The use of psoriasis biomarkers, including trajectory of clinical response, to predict clearance and remission duration to UVB phototherapy.

BACKGROUND: Remission duration and treatment response following phototherapy for psoriasis are highly variable and factors influencing these are poorly understood. OBJECTIVES: Our primary outcome was to investigate whether selected clinical/serum biomarkers were associated with remission duration, and secondly with psoriasis clearance at the end of phototherapy. In addition, we looked at whether early trajectory of UVB clearance was associated with final clearance outcome. METHODS: We performed a prospective cohort study of 100 psoriasis patients, routinely prescribed Narrowband UVB and measured selected clinical and biochemical biomarkers, including weekly PASI (psoriasis area and severity index) scores. Patients were followed up for 18 months. RESULTS: The median time to relapse was 6 months (95% CI 5-18) if PASI90 was achieved, and 4 months (95% CI 3-9) if less than PASI90 was achieved. Achieving PASI100 did not result in prolonged remission. On UVB completion, the median final PASI (n = 96) was 1.0 (IQR 0.5, 1.6) with 78 (81%) achieving PASI75 and 39 (41%) achieving PASI90. Improved PASI90 response was significantly associated with lower BMI, higher baseline PASI, non-smoking status and lower cumulative NbUVB. Serum levels of C-reactive protein (CRP) and vitamin D were not associated with clearance or remission duration. Early treatment response from weeks 2-3 was predictive of final outcome. For example, achieving PASI30 at week 3 was significantly associated with PASI90 at the end of the course [36/77 (51%) vs. 2/24 (8%), P < 0.001]. CONCLUSIONS: Raised BMI and positive smoking status predicted poorer phototherapy response. For the first time, we have shown that PASI clearance trajectory over the first 2-3 weeks of UVB, can predict psoriasis clearance. This is an important new step towards developing psoriasis personalized prescribing, which can now be formally tested in clinical trials. These simple clinical measures can be used to inform patient treatment expectations; allowing treatment modifications and/or switching to alternative therapies.

Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study.

Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

The outcome of septorhinoplasty surgery on olfactory function.

OBJECTIVES: To assess olfactory outcomes in patients undergoing septorhinoplasty surgery in our unit. DESIGN: Prospective cohort study. SETTING: The Royal National Throat Nose and Ear Hospital, London. PARTICIPANTS: Forty-three patients undergoing functional septorhinoplasty (Males = 26; mean age = 34.1 ± 12.2) were recruited into the study. MAIN OUTCOME MEASURES: The primary outcome of olfactory function was assessed using 'Sniffin sticks'. Our secondary outcomes were assessment of patient quality of life using the disease specific Sino-nasal Outcome Test-23 questionnaire (SNOT-23) and a visual analogue scale for sense of smell. These measures were repeated at 12 weeks post operatively. RESULTS: There was a significant change in the Sniffin' sticks score post-operatively (8.3 versus 9.6; P < 0.001). The SNOT-23 score also showed a significant improvement post-operatively (53.5 versus 40.4; P < 0.001). A significant improvement was not found in the smell/taste question (question 21) of the SNOT-23 questionnaire as well as the visual analogue scale for sense of smell. A difference in olfactory outcome was not found between open versus closed approaches, primary versus revision surgery and traumatic versus non traumatic cases. CONCLUSIONS: The results show a measured significant improvement in olfaction following functional Septorhinoplasty but not a subjective improvement in the patients perception of their sense of smell and hence not a clinically significant difference. The reasons for the measured improvement are not clear and are likely to be multifactorial.

Anal bulking agents for faecal incontinence.

