Probing Computation in the Primate Visual System at Single-Cone Resolution.

Daylight vision begins when light activates cone photoreceptors in the retina, creating spatial patterns of neural activity. These cone signals are then combined and processed in downstream neural circuits, ultimately producing visual perception. Recent technical advances have made it possible to deliver visual stimuli to the retina that probe this processing by the visual system at its elementary resolution of individual cones. Physiological recordings from nonhuman primate retinas reveal the spatial organization of cone signals in retinal ganglion cells, including how signals from cones of different types are combined to support both spatial and color vision. Psychophysical experiments with human subjects characterize the visual sensations evoked by stimulating a single cone, including the perception of color. Future combined physiological and psychophysical experiments focusing on probing the elementary visual inputs are likely to clarify how neural processing generates our perception of the visual world.

APPLICATION OF DROPLET DETECTORS TO ALPHA RADIATION DETECTION.

Superheated droplet detectors (SDDs) are traditionally employed in the detection of neutrons. In this work the focus is on the detection of alpha particles using C2ClF5 as the target liquid. The alpha-droplet interaction is examined via computational studies, and a geometric model developed to describe the expected detector response. Experiments with alpha-emitting uranium- and samarium-doped SDDs at temperatures of 5-12°C confirm that the event rate is related to the size of the droplets, and are in model agreement for temperatures below 8°C; above this temperature, the acoustic sensitivity is reduced by signal attenuation as a result of the increasing bubble population, for which the addition of an attenuation coefficient restores the agreement with experiment. The results suggest the viability of a SDD-based alpha spectrometer using mono-sized droplets.

Clinical on-site monitoring of ß-lactam antibiotics for a personalized antibiotherapy.

An appropriate antibiotherapy is crucial for the safety and recovery of patients. Depending on the clinical conditions of patients, the required dose to effectively eradicate an infection may vary. An inadequate dosing not only reduces the efficacy of the antibiotic, but also promotes the emergence of antimicrobial resistances. Therefore, a personalized therapy is of great interest for improved patients' outcome and will reduce in long-term the prevalence of multidrug-resistances. In this context, on-site monitoring of the antibiotic blood concentration is fundamental to facilitate an individual adjustment of the antibiotherapy. Herein, we present a bioinspired approach for the bedside monitoring of free accessible ß-lactam antibiotics, including penicillins (piperacillin) and cephalosporins (cefuroxime and cefazolin) in untreated plasma samples. The introduced system combines a disposable microfluidic chip with a naturally occurring penicillin-binding protein, resulting in a high-performance platform, capable of gauging very low antibiotic concentrations (less than 6 ng ml-1) from only 1 µl of serum. The system's applicability to a personalized antibiotherapy was successfully demonstrated by monitoring the pharmacokinetics of patients, treated with ß-lactam antibiotics, undergoing surgery.

Estimation of 99Mo production rates from natural molybdenum in research reactors.

Molybdenum-99 is one of the most important radionuclides for medical diagnostics. In 2015, the International Atomic Energy Agency organized a round-robin exercise where the participants measured and calculated specific saturation activities achievable for the 98Mo(n,γ)99Mo reaction. This reaction is of interest as a means to locally, and on a small scale, produce 99Mo from natural molybdenum. The current paper summarises a set of experimental results and reviews the methodology for calculating the corresponding saturation activities. Activation by epithermal neutrons and also epithermal neutron self-shielding are found to be of high importance in this case.

Designed miniaturization of microfluidic biosensor platforms using the stop-flow technique.

