Novel insights into the pathobiology of pulmonary hypertension in heart failure with preserved ejection fraction.

Heart failure (HF) with preserved ejection fraction (HFpEF) is the most common cause of pulmonary hypertension (PH) worldwide and is strongly associated with adverse clinical outcomes. The American Heart Association recently highlighted a call to action regarding the distinct lack of evidence-based treatments for PH due to poorly understood pathophysiology of PH attributable to HFpEF (PH-HFpEF). Prior studies have described cardiophysiological mechanisms to explain the development of isolated postcapillary PH (ipc-PH); however, the consequent increase in pulmonary vascular (PV) resistance (PVR) may lead to the less understood and more fatal combined pre- and postcapillary PH (cpc-PH). Metabolic disease and inflammatory dysregulation have been suggested to predispose PH, yet the molecular mechanisms are unknown. Although PH-HFpEF has been studied to partly share vasoactive neurohormonal mediators with primary pulmonary arterial hypertension (PAH), clinical trials that have targeted these pathways have been unsuccessful. The increased mortality of patients with PH-HFpEF necessitates further study into viable mechanistic targets involved in disease progression. We aim to summarize the current pathophysiological and clinical understanding of PH-HFpEF, highlight the role of known molecular mechanisms in the progression of PV disease, and introduce a novel concept that lipid metabolism may be attenuating and propagating PH-HFpEF.NEW & NOTEWORTHY Our review addresses pulmonary hypertension (PH) attributable to heart failure (HF) with preserved ejection fraction (HFpEF; PH-HFpEF). Current knowledge gaps in PH-HFpEF pathophysiology have led to a lack of therapeutic targets. Thus, we address identified knowledge gaps in a comprehensive review, focusing on current clinical epidemiology, known pathophysiology, and previously studied molecular mechanisms. We also introduce a comprehensive review of polyunsaturated fatty acid (PUFA) lipid inflammatory mediators in PH-HFpEF.

Paraoxonases at the Heart of Neurological Disorders.

Paraoxonase enzymes serve as an important physiological redox system that participates in the protection against cellular injury caused by oxidative stress. The PON enzymes family consists of three members (PON-1, PON-2, and PON-3) that share a similar structure and location as a cluster on human chromosome 7. These enzymes exhibit anti-inflammatory and antioxidant properties with well-described roles in preventing cardiovascular disease. Perturbations in PON enzyme levels and their activity have also been linked with the development and progression of many neurological disorders and neurodegenerative diseases. The current review summarizes the available evidence on the role of PONs in these diseases and their ability to modify risk factors for neurological disorders. We present the current findings on the role of PONs in Alzheimer's disease, Parkinson's disease, and other neurodegenerative and neurological diseases.

Novel Model of Oxalate Diet-Induced Chronic Kidney Disease in Dahl-Salt-Sensitive Rats.

Diet-induced models of chronic kidney disease (CKD) offer several advantages, including clinical relevance and animal welfare, compared with surgical models. Oxalate is a plant-based, terminal toxic metabolite that is eliminated by the kidneys through glomerular filtration and tubular secretion. An increased load of dietary oxalate leads to supersaturation, calcium oxalate crystal formation, renal tubular obstruction, and eventually CKD. Dahl-Salt-Sensitive (SS) rats are a common strain used to study hypertensive renal disease; however, the characterization of other diet-induced models on this background would allow for comparative studies of CKD within the same strain. In the present study, we hypothesized that SS rats on a low-salt, oxalate rich diet would have increased renal injury and serve as novel, clinically relevant and reproducible CKD rat models. Ten-week-old male SS rats were fed either 0.2% salt normal chow (SS-NC) or a 0.2% salt diet containing 0.67% sodium oxalate (SS-OX) for five weeks.Real-time PCR demonstrated an increased expression of inflammatory marker interleukin-6 (IL-6) (p < 0.0001) and fibrotic marker Timp-1 metalloproteinase (p < 0.0001) in the renal cortex of SS-OX rat kidneys compared with SS-NC. The immunohistochemistry of kidney tissue demonstrated an increase in CD-68 levels, a marker of macrophage infiltration in SS-OX rats (p < 0.001). In addition, SS-OX rats displayed increased 24 h urinary protein excretion (UPE) (p < 0.01) as well as significant elevations in plasma Cystatin C (p < 0.01). Furthermore, the oxalate diet induced hypertension (p < 0.05). A renin-angiotensin-aldosterone system (RAAS) profiling (via liquid chromatography-mass spectrometry; LC-MS) in the SS-OX plasma showed significant (p < 0.05) increases in multiple RAAS metabolites including angiotensin (1-5), angiotensin (1-7), and aldosterone. The oxalate diet induces significant renal inflammation, fibrosis, and renal dysfunction as well as RAAS activation and hypertension in SS rats compared with a normal chow diet. This study introduces a novel diet-induced model to study hypertension and CKD that is more clinically translatable and reproducible than the currently available models.

