Peripheral Activation of Formyl Peptide Receptor 2/ALX by Electroacupuncture Alleviates Inflammatory Pain by Increasing Interleukin-10 Levels and Catalase Activity in Mice.

In the context of the electroacupuncture (EA) neurobiological mechanisms, we have previously demonstrated the involvement of formyl peptide receptor 2 (FPR2/ALX) in the antihyperalgesic effect of EA. The present study investigated the involvement of peripheral FPR2/ALX in the antihyperalgesic effect of EA on inflammatory cytokines levels, oxidative stress markers and antioxidant enzymes in an animal model of persistent inflammatory pain. Male Swiss mice underwent intraplantar (i.pl.) injection with complete Freund's adjuvant (CFA). Mechanical hyperalgesia was assessed with von Frey monofilaments. Animals were treated with EA (2/10 Hz, ST36-SP6, 20 minutes) for 4 consecutive days. From the first to the fourth day after CFA injection, animals received i.pl. WRW4 (FPR2/ALX antagonist) or saline before EA. Levels of inflammatory cytokines (TNF, IL-6, IL-4 and IL-10), antioxidant enzymes (catalase and superoxide dismutase), oxidative stress markers (TBARS, protein carbonyl, nitrite/nitrate ratio), and myeloperoxidase activity were measured in paw tissue samples. As previously demonstrated, i.pl. injection of the FPR2/ALX antagonist prevented the antihyperalgesic effect induced by EA. Furthermore, animals treated with EA showed higher levels of IL-10 and catalase activity in the inflamed paw, and these effects were prevented by the antagonist WRW4. EA did not change levels of TNF and IL-6, SOD and MPO activity, and oxidative stress markers. Our work demonstrates that the antihyperalgesic effect of EA on CFA-induced inflammatory pain could be partially associated with higher IL-10 levels and catalase activity, and that these effects may be dependent, at least in part, on the activation of peripheral FPR2/ALX.

A Highly Miniaturized, Chronically Implanted ASIC for Electrical Nerve Stimulation.

We present a wireless, fully implantable device for electrical stimulation of peripheral nerves consisting of a powering coil, a tuning network, a Zener diode, selectable stimulation parameters, and a stimulator IC, all encapsulated in biocompatible silicone. A wireless RF signal at 13.56 MHz powers the implant through the on-chip rectifier. The ASIC, designed in TSMC's 180 nm MS RF G process, occupies an area of less than 1.2 mm2. The IC enables externally selectable current-controlled stimulation through an on-chip read-only memory with a wide range of 32 stimulation parameters (90-750 µA amplitude, 100 µs or 1 ms pulse width, 15 or 50 Hz frequency). The IC generates the constant current waveform using an 8-bit binary weighted DAC and an H-Bridge. At the most power-hungry stimulation parameter, the average power consumption during a stimulus pulse is 2.6 mW with a power transfer efficiency of ∼5.2%. In addition to benchtop and acute testing, we chronically implanted two versions of the device (a design with leads and a leadless design) on two rats' sciatic nerves to verify the long-term efficacy of the IC and the full system. The leadless device had the following dimensions: height of 0.45 cm, major axis of 1.85 cm, and minor axis of 1.34 cm, with similar dimensions for the device with leads. Both devices were implanted and worked for experiments lasting from 21-90 days. To the best of our knowledge, the fabricated IC is the smallest constant-current stimulator that has been tested chronically.

Clinical Study of the IOPTx™ System - an Electroceutical Wearable to Lower Intraocular Pressure.

Purpose: To investigate the safety and efficacy of the IOPTx™ system - a novel wearable, electroceutical treatment to lower intraocular pressure. Methods: Patients wear the customized contact lens and spectacles of the IOPTx™ system and undergo three 15-minute randomized stimulation trials at different stimulus amplitudes with 15 minutes of rest in between. The parameters for the stimulation trials include a frequency of 50 Hz, a pulse width of 100 µs, and current amplitudes between 90-150 µA. The optometrist measures the intraocular pressure (IOP) before, immediately after, and 15 minutes after the trial, and performs topography, a slit eye examination, and specular microscopy before and after the entire study to check the health of the eye and confirm the safety of the system. Results: The IOPTx™ system successfully modulates a patient's IOP. By testing various currents, we create individual tuning curves examining the effect of the stimulation amplitude on the change in IOP. Each patient may have an optimal dose-response curve and by normalizing to this value, the IOPTx™ system decreased IOP by an average of 17.7% with fifteen minutes of therapy. No Adverse Events or Adverse Device Effects occurred.Conclusions: The results of this clinical case series provide preliminary evidence of efficacy and safety of the IOPTx™ system and its potential usefulness to lower IOP in glaucoma and ocular hypertension.