Here, we present a novel approach to increase the degree of miniaturization as well as the sensitivity of biosensor platforms by the optimization of microfluidic stop-flow techniques independent of the applied detection technique (e.g. electrochemical or optical). The readout of the labeled bioassays, immobilized in a microfluidic channel, under stop-flow conditions leads to a rectangular shaped peak signal. Data evaluation using the peak height allows for a high level miniaturization of the channel geometries. To study the main advantages and limitations of this method by numerical simulations, a universally applicable model system is introduced for the first time. Consequently, proof-of-principle experiments were successfully performed with standard and miniaturized versions of an electrochemical biosensor platform utilizing a repressor protein-based assay for tetracycline antibiotics. Herein, the measured current peak heights are the same despite the sextuple reduction of the channel dimensions. Thus, this results in a 22-fold signal amplification compared to the constant flow measurements in the case of the miniaturized version.

Self-assembled magnetic bead chains for sensitivity enhancement of microfluidic electrochemical biosensor platforms.

In this paper, we present a novel approach to enhance the sensitivity of microfluidic biosensor platforms with self-assembled magnetic bead chains. An adjustable, more than 5-fold sensitivity enhancement is achieved by introducing a magnetic field gradient along a microfluidic channel by means of a soft-magnetic lattice with a 350 µm spacing. The alternating magnetic field induces the self-assembly of the magnetic beads in chains or clusters and thus improves the perfusion and active contact between the analyte and the beads. The soft-magnetic lattices can be applied independent of the channel geometry or chip material to any microfluidic biosensing platform. At the same time, the bead-based approach achieves chip reusability and shortened measurement times. The bead chain properties and the maximum flow velocity for bead retention were validated by optical microscopy in a glass capillary. The magnetic actuation system was successfully validated with a biotin-streptavidin model assay on a low-cost electrochemical microfluidic chip, fabricated by dry-film photoresist technology (DFR). Labelling with glucose oxidase (GOx) permits rapid electrochemical detection of enzymatically produced H2O2.

Surveillance of infant pertussis in Sweden 1998-2012; severity of disease in relation to the national vaccination programme.

In Sweden, pertussis was excluded from the national vaccination programme in 1979 until acellular vaccination was introduced in a highly endemic setting in 1996. The general incidence dropped 10-fold within a decade, less in infants. Infant pertussis reached 40-45 cases per 100,000 in 2008 to 2012; few of these cases were older than five months. We present an observational 15-year study on the severity of infant pertussis based on 1,443 laboratory-confirmed cases prospectively identified from 1998 to 2012 in the national mandatory reporting system and followed up by telephone contact. Analyses were made in relation to age at onset of symptoms and vaccination history. Pertussis decreased in non-vaccinated infants (2003 to 2012, p<0.001), indicating herd immunity, both in those too young to be vaccinated and those older than three months. The hospitalisation rates also decreased (last five-year period vs the previous five-year periods, p <0.001), but 70% of all cases in under three month-old infants and 99% of cases with apnoea due to pertussis were admitted to hospital in 1998 to 2012. Median duration of hospitalisation was seven days for unvaccinated vs four days for vaccinated infants aged 3-5 months. Nine unvaccinated infants died during the study period.

Two geographically separated food-borne outbreaks in Sweden linked by an unusual Cryptosporidium parvum subtype, October 2010.

The number of sporadic cases of Cryptosporidium identified in the Stockholm county area increased above the expected limit during October 2010. Additionally, two food-borne outbreaks of cryptosporidiosis occurred in two other Swedish cities: Umeå (4 October) and Örebro (9 October). The outbreak investigations did not reveal any responsible food item, however fresh herbs were suspected. Thirty stool samples, originating from all three events, tested positive for Cryptosporidium oocysts. Polymerase chain reaction (PCR) and subsequent restriction fragment length polymorphism (RFLP) revealed that 27 individuals were infected with C. parvum, two with C. hominis, and one with C. felis. Using sequence analysis of the GP60 glycoprotein gene, a polymorphic marker with high intra-species diversity, we identified the same C. parvum subtype IIdA24G1 in samples from both the Umeå outbreak and the Stockholm area cases, thus indicating a possible outbreak in the Stockholm area and establishing a link between these two events. C. parvum IIdA24G1 has not previously been described in connection with a food-borne outbreak. For the outbreak in Örebro, another subtype was identified: C. parvum IIdA20G1e. These findings demonstrate that subtyping C. parvum isolates using GP60 gene amplification can be used to link cases in an outbreak investigation and we recommend its use in future similar events.

