Profession-based manual therapy nomenclature: exploring history, limitations, and opportunities.

OBJECTIVE: The International Consortium on Manual Therapies (ICMT) is a grassroots interprofessional association open to any formally trained practitioner of manual therapy (MT) and basic scientists promoting research related to the practice of MT. Currently, MT research is impeded by professions' lack of communication with other MT professions, biases, and vernacular. Current ICMT goals are to minimize these barriers, compare MT techniques, and establish an interprofessional MT glossary. METHODS: Practitioners from all professions with training in manual therapies were encouraged by e-mail and website to participate (www.ICMTConferene.org). Video conferences were conducted at least bimonthly for 2.5 years by profession-specific and interprofessional focus groups (FGs). Members summarized scopes of practice, technique descriptions, associated mechanisms of action (MOA), and glossary terms. Each profession presented their work to the interprofessional FG to promote dialogue, understanding and consensus. Outcomes were reported and refined at numerous public events. RESULTS: Focus groups with representatives from 5 MT professions, chiropractic, massage therapy, osteopathic, physical therapy and structural integration identified 17 targeting osseous structures and 49 targeting nonosseous structures. Thirty-two techniques appeared distinct to a specific profession, and 13 were used by more than 1. Comparing descriptions identified additional commonalities. All professions agreed on 4 MOA categories for MT. A glossary of 280 terms and definitions was consolidated, representing key concepts in MT. Twenty-one terms were used by all MT professions and basic scientists. Five terms were used by MT professions exclusive of basic scientists. CONCLUSION: Outcomes suggested a third to a half of techniques used in MT are similar across professions. Additional research is needed to better define the extent of similarity and how to consistently identify those approaches. Ongoing expansion and refinement of the glossary is necessary to promote descriptive clarity and facilitate communication between practitioners and basic scientists.

Patients' experiences treated with open-label placebo versus double-blind placebo: a mixed methods qualitative study.

BACKGROUND: There is increasing evidence suggesting that open-label placebo (OLP) is an effective treatment for several medical conditions defined by self-report. However, little is known about patients' experiences with OLP, and no studies have directly compared patients' experiences in double-blind placebo (DBP) conditions. METHODS: This study was nested in a large randomized-controlled trial comparing the effects of OLP and DBP treatments in individuals with irritable bowel syndrome (IBS). We randomly selected 33 participants for interviews concerning their experiences in the parent trial. The data were qualitatively analyzed using an iterative immersion/crystallization approach. We then compared the qualitative interview data to the quantitative IBS severity data assessed during the parent trial, using a mixed methods approach. RESULTS: Two prominent interview themes were identified: (1) the participants' feelings about their treatment allocation and (2) their reflections about the treatment. Both OLP and DBP participants mentioned hope and curiosity as major feelings driving them to engage with their treatment. However, while DBP participants tended to be more enthusiastic about their allocation, OLP participants were more ambivalent. Furthermore, OLP participants reflected more on their treatment, often involving noticeable cognitive and emotional processes of self-reflection. They offered a variety of explanations for their symptom improvement and were significantly less likely to attribute it to the treatment itself than DBP participants (Χ2 [3] = 8.28; p = .041). Similarly, the participants' retrospective narratives of symptom improvement were significantly correlated with their corresponding quantitative IBS severity scores only in DBP (p's ≤ .006) but not in OLP (p's ≥ .637). CONCLUSION: OLP and DBP participants share feelings of hope, uncertainty and curiosity but differ in the extent of conscious reflection. The counter-intuitive OLP prompts more self-examination, ambivalent feelings and active engagement compared to DBP. At the same time, OLP participants are more reluctant to attribute symptom improvement to their treatment. Our findings substantially add to the emerging picture of factors that distinguish OLP and DBP and their potential mechanisms.

Diagnosis of Gulf War Illness Using Laser-Induced Spectra Acquired from Blood Samples.

