Ralph H. Johnson VA Medical Center

BACKGROUND: We compared the angiotensin receptor-neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients. METHODS: In this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes. RESULTS: The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P=0.001). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group. CONCLUSIONS: LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF ClinicalTrials.gov number, NCT01035255.).

These guidelines provide an up-date of previous IFCN report on "Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application" (Rossini et al., 1994). A new Committee, composed of international experts, some of whom were in the panel of the 1994 "Report", was selected to produce a current state-of-the-art review of non-invasive stimulation both for clinical application and research in neuroscience. Since 1994, the international scientific community has seen a rapid increase in non-invasive brain stimulation in studying cognition, brain-behavior relationship and pathophysiology of various neurologic and psychiatric disorders. New paradigms of stimulation and new techniques have been developed. Furthermore, a large number of studies and clinical trials have demonstrated potential therapeutic applications of non-invasive brain stimulation, especially for TMS. Recent guidelines can be found in the literature covering specific aspects of non-invasive brain stimulation, such as safety (Rossi et al., 2009), methodology (Groppa et al., 2012) and therapeutic applications (Lefaucheur et al., 2014). This up-dated review covers theoretical, physiological and practical aspects of non-invasive stimulation of brain, spinal cord, nerve roots and peripheral nerves in the light of more updated knowledge, and include some recent extensions and developments.

BACKGROUND: The angiotensin receptor-neprilysin inhibitor sacubitril-valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure and reduced ejection fraction. The effect of angiotensin receptor-neprilysin inhibition in patients with heart failure with preserved ejection fraction is unclear. METHODS: We randomly assigned 4822 patients with New York Heart Association (NYHA) class II to IV heart failure, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (target dose, 160 mg twice daily). The primary outcome was a composite of total hospitalizations for heart failure and death from cardiovascular causes. Primary outcome components, secondary outcomes (including NYHA class change, worsening renal function, and change in Kansas City Cardiomyopathy Questionnaire [KCCQ] clinical summary score [scale, 0 to 100, with higher scores indicating fewer symptoms and physical limitations]), and safety were also assessed. RESULTS: There were 894 primary events in 526 patients in the sacubitril-valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P = 0.06). The incidence of death from cardiovascular causes was 8.5% in the sacubitril-valsartan group and 8.9% in the valsartan group (hazard ratio, 0.95; 95% CI, 0.79 to 1.16); there were 690 and 797 total hospitalizations for heart failure, respectively (rate ratio, 0.85; 95% CI, 0.72 to 1.00). NYHA class improved in 15.0% of the patients in the sacubitril-valsartan group and in 12.6% of those in the valsartan group (odds ratio, 1.45; 95% CI, 1.13 to 1.86); renal function worsened in 1.4% and 2.7%, respectively (hazard ratio, 0.50; 95% CI, 0.33 to 0.77). The mean change in the KCCQ clinical summary score at 8 months was 1.0 point (95% CI, 0.0 to 2.1) higher in the sacubitril-valsartan group. Patients in the sacubitril-valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia. Among 12 prespecified subgroups, there was suggestion of heterogeneity with possible benefit with sacubitril-valsartan in patients with lower ejection fraction and in women. CONCLUSIONS: Sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher. (Funded by Novartis; PARAGON-HF ClinicalTrials.gov number, NCT01920711.).

BACKGROUND: Approximately 50% of patients with heart failure have a left ventricular ejection fraction of at least 45%, but no therapies have been shown to improve the outcome of these patients. Therefore, we studied the effects of irbesartan in patients with this syndrome. METHODS: We enrolled 4128 patients who were at least 60 years of age and had New York Heart Association class II, III, or IV heart failure and an ejection fraction of at least 45% and randomly assigned them to receive 300 mg of irbesartan or placebo per day. The primary composite outcome was death from any cause or hospitalization for a cardiovascular cause (heart failure, myocardial infarction, unstable angina, arrhythmia, or stroke). Secondary outcomes included death from heart failure or hospitalization for heart failure, death from any cause and from cardiovascular causes, and quality of life. RESULTS: During a mean follow-up of 49.5 months, the primary outcome occurred in 742 patients in the irbesartan group and 763 in the placebo group. Primary event rates in the irbesartan and placebo groups were 100.4 and 105.4 per 1000 patient-years, respectively (hazard ratio, 0.95; 95% confidence interval [CI], 0.86 to 1.05; P=0.35). Overall rates of death were 52.6 and 52.3 per 1000 patient-years, respectively (hazard ratio, 1.00; 95% CI, 0.88 to 1.14; P=0.98). Rates of hospitalization for cardiovascular causes that contributed to the primary outcome were 70.6 and 74.3 per 1000 patient-years, respectively (hazard ratio, 0.95; 95% CI, 0.85 to 1.08; P=0.44). There were no significant differences in the other prespecified outcomes. CONCLUSIONS: Irbesartan did not improve the outcomes of patients with heart failure and a preserved left ventricular ejection fraction. (ClinicalTrials.gov number, NCT00095238.)

Available evidence indicates that qualitative changes in hematopoietic stem cells and progenitors, such as the decision of stem cells to self-renew or differentiate, or selection of lineage potentials by the multipotential progenitors during differentiation (commitment), are intrinsic properties of the progenitors and are stochastic in nature. In-contrast, proliferative kinetics of the progenitors, namely survival and expansion of the progenitors, appear to be controlled by a number of interacting cytokines. While proliferation and maturation of committed progenitors is controlled by late-acting lineage-specific factors such as Ep, M-CSF, G-CSF, and IL-5, progenitors at earlier stages of development are controlled by a group of several overlapping cytokines. IL-3, GM-CSF, and IL-4 regulate proliferation of multipotential progenitors only after they exit from G0 and begin active cell proliferation. Triggering of cycling by dormant primitive progenitors and maintenance of B-cell potential of the primitive progenitors appears to require interactions of early acting cytokines including IL-6, G-CSF, IL-11, IL-12, LIF, and SF. Currently, this simple model fits our understanding of the interactions of growth factors with hematopoietic progenitors. Naturally the model risks oversimplification of a very complex process. However, because the model is testable, it will hopefully challenge investigators to design new experiments to examine its validity.