Metabolic Acidosis, Hyperkalemia, and Renal Unresponsiveness to Aldosterone Syndrome: Response to Treatment with Low-Potassium Diet.

Gordon syndrome involves hyperkalemia, acidosis, and severe hypertension (HTN) with hypercalciuria, low renin and aldosterone levels. It is commonly observed in children and adolescents. Such patients respond successfully to sodium restriction and thiazide diuretics. In this article, we present three cases of metabolic acidosis, hyperkalemia, and renal unresponsiveness to aldosterone (MeHandRU Syndrome). All three patients did not have HTN or hypercalciuria and demonstrated normal renin and aldosterone levels. These patients did not respond to thiazide-type diuretic therapy and salt restriction. Two males (aged 55- and 62-year) and a female patient (aged 68-year) presented to the clinic with unexplained hyperkalemia (5.9 mEq/L, 5.9 mEq/L and 6.2 mEq/L, respectively). On physical examination, blood pressure (BP) was found to be normal (<140/90 mm Hg). Over the counter potassium supplement, nonsteroidal anti-inflammatory drugs, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, potassium sparing diuretic use, as well as hyporeninemic hypoaldosteronism states such as diabetes mellitus were excluded. Plasma renin and aldosterone levels were normal. All three patients had low transtubular potassium gradient, despite high serum potassium levels. None of the patients reported a family history of hyperkalemia or kidney failure. All failed to demonstrate a response to hydrochlorothiazide and salt restriction. After careful consideration, strict low potassium diet (<2 g/day) was initiated in consultation with the dietician. Diuretic therapy was discontinued while BP remained within normal range (<140/90 mm Hg). At eight weeks, all three patients demonstrated normalization of potassium and correction of acidosis. At follow-up of six months, all patients are maintaining a normal potassium level. We suggest that potassium restriction can be successful in patients presenting with MeHandRU syndrome.

A Systematic Literature Review of Peripheral Nerve Stimulation Therapies for the Treatment of Pain.

OBJECTIVE: To conduct a systematic literature review of peripheral nerve stimulation (PNS) for pain. DESIGN: Grade the evidence for PNS. METHODS: An international interdisciplinary work group conducted a literature search for PNS. Abstracts were reviewed to select studies for grading. Inclusion/exclusion criteria included prospective randomized controlled trials (RCTs) with meaningful clinical outcomes that were not part of a larger or previously reported group. Excluded studies were retrospective, had less than two months of follow-up, or existed only as abstracts. Full studies were graded by two independent reviewers using the modified Interventional Pain Management Techniques-Quality Appraisal of Reliability and Risk of Bias Assessment, the Cochrane Collaborations Risk of Bias assessment, and the US Preventative Services Task Force level-of-evidence criteria. RESULTS: Peripheral nerve stimulation was studied in 14 RCTs for a variety of painful conditions (headache, shoulder, pelvic, back, extremity, and trunk pain). Moderate to strong evidence supported the use of PNS to treat pain. CONCLUSION: Peripheral nerve stimulation has moderate/strong evidence. Additional prospective trials could further refine appropriate populations and pain diagnoses.

Meta-analysis Comparing Combined Use of Eicosapentaenoic Acid and Statin to Statin Alone.