The aim of this review was to assess and evaluate reports of studies on the efficacy of anal bulking agents used in the treatment of faecal incontinence. A systematic review of the literature was carried out to identify studies that have reported on the use of anal bulking agents. A variety of biomaterials have been employed for anal bulking. These include autologous fat, bovine glutaraldehyde cross-linked collagen, carbon-coated zirconium oxide beads, dextranomer microspheres in a gel, hydrogel cross-linked with polyacrylamide, polydimethylsiloxane elastomer in a gel, porcine dermal collagen and synthetic calcium hydroxylapatitie ceramic microspheres. Although the ideal site of injection (submucosal or intramuscular) and the mechanism of action remain the subject of debate, most published studies report a significant improvement in continence in at least 50% of subjects with mild to moderate symptoms with little or no associated morbidity.We concluded that anal bulking agents may be used to alleviate symptoms of faecal seepage and soilage.

Deficiency of haematopoietic-cell-derived IL-10 does not exacerbate high-fat-diet-induced inflammation or insulin resistance in mice.

AIMS/HYPOTHESIS: Recent work has identified the important roles of M1 pro-inflammatory and M2 anti-inflammatory macrophages in the regulation of insulin sensitivity. Specifically, increased numbers of M2 macrophages and a decrease in M1 macrophages within the adipose tissue are associated with a state of enhanced insulin sensitivity. IL-10 is an anti-inflammatory cytokine and is a critical effector molecule of M2 macrophages. METHODS: In the present study, we examined the contribution of haematopoietic-cell-derived IL-10 to the development of obesity-induced inflammation and insulin resistance. We hypothesised that haematopoietic-cell-restricted deletion of IL-10 would exacerbate obesity-induced inflammation and insulin resistance. Lethally irradiated wild-type recipient mice receiving bone marrow from either wild-type or Il10-knockout mice were placed on either a chow or a high-fat diet for a period of 12 weeks and assessed for alterations in body composition, tissue inflammation and glucose and insulin tolerance. RESULTS: Contrary to our hypothesis, neither inflammation, as measured by the activation of pro-inflammatory stress kinases and gene expression of several pro-inflammatory cytokines in the adipose tissue and liver, nor diet-induced obesity and insulin resistance were exacerbated by the deletion of haematopoietic-cell-derived IL-10. Interestingly, however, Il10 mRNA expression and IL-10 protein production in liver and/or adipose tissue were markedly elevated in Il10-knockout bone-marrow-transplanted mice relative to wild-type bone marrow-transplanted mice. CONCLUSIONS/INTERPRETATION: These data show that deletion of IL-10 from the haematopoietic system does not potentiate high-fat diet-induced inflammation or insulin resistance.

Ovine Hemisection Model of Spinal Cord Injury.

INTRODUCTION: We are developing ovine models of spinal cord injury to test novel neuromodulation-based methods on spasticity. The hemisection has been reported in a number of large animal studies. Our aim is to duplicate a hemisection injury in the sheep. Our effort is explored here. Methods and Results: Three sheep underwent hemi-sectioning of the spinal cord. Quantitative gait analysis was completed both pre- and post-injury. While measurable differences in most of the 20 gait metrics were observed, relatively few were above the predicted thresholds based on error levels expected from the data. Variations in severity of injury across the three sheep were observed. Conclusions: The hemisection ovine model of spinal cord injury shows promise as a large-animal platform for developing new therapies for treating spinal cord injuries. While variability in injury severity was observed across animals, as has been observed with weight drop-based SCI models, the hemi-section approach has the advantages of procedural ease and reduced technical complexity.

Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance.

