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Microvascular disease plays critical roles in the dysfunction of all organ systems, and there are many methods available to assess the microvasculature. These methods can either assess the target organ directly or assess an easily accessible organ such as the skin or retina so that inferences can be extrapolated to the other systems and/or related diseases. Despite the abundance of exploratory research on some of these modalities and their possible applications, there is a general lack of clinical use. This deficiency is likely due to two main reasons: the need for standardization of protocols to establish a role in clinical practice or the lack of therapies targeted toward microvascular dysfunction. Also, there remain some questions to be answered about the coronary microvasculature, as it is complex, heterogeneous, and difficult to visualize in vivo even with advanced imaging technology. This review will discuss novel approaches that are being used to assess microvasculature health in several key organ systems, and evaluate their clinical utility and scope for further development.

Opioids are potent analgesics, but their pain-relieving effects diminish with repeated use. The reduction in analgesic potency is a hallmark of opioid analgesic tolerance, which hampers opioid pain therapy. In the central nervous system, opioid analgesia is critically modulated by adenosine, a purine nucleoside implicated in the beneficial and detrimental actions of opioid medications. Here, we focus on the A3 adenosine receptor (A3 AR) in opioid analgesic tolerance. Intrathecal administration of the A3 AR agonist MRS5698 with daily systemic morphine in male rats attenuated the reduction in morphine antinociception over 7 days. In rats with established morphine tolerance, intrathecal MRS5698 partially restored the antinociceptive effects of morphine. However, when MRS5698 was discontinued, these animals displayed a reduced antinociceptive response to morphine. Our results suggest that MRS5698 acutely and transiently potentiates morphine antinociception in tolerant rats. By contrast, in morphine-naive rats MRS5698 treatment did not impact thermal nociceptive threshold or affect antinociceptive response to a single injection of morphine. Furthermore, we found that morphine-induced adenosine release in cerebrospinal fluid was blunted in tolerant animals, but total spinal A3 AR expression was not affected. Collectively, our findings indicate that spinal A3 AR activation acutely potentiates morphine antinociception in the opioid tolerant state.

Background Endovascular treatment of mesenteric lesions has become increasingly prevalent. Mesenteric bypass, however, remains the optimal treatment in the cases of chronic mesenteric ischemia (CMI) in young, medically fit patients given its durability. Endarterectomy, has gone by the wayside, but in certain situations, this technique remains surgically relevant and should still be employed. Herein we present two cases of distal superior mesenteric artery (SMA) endarterectomy for mesenteric revascularization. Case Reports Case 1 is a 40-year-old male with history of antithrombin III deficiency, myocardial infarction, bilateral pulmonary embolism, acute aortic thrombus, and mesenteric ischemia status post placement of a proximal SMA stent, and was transferred to our institution due to concern for ischemic bowel. Intraoperative angiography showed mid to distal SMA chronic thromboembolism with narrow lumen of recanalization and distal flow. No intervention was performed at that time. He developed worsening abdominal pain and weight loss over several months which required initiation of total parenteral nutrition, complicated by line-associated sepsis. Subsequent distal SMA endarterectomy was performed. He recovered well and had improved enteral intake at 1-month follow-up and radiographic imaging at 2-months showed patent vessels. Case 2 is a 50-year-old female with extensive smoking history and hyperlipidemia and gastroesophageal reflux who presented with post-prandial abdominal pain and a forty-pound weight loss over the past year. Attempted angiographic cannulation with stent was not successful due to flush occlusion of the SMA approximately one centimeter distal to the ostium that was unable to be crossed. Computed tomography angiography confirmed that the SMA origin was free of atherosclerotic disease with a distal focal segment of occlusion. She underwent successful endarterectomy of this occlusion. The post-operative course was uneventful and at 1-month follow up, she reported continued improvement in pain and appetite. Conclusion SMA endarterectomy can be successfully performed on mid- to distal-lesions of the SMA. This operation should remain a viable option in the management of CMI.

Background Gliosis is common among neuropsychiatric diseases, but the relationship between gliosis and response to therapeutics targeting effects of gliosis is largely unknown. Translocator protein total distribution volume (TSPO VT), measured with positron emission tomography, mainly reflects gliosis in neuropsychiatric disease. Here, the primary objective was to determine whether TSPO VT in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC) predicts reduction of depressive symptoms following open-label celecoxib administration in treatment-resistant major depressive disorder. Methods A total of 41 subjects with treatment-resistant major depressive disorder underwent one [18F]FEPPA positron emission tomography scan to measure PFC and ACC TSPO VT. Open-label oral celecoxib (200 mg, twice daily) was administered for 8 weeks. Change in symptoms was measured with the 17-item Hamilton Depression Rating Scale (HDRS). Results Cumulative mean change in HDRS scores between 0 and 8 weeks of treatment was plotted against PFC and ACC TSPO VT, showing a significant nonlinear relationship. At low TSPO VT values, there was no reduction in HDRS scores, but as TSPO VT values increased, there was a reduction in HDRS scores that then plateaued. This was modeled with a 4-parameter sigmoidal model in which PFC and ACC TSPO VT accounted for 84% and 92% of the variance, respectively. Conclusions Celecoxib administration in the presence of gliosis labeled by TSPO VT is associated with greater reduction of symptoms. Given the predictiveness of TSPO VT on symptom reduction, this personalized medicine approach of matching a marker of gliosis to medication targeting effects of gliosis should be applied in early development of novel therapeutics, in particular for treatment-resistant major depressive disorder.