OBJECTIVES: We estimated prevalence and assessed correlates of emotional, physical, sexual, and financial mistreatment and potential neglect (defined as an identified need for assistance that no one was actively addressing) of adults aged 60 years or older in a randomly selected national sample. METHODS: We compiled a representative sample by random digit dialing across geographic strata. We used computer-assisted telephone interviewing to standardize collection of demographic, risk factor, and mistreatment data. We subjected prevalence estimates and mistreatment correlates to logistic regression. RESULTS: We analyzed data from 5777 respondents. One-year prevalence was 4.6% for emotional abuse, 1.6% for physical abuse, 0.6% for sexual abuse, 5.1% for potential neglect, and 5.2% for current financial abuse by a family member. One in 10 respondents reported emotional, physical, or sexual mistreatment or potential neglect in the past year. The most consistent correlates of mistreatment across abuse types were low social support and previous traumatic event exposure. CONCLUSIONS: Our data showed that abuse of the elderly is prevalent. Addressing low social support with preventive interventions could have significant public health implications.

BACKGROUND: Few long-term or controlled studies of bariatric surgery have been conducted to date. We report the 12-year follow-up results of an observational, prospective study of Roux-en-Y gastric bypass that was conducted in the United States. METHODS: A total of 1156 patients with severe obesity comprised three groups: 418 patients who sought and underwent Roux-en-Y gastric bypass (surgery group), 417 patients who sought but did not undergo surgery (primarily for insurance reasons) (nonsurgery group 1), and 321 patients who did not seek surgery (nonsurgery group 2). We performed clinical examinations at baseline and at 2 years, 6 years, and 12 years to ascertain the presence of type 2 diabetes, hypertension, and dyslipidemia. RESULTS: The follow-up rate exceeded 90% at 12 years. The adjusted mean change from baseline in body weight in the surgery group was -45.0 kg (95% confidence interval [CI], -47.2 to -42.9; mean percent change, -35.0) at 2 years, -36.3 kg (95% CI, -39.0 to -33.5; mean percent change, -28.0) at 6 years, and -35.0 kg (95% CI, -38.4 to -31.7; mean percent change, -26.9) at 12 years; the mean change at 12 years in nonsurgery group 1 was -2.9 kg (95% CI, -6.9 to 1.0; mean percent change, -2.0), and the mean change at 12 years in nonsurgery group 2 was 0 kg (95% CI, -3.5 to 3.5; mean percent change, -0.9). Among the patients in the surgery group who had type 2 diabetes at baseline, type 2 diabetes remitted in 66 of 88 patients (75%) at 2 years, in 54 of 87 patients (62%) at 6 years, and in 43 of 84 patients (51%) at 12 years. The odds ratio for the incidence of type 2 diabetes at 12 years was 0.08 (95% CI, 0.03 to 0.24) for the surgery group versus nonsurgery group 1 and 0.09 (95% CI, 0.03 to 0.29) for the surgery group versus nonsurgery group 2 (P<0.001 for both comparisons). The surgery group had higher remission rates and lower incidence rates of hypertension and dyslipidemia than did nonsurgery group 1 (P<0.05 for all comparisons). CONCLUSIONS: This study showed long-term durability of weight loss and effective remission and prevention of type 2 diabetes, hypertension, and dyslipidemia after Roux-en-Y gastric bypass. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

sphingosine 1-phosphate sphingomyelin sphingomyelinase ceramidase tumor necrosis factor glucosylceramide synthase serine palmitoyltransferase protein kinase C interleukin-1 diacylglycerol neutral sphingomyelinase Whereas regulated turnover of glycerolipids has been observed and studied for more than six decades, dogma has held sphingolipids to be mostly structural molecules with inert metabolism. If anything, investigation over the past 15 years or so has taught us that sphingolipid metabolism comprises a set of highly regulated pathways that serve to control the levels of individual molecules, their interconversions, and their function. Most notable of these bioactive molecules are the sphingoid bases, ceramide, and sphingosine 1-phosphate (S1P)1; other emerging bioactive sphingolipids include sphingosylphosphorylcholine, psychosine, lactosylceramide, and cerebroside (1Hannun Y.A. Luberto C. Argraves K.M. Biochemistry. 2001; 40: 4893-4903Crossref PubMed Scopus (443) Google Scholar). Much attention in the last decade has focused on ceramide metabolism and function because of the increased appreciation of the involvement of pathways involving this lipid in regulating key biologic responses such as stress responses, cell senescence, and apoptosis. Indeed, there have been more than 5000 publications on the biochemistry and cellular activities of ceramide during this period. The excitement and anticipation of rapid progress in elucidating the molecular/biochemical mechanisms of these pathways and their specific contributions to emerging fields of cell biology have been tempered by the serious lag in studies on sphingolipids when compared with other fields of biochemical study. Most of the key enzymes regulating ceramide metabolism have been poorly studied, and there has been a paucity of molecular and pharmacologic tools to probe these pathways and their functions. Luckily, there has been an advancing crescendo of studies that have begun to