Gulf War illness (GWI) is a chronic illness with no known validated biomarkers that affects the lives of hundreds of thousands of people. As a result, there is an urgent need for the development of an untargeted and unbiased method to distinguish GWI patients from non-GWI patients. We report on the application of laser-induced breakdown spectroscopy (LIBS) to distinguish blood plasma samples from a group of subjects with GWI and from subjects with chronic low back pain as controls. We initially obtained LIBS data from blood plasma samples of four GWI patients and four non-GWI patients. We used an analytical method based on taking the difference between a mean LIBS spectrum obtained with those of GWI patients from the mean LIBS spectrum of those of the control group, to generate a "difference" spectrum for our classification model. This model was cross-validated using different numbers of differential LIBS emission peaks. A subset of 17 of the 82 atomic and ionic transitions that provided 70% of correct diagnosis was selected test in a blinded fashion using 10 additional samples and was found to yield 90% classification accuracy, 100% sensitivity, and 83.3% specificity. Of the 17 atomic and ionic transitions, eight could be assigned unambiguously to species of Na, K, and Fe.

Suppression of Breast Cancer by Small Molecules That Block the Prolactin Receptor.

Prolactin (PRL) is a protein hormone which in humans is secreted by pituitary lactotrophs as well as by many normal and malignant non-pituitary sites. Many lines of evidence demonstrate that both circulating and locally produced PRL increase breast cancer (BC) growth and metastases and confer chemoresistance. Our objective was to identify and then characterize small molecules that block the tumorigenic actions of PRL in BC. We employed three cell-based assays in high throughput screening (HTS) of 51,000 small molecules and identified two small molecule inhibitors (SMIs), named SMI-1 and SMI-6. Both compounds bound to the extracellular domain (ECD) of the PRL receptor (PRLR) at 1-3 micromolar affinity and abrogated PRL-induced breast cancer cell (BCC) invasion and malignant lymphocyte proliferation. SMI-6 effectively reduced the viability of multiple BCC types, had much lower activity against various non-malignant cells, displayed high selectivity, and showed no apparent in vitro or in vivo toxicity. In athymic nude mice, SMI-6 rapidly and dramatically suppressed the growth of PRL-expressing BC xenografts. This report represents a pre-clinical phase of developing novel anti-cancer agents with the potential to become effective therapeutics in breast cancer patients.

Can Reliability of the Chinese Medicine Diagnostic Process Be Improved? Results of a Prospective Randomized Controlled Trial.

Background: The diagnostic framework and clinical reasoning process of Chinese medicine are central to the practice of acupuncture and other related disciplines. There is growing interest in integrating it into clinical trials of acupuncture and Chinese herbal medicine to guide individualized treatment protocols and evaluate outcomes. Strategies that enhance diagnostic reliability may contribute to this integration. Objectives: (1) To evaluate inter-rater reliability among practitioners of Traditional Chinese Medicine (TCM) when assessing women with dysmenorrhea using a structured assessment questionnaire (Traditional East Asian Medicine Structure Interview [TEAMSI]-TCM) compared to using a TCM questionnaire from routine clinical practice, not developed for research purposes (CONTROL); and (2) To evaluate the impact of training in the use of each approach on reliability. Design: Thirty-eight acupuncturists were asked to complete assessments of 10 subjects based on the viewing of a videotape of the initial assessment interview, a picture of the tongue, and a description of the pulse. Acupuncturists were randomized into one of four groups comparing the use of two questionnaires, TEAMSI-TCM versus CONTROL, and comparing training in the use of each versus no training. Analysis: The authors used Cohen's kappa to estimate agreement on TCM diagnostic categories relevant to dysmenorrhea between 2 practitioners with respect to questionnaires and training over all 10 patients and all 10 TCM diagnostic categories. For all analyses, the authors estimated kappa values for questionnaire, training, and experience level. Analysis of variance was used to test agreement among various groupings. Results: Regardless of the questionnaire used or training, analysis of inter-rater reliability indicated overall agreement to be low among practitioners (median 0.26). Kappa varied slightly by questionnaire and training, among 38 practitioners, but the difference was not statistically significant (p = 0.227 and p = 0.126, respectively). Conclusions: A structured assessment interview instrument designed for research purposes with or without training did not significantly improve reliability of TCM diagnosis of dysmenorrhea compared to a commonly used instrument. Challenges in assessing reliability in TCM remain.

Experimental Studies of Inter-Rater Agreement in Traditional Chinese Medicine: A Systematic Review.