Final analysis and results of the Phase II SIMPLE dark matter search.

We report the final results of the Phase II SIMPLE measurements, comprising two run stages of 15 superheated droplet detectors each, with the second stage including an improved neutron shielding. The analyses include a refined signal analysis, and revised nucleation efficiency based on a reanalysis of previously reported monochromatic neutron irradiations. The combined results yield a contour minimum of σp=5.7×10(-3) pb at 35 GeV/c2 in the spin-dependent sector of weakly interacting massive particle (WIMP) proton interactions, the most restrictive to date for MW}≤60 GeV/c2 from a direct search experiment and overlapping, for the first time, with results previously obtained only indirectly. In the spin-independent sector, a minimum of 4.7×10(-6) pb at 35 GeV/c2 is achieved, with the exclusion contour challenging a significant part of the light mass WIMP region of current interest.

Optimization of a bolometer detector for ITER based on Pt absorber on SiN membrane.

Any plasma diagnostic in ITER must be able to operate at temperatures in excess of 200 °C and neutron loads corresponding to 0.1 dpa over its lifetime. To achieve this aim for the bolometer diagnostic, a miniaturized metal resistor bolometer detector based on Pt absorbers galvanically deposited on SiN membranes is being developed. The first two generations of detectors featured up to 4.5 µm thick absorbers. Results from laboratory tests are presented characterizing the dependence of their calibration constants under thermal loads up to 450 °C. Several detectors have been tested in ASDEX Upgrade providing reliable data but also pointing out the need for further optimization. A laser trimming procedure has been implemented to reduce the mismatch in meander resistances below 1% for one detector and the thermal drifts from this mismatch.

Genetic variations in the serotonin 5-HT2A receptor gene (HTR2A) are associated with rheumatoid arthritis.

OBJECTIVES: To analyse the association between the genetic polymorphisms within the HTR2A gene for the serotonin receptor and rheumatoid arthritis (RA). METHODS: HTR2A gene polymorphisms were analysed in patients with RA and controls from two study populations using PCR based restriction endonuclease mapping or TaqMan allelic discrimination with more than 4000 individuals included in the current study. RESULTS: At the discovery stage we detected significant differences in frequency of rs6313 (T102C polymorphism) between the patients with RA and controls (p = 0.006). Following validation with an extended set of single nucleotide polymorphisms (SNPs) and number of DNA samples, a trend in associations in allelic model for SNPs rs6314, rs1328674, rs6313 and rs6311 (p = 0.006, 0.002, 0.006, 0.009) was seen, although it was lost after correction for multi-comparison for all but rs1328674 (empirical p value = 0.021). However, haplotype frequency analysis based on these four SNPs showed significantly low representation of TCTT combination in patients with RA in comparison with controls (3.6% and 5.6%, p<0.001 on chi(2) test, empirical p = 0.004 after 100 000 permutations) and a significantly higher frequency of CTCC combination in patients with RA in comparison with controls (3.6% and 2.2%, p = 0.002 on chi(2) test, empirical p = 0.022 after 100 000 permutations). CONCLUSIONS: In our study, genetic polymorphisms at the HTR2A gene are associated with susceptibility for RA, suggesting possible links between the serotonergic system and development of the disease.

Decreased density of serotonin 5-HT2A receptors in rheumatoid arthritis.

