AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity.

AMP-activated protein kinase (AMPK) is a metabolic fuel gauge conserved along the evolutionary scale in eukaryotes that senses changes in the intracellular AMP/ATP ratio. Recent evidence indicated an important role for AMPK in the therapeutic benefits of metformin, thiazolidinediones and exercise, which form the cornerstones of the clinical management of type 2 diabetes and associated metabolic disorders. In general, activation of AMPK acts to maintain cellular energy stores, switching on catabolic pathways that produce ATP, mostly by enhancing oxidative metabolism and mitochondrial biogenesis, while switching off anabolic pathways that consume ATP. This regulation can take place acutely, through the regulation of fast post-translational events, but also by transcriptionally reprogramming the cell to meet energetic needs. Here we demonstrate that AMPK controls the expression of genes involved in energy metabolism in mouse skeletal muscle by acting in coordination with another metabolic sensor, the NAD+-dependent type III deacetylase SIRT1. AMPK enhances SIRT1 activity by increasing cellular NAD+ levels, resulting in the deacetylation and modulation of the activity of downstream SIRT1 targets that include the peroxisome proliferator-activated receptor-gamma coactivator 1alpha and the forkhead box O1 (FOXO1) and O3 (FOXO3a) transcription factors. The AMPK-induced SIRT1-mediated deacetylation of these targets explains many of the convergent biological effects of AMPK and SIRT1 on energy metabolism.

A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange.

During early fasting, increases in skeletal muscle proteolysis liberate free amino acids for hepatic gluconeogenesis in response to pancreatic glucagon. Hepatic glucose output diminishes during the late protein-sparing phase of fasting, when ketone body production by the liver supplies compensatory fuel for glucose-dependent tissues. Glucagon stimulates the gluconeogenic program by triggering the dephosphorylation and nuclear translocation of the CREB regulated transcription coactivator 2 (CRTC2; also known as TORC2), while parallel decreases in insulin signalling augment gluconeogenic gene expression through the dephosphorylation and nuclear shuttling of forkhead box O1 (FOXO1). Here we show that a fasting-inducible switch, consisting of the histone acetyltransferase p300 and the nutrient-sensing deacetylase sirtuin 1 (SIRT1), maintains energy balance in mice through the sequential induction of CRTC2 and FOXO1. After glucagon induction, CRTC2 stimulated gluconeogenic gene expression by an association with p300, which we show here is also activated by dephosphorylation at Ser 89 during fasting. In turn, p300 increased hepatic CRTC2 activity by acetylating it at Lys 628, a site that also targets CRTC2 for degradation after its ubiquitination by the E3 ligase constitutive photomorphogenic protein (COP1). Glucagon effects were attenuated during late fasting, when CRTC2 was downregulated owing to SIRT1-mediated deacetylation and when FOXO1 supported expression of the gluconeogenic program. Disrupting SIRT1 activity, by liver-specific knockout of the Sirt1 gene or by administration of a SIRT1 antagonist, increased CRTC2 activity and glucose output, whereas exposure to SIRT1 agonists reduced them. In view of the reciprocal activation of FOXO1 and its coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha, encoded by Ppargc1a) by SIRT1 activators, our results illustrate how the exchange of two gluconeogenic regulators during fasting maintains energy balance.

Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.

Is it possible to estimate the minimal clinically important treatment effect needed to change practice in preterm birth prevention? Results of an obstetrician survey used to support the design of a trial.

BACKGROUND: Sample sizes for obstetrical trials are often based on the opinion of investigators about clinically important effect size. We surveyed Canadian obstetricians to investigate clinically important effect sizes required before introducing new treatments into practice to prevent preterm birth. METHODS: Questionnaires were mailed to practicing obstetricians, asking the magnitude of pregnancy prolongation required to introduce treatments into practice. The three prophylactic treatments were of increasing invasiveness: vaginal progesterone, intramuscular progesterone, and cervical cerclage. We also asked about the perceived most relevant outcome measures for obstetrical trials and current obstetrical practice in preterm birth prevention. RESULTS: 544/1293(42.1%) completed questionnaires were received. The majority of respondents required one or two weeks' increase in length of gestation before introducing vaginal (372,77.1%), and intramuscular progesterone(354,67.9%). At least three weeks increase was required before introducing prophylactic cervical cerclage(326,62.8%). Clinicians who already used a treatment required a smaller difference before introducing it into practice. Decreasing neonatal morbidity was cited as the most important outcome for obstetrical trials (349,72.2%). CONCLUSION: Obstetricians would require a larger increase in treatment effect before introducing more invasive treatments into practice. Although infant morbidity was perceived as a more important outcome, clinicians appeared willing to change practice on the basis of prolongation of pregnancy, a surrogate outcome. We found that there is not a single minimum clinically important treatment effect that will influence all practising clinicians: rather the effect size that will influence physicians is affected by the nature of the treatment, the reported outcome measure and the clinician's own current clinical practice.