Quantification of Cardiotonic Steroids Potentially Regulated by Paraoxonase 3 in a Rat Model of Chronic Kidney Disease Using UHPLC-Orbitrap-MS.

Endogenous cardiotonic steroids (CTSs), such as telocinobufagin (TCB) and marinobufagin (MBG) contain a lactone moiety critical to their binding and signaling through the Na+/K+-ATPase. Their concentrations elevate in response to sodium intake and under volume-expanded conditions. Paraoxonase 3 (PON3) is an enzyme that can hydrolyze lactone substrates. Here, we examine the role of PON3 in regulating CTS levels in a rat model of chronic kidney diseases (CKD). TCB and MBG were extracted from rat urine samples, and the analyses were carried out using ultra-high pressure liquid chromatography−Orbitrap-mass spectrometry (UHPLC-Orbitrap-MS). Ten-week-old Dahl salt-sensitive wild type (SS-WT) and Dahl salt-sensitive PON3 knockout (SS-PON3 KO) rats were maintained on a high-salt diet (8% NaCl) for 8 weeks to initiate salt-sensitive hypertensive renal disease characteristic of this model. CTS extraction recovery from urine >80% was achieved. For animals maintained on a normal chow diet, the baseline amount of TCB excreted in 24 h urine of SS-PON3 KO rats (6.08 ± 1.47 ng/24 h; or 15.09 ± 3.25 pmol) was significantly higher than for SS-WT rats (1.48 ± 0.69 ng/24 h; or 3.67 ± 1.54 pmol, p < 0.05). Similarly, for the same animals, the amount of excreted MBG was higher in the urine of SS-PON3 KO rats (4.74 ± 1.30 ng/24 h versus 1.03 ± 0.25 ng/24 h in SS-WT; or 11.83 ± 2.91 pmol versus 2.57 ± 0.56 pmol in SS-WT, p < 0.05). For animals on a high-salt diet, the SS-PON3 KO rats had significantly increased levels of TCB (714.52 ± 79.46 ng/24 h; or 1774.85 ± 175.55 pmol) compared to SS-WT control (343.84 ± 157.54 ng/24 h; or 854.09 ± 350.02 pmol, p < 0.05), and comparatively higher levels of MBG were measured for SS-PON3 KO (225.55 ± 82.61 ng/24 h; or 563.19 ± 184.5 pmol) versus SS-WT (157.56 ± 85.53 ng/24 h; or 393.43 ± 191.01 pmol, p > 0.05) rats. These findings suggest that the presence and absence of PON3 dramatically affect the level of endogenous CTSs, indicating its potential role in CTS regulation.

Microcystin-LR (MC-LR) Triggers Inflammatory Responses in Macrophages.

We were the first to previously report that microcystin-LR (MC-LR) has limited effects within the colons of healthy mice but has toxic effects within colons of mice with pre-existing inflammatory bowel disease. In the current investigation, we aimed to elucidate the mechanism by which MC-LR exacerbates colitis and to identify effective therapeutic targets. Through our current investigation, we report that there is a significantly greater recruitment of macrophages into colonic tissue with pre-existing colitis in the presence of MC-LR than in the absence of MC-LR. This is seen quantitatively through IHC staining and the enumeration of F4/80-positive macrophages and through gene expression analysis for Cd68, Cd11b, and Cd163. Exposure of isolated macrophages to MC-LR was found to directly upregulate macrophage activation markers Tnf and Il1b. Through a high-throughput, unbiased kinase activity profiling strategy, MC-LR-induced phosphorylation events were compared with potential inhibitors, and doramapimod was found to effectively prevent MC-LR-induced inflammatory responses in macrophages.

Regulation of Na/K-ATPase expression by cholesterol: isoform specificity and the molecular mechanism.