shed significant light on our understanding of ceramide metabolism and function. This minireview will highlight these major advances, elucidate organizing principles, and advance key questions for future research. By necessity, this minireview adopts a ceramide-centric view of sphingolipid metabolism and function. Borrowing from physics, it is easier to organize information and reconstruct pathways for a fixed observer with a fixed frame of reference. This does not change the validity of conclusions, only their relative perspective. Ceramide is at the hub of sphingolipid metabolism, and it serves as the first point of significant accumulation of sphingolipids in thede novo pathway (see minireview by Merrill (55Merrill A.H., Jr. J. Biol. Chem. 2002; 277: 25843-25846Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar)). Ceramide then serves as the precursor for all major sphingolipids in eukaryotes (such as sphingomyelin (SM) or glucosylceramide) (Fig.1 and see minireview by Kolter et al. (56Kolter T. Proia R.L. Sandhoff K. J. Biol. Chem. 2002; 277: 25859-25862Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar)). The breakdown of complex sphingolipids results in the formation of ceramide through the action of either sphingomyelinases (SMases) or glycosidases. The breakdown of ceramide proceeds through the action of ceramidases (CDases), and the resulting sphingoid bases serve as substrates for sphingosine kinases to form S1P or are recycled into ceramide and complex sphingolipids through the action of ceramide synthases (for reviews see Refs. 1Hannun Y.A. Luberto C. Argraves K.M. Biochemistry. 2001; 40: 4893-4903Crossref PubMed Scopus (443) Google Scholar and 2Merrill A.H., Jr. Sullards M.C. Wang E. Voss K.A. Riley R.T. Environ. Health Perspect. 2001; 109: 283-289Crossref PubMed Scopus (334) Google Scholar). Functionally, ceramide has been proposed as a "coordinator" of eukaryotic stress responses (3Hannun Y.A. Science. 1996; 274: 1855-1859Crossref PubMed Scopus (1500) Google Scholar). This paradigm is supported by the repeated findings that many inducers of stress response (not limited to those inducing apoptosis) result in ceramide accumulation, usually as a result of activation of either SMases (4Andrieu-Abadie N. Gouazé V. Salvayre R. Levade T. Free Radic. Biol. Med. 2001; 31: 717-728Crossref PubMed Scopus (230) Google Scholar) or the de novo pathway (5Perry D.K. Ann. N. Y. Acad. Sci. 2000; 905: 91-96Crossref PubMed Scopus (37) Google Scholar) but sometimes as a result of inhibition of ceramide clearance (through SM synthase or CDases). These inducers include cytokines (TNF, Fas, nerve growth factor), "environmental" stresses (heat, UV radiation, hypoxia/reperfusion), chemotherapeutic agents (Ara-C, doxorubicin, etoposide, and many others), and other miscellaneous agents (dexamethasone, lipopolysaccharide, sitosterol, and B-cell receptor stimulation). Several lines of investigation (see next section) now support roles for endogenous ceramide in mediating/regulating many key and specific cellular responses. A major biochemical breakthrough in the past few years centered on the identification of the genes for all known enzymes of sphingolipid metabolism in the yeast Saccharomyces cerevisiae (1Hannun Y.A. Luberto C. Argraves K.M. Biochemistry. 2001; 40: 4893-4903Crossref PubMed Scopus (443) Google Scholar, 6Dickson R.C. Lester R.L. Biochim. Biophys. Acta. 1999; 1426: 347-357Crossref PubMed Scopus (171) Google Scholar). Importantly, most of these enzymes have either homologues or orthologues in mammalian species (1Hannun Y.A. Luberto C. Argraves K.M. Biochemistry. 2001; 40: 4893-4903Crossref PubMed Scopus (443) Google Scholar), and this is already paying dividends in the identification of mammalian counterparts (7Mao C.G., Xu, R.J. Szulc Z.M. Bielawska A. Galadari S.H. Obeid L.M. J. Biol. Chem. 2001; 276: 26577-26588Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). The diacylglycerol kinase assay for ceramide quantitation has emerged as the workhorse for quantitative analysis of this lipid, and some shortfalls in its application (especially poor attention to quantitative conversion of ceramide) have recently been identified and clarified (8Perry D.K. Bielawska A. Hannun Y.A. Methods Enzymol. 2000; 312: 22-31Crossref PubMed Google Scholar). Also quite promising are various newly developed mass spectroscopy-based assays for qualitative and semi-quantitative analysis of ceramide and its molecular species that may allow dissection of specific pathways of ceramide metabolism and/or function (9Sullards M.C. Methods Enzymol. 2000; 312: 32-45Crossref PubMed Google Scholar, 10Kroesen B.J. Pettus B. Luberto C. Busman M. Sietsma H., De Leij L. Hannun Y.A. J. Biol. Chem. 2001; 276: 13606-13614Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). The first decade of investigation on ceramide biology relied heavily on the use of short chain soluble ceramides such as C2- and C6-ceramide. Although this approach suffers the usual limitations that arise from the use of lipid reagents (11Ghidoni R. Sala G. Giuliani A. Biochim. Biophys. Acta. 1999; 1439: 17-39Crossref PubMed Scopus (40) Google Scholar), its utility has been reinforced by the determination of the specificity of action of these molecules (especially the lack of activity of dihydroceramide, the metabolic precursor of ceramide) (12Bielawska A. Crane H.M. Liotta D. Obeid L.M. Hannun Y.A. J. Biol. Chem. 1993; 268: 26226-26232Abstract Full Text PDF PubMed Google Scholar). Results using these reagents have led to the generation of several hypotheses on the roles of ceramide in mediating specific effects in apoptosis and stress responses (1Hannun Y.A. Luberto C. Argraves K.M. Biochemistry. 