Incidence of stress urinary incontinence following vaginal repair of pelvic organ prolapse in objectively continent women.

OBJECTIVE: To estimate the incidence of stress urinary incontinence (SUI) following vaginal repair of pelvic organ prolapse (POP) in preoperatively continent women and to evaluate the impact of the problem. METHODS: Women were eligible if they had undergone vaginal repairs for any degree or type of POP with no anti-incontinence procedure between July 1, 2004 and June 30, 2006, and had been continent preoperatively, as defined by a negative cough stress test with or without reduction of prolapse. Demographic, preoperative, operative, and postoperative data were retrieved from hospital charts. The incidence of postoperative SUI (POSUI) and its quality of life (QoL) impact were assessed by mailed questionnaire. The POSUI endpoint was defined by the report of SUI symptoms on the mailed questionnaire and/or affirmation of postoperative treatment for SUI. RESULTS: Forty-two out of 100 respondents reported POSUI within the 2-year average follow-up period. Twelve of 37 symptomatic women (32%) were moderately or greatly bothered by their symptoms. The QoL impact score was generally low but was statistically greater in women with POSUI compared to those with no POSUI (13 vs. 3, P=0.0006). CONCLUSION: The risk of POSUI following vaginal repairs of POP may be higher than previously reported and approximately one-third of women are bothered by these symptoms. These findings deserve further investigation.

How well informed are women who undergo urodynamic testing?

AIMS: Urodynamic studies (UDS) are complex, invasive and may be emotionally and physically distressing. Inadequate information may heighten distress. Prior to UDS, our patients receive written and verbal information, yet concerns remains that some women may not be adequately informed. This study examined how informed women believe they are to undergo UDS in our clinic. METHODS: This was a before-after questionnaire-based study. Data were collected from a convenience sample of 200 women prior to UD testing, and within 3 days of completion. Participants rated their level of agreement/disagreement with the following statements: I understand why I am having the test; I have been given enough information about the test; I understand what the test will involve. Women also reported their perceived levels of distress (anxiety, embarrassment, and discomfort). RESULTS: One hundred fifty-one women returned both pre- and post-UD questionnaires. Most (88.9%) had read the information sheet and agreed that they understood the indications for the testing (78.1%). Fewer agreed that they understood what the tests would involve (68.2%), or that they had been given enough information about the test (64.9%). The overall distress score (anxiety, embarrassment, and discomfort) was 6 (IQR 5-7; possible range 3-9). CONCLUSIONS: Urodynamic testing remains an invasive yet prevalent form of urogynecological assessment. One-third of our patients may not understand what UD testing involves and may not feel adequately informed about the tests. Additional research to explore informational needs is important.

SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity.

Chronic inflammation is an important etiology underlying obesity-related disorders such as insulin resistance and type 2 diabetes, and recent findings indicate that the macrophage can be the initiating cell type responsible for this chronic inflammatory state. The mammalian silent information regulator 2 homolog SIRT1 modulates several physiological processes important for life span, and a potential role of SIRT1 in the regulation of insulin sensitivity has been shown. However, with respect to inflammation, the role of SIRT1 in regulating the proinflammatory pathway within macrophages is poorly understood. Here, we show that knockdown of SIRT1 in the mouse macrophage RAW264.7 cell line and in intraperitoneal macrophages broadly activates the JNK and IKK inflammatory pathways and increases LPS-stimulated TNFalpha secretion. Moreover, gene expression profiles reveal that SIRT1 knockdown leads to an increase in inflammatory gene expression. We also demonstrate that SIRT1 activators inhibit LPS-stimulated inflammatory pathways, as well as secretion of TNFalpha, in a SIRT1-dependent manner in RAW264.7 cells and in primary intraperitoneal macrophages. Treatment of Zucker fatty rats with a SIRT1 activator leads to greatly improved glucose tolerance, reduced hyperinsulinemia, and enhanced systemic insulin sensitivity during glucose clamp studies. These in vivo insulin-sensitizing effects were accompanied by a reduction in tissue inflammation markers and a decrease in the adipose tissue macrophage proinflammatory state, fully consistent with the in vitro effects of SIRT1 in macrophages. In conclusion, these results define a novel role for SIRT1 as an important regulator of macrophage inflammatory responses in the context of insulin resistance and raise the possibility that targeting of SIRT1 might be a useful strategy for treating the inflammatory component of metabolic diseases.

