration K concentration lowers milk urea concentration with a magnitude significant for the interpretation of milk urea values, but other sources of variation, such as sampling time relative to feeding, may be even more important.

Inhibition of sodium-linked glucose reabsorption normalizes diabetes-induced glomerular hyperfiltration in conscious adenosine A1-receptor deficient mice.

AIM: Glomerular hyperfiltration is commonly observed in diabetics early after the onset of the disease and predicts the progression of nephropathy. Sustained hyperglycaemia is also closely associated with kidney hypertrophy and increased electrolyte and glucose reabsorption in the proximal tubule. In this study, we investigated the role of the increased tubular sodium/glucose cotransport for diabetes-induced glomerular hyperfiltration. To eliminate any potential confounding effect of the tubuloglomerular feedback (TGF) mechanism, we used adenosine A1-receptor deficient (A1AR(-/-)) mice known to lack a functional TGF mechanism and compared the results to corresponding wild-type animals (A1AR(+/+)). METHODS: Diabetes was induced by an intravenous bolus injection of alloxan. Glomerular filtration rate (GFR) was determined in conscious mice by a single bolus injection of inulin. The sodium/glucose cotransporters were inhibited by phlorizin 30 min prior to GFR measurements. RESULTS: Normoglycaemic animals had a similar GFR independent of genotype (A1AR(+/+) 233 ± 11 vs. A1AR(-/-) 241 ± 25 µL min(-1)), and induction of diabetes resulted in glomerular hyperfiltration in both groups (A1AR(+/+) 380 ± 25 vs. A1AR(-/-) 336 ± 35 µL min(-1); both P < 0.05). Phlorizin had no effect on GFR in normoglycaemic mice, whereas it reduced GFR in both genotypes during diabetes (A1AR(+/+) 365 ± 18 to 295 ± 19, A1AR(-/-) 354 ± 38 to 199 ± 15 µL min(-1); both P < 0.05). Notably, the reduction was more pronounced in the A1AR(-/-) (P < 0.05). CONCLUSION: This study demonstrates that increased tubular sodium/glucose reabsorption is important for diabetes-induced hyperfiltration, and that the TGF mechanism is not involved in these alterations, but rather functions to reduce any deviations from a new set-point.

Modulation formats for multi-core fiber transmission.

We investigate high dimensional modulation formats for multi-core fibers (MCFs) and spatial superchannels. We show that the low skew variations between MCF cores maybe exploited to generate 'multi-core' formats that offer significant advantages over independently transmitting conventional 4-dimensional formats in each core. We describe how pulse position modulation formats may be transposed to the spatial domain and then investigate a family of modulation formats referred to as core-coding, one of which has the same power and spectral efficiency as polarization switched quaternary phase shift keying but with half of the optical power, potentially improving non-linear tolerance for long distance transmission, albeit at the cost of implementation challenges. Finally, we investigate the application of set-partitioning to multi-core formats using a single-parity check bit transmitted in one quadrature of one polarization in one of the cores and polarization-division multiplexing quadrature phase shift keying data in all remaining cores. We observe that for high core counts, an advantage of almost 3 dB in asymptotic power efficiency may be obtained with negligible impact on spectral efficiency, which translates into experimentally measured reduction in the required optical signal-to-noise ratio of up to 1.8 dB at a bit-error-rate of 10-5 and the same data-rate, and additional transmission reach of up to 20%.

Predictive value of modelled tumour control probability based on individual measurements of in vitro radiosensitivity and potential doubling time.

OBJECTIVE: The aim of this study was to compare patient-specific radiobiological parameters with population averages in predicting the clinical outcome after radiotherapy (RT) using a tumour control probability (TCP) model based on the biological effective dose (BED). METHODS: A previously published study of 46 head and neck carcinomas with individually identified radiobiological parameters, radiosensitivity and potential doubling time (Tpot), and known tumour size was investigated. These patients had all been treated with external beam RT, and the majority had also received brachytherapy. The TCP for each individual based on the BED using patient-specific radiobiological parameters was compared with the TCP based on the BED using average radiobiological parameters (α=0.3 Gy(-1), Tpot=3 days). RESULTS: 43 patients remained in the final analysis. There was only a weak trend for increasing local tumour control with increasing BED in both groups. However, when the TCP was calculated, the use of patient-specific parameters was better for identifying local control correctly. The sensitivity and specificity for tumour-specific parameters were 63% and 80%, respectively. The corresponding values for population-based averages were 0% and 91%, respectively. The positive predictive value was 92% when tumour-specific parameters were used compared with 0% for population-based averages. A receiver operating characteristic curve confirmed the superiority of patient-specific parameters over population averages in predicting local control. CONCLUSION: Individual radiobiological parameters are better than population-derived averages when used in a mathematical model to predict TCP after curative RT in head and neck carcinomas. ADVANCES IN KNOWLEDGE: TCP based on individual radiobiological parameters is better than TCP based on population-based averages for identifying local control correctly.

