A gene network regulated by the transcription factor VGLL3 as a promoter of sex-biased autoimmune diseases.

Autoimmune diseases affect 7.5% of the US population, and they are among the leading causes of death and disability. A notable feature of many autoimmune diseases is their greater prevalence in females than in males, but the underlying mechanisms of this have remained unclear. Through the use of high-resolution global transcriptome analyses, we demonstrated a female-biased molecular signature associated with susceptibility to autoimmune disease and linked this to extensive sex-dependent co-expression networks. This signature was independent of biological age and sex-hormone regulation and was regulated by the transcription factor VGLL3, which also had a strong female-biased expression. On a genome-wide level, VGLL3-regulated genes had a strong association with multiple autoimmune diseases, including lupus, scleroderma and Sjögren's syndrome, and had a prominent transcriptomic overlap with inflammatory processes in cutaneous lupus. These results identified a VGLL3-regulated network as a previously unknown inflammatory pathway that promotes female-biased autoimmunity. They demonstrate the importance of studying immunological processes in females and males separately and suggest new avenues for therapeutic development.

Single-cell phenotyping within transparent intact tissue through whole-body clearing.

Understanding the structure-function relationships at cellular, circuit, and organ-wide scale requires 3D anatomical and phenotypical maps, currently unavailable for many organs across species. At the root of this knowledge gap is the absence of a method that enables whole-organ imaging. Herein, we present techniques for tissue clearing in which whole organs and bodies are rendered macromolecule-permeable and optically transparent, thereby exposing their cellular structure with intact connectivity. We describe PACT (passive clarity technique), a protocol for passive tissue clearing and immunostaining of intact organs; RIMS (refractive index matching solution), a mounting media for imaging thick tissue; and PARS (perfusion-assisted agent release in situ), a method for whole-body clearing and immunolabeling. We show that in rodents PACT, RIMS, and PARS are compatible with endogenous-fluorescence, immunohistochemistry, RNA single-molecule FISH, long-term storage, and microscopy with cellular and subcellular resolution. These methods are applicable for high-resolution, high-content mapping and phenotyping of normal and pathological elements within intact organs and bodies.

Shared Genetic Risk Factors for Multiple Sclerosis/Psoriasis Suggest Involvement of Interleukin-17 and Janus Kinase-Signal Transducers and Activators of Transcription Signaling.

OBJECTIVE: Psoriasis and multiple sclerosis (MS) are complex immune diseases that are mediated by T cells and share multiple comorbidities. Previous studies have suggested psoriatic patients are at higher risk of MS; however, causal relationships between the two conditions remain unclear. Through epidemiology and genetics, we provide a comprehensive understanding of the relationship, and share molecular factors between psoriasis and MS. METHODS: We used logistic regression, trans-disease meta-analysis and Mendelian randomization. Medical claims data were included from 30 million patients, including 141,544 with MS and 742,919 with psoriasis. We used genome-wide association study summary statistics from 11,024 psoriatic, 14,802 MS cases, and 43,039 controls for trans-disease meta-analysis, with additional summary statistics from 5 million individuals for Mendelian randomization. RESULTS: Psoriatic patients have a significantly higher risk of MS (4,637 patients with both diseases; odds ratio [OR] 1.07, p = 1.2 × 10-5 ) after controlling for potential confounders. Using inverse variance and equally weighted trans-disease meta-analysis, we revealed >20 shared and opposing (direction of effect) genetic loci outside the major histocompatibility complex that showed significant genetic colocalization (in COLOC and COLOC-SuSiE v5.1.0). Co-expression analysis of genes from these loci further identified distinct clusters that were enriched among pathways for interleukin-17/tumor necrosis factor-α (OR >39, p < 1.6 × 10-3 ) and Janus kinase-signal transducers and activators of transcription (OR 35, p = 1.1 × 10-5 ), including genes, such as TNFAIP3, TYK2, and TNFRSF1A. Mendelian randomization found psoriasis as an exposure has a significant causal effect on MS (OR 1.04, p = 5.8 × 10-3 ), independent of type 1 diabetes (OR 1.05, p = 4.3 × 10-7 ), type 2 diabetes (OR 1.08, p = 2.3 × 10-3 ), inflammatory bowel disease (OR 1.11, p = 1.6 × 10-11 ), and vitamin D level (OR 0.75, p = 9.4 × 10-3 ). INTERPRETATION: By investigating the shared genetics of psoriasis and MS, along with their modifiable risk factors, our findings will advance innovations in treatment for patients suffering from comorbidities. ANN NEUROL 2023;94:384-397.