BACKGROUND: Animal studies have indicated that 5-HT2A receptors could play a role in arthritic diseases. OBJECTIVE: To analyse the binding properties of 5-HT2A receptors in patients with rheumatoid arthritis. METHODS: Using a radioactive binding assay, 43 patients with rheumatoid arthritis were compared with 49 sex and age matched controls for density and affinity (measured as Bmax and Kd) of 5-HT2A serotonin receptors. Genotyping, using polymerase chain reaction, was undertaken to exclude the possibility that differences in the genetic polymorphism T102C for the 5-HT2A receptor determine differences in receptor density. RESULTS: Mean of Bmax of 5-HT2A receptors in rheumatoid patients was significantly lower than in controls, at 45.3 v 57.4 fmol/mg protein (p = 0.004), but there was no significant difference in Kd. The T102C receptor polymorphism genotypes showed a skewed distribution between the two groups. Even when adjusted for this, there was a significant difference in Bmax between the groups. CONCLUSIONS: The density of 5-HT2A serotonin receptors in patients with rheumatoid arthritis is markedly reduced. This could either reflect a difference involved in the susceptibility to the disease or be a secondary effect of the disease.

Dosimetry at the Portuguese research reactor using thermoluminescence measurements and Monte Carlo calculations.

This work presents an extensive study on Monte Carlo radiation transport simulation and thermoluminescent (TL) dosimetry for characterising mixed radiation fields (neutrons and photons) occurring in nuclear reactors. The feasibility of these methods is investigated for radiation fields at various locations of the Portuguese Research Reactor (RPI). The performance of the approaches developed in this work is compared with dosimetric techniques already existing at RPI. The Monte Carlo MCNP-4C code was used for a detailed modelling of the reactor core, the fast neutron beam and the thermal column of RPI. Simulations using these models allow to reproduce the energy and spatial distributions of the neutron field very well (agreement better than 80%). In the case of the photon field, the agreement improves with decreasing intensity of the component related to fission and activation products. (7)LiF:Mg,Ti, (7)LiF:Mg,Cu,P and Al(2)O(3):Mg,Y TL detectors (TLDs) with low neutron sensitivity are able to determine photon dose and dose profiles with high spatial resolution. On the other hand, (nat)LiF:Mg,Ti TLDs with increased neutron sensitivity show a remarkable loss of sensitivity and a high supralinearity in high-intensity fields hampering their application at nuclear reactors.

Thermoluminescence dosimetry of a thermal neutron field and comparison with Monte Carlo calculations.

The characteristics of thermoluminescence dosemeters (TLDs) regarding the determination of photon and neutron absorbed doses were investigated in a thermal neutron beam. Harshaw TLD-100 (LiF:Mg,Ti) and TLD-700 (7LiF:Mg,Ti) were compared with similar materials from Solid Dosimetric Detector and Method Laboratory (People's Republic of China). Harshaw TLD-700H (7LiF:Mg,Cu,P) and aluminium oxide (Al2O3:Mg,Y) from Hungary were also considered for photon dose measurement. The neutron sensitivity of the investigated materials was measured and found to be consistent with values reported by other authors. A comparison was made between the TL dose measurements and results obtained via conventional methods. An agreement within 20% was obtained, which demonstrates the ability of TLD for measuring neutron and photon doses in a mixed field, using careful calibration procedures and determining the neutron sensitivity for the usage conditions.

Sepsis as a possible adverse drug reaction in patients with rheumatoid arthritis treated with TNFalpha antagonists.

BACKGROUND: Clinical improvement during the treatment of rheumatoid arthritis (RA) with the TNFalpha antagonists has been well documented. Our knowledge of uncommon adverse drug reactions (ADRs) with these new drugs is more restricted. Concerns have been raised that these types of drugs could cause an increased frequency of infections, and already existing infections are named as contraindications in the product labels. METHODS: In Sweden, it is compulsory for healthcare professionals with permission to prescribe drugs to report suspected ADRs to the regulatory authority, the Medical Product Agency (MPA). At the 6 regional centers that are established in Sweden, a preliminary causality assessment is made and the data is transferred online to a database. RESULTS: Between January 1, 1999, and June 30, 2003, 29 cases of sepsis were reported as suspected adverse effects caused by drugs. Seventeen of these cases concerned TNFalpha antagonists. The MPA has received 3 reports of septicemia in patients from Northern Sweden treated with the TNFalpha antagonist etanercept. In submitting these reports, factors that can contribute to susceptibility and to more fatal courses of serious infections are taken into consideration. Demographic and pharmaceutical factors as well as risks from predisposing conditions are discussed in connection with the cases in this report. CONCLUSION: There is a need for more information to physicians to be aware of sepsis as a possible and serious ADR during treatment with TNF antagonists, and that patients with predisposing diseases or those who do not regularly visit their rheumatologist could be at higher risk.