2001; 40: 4893-4903Crossref PubMed Scopus (443) Google Scholar). The availability of specific pharmacologic inhibitors of some enzymes of ceramide metabolism (e.g. glucosylceramide synthase (GCS) and CDases) and the ongoing molecular cloning of some of the key enzymes of ceramide formation (SMases and serine palmitoyltransferase (SPT)) have allowed the examination of the cellular consequences of inducing levels of endogenous ceramide, and the results, for the most part, have agreed with those obtained with exogenous ceramides. For example, inhibitors of GCS and of CDases have been shown to induce increases in ceramide levels and cause apoptosis and/or cell cycle arrest, especially of cancer cells, and overexpression of bacterial SMase has been shown to induce apoptosis and cell cycle arrest (1Hannun Y.A. Luberto C. Argraves K.M. Biochemistry. 2001; 40: 4893-4903Crossref PubMed Scopus (443) Google Scholar). The cloning of enzymes that clear ceramide such as GCS and CDases (1Hannun Y.A. Luberto C. Argraves K.M. Biochemistry. 2001; 40: 4893-4903Crossref PubMed Scopus (443) Google Scholar, 2Merrill A.H., Jr. Sullards M.C. Wang E. Voss K.A. Riley R.T. Environ. Health Perspect. 2001; 109: 283-289Crossref PubMed Scopus (334) Google Scholar), the generation of knock-out mice in acid SMase (13Horinouchi K. Erlich S. Perl D.P. Ferlinz K. Bisgaier C.L. Sandhoff K. Desnick R.J. Stewart C.L. Schuchman E.H. Nat. Genet. 1995; 10: 288-293Crossref PubMed Scopus (418) Google Scholar), and the development/discovery of specific inhibitors of enzymes of ceramide generation (myriocin/ISP1 for SPT and fumonisin B1 for ceramide synthase) (2Merrill A.H., Jr. Sullards M.C. Wang E. Voss K.A. Riley R.T. Environ. Health Perspect. 2001; 109: 283-289Crossref PubMed Scopus (334) Google Scholar) have begun to provide substantial evidence on the roles of ceramide in mediating key cellular activities. For example, fumonisin B1 has been shown to inhibit various aspects of apoptosis in response to many agents (e.g. angiotensin II (14Lehtonen J.Y.A. Horiuchi M. Daviet L. Akishita M. Dzau V.J. J. Biol. Chem. 1999; 274: 16901-16906Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar), anti-IgM (10Kroesen B.J. Pettus B. Luberto C. Busman M. Sietsma H., De Leij L. Hannun Y.A. J. Biol. Chem. 2001; 276: 13606-13614Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar), and some cancer chemotherapy agents (5Perry D.K. Ann. N. Y. Acad. Sci. 2000; 905: 91-96Crossref PubMed Scopus (37) Google Scholar)). The overexpression of GCS (15Sanchenkov A. Litvak D.A. Cabot M.C. J. Natl. Cancer Inst. 2001; 93: 347-357Crossref PubMed Scopus (278) Google Scholar) or CDase (16Strelow A. Bernardo K. Adam-Klages S. Linke T. Sandhoff K. Krönke M. Adam D. J. Exp. Med. 2000; 192: 601-611Crossref PubMed Scopus (151) Google Scholar) has been shown to attenuate the induced levels of ceramide in response to TNF and other agents and to ameliorate the apoptotic response, thus providing substantial evidence for the role of endogenous ceramide in regulating apoptosis. Recent studies have begun to identify key direct targets for ceramide action. These include the ceramide-activated protein phosphatases PP1 and PP2A, which are activated by ceramide in vitro. Increasing evidence points to roles for these phosphatases in mediating many of the actions of ceramide in cells. For example, phosphatase inhibitors have been shown to inhibit the ability of ceramide (and agents that induce ceramide formation) to cause dephosphorylation of several cellular proteins including PKCα, Akt/PKB, c-Jun, and Bcl-2 (17Chalfant C.E. Hannun Y. Futerman A.H. Ceramide Signaling. Landes Bioscience, Austin, TX2002Google Scholar). Cathepsin D was discovered as a ceramide-binding protein, and evidence has been provided that ceramide activates this lysosomal protease in cells (18Heinrich M. Wickel M. Winoto-Morbach S. Schneider-Brachert W. Weber T. Brunner J. Saftig P. Peters C. Krönke M. Schütze S. Adv. Exp. Med. Biol. 2000; 477: 305-315Crossref PubMed Google Scholar). Kinase suppressor of Ras has been advanced as a mediator of the effects of ceramide on Ras, Raf, and ERKs (extracellular signal-regulated kinases) (19Xing H.R. Lozano J. Kolesnick R. J. Biol. Chem. 2000; 275: 17276-17280Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar). Similarly, it has been shown that ceramide activates PKCζ and that this may couple the action of ceramide to activation of the transcription factor NF-κB and the activation of the stress-activated kinases (20Lozano J. Berra E. Municio M.M. Diaz-Meco M.T. Dominguez I. Sanz L. Moscat J. J. Biol. Chem. 1994; 269: 19200-19202Abstract Full Text PDF PubMed Google Scholar, 21Bourbon N.A. Yun J. Kester M. J. Biol. Chem. 2000; 275: 35617-35623Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar). Numerous studies point to a role for changes in intracellular redox in regulation of neutral SMase (4Andrieu-Abadie N. Gouazé V. Salvayre R. Levade T. Free Radic. Biol. Med. 2001; 31: 717-728Crossref PubMed Scopus (230) Google Scholar). For example, it has been shown that the action of TNF in inducing apoptosis is closely related to intracellular oxidation