Retrospective pharmacogenetic study of psoriasis highlights the role of KLK7 in tumour necrosis factor signalling.

BACKGROUND: Multiple treatment options are available for the management of psoriasis, but clinical response varies among individual patients and no biomarkers are available to facilitate treatment selection for improved patient outcomes. OBJECTIVES: To utilize retrospective data to conduct a pharmacogenetic study to explore the potential genetic pathways associated with drug response in the treatment of psoriasis. METHODS: We conducted a retrospective pharmacogenetic study using self-evaluated treatment response from 1942 genotyped patients with psoriasis. We examined 6 502 658 genetic markers to model their associations with response to six treatment options using linear regression, adjusting for cohort variables and demographic features. We further utilized an integrative approach incorporating epigenomics, transcriptomics and a longitudinal clinical cohort to provide biological implications for the topmost signals associated with drug response. RESULTS: Two novel markers were revealed to be associated with treatment response: rs1991820 (P = 1.30 × 10-6) for anti-tumour necrosis factor (TNF) biologics; and rs62264137 (P = 2.94 × 10-6) for methotrexate, which was also associated with cutaneous mRNA expression levels of two known psoriasis-related genes KLK7 (P = 1.0 × 10-12) and CD200 (P = 5.4 × 10-6). We demonstrated that KLK7 expression was increased in the psoriatic epidermis, as shown by immunohistochemistry, as well as single-cell RNA sequencing, and its responsiveness to anti-TNF treatment was highlighted. By inhibiting the expression of KLK7, we further illustrated that keratinocytes have decreased proinflammatory responses to TNF. CONCLUSIONS: Our study implicates the genetic regulation of cytokine responses in predicting clinical drug response and supports the association between pharmacogenetic loci and anti-TNF response, as shown here for KLK7.

Epicardial adipose tissue volume is greater in men with severe psoriasis, implying an increased cardiovascular disease risk: A cross-sectional study.

BACKGROUND: Patients with psoriasis have elevated risk of coronary artery disease. OBJECTIVE: Do patients with severe psoriasis have larger epicardial adipose tissue volumes (EAT-V) that are associated with cardiovascular risk? METHODS: For this cross-sectional study, we recruited dermatology patients with severe psoriasis and control patients without psoriasis or rheumatologic disease themselves or in a first-degree relative. Participants aged 34 to 55 years without known coronary artery disease or diabetes mellitus underwent computed tomography (CT); EAT-V was obtained from noncontrast CT heart images. RESULTS: Twenty-five patients with psoriasis (14 men, 11 women) and 16 controls (5 men, 11 women) participated. Groups had no statistical difference in age, body mass index, various cardiovascular risk factors (except high-sensitivity C-reactive protein in men), CT-determined coronary artery calcium scores or plaque, or family history of premature cardiovascular disease. Mean EAT-V was greater in the psoriasis group compared to controls (P = .04). There was no statistically significant difference among women; however, male patients with psoriasis had significantly higher EAT-V than controls (P = .03), even when corrected for elevated high-sensitivity C-reactive protein (P = .05). LIMITATIONS: A single-center convenience sample may not be representative. CONCLUSION: Males with psoriasis without known coronary disease or diabetes had greater EAT-V than controls. EAT-V may be an early identifier of those at increased risk for cardiovascular events.

Mechanisms of dermatological toxicities to immune checkpoint inhibitor cancer therapies.

