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Contains fulltext : 291531.pdf (Publisher’s version ) (Open Access) BACKGROUND: Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) share pathogenic pathways related to amyloid-β deposition. Whereas AD is known to affect synaptic function, such an association for CAA remains yet unknown. OBJECTIVE: We therefore aimed to investigate synaptic dysfunction in CAA. METHODS: Multiple reaction monitoring mass spectrometry was used to quantify cerebrospinal fluid (CSF) concentrations of 15 synaptic proteins in CAA and AD patients, and age- and sex-matched cognitively unimpaired controls. RESULTS: We included 25 patients with CAA, 49 patients with AD, and 25 controls. Only neuronal pentraxin-2 levels were decreased in the CSF of CAA patients compared with controls (p = 0.04). CSF concentrations of 12 other synaptic proteins were all increased in AD compared with CAA or controls (all p≤0.01) and were unchanged between CAA and controls. Synaptic protein concentrations in the subgroup of CAA patients positive for AD biomarkers (CAA/ATN+; n = 6) were similar to AD patients, while levels in CAA/ATN- (n = 19) were comparable with those in controls. A regression model including all synaptic proteins differentiated CAA from AD at high accuracy levels (area under the curve 0.987). CONCLUSION: In contrast to AD, synaptic CSF biomarkers were found to be largely unchanged in CAA. Moreover, concomitant AD pathology in CAA is associated with abnormal synaptic protein levels. Impaired synaptic function in AD was confirmed in this independent cohort. Our findings support an apparent differential involvement of synaptic dysfunction in CAA and AD and may reflect distinct pathological mechanisms.

Introduction Anxiety and depression during pregnancy could imply difficulties in the attachment to the unborn baby. The objective of this study was to investigate the prevalence and change in anxiety and depressive symptoms in pregnant women with fear of birth. Another aim was to explore associations between symptoms of anxiety and depression on prenatal attachment. Methods This is a longitudinal cohort study of 77 pregnant women with fear of birth in three hospitals in Sweden. Data were collected by three questionnaires in mid and late pregnancy and two months after birth. Results Anxiety symptoms were more often reported than depressive symptoms, significantly decreasing over time in both conditions. Anxiety symptoms were associated with low education level, negative feelings towards the upcoming birth, and levels of fear of birth. Depressive symptoms were associated with levels of fear of birth. One in five women presented with fear of birth, anxiety, and depressive symptoms, suggesting that co-morbidity was quite common in this sample. Depressive symptoms and co-morbidity were negatively associated with prenatal attachment. Conclusions This study shows that symptoms of anxiety and depression in women with fear of birth vary over time and that co-morbidity is quite common. Lack of emotional well-being was related to prenatal attachment. Healthcare professionals must identify and support women with anxiety and depressive symptoms and fear of birth so that difficulties in the relationship between the mother and the newborn baby might be reduced.

The aim of the study was to assess if there is a time difference (operative time, ischemia time, planning time and hospitalization) between computer-assisted surgery (CAS) and conventional planning in cranio-maxillofacial surgery. An electronic search was performed in June 2018. Studies comparing time difference between CAS and traditional planning were included. 28 publications were included, with 536 patients in the CAS group and 784 in the control group. 18 studies reported on mandibular/maxillary reconstruction and a meta-analysis was conducted on 15 of these studies. This meta-analysis was undertaken to demonstrate the difference between the groups regarding operative time, ischemia time and hospitalization for mandibular/maxillary reconstruction and showed a decreased operative time for the CAS group with a mean difference of -84.61 min, 95% confidence interval [-106.77, -62,45], p 0.001. Ischemia time was also decreased, with a mean difference of -36.14 min, 95% confidence interval [-50.57, -21.71], p 0.001. This systematic review and meta-analysis suggests that CAS is shortening the operative time and ischemia time for mandibular/maxillary reconstruction. It also leads to a reduction in hospitalization. Additionally, CAS seems to shorten the preoperative planning time for orthognathic surgery.