Objectives: It has been recommended that clinical trials of Traditional Chinese Medicine (TCM) would be more ecologically valid if its characteristic mode of diagnostic reasoning were integrated into their design. In that context, however, it is also widely held that demonstrating a high level of agreement on initial TCM diagnoses is necessary for the replicability that the biomedical paradigm requires for the conclusions from such trials. Our aim was to review, summarize, and critique quantitative experimental studies of inter-rater agreement in TCM, and some of their underlying assumptions. Design: Systematic electronic searches were conducted for articles that reported a quantitative measure of inter-rater agreement across a number of rating choices based on examinations of human subjects in person by TCM practitioners, and published in English language peer-reviewed journals. Publications in languages other than English were not included, nor those appearing in other than peer-reviewed journals. Predefined categories of information were extracted from full texts by two investigators working independently. Each article was scored for methodological quality. Outcome measures: Design features across all studies and levels of inter-rater agreement across studies that reported the same type of outcome statistic were compared. Results: Twenty-one articles met inclusion criteria. Fourteen assessed inter-rater agreement on TCM diagnoses, two on diagnostic signs found upon traditional TCM examination, and five on novel rating schemes derived from TCM theory and practice. Raters were students of TCM colleges or graduates of TCM training programs with 3 or more years experience and licensure. Type of outcome statistic varied. Mean rates of pairwise agreement averaged 57% (median 65, range 19-96) across the 9 studies reporting them. Mean Cohen's kappa averaged 0.34 (median 0.34, range 0.07-0.59) across the seven studies reporting them. Meta-analysis was not possible due to variations in study design and outcome statistics. High risks of bias and confounding, and deficits in statistical reporting were common. Conclusions: With a few exceptions, the levels of agreement were low to moderate. Most studies had significant deficits of both methodology and reporting. Results overall suggest a few design features that might contribute to higher levels of agreement. These should be studied further with better experimental controls and more thorough reporting of outcomes. In addition, methods of complex systems analysis should be explored to more adequately model the relationship between clinical outcomes, and the series of diagnoses and treatments that are the norm in actual TCM practice.

Frontiers in fascia research.

Basic sciences are the backbone of every clear understanding of how the body is composed and how different structures and functions are connected with each other. It is obvious that there is a huge variability in human beings - not only in terms of the outer appearance such as measurements of height, weight, muscle mass and other physical properties, but also with respect to metabolic and functional parameters. This article highlights recent developments of research activities in the field of fascia sciences with a special emphasis on assessment strategies as the basis of further studies. Anatomical and histological studies show that fascial tissue is highly variable in terms of density, stiffness, and other parameters such as metabolic and humoral activity. Moreover, it encompasses nerves and harbours a system of micro-channels, also known as the primo vascular system. As ultrasound is a widely available method, its use is appealing not only for imaging of fascial structures, but also for thorough scientific analysis. Unlike most other imaging technologies, US has the advantage of real-time analysis of active or passive movements. In addition, other assessment methods for fascial tissue are discussed. In conclusion, fascial tissue plays an important role not only in functional anatomy, but also in evolutionary and molecular biology, sport, and exercise science as well as in numerous therapeutic approaches. A high density of nerves is found in fascial tissue. Knowledge of individual characteristics, especially by visualizing with ultrasound, leads to personalized therapeutic approaches, such as in pain therapy.

Prolonged Field Care in Support of Operation Inherent Resolve, 2016.

The authors present their experience in emergency and longterm medical care by Special Operations Forces (SOF) medical providers in an austere environment. In this case, a Special Forces Operational Detachment-Alpha (SFOD-A) was deployed in support of Operation Inherent Resolve, partnered with indigenous combat forces.

Evaluation of negative pressure wound therapy to closed laparotomy incisions in acute care surgery.

BACKGROUND: Surgical site complications in the form of wound infections are a major burden to the healthcare system. Negative pressure wound therapy (NPWT) as delivered by a surgical incision management system (SIMS) is a novel approach to improve wound healing when applied to closed incisions. However, data is limited in its application to laparotomy incisions in the acute care surgery setting. METHODS: A retrospective case-control study was performed to evaluate the outcomes of SIMS with regard to surgical site infections in a series of 48 consecutive patients in which SIMS was applied to closed laparotomy incisions in the acute care surgery setting. RESULTS: 48 cases were matched with equivalent controls without significant differences between groups. Patients who received the SIMS had significantly lower rates of surgical site infection and readmission rates. CONCLUSIONS: Negative pressure surgical incision management systems may be a novel approach to reduce surgical site infections in acute care surgery.

Open-label versus double-blind placebo treatment in irritable bowel syndrome: study protocol for a randomized controlled trial.