Greater activation of glia, a key component of neuroinflammation, is an important process to target in neuropsychiatric illnesses. However, the magnitude of gliosis varies across cases so low-cost predictors are needed to stratify subjects for clinical trials. Here, several such blood serum measures were assessed in relation to TSPO V(T), an index of translocator protein density, measured with positron emission tomography. Blood serum concentration of several products known to be synthesized by activated microglia (and to some extent astroglia) [prostaglandin E(2) (PGE(2)), prostaglandin F(2) alpha (PGF(2α)), and tumor necrosis factor alpha (TNF(α))], controlled by an index of peripheral inflammation [C-reactive protein (CRP)] and TSPO V(T) were measured in 3 cohorts: prefrontal cortex TSPO V(T) of 20 subjects with major depressive episodes (MDEs) from major depressive disorder (MDD); and 56 subjects with treatment resistant MDEs from MDD; and dorsal caudate TSPO V(T) of 20 subjects with obsessive-compulsive disorder. Ln(PGE(2)/CRP) and ln(TNF(α)/CRP) consistently correlated with TSPO V(T) (R(2) = 0.36 to 0.11, p = 0.0030 to p = 0.0076). Assessment of threshold serum values to predict highly elevated TSPO V(T), demonstrated that a positive predictive value (PPV) of 80% was possible while retaining 40% of participant samples and that receiver operating curves (ROC) ranged from 75 to 81%. Post-hoc selection of ln(CRP) was more predictive (R(2) = 0.23 to 0.39, p = 0.0058 to p = 0.00013; ROC > 80%). Systematic assessment of selected peripheral inflammatory markers is promising for developing low cost predictors of TSPO V(T). Marker thresholds with high PPV will improve subject stratification for clinical trials of glial targeting therapeutics.

Engineered proteins provide an interesting template for designing fluorine-19 (19F) magnetic resonance imaging (MRI) contrast agents, yet progress has been hindered by the unpredictable relaxation properties of fluorine. Herein, we present the biosynthesis of a protein block copolymer, termed "fluorinated thermoresponsive assembled protein" (F-TRAP), which assembles into a monodisperse nanoscale micelle with interesting 19F NMR properties and the ability to encapsulate and release small therapeutic molecules, imparting potential as a diagnostic and therapeutic (theranostic) agent. The assembly of the F-TRAP micelle, composed of a coiled-coil pentamer corona and a hydrophobic, thermoresponsive elastin-like polypeptide core, results in a drastic depression in spin-spin relaxation ( T2) times and unaffected spin-lattice relaxation ( T1) times. The nearly unchanging T1 relaxation rates and linearly dependent T2 relaxation rates have allowed for detection via zero echo time 19F MRI, and the in vivo MR potential has been preliminarily explored using 19F magnetic resonance spectroscopy (MRS). This fluorinated micelle has also demonstrated the ability to encapsulate the small-molecule chemotherapeutic doxorubicin and release its cargo in a thermoresponsive manner owing to its inherent stimuli-responsive properties, presenting an interesting avenue for the development of thermoresponsive 19F MRI/MRS-traceable theranostic agents.