A protein deacetylase SIRT1 is a negative regulator of metalloproteinase-9.

Inappropriate elevation of matrix metalloproteinase-9 (MMP9) is reported to be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The object of this study was to identify the molecular mechanism underlying this increase of MMP9 expression, and here we show that oxidative stress-dependent reduction of a protein deacetylase, SIRT1, known as a putative antiaging enzyme, causes elevation of MMP9 expression. A sirtuin inhibitor, splitomycin, and SIRT1 knockdown by RNA interference led an increase in MMP9 expression in human monocytic U937 cells and in primary sputum macrophages, which was detected by RT-PCR, Western blot, activity assay, and zymography. In fact, the SIRT1 level was significantly decreased in peripheral lungs of patients with COPD, and this increase was inversely correlated with MMP9 expression and MMP9 promoter activation detected by a chromatin immunoprecipitation assay. H(2)O(2) reduced SIRT1 expression and activity in U937 cells; furthermore, cigarette smoke exposure also caused reduction of SIRT1 expression in lung tissue of A/J mice, with concomitant elevation of MMP9. Intranasal treatment of a selective and novel SIRT1 small molecule activator, SRT2172, blocked the increase of MMP9 expression in the lung as well as pulmonary neutrophilia and the reduction in exercise tolerance. Thus, SIRT1 is a negative regulator of MMP9 expression, and SIRT1 activation is implicated as a novel therapeutic approach to treating chronic inflammatory diseases, in which MMP9 is abundant.

The Sirtuin family: therapeutic targets to treat diseases of aging.

Sirtuins have emerged as therapeutic targets to treat age-related diseases. There are seven human Sirtuins (SIRT1-7) that display diversity in cellular localization and function. Growing evidence suggests that small-molecule activators of SIRT1 may counteract age-related afflictions such as type 2 diabetes. Alternatively, inhibitors of SIRT2 may be useful in the treatment of neurodegenerative diseases such as Parkinson's disease. Recent discoveries of small-molecule and protein modulators of Sirtuin deacetylation activity have provided enormous insight into the biological and molecular functions of Sirtuins and have validated their potential as therapeutics.

Discovery of benzothiazole derivatives as efficacious and enterocyte-specific MTP inhibitors.

A series of triamide derivatives bearing a benzothiazole core is shown to be potent microsomal triglyceride transfer protein (MTP) inhibitors. In order to minimize liver toxicity, these compounds have been optimized to have activity only in the enterocytes and have limited systemic bioavailability. Upon oral administration, selected analogs within this series have been further demonstrated to reduce food intake along with body weight and thereby improve glucose homeostasis and insulin sensitivity in a 28-day mice diet-induced obesity (DIO) model.

Discovery of oxazolo[4,5-b]pyridines and related heterocyclic analogs as novel SIRT1 activators.

SIRT1 is an NAD(+)-dependent protein deacetylase that appears to produce beneficial effects on metabolic parameters such as glucose and insulin homeostasis. Activation of SIRT1 by resveratrol (1) has been shown to modulate insulin resistance, increase mitochondrial content and prolong survival in lower organisms and in mice on a high fat diet. Herein, we describe the identification and SAR of a series of oxazolo[4,5-b]pyridines as novel small molecule activators of SIRT1 which are structurally unrelated to and more potent than resveratrol.

Developing and pre-testing a decision board to facilitate informed choice about delivery approach in uncomplicated pregnancy.