Role of omega-3-Fatty acids, especially eicosapentaenoic acid (EPA), in reducing cardiovascular events is not clear. We conducted a meta-analysis including trial sequential analysis (TSA) of all available randomized controlled trials (RCTs) assessing the impact of EPA + statin on cardiovascular risk reduction. The aim is to appraise cardiovascular risk reduction with EPA and statin taken together. A comprehensive search of PubMed and EMBASE databases was conducted for all RCTs that compared EPA + Statin versus statin alone and included outcomes related to cardiovascular health. We calculated a comprehensive odds ratio (ORs) and 95% confidence intervals (CIs) using a random-effects model. We included 5 RCTs totaling 27,415 patients. Our results demonstrated that EPA + statin resulted in 18% reduction in the incidence of MACE (OR = 0.78; 95% CI: 0.65 to 0.93, I2 = 54%, p value <0.01) and 30% reduction in myocardial infarction (MI) (OR = 0.71; 95% CI: 0.61 to 0.82, I2 = 0% p value <0.01) as compared with statin alone. With respect to MACE, the number needed to treat was 49. The statistical significance for reduction in the incidence of MACE with EPA+ statin was further augmented with trial sequential analysis. However, combined therapy of EPA + statin demonstrated no significant association on incidence of stroke when compared with statin alone or all-cause mortality. In conclusion, this meta-analysis demonstrated that EPA significantly reduced the incidence of MACE when combined with statin therapy, which is mainly driven by a significant reduction in myocardial infarction.

ICUD-SIU International Consultation on Bladder Cancer 2017: management of non-muscle invasive bladder cancer.

PURPOSE: To provide a summary of the Third International Consultation on Bladder Cancer recommendations for the management of non-muscle invasive bladder cancer (NMIBC). METHODS: A detailed review of the literature was performed focusing on original articles for the management of NMIBC. An international committee assessed and graded the articles based on the Oxford Centre for Evidence-based Medicine system. The entire spectrum of NMIBC was covered such as prognostic factors of recurrence and progression, risk stratification, staging, management of positive urine cytology with negative white light cystoscopy, indications of bladder and prostatic urethral biopsies, management of Ta low grade (LG) and high risk tumors (Ta high grade [HG], T1, carcinoma in situ [CIS]), impact of BCG strain and host on outcomes, management of complications of intravesical therapy, role of alternative therapies, indications for early cystectomy, surveillance strategies, and new treatments. The working group provides several recommendations on the management of NMIBC. RESULTS: Recommendations were summarized with regard to staging; management of primary and recurrent LG Ta and high risk disease, positive urine cytology with negative white light cystoscopy and prostatic urethral involvement; indications for timely cystectomy; and surveillance strategies. CONCLUSION: NMIBC remains a common and challenging malignancy to manage. Accurate staging, grading, and risk stratification are critical determinants of the management and outcomes of these patients. Current tools for risk stratification are limited but informative, and should be used in clinical practice when determining diagnosis, surveillance, and treatment of NMIBC.

Increase in Lactate Without Change in Nutritive Blood Flow or Glucose at Active Trigger Points Following Massage: A Randomized Clinical Trial.

OBJECTIVE: To investigate changes in nutritive blood flow as well as interstitial glucose and lactate within an active myofascial trigger point (MTrP) following massage. DESIGN: Randomized, placebo-controlled trial. SETTING: Subjects were recruited from the general population; procedures were conducted at a research center affiliated with a university hospital. PARTICIPANTS: Adults (N=25) (18-49y old) with episodic or chronic tension-type headache and an active MTrP in the upper trapezius muscle. INTERVENTIONS: Subjects were randomized to receive a single trigger point (TrP) release massage or sham ultrasound (US) treatment at an active MTrP in the upper trapezius muscle. Microdialysis was used to continuously sample interstitial fluid from the MTrP before, during, and for 60 minutes following intervention. MAIN OUTCOME MEASURES: The primary outcome measure was nutritive blood flow within the MTrP as measured by microdialysis ethanol clearance; secondary measures included dialysate glucose, dialysate lactate, and subject discomfort with the procedures. Pressure-pain threshold (PPT) was determined to assess treatment effectiveness. RESULTS: There was no treatment effect of TrP release massage on nutritive blood flow (P=.663) or dialysate glucose (P=.766). The interaction for lactate was significant indicating that dialysate lactate increased for TrP release massage vs sham US (P=.04); maximum lactate increase over baseline was observed at 60 minutes after TrP release massage (P=.007, 0.128 µM, 95% confidence interval 0.045-0.212). Pain evoked by probe placement into an active MTrP was low. An interaction effect on PPT was significant (P=.005). CONCLUSION: TrP release massage of an active MTrP affected anaerobic metabolism as represented by an increase in dialysate lactate without change in nutritive blood flow or dialysate glucose. The lack of a treatment effect on blood flow is discussed.