AIMS/HYPOTHESIS: The role of IL-6 in the development of obesity and hepatic insulin resistance is unclear and still the subject of controversy. We aimed to determine whether global deletion of Il6 in mice (Il6 (-/-)) results in standard chow-induced and high-fat diet (HFD)-induced obesity, hepatosteatosis, inflammation and insulin resistance. METHODS: Male, 8-week-old Il6 (-/-) and littermate control mice were fed a standard chow or HFD for 12 weeks and phenotyped accordingly. RESULTS: Il6 (-/-) mice displayed obesity, hepatosteatosis, liver inflammation and insulin resistance when compared with control mice on a standard chow diet. When fed a HFD, the Il6 (-/-) and control mice had marked, equivalent gains in body weight, fat mass and ectopic lipid deposition in the liver relative to chow-fed animals. Despite this normalisation, the greater liver inflammation, damage and insulin resistance observed in chow-fed Il6 (-/-) mice relative to control persisted when both were fed the HFD. Microarray analysis from livers of mice fed a HFD revealed that genes associated with oxidative phosphorylation, the electron transport chain and tricarboxylic acid cycle were uniformly decreased in Il6 (-/-) relative to control mice. This coincided with reduced maximal activity of the mitochondrial enzyme ß-hydroxyacyl-CoA-dehydrogenase and decreased levels of mitochondrial respiratory chain proteins. CONCLUSIONS/INTERPRETATION: Our data suggest that IL-6 deficiency exacerbates HFD-induced hepatic insulin resistance and inflammation, a process that appears to be related to defects in mitochondrial metabolism.

Male and female secondary sexual traits show different patterns of quantitative genetic and environmental variation in the horned beetle Onthophagus sagittarius.

The expression of secondary sexual traits in females has often been attributed to a correlated response to selection on male traits. In rare cases, females have secondary sexual traits that are not homologous structures to secondary sexual traits in males and are thus less likely to have evolved in females because of correlated selection. In this study, we used the dung beetle Onthophagus sagittarius, a species with sex-specific horns, to examine the environmental and quantitative genetic control of horn expression in males and females. Offspring subjected to different brood mass manipulations (dung addition/removal) were found to differ significantly in body size. Brood mass manipulation also had a significant effect on the length of male horns; however, female horn length was found to be relatively impervious to the treatment, showing stronger patterns of additive genetic variance than males. We found no correlations between horn expression in males and females. We therefore conclude that the horns of O. sagittarius females are unlikely to result from genetic correlations between males and females. Rather, our data suggest that they may be under independent genetic control.

The Hemisection Approach in Large Animal Models of Spinal Cord Injury: Overview of Methods and Applications.

Introduction: Translating basic science research into a safe and effective therapy for spinal cord injury (SCI) requires suitable large animal models for testing both implantable devices and biologic approaches to better approximate human anatomy and function. Hemisection lesions, routinely used for investigational purposes in small animals, are less frequently described in large animals that might be appropriate for translational studies. Size constraints of small animals (mice and rats) limits the predictability of the findings when scaled up. Our goal is to review the status of hemisection SCI in large animals across species and time to prepare for the testing of a novel intradural spinal cord stimulation device for control of spasticity in an ovine model. Methods and Results: We surveyed the literature on hemisection in quadrupeds and nonhuman primates, and catalogued the species, protocols and outcomes of the experimental work in this field. Feline, lapine, canine, simian, porcine, ovine and bovine models were the primary focal points. There is a consistent body of literature reporting use of the hemisection approach in large animals, but with differences in surgical technique depending on the goals and nature of the individual studies. While the injuries are not always consistent, the experimental variability is generally lower than that of the contusion-based approach. In general, as the body size of the animal increases, animal care requirements and the associated costs follow. In most cases, this is inversely correlated with the number of animals used in hemisection models. Conclusions: The hemisection approach to modeling SCI is straightforward compared with other methods such as the contusive impact and enables the transection of isolated ascending and descending tracts and segment specific cell bodies. This has certain advantages in models investigating post-injury axonal regrowth. However, this approach is not generally in line with the patho-physiologies encountered in SCI patients. Even so, the ability to achieve more control over the level of injury makes it a useful adjunct to contusive and ischemic approaches, and suggests a useful role in future translational studies.

Coronary Disease in Spawning Steelhead Trout Salmo gairdnerii.

Coronary degeneration was absent in young trout taken in fresh water and rare in immature fish at sea, but the incidence and severity were sharply greater in migrating fish and almost uniformly present in spawning fish. Several fish taken after they had reentered salt water after spawning had no lesions; lesions in fish taken during their second spawning migration were not cumulative. These facts suggest that the process is reversible.