Radionuclide production for therapeutic radiopharmaceuticals.

A fundamental task within the framework of a project searching for new radiopharmaceuticals for systemic therapy was the evaluation of the capabilities of the Portuguese Research Reactor (RPI) for the production of several important radionuclides. The feasibility of producing 64Cu, 77As, 153Sm, 165Dy, 166Ho, 170Tm, 177Lu, 186Re, 199Au and 111Ag in useful quantities was evaluated for the present RPI operation schedule (12 h cycles) and for continuous operation. The main evaluation criteria are expressed in terms of specific activity for continuous irradiation and/or 12 h cycle and the use of natural or enriched targets if necessary. Selected samples were irradiated and a comparison between measured activities and values calculated according to the irradiation schedule and using the same software was performed.

Increased regional cerebral perfusion by 99mTc hexamethyl propylene amine oxime single photon emission computed tomography in post-traumatic stress disorder.

OBJECTIVE: Because of the treatment resistance and chronic affective lability of many post-traumatic stress disorder (PTSD) patients and the hypothesized association of these behaviors with temporal and limbic structures, a study was conducted to determine whether these patients would exhibit alterations in regional cerebral perfusion in the temporal and limbic regions compared with age-matched normal volunteers at rest. METHOD: We studied 17 patients using 99mTc hexamethyl propylene amine oxime single photon emission computed tomography. Seven of the patients were on a selective serotonin reuptake inhibitor, five were on a tricyclic antidepressant, and five were on no medication at the time of the study. Patients were compared with eight age-matched normal controls. RESULTS: All PTSD patients showed a relative increase in regional cerebral perfusion in the anterior and posterior cingulate regions bilaterally, the right temporal and parietal regions, the right caudate/putamen region, and the left orbital and hippocampal regions compared with the control group. When the group of PTSD patients who were free of medication were compared with the control group, increased regional cerebral perfusion was found in the right and left caudate/putamen regions and the right orbital and anterior cingulate cortex bilaterally. CONCLUSIONS: PTSD is associated with increased regional blood flow in limbic areas and the right temporal and parietal cortex compared with age-matched normal volunteers.

Discovery and synthesis of (S)-3-[2-(3,4-dimethoxyphenyl)ethoxy]-2- (4,6-dimethylpyrimidin-2-yloxy)-3,3-diphenylpropionic acid (LU 302872), a novel orally active mixed ET(A)/ET(B) receptor antagonist.

Structural variation of the endothelin A-selective antagonist (S)-3-methoxy-2-(4,6-dimethoxypyrimidin-2-yloxy)-3, 3-diphenylpropionic acid (LU 135252) led to analogues which retain ET(A) affinity but exhibit substantial ET(B) affinity as well. The most active derivative obtained is (S)-3-[2-(3, 4-dimethoxyphenyl)ethoxy]-2-(4,6-dimethylpyrimidin-2-yloxy)- 3, 3-diphenylpropionic acid (LU 302872), which can be prepared in enantiomerically pure form in eight steps via an acid-catalyzed transetherification. It has a K(i) = 2.15 nM for binding to the ET(A) receptor and a K(i) = 4.75 nM for binding to the ET(B) receptor, is orally available, and antagonizes the big ET-induced blood pressure increase in rats and the big ET-induced bronchospasm in guinea pigs each time at a dose of 10 mg/kg.