and a drop in the levels of GSH. In turn, this has been demonstrated as a necessary condition for activation of SMase in response to TNF. Similarly, GSH may regulate activation of SMase in response to hypoxia, xenobiotics, and chemotherapeutic agents (4Andrieu-Abadie N. Gouazé V. Salvayre R. Levade T. Free Radic. Biol. Med. 2001; 31: 717-728Crossref PubMed Scopus (230) Google Scholar). A novel CDase has been localized to mitochondria, demonstrating unequivocally the existence of a mitochondrial pathway of ceramide metabolism (22El Bawab S. Roddy P. Qian T. Bielawska A. Lemasters J.J. Hannun Y.A. J. Biol. Chem. 2000; 275: 21508-21513Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar). Ceramide levels have been detected in mitochondria (23Ardail D. Popa I. Alcantara K. Pons A. Zanetta J.P. Louisot P. Thomas L. Portoukalian J. FEBS Lett. 2001; 488: 160-164Crossref PubMed Scopus (62) Google Scholar), and TNF was shown to induce accumulation of ceramide in the heavy membrane compartment (10,000 × g pellet) (24Garcı́a-Ruiz C. Colell A. Marı́ M. Morales A. Fernández-Checa J.C. J. Biol. Chem. 1997; 272: 11369-11377Abstract Full Text Full Text PDF PubMed Scopus (718) Google Scholar). The addition of exogenous ceramide to purified mitochondria results in inhibition of the respiratory chain, the generation of reactive oxygen species, and the release of cytochrome c(24Garcı́a-Ruiz C. Colell A. Marı́ M. Morales A. Fernández-Checa J.C. J. Biol. Chem. 1997; 272: 11369-11377Abstract Full Text Full Text PDF PubMed Scopus (718) Google Scholar, 25Gudz T.I. Tserng K.Y. Hoppel C.L. J. Biol. Chem. 1997; 272: 24154-24158Abstract Full Text Full Text PDF PubMed Scopus (375) Google Scholar, 26Ghafourifar P. Klein S.D. Schucht O. Schenk U. Pruschy M. Rocha S. Richter C. J. Biol. Chem. 1999; 274: 6080-6084Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar, 27Guidarelli A. Clementi E., De Nadai C. Bersacchi R. Cantoni O. Exp. Cell Res. 2001; 270: 56-65Crossref PubMed Scopus (14) Google Scholar). The expression of bacterial SMase in mitochondria, but not other subcellular compartments, resulted in induction of apoptosis (28Birbes H., El Bawab S. Hannun Y. Obeid L. FASEB J. 2001; 15: 2669-2679Crossref PubMed Scopus (223) Google Scholar), suggesting a role for endogenous mitochondrial ceramide in regulating apoptosis. One of the most exciting areas of development in sphingolipid biology has been the increasing evidence pointing to roles for these pathways in disease pathogenesis. For example, the primary mutation responsible for hereditary neuropathy has been mapped to the LCB1 subunit of SPT, and it was suggested to induce apoptosis of susceptible sensory neurons (29Dawkins J.L. Hulme D.J. Brahmbhatt S.B. Auer-Grumg M. Nicholson G.A. Nat. Genet. 2001; 27: 309-312Crossref PubMed Scopus (350) Google Scholar, 30Bejaoui K., Wu, C. Scheffler M.D. Haan G. Ashby P., Wu, L. de Jong P. Brown R.H., Jr. Nat. Genet. 2001; 27: 261-262Crossref PubMed Scopus (249) Google Scholar). Ceramide levels have been shown to be elevated in a number of neurodegenerative disorders such as Batten's disease, and two of the genes responsible for subtypes of this disorder, CLN3 and protein palmitoyl thioesterase, have been shown to attenuate ceramide levels in response to apoptotic stimuli, suggesting a role for the ceramide pathway in mediating cell dysfunction and death in these disorders (31Puranam K.L. Guo W.X. Qian W.H. Nikbakht K. Boustany R.M. Mol. Genet. Metab. 1999; 66: 294-308Crossref PubMed Scopus (89) Google Scholar,32Cho S.G. Dawson P.E. Dawson G. J. Neurosci. Res. 2000; 62: 234-240Crossref PubMed Scopus (42) Google Scholar). A flurry of recent studies have begun to implicate ceramide and sphingolipid metabolism in the pathogenesis of diabetes and its complications. Ceramide has been shown to induce dephosphorylation and inactivation of the Akt/PKB protein kinases which play key roles in insulin action (33Summers S.A. Garza L.A. Zhou H.L. Birnbaum M.J. Mol. Cell. Biol. 1998; 18: 5457-5464Crossref PubMed Scopus (368) Google Scholar). Unger and co-workers (34Shimabukuro M. Higa M. Zhou Y.T. Wang M.Y. Newgard C.B. Unger R.H. J. Biol. Chem. 1998; 273: 32487-32490Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar) have proposed that conditions of free fatty acid overload (especially palmitate), as would occur in obesity or diabetes, drive the de novopathway of ceramide synthesis leading to induction of ceramide-mediated responses (e.g. dysfunction and death of islet cells). The emerging intimate role for ceramide in regulating stress responses and apoptosis has led to implicating this lipid in mediating the apoptotic and cytotoxic actions of various chemotherapeutic agents (35Radin N.S. Eur. J. Biochem. 2001; 268: 193-204Crossref PubMed Scopus (107) Google Scholar). Moreover, it has been shown that drug resistance often involves up-regulation of GCS and the failure to sustain an accumulation of ceramide in response to chemotherapy agents (15Sanchenkov A. Litvak D.A. Cabot M.C. J. Natl. Cancer Inst. 2001; 93: 347-357Crossref PubMed Scopus (278) Google Scholar, 36Sietsma H. Veldman R.J. Kok J.W. J. Membr. Biol. 2001; 181: 153-162Crossref PubMed Scopus (71) Google Scholar). Deficiency in acid SMase has also been shown to diminish the response of endothelial and neuronal cells to radiation-induced apoptosis (37Paris F. Fuks Z. Kang A. Capodieci P. Juan G. Ehleiter D. Haimovitz-Friedman A. Cordon-Cardo C. Kolesnick R. Science. 