Relating Chronic Pelvic Pain and Endometriosis to Signs of Sensitization and Myofascial Pain and Dysfunction.

Chronic pelvic pain is a frustrating symptom for patients with endometriosis and is frequently refractory to hormonal and surgical management. While these therapies target ectopic endometrial lesions, they do not directly address pain due to central sensitization of the nervous system and myofascial dysfunction, which can continue to generate pain from myofascial trigger points even after traditional treatments are optimized. This article provides a background for understanding how endometriosis facilitates remodeling of neural networks, contributing to sensitization and generation of myofascial trigger points. A framework for evaluating such sensitization and myofascial trigger points in a clinical setting is presented. Treatments that specifically address myofascial pain secondary to spontaneously painful myofascial trigger points and their putative mechanisms of action are also reviewed, including physical therapy, dry needling, anesthetic injections, and botulinum toxin injections.

Beneficial Effects of Dry Needling for Treatment of Chronic Myofascial Pain Persist for 6 Weeks After Treatment Completion.

BACKGROUND: Dry needling is an effective treatment for reducing pain associated with active myofascial trigger points (a-MTrPs) in the short term. The duration of the benefits of this treatment have not been fully assessed. OBJECTIVE: To determine whether the benefits of dry needling (DN) of a-MTrPs are sustained 6 weeks posttreatment. DESIGN: Follow-up of a prospective study. SETTING: University. PARTICIPANTS: A total of 45 patients (13 male and 32 female) with cervical pain >3 months and a-MTrPs in the upper trapezius who completed 3 DN treatments and who were evaluated 6 weeks posttreatment. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Primary outcomes were changes from baseline to follow-up in scores for the verbal analogue scale (VAS), Brief Pain Inventory (BPI), and MTrP status. MTrPs were rated as active (spontaneously painful), latent (painful only on compression), and nonpalpable nodule. Responders were patients whose MTrP status changed from active to latent or nonpalpable nodule (resolved). Secondary outcomes were pain pressure threshold (PPT), Profile of Mood States, Oswestry Disability Index (ODI), MOS 36-Item Short-Form Health Survey (SF-36), and cervical range of motion. RESULTS: Pain measures remained significantly improved 6 weeks posttreatment (P < .003), as did the SF-36 physical functioning score (0.01) and ODI (P = .002). Side bending and PPT for subjects with unilateral MTrPs had sustained improvement (P = .002). The number of subjects with sustained MTrP response at 6 weeks was significant (P < .001). Comparing responders to nonresponders, the changes in VAS and BPI were statistically significant (P = .006, P = .03) but the change in PPT was not. Patients with higher baseline VAS scores had a higher risk of not responding to DN; those with a greater drop in VAS score from baseline had a higher probability of sustained response. A 1-unit decrease in VAS at baseline resulted in a 6.3-fold increase in the odds of being a responder versus a nonresponder (P = .008). CONCLUSIONS: In this study, there was sustained reduction of pain scores after completion of DN, which is more likely with a greater drop in VAS score. Patients with higher baseline VAS scores are less likely to respond to DN. Early intervention toward significant pain reduction is likely to be associated with sustained clinical response. LEVEL OF EVIDENCE: IV.

Hypodermis Tension Loop: A New Preventative Measure for Lead Migration in the Morbidly Obese.

Electrode migration/displacement is reported to be the most common complication of spinal cord stimulator (SCS) implantation, with the literature reporting incidences from 13.2% to 22.6%. There have been numerous publications describing techniques preventing lead migration, with most involving tying leads to skin and fascia for trial and permanent leads, respectively. However, few have addressed how to prevent migration in the case of hypermobile tissue seen in the morbidly obese. We describe the creation of subcutaneous tension loops to prevent lead migration.

Novel Use of Ultrasound Elastography to Quantify Muscle Tissue Changes After Dry Needling of Myofascial Trigger Points in Patients With Chronic Myofascial Pain.