BACKGROUND: The rate of caesarean sections is increasing worldwide, yet medical literature informing women with uncomplicated pregnancies about relative risks and benefits of elective caesarean section (CS) compared with vaginal delivery (VD) remains scarce. A decision board may address this gap, providing systematic evidence-based information so that patients can more fully understand their treatment options. The objective of our study was to design and pre-test a decision board to guide clinical discussions and enhance informed decision-making related to delivery approach (CS or VD) in uncomplicated pregnancy. METHODS: Development of the decision board involved two preliminary studies to determine women's preferred mode of risk presentation and a systematic literature review for the most comprehensive presentation of medical risks at the time (VD and CS). Forty women were recruited to pre-test the tool. Eligible subjects were of childbearing age (18-40 years) but were not pregnant in order to avoid raising the expectation among pregnant women that CS was a universally available birth option. Women selected their preferred delivery approach and completed the Decisional Conflict Scale to measure decisional uncertainty before and after reviewing the decision board. They also answered open-ended questions reflecting what they had learned, whether or not the information had helped them to choose between birth methods, and additional information that should be included. Descriptive statistics were used to analyse sample characteristics and women's choice of delivery approach pre/post decision board. Change in decisional conflict was measured using Wilcoxon's sign rank test for each of the three subscales. RESULTS: The majority of women reported that they had learned something new (n = 37, 92%) and that the tool had helped them make a hypothetical choice between delivery approaches (n = 34, 85%). Women wanted more information about neonatal risks and personal experiences. Decisional uncertainty decreased (p < 0.001) and perceived effectiveness of decisions increased (p < 0.001) post-intervention. CONCLUSION: Non-pregnant women of childbearing age were positive about the decision board and stated their hypothetical delivery choices were informed by risk presentation, but wanted additional information about benefits and experiences. This study represents a preliminary but integral step towards ensuring women considering delivery approaches in uncomplicated pregnancies are fully informed.

Goal achievement as a patient-generated outcome measure for stress urinary incontinence.

OBJECTIVES: To explore women's goals and goal attainment for the conservative and surgical treatment of stress urinary incontinence (SUI), and to examine the feasibility of Goal Attainment Scaling (GAS) as an outcome measure in this population. BACKGROUND: Despite the range of treatments for SUI, little is known about the outcomes patients consider important. Current instruments measure the impact of SUI on the ability to live a 'normal' life without addressing what normal looks like for the patient. Patient-generated measures that address what a patient aims to achieve may fill this gap. DESIGN: A mixed-methods exploratory design combined semi-structured interviews with validated questionnaires and individualized rating of goal achievement. SETTING AND PARTICIPANTS PARTICIPANTS: with SUI (n = 18) were interviewed in their homes prior to initiation of treatment and 3-6 months afterwards. MAIN VARIABLES: Participants reported individualized goals pre-treatment and rated goal attainment after surgical and conservative therapy. Quality of life impact and change were measured using short forms of the Incontinence Impact Questionnaire and Urinary Distress Inventory. RESULTS: Women expressed a median of four highly individualized treatment-related goals but goal achievement following conservative treatment was poor. GAS was not feasible as an outcome measure; women readily identified personal goals but could not independently identify graded levels of attainment for each goal. CONCLUSIONS: Although further work is needed to examine the most feasible, valid, and reliable method of measuring goal achievement in research, asking patients with UI to identify pre-treatment goals may provide useful information to guide treatment-related decision making.

Men's experiences following laparoscopic radical prostatectomy: a qualitative descriptive study.

BACKGROUND: Laparoscopic radical prostatectomy is a less invasive surgical option to the open retropubic approach for prostate cancer that will likely grow in popularity commensurate with availability. However, since little is known about what men experience throughout the postoperative period, our ability to ensure informed decision-making remains compromised. OBJECTIVES: The aim of this study was to explore what men experience following laparoscopic radical prostatectomy and how adequately their pre- and postoperative needs are being met. DESIGN: This was a qualitative descriptive study. PARTICIPANTS: Nineteen men, aged 46-76, who had undergone laparoscopic radical prostatectomy within the previous 3-6 months period were recruited from the treatment and control arms of a randomized controlled trial. Men who were not in the trial were recruited via letters mailed from surgeons' offices. METHODS: Data were generated during loosely structured individual (n=5) and focus group interviews (n=3). Inductive content analysis helped to ensure that participants' perspectives were accurately represented. RESULTS: Men had actively sought information prior to surgery but seemed unprepared for the intensity of discomfort and incontinence they experienced. They particularly valued opportunities for informal discussion with former prostatectomy patients; however, erectile dysfunction remained a major concern and most did not know where to turn for help. CONCLUSION: Nurses could play a pivotal role in the laparoscopic radical prostatectomy experience by ensuring men are well informed both pre- and postoperatively. Facilitating contact with other men who have undergone laparoscopic radical prostatectomy (LRP) and initiating conversation about potential side-effects such as urinary incontinence and erectile dysfunction would be an important starting point. Particularly in light of early discharge and concerns regarding erectile dysfunction, additional follow-up seems warranted.