We have reported that the reduction in plasma membrane cholesterol could decrease cellular Na/K-ATPase α1-expression through a Src-dependent pathway. However, it is unclear whether cholesterol could regulate other Na/K-ATPase α-isoforms and the molecular mechanisms of this regulation are not fully understood. Here we used cells expressing different Na/K-ATPase α isoforms and found that membrane cholesterol reduction by U18666A decreased expression of the α1-isoform but not the α2- or α3-isoform. Imaging analyses showed the cellular redistribution of α1 and α3 but not α2. Moreover, U18666A led to redistribution of α1 to late endosomes/lysosomes, while the proteasome inhibitor blocked α1-reduction by U18666A. These results suggest that the regulation of the Na/K-ATPase α-subunit by cholesterol is isoform specific and α1 is unique in this regulation through the endocytosis-proteasome pathway. Mechanistically, loss-of-Src binding mutation of A425P in α1 lost its capacity for regulation by cholesterol. Meanwhile, gain-of-Src binding mutations in α2 partially restored the regulation. Furthermore, through studies in caveolin-1 knockdown cells, as well as subcellular distribution studies in cell lines with different α-isoforms, we found that Na/K-ATPase, Src, and caveolin-1 worked together for the cholesterol regulation. Taken together, these new findings reveal that the putative Src-binding domain and the intact Na/K-ATPase/Src/caveolin-1 complex are indispensable for the isoform-specific regulation of Na/K-ATPase by cholesterol.

CD36 Enhances Vascular Smooth Muscle Cell Proliferation and Development of Neointimal Hyperplasia.

Objective- Dysregulated proliferation of vascular smooth muscle cells (VSMC) plays an essential role in neointimal hyperplasia. CD36 functions critically in atherogenesis and thrombosis. We hypothesize that CD36 regulates VSMC proliferation and contributes to the development of obstructive vascular diseases. Approach and Results- We found by immunofluorescent staining that CD36 was highly expressed in human vessels with obstructive diseases. Using guidewire-induced carotid artery injury and shear stress-induced intima thickening models, we compared neointimal hyperplasia in Apoe-/-, Cd36-/- /Apoe-/-, and CD36 specifically deleted in VSMC (VSMC cd36-/-) mice. CD36 deficiency, either global or VSMC-specific, dramatically reduced injury-induced neointimal thickening. Correspondingly, carotid artery blood flow was significantly increased in Cd36-/- /Apoe-/- compared with Apoe-/- mice. In cultured VSMCs from thoracic aorta of wild-type and Cd36-/- mice, we found that loss of CD36 significantly decreased serum-stimulated proliferation and increased cell populations in S phase, suggesting that CD36 is necessary for VSMC S/G2-M-phase transition. Treatment of VSMCs with a TSR (thrombospondin type 1 repeat) peptide significantly increased wild-type, but not Cd36-/- VSMC proliferation. TSR or serum treatment significantly increased cyclin A expression in wild-type, but not in Cd36-/- VSMCs. STAT3 (signal transducer and activator of transcription), which reportedly enhances both VSMC differentiation and maturation, was higher in Cd36-/- VSMCs. CD36 deficiency significantly decreased expression of Col1A1 (type 1 collagen A1 chain) and TGF-ß1 (transforming growth factor beta 1), and increased expression of contractile proteins, including calponin 1 and smooth muscle α actin, and dramatically increased cell contraction. Conclusions- CD36 promotes VSMC proliferation via upregulation of cyclin A expression that contributes to the development of neointimal hyperplasia, collagen deposition, and obstructive vascular diseases.

Antiplatelet and Anticoagulant Risk for Select Spine Interventions: A Retrospective Cohort.

OBJECTIVES: To identify significant bleeding complications following spinal interventions in patients taking medications with antiplatelet or anticoagulation effect. DESIGN: Retrospective chart review of a 12-month period. SETTING: Outpatient academic medical practice. INTERVENTIONS: Injections during outpatient interventional spine clinical encounters, including 14 cervical transforaminal epidural steroid injections, 26 cervical medial branch blocks, seven cervical radiofrequency neurotomies, three cervical facet joint injections, 88 lumbar transforaminal epidural steroid injections, 66 lumbosacral medial branch blocks, 18 lumbosacral radiofrequency neurotomies, 13 lumbar facet joint injections, one caudal epidural steroid injection, 11 sacral transforaminal epidural steroid injections, and 32 sacroiliac joint injections. MAIN OUTCOME MEASURE: Epidural hematoma or other serious bleeding. RESULTS: In this cohort of 275 consecutive encounters with available records in which patients underwent a spinal injection while continuing medications with antiplatelet or anticoagulant effect, zero of the 275 clinical encounters (0%, 95% confidence interval = 0-1.4%) resulted in epidural hematoma or other serious bleeding. For antiplatelet medication, nonsteroidal anti-inflammatory drugs were continued in 102 procedures, aspirin in 142, clopidogrel in 21, and meloxicam and/or Celebrex in 81; for anticoagulation medication, warfarin was continued in four procedures, apixaban in six, dabigatran in one, and fondaparinux in two. Of note, one patient suffered a deep vein thrombosis, which was identified at two-week follow-up despite continuing aspirin therapy. CONCLUSIONS: This cohort adds to the growing evidence that the risk of serious bleeding complications from select spine interventions while continuing medications with antiplatelet or anticoagulant effect appears low.