The discovery of immune checkpoint inhibition (ICI) sparked a revolution in the era of targeted anticancer therapy. However, although monoclonal antibodies targeting the cytotoxic T-lymphocyte antigen-4 and programmed death-1 axes have improved survival in patients with advanced cancers, these immunotherapies are associated with a wide spectrum of dermatological immune-related adverse events (irAEs), ranging from mild to life-threatening. Several publications have addressed the clinical and histopathological classification of these skin-directed irAEs, their impact on anti-tumour immunity and survival, and the critical role of supportive oncological dermatology in their management. In this paper, we review the current understanding of the mechanistic drivers of immune-related skin toxicities with a focus on inflammatory, immunobullous and melanocyte/pigment-related reactions. We detail the specific immune-based mechanisms that may underlie different cutaneous reactions. We also discuss potential mechanisms as they relate to extracutaneous irAEs and the lessons learned from these, the potential overlap with cutaneous irAEs, techniques to study differences in immune-related vs. de novo skin reactions, and how treatment of these AEs impacts cancer treatment, patient quality of life and overall survival. An improved understanding of the mechanistic basis of cutaneous irAEs will allow clinicians to develop and use blood-based biomarkers that could help ultimately predict onset and/or severity of these irAEs, and to implement rational mechanistic-based treatment strategies that are targeted to the irAEs while potentially avoiding reducing the anti-tumour effect of ICIs.

Thinning of the Skull Base and Calvarial Thickness in Patients With Idiopathic Intracranial Hypertension.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a disorder characterized by elevated intracranial pressure without secondary causes on neuroimaging. IIH typically occurs in young, obese female patients and, when severe, can cause permanent and irreversible vision loss. The association between skull base thinning in patients with intracranial hypertension and obesity has been previously reported; however, no study has reported these findings in IIH. The goal of our study is to determine whether IIH is independently associated with skull base and calvarial thinning. METHODS: A retrospective, matched case-control study was performed. Each patient diagnosed with IIH (case) was matched with a patient diagnosed with headache (control) by age, gender, and race. Patients were included if they underwent computed tomographic imaging of the head, maxillofacial, or orbits within 3 months of their diagnosis. Exclusion criteria were history of skull base or frontal bone pathology because of surgery or skull trauma, central nervous system infections, or incomplete radiologic data. Patient demographics, medical history, clinical examination, and skull base, calvarial, and zygoma thickness were recorded. Skull base thickness was measured by the height of the auditory canal in the coronal plane. Calvarial thickness was measured just anterior to the foramen rotundum in the coronal plane. Extracranial zygoma thickness was measured and used as an internal imaging control because the zygoma is not subject to intracranial forces. RESULTS: One hundred twenty-six patients were included in the study, 63 cases and 63 controls. Each group comprised 61 female patients (97%), 24 (38%) Caucasian, 23 (37%) black, 1 (2%) Asian, and 15 (24%) others. The average age was 31.5 ± 8.7 years. Patients with IIH were more likely to be obese (n = 60, 95%) compared with the control patients (n = 23, 37%, P < 0.001). All patients with IIH underwent lumbar puncture (LP) with an average opening pressure (OP) of 40.5 ± 15.6 cm H2O, whereas only 13 (20%) controls underwent an LP with a mean OP of 19.5 ± 8.5 cm H2O. There was no statistical difference in mean visual acuity between the IIH and control groups (logMar 0.22 [20/30] ± 0.45 vs logMar 0.09 [20/25] ± 0.30, P = 0.093, respectively). Compared with the controls, patients with IIH were more likely to have headache (97% vs 74%, P = 0.001), pulsatile tinnitus (48% vs 7%, P < 0.001), horizontal binocular diplopia (24% vs 4%, P = 0.006), confrontational visual field deficit (23% vs 2%, P = 0.003), and papilledema (74% vs 0%, P < 0.001). Patients with IIH had thinner skull base and calvarium width compared with the controls (mean skull base thickness 4.17 ± 0.94 mm vs 5.05 ± 1.12 mm, P < 0.001 and mean calvarial width 1.50 ± 0.50 mm vs 1.71 ± 0.61 mm, P = 0.024). Zygoma thickness was similar in both groups (mean zygoma thickness 1.18 ± 0.30 mm in the IIH group vs 1.26 ± 0.35 mm in the control group, P = 0.105). In a subgroup analysis controlling for obesity (body mass index >30 kg/m2), there was no statistically significant difference in skull base, calvarial, or zygoma thickness between obese and nonobese patients. CONCLUSIONS: Patients with IIH have thinner mean skull base and calvarial thickness compared with the controls. There was no difference in the mean extracranial zygoma thickness, which was the internal imaging control. Contrary to previous reports, we did not find an association between obesity and skull base or calvarial thinning. These findings suggest that IIH is associated with skull base and calvarial thinning.

Challenges faced by Otorhinolaryngology (ORL) services, Malaysia, in the current pandemic.

No abstract provided.