2001; 293: 293-297Crossref PubMed Scopus (1056) Google Scholar). The results demonstrating causative roles for oxidative stress in activating SMases begin to point to important coupling of oxidative stress to ceramide signaling. 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A major in understanding ceramide metabolism to all other bioactive that individual enzymes function as in cell regulation that an activating to an response to the changes in the has thus that of be at the of individual pathways and Indeed, enzymes of ceramide metabolism subcellular and (see minireview by and G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar)). The membrane a of acid SMase and a neutral SMase (4Andrieu-Abadie N. Gouazé V. Salvayre R. Levade T. Free Radic. Biol. Med. 2001; 31: 717-728Crossref PubMed Scopus (230) Google Scholar), and generation of ceramide at the membrane and specific such as inhibition of inhibition of and of the receptor (1Hannun Y.A. Luberto C. Argraves K.M. Biochemistry. 2001; 40: 4893-4903Crossref PubMed Scopus (443) Google Scholar, F. H. A. J. A. Fuks Z. E. Kolesnick R. J. Biol. 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The has also been as a of ceramide generation with roles in and apoptosis A. S. Mol. Cell. Biochem. 1995; PubMed Scopus Google Scholar). of the intimate of lipid metabolism, many of the enzymes that regulate bioactive also function as by regulating the levels of bioactive substrates and For example, ceramidases regulate the levels of ceramide and/or sphingosine and S1P with S1P often effects that ceramide-mediated responses (see minireview by and S. S. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar)). TNF has been shown to and this was with lack of accumulation of ceramide and of an apoptotic the action of was shown to induce activation of CDase especially at of the thus leading to responses. of ceramide and effects of on expression of (2Merrill A.H., Jr. Sullards M.C. Wang E. Voss K.A. Riley R.T. Environ. Health Perspect. 2001; 109: 283-289Crossref PubMed Scopus (334) Google Scholar). SM synthase synthase in the levels of ceramide and in a Indeed, evidence has been provided that SM synthase a response from by ceramide of to by of C. Hannun Y.A. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). many of the enzymes of sphingolipid metabolism are emerging as regulated the relative levels of more than bioactive Although these may be for the of bioactive provide the cell with a for cell responses. this of bioactive the of the levels of many the is at of its For example, activation of SMase results in the accumulation of the coupling of ceramide metabolism to that of and glucosylceramide (and other for an number of in the of bioactive of these is to its direct then the of responses by the of these pathways all bioactive effects on their direct the consequences of changes in levels of bioactive be from or that a more of an of the levels of its endogenous bioactive the is a clear for the molecular identification of sphingomyelin and ceramide the known enzymes of ceramide metabolism. have on the cloning of two neutral sphingomyelinases and K. S. G. W. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar) evidence was provided that which to the as a C H. N. N. Hannun Y.A. J. Biol. Chem. 1999; 274: Full Text Full Text PDF Scopus Google Scholar). to the and its substrates have not been and studies the of at a membrane and mitochondrial Similarly, is known SM of the most enzymes that has at and The of ceramide and sphingolipid function has from the availability of and fumonisin B1 as specific inhibitors of SPT and ceramide These reagents have in key roles for the de novo pathway of ceramide formation in apoptosis and action (see there are important to especially for SM and The identification of these mechanisms (e.g. to activation of by direct the specific biochemical that are responsible for activation of of these a in cell these mechanisms to be and as such allow an advanced of understanding of these pathways and the of when are to be Similarly, the mechanisms of action of ceramide and related provide direct into the biochemical of these specific studies are to which targets of ceramide are activated in cells and specific is that specific and pathways of ceramide formation and clearance specific (such as the regulation of proteins in response to de novo ceramide, the development of molecular and pharmacologic tools and the identification of direct cellular targets for ceramide (and related the of specific for ceramide in response to individual is quite that the identified pathways of sphingolipid metabolism with other to be For example, recent studies have shown the of for and psychosine, is known as to enzymes regulate the metabolism of these is that other pathways may that to novel Ceramide and inhibitors of ceramide metabolism are their into research. with significant effects on and R. L. Yun J. N. R. Kester M. Res. 2000; PubMed Scopus Google Scholar). ceramides shown to in K. I. H. Y. J. Metab. 2001; PubMed Scopus Google Scholar). a ceramidase of cancer to in a M. Bielawska A. D. Hannun Y.A. Cancer Res. 2001; Google Scholar). metabolism and function is not only an exciting and now but is of the few in and of its biochemical mechanisms and important is our that key areas of cell biology senescence, and membrane and stress and disease diabetes, and understanding sphingolipid metabolism.