Validity of Physical Exam Maneuvers in the Diagnosis of Sacroiliac Joint Pathology.

BACKGROUND: A combination of physical examination maneuvers is currently considered necessary to help predict who will respond to injections in the sacroiliac joint. However, the literature on this topic currently consists of conflicting studies, with one showing the value of a combination of exam maneuvers and the other showing no real value. OBJECTIVE: To determine the diagnostic validity of sacroiliac joint (SIJ) physical exam maneuvers using anesthetic intra-articular injection as a reference standard. DESIGN: A single institution prospective study. PARTICIPANTS: Patients with the clinical diagnosis of SIJ pain and referred for SIJ injection were enrolled. MAIN OUTCOME MEASURE: Numeric rating scale (NRS) to assess pain intensity. RESULTS: Participants underwent fluoroscopically guided SIJ intra-articular injection with 1 cc of 2% lidocaine and 1 cc of triamcinolone 40 mg. Patients' pain was assessed via 0-10 NRS pre-injection and immediately postinjection to determine positive anesthetic response to the injection. Six physical exam maneuvers (thigh thrust, Geanslen's test, FABER test, distraction test, compression test, and sacral thrust) were performed pre-injection and 15 minutes postinjection. The results of these SIJ physical exam maneuvers were evaluated singly and in combinations for diagnostic power in relation to a positive anesthetic response (>80% relief) to the injection. No association was found between a single SIJ physical exam maneuver or combination of maneuvers and anesthetic response to the injection. CONCLUSIONS: In this cohort, patient physical exam maneuvers to identify intra-articular SIJ pain did not demonstrate diagnostic value when compared with the reference standard of an intra-articular anesthetic block.

Pain and Functional Outcomes After Sacroiliac Joint Injection with Anesthetic and Corticosteroid at Six Months, Stratified by Anesthetic Response and Physical Exam Maneuvers.

OBJECTIVE: To evaluate sacroiliac joint (SIJ) injection outcomes with local anesthetic and corticosteroid. DESIGN: Prospective cohort. SETTING: Single academic medical center. METHODS: Thirty-four patients referred for SIJ injection with a clinical diagnosis of SIJ pain underwent injections with 1:1 mixture of 2% lidocaine and triamcinolone 40 mg/mL. Pain provocation physical exam (PE) maneuvers were recorded immediately before and after injection. Outcome measures at two to four weeks and six months included pain numeric rating scale (NRS) and Oswestry Disability Index (ODI). RESULTS: For the analysis of outcomes by the overall group (not stratified by PE and/or anesthetic block), a 58.8% (95% confidence interval [CI] = +/-16.5%) ≥2 NRS reduction, a 32.4% (95% CI = +/-15.7%) ≥50% NRS reduction, and a 38.2% (95% CI = +/-16.3%) ≥30% ODI reduction were observed at two to four weeks, with similar improvements at six months. Outcomes stratified based on pre-injection PE did not reveal significant differences at either time point. The stratification based on the presence of 100% postinjection anesthetic response demonstrated a significant difference at two to four weeks for ≥50% NRS improvement. The true positive/true negative group (TP/TN) stratification demonstrated a significant difference for ≥50% NRS improvement at two to four weeks, whereas six-month outcomes for TP/TN demonstrated significant differences for ≥50% NRS and ≥30% ODI improvement. An increased injection response was observed with stratification of patients more likely to have true SIJ pain (i.e., TP), with TP/TN stratification demonstrating a 75% (95% CI = +/-30.0%) ≥2 NRS improvement and a 62.5% (95% CI = +/-33.5%) improvement of ≥50% NRS and ≥30% ODI for the TP group at two to four weeks, with similar results at six months. CONCLUSIONS: SIJ steroid injection based on referral clinical diagnosis is unlikely to demonstrate true injection efficacy, and more specific selection criteria are warranted.

Pain Management Best Practices from Multispecialty Organizations During the COVID-19 Pandemic and Public Health Crises.