Sepsis is a severe condition which affects 300-800/100,000 persons each year. There are indications that the prehospital identification of patients with sepsis is difficult. The aim of the study was, among patients with a final hospital diagnosis of sepsis, to compare emergency medical service (EMS) field assessments of patients in whom there was a prehospital suspicion of sepsis with those without this suspicion.The study had a retrospective, observational design. The data used in the study were retrieved from the prehospital and hospital medical records of patients with a final hospital diagnosis of sepsis, transported to hospital by the EMS within a region in the south west of Sweden during a period of one year.Among patients with a final diagnosis of sepsis (n=353), the EMS identified the condition in 36% of the cases. These patients were characterised by more abnormal vital signs (a higher respiratory rate and heart rate and more frequent temperature abnormalities) and were more ambitiously assessed (more lung auscultations and more assessments of the degree of consciousness).The EMS was already able to identify 36% of patients with a final diagnosis of sepsis in the prehospital phase. There were minor differences in the prehospital assessment between patients who were identified by the EMS nurse and those who were not.

A solid understanding of the mechanisms governing ligand binding is crucial for rational design of therapeutics targeting the dopamine D2 receptor (D2R). Here, we use G protein-coupled inward rectifier potassium (GIRK) channel activation in Xenopus oocytes to measure the kinetics of D2R antagonism by a series of aripiprazole analogues, as well as the recovery of dopamine (DA) responsivity upon washout. The aripiprazole analogues comprise an orthosteric and a secondary pharmacophore and differ by the length of the saturated carbon linker joining these two pharmacophores. Two compounds containing 3- and 5-carbon linkers allowed for a similar extent of recovery from antagonism in the presence of 1 or 100 μM DA (>25 and >90% of control, respectively), whereas recovery was less prominent (∼20%) upon washout of the 4-carbon linker compound, SV-III-130, both with 1 and 100 μM DA. Prolonging the coincubation time with SV-III-130 further diminished recovery. Curve-shift experiments were consistent with competition between SV-III-130 and DA. Two mutations in the secondary binding pocket (V91A and E95A) of D2R decreased antagonistic potency and increased recovery from SV-III-130 antagonism, whereas a third mutation (L94A) only increased recovery. Our results suggest that the secondary binding pocket influences recovery from inhibition by the studied aripiprazole analogues. We propose a mechanism, supported by in silico modeling, whereby SV-III-130 initially binds reversibly to the D2R, after which the drug-receptor complex undergoes a slow transition to a second ligand-bound state, which is dependent on secondary binding pocket integrity and irreversible during the time frame of our experiments.

Background Previous evidence suggests that UNC9994 is a beta-arrestin2-selective agonist at the dopamine D2 receptor, lacking ability both to activate and antagonize G protein-dependent signaling. However, this has only been reported by one laboratory using a single assay. Methods We used G protein-coupled inward rectifier potassium channel activation in Xenopus oocytes to investigate UNC9994-induced modulation of G protein-dependent signaling at dopamine D2 receptor and dopamine D3 receptor. Results At dopamine D2 receptor, UNC9994 induced G protein-coupled inward rectifier potassium channel currents that were 15% of the maximal response to dopamine, with an EC50 of 185 nM. At dopamine D3 receptor, the ligand elicited 89% of the maximal dopamine response with an EC50 of 62 nM. Pertussis toxin abolished G protein-coupled inward rectifier potassium channel activation. Furthermore, UNC9994 antagonized dopamine-induced G protein-coupled inward rectifier potassium channel activation at dopamine D2 receptor. Conclusions UNC9994 modulates G protein-coupled inward rectifier potassium channel channel activation via pertussis toxin-sensitive G proteins at dopamine D2 receptor and dopamine D3 receptor. These findings may have implications for the interpretation of data obtained with this ligand.