Background: Vagus nerve stimulation (VNS) alters both concentrations of neurotransmitters or their metabolites and functional activity of central nervous system regions dysregulated in mood disorders. An open trial has suggested efficacy.\nMethods: This 10-week, acute, randomized, controlled, masked trial compared adjunctive VNS with sham treatment in 235 outpatients with nonpsychotic major depressive disorder (n = 210) or nonpsychotic, depressed phase, bipolar disorder (n = 25). In the current episode, participants had not responded adequately to between two and six research-qualified medication trials. A two-week, single-blind recovery period (no stimulation) and then 10 weeks of masked active or sham VNS followed implantation. Medications were kept stable. Primary efficacy outcome among 222 evaluable participants was based on response rates (≥ 50% reduction from baseline on the 24-item Hamilton Rating Scale for Depression [HRSD24]).\nResults: At 10-weeks, HRSD24 response rates were 15.2% for the active (n = 112) and 10.0% for the sham (n = 110) groups (p = .251, last observation carried forward [LOCF]). Response rates with a secondary outcome, the Inventory of Depressive Symptomatology – Self-Report (IDS-SR30), were 17.0% (active) and 7.3% (sham) (p = .032, LOCF). VNS was well tolerated; 1% (3/235) left the study because of adverse events.\nConclusions: This study did not yield definitive evidence of short-term efficacy for adjunctive VNS in treatment-resistant depression.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

OBJECTIVE: To provide expert recommendations for the safe and effective application of repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depressive disorder (MDD). PARTICIPANTS: Participants included a group of 17 expert clinicians and researchers with expertise in the clinical application of rTMS, representing both the National Network of Depression Centers (NNDC) rTMS Task Group and the American Psychiatric Association Council on Research (APA CoR) Task Force on Novel Biomarkers and Treatments. EVIDENCE: The consensus statement is based on a review of extensive literature from 2 databases (OvidSP MEDLINE and PsycINFO) searched from 1990 through 2016. The search terms included variants of major depressive disorder and transcranial magnetic stimulation. The results were limited to articles written in English that focused on adult populations. Of the approximately 1,500 retrieved studies, a total of 118 publications were included in the consensus statement and were supplemented with expert opinion to achieve consensus recommendations on key issues surrounding the administration of rTMS for MDD in clinical practice settings. CONSENSUS PROCESS: In cases in which the research evidence was equivocal or unclear, a consensus decision on how rTMS should be administered was reached by the authors of this article and is denoted in the article as "expert opinion." CONCLUSIONS: Multiple randomized controlled trials and published literature have supported the safety and efficacy of rTMS antidepressant therapy. These consensus recommendations, developed by the NNDC rTMS Task Group and APA CoR Task Force on Novel Biomarkers and Treatments, provide comprehensive information for the safe and effective clinical application of rTMS in the treatment of MDD.

Adiponectin is secreted from adipocytes, and low circulating levels have been epidemiologically associated with obesity, insulin resistance, type 2 diabetes, and cardiovascular disease. To investigate whether adiponectin could exert autocrine effects in adipocytes, we expressed the adiponectin gene in 3T3-L1 fibroblasts. We observed that 3T3-L1 fibroblasts expressing adiponectin have a fast growth phase and reach confluence with with adiponectin observed and and gene and and and adipocytes, and with adiponectin gene and the a adiponectin autocrine in and from adipocytes, gene and and insulin the in Adiponectin is secreted from adipocytes, and low circulating levels have been epidemiologically associated with obesity, insulin resistance, type 2 diabetes, and cardiovascular disease. To investigate whether adiponectin could exert autocrine effects in adipocytes, we expressed the adiponectin gene in 3T3-L1 fibroblasts. We observed that 3T3-L1 fibroblasts expressing adiponectin have a fast growth phase and reach confluence with with adiponectin observed and and gene and and and adipocytes, and with adiponectin gene and the a adiponectin autocrine in and from adipocytes, gene and and insulin the in is a and that in and and and and and insulin and Adiponectin and is that circulating adiponectin levels in with insulin resistance, type 2 diabetes, obesity, cardiovascular in Adiponectin and type 2 in the adiponectin in the adiponectin levels in adiponectin gene in the adiponectin in with insulin the type 2 in in and type 2 with insulin and is that adiponectin gene associated with with insulin and type 2 adiponectin associated with and low levels adiponectin and adiponectin gene have been associated with and insulin effects and adiponectin Adiponectin been in and in and in adiponectin insulin associated with and and in and insulin is the adiponectin and in and in adiponectin insulin associated with and 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and in a in and and 2 in and in and 2 with and in the the and the the adipocytes, with insulin from with the and and with and and with 3T3-L1 in with with a and with in 3T3-L1 and a and from 3T3-L1 and and with a from the from with a from with 2 and and in in the and insulin in and insulin insulin in effects gene the with the and the from in 3T3-L1 with 3T3-L1 2 the in in the and a insulin the with and and with 2 and and in a and with a the in and in and and the the in 3T3-L1 effects and and and insulin in 3T3-L1 in and insulin in 3T3-L1 the and the in the with the and with the and and from the with and and from and with in with the with in and with with the the the 3T3-L1 fibroblasts and with and with the the with the the in the gene and gene a and from in in a and a with and the in the gene and and and and and and and adiponectin gene and and and and in a and the and adiponectin in Adiponectin from the the a with a adiponectin with the and adiponectin in the a the the with the from 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the is with and adiponectin is with from 3T3-L1 that adiponectin adiponectin from 3T3-L1 fibroblasts. adiponectin gene the adiponectin adiponectin in the a low adiponectin in the fibroblasts with the in in adiponectin levels in the in in the adiponectin and adiponectin in a the adiponectin the the from the in 3T3-L1 3T3-L1 we observed that in with the that in the confluence growth expressing the gene is a that is expressed in and been a in and a growth in the we in fibroblasts and that in the fibroblasts with the with the observed in the 3T3-L1 fibroblasts. adiponectin and 3T3-L1 fibroblasts. 3T3-L1 fibroblasts expressing adiponectin and 3T3-L1 fibroblasts with and the from in growth from and 3T3-L1 fibroblasts and with and fibroblasts. in the in and with with the in in the in 3T3-L1 whether with adiponectin the that and in the in adiponectin the We the in and been a and is the is the in and in To investigate whether the adiponectin gene we and in and and in with in the gene the in the 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IMPORTANCE: Although vitamin E and memantine have been shown to have beneficial effects in moderately severe Alzheimer disease (AD), evidence is limited in mild to moderate AD. OBJECTIVE: To determine if vitamin E (alpha tocopherol), memantine, or both slow progression of mild to moderate AD in patients taking an acetylcholinesterase inhibitor. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, placebo-controlled, parallel-group, randomized clinical trial involving 613 patients with mild to moderate AD initiated in August 2007 and concluded in September 2012 at 14 Veterans Affairs medical centers. INTERVENTIONS: Participants received either 2000 IU/d of alpha tocopherol (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or placebo (n = 152). MAIN OUTCOMES AND MEASURES: Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score (range, 0-78). Secondary outcomes included cognitive, neuropsychiatric, functional, and caregiver measures. RESULTS: Data from 561 participants were analyzed (alpha tocopherol = 140, memantine = 142, combination = 139, placebo = 140), with 52 excluded because of a lack of any follow-up data. Over the mean (SD) follow-up of 2.27 (1.22) years, ADCS-ADL Inventory scores declined by 3.15 units (95% CI, 0.92 to 5.39; adjusted P = .03) less in the alpha tocopherol group compared with the placebo group. In the memantine group, these scores declined 1.98 units less (95% CI, -0.24 to 4.20; adjusted P = .40) than the placebo group's decline. This change in the alpha tocopherol group translates into a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period. Caregiver time increased least in the alpha tocopherol group. All-cause mortality and safety analyses showed a difference only on the serious adverse event of "infections or infestations," with greater frequencies in the memantine (31 events in 23 participants) and combination groups (44 events in 31 participants) compared with placebo (13 events in 11 participants). CONCLUSIONS AND RELEVANCE: Among patients with mild to moderate AD, 2000 IU/d of alpha tocopherol compared with placebo resulted in slower functional decline. There were no significant differences in the groups receiving memantine alone or memantine plus alpha tocopherol. These findings suggest benefit of alpha tocopherol in mild to moderate AD by slowing functional decline and decreasing caregiver burden. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00235716.

