Cardio-rheumatology: the cardiovascular, pharmacological, and surgical risks associated with rheumatological diseases in women.

Cardiovascular disease (CVD) remains the number one cause of death worldwide. Women are at increased risk of death from CVD, but the mechanisms for how and why this occurs remain elusive. One subset of women who are exceptionally vulnerable to CVD are those with rheumatic diseases (RDs). Indeed, women account for 80% of all RDs, disorders that encompass a broad range of autoimmune and autoinflammatory diseases that lead to chronic inflammation and pathology. The clear association of increased CVD risk in women with RD is thought to be mediated by a number of factors, including RD pathology itself, pharmacological induction of CVD, and/or as yet unidentified mechanisms. As such, elucidation of the causes and treatments of these pathologies has given rise to a new subspecialty of cardiology: cardio-rheumatology. Here, we review and discuss the CVD risks in patients with RDs, the associated sex disparities in RD and CVD care, as well as the current therapeutic and interventional options available to specifically help women with RDs. We hope this discussion will provide guidance and support to patients, as well as to cardio-rheumatologists, as these groups are the most uniquely positioned to radically improve CVD care in these individuals. Moreover, we are hopeful this discussion may lead to better, more efficacious approaches to treating these disorders in women in the near future.

The rising tide raises all ships.

It is easy to feel as if you are alone in academia, especially if you face challenges that not everyone does, or can, understand. Community is essential in facing these challenges, and we each have a role to play in creating a more equitable research community. Here, I discuss the importance of community, finding your village and being part of the academic support system.

Eosinophilic pericardial effusion and pericarditis in a cat.

Case summary: A 10-year-old domestic shorthair cat presented for lethargy, anorexia and labored breathing. Significant pleural and pericardial effusions prompted thoracocentesis and pericardiocentesis. Cytologic evaluation of the pericardial effusion revealed a highly cellular hemorrhagic, eosinophilic (12%) effusion, with many markedly atypical suspected mesothelial cells, interpreted as concerning for neoplasia. Thoracoscopic subtotal pericardiectomy and histology of the pericardium revealed predominantly eosinophilic inflammation with multifocal mesothelial hypertrophy and ulceration. A peripheral eosinophilia was not present on serial complete blood counts. Initial infectious disease testing was mostly negative. Toxoplasma gondii titers were most consistent with prior exposure, although reactivation could not be excluded. The owner's medical history included a prior diagnosis of bartonellosis. Owing to the challenges of definitive Bartonella species exclusion, the cat was treated empirically with pradofloxacin and doxycycline, and a subtotal pericardectomy. There was improvement at first but pleural effusion recurred approximately 3 months after discharge. The cat was euthanized and a necropsy was not performed. Subsequent pericardial effusion Piroplasma/Bartonella/Borrelia droplet digital PCR detected DNA of Bartonella vinsonii subspecies berkhoffii, and peripheral blood culture and sequencing revealed a rare apicomplexan organism (90% homology with Colpodella species) of unknown clinical significance. Testing for filamentous bacteria and fungal pathogens was not performed. Relevance and novel information: This case offers several unique entities - eosinophilic pericardial effusion and eosinophilic pericarditis of unknown etiology - and illustrates the well-known marked atypia that may occur in reactive and hyperplastic mesothelial cells, particularly of infrequently sampled and cytologically described feline pericardial effusion, supporting a cautious interpretation of this cytology finding.

Imaging Diagnosis: Thoracic radiographic features of toxoplasmosis in a 14-month-old Red Kangaroo (Macropus rufus).

A privately owned 14-month-old intact female red kangaroo (Macropus rufus) was presented for acute onset respiratory distress and lethargy. On presentation, the kangaroo was laterally recumbent, tachypneic, dyspneic, lethargic, and obtunded. Thoracic radiographs revealed a severe diffuse mixed pulmonary pattern (alveolar pattern superimposed on a bronchial pattern) and subjective mild generalized cardiomegaly. Due to the severity of clinical signs and grave prognosis, euthanasia was elected. Postmortem examination was consistent with systemic toxoplasmosis. Histopathology and immunohistochemistry staining on infected tissues confirmed Toxoplasma gondii. This is the first published report of radiographic findings for confirmed toxoplasmosis in a red kangaroo or marsupial.