T-cell responses in osteosarcoma patients vaccinated with an anti-idiotypic antibody, 105AD7, mimicking CD55.

We assessed T-cell responses in young osteosarcoma patients vaccinated with 105AD7, 1-6 months after having received chemotherapy. 105AD7 is a human anti-idiotypic antibody mimicking CD55, a glycoprotein that protects from attack by complement and which is overexpressed on osteosarcoma cells. Seven out of 21 investigated patients made a IFN-gamma T-cell response against the vaccine, 105AD7 as assessed by ELISPOT. Cytokine secretion was analysed using Luminex assays and revealed TNF-alpha and GM-CSF responses not only to the vaccine but also towards the native antigen, CD55, in 5 / 14 (36%) of investigated patients. Importantly, the Luminex assay was found to be more sensitive than the more established T-cell assays (ELISPOT and proliferation assay), since responses towards the native antigen were recorded in this assay. Clinical responses and induction of immune responses to both the anti-idiotype and the native CD55 antigen support the use of CD55 as a target in cancer treatment.

RGS-GAIP, a GTPase-activating protein for Galphai heterotrimeric G proteins, is located on clathrin-coated vesicles.

RGS-GAIP (Galpha-interacting protein) is a member of the RGS (regulator of G protein signaling) family of proteins that functions to down-regulate Galphai/Galphaq-linked signaling. GAIP is a GAP or guanosine triphosphatase-activating protein that was initially discovered by virtue of its ability to bind to the heterotrimeric G protein Galphai3, which is found on both the plasma membrane (PM) and Golgi membranes. Previously, we demonstrated that, in contrast to most other GAPs, GAIP is membrane anchored and palmitoylated. In this work we used cell fractionation and immunocytochemistry to determine with what particular membranes GAIP is associated. In pituitary cells we found that GAIP fractionated with intracellular membranes, not the PM; by immunogold labeling GAIP was found on clathrin-coated buds or vesicles (CCVs) in the Golgi region. In rat liver GAIP was concentrated in vesicular carrier fractions; it was not found in either Golgi- or PM-enriched fractions. By immunogold labeling it was detected on clathrin-coated pits or CCVs located near the sinusoidal PM. These results suggest that GAIP may be associated with both TGN-derived and PM-derived CCVs. GAIP represents the first GAP found on CCVs or any other intracellular membranes. The presence of GAIP on CCVs suggests a model whereby a GAP is separated in space from its target G protein with the two coming into contact at the time of vesicle fusion.

Chemical stability of morphine and methadone, and of methadone in combination with acepromazine, medetomidine or xylazine, during prolonged storage in syringes.

OBJECTIVE: To assess the chemical and physical stability of morphine and methadone stored in syringes for 12 months and of methadone when mixed with acepromazine, medetomidine or xylazine. METHODS: A high-performance liquid chromatography (HPLC) technique was developed and validated for the analysis of morphine and methadone. Morphine and methadone were dispensed into syringes and stored at 25°C/60% relative humidity (RH) and 40°C/75% RH. Solutions containing mixtures of methadone combined with acepromazine, medetomidine or xylazine were stored in syringes at 25°C/60%RH. At initiation, after 1 week and then 1, 3, 6, 9 and 12 months, samples were analysed by HPLC for the quantification of the morphine or methadone. Measured concentrations were assessed as a function of storage time and temperature using linear regression statistics to calculate stability. RESULTS: When stored at 40°C/75%RH as pre-dispensed syringes, severe physical and chemical changes were observed after the third month for both morphine and methadone. In contrast, at 25°C/60%RH both drugs remained chemically stable for 12 months, with concentration variations not exceeding a 5% change from initiation as stipulated in VICH stability guidelines. When in combination with acepromazine or xylazine, methadone also remained chemically stable, but the combination with medetomidine failed stability criteria prior to 6 months. Precipitation compromised the physical stability of methadone in all unsealed syringes prior to 9 months' storage. CONCLUSION: Pre-dispensing morphine or methadone into unsealed syringes compromises the drugs' physical stability. Mixing of methadone with other drugs can degrade its chemical stability.