BACKGROUND: Placebo medications, by definition, are composed of inactive ingredients that have no physiological effect on symptoms. Nonetheless, administration of placebo in randomized controlled trials (RCTs) and in clinical settings has been demonstrated to have significant impact on many physical and psychological complaints. Until recently, conventional wisdom has suggested that patients must believe that placebo pills actually contain (or, at least, might possibly contain) active medication in order to elicit a response to placebo. However, several recent RCTs, including patients with irritable bowel syndrome (IBS), chronic low back pain, and episodic migraine, have demonstrated that individuals receiving open-label placebo (OLP) can still experience symptomatic improvement and benefit from honestly described placebo treatment. METHODS AND DESIGN: This paper describes an innovative multidisciplinary trial design (n = 280) that attempts to replicate and expand upon an earlier IBS OLP study. The current study will compare OLP to double-blind placebo (DBP) administration which is made possible by including a nested, double-blind RCT comparing DBP and peppermint oil. The study also examines possible genetic and psychological predictors of OLP and seeks to better understand participants' experiences with OLP and DBP through a series of extensive interviews with a randomly selected subgroup. DISCUSSION: OLP treatment is a novel strategy for ethically harnessing placebo effects. It has potential to re-frame theories of placebo and to influence how physicians can optimize watch-and-wait strategies for common, subjective symptoms. The current study aims to dramatically expand what we know about OLP by comparing, for the first time, OLP and DBP administration. Adopting a unique, multidisciplinary approach, the study also explores genetic, psychological and experiential dimensions of OLP. The paper ends with an extensive discussion of the "culture" of the trial as well as potential mechanisms of OLP and ethical implications. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02802241 . Registered on 14 June 2016.

Screening for novel central nervous system biomarkers in veterans with Gulf War Illness.

Gulf War illness (GWI) is primarily diagnosed by symptom report; objective biomarkers are needed that distinguish those with GWI. Prior chemical exposures during deployment have been associated in epidemiologic studies with altered central nervous system functioning in veterans with GWI. Previous studies from our group have demonstrated the presence of autoantibodies to essential neuronal and glial proteins in patients with brain injury and autoantibodies have been identified as candidate objective markers that may distinguish GWI. Here, we screened the serum of 20 veterans with GWI and 10 non-veteran symptomatic (low back pain) controls for the presence of such autoantibodies using Western blot analysis against the following proteins: neurofilament triplet proteins (NFP), tubulin, microtubule associated tau proteins (Tau), microtubule associated protein-2 (MAP-2), myelin basic protein (MBP), myelin associated glycoprotein (MAG), glial fibrillary acidic protein (GFAP), calcium-calmodulin kinase II (CaMKII) and glial S-100B protein. Serum reactivity was measured as arbitrary chemiluminescence units. As a group, veterans with GWI had statistically significantly higher levels of autoantibody reactivity in all proteins examined except S-100B. Fold increase of the cases relative to controls in descending order were: CaMKII 9.27, GFAP 6.60, Tau 4.83, Tubulin 4.41, MAG 3.60, MBP 2.50, NFP 2.45, MAP-2 2.30, S-100B 1.03. These results confirm the continuing presence of neuronal injury/gliosis in these veterans and are in agreement with the recent reports indicating that 25years after the war, the health of veterans with GWI is not improving and may be getting worse. Such serum autoantibodies may prove useful as biomarkers of GWI, upon validation of the findings using larger cohorts.

Effects of the small molecule SIRT1 activator, SRT2104 on arterial stiffness in otherwise healthy cigarette smokers and subjects with type 2 diabetes mellitus.