Creation of a Continent Urinary Bladder Reservoir Vascularized by Omentum as a Possible Surgical Option for Canine Trigonal/Urethral Urothelial Carcinoma.

Surgical procedures that maintain continence with minimal complication following resection of trigono-urethral urothelial carcinoma (UC) are limited in canines; therefore, palliative options are often pursued. A feasible tumor resection option may improve disease control and survival. The study's objective was to evaluate a continent urine reservoir created from the urinary bladder body and vascularized solely by omentum. We hypothesized that a viable urine reservoir could be created, and staged omentalization would provide improved vascularity. Nine normal female Beagles were randomized to one of three groups. Group A urinary bladders were transected cranial to the ureteral papillae to create a closed bladder vesicle which was concomitantly omentalized. Group B underwent omentalization two weeks prior to vesicle creation. Based on Group A and B results, Group C underwent neoureterocystostomy and omentalization followed by neoreservoir formation and tube cystostomy 2 weeks later. Serial ultrasounds and histopathology confirmed adequate omental neovascularization in Groups B and C with continent Group C neoreservoirs maintained for 2 months. Some pylectasia and ureteral dilation was documented in all Group C dogs at variable timepoints. Progressive hydroureteronephrosis developed in 2/6 kidneys. Transient azotemia was noted in only 1 Group C dog, although all developed treatable urinary tract infections. The sample size is limited, and the efficacy of this technique in providing disease control for UC is unknown. However, this novel option could allow for primary UC resection while providing continence and limiting complications. Postoperative local or systemic adjuvant therapy, ultrasonographic neoreservoir monitoring, and BRAF analysis would be indicated.

A novel device to measure static hindlimb weight-bearing forces in pronograde rodents.

BACKGROUND: Joint pain is composed of both spontaneous and movement-induced pain. In animal models, static bodyweight distribution is a surrogate for spontaneous joint pain. However, there are no commercially-available instruments that measure static bodyweight distribution in normal, pronograde rodents. NEW METHOD: We designed a Static Horizontal Incapacitance Meter (SHIM) to measure bodyweight distribution in pronograde standing rodents. We assessed the device for feasibility, repeatability, and sensitivity to quantify hindlimb bodyweight distribution. Mice and rats with unilateral inflammatory pain induced by subcutaneous injections of capsaicin or Complete Freund's Adjuvant (CFA) into the plantar surface of the left hind paw were used to measure static weight-bearing. The ability to attenuate inflammatory pain-associated weight-bearing asymmetry was tested by administering a non-steroidal anti-inflammatory drug, meloxicam. RESULTS: The SHIM's ability to detect significant reductions in limb loading on the injected hindlimb in mice and rats was validated using both acute and sub-chronic pain models. Treatment with meloxicam partially reversed CFA-induced effects. COMPARISON WITH EXISTING METHODS: In contrast with assays that measure kinetic or static weight-bearing forces (e.g., walking, or standing at a 45 ° incline), the SHIM allows evaluation of weight-bearing in rodents that are standing at rest in their normal pronograde position. CONCLUSIONS: The SHIM successfully detected: (a) asymmetric weight-bearing in acute and sub-chronic pain models; and (b) the analgesic effects of meloxicam. This study provides a novel tool to objectively evaluate limb use dysfunction in rodents.

Web-based Assessment of Social-Emotional Skills in School-Aged Youth with Autism Spectrum Disorder.

Few tools are available to comprehensively describe the unique social-emotional skill profiles of youth with autism spectrum disorder (ASD). The present study describes the usability, reliability, and validity of SELweb, a normed, web-based assessment designed to measure four core social-emotional domains, when used to measure these skills in a sample of 57 well-characterized youth with ASD (ages 6-10 years with IQ ≥ 80). SELweb measures facial emotion recognition, theory of mind, social problem solving, and self-control. SELweb was well tolerated and yielded scores with reliabilities comparable to those found in normative samples. SELweb scores showed good evidence of convergent and discriminant validity for three of the four skills it was designed to assess. Mean deficits were found for theory of mind, social problem solving, and self-control, whereas no mean deficits were found for emotion recognition. Individual profiles varied considerably, suggesting the sensitivity of SELweb to the within- and between-person individual differences among youth with ASD. Findings support the usefulness and accessibility of SELweb as a tool for measuring complex social-emotional skill profiles in youth with ASD. Autism Res 2019, 12: 1260-1271. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: No single, simple, high-quality test exists that measures multiple social thinking skills directly in children with autism spectrum disorder (ASD). The present study suggests that SELweb, a web-based assessment system, is an effective and valid way to measure how children with ASD think about and understand social and emotional information, and is able to capture strengths and weaknesses experienced by children with ASD.