Experimental fossilization of mat-forming cyanobacteria in coarse-grained siliciclastic sediments.

Microbial fossils and textures are commonly preserved in Ediacaran and early Cambrian coarse-grained siliciclastic sediments that were deposited in tidal and intertidal marine settings. In contrast, the fossilization of micro-organisms in similar marine environments of post-Cambrian age is less frequently reported. Thus, temporal discrepancies in microbial preservation may have resulted from the opening and closing of a unique taphonomic window during the terminal Proterozoic and early Phanerozoic, respectively. Here, we expand upon previous work to identify environmental factors which may have facilitated the preservation of cyanobacteria growing on siliciclastic sand, by experimentally determining the ability of microbial mats to trap small, suspended mineral grains, and precipitate minerals from ions in solution. We show that (i) fine grains coat the sheaths of filamentous cyanobacteria (e.g., Nodosilinea sp.) residing within the mat, after less than 1 week of cell growth under aerobic conditions, (ii) clay minerals do not coat sterile cellulose fibers and rarely coat unsheathed cyanobacterial cells (e.g., Nostoc sp.), (iii) stronger disturbances (where culture jars were agitated at 170 rpm; 3 mm orbital diameter) produce the smoothest and most extensive mineral veneers around cells, compared with those agitated at slower rotational speeds (150 and 0 rpm), and (iv) mineral veneers coating cyanobacterial cells are ~1 µm in width. These new findings suggest that sheathed filamentous cyanobacteria may be preferentially preserved under conditions of high fluid energy. We integrate these results into a mechanistic model that explains the preservation of microbial fossils and textures in Ediacaran sandstones and siltstones, and in fine-grained siliciclastic deposits that contain exceptionally preserved microbial mats.

Transcriptional Signatures of Sleep Duration Discordance in Monozygotic Twins.

Introduction: Habitual short sleep duration is associated with adverse metabolic, cardiovascular, and inflammatory effects. Co-twin study methodologies account for familial (eg, genetics and shared environmental) confounding, allowing assessment of subtle environmental effects, such as the effect of habitual short sleep duration on gene expression. Therefore, we investigated gene expression in monozygotic twins discordant for actigraphically phenotyped habitual sleep duration. Methods: Eleven healthy monozygotic twin pairs (82% female; mean age 42.7 years; SD = 18.1), selected based on subjective sleep duration discordance, were objectively phenotyped for habitual sleep duration with 2 weeks of wrist actigraphy. Peripheral blood leukocyte (PBL) RNA from fasting blood samples was obtained on the final day of actigraphic measurement and hybridized to Illumina humanHT-12 microarrays. Differential gene expression was determined between paired samples and mapped to functional categories using Gene Ontology. Finally, a more comprehensive gene set enrichment analysis was performed based on the entire PBL transcriptome. Results: The mean 24-hour sleep duration of the total sample was 439.2 minutes (SD = 46.8 minutes; range 325.4-521.6 minutes). Mean within-pair sleep duration difference per 24 hours was 64.4 minutes (SD = 21.2; range 45.9-114.6 minutes). The twin cohort displayed distinctive pathway enrichment based on sleep duration differences. Habitual short sleep was associated with up-regulation of genes involved in transcription, ribosome, translation, and oxidative phosphorylation. Unexpectedly, genes down-regulated in short sleep twins were highly enriched in immuno-inflammatory pathways such as interleukin signaling and leukocyte activation, as well as developmental programs, coagulation cascade, and cell adhesion. Conclusions: Objectively assessed habitual sleep duration in monozygotic twin pairs appears to be associated with distinct patterns of differential gene expression and pathway enrichment. By accounting for familial confounding and measuring real life sleep duration, our study shows the transcriptomic effects of habitual short sleep on dysregulated immune response and provides a potential link between sleep deprivation and adverse metabolic, cardiovascular, and inflammatory outcomes.