Facial fractures often result in changes of the orbital volume. These changes can be measured in three-dimensional (3D) computed tomography (CT) scans for preoperative planning and postoperative evaluation. The aim of this study was to analyze the orbital volume and shape before and after surgical treatment of unilateral orbital fractures using semi-automatic image segmentation and registration techniques. The orbital volume in 21 patients was assessed by a semi-automatic model-based segmentation method. The fractured orbit was compared relative to the contralateral orbit. The same procedure was performed for the postoperative evaluation. Two observers performed the segmentation procedure, and the inter- and intraobserver variability was evaluated. The interobserver variability (mean volume difference ± 1.96 SD) was -0.6 ± 1.0 ml in the first trial and 0.7 ± 0.8 ml in the second trial. The intra-observer variability was -0.2 ± 0.7 ml for the first observer and 1.1 ± 0.9 ml for the second observer. The average volume overlap (Dice similarity coefficient) between the fractured and contralateral side increased after surgery, while the mean and maximum surface distance decreased, indicating that the surgery contributed to a re-establishment of size and shape. In conclusion, our study shows that the semi-automatic segmentation method has precision for detecting volume differences down to 1.0 ml. The combination of semi-automatic segmentation and 3D shape analysis provides a powerful tool for planning and evaluating treatment of orbital fractures.

Three-dimensional (3D) computer-assisted planning requires detailed visualisation of the craniomaxillofacial region and interocclusal relationship. The aim of this study was to establish and evaluate a method to create a 3D model of the craniomaxillofacial region and to adopt intraoral digital scanning to place the lower jaw into a centric relation (CR) without the need of additional plaster casts and model surgery. A standard plastic skull modified by metallic dental wires and brackets was subjected to computed tomography (CT), cone beam computed tomography (CBCT), and intraoral digital scanning. We evaluated two different virtual bite registrations, a digital scan of the buccal dental surfaces and scanning of the wax bites to position the lower jaw into a CR, and assessed the accuracy of the integration of intraoral scanning to the CT/CBCT scans. The mean registration error of corresponding mesh points for the CT and intraoral scanned images was 0.15 ± 0.12 mm, while this error was 0.18 ± 0.13 mm for the CBCT and intraoral scanned images. The mean accuracy of the two virtual bite registrations ranged from 0.41 to 0.49 mm (buccal scan technique) and from 0.65 to 1.3 mm (virtualised wax bite technique). A method for virtual bite registration was developed. It has the potential to eliminate plaster casts and model surgery and may facilitate 3D computer-assisted planning of orthognathic surgery cases.

Newer, "atypical" antipsychotics carry a lower risk of motor side-effects than older, "typical" compounds. It has been proposed that a ~100-fold faster dissociation from the dopamine D2 receptor (D2R) distinguishes atypical from typical antipsychotics. Furthermore, differing antipsychotic D2R affinities have been suggested to reflect differences in dissociation rate constants (koff), while association rate constants (kon) were assumed to be similar. However, it was recently demonstrated that lipophilic accumulation of ligand in the cell interior and/or membrane can cause underestimation of koff, and as high-affinity D2R antagonists are frequently lipophilic, this may have been a confounding factor in previous studies. In the present work, a functional electrophysiology assay was used to measure the recovery of dopamine-mediated D2R responsivity from antipsychotic antagonism, using elevated concentrations of dopamine to prevent the potential bias of re-binding of lipophilic ligands. The variability of antipsychotic kon was also reexamined, capitalizing on the temporal resolution of the assay. kon was estimated from the experimental recordings using a simple mathematical model assumed to describe the binding process. The time course of recovery from haloperidol (typical antipsychotic) was only 6.4- to 2.5-fold slower than that of the atypical antipsychotics, amisulpride, clozapine, and quetiapine, while antipsychotic kons were found to vary more widely than previously suggested. Finally, affinities calculated using our kon and koff estimates correlated well with functional potency and with affinities reported from radioligand binding studies. In light of these findings, it appears unlikely that typical and atypical antipsychotics are primarily distinguished by their D2R binding kinetics.

We describe a slowly progressive myopathy in 7 unrelated adult patients with storage of polyglucosan in muscle fibers. Genetic investigation revealed homozygous or compound heterozygous deleterious variants in the glycogenin-1 gene (GYG1). Most patients showed depletion of glycogenin-1 in skeletal muscle, whereas 1 showed presence of glycogenin-1 lacking the C-terminal that normally binds glycogen synthase. Our results indicate that either depletion of glycogenin-1 or impaired interaction with glycogen synthase underlies this new form of glycogen storage disease that differs from a previously reported patient with GYG1 mutations who showed profound glycogen depletion in skeletal muscle and accumulation of glycogenin-1.