Deficiency in Protein Tyrosine Phosphatase PTP1B Shortens Lifespan and Leads to Development of Acute Leukemia.

Protein tyrosine phosphatase PTP1B is a critical regulator of signaling pathways controlling metabolic homeostasis, cell proliferation, and immunity. In this study, we report that global or myeloid-specific deficiency of PTP1B in mice decreases lifespan. We demonstrate that myeloid-specific deficiency of PTP1B is sufficient to promote the development of acute myeloid leukemia. LysM-PTP1B-/- mice lacking PTP1B in the innate myeloid cell lineage displayed a dysregulation of bone marrow cells with a rapid decline in population at midlife and a concomitant increase in peripheral blood blast cells. This phenotype manifested further with extramedullary tumors, hepatic macrophage infiltration, and metabolic reprogramming, suggesting increased hepatic lipid metabolism prior to overt tumor development. Mechanistic investigations revealed an increase in anti-inflammatory M2 macrophage responses in liver and spleen, as associated with increased expression of arginase I and the cytokines IL10 and IL4. We also documented STAT3 hypersphosphorylation and signaling along with JAK-dependent upregulation of antiapoptotic proteins Bcl2 and BclXL. Our results establish a tumor suppressor role for PTP1B in the myeloid lineage cells, with evidence that its genetic inactivation in mice is sufficient to drive acute myeloid leukemia.Significance: This study defines a tumor suppressor function for the protein tyrosine phosphatase PTP1B in myeloid lineage cells, with evidence that its genetic inactivation in mice is sufficient to drive acute myeloid leukemia. Cancer Res; 78(1); 75-87. ©2017 AACR.

Pharmacological inhibition of protein tyrosine phosphatase 1B protects against atherosclerotic plaque formation in the LDLR-/- mouse model of atherosclerosis.

Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with type 1 or type 2 diabetes, due to accelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance, due to impaired insulin receptor (IR) signalling. Here, we demonstrate that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR prevents and reverses atherosclerotic plaque formation in an LDLR-/- mouse model of atherosclerosis. Acute (single dose) or chronic PTP1B inhibitor (trodusquemine) treatment of LDLR-/- mice decreased weight gain and adiposity, improved glucose homeostasis and attenuated atherosclerotic plaque formation. This was accompanied by a reduction in both, circulating total cholesterol and triglycerides, a decrease in aortic monocyte chemoattractant protein-1 (MCP-1) expression levels and hyperphosphorylation of aortic Akt/PKB and AMPKα. Our findings are the first to demonstrate that PTP1B inhibitors could be used in prevention and reversal of atherosclerosis development and reduction in CVD risk.

Selection for a Single Self-Assembled Macrocycle from a Hybrid Metal-Ligand Hydrogen-Bonded (MLHB) Ligand Subunit.

To expand the interface between self-assembled metal-ligand and hydrogen-bonded architectures, here we report the preparation, self-assembly, and metal-ligand binding of a pyridyl quinolone ligand (5-PYQ). The 5-PYQ ligand self-associates through quinolone hydrogen bonding, and it binds to metal centers through the pyridine ligand component. As a first step toward investigating more-complex hybrid metal-ligand hydrogen-bonded (MLHB) architectures, we report investigations of 5-PYQ with mono- and bis-platinated anthracene precursors. These results demonstrate that the 5-PYQ ligand maintains hydrogen bonding interactions while binding to square-planar platinum centers, but that generation of coordination compounds with closed topology erodes the hydrogen bonding fidelity to favor ambidentate coordination modes of the 5-PYQ ligand.

Probing the Protonation State and the Redox-Active Sites of Pendant Base Iron(II) and Zinc(II) Pyridinediimine Complexes.