OBJECTIVES: To compare a mechanical heterogeneity index derived from ultrasound vibration elastography with physical findings before and after dry-needling treatment of spontaneously painful active myofascial trigger points in the upper trapezius muscle. METHODS: Forty-eight patients with chronic myofascial pain enrolled in a prospective interventional trial of 3 weekly dry-needling treatments for active myofascial trigger points. Trigger points were evaluated at baseline and at treatment completion using palpation, the pressure-pain threshold, and the mechanical heterogeneity index. Thirty patients were reevaluated at 8 weeks. Trigger points that "responded" changed to tissue that was no longer spontaneously painful, with or without the presence of a palpable nodule. Trigger points that "resolved" changed to tissue without a palpable nodule. The mechanical heterogeneity index was defined as the proportion of the upper trapezius muscle that appeared mechanically stiffer on elastography. Statistical significance for comparisons was determined at P < .05. RESULTS: Following 3 dry needle treatments, the mechanical heterogeneity index decreased significantly for the 38 myofascial trigger points (79% of 48) that responded to treatment. Among these, the baseline mechanical heterogeneity index was significantly lower for the 13 trigger points (27% of 38) that resolved, but the decrease after 3 dry needle treatments did not reach significance. The pressure-pain threshold improved significantly for both groups. At 8 weeks, the mechanical heterogeneity index decreased significantly for the 22 trigger points (73% of 30) that responded and for the 10 (45% of 22) that resolved. The pressure-pain threshold improvement was significant for trigger points that responded but did not reach significance for resolved trigger points. CONCLUSIONS: The mechanical heterogeneity index identifies changes in muscle tissue properties that correlate with changes in the myofascial trigger point status after dry needling.

Real-Time MRI-Guided Catheter Tracking Using Hyperpolarized Silicon Particles.

Visualizing the movement of angiocatheters during endovascular interventions is typically accomplished using x-ray fluoroscopy. There are many potential advantages to developing magnetic resonance imaging-based approaches that will allow three-dimensional imaging of the tissue/vasculature interface while monitoring other physiologically-relevant criteria, without exposing the patient or clinician team to ionizing radiation. Here we introduce a proof-of-concept development of a magnetic resonance imaging-guided catheter tracking method that utilizes hyperpolarized silicon particles. The increased signal of the silicon particles is generated via low-temperature, solid-state dynamic nuclear polarization, and the particles retain their enhanced signal for ≥ 40 minutes--allowing imaging experiments over extended time durations. The particles are affixed to the tip of standard medical-grade catheters and are used to track passage under set distal and temporal points in phantoms and live mouse models. With continued development, this method has the potential to supplement x-ray fluoroscopy and other MRI-guided catheter tracking methods as a zero-background, positive contrast agent that does not require ionizing radiation.

Design, synthesis and evaluation of benzotriazole derivatives as novel antifungal agents.

Considering the need for discovery of new antifungal drugs with greater potency and broader spectrum of activity, a new series of 5-substituted benzotriazole derivatives were designed, through structure based design, as inhibitors of fungal cytochrome P450 lanosterol 14-α demethylase. These were further optimized by a combination of iterative medicinal chemistry principles and molecular docking. Based on the best docking scores, some benzotriazole derivatives were synthesized and characterized by IR, (1)H NMR and MS/MS. The molecules were evaluated for their antifungal action against Candida albicans by cup plate method and ergosterol quantification method by UV spectroscopy. Reasonably good correlation between docking scores and antifungal activity were observed. The computational predictions were in consensus with the experimental results.

Dry Needling Alters Trigger Points in the Upper Trapezius Muscle and Reduces Pain in Subjects With Chronic Myofascial Pain.