Development of workflow for recording virtual bite in the planning of orthognathic operations

Glycogen synthesis is initiated by self-glucosylation of the glycosyltransferases glycogenin-1 and -2 that, in the presence of UDP-glucose, form both the first glucose-O-tyrosine linkage, and then stepwise add a series of α1,4-linked glucoses to a growing chain of variable length. Glycogen-1 and -2 coexist in liver glycogen preparations where the proteins are known to form homodimers, and they also have been shown to interact with each other. In order to study how glycogenin-1 and -2 interactions may influence each other's glucosylations we setup a cell-free expression system for in vitro production and glucosylation of glycogenin-1 and -2 in various combinations, and used a mass spectrometry based workflow for the characterization and quantitation of tryptic glycopeptides originating from glycogenin-1 and -2. The analysis revealed that the self-glucosylation endpoint was the incorporation of 4-8 glucose units on Tyr 195 of glycogenin-1, but only 0-4 glucose units on Tyr-228 of glycogenin-2. The glucosylation of glycogenin-2 was enhanced to 2-4 glucose units by the co-presence of enzymatically active glycogenin-1. Glycogenin-2 was, however, unable to glucosylate inactive glycogenin-1, at least not an enzymatically inactivated Thr83Met glycogenin-1 mutant, recently identified in a patient with severe glycogen depletion.

Born and raised in the countryside in Voinjama, Lofa County, in northern Liberia, Black Diamond became a rebel leader in one of the most brutal conflicts in modern history at only 16 years of age. ...

Three conservation methods were executed on bonnets in plain monochrome silk, to investigate which method is perceived as the most visually aesthetic; 11 bonnets were produced, 10 given identical damages, and 9 were conserved, 3 with each method. The damage was secured onto a support fabric with laid couching, a long stitch fastened with short perpendicular stitches, or brick couching, short stitches placed like brick-work, or covered with crepeline (a semi-transparent silk). The participants were 30 Swedish textile conservators (29 women; ages 29–78 years, M = 51.9, SD = 12.9), and 30 museum visitors (20 women; ages 15–74 years, M = 41.1, SD = 18.3). The participants’ task was to rate the bonnets on a 100-point continuous preference scale, based on how visually attractive they found each bonnet. Preferences were compared between the two groups of participants and the conservation methods. The bonnets with crepeline were the most preferred, and those with laid couching were the least preferred, among both groups of participants.

To assess the survival rate of craniofacial implants (CIs) to support facial prosthesis/epithesis and the prevalence of surgical/biological complications based on previously published studies.An electronic search was undertaken in March/2016. Only studies with a minimum of 5 patients were included. Untransformed proportions of implant failures for different regions were calculated. A meta-analysis evaluated the influence of radiotherapy on the failure rates. A meta-regression was performed considering the follow-up period as covariate.Seventy publications included 2355 patients and 8184 CIs (545 failures). The probability of a failure was 5.5% for all CIs (95%CI 4.5-6.5, P 0.001), 1.2% for CIs in the auricular region (95%CI 0.8-1.5, P 0.001), 12.2% for the nasal region (95%CI 9.0-15.5, P = 0.017), and 12.1% for the orbital region (95%CI 9.3-15.0, P 0.001). Radiotherapy statistically affected the CIs rates (OR 5.80, 95%CI 3.77-8.92, P 0.00001). There was no statistically significant influence of the follow-up time on the proportion of implant failures (P = 0.814). Soft tissue adverse reactions were the most common complications.Implants placed in the auricular region have a lower probability of failure than those in the nasal and orbital regions. Soft tissue adverse reactions were the most common complications. Radiotherapy significantly affected the CIs failure rates.