Otorhinolaryngology services at a district hospital in Sabah, Malaysia during the COVID-19 Pandemic.

No abstract provided.

Efficacy of Active Immunization With Attenuated α-Hemolysin and Panton-Valentine Leukocidin in a Rabbit Model of Staphylococcus aureus Necrotizing Pneumonia.

Staphylococcus aureus is a common pathogen causing infections in humans with various degrees of severity, with pneumonia being one of the most severe infections. In as much as staphylococcal pneumonia is a disease driven in large part by α-hemolysin (Hla) and Panton-Valentine leukocidin (PVL), we evaluated whether active immunization with attenuated forms of Hla (HlaH35L/H48L) alone, PVL components (LukS-PVT28F/K97A/S209A and LukF-PVK102A) alone, or combination of all 3 toxoids could prevent lethal challenge in a rabbit model of necrotizing pneumonia caused by the USA300 community-associated methicillin-resistant S. aureus (MRSA). Rabbits vaccinated with Hla toxoid alone or PVL components alone were only partially protected against lethal pneumonia, whereas those vaccinated with all 3 toxoids had 100% protection against lethality. Vaccine-mediated protection correlated with induction of polyclonal antibody response that neutralized not only α-hemolysin and PVL, but also other related toxins, produced by USA300 and other epidemic MRSA clones.

Systemic evaluation of the relationship between psoriasis, psoriatic arthritis and osteoporosis: observational and Mendelian randomisation study.

OBJECTIVES AND METHODS: With 432 513 samples from UK Biobank dataset, multivariable linear/logistic regression were used to estimate the relationship between psoriasis/psoriatic arthritis (PsA) and estimated bone mineral density (eBMD)/osteoporosis, controlling for potential confounders. Here, confounders were set in three ways: model0 (including age, height, weight, smoking and drinking), model1 (model0 +regular physical activity) and model2 (model1 +medication treatments). The eBMD was derived from heel ultrasound measurement. And 4904 patients with psoriasis and 847 patients with PsA were included in final analysis. Mendelian randomisation (MR) approach was used to evaluate the causal effect between them. RESULTS: Lower eBMD were observed in patients with PsA than in controls in both model0 (ß-coefficient=-0.014, p=0.0006) and model1 (ß-coefficient=-0.013, p=0.002); however, the association disappeared when conditioning on treatment with methotrexate or ciclosporin (model2) (ß-coefficient=-0.005, p=0.28), mediation analysis showed that 63% of the intermediary effect on eBMD was mediated by medication treatment (p<2E-16). Patients with psoriasis without arthritis showed no difference of eBMD compared with controls. Similarly, the significance of higher risk of osteopenia in patients with PsA (OR=1.27, p=0.002 in model0) could be eliminated by conditioning on medication treatment (p=0.244 in model2). Psoriasis without arthritis was not related to osteopenia and osteoporosis. The weighted Genetic Risk Score analysis found that genetically determined psoriasis/PsA were not associated with eBMD (p=0.24 and p=0.88). Finally, MR analysis showed that psoriasis/PsA had no causal effect on eBMD, osteoporosis and fracture. CONCLUSIONS: The effect of PsA on osteoporosis was secondary (eg, medication) but not causal. Under this hypothesis, psoriasis without arthritis was not a risk factor for osteoporosis.

Topological Arrangement of Cardiac Fibroblasts Regulates Cellular Plasticity.

RATIONALE: Cardiac fibroblasts do not form a syncytium but reside in the interstitium between myocytes. This topological relationship between fibroblasts and myocytes is maintained throughout postnatal life until an acute myocardial injury occurs, when fibroblasts are recruited to, proliferate and aggregate in the region of myocyte necrosis. The accumulation or aggregation of fibroblasts in the area of injury thus represents a unique event in the life cycle of the fibroblast, but little is known about how changes in the topological arrangement of fibroblasts after cardiac injury affect fibroblast function. OBJECTIVE: The objective of the study was to investigate how changes in topological states of cardiac fibroblasts (such as after cardiac injury) affect cellular phenotype. METHODS AND RESULTS: Using 2 and 3-dimensional (2D versus 3D) culture conditions, we show that simple aggregation of cardiac fibroblasts is sufficient by itself to induce genome-wide changes in gene expression and chromatin remodeling. Remarkably, gene expression changes are reversible after the transition from a 3D back to 2D state demonstrating a topological regulation of cellular plasticity. Genes induced by fibroblast aggregation are strongly associated and predictive of adverse cardiac outcomes and remodeling in mouse models of cardiac hypertrophy and failure. Using solvent-based tissue clearing techniques to create optically transparent cardiac scar tissue, we show that fibroblasts in the region of dense scar tissue express markers that are induced by fibroblasts in the 3D conformation. Finally, using live cell interferometry, a quantitative phase microscopy technique to detect absolute changes in single cell biomass, we demonstrate that conditioned medium collected from fibroblasts in 3D conformation compared with that from a 2D state significantly increases cardiomyocyte cell hypertrophy. CONCLUSIONS: Taken together, these findings demonstrate that simple topological changes in cardiac fibroblast organization are sufficient to induce chromatin remodeling and global changes in gene expression with potential functional consequences for the healing heart.