OBJECTIVE: To determine whether dry needling of an active myofascial trigger point (MTrP) reduces pain and alters the status of the trigger point to either a non-spontaneously tender nodule or its resolution. DESIGN: A prospective, nonrandomized, controlled, interventional clinical study. SETTING: University campus. PARTICIPANTS: A total of 56 subjects with neck or shoulder girdle pain of more than 3 months duration and active MTrPs were recruited from a campus-wide volunteer sample. Of these, 52 completed the study (23 male and 33 female). Their mean age was 35.8 years. INTERVENTIONS: Three weekly dry needling treatments of a single active MTrP. PRIMARY OUTCOMES: Baseline and posttreatment evaluations of pain using a verbal analogue scale, the Brief Pain Inventory, and the status of the MTrP as determined by digital palpation. Trigger points were rated as active (spontaneously painful), latent (requiring palpation to reproduce the characteristic pain), or resolved (no palpable nodule). SECONDARY OUTCOMES: Profile of Mood States, Oswestry Disability Index, and Short Form 36 scores, and cervical range of motion. PRIMARY OUTCOMES: A total of 41 subjects had a change in trigger point status from active to latent or resolved, and 11 subjects had no change (P < .001). Reduction in all pain scores was significant (P < .001). SECONDARY OUTCOMES: Significant improvement in posttreatment cervical rotational asymmetry in subjects as follows: unilateral/bilateral MTrPs (P = .001 and P = 21, respectively); in pain pressure threshold in subjects with unilateral/bilateral MTrPs, (P = .006 and P = .012, respectively); improvement in the SF-36 mental health and physical functioning subscale scores (P = .019 and P = .03), respectively; and a decrease in the Oswestry Disability Index score (P = .003). CONCLUSIONS: Dry needling reduces pain and changes MTrP status. Change in trigger point status is associated with a statistically and clinically significant reduction in pain. Reduction of pain is associated with improved mood, function, and level of disability.

Reduction of hypoxia-induced angiogenesis in ovarian cancer cells by inhibition of HIF-1 alpha gene expression.

PURPOSE: The goal of this study was to investigate the effects of silencing HIF-1 alpha gene expression with specific small interfering RNA (siRNA) on VEGF production and angiogenesis in epithelial ovarian cancer (EOC) cells. METHODS: Two EOC cell lines, MDAH-2774 and SKOV-3, were cultured under normoxic (20% O(2)) and hypoxic (2% O(2)) conditions using standard techniques. After EOC cells were transfected with siRNA, HIF-1 alpha and VEGF mRNA levels were measured by real-time RT-PCR. Angiogenesis was evaluated utilizing an in vitro assay model consisting of human umbilical vein endothelial cells (HUVEC) and polymerized ECM Matrix. RESULTS: Both EOC cell lines evaluated constitutively expressed HIF-1 alpha and VEGF mRNA. HIF-1 alpha and VEGF mRNA levels were significantly increased in response to hypoxia (P < 0.05). Under hypoxic conditions, inhibition of HIF-1 alpha gene expression by a specific siRNA resulted in a significant reduction in HIF-1 alpha and VEGF mRNA levels (P < 0.05). In the in vitro angiogenesis model, supernatant from the hypoxic EOC cells induced the HUVEC to form a complex tubular network, a hallmark of angiogenesis. Semi-quantitative analysis of the angiogenesis assay revealed a significant reduction in tube formation when supernatant from HIF-1 alpha siRNA-treated hypoxic EOC cell was used (P < 0.05). CONCLUSION: Inhibition of HIF-1 alpha expression by specific siRNA resulted in a significant decrease in VEGF production and angiogenesis. Further investigation of HIF-1 alpha inhibition for anti-tumor activity is warranted and may potentially prove HIF-1 alpha as a therapeutic target in the management ovarian cancer.

Uncovering the biochemical milieu of myofascial trigger points using in vivo microdialysis: an application of muscle pain concepts to myofascial pain syndrome.

This article discusses muscle pain concepts in the context of myofascial pain syndrome (MPS) and summarizes microdialysis studies that have surveyed the biochemical basis of this musculoskeletal pain condition. Though MPS is a common type of non-articular pain, its pathophysiology is only beginning to be understood due to its enormous complexity. MPS is characterized by the presence of myofascial trigger points (MTrPs), which are defined as hyperirritable nodules located within a taut band of skeletal muscle. MTrPs may be active (spontaneously painful and symptomatic) or latent (non-spontaneously painful). Painful MTrPs activate muscle nociceptors that, upon sustained noxious stimulation, initiate motor and sensory changes in the peripheral and central nervous systems. This process is called sensitization. In order to investigate the peripheral factors that influence the sensitization process, a microdialysis technique was developed to quantitatively measure the biochemical milieu of skeletal muscle. Biochemical differences were found between active and latent MTrPs, as well as in comparison with healthy muscle tissue. In this paper we relate the findings of elevated levels of sensitizing substances within painful muscle to the current theoretical framework of muscle pain and MTrP development.