OBJECTIVE: Arterial stiffness increases with age, and is associated with adverse cardiovascular outcome including increased mortality. The effect of the oral small molecule SIRT1 activator, SRT2104, on arterial stiffness was examined in otherwise healthy cigarette smokers and participants with type 2 diabetes mellitus. METHODS: 24 otherwise healthy cigarette smokers and 15 people with stable type 2 diabetes were randomised in a double-blind placebo-controlled crossover trial and received 28 days of oral SRT2104 (2.0 g/day) or matched placebo. Blood pressure was measured using non-invasive oscillatory sphygmomanometry. Pulse wave analysis and velocity were measured using applanation tonometry at baseline and the end of each treatment period. Owing to the small sample size and similar trends for both groups, data for the two groups were pooled (post hoc analysis). RESULTS: Compared to placebo, treatment with SRT2104 was associated with a significant reduction in augmentation pressure (p=0.0273) and a trend towards improvement in the augmentation index and corrected augmentation index (p>0.05 for both). However, no changes were observed in pulse wave velocity and time to wave reflection (p>0.05). Systolic and diastolic blood pressures remained unchanged throughout the study. Treatment by cohort interaction was not significant for any of the pulse wave parameters, suggesting that the response to SRT2104 in otherwise healthy smokers and people with diabetes was consistent. CONCLUSIONS: SRT2104 may improve measures of arterial stiffness in otherwise healthy cigarette smokers and in participants with type 2 diabetes. Definitive conclusions are not possible given the small sample size and exploratory nature of this analysis. TRIAL REGISTRATION NUMBER: NCT01031108.

Embedded Fragment Removal and Wound Debridement in a Non-US Partner Force Soldier.

OBJECTIVE: Review application of telemedicine support for removal of fragment and wound management. Clinical context: Special Forces Operational Detachment- Alpha deployed in Central Command area of responsibility operating out of a small aid station ("house" phase of prolonged field care) Organic expertise: 18D Special Operations Combat medic Closest medical support: Combined Joint Special Operations Task Force (CJSOTF) surgeon located in another country; thus, all consults were either via telephone or over Secret Internet Protocol Router e-mail. Earliest evacuation: NA.

Assessing Colonic Exposure, Safety, and Clinical Activity of SRT2104, a Novel Oral SIRT1 Activator, in Patients with Mild to Moderate Ulcerative Colitis.

BACKGROUND: Sirtuins are a class of proteins with important physiologic roles in metabolism and inflammation. Sirtuin (silent mating type information regulation 2 homolog) 1, or SIRT1, activation is an unexplored therapeutic approach for the treatment of ulcerative colitis (UC). METHODS: Patients with mild to moderately active UC were blindly randomized to 50 mg or 500 mg daily of SRT2104, a selective activator of SIRT1, for 8 weeks. Colonic exposure and safety were assessed, as well as blinded endoscopic scoring and disease activity by Mayo score, Simple Clinical Colitis Activity Index and fecal calprotectin. RESULTS: Across both SRT2104 groups, only 3 of 26 evaluable subjects achieved remission on blinded endoscopic assessment. Clinical remission (Mayo score ≤2, no subscore >1) was achieved in 4 patients (2 of 13 evaluable patients in each dose group). Fecal calprotectin levels declined with treatment in both groups, but after 56 days of treatment subjects were still found to have levels approximately 4-fold elevated above normal. One subject experienced an SAE requiring study withdrawal and another was withdrawn for a severe UC flare; 19 subjects (61%) across both treatment groups experienced at least 1 treatment emergent adverse event. Average drug exposure increased in a dose-dependent manner for escalating doses of SRT2104, and colonic exposure was 140 to 160 times higher than plasma exposures. CONCLUSIONS: SRT2104 did not demonstrate significant clinical activity in mild to moderately active UC. This suggests that further evaluation of SRT2104 as a therapeutic strategy for the treatment of UC is not warranted.

Identifying a Small Molecule Blocking Antigen Presentation in Autoimmune Thyroiditis.

We previously showed that an HLA-DR variant containing arginine at position 74 of the DRß1 chain (DRß1-Arg74) is the specific HLA class II variant conferring risk for autoimmune thyroid diseases (AITD). We also identified 5 thyroglobulin (Tg) peptides that bound to DRß1-Arg74. We hypothesized that blocking the binding of these peptides to DRß1-Arg74 could block the continuous T-cell activation in thyroiditis needed to maintain the autoimmune response to the thyroid. The aim of the current study was to identify small molecules that can block T-cell activation by Tg peptides presented within DRß1-Arg74 pockets. We screened a large and diverse library of compounds and identified one compound, cepharanthine that was able to block peptide binding to DRß1-Arg74. We then showed that Tg.2098 is the dominant peptide when inducing experimental autoimmune thyroiditis (EAT) in NOD mice expressing human DRß1-Arg74. Furthermore, cepharanthine blocked T-cell activation by thyroglobulin peptides, in particular Tg.2098 in mice that were induced with EAT. For the first time we identified a small molecule that can block Tg peptide binding and presentation to T-cells in autoimmune thyroiditis. If confirmed cepharanthine could potentially have a role in treating human AITD.