Objective Upper extremity (UE) deep vein thrombosis (DVT) is a common and increasing complication in hospitalized patients. The objective of the present study was to determine the prevalence, treatment strategies, complications, and outcomes of UE-DVT. Methods We performed a retrospective single-institution study of patients with a diagnosis of UE-DVT from January 2016 through February 2018 (26 months). Patients aged ≥18 years who had been admitted to the hospital and who had had positive UE duplex ultrasound findings for acute UE-DVT were included in the present study. The outcomes were in-hospital mortality, major bleeding, pulmonary embolism (PE), and recurrent UE-DVT. Results Among 63,045 patients admitted to the hospital, 1000 (1.6%) had been diagnosed with UE-DVT. Of 3695 UE venous duplex ultrasound examinations performed during the study period, almost one third (27.0%) were positive for acute UE-DVT. The mean age was 55.0 ± 17.2 years, and most patients were men (58.3%), white (49.2%), and overweight (mean body mass index, 29.4 ± 10.3 kg/m2). The most affected vein was the right internal jugular vein (54.8%). Most of the patients (96.9%) has been receiving venous thromboembolism prophylaxis or anticoagulation therapy at the diagnosis. Most patients (77.8%) had had an intravenous device (IVD) in place at the diagnosis. Most of the patients (84.4%) were treated with anticoagulation therapy in the hospital but only one half (54.5%) were discharged with anticoagulation therapy. In-hospital mortality was 12.1% unrelated to UE-DVT, major bleeding occurred in 47.6% of the patients during hospitalization (fatal bleeding, 1%), PE was diagnosed in 4.8% of the patients, and 0.7% were fatal. Recurrent UE-DVT occurred in 6.1% of the patients. On multivariable analysis, the risk of death was increased by older age, cancer, intensive care unit admission, concomitant lower extremity DVT, and bleeding before the UE-DVT diagnosis. The presence of an IVD increased the risk of PE and the risk of recurrent UE-DVT. The risk of major bleeding was increased by the presence of an IVD, female sex, and concomitant lower extremity DVT. Conclusions UE-DVT is a common complication in hospitalized patients (1.6%). Consequent acute PE and recurrent DVT remain important complications, as does bleeding. It is unclear whether standard thromboprophylaxis effectively protects against UE-DVT. More studies dedicated to UE-DVT are required to provide appropriate guidance on prophylaxis and treatment.

Opioids are potent analgesics, but their pain-relieving effects diminish with repeated use. The reduction in analgesic potency is a hallmark of opioid analgesic tolerance, which hampers opioid pain therapy. In the central nervous system, opioid analgesia is critically modulated by adenosine, a purine nucleoside implicated in the beneficial and detrimental actions of opioid medications. Here, we focus on the A(3) adenosine receptor (A(3)AR) in opioid analgesic tolerance. Intrathecal administration of the A(3)AR agonist MRS5698 with daily systemic morphine in male rats attenuated the reduction in morphine antinociception over 7 days. In rats with established morphine tolerance, intrathecal MRS5698 partially restored the antinociceptive effects of morphine. However, when MRS5698 was discontinued, these animals displayed a reduced antinociceptive response to morphine. Our results suggest that MRS5698 acutely and transiently potentiates morphine antinociception in tolerant rats. By contrast, in morphine-naïve rats MRS5698 treatment did not impact thermal nociceptive threshold or affect antinociceptive response to a single injection of morphine. Furthermore, we found that morphine-induced adenosine release in cerebrospinal fluid was blunted in tolerant animals, but total spinal A(3)AR expression was not affected. Collectively, our findings indicate that spinal A(3)AR activation acutely potentiates morphine antinociception in the opioid tolerant state.

Impact investing has grown significantly over the past 15 years. From a niche investing segment with only $25 billion AUM in 2013 (WEF 2013), it experienced double-digit growth and developed into a market with an estimated $502 billion AUM (Mudaliapar and Dithrich 2019). Despite the growth and maturation of impact investing, gathering complete and accurate data on the characteristics of this industry continues to be a challenge. This paper describes the creation of a new dataset on both impact investors and the portfolio companies they fund, comprising 445 impact investors and 14,165 portfolio companies. We code impact investors according to established categories such as legal form, types of investments and return objectives. We then develop measures of the relative importance of social impact for each investor in an effort to add a new analytic categorization. We conclude by describing the distribution of investors and firms across these various categories.

Engineered proteins provide an interesting template for designing fluorine-19 ((19)F) magnetic resonance imaging (MRI) contrast agents, yet progress has been hindered by the unpredictable relaxation properties of fluorine. Herein, we present the biosynthesis of a protein block copolymer, termed “fluorinated thermoresponsive assembled protein” (F-TRAP), which assembles into a monodisperse nanoscale micelle with interesting (19)F NMR properties and the ability to encapsulate and release small therapeutic molecules, imparting potential as a diagnostic and therapeutic (theranostic) agent. The assembly of the F-TRAP micelle, composed of a coiled-coil pentamer corona and a hydrophobic, thermoresponsive elastin-like polypeptide core, results in a drastic depression in spin-spin relaxation (T(2)) times and unaffected spin-lattice relaxation (T(1)) times. The nearly unchanging T(1) relaxation rates and linearly dependent T(2) relaxation rates have allowed for detection via zero echo time (19)F MRI, and the in vivo MR potential has been preliminarily explored using (19)F magnetic resonance spectroscopy (MRS). This fluorinated micelle has also demonstrated the ability to encapsulate the small-molecule chemotherapeutic doxorubicin and release its cargo in a thermoresponsive manner owing to its inherent stimuli-responsive properties, presenting an interesting avenue for the development of thermoresponsive (19)F MRI/MRS-traceable theranostic agents.