Factors associated with skin graft take in fibula and radial forearm free flap donor sites.

LEARNING OBJECTIVES: Identify factors associated with skin graft take in fibula free flaps (FFF) and radial forearm free flaps (RFFF) donor sites. STUDY OBJECTIVES: To determine which factors are associated with decreased skin graft take at the donor site in FFF and RFFF in head and neck patients. DESIGN: Retrospective Chart Review Case Series. SETTING: Multicenter Tertiary Care. METHODS: A multicenter retrospective review was performed at three institutions identifying patients who underwent free tissue transfer, specifically either FFF or RFFF, between 2007 and 2017. Patient demographics, medical history, and social history were examined including age, gender, BMI, smoking status, diabetes and preoperative anticoagulation use. Preoperative, intraoperative data, and postoperative data were also examined including tourniquet use, type of flap, area of skin graft, if the skin graft had a donor site or if it was taken from the flap, wound NPWT use, cast use, use of physical therapy, DVT prophylaxis, limb ischemia, heparin drip, and postoperative aspirin use. Statistical analysis was used to determine which factors were significantly associated with skin graft take. RESULTS: 1415 patients underwent a forearm or fibula flap and 938 patients underwent split-thickness skin graft. Of these, 592 patients had sufficient information and were included in the final analysis. There were 371 males and 220 females. The average age was 55.7. Complete skin graft take was seen in 480 patients (81.1%). On univariate analysis, patients with diabetes (p = .003), type of flap (fibula p < .001), skin graft area (p = .006), tourniquet use (p = .003), DVT prophylaxis (p = .008) and casting (p = .003) were significantly associated with decreased skin graft take rate. In a multivariate analysis, diabetes (OR 2.17 (95%CI 1.16-3.98)), fibula flaps (OR 2.86 (95%CI 1.79-4.76)), an increase in skin graft area (OR 1.01 (95%CI 1.01-1.01)), post-operative aspirin (OR 2.63 (95%CI 1.15-5.88), and casting (OR 2.94 (95%CI 1.22-7.14)) were associated with poor rates of skin graft take. CONCLUSION: Several factors affect skin graft take rate and should be considered when performing a skin graft for a donor site defect.

Tourniquet use and factors associated with hematoma formation in free tissue transfer.

PURPOSE: Our objective was to understand which variables are associated with hematoma formation at both the donor and recipient sites in head and neck free tissue transfer and if hematoma rates are affected by tourniquet use. METHODS: Patients were identified who underwent free tissue transfer at three institutions, specifically either a radial forearm free flap (RFFF) or a fibula free flap (FFF), between 2007 and 2017. Variables including use of tourniquet, anticoagulation, treatment factors, demographics, and post-operative factors were examined to see if they influenced hematoma formation at either the free tissue donor or recipient site. RESULTS: 1410 patients at three institutions were included in the analysis. There were 692 (49.1%) RFFF and 718 (50.9%) FFF. Tourniquets were used in 764 (54.1%) cases. There were 121 (8.5%) hematomas. Heparin drips (p < .001) and DVT prophylaxis (p = .03) were significantly associated with hematoma formation (OR 95% CI 12.23 (4.98-30.07), 3.46 (1.15-10.44) respectively) on multivariable analysis. CONCLUSIONS: Heparin Drips and DVT prophylaxis significantly increased hematoma rates in free flap patients while tourniquets did not affect rates of hematoma.

The Act1 D10N missense variant impairs CD40 signaling in human B-cells.