A Randomized, Placebo-Controlled Study of SRT2104, a SIRT1 Activator, in Patients with Moderate to Severe Psoriasis.

UNLABELLED: Activation of Sirtuin (silent mating type information regulation 2 homolog) 1, or SIRT1, is an unexplored therapeutic approach for treatment of inflammatory diseases. We randomized 40 patients with moderate-to-severe psoriasis (4:1) to three escalating doses of SRT2104, a selective activator of SIRT1, or placebo. Across all SRT2104 groups, 35% of patients (p<0.0001) achieved good to excellent histological improvement based on skin biopsies taken at baseline and day 84 but was not consistently in agreement with PASI. Improvement in histology was associated with modulation of IL-17 and TNF-α signaling pathways and keratinocyte differentiation target genes. 27 subjects (69%) across all treatment groups, including placebo, experienced at least one treatment emergent adverse event. The majority of AEs were either mild or moderate. Most common were headache (8%), dizziness (8%), upper respiratory tract infection (8%), and psoriatic arthropathy (8%). Average drug exposure increased in a dose-dependent manner for escalating doses of SRT2104 and had high intra-subject variability in exposure (AUC %CV: 51­89%). Given the interesting signals of clinical activity, impact on gene expression and the generally favorable safety profile seen in this study, further investigation of SIRT1 activators for the treatment of psoriasis is warranted. TRIAL REGISTRATION: Clinicaltrials.gov NCT01154101.

The Selective Sirtuin 1 Activator SRT2104 Reduces Endotoxin-Induced Cytokine Release and Coagulation Activation in Humans.

OBJECTIVES: Sirtuin 1 influences gene expression and other cellular functions through deacetylation of histone and nonhistone proteins. We here sought to determine the effects of a small molecule sirtuin 1 activator, SRT2104, on inflammation and coagulation induced by lipopolysaccharide in humans. DESIGN: A randomized, double-blind, placebo-controlled study. SETTING: An academic hospital. SUBJECTS: Twenty-four healthy humans. INTERVENTIONS: All subjects received an intravenous injection with lipopolysaccharide. Subjects were randomized to one of three groups (n=8 per group): 1) pretreatment with oral SRT2104 for 7 days (2 g/d), 2) pretreatment with a single SRT2104 dose (2 g), or 3) placebo. MEASUREMENTS AND MAIN RESULTS: SRT2104 attenuated lipopolysaccharide-induced release of the cytokines interleukin-6 (mean peak levels of 58.8% [p<0.05] and 80.9% [p=0.078] after single and repeated SRT2104 administration, respectively, relative to those measured after placebo treatment) and interleukin-8 (mean peak levels of 57.0% [p<0.05 vs placebo] and 77.1% [p<0.05 vs placebo] after single and repeated SRT2104 ingestion, respectively, while not affecting tumor necrosis factor-α and interleukin-10 release). SRT2104 also reduced the lipopolysaccharide-induced acute phase protein response (C-reactive protein). SRT2104 inhibited activation of coagulation, as reflected by lower plasma levels of the prothrombin fragment F1+2 (mean peak levels 57.9% [p<0.05] and 64.2% [p<0.05] after single and repeated SRT2104 administration, respectively, relative to those measured after placebo treatment). Activation of the vascular endothelium (plasma von Willebrand levels) and the fibrinolytic system (plasma tissue-type plasminogen activator and plasminogen activator inhibitor type I) was not influenced by SRT2104. CONCLUSIONS: This is the first human study to demonstrate biological anti-inflammatory and anticoagulant responses consistent with the activation of sirtuin 1 by a small molecule.

Structural integration as an adjunct to outpatient rehabilitation for chronic nonspecific low back pain: a randomized pilot clinical trial.