CAT-2003: A novel sterol regulatory element-binding protein inhibitor that reduces steatohepatitis, plasma lipids, and atherosclerosis in apolipoprotein E*3-Leiden mice.

CAT-2003 is a novel conjugate of eicosapentaenoic acid (EPA) and niacin designed to be hydrolyzed by fatty acid amide hydrolase to release EPA inside cells at the endoplasmic reticulum. In cultured liver cells, CAT-2003 blocked the maturation of sterol regulatory element-binding protein (SREBP)-1 and SREBP-2 proteins and decreased the expression of multiple SREBP target genes, including HMGCR and PCSK9. Consistent with proprotein convertase subtilisin/kexin type 9 (PCSK9) reduction, both low-density lipoprotein receptor protein at the cell surface and low-density lipoprotein particle uptake were increased. In apolipoprotein E*3-Leiden mice fed a cholesterol-containing western diet, CAT-2003 decreased hepatic inflammation and steatosis as evidenced by fewer inflammatory cell aggregates in histopathologic sections, decreased nuclear factor kappa B activity in liver lysates, reduced inflammatory gene expression, reduced intrahepatic cholesteryl ester and triglyceride levels, and decreased liver mass. Plasma PCSK9 was reduced and hepatic low-density lipoprotein receptor protein expression was increased; plasma cholesterol and triglyceride levels were lowered. Aortic root segments showed reduction of several atherosclerotic markers, including lesion size, number, and severity. CAT-2003, when dosed in combination with atorvastatin, further lowered plasma cholesterol levels and decreased hepatic expression of SREBP target genes. Conclusion: SREBP inhibition is a promising new strategy for the prevention and treatment of diseases associated with abnormal lipid metabolism, such as atherosclerosis and nonalcoholic steatohepatitis. (Hepatology Communications 2017;1:311-325).

Perceived effects on patients' health of participation in the atrial fibrillation follow-up investigation of rhythm management study.

BACKGROUND: Patients' views about participation in clinical trials have been explored using end-of-study questionnaires for various disease entities. However, little is known about why individuals with atrial fibrillation (AF) choose to participate in clinical trials or how they view their research experience. Understanding these perceptions should provide valuable information for future studies in developing methods to enhance enrollment, optimize adherence to therapies, and maximize patient retention. METHODS: The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Study was a randomized trial of rate-control versus rhythm-control for the management of AF. This descriptive ancillary study used a 7-item questionnaire comprising closed and open-ended items that explored: (1) perceptions of benefits from participation, (2) motivation for enrolling, and (3) satisfaction with research staff and operations. RESULTS: A total of 741/1,032 participants (72%) at 34 of 213 participating AFFIRM sites responded, representing 18% of the 4,060 patients enrolled. The mean follow-up of these respondents was 3.8 +/- 1.1 years. Most respondents (91%) felt that they received enough information about AFFIRM before enrolling and that the results would benefit themselves (88%) and others (91%). Most respondents felt study participation improved awareness about AF (90%) and facilitated coordination of their healthcare (89%). Virtually all were satisfied with information received from AFFIRM personnel (96%), and most (98%) reported that they had received "good care." Responses were similar between randomization groups (rate-control or rhythm-control) and between those younger than 65 years and those 65 years or older. Participants in sinus rhythm at last follow-up were more likely to believe that their medical care in AFFIRM was better than what they would otherwise have received, and were more likely to perceive their treatment course as entailing fewer emergency room visits, hospitalizations, and doctor visits. Regularly scheduled appointments and ongoing availability of staff to answer questions appeared to increase participants' confidence and reduce anxiety. CONCLUSIONS: Patients enrolled in a long-term clinical trial for management of AF were overwhelmingly satisfied with participation.

Factors impacting self-care for urinary incontinence.