The TRAF3IP2 gene resides within one of at least 63 psoriasis susceptibility loci and encodes Act1, an adapter protein involved in IL-17 receptor and CD40 signaling pathways. TRAF3IP2 is distinctive (among <10% of candidate susceptibility genes) in that a strongly disease-associated variant encodes a missense SNP predicted to be functionally relevant (SNP rs33980500 C/T encoding Act1 pD10N). As assessed by flow cytometry, Act1 protein was expressed at the highest levels in monocytes, with lower levels in T-cells and B-cells. However, monocytes, T-cells and B-cells failed to respond to IL-17A stimulation of PBMC, as measured by flow cytometric determination of NF-κB phospho-p65. As an alternative stimulus, we treated PBMCs with trimerized recombinant human CD40L and assessed p65, p38 and Erk phosphorylation in CD19+ B-cells as a function of D10N genotype. The increase of phosphorylated p65, p38, and Erk was well-correlated across individuals, and CD40L-induced phosphorylation of p65, p38, and Erk was significantly attenuated in B-cells from Act1 D10N homozygotes, compared to heterozygotes and nullizygotes. Our results indicate that the Act1 D10N variant is a relevant genetic determinant of CD40L responsiveness in human B-cells, with the risk allele being associated with lower B-cell responses in an acute signaling context.

Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling.

Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 × 10-8, OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency < 0.01) via gene-wide aggregation testing (IFIH1: pburden = 2.53 × 10-7, OR = 0.707; TYK2: pburden = 6.17 × 10-4, OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted.

Brain Tumor Detection and Segmentation by Intensity Adjustment.

In recent years, Brain tumor detection and segmentation has created an interest on research areas. The process of identifying and segmenting brain tumor is a very tedious and time consuming task, since human physique has anatomical structure naturally. Magnetic Resonance Image (MRI) scan analysis is a powerful tool that makes effective detection of the abnormal tissues from the brain. Among different techniques, Magnetic Resonance Image (MRI) is a liable one which contains several modalities in scanning the images captured from interior structure of human brain. A novel hybrid energy-efficient method is proposed for automatic tumor detection and segmentation. The proposed system follows K-means clustering, integrated with Fuzzy C-Means (KMFCM) and active contour by level set for tumor segmentation. An effective segmentation, edge detection and intensity enhancement can detect brain tumor easily. For that, active contour with level set method has been utilized. The performance of the proposed approach has been evaluated in terms of white pixels, black pixels, tumor detected area, and the processing time. This technique can deal with a higher number of segmentation problem and minimum execution time by ensuring segmentation quality. Additionally, tumor area length in vertical and horizontal positions is determined to measure sensitivity, specificity, accuracy, and similarity index values. Further, tumor volume is computed. Knowledge of the information of tumor is helpful for the physicians for effective diagnosing in tumor for treatments. The entire experimentation was implemented in MATLAB environment and simulation results were compared with existing approaches.

Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture.

Psoriasis vulgaris (PsV) is a common inflammatory and hyperproliferative skin disease. Up to 30% of people with PsV eventually develop psoriatic arthritis (PsA), an inflammatory musculoskeletal condition. To discern differences in genetic risk factors for PsA and cutaneous-only psoriasis (PsC), we carried out a genome-wide association study (GWAS) of 1,430 PsA case subjects and 1,417 unaffected control subjects. Meta-analysis of this study with three other GWASs and two targeted genotyping studies, encompassing a total of 9,293 PsV case subjects, 3,061 PsA case subjects, 3,110 PsC case subjects, and 13,670 unaffected control subjects of European descent, detected 10 regions associated with PsA and 11 with PsC at genome-wide (GW) significance. Several of these association signals (IFNLR1, IFIH1, NFKBIA for PsA; TNFRSF9, LCE3C/B, TRAF3IP2, IL23A, NFKBIA for PsC) have not previously achieved GW significance. After replication, we also identified a PsV-associated SNP near CDKAL1 (rs4712528, odds ratio [OR] = 1.16, p = 8.4 × 10(-11)). Among identified psoriasis risk variants, three were more strongly associated with PsC than PsA (rs12189871 near HLA-C, p = 5.0 × 10(-19); rs4908742 near TNFRSF9, p = 0.00020; rs10888503 near LCE3A, p = 0.0014), and two were more strongly associated with PsA than PsC (rs12044149 near IL23R, p = 0.00018; rs9321623 near TNFAIP3, p = 0.00022). The PsA-specific variants were independent of previously identified psoriasis variants near IL23R and TNFAIP3. We also found multiple independent susceptibility variants in the IL12B, NOS2, and IFIH1 regions. These results provide insights into the pathogenetic similarities and differences between PsC and PsA.