Bidirectional regulation of emotional memory by 5-HT1B receptors involves hippocampal p11.

Cognitive impairments are common in depression and involve dysfunctional serotonin neurotransmission. The 5-HT1B receptor (5-HT(1B)R) regulates serotonin transmission, via presynaptic receptors, but can also affect transmitter release at heterosynaptic sites. This study aimed at investigating the roles of the 5-HT(1B)R, and its adapter protein p11, in emotional memory and object recognition memory processes by the use of p11 knockout (p11KO) mice, a genetic model for aspects of depression-related states. 5-HT(1B)R agonist treatment induced an impairing effect on emotional memory in wild type (WT) mice. In comparison, p11KO mice displayed reduced long-term emotional memory performance. Unexpectedly, 5-HT(1B)R agonist stimulation enhanced memory in p11KO mice, and this atypical switch was reversed after hippocampal adeno-associated virus mediated gene transfer of p11. Notably, 5-HT(1B)R stimulation increased glutamatergic neurotransmission in the hippocampus in p11KO mice, but not in WT mice, as measured by both pre- and postsynaptic criteria. Magnetic resonance spectroscopy demonstrated global hippocampal reductions of inhibitory GABA, which may contribute to the memory enhancement and potentiation of pre- and post-synaptic measures of glutamate transmission by a 5-HT(1B)R agonist in p11KO mice. It is concluded that the level of hippocampal p11 determines the directionality of 5-HT(1B)R action on emotional memory processing and modulates hippocampal functionality. These results emphasize the importance of using relevant disease models when evaluating the role of serotonin neurotransmission in cognitive deficits related to psychiatric disorders.

Clinical implementation of systematic medication reconciliation and review as part of the Lund Integrated Medicines Management model--impact on all-cause emergency department revisits.

WHAT IS KNOWN AND OBJECTIVE: Interventions involving medication reconciliation and review by clinical pharmacists can reduce drug-related problems and improve therapeutic outcomes. The objective of this study was to examine the impact of routine admission medication reconciliation and inpatient medication review on emergency department (ED) revisits after discharge. Secondary outcomes included the combined rate of post-discharge hospital revisits or death. METHODS: This prospective, controlled study included all patients hospitalized in three internal medicine wards in a university hospital, between 1 January 2006 and 31 May 2008. Medication reconciliation on admission and inpatient medication review, conducted by clinical pharmacists in a multiprofessional team, were implemented in these wards at different times during 2007 and 2008 (intervention periods). A discharge medication reconciliation was undertaken in all the study wards, during both control and intervention periods. Patients were included in the intervention group (n = 1216) if they attended a ward with medication reconciliation and review, whether they had received the intervention or not. Control patients (n = 2758) attended the wards before implementation of the intervention. RESULTS AND DISCUSSION: No impact of medication reconciliation and reviews on ED revisits [hazard ratio (HR), 0.95; 95% confidence interval (CI), 0.86-1.04]or event-free survival (HR, 0.96; 95% CI, 0.88-1.04) was demonstrated. In the intervention group, 594 patients (48.8%) visited the ED, compared with 1416 (51.3%) control patients. In total, 716 intervention (58.9%) and 1688 (61.2%) control patients experienced any event (ED visit, hospitalization or death). Because the time to a subsequent ED visit was longer for the control as well as the intervention groups in 2007 than in 2006 (P < 0.05), we re-examined this cohort of patients; the proportion of patients revisiting the ED was similar in both groups in 2007 (P = 0.608). WHAT IS NEW AND CONCLUSION: Routine implementation of medication reconciliation and reviews on admission and during the hospital stay did not appear to have any impact on ED revisits, re-hospitalizations or mortality over 6-month follow-up.

High beam current operation of a PETtrace™ cyclotron for 18F- production.

Upgrades and optimisation achieved 160 µA total target current operation of a GE PETtrace cyclotron in dual target mode for the routine production of [(18)F]FDG for >2 years. Approximately 900 GBq of (18)F(-) and >500 GBq of [(18)F]FDG can be produced routinely in a single production run, meeting the routine [(18)F]FDG requirements with our customer base and achieving economies of scale. Production of >1 TBq of (18)F(-) in a single run was achieved. Reliability, saturation and synthesis yields were not adversely affected.

L10 FePtCu bit patterned media.