Glycogenin-1 initiates the glycogen synthesis in skeletal muscle by the autocatalytic formation of a short oligosaccharide at tyrosine 195. Glycogenin-1 catalyzes both the glucose-O-tyrosine linkage and the α1,4 glucosidic bonds linking the glucose molecules in the oligosaccharide. We recently described a patient with glycogen depletion in skeletal muscle as a result of a non-functional glycogenin-1. The patient carried a Thr83Met substitution in glycogenin-1. In this study we have investigated the importance of threonine 83 for the catalytic activity of glycogenin-1. Non-glucosylated glycogenin-1 constructs, with various amino acid substitutions in position 83 and 195, were expressed in a cell-free expression system and autoglucosylated in vitro. The autoglucosylation was analyzed by gel-shift on western blot, incorporation of radiolabeled UDP-14C-glucose and nano-liquid chromatography with tandem mass spectrometry (LC/MS/MS). We demonstrate that glycogenin-1 with the Thr83Met substitution is unable to form the glucose-O-tyrosine linkage at tyrosine 195 unless co-expressed with the catalytically active Tyr195Phe glycogenin-1. Our results explain the glycogen depletion in the patient expressing only Thr83Met glycogenin-1 and why heterozygous carriers without clinical symptoms show a small proportion of unglucosylated glycogenin-1.

The glycosylation of the extracellular protein alpha-dystroglycan is important for its ligand-binding activity, and altered or blocked glycosylation is associated with several forms of congenital muscular dystrophies. By immunoprecipitation and sialic acid capture-and-release enrichment strategies, we isolated tryptic glycopeptides of alpha-dystroglycan from human skeletal muscle. Nano-liquid chromatography tandem mass spectrometry was used to identify both glycopeptides and peptides corresponding to the mucin-like and C-terminal domain of alpha-dystroglycan. The O-glycans found had either Hex-O-Thr or HexNAc-O-Ser/Thr anchored structures, which were often elongated and frequently, but not always, terminated with sialic acid. The HexNAc-O-Ser/Thr, but not Hex-O-Thr glycopeptides, displayed heterogeneity regarding glycan core structures and level of glycosylation site occupancy. We demonstrate for the first time glycan attachment sites of the NeuAcHexHexNAcHex-O structure corresponding to the anticipated Neu5Acalpha3Galbeta4GlcNAcbeta2Man-O-glycan (sLacNAc-Man), within the mucin-like domain of human alpha-dystroglycan from human skeletal muscle. Twenty-five glycopeptides were characterized from human alpha-dystroglycan, which provide insight to the complex in vivo O-glycosylation of alpha-dystroglycan.

Voltage-gated ion channels are key players in fast neuronal signalling. Detailed knowledge about channel gating is essential for our understanding of channel function in general and of drug action of channels in particular. Despite a number of recent atomic channel structures, the opening of voltage-gated channels is the subject of heated debates. Here we will discuss two of the controversies: one concerning the mechanism of opening and closing the pore, and the other concerning the location and movement of the voltage sensor. The channels were originally suggested to open at a conserved proline rich sequence (PVP) at the intracellular end of the transmembrane segment 6 (S6). The crystallization of a channel in the open state instead suggested an opening involving a conserved glycine hinge located in the middle portion of S6. Based on pharmacological studies, autodocking and molecular dynamics simulations we have found support for the PVP-bend model. The voltage sensor, transmembrane segment 4 (S4), was originally suggested to be buried in the channel protein, undergoing a helical-screw-like motion to open the channel. A recent crystallographic study suggested that S4 is located in the periphery, facing lipid, and undergoing a paddle-like motion to open the channel. We have found experimental evidence for a novel helical-screw model; with the voltage sensor moving in a screw-like fashion but being located in the periphery of the channel. This model opens up for understanding how lipophilic drugs and toxins directly affect the voltage sensor.