Background Endovascular aneurysm repair (EVAR) became the procedure of first choice for the repair of the abdominal aortic aneurysms (AAAs) in the last decades. However, narrow distal aorta remains to be the main limiting factor for the use of EVAR. A limited number of bail-out procedures have been described in the literature to overcome this problem. Methods A 69-year-old male was transferred to our institution for the repair of a ruptured AAA. His initial presentation mimicked an acute coronary syndrome, provoking a cardiac catheterization that documented a ruptured AAA. Results The patient was brought to the operating room for EVAR, but his distal aorta was severely narrowed, preventing the use of a bifurcated graft. We had to convert the bifurcated graft to a unigraft and place two additional grafts extending into the iliac arteries to fix the type I endoleak that we encountered at the distal end of the unigraft. He recovered well postoperatively, and his repair was found to be stable at 6-month follow-up. Conclusion The surgical technique that we are presenting here is a unique bail-out procedure that can be used as an alternative solution to the narrow distal aortas.

The human genome contains approximately 50 copies of the replication-defective human endogenous retrovirus 9 (ERV-9) and thousands of copies of its solitary long term repeat (sLTR) element. While some sLTRs are located upstream of critical genes and have enhancer activity, other sLTRs are located within introns and may be transcribed as RNAs. We found that intronic RNAs arising from U3 sLTRs of ERV-9 were expressed as both sense (S) and antisense (AS) transcripts in all human cells tested but that expression levels differed in malignant versus nonmalignant cells. In nonmalignant cells, AS was expressed at higher levels than S and at higher levels than in malignant cells; in malignant cells, AS was expressed at amounts equivalent to those of S RNA. Critically, U3 AS RNA was found to physically bind to key transcription factors for cellular proliferation, including NF-Y, p53, and sp1, indicating that such RNA transcripts may function as decoy targets or traps for NF-Y and thus inhibit the growth of human cancer cells. Indeed, short U3 oligodeoxynucleotides (ODNs) based on these RNA sequences ably inhibited proliferation of cancer cell lines driven by cyclins B1/B2, the gene targets of NF-Y.

Importance For a small percentage of obsessive-compulsive disorder (OCD) cases exhibiting additional neuropsychiatric symptoms, it was proposed that neuroinflammation occurs in the basal ganglia as an autoimmune response to infections. However, it is possible that elevated neuroinflammation, inducible by a diverse range of mechanisms, is important throughout the cortico-striato-thalamo-cortical circuit of OCD. Identifying brain inflammation is possible with the recent advance in positron emission tomography (PET) radioligands that bind to the translocator protein (TSPO). Translocator protein density increases when microglia are activated during neuroinflammation and the TSPO distribution volume (V T ) is an index of TSPO density. Objective To determine whether TSPO V T is elevated in the dorsal caudate, orbitofrontal cortex, thalamus, ventral striatum, dorsal putamen, and anterior cingulate cortex in OCD. Design, Setting, and Participants This case-control study was conducted at a tertiary care psychiatric hospital from May 1, 2010, to November 30, 2016. Participants with OCD (n = 20) and age-matched healthy control individuals (n = 20) underwent a fluorine F 18–labeled N -(2-(2-fluoroethoxy)benzyl)- N -(4-phenoxypyridin-3-yl)acetamide PET scan. It is a high-quality second-generation TSPO-binding PET radiotracer. All participants were drug and medication free, nonsmoking, and otherwise healthy. Main Outcomes and Measures The TSPO V T was measured in the dorsal caudate, orbitofrontal cortex, thalamus, ventral striatum, dorsal putamen, and anterior cingulate cortex. Compulsions were assessed with the Yale-Brown Obsessive Compulsive Scale. Results In the OCD and healthy groups, the mean (SD) ages were 27.4 (7.1) years and 27.6 (6.6) years, respectively, and 11 (55%) and 8 (40%) were women, respectively. In OCD, TSPO V T was significantly elevated in these brain regions (mean, 32%; range, 31%-36% except anterior cingulate cortex, 24%; analysis of variance, effect of diagnosis: P P = .004). Slightly lower elevations in TSPO V T (22%-29%) were present in other gray matter regions. The Yale-Brown Obsessive Compulsive Scale measure of distress associated with preventing compulsive behaviors significantly correlated with TSPO V T in the orbitofrontal cortex (uncorrected Pearson correlation r = 0.62; P = .005). Conclusions and Relevance To our knowledge, this is the first study demonstrating inflammation within the neurocircuitry of OCD. The regional distribution of elevated TSPO V T argues that the autoimmune/neuroinflammatory theories of OCD should extend beyond the basal ganglia to include the cortico-striato-thalamo-cortical circuit. Immunomodulatory therapies should be investigated in adult OCD, rather than solely childhood OCD, particularly in cases with prominent distress when preventing compulsions.