Patients as researchers - innovative experiences in UK National Health Service research

Consumer involvement is an established priority in UK health and social care service development and research. To date, little has been published describing the process of consumer involvement and assessing ‘consumers’ contributions to research. This paper provides a practical account of the effective incorporation of consumers into a research team, and outlines the extent to which they can enhance the research cycle; from project development and conduct, through data analysis and interpretation, to dissemination. Salient points are illustrated using the example of their collaboration in a research project. Of particular note were consumers’ contributions to the development of an ethically enhanced, more robust project design, and enriched data interpretation, which may not have resulted had consumers not been an integral part of the research team

Overview and status of the 0.5NA EUV microfield exposure tool at Berkeley Lab

A 0.5-NA extreme ultraviolet micro-field exposure tool has been installed and commissioned at beamline 12.0.1.4 of the Advanced Light Source synchrotron facility at Lawrence Berkeley National Laboratory. Commissioning has demonstrated a patterning resolution of 13 nm half-pitch with annular 0.35-0.55 illumination; a patterning resolution of 8 nm half-pitch with annular 0.1-0.2 illumination; critical dimension (CD) uniformity of 0.7 nm 1σ on 16 nm nominal CD across 80% of the 200 um x 30 um aberration corrected field of view; aerial image vibration relative to the wafer of 0.75 nn RMS and focus control and focus stepping better than 15 nm

Lateral mobility of L-type calcium channels in synaptic terminals of retinal bipolar cells.

PURPOSE: Efficient and precise release of glutamate from retinal bipolar cells is ensured by the positioning of L-type Ca(2+) channels close to release sites at the base of the synaptic ribbon. We investigated whether Ca(2+) channels at bipolar cell ribbon synapses are fixed in position or capable of moving in the membrane. METHODS: We tracked the movements of individual L-type Ca(2+) channels in bipolar cell terminals after labeling channels with quantum dots (QDs) attached to α(2)δ(4) accessory Ca(2+) channel subunits via intermediary antibodies. RESULTS: We found that individual Ca(2+) channels moved within a confined domain of 0.13-0.15 μm(2) in bipolar cell terminals, similar to ultrastructural estimates of the surface area of the active zone beneath the ribbon. Disruption of actin expanded the confinement domain indicating that cytoskeletal interactions help to confine channels at the synapse, but the relatively large diffusion coefficients of 0.3-0.45 μm(2)/s suggest that channels are not directly anchored to actin. Unlike photoreceptor synapses, removing membrane cholesterol did not change domain size, indicating that lipid rafts are not required to confine Ca(2+) channels at bipolar cell ribbon synapses. CONCLUSIONS: The ability of Ca(2+) channels to move within the presynaptic active zone suggests that regulating channel mobility may affect release from bipolar cell terminals

Achieving diffraction-limited performance on the Berkeley MET5

The Berkeley MET5, funded by EUREKA, is a 0.5-NA EUV projection lithography tool located at the Advanced Light Source at Berkeley National Lab. Wavefront measurements of the MET5 optic have been performed using a custom in-situ lateral shearing interferometer suitable for high-NA interferometry. In this paper, we report on the most recent characterization of the MET5 optic demonstrating an RMS wavefront 0.31 nm, and discuss the specialized mask patterns, gratings, and illumination geometries that were employed to accommodate the many challenges associated with high-NA EUV interferometry

The effect of an emollient containing urea, ceramide NP, and lactate on skin barrier structure and function in older people with dry skin