Measure plans are currently being developed for the Water Framework Directive (WFD) by European water authorities. In Sweden, such plans include measures for good ecological status in the coastal ecosystem. However, the effect of suggested measures is not yet known. We therefore experimented with different nutrient reduction measures on land and in the sea, using a model system of two coupled dynamic models for a semi-enclosed bay and its catchment. The science question was whether it is worthwhile to implement measures in the local catchment area to reach local environmental goals, or if the status of the Bay is more governed by the water exchange with the Sea. The results indicate that by combining several measures in the catchment, the nutrient load can be reduced by 15%-20%. To reach the same effect on nutrient concentrations in the Bay, the concentrations of the sea must be reduced by 80%. Hence, in this case, local measures have a stronger impact on coastal water quality. The experiment also show that the present targets for good ecological status set up by the Swedish water authorities may be unrealistic for this Bay. Finally, we discuss when and how to use hydro-ecological models for societal needs.

Aesthetic quality is central to textile conservators when evaluating a conservation method. However, the literature on textile conservation chiefly focuses on physical properties, and little is known about what factors determine aesthetic quality according to textile conservators. The latter was explored through two experiments. Experiment 1 explored the underlying attributes of aesthetic quality of textile conservation interventions. Experiment 2 explored the relationships between these attributes and how well they predicted aesthetic quality. Rank-order correlation analyses revealed two latent factors called Coherence and Completeness. Ordinal regression analysis revealed that Coherence was the most important predictor of aesthetic quality. This means that a successful conservation intervention is visually well-integrated with the textile item in terms of the material and method.

Dizziness is a common and often untreated symptom in the general population. The aim of this study was to investigate the effects of a combined cognitive-behavioral/vestibular rehabilitation (VR) program, using a randomized control design. A total of 29 participants were randomized to treatment consisting of psychoeducation, vestibular exercises, relaxation and cognitive interventions, or to serve as waiting list controls. Measures of dizziness-related handicap, dizziness-provoking movements, and daily diary registrations of dizziness symptoms at pre- and post-treatment showed statistically significant improvements in many domains, which translated to moderate effect sizes. These findings provide preliminary support for the combination of Cognitive-behavioral therapy (CBT) and VR methods in the treatment of dizziness.

The mechanisms of anesthesia are surprisingly little understood. The present article summarizes current knowledge about the function of general anesthetics at different organization levels of the nervous system. It argues that a consensus view can be constructed, assuming that general anesthetics modulate the activity of ion channels, the main targets being GABA and NMDA channels and possibly voltage-gated and background channels, thereby hyperpolarizing neurons in thalamocortical loops, which lead to disruption of coherent oscillatory activity in the cortex. Two computational cases are used to illustrate the possible importance of molecular level effects on cellular level activity. Subtle differences in the mechanism of ion channel block can be shown to cause considerable differences in the modification of the oscillatory activity in a single neuron, and consequently in an associated network. Finally, the relation between the anesthesia problem and the classical consciousness problem is discussed, and some consequences of introducing the phenomenon of degeneracy into the picture are pointed out.

Objective Transcranial magnetic stimulation (TMS) can be used to map the corticomotor representations of hand muscles in the precentral motor-cortex (PMC). The spatial peak of the corticomotor representations is often not located in the primary motor cortex (M1HAND), but shows an anterior shift towards the dorsal premotor cortex (PMd). Here we used magnetic resonance imaging (MRI) to test the hypothesis that the PMC shows different structural and functional properties in individuals with a clear “premotor” representation compared to individuals with a preponderant “primary-motor” representation of hand muscles. Methods MRI-measurements and neuronavigated-TMS were performed on twenty-four volunteers (mean age: 24.3 ± 0.9 SE, 12 women). Participants underwent structural MRI to evaluate cortical thickness and curvature of the PMC. We also performed fMRI to evaluate precentral functional activation in the hand-knob during a simple motor task. Sulcus-shape based TMS-mapping was used to obtain mediolateral and posterior-anterior corticomotor excitability profiles of the left abductor-digiti-minimi and first-dorsal-interosseus muscles. Results In 14 out of 24 individuals (58%), TMS mapping disclosed a clear spatial peak in the stimulation lines overlying the PMd, whereas the remaining 10 subjects (42%) showed maximal motor responses more posteriorly along M1HAND. During fMRI, the “premotor” group displayed a stronger task-related activation in the PMd relative to the “primary-motor” group ( p = 0.002). No difference between two groups was evident for curvature and cortical thickness. Conclusion The results confirm that many individuals have a more premotor corticomotor representation of small hand muscles when measured with TMS. This premotor phenotype in terms of corticomotor representation is associated with a stronger premotor activation during simple movements. This association supports the notion of two distinct functional phenotypes of corticomotor hand representations in human PMC: a primary motor and a premotor phenotype.