BACKGROUND: It is nearly impossible to overestimate the burden of chronic pain, which is associated with enormous personal and socioeconomic costs. Chronic pain is the leading cause of disability in the world, is associated with multiple psychiatric comorbidities, and has been causally linked to the opioid crisis. Access to pain treatment has been called a fundamental human right by numerous organizations. The current COVID-19 pandemic has strained medical resources, creating a dilemma for physicians charged with the responsibility to limit spread of the contagion and to treat the patients they are entrusted to care for. METHODS: To address these issues, an expert panel was convened that included pain management experts from the military, Veterans Health Administration, and academia. Endorsement from stakeholder societies was sought upon completion of the document within a one-week period. RESULTS: In these guidelines, we provide a framework for pain practitioners and institutions to balance the often-conflicting goals of risk mitigation for health care providers, risk mitigation for patients, conservation of resources, and access to pain management services. Specific issues discussed include general and intervention-specific risk mitigation, patient flow issues and staffing plans, telemedicine options, triaging recommendations, strategies to reduce psychological sequelae in health care providers, and resource utilization. CONCLUSIONS: The COVID-19 public health crisis has strained health care systems, creating a conundrum for patients, pain medicine practitioners, hospital leaders, and regulatory officials. Although this document provides a framework for pain management services, systems-wide and individual decisions must take into account clinical considerations, regional health conditions, government and hospital directives, resource availability, and the welfare of health care providers.

Digital Care for Chronic Musculoskeletal Pain: 10,000 Participant Longitudinal Cohort Study.

BACKGROUND: Chronic musculoskeletal pain has a vast global prevalence and economic burden. Conservative therapies are universally recommended but require patient engagement and self-management to be effective. OBJECTIVE: This study aimed to evaluate the efficacy of a 12-week digital care program (DCP) in a large population of patients with chronic knee and back pain. METHODS: A longitudinal observational study was conducted using a remote DCP available through a mobile app. Subjects participated in a 12-week multimodal DCP incorporating education, sensor-guided exercise therapy (ET), and behavioral health support with 1-on-1 remote health coaching. The primary outcome was pain measured by the visual analog scale (VAS). Secondary measures included engagement levels, program completion, program satisfaction, condition-specific pain measures, depression, anxiety, and work productivity. RESULTS: A total of 10,264 adults with either knee (n=3796) or low back (n=6468) pain for at least three months were included in the study. Participants experienced a 68.45% average improvement in VAS pain between baseline intake and 12 weeks. In all, 73.04% (7497/10,264) participants completed the DCP into the final month. In total, 78.60% (5893/7497) of program completers (7144/10,264, 69.60% of all participants) achieved minimally important change in pain. Furthermore, the number of ET sessions and coaching interactions were both positively associated with improvement in pain, suggesting that the amount of engagement influenced outcomes. Secondary outcomes included a 57.9% and 58.3% decrease in depression and anxiety scores, respectively, and 61.5% improvement in work productivity. Finally, 3 distinct clusters of pain response trajectories were identified, which could be predicted with a mean 76% accuracy using baseline measures. CONCLUSIONS: These results support the efficacy and scalability of a DCP for chronic low back and knee pain in a large, diverse, real-world population. Participants demonstrated high completion and engagement rates and a significant positive relationship between engagement and pain reduction was identified, a finding that has not been previously demonstrated in a DCP. Furthermore, the large sample size allowed for the identification of distinct pain response subgroups, which may prove beneficial in predicting recovery and tailoring future interventions. This is the first longitudinal digital health study to analyze pain outcomes in a sample of this magnitude, and it supports the prospect for DCPs to serve the overwhelming number of musculoskeletal pain sufferers worldwide.

Intra-articular Steroids vs Saline for Lumbar Z-Joint Pain: A Prospective, Randomized, Double-Blind Placebo-Controlled Trial.

OBJECTIVE: To determine if intra-articular (IA) injection of corticosteroids is effective in reducing the need for radiofrequency ablation (RFA) in those with dual comparative medial branch block (MBB)-confirmed lumbar z-joint pain. DESIGN: This was a randomized, double blind, placebo-controlled study. SETTING: Two academic medical centers. SUBJECTS: Fifty-six consecutive subjects who had ≥80% pain relief during an initial screening MBB were recruited. METHODS: Patients received a second confirmatory MBB and concurrent IA injection of either corticosteroid or saline per randomization. Twenty-nine of 56 received intra-articular corticosteroid (triamcinolone 20 mg), of whom 24 also had a positive confirmatory MBB per Spine Interventional Society guidelines, with ≥80% pain relief from both MBBs. Twenty-seven of 56 received IA saline into the z-joint during the confirmatory MBB, of whom 22 also had a positive confirmatory MBB. The primary outcome measure was the categorical need for RFA due to insufficient pain relief with intra-articular injection, and the secondary outcome was time to RFA. RESULTS: There was no statistically significant difference in the need for an RFA between the groups (16/24 steroid, 67%, 95% confidence interval [CI] = 47-82%) vs 15/22 saline (68%, 95% CI = 47-84%, P = 1.00). The average time to RFA was also not different, at 6.00 weeks for steroids vs 6.55 weeks for saline (P = 0.82). CONCLUSIONS: Intra-articular corticosteroids were not effective in reducing the need for or the time to a radiofrequency ablation of the medial branches in those with dual MBB-confirmed lumbar z-joint pain.