Xerosis affects up to 75% of older people and develops as a result of a skin barrier defect. Emollients are widely used to treat xerosis; however, there is limited understanding of the differences between them and their effects on the skin barrier in older people. This study aimed to compare the effect of a commercially available emollient containing 5% urea, ceramide NP and lactate (test emollient) to an alternative emollient without these additives (control emollient) on the properties of the skin barrier in older people. Two cohorts of 21 volunteers aged 60+ years with dry skin were recruited. The first applied the test emollient to one forearm and no treatment to the other for 28-days. The second compared the test emollient to the control emollient observing the same parameters. Effects on the skin barrier were determined by measuring skin barrier function, hydration, skin surface pH and by analyzing FTIR spectra before and after treatment. A third cohort of 6 young adults was recruited to investigate the effect of a single treatment with the test emollient on the molecular structure of the skin barrier at greater depths by employing the tape-stripping technique. The test emollient hydrated the skin to a significantly greater extent and for a longer period of time compared to the control emollient, an effect associated with a significant elevation of carboxylate groups (a marker of NMF content) within the stratum corneum. Furthermore, the test emollient imparted additional benefits to the structure and function of the skin barrier not exhibited by the control emollient. In conclusion the test emollient addressed the pathological features of xerotic aged skin, supporting its use as first-line therapy for xerotic skin conditions in this population

Modern therapies in atopic dermatitis: biologics and small molecule drugs

Atopic dermatitis (AD) is a frequent, chronic remittent skin disease. The pathophysiology of AD has been increasingly understood within the last years, which may help to identify different endotypes suitable for defined therapies in the future. A patient-oriented therapy considers phenotypical features in addition to genetic and biological markers. The most recent developments in biologics and small-molecule drugs for AD treatment are presented in this article. These molecules, if approved, could change the perspectives for future therapies. Dupilumab is the first approved biologic for the treatment of moderate to severe atopic dermatitis in adolescence and adulthood and has led to a significant improvement in the treatment of this chronic disease. In the present article we present real-life data on the efficacy of dupilumab in adult dermatitis patients. We also discuss other data relevant to the use of dupilumab, and address open questions important for the standard care of atopic dermatitis patients

Social Deprivation of Infant Rhesus Monkeys Alters the Chemoarchitecture of the Brain: I. Subcortical Regions

Rhesus monkeys (Macaca mulatta) reared during the first year of life without social contact develop persistent stereotyped movements, self-directed behaviors, and psychosocial abnormalities, but neurobiological mechanisms underlying the behaviors of socially deprived (SD) monkeys are unknown. Monkeys were reared in total social deprivation for the first 9 months of life; control monkeys were reared socially (SR) with mothers and peers. Subjects were killed at 19-24 yr of age. Because the behaviors of SD monkeys are reminiscent of changes in striatal or amygdalar function, we used immunocytochemistry for substance P (SP), leutine-enkephalin (LENK), somatostatin, calbindin, and tyrosine hydroxylase (TH) to evaluate qualitatively and quantitatively patterns of neurotransmitter marker immunoreactivity within subcortical regions. In SD monkeys, the chemoarchitecture of the striatum was altered. Neuronal cell bodies and processes immunoreactive for SP and LENK were depleted markedly in patch (striosome) and matrix regions of the caudate nucleus and putamen; the average density of SP-immunoreactive neurons was reduced 58% relative to SR monkeys. Calbindin and TH immunoreactivities were diminished in the matrix of caudate and putamen of SD monkeys. TH-immunoreactive neurons, but not cresyl violet-stained neurons, in the substantia nigra pars compacta were decreased (43%) in SD monkeys. Peptide-immunoreactive terminals were reduced in the globus pallidus and substantia nigra in SD monkeys. The nucleus accumbens was the least affected of striatal regions. Striatal somatostatin immunoreactivity was qualitatively and quantitatively similar in SD and SR monkeys. Several regions, for example, bed nucleus of the stria terminalis, amygdala, and basal forebrain magnocellular complex, that were in the same sections and are enriched in these markers did not appear altered in SD monkeys, suggesting a regional specificity for vulnerability. The altered chemoarchitecture of some basal ganglia regions in adult monkeys that experienced social deprivation as infants suggests that the postnatal maturation of neurotransmitter phenotypes in some structures is influenced by social environment. Abnormal motor and psychosocial behaviors resulting from this form of social/sensory deprivation may result from alterations in peptidergic and dopaminergic systems within the basal ganglia

Calmodulin enhances ribbon replenishment and shapes filtering of synaptic transmission by cone photoreceptors.