Glycogen, which serves as a major energy reserve in cells, is a large, branched polymer of glucose molecules. We describe a patient who had muscle weakness, associated with the depletion of glycogen in skeletal muscle, and cardiac arrhythmia, associated with the accumulation of abnormal storage material in the heart. The skeletal muscle showed a marked predominance of slow-twitch, oxidative muscle fibers and mitochondrial proliferation. Western blotting showed the presence of unglucosylated glycogenin-1 in the muscle and heart. Sequencing of the glycogenin-1 gene, GYG1, revealed a nonsense mutation in one allele and a missense mutation, Thr83Met, in the other. The missense mutation resulted in inactivation of the autoglucosylation of glycogenin-1 that is necessary for the priming of glycogen synthesis in muscle.

Suitable analytical markers to assess the degree of degradation of historic silk textiles at molecular and macroscopic levels have been identified and compared with silk textiles aged artificially in different environments, namely (i) ultraviolet (UV) exposure, (ii) thermo-oxidation, (iii) controlled humidity and (iv) pH. The changes at the molecular level in the amino acid composition, the formation of oxidative moieties, crystallinity and molecular weight correlate well with the changes in the macroscopic properties such as brightness, pH and mechanical properties. These analytical markers are useful to understand the degradation mechanisms that silk textiles undergo under different degradation environments, involving oxidation processes, hydrolysis, chain scission and physical arrangements. Thermo-oxidation at high temperatures proves to be the accelerated ageing procedure producing silk samples that most resembled the degree of degradation of early seventeenth-century silk. These analytical markers will be valuable to support the textile conservation tasks currently being performed in museums to preserve our heritage. Electronic supplementary material The online version of this article (doi:10.1007/s00216-014-8361-z) contains supplementary material, which is available to authorized users.

Agonist potency at some neurotransmitter receptors has been shown to be regulated by voltage, a mechanism which has been suggested to play a crucial role in the regulation of neurotransmitter release by inhibitory autoreceptors. Likewise, receptor deactivation rates upon agonist removal have been implicated in autoreceptor function. Using G protein-coupled potassium (GIRK) channel activation in Xenopus oocytes as readout of receptor activity, we have investigated the voltage sensitivities and signaling kinetics of the hH3445 and hH3365 isoforms of the human histamine H3 receptor, which functions as an inhibitory auto- and heteroreceptor in the nervous system. We have also investigated both the human and the mouse homologues of the related histamine H4 receptor, which is expressed mainly on hematopoietic cells. We found that the hH3445 receptor is the most sensitive to voltage, whereas the hH3365 and H4 receptors are less affected. We further observed a marked difference in response deactivation kinetics between the hH3445 and hH3365 isoforms, with the hH3365 isoform being five to six-fold slower than the hH3445 receptor. Finally, using synthetic agonists, we found evidence for agonist-specific voltage sensitivity at the hH4 receptor. The differences in voltage sensitivities and deactivation kinetics between the hH3445, hH3365, and H4 receptors might be relevant to their respective physiological roles.

Background Increased nociceptive neuronal excitability underlies chronic pain conditions. Various ion channels, including sodium, calcium and potassium channels have pivotal roles in the control of neuronal excitability. The members of the family of G protein-gated inwardly rectifying potassium (GIRK) channels, GIRK1–4, have been implicated in modulating excitability. Here, we investigated the expression and distribution of GIRK1 and GIRK2 in normal and injured dorsal root ganglia (DRGs) and spinal cord of rats. Results We found that ~70% of the DRG neurons expressed GIRK1, while only