Na/K-ATPase/src complex mediates regulation of CD40 in renal parenchyma.

Background: Recent studies have highlighted a critical role for CD40 in the pathogenesis of renal injury and fibrosis. However, little is currently understood about the regulation of CD40 in this setting. Methods: We use novel Na/K-ATPase cell lines and inhibitors in order to demonstrate the regulatory function of Na/K-ATPase with regards to CD40 expression and function. We utilize 5/6 partial nephrectomy as well as direct infusion of a Na/K-ATPase ligand to demonstrate this mechanism exists in vivo. Results: We demonstrate that knockdown of the α1 isoform of Na/K-ATPase causes a reduction in CD40 while rescue of the α1 but not the α2 isoform restores CD40 expression in renal epithelial cells. Second, because the major functional difference between α1 and α2 is the ability of α1 to form a functional signaling complex with Src, we examined whether the Na/K-ATPase/Src complex is important for CD40 expression. We show that a gain-of-Src binding α2 mutant restores CD40 expression while loss-of-Src binding α1 reduces CD40 expression. Furthermore, loss of a functional Na/K-ATPase/Src complex also disrupts CD40 signaling. Importantly, we show that use of a specific Na/K-ATPase/Src complex antagonist, pNaKtide, can attenuate cardiotonic steroid (CTS)-induced induction of CD40 expression in vitro. Conclusions: Because the Na/K-ATPase/Src complex is also a key player in the pathogenesis of renal injury and fibrosis, our new findings suggest that Na/K-ATPase and CD40 may comprise a pro-fibrotic feed-forward loop in the kidney and that pharmacological inhibition of this loop may be useful in the treatment of renal fibrosis.

Does Immediate Pain Relief After an Injection into the Sacroiliac Joint with Anesthetic and Corticosteroid Predict Subsequent Pain Relief?

Objectives: To determine if immediate pain response following an injection with local anesthetic and corticosteroid predicts subsequent relief. Design: Prospective observational cohort. Setting: An institutional review board-approved prospective study from a single academic medical center. Methods: Patients with clinical diagnosis of sacroiliac (SIJ) pain and referred for SIJ injection were enrolled; 1 cc of 2% lidocaine and 1 cc of triamcinolone 40 mg/mL were injected into the SIJ. Pain score on 0-10 numeric rating scale (NRS) during provocation maneuvers was recorded immediately before injection, immediately after injection, and at two and four weeks of follow-up. Oswestry Disability Index (ODI) was also recorded. Results: Various cutoffs were identified to establish positive anesthetic response and successful outcomes at follow-up. These were used to calculated likelihood ratios. Of those with 100% anesthetic response, six of 11 (54.5%, 95% confidence interval [CI]+/-29.4%, +LR 2.6, 95% CI = 1.1-5.9) demonstrated 50% or greater pain relief at follow-up, and four of 11 (36.5%, 95% CI+/-28.4%, +LR 3.00, 95% CI = 1.4-5.1) had 100% relief at two to four weeks. Fourteen of 14 (100%, 95% CI+/-21.5%, -LR 0.0, 95% CI = 0.0-2.1) with an initial negative block failed to achieve 100% relief at follow-up. Conclusions: Patients who fail to achieve initial relief after SIJ injection with anesthetic and steroid are very unlikely to achieve significant pain relief at follow-up; negative likelihood ratios (LR) in this study, based on how success is defined, range between 0 and 0.9. Clinically significant positive likelihood ratios of anesthetic response to SIJ injection are more limited and less robust, but are valuable in predicting 50% relief or 100% relief at two to four weeks.

Cardiotonic Steroids and the Sodium Trade Balance: New Insights into Trade-Off Mechanisms Mediated by the Na⁺/K⁺-ATPase.