At the first synapse in the vertebrate visual pathway, light-evoked changes in photoreceptor membrane potential alter the rate of glutamate release onto second-order retinal neurons. This process depends on the synaptic ribbon, a specialized structure found at various sensory synapses, to provide a supply of primed vesicles for release. Calcium (Ca(2+)) accelerates the replenishment of vesicles at cone ribbon synapses, but the mechanisms underlying this acceleration and its functional implications for vision are unknown. We studied vesicle replenishment using paired whole-cell recordings of cones and postsynaptic neurons in tiger salamander retinas and found that it involves two kinetic mechanisms, the faster of which was diminished by calmodulin (CaM) inhibitors. We developed an analytical model that can be applied to both conventional and ribbon synapses and showed that vesicle resupply is limited by a simple time constant, τ = 1/(Dρδs), where D is the vesicle diffusion coefficient, δ is the vesicle diameter, ρ is the vesicle density, and s is the probability of vesicle attachment. The combination of electrophysiological measurements, modeling, and total internal reflection fluorescence microscopy of single synaptic vesicles suggested that CaM speeds replenishment by enhancing vesicle attachment to the ribbon. Using electroretinogram and whole-cell recordings of light responses, we found that enhanced replenishment improves the ability of cone synapses to signal darkness after brief flashes of light and enhances the amplitude of responses to higher-frequency stimuli. By accelerating the resupply of vesicles to the ribbon, CaM extends the temporal range of synaptic transmission, allowing cones to transmit higher-frequency visual information to downstream neurons. Thus, the ability of the visual system to encode time-varying stimuli is shaped by the dynamics of vesicle replenishment at photoreceptor synaptic ribbons

Social deprivation of infant rhesus monkeys alters the chemoarchitecture of the brain: I. Subcortical regions

Rhesus monkeys (Macaca mulatta) reared during the first year of life without social contact develop persistent stereotyped movements, self- directed behaviors, and psychosocial abnormalities, but neurobiological mechanisms underlying the behaviors of socially deprived (SD) monkeys are unknown. Monkeys were reared in total social deprivation for the first 9 months of life; control monkeys were reared socially (SR) with mothers and peers. Subjects were killed at 19-24 yr of age. Because the behaviors of SD monkeys are reminiscent of changes in striatal or amygdalar function, we used immunocytochemistry for substance P (SP), leucine-enkephalin (LENK), somatostatin, calbindin, and tyrosine hydroxylase (TH) to evaluate qualitatively and quantitatively patterns of neurotransmitter marker immunoreactivity within subcortical regions. In SD monkeys, the chemoarchitecture of the striatum was altered. Neuronal cell bodies and processes immunoreactive for SP and LENK were depleted markedly in patch (striosome) and matrix regions of the caudate nucleus and putamen; the average density of SP-immunoreactive neurons was reduced 58% relative to SR monkeys. Calbindin and TH immunoreactivities were diminished in the matrix of caudate and putamen of SD monkeys. TH-immunoreactive neurons, but not cresyl violet-stained neurons, in the substantia nigra pars compacta were decreased (43%) in SD monkeys. Peptide-immunoreactive terminals were reduced in the globus pallidus and substantia nigra in SD monkeys. The nucleus accumbens was the least affected of striatal regions. Striatal somatostatin immunoreactivity wa qualitatively and quantitatively similar in SD and SR monkeys. Several regions, for example, bed nucleus of the stria terminalis, amygdala, and basal forebrain magnocellular complex, that were in the same sections and are enriched in these markers did not appear altered in SD monkeys, suggesting a regional specificity for vulnerability. The altered chemoarchitecture of some basal ganglia regions in adult monkeys that experienced social deprivation as infants suggests that the postnatal maturation of neurotransmitter phenotypes in some structures is influenced by social environment. Abnormal motor and psychosocial behaviors resulting from this form of social/sensory deprivation may result from alterations in peptidergic and dopaminergic systems within the basal ganglia