INTRODUCTION: Behavioral strategies such as pelvic floor muscle exercises (PFME), bladder retraining, and dietary modifications are generally considered to be the first line of treatment for urinary incontinence (UI). Yet little is understood about the client's abilities/motivation to manage their UI in the home setting. Self-care, the ability of clients to act on their own behalf to achieve and maintain health, is a fundamental component of these strategies. Despite the frequently chronic nature of UI, there is growing evidence that such maintenance of behavioral therapies is sporadic at best. OBJECTIVE: The purpose of this study was to enhance understanding of self-care strategies that individuals with UI employ, the perceived benefits of these strategies, the factors that influence their self-care choices, and the factors that impede or facilitate maintenance of behavioral therapies. METHOD: In this qualitative descriptive study, individual and focus group interviews with community-dwelling participants were conducted to enhance understanding regarding the participants' management of UI at home and why they maintain certain strategies and not others. Data were collected via loosely constructed individual (n=25) and focus group (n=3) interviews to facilitate open discussion of participants' perceptions. RESULTS: Thirty-eight individuals (33 women and 5 men) participated in the study. Analysis of data resulted in a major category of self-care strategies related to UI that was further subcategorized into factors that facilitated PFME and barriers to PFME performance. Factors that facilitated PFME included: (a) realistic goals and expectation, (b) positive affirmation, (c) follow up, and (d) maintaining an exercise routine. Barriers noted were: (a) insufficient information, (b) characteristics of the exercises, (c) competing interests, (d) financial cost, and (e) minor psychosocial impact. CONCLUSIONS: This study described the self-care strategies that participants with UI had initiated and maintained and additionally explored the perceived facilitators and barriers to self-care choices. Two major themes emerged: (a) self-care efforts were motivated by desire for a normal daily lifestyle and (b) participants were motivated to maintain strategies by the ability to visualize progress and by knowledge that they were progressing. These findings support the need for client-focused teaching that is grounded in the individual's daily realities and goals.

Synthesis and Characterization of Fatty Acid Conjugates of Niacin and Salicylic Acid.

This report describes the synthesis and preliminary biological characterization of novel fatty acid niacin conjugates and fatty acid salicylate conjugates. These molecular entities were created by covalently linking two bioactive molecules, either niacin or salicylic acid, to an omega-3 fatty acid. This methodology allows the simultaneous intracellular delivery of two bioactives in order to elicit a pharmacological response that could not be replicated by administering the bioactives individually or in combination. The fatty acid niacin conjugate 5 has been shown to be an inhibitor of the sterol regulatory element binding protein (SREBP), a key regulator of cholesterol metabolism proteins such as PCSK9, HMG-CoA reductase, ATP citrate lyase, and NPC1L1. On the other hand, the fatty acid salicylate conjugate 11 has been shown to have a unique anti-inflammatory profile based on its ability to modulate the NF-κB pathway through the intracellular release of the two bioactives.

An exploratory study of continence care services worldwide.

Urinary incontinence (UI) is a complex symptom of underlying disorders that affects over one and a half million Canadians. Although there is good evidence that incontinence can be treated effectively, the most efficient and cost-effective method for delivery of treatment is uncertain. The purpose of this study was to explore and describe the continence services that exist internationally and in Canada in order to provide the background for a Canadian model of continence service. Data were collected by communication with international health care professionals with expertise in UI, and distribution of a questionnaire to international and Canadian continence care providers. Findings suggest that although physicians, nurses, and/or physiotherapists currently provide continence care, services are scattered and inconsistent and discrepancies exist in how they are funded. The major themes that emerged are the need for enhanced accessibility of continence care and the importance of multidisciplinary teamwork.

Vaginal paravaginal repair with porcine small intestine submucosa: midterm outcomes.

OBJECTIVE: : This study aimed to determine the midterm efficacy of porcine small intestine submucosa for paravaginal repairs of anterior vaginal prolapse. METHODS: : One hundred five women underwent repairs between 2003 and 2006 and met our inclusion criteria. Women were invited to return for a pelvic examination and to fill out validated questionnaires. Objective failure was defined as anterior prolapse recurrence at or beyond the hymen. RESULTS: : Fifty-nine women (56%) were available for follow-up. Median age of patients was 60 years (range, 26-80 years) and 83% had a parity of 2 or more. Ninety-seven percent of patients had a preoperative prolapse stage of 2 or more. Follow-up ranged from 1 to 5 years (median, 27.5 months; interquartile range, 14.5). The most common postoperative complication was transient voiding dysfunction (23.7%). Objective cure rate was 68.8%. A positive change in bladder, vaginal, and bowel symptoms (a little better, much better, or very much better) was reported by 69.5%, 59.3%, and 25.5% of women, respectively. Thirty-one women (52.5%) were sexually active at postoperative follow-up. Only 4 women (6.8%) were not sexually active because of pelvic symptoms. Dyspareunia was reported by 8.3% of the 48 women who returned for a clinic follow-up. Twenty-four women (40.7%) were not sexually active postoperatively, for reasons unrelated to their surgeries. CONCLUSIONS: : Vaginal paravaginal repair using porcine xenograft is a safe procedure whose long-term efficacy needs further evaluation through prospective trials.