In 1972 Neal Bricker presented the "trade-off" hypothesis in which he detailed the role of physiological adaptation processes in mediating some of the pathophysiology associated with declines in renal function. In the late 1990's Xie and Askari published seminal studies indicating that the Na⁺/K⁺-ATPase (NKA) was not only an ion pump, but also a signal transducer that interacts with several signaling partners. Since this discovery, numerous studies from multiple laboratories have shown that the NKA is a central player in mediating some of these long-term "trade-offs" of the physiological adaptation processes which Bricker originally proposed in the 1970's. In fact, NKA ligands such as cardiotonic steroids (CTS), have been shown to signal through NKA, and consequently been implicated in mediating both adaptive and maladaptive responses to volume overload such as fibrosis and oxidative stress. In this review we will emphasize the role the NKA plays in this "trade-off" with respect to CTS signaling and its implication in inflammation and fibrosis in target organs including the heart, kidney, and vasculature. As inflammation and fibrosis exhibit key roles in the pathogenesis of a number of clinical disorders such as chronic kidney disease, heart failure, atherosclerosis, obesity, preeclampsia, and aging, this review will also highlight the role of newly discovered NKA signaling partners in mediating some of these conditions.

Telocinobufagin, a Novel Cardiotonic Steroid, Promotes Renal Fibrosis via Na⁺/K⁺-ATPase Profibrotic Signaling Pathways.

Cardiotonic steroids (CTS) are Na⁺/K⁺-ATPase (NKA) ligands that are elevated in volume-expanded states and associated with cardiac and renal dysfunction in both clinical and experimental settings. We test the hypothesis that the CTS telocinobufagin (TCB) promotes renal dysfunction in a process involving signaling through the NKA α-1 in the following studies. First, we infuse TCB (4 weeks at 0.1 µg/g/day) or a vehicle into mice expressing wild-type (WT) NKA α-1, as well as mice with a genetic reduction (~40%) of NKA α-1 (NKA α-1+/-). Continuous TCB infusion results in increased proteinuria and cystatin C in WT mice which are significantly attenuated in NKA α-1+/- mice (all p < 0.05), despite similar increases in blood pressure. In a series of in vitro experiments, 24-h treatment of HK2 renal proximal tubular cells with TCB results in significant dose-dependent increases in both Collagens 1 and 3 mRNA (2-fold increases at 10 nM, 5-fold increases at 100 nM, p < 0.05). Similar effects are seen in primary human renal mesangial cells. TCB treatment (100 nM) of SYF fibroblasts reconstituted with cSrc results in a 1.5-fold increase in Collagens 1 and 3 mRNA (p < 0.05), as well as increases in both Transforming Growth factor beta (TGFb, 1.5 fold, p < 0.05) and Connective Tissue Growth Factor (CTGF, 2 fold, p < 0.05), while these effects are absent in SYF cells without Src kinase. In a patient study of subjects with chronic kidney disease, TCB is elevated compared to healthy volunteers. These studies suggest that the pro-fibrotic effects of TCB in the kidney are mediated though the NKA-Src kinase signaling pathway and may have relevance to volume-overloaded conditions, such as chronic kidney disease where TCB is elevated.

A randomized trial of epidural glucocorticoid injections for spinal stenosis.

BACKGROUND: Epidural glucocorticoid injections are widely used to treat symptoms of lumbar spinal stenosis, a common cause of pain and disability in older adults. However, rigorous data are lacking regarding the effectiveness and safety of these injections. METHODS: In a double-blind, multisite trial, we randomly assigned 400 patients who had lumbar central spinal stenosis and moderate-to-severe leg pain and disability to receive epidural injections of glucocorticoids plus lidocaine or lidocaine alone. The patients received one or two injections before the primary outcome evaluation, performed 6 weeks after randomization and the first injection. The primary outcomes were the score on the Roland-Morris Disability Questionnaire (RMDQ, in which scores range from 0 to 24, with higher scores indicating greater physical disability) and the rating of the intensity of leg pain (on a scale from 0 to 10, with 0 indicating no pain and 10 indicating "pain as bad as you can imagine"). RESULTS: At 6 weeks, there were no significant between-group differences in the RMDQ score (adjusted difference in the average treatment effect between the glucocorticoid-lidocaine group and the lidocaine-alone group, -1.0 points; 95% confidence interval [CI], -2.1 to 0.1; P=0.07) or the intensity of leg pain (adjusted difference in the average treatment effect, -0.2 points; 95% CI, -0.8 to 0.4; P=0.48). A prespecified secondary subgroup analysis with stratification according to type of injection (interlaminar vs. transforaminal) likewise showed no significant differences at 6 weeks. CONCLUSIONS: In the treatment of lumbar spinal stenosis, epidural injection of glucocorticoids plus lidocaine offered minimal or no short-term benefit as compared with epidural injection of lidocaine alone. (Funded by the Agency for Healthcare Research and Quality; ClinicalTrials.gov number, NCT01238536.).

Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease.

RATIONALE: Trimethylamine-N-oxide (TMAO), a gut microbial-dependent metabolite of dietary choline, phosphatidylcholine (lecithin), and l-carnitine, is elevated in chronic kidney diseases (CKD) and associated with coronary artery disease pathogenesis. OBJECTIVE: To both investigate the clinical prognostic value of TMAO in subjects with versus without CKD, and test the hypothesis that TMAO plays a direct contributory role in the development and progression of renal dysfunction. METHODS AND RESULTS: We first examined the relationship between fasting plasma TMAO and all-cause mortality over 5-year follow-up in 521 stable subjects with CKD (estimated glomerular filtration rate, <60 mL/min per 1.73 m(2)). Median TMAO level among CKD subjects was 7.9 µmol/L (interquartile range, 5.2-12.4 µmol/L), which was markedly higher (P<0.001) than in non-CKD subjects (n=3166). Within CKD subjects, higher (fourth versus first quartile) plasma TMAO level was associated with a 2.8-fold increased mortality risk. After adjustments for traditional risk factors, high-sensitivity C-reactive protein, estimated glomerular filtration rate, elevated TMAO levels remained predictive of 5-year mortality risk (hazard ratio, 1.93; 95% confidence interval, 1.13-3.29; P<0.05). TMAO provided significant incremental prognostic value (net reclassification index, 17.26%; P<0.001 and differences in area under receiver operator characteristic curve, 63.26% versus 65.95%; P=0.036). Among non-CKD subjects, elevated TMAO levels portend poorer prognosis within cohorts of high and low cystatin C. In animal models, elevated dietary choline or TMAO directly led to progressive renal tubulointerstitial fibrosis and dysfunction. CONCLUSIONS: Plasma TMAO levels are both elevated in patients with CKD and portend poorer long-term survival. Chronic dietary exposures that increase TMAO directly contributes to progressive renal fibrosis and dysfunction in animal models.

Guidelines for Composing and Assessing a Paper on Treatment of Pain.

Authors, readers, and editors share a common focus. Authors want to publish their work. Readers want to see high-quality, new information. Referees and editors serve to ensure that authors provide valid conclusions based on the quality of information that readers want.Common to each of these roles are instructions to authors. However, these are typically written in an uninspiring, legalistic style, as if they are a set of rules that authors must obey if they expect to get published. This renders the instructions boring and oppressive, if not forbidding. Yet they need not be so, if they are set in context.Instructions to authors can be cast in a way as to reflect common purpose. They can remind authors what perceptive readers want to see in a paper and, thereby, prompt authors to include all necessary information. If cast in this way, instructions to authors are not a set of rules by which to satisfy publishers; they become guidelines for the etiquette of communication between authors and their readers.Against this background, the present article has been composed to serve several purposes. Foremost, it amplifies instructions to authors beyond the conventional technicalities such as headings, layout, font size, and line spacing. It prescribes the type of information that should be communicated and explains the reasons for those recommendations. Doing so not only informs authors about what to write, but also informs readers and referees about what to look for in a good paper. Secondarily, the article publicizes examples of errors and deficiencies of manuscripts submitted to the Journal in the past that have delayed their acceptance and publication, which could have been avoided had the forthcoming recommendations been followed. The recommendations also reprise the elements taught in courses conducted by the Spine Intervention Society in their extended program on evidence-based medicine. Doing so underscores that instructions for authors are not a procedural technicality but a way to ensure that what authors write, what readers read, and what the Journal publishes comply with contemporary precepts of good evidence.Some 20 years ago, the Journal of the American Medical Association published a comprehensive series of articles with a common title: "Users' Guides to the Medical Literature" [1,2]. These articles focused on the science of statistical tests and critical appraisal, and their importance for properly understanding the literature. The present article differs in that it does not presume to teach technicalities. Instead, it describes and explains, step by step, the critical components of an article, what authors should include, and what readers should look for, so that the Journal can ensure that consistent, high-quality information is shared between its authors and readers.The present article focuses on articles concerning treatment of pain, largely because this type of article is more commonly submitted than articles on reliability or validity of diagnostic procedures. Although the present article principally focuses on papers for the Spine Section of the Journal, the same principles, appropriately adapted, serve for other sections.