Chemically ordered 5 nm-thick L10 FePtCu films with strong perpendicular magnetic anisotropy were post-patterned by nanoimprint lithography into a dot array over a 3 mm-wide circumferential band on a 3 inch Si wafer. The dots with a diameter of 30 nm and a center-to-center pitch of 60 nm appear as single domain and reveal an enhanced switching field as compared to the continuous film. We demonstrate successful recording on a single track using shingled writing with a conventional hard disk drive write/read head.

Emotional memory impairments in a genetic rat model of depression: involvement of 5-HT/MEK/Arc signaling in restoration.

Cognitive dysfunctions are common in major depressive disorder, but have been difficult to recapitulate in animal models. This study shows that Flinders sensitive line (FSL) rats, a genetic rat model of depression, display a pronounced impairment of emotional memory function in the passive avoidance (PA) task, accompanied by reduced transcription of Arc in prefrontal cortex and hippocampus. At the cellular level, FSL rats have selective reductions in levels of NMDA receptor subunits, serotonin 5-HT(1A) receptors and MEK activity. Treatment with chronic escitalopram, but not with an antidepressant regimen of nortriptyline, restored memory performance and increased Arc transcription in FSL rats. Multiple pharmacological manipulations demonstrated that procognitive effects could also be achieved by either disinhibition of 5-HT(1A)R/MEK/Arc or stimulation of 5-HT4R/MEK/Arc signaling cascades. Taken together, studies of FSL rats in the PA task revealed reversible deficits in emotional memory processing, providing a potential model with predictive and construct validity for assessments of procognitive actions of antidepressant drug therapies.

Multiple strategies for quality improvement and patient safety--money alone is not the answer, nor is trust. Conclusions of the 6th EQuiP Invitational Conference April 2011.

On 7-9 April 2011 the 6th EQuiP Invitational Conference took place in Copenhagen. Key note lectures were delivered by Professor Frede Olesen (Denmark), Professor Andreas Christian Soennichsen (Austria), Professor Martin Roland (UK) and Professor Richard Roberts (US), and a key note panel discussion was held on the pros and cons of pay-for-performance led by Doctors Iona Heath (UK) and José Braspenning (The Netherlands). In addition, there were 9 workshops and 23 oral presentations. Videos of many presentations as well as PowerPoint and other materials can be found at EQuiP's website: http://www.equip.ch .

Molecular phylogenetics of Alchemilla, Aphanes and Lachemilla (Rosaceae) inferred from plastid and nuclear intron and spacer DNA sequences, with comments on generic classification.

Alchemilla (the lady's mantles) is a well known but inconspicuous group in the Rosaceae, notable for its ornamental leaves and pharmaceutical properties. The systematics of Alchemilla has remained poorly understood, most likely due to confusion resulting from apomixis, polyploidisation and hybridisation, which are frequently observed in the group, and which have led to the description of a large number of (micro-) species. A molecular phylogeny of the genus, including all sections of Alchemilla and Lachemilla as well as five representatives of Aphanes, based on the analysis of the chloroplast trnL-trnF and the nuclear ITS regions is presented here. Gene phylogenies reconstructed from the nuclear and chloroplast sequence data were largely congruent. Limited conflict between the data partitions was observed with respect to a small number of taxa. This is likely to be the result of hybridisation/introgression or incomplete lineage sorting. Four distinct clades were resolved, corresponding to major geographical division and life forms: Eurasian Alchemilla, annual Aphanes, South American Lachemilla and African Alchemilla. We argue for a wider circumscription of the genus Alchemilla, including Lachemilla and Aphanes, based on the morphology and the phylogenetic relationships between the different clades.

Superiority of intensity-modulated radiotherapy over three-dimensional conformal radiotherapy combined with brachytherapy in nasopharyngeal carcinoma: a planning study.

A planning study was performed in order to investigate the potential benefits of intensity-modulated radiotherapy using a simultaneous integrated multi-target treatment technique (SIMT-IMRT) over highly optimized three-dimensional conformal radiotherapy combined with intracavitary brachytherapy (3D-CRT + IBT) for the treatment of nasopharyngeal carcinoma (NPC). The subjects were eight patients with Stages I-IV NPC. For each case, two sets of plans were prepared after delineation of gross tumour volumes, three planning target volumes (PTVs) and 17 organs at risk (OARs). Dose prescriptions for PTVs were 72.6 Gy, 66 Gy and 52.8 Gy in 33 fractions for SIMT-IMRT vs 72 Gy (66 Gy in 33 fractions for 3D-CRT and 3 Gy twice for IBT), 66 Gy (in 33 fractions) and 46 Gy (in 23 fractions) for 3D-CRT + IBT plans. Compared with the combined plans, SIMT-IMRT provided superior results for the primary tumour (PT) in terms of mean equivalent uniform dose (67 Gy vs 63.7 Gy, p = 0.016). IMRT plans increased the mean tumour control probability (TCP) values (both uncorrected and corrected for accelerated tumour repopulation after 28 days) for PT when compared with 3D-CRT + IBT (98% and 94.3% vs 95.8% and 89.9%, respectively, p = 0.016). Mean doses to middle/external ears, parotid glands and temporomandibular joints were significantly lower in IMRT plans. Our conclusion is that, for all stages of NPC, SIMT-IMRT was superior to highly optimized 3D-CRT + IBT in terms of tumour coverage, increased local TCP, and dose reduction to some OARs. We recommend that SIMT-IMRT should be considered as a first-line radiotherapy technique for NPC.