Structural Integration (SI) is an alternative method of manipulation and movement education. To obtain preliminary data on feasibility, effectiveness, and adverse events (AE), 46 outpatients from Boston area with chronic nonspecific low back pain (CNSLBP) were randomized to parallel treatment groups of SI plus outpatient rehabilitation (OR) versus OR alone. Feasibility data were acceptable except for low compliance with OR and lengthy recruitment time. Intent-to-treat data on effectiveness were analyzed by Wilcoxon rank sum, n = 23 per group. Median reductions in VAS Pain, the primary outcome, of -26 mm in SI + OR versus 0 in OR alone were not significantly different (P = 0.075). Median reductions in RMDQ, the secondary outcome, of -2 points in SI + OR versus 0 in OR alone were significantly different (P = 0.007). Neither the proportions of participants with nor the seriousness of AE were significantly different. SI as an adjunct to OR for CNSLBP is not likely to provide additional reductions in pain but is likely to augment short term improvements in disability with a low additional burden of AE. A more definitive trial is feasible, but OR compliance and recruitment might be challenging. This trial is registered with ClinicalTrials.gov (NCT01322399).

A phase II, randomized, placebo-controlled, double-blind, multi-dose study of SRT2104, a SIRT1 activator, in subjects with type 2 diabetes.

AIM: SRT2104 is a selective activator of SIRT1. In animal models, SRT2104 improves glucose homeostasis and increases insulin sensitivity. We evaluated the tolerability and pharmacokinetics of SRT2104, and its effects on glycaemic control, in adults with type 2 diabetes mellitus. METHOD: Type 2 diabetics with glycosylated haemoglobin (HbA1c) ≥ 7.5% and ≤10.5%, fasting glucose ≥160 and ≤240 mg dl(-1) , and on stable doses of metformin were evenly randomized to placebo or SRT2104 0.25 g, 0.5 g, 1.0 g or 2.0 g, administered orally once daily for 28 days. Changes in fasting and post-prandial glucose and insulin were analyzed. RESULTS: Safety evaluation found no major differences between groups in the frequency of adverse events. SRT2104 concentrations did not increase in a dose-proportional fashion. Significant variability in exposure was observed. Treatment with SRT2104 did not lead to any consistent, dose-related changes in glucose or insulin. Day 28 change from baseline (mean (SD)): fasting glucose (mmol l(-1) ) = -1.17 (2.42), -1.11 (3.45), -0.52 (2.60), -0.97 (2.83) and -0.15 (2.38) for placebo, 0.25 g, 0.5 g, 1.0 g and 2.0 g, respectively. Day 28 change from baseline (mean (SD)): fasting insulin (mmol l(-1) ) = 1.0 (51.66), 8.9 (95.04), -6.9 (41.45), 4.1 (57.16) and 15.2 (138.79) for placebo, 0.25 g, 0.5 g, 1.0 g and 2.0 g, respectively) Treatment with SRT2104 was associated with improvement in lipid profiles. CONCLUSION: Treatment with SRT2104 for 28 days did not result in improved glucose or insulin control which is likely due to the observed pharmacokinetics which were not dose proportional and had large between subject variability.

Cardiovascular effects of a novel SIRT1 activator, SRT2104, in otherwise healthy cigarette smokers.

BACKGROUND: We examined the effect of the oral SIRT1 activator SRT2104 on cardiovascular function in otherwise healthy cigarette smokers. METHODS AND RESULTS: Twenty-four otherwise healthy cigarette smokers participated in a randomized double-blind, placebo-controlled crossover trial and received 28 days of oral SRT2104 (2.0 g/day) or matched placebo. Plasma SRT2104 concentrations, serum lipid profile, plasma fibrinolytic factors, and markers of platelet and monocyte activation were measured at baseline and at the end of each treatment period together with an assessment of forearm blood flow during intra-arterial bradykinin, acetylcholine, and sodium nitroprusside infusions. Three hours postdose, mean plasma SRT2104 concentration was 1328 ± 748 ng/mL after 28 days of active treatment. Compared with placebo, serum lipid profile improved during SRT2104 administration, with reductions in serum total cholesterol (-11.6 ± 20 versus 6 ± 21 mg/dL), low-density lipoprotein cholesterol (-10 ± 17 versus 3 ± 21 mg/dL), and triglyceride (-39.8 ± 77 versus 13.3 ± 57 mg/dL) concentrations (P<0.05 for all). All vasodilators produced a dose-dependent increase in blood flow (P<0.0001) that was similar during each treatment period (P>0.05 for all). No significant differences in fibrinolytic or blood flow parameters were observed between placebo and SRT2014. CONCLUSIONS: SRT2104 appears to be safe and well tolerated and associated with an improved lipid profile without demonstrable differences in vascular or platelet function in otherwise healthy cigarette smokers. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01031108.