Utilizing the pyridinediimine ligand [(2,6-(i)PrC6H3)N═CMe)(N((i)Pr)2C2H4)N═CMe)C5H3N] (didpa), the zinc(II) and iron(II) complexes Zn(didpa)Cl2 (1), Fe(didpa)Cl2 (2), [Zn(Hdidpa)Cl2][PF6] (3), [Fe(Hdidpa)Cl2][PF6] (4), Zn(didpa)Br2 (5), and [Zn(Hdidpa)Br2][PF6] (6), Fe(didpa)(CO)2 (7), and [Fe(Hdidpa)(CO)2][PF6] (8) were synthesized and characterized. These complexes allowed for the study of the secondary coordination sphere pendant base and the redox-activity of the didpa ligand scaffold. The protonated didpa ligand is capable of forming metal halogen hydrogen bonds (MHHBs) in complexes 3, 4, and 6. The solution behavior of the MHHBs was probed via pKa measurements and (1)H NMR titrations of 3 and 6 with solvents of varying H-bond accepting strength. The H-bond strength in 3 and 6 was calculated in silico to be 5.9 and 4.9 kcal/mol, respectively. The relationship between the protonation state and the ligand-based redox activity was probed utilizing 7 and 8, where the reduction potential of the didpa scaffold was found to shift by 105 mV upon protonation of the reduced ligand in Fe(didpa)(CO)2.

A key role for PTP1B in dendritic cell maturation, migration, and T cell activation.

Dendritic cells (DC) are the major antigen-presenting cells bridging innate and adaptive immunity, a function they perform by converting quiescent DC to active, mature DC with the capacity to activate naïve T cells. They do this by migrating from the tissues to the T cell area of the secondary lymphoid tissues. Here, we demonstrate that myeloid cell-specific genetic deletion of PTP1B (LysM PTP1B) leads to defects in lipopolysaccharide-driven bone marrow-derived DC (BMDC) activation associated with increased levels of phosphorylated Stat3. We show that myeloid cell-specific PTP1B deletion also causes decreased migratory capacity of epidermal DC, as well as reduced CCR7 expression and chemotaxis to CCL19 by BMDC. PTP1B deficiency in BMDC also impairs their migration in vivo. Further, immature LysM PTP1B BMDC display fewer podosomes, increased levels of phosphorylated Src at tyrosine 527, and loss of Src localization to podosome puncta. In co-culture with T cells, LysM PTP1B BMDC establish fewer and shorter contacts than control BMDC. Finally, LysM PTP1B BMDC fail to present antigen to T cells as efficiently as control BMDC. These data provide first evidence for a key regulatory role for PTP1B in mediating a central DC function of initiating adaptive immune responses in response to innate immune cell activation.

Design, synthesis, and characterization of hybrid metal-ligand hydrogen-bonded (MLHB) supramolecular architectures.

Despite the prevalence of supramolecular architectures derived from metal-ligand or hydrogen-bonding interactions, few studies have focused on the simultaneous use of these two strategies to form discrete assemblies. Here we report the use of a supramolecular tecton containing both metal-binding and self-complementary hydrogen-bonding interactions that upon treatment with metal precursors assembles into discrete hybrid metal-ligand hydrogen-bonded assemblies with closed topology. (1)H NMR DOSY experiments established the stability of the structures in solution, and the measured hydrodynamic radii match those determined crystallographically, suggesting that the closed topology is maintained both in solution and in the solid state. Taken together, these results demonstrate the validity of using both hydrogen-bonding and metal-ligand interactions to form stable supramolecular architectures.

Chemically reversible reactions of hydrogen sulfide with metal phthalocyanines.

Hydrogen sulfide (H2S) is an important signaling molecule that exerts action on various bioinorganic targets. Despite this importance, few studies have investigated the differential reactivity of the physiologically relevant H2S and HS(-) protonation states with metal complexes. Here we report the distinct reactivity of H2S and HS(-) with zinc(II) and cobalt(II) phthalocyanine (Pc) complexes and highlight the chemical reversibility and cyclability of each metal. ZnPc reacts with HS(-), but not H2S, to generate [ZnPc-SH](-), which can be converted back to ZnPc by protonation. CoPc reacts with HS(-), but not H2S, to form [Co(I)Pc](-), which can be reoxidized to CoPc by air. Taken together, these results demonstrate the chemically reversible reaction of HS(-) with metal phthalocyanine complexes and highlight the importance of H2S protonation state in understanding the reactivity profile of H2S with biologically relevant metal scaffolds.