TIARA: treatment initiatives after radiological accidents.

This paper describes the objectives, and reviews the progress, of the European project 'Treatment Initiatives After Radiological Accidents' (TIARA). TIARA forms part of the 'Preparatory Action for Security Research' (PASR) launched by the European Commission in 2004. The Preparatory Action is intended to reach preliminary conclusions on the needs for the security of EU citizens. It prepared a comprehensive Security Research Programme as part of the Commission's Seventh Framework Programme proposal, which was adopted in 2006 and launched in 2007. The principal purpose of TIARA is to constitute a European network that will participate in facilitating the management of a crisis in the event of the malevolent dispersal of radionuclides into the public environment.

Retinal function and histopathology in rabbits treated with Topiramate.

PURPOSE: To evaluate retinal function and histopathology in rabbits treated orally with the anti-epileptic drug topiramate. METHODS: Six rabbits were treated with a daily oral dose of topiramate during a period of eight months. Six rabbits receiving water served as controls. Blood samples were analyzed for determination of topiramate serum levels in order to ensure successful drug exposition. Standardized full-field electroretinograms (ERGs) were performed before treatment and then at 2, 3 and 8 months during the treatment period. After terminating treatment the rabbits were sacrificed and the morphology of the sectioned retina was studied. RESULTS: After eight months of treatment the full-field ERG demonstrated normal rod function in treated and control rabbits, but the light adapted 30 Hz flicker b-wave amplitude was significantly reduced in the treated rabbits. This was the case for both the light adapted (Wilcoxon signed ranks test, P = 0.046) and the dark adapted (Wilcoxon signed ranks test, P = 0.028) 30 Hz flicker response from the treated rabbits. Retinal immunohistology revealed a severe accumulation of GABA in amacrine cells and in the inner plexiform layer in 4 of 6 treated rabbits compared to the controls. CONCLUSIONS: Topiramate, orally administrated to rabbits, may cause a significant reduction of the retinal function demonstrated by the reduced b-wave amplitude in the full-field ERG, as well as changes in immunohistology characterized by a severe accumulation of GABA in the inner retina. The retinal dysfunction and the morphological changes indicate that topiramat may damage the retina, similarly to vigabatrin (another anti-epileptic drug).

N-methyl-D-aspartate receptors in the medial septal area have a role in spatial and emotional learning in the rat.

Cholinergic and GABAergic neurons in the medial septal/vertical limb of the diagonal band of Broca (MS/vDB) area project to the hippocampus and constitute the septohippocampal pathway, which has been implicated in learning and memory. There is also evidence for extrinsic and intrinsic glutamatergic neurons in the MS/vDB, which by regulating septohippocampal neurons can influence hippocampal functions. The potential role of glutamatergic N-methyl-D-aspartate (NMDA) receptors within the MS/vDB for spatial and emotional learning was studied using the water maze and step-through passive avoidance (PA) tasks, which are both hippocampal-dependent. Blockade of septal NMDA receptors by infusion of the competitive NMDA receptor antagonist D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5) (0.3-5 microg/rat), infused 15 min prior to training, impaired spatial learning and memory at the 5 microg dose of D-AP5, while doses of 0.3 and 1 microg per rat had no effect. The impairment in spatial learning appears not to be caused by sensorimotor or motivational disturbances, or anxiogenic-like behavior. Thus, d-AP5-treated rats were not impaired in swim performance or visuospatial abilities and spent more time in the open arms of the elevated plus-maze. In the PA task, intraseptal D-AP5 infused 15 min before training impaired retention as examined 24 h after training. This impairment was observed already at the 0.3 microg dose, suggesting that NMDA receptors within the MS/vDB may be more important for emotional than spatial memory. In summary, the present data indicate that changes in septal glutamate transmission and NMDA receptor activity can influence activity-dependent synaptic plasticity in the hippocampus and thereby learning and memory.