Effects of teriparatide on morphology of aortic calcification in aged hyperlipidemic mice.

Calcific aortic vasculopathy correlates with bone loss in osteoporosis in an age-independent manner. Prior work suggests that teriparatide, the bone anabolic treatment for postmenopausal osteoporosis, may inhibit the onset of aortic calcification. Whether teriparatide affects the progression of preexisting aortic calcification, widespread among this patient population, is unknown. Female apolipoprotein E-deficient mice were aged for over 1 yr to induce aortic calcification, treated for 4.5 wk with daily injections of control vehicle (PBS), 40 µg/kg teriparatide (PTH40), or 400 µg/kg teriparatide (PTH400), and assayed for aortic calcification by microcomputed tomography (microCT) before and after treatment. In a followup cohort, aged female apolipoprotein E-deficient mice were treated with PBS or PTH400 and assayed for aortic calcification by serial microCT and micropositron emission tomography. In both cohorts, aortic calcification detected by microCT progressed similarly in all groups. Mean aortic 18F-NaF incorporation, detected by serial micropositron emission tomography, increased in the PBS-treated group (+14 ± 5%). In contrast, 18F-NaF incorporation decreased in the PTH400-treated group (-33 ± 20%, P = 0.03). Quantitative histochemical analysis by Alizarin red staining revealed a lower mineral surface area index in the PTH400-treated group compared with the PBS-treated group ( P = 0.04). Furthermore, Masson trichrome staining showed a significant increase in collagen deposition in the left ventricular myocardium of mice that received PTH400 [2.1 ± 0.6% vs. control mice (0.5 ± 0.1%), P = 0.02]. In summary, although teriparatide may not affect the calcium mineral content of aortic calcification, it reduces 18F-NaF uptake in calcified lesions, suggesting the possibility that it may reduce mineral surface area with potential impact on plaque stability. NEW & NOTEWORTHY Parathyroid hormone regulates bone mineralization and may also affect vascular calcification, which is an important issue, given that its active fragment, teriparatide, is widely used for the treatment of osteoporosis. To determine whether teriparatide alters vascular calcification, we imaged aortic calcification in mice treated with teriparatide and control mice. Although teriparatide did not affect the calcium content of cardiovascular deposits, it reduced their fluoride tracer uptake.

Phase-contrast cerebrospinal fluid flow magnetic resonance imaging in qualitative evaluation of patency of CSF flow pathways prior to infusion of chemotherapeutic and other agents into the fourth ventricle.

PURPOSE: Nuclear medicine studies have previously been utilized to assess for blockage of cerebrospinal fluid (CSF) flow prior to intraventricular chemotherapy infusions. To assess CSF flow without nuclear medicine studies, we obtained cine phase-contrast MRI sequences that assess CSF flow from the fourth ventricle down to the sacrum. METHODS: In three clinical trials, 18 patients with recurrent malignant posterior fossa tumors underwent implantation of a ventricular access device (VAD) into the fourth ventricle, either with or without simultaneous tumor resection. Prior to infusing therapeutic agents into the VAD, cine MRI phase-contrast CSF flow sequences of the brain and total spine were performed. Velocity encoding (VENC) of 5 and 10 cm/s was used to confirm CSF flow from the fourth ventricular outlets to the cervical, thoracic, and lumbar spine. Qualitative CSF flow was characterized by neuroradiologists as present or absent. RESULTS: All 18 patients demonstrated CSF flow from the outlets of the fourth ventricle down to the sacrum with no evidence of obstruction. One of these patients, after disease progression, subsequently showed obstruction of CSF flow. No patient required a nuclear medicine study to assess CSF flow prior to initiation of infusions. Fourteen patients have received infusions to date, and none has had neurological toxicity. CONCLUSIONS: CSF flow including the fourth ventricle and the total spine can be assessed noninvasively with phase-contrast MRI sequences. Advantages over nuclear medicine studies include avoiding both an invasive procedure and radiation exposure.