The insulin resistance syndrome (IRS) is associated with dyslipidemia and increased cardiovascular disease risk. A novel method for detailed analyses of lipoprotein subclass sizes and particle concentrations that uses nuclear magnetic resonance (NMR) of whole sera has become available. To define the effects of insulin resistance, we measured dyslipidemia using both NMR lipoprotein subclass analysis and conventional lipid panel, and insulin sensitivity as the maximal glucose disposal rate (GDR) during hyperinsulinemic clamps in 56 insulin sensitive (IS; mean +/- SD: GDR 15.8 +/- 2.0 mg. kg(-1). min(-1), fasting blood glucose [FBG] 4.7 +/- 0.3 mmol/l, BMI 26 +/- 5), 46 insulin resistant (IR; GDR 10.2 +/- 1.9, FBG 4.9 +/- 0.5, BMI 29 +/- 5), and 46 untreated subjects with type 2 diabetes (GDR 7.4 +/- 2.8, FBG 10.8 +/- 3.7, BMI 30 +/- 5). In the group as a whole, regression analyses with GDR showed that progressive insulin resistance was associated with an increase in VLDL size (r = -0.40) and an increase in large VLDL particle concentrations (r = -0.42), a decrease in LDL size (r = 0.42) as a result of a marked increase in small LDL particles (r = -0.34) and reduced large LDL (r = 0.34), an overall increase in the number of LDL particles (r = -0.44), and a decrease in HDL size (r = 0.41) as a result of depletion of large HDL particles (r = 0.38) and a modest increase in small HDL (r = -0.21; all P < 0.01). These correlations were also evident when only normoglycemic individuals were included in the analyses (i.e., IS + IR but no diabetes), and persisted in multiple regression analyses adjusting for age, BMI, sex, and race. Discontinuous analyses were also performed. When compared with IS, the IR and diabetes subgroups exhibited a two- to threefold increase in large VLDL particle concentrations (no change in medium or small VLDL), which produced an increase in serum triglycerides; a decrease in LDL size as a result of an increase in small and a reduction in large LDL subclasses, plus an increase in overall LDL particle concentration, which together led to no difference (IS versus IR) or a minimal difference (IS versus diabetes) in LDL cholesterol; and a decrease in large cardioprotective HDL combined with an increase in the small HDL subclass such that there was no net significant difference in HDL cholesterol. We conclude that 1) insulin resistance had profound effects on lipoprotein size and subclass particle concentrations for VLDL, LDL, and HDL when measured by NMR; 2) in type 2 diabetes, the lipoprotein subclass alterations are moderately exacerbated but can be attributed primarily to the underlying insulin resistance; and 3) these insulin resistance-induced changes in the NMR lipoprotein subclass profile predictably increase risk of cardiovascular disease but were not fully apparent in the conventional lipid panel. It will be important to study whether NMR lipoprotein subclass parameters can be used to manage risk more effectively and prevent cardiovascular disease in patients with the IRS.

BACKGROUND: Despite progress, many hypertensive patients remain uncontrolled. Defining characteristics of uncontrolled hypertensives may facilitate efforts to improve blood pressure control. METHODS AND RESULTS: Subjects included 13,375 hypertensive adults from National Health and Nutrition Examination Surveys (NHANESs) subdivided into 1988 to 1994, 1999 to 2004, and 2005 to 2008. Uncontrolled hypertension was defined as blood pressure ≥140/≥90 mm Hg and apparent treatment-resistant hypertension (aTRH) when subjects reported taking ≥3 antihypertensive medications. Framingham 10-year coronary risk was calculated. Multivariable logistic regression was used to identify clinical characteristics associated with untreated, treated uncontrolled on 1 to 2 blood pressure medications, and aTRH across all 3 survey periods. More than half of uncontrolled hypertensives were untreated across surveys, including 52.2% in 2005 to 2008. Clinical factors linked with untreated hypertension included male sex, infrequent healthcare visits (0 to 1 per year), body mass index <25 kg/m2, absence of chronic kidney disease, and Framingham 10-year coronary risk <10% (P<0.01). Most treated uncontrolled patients reported taking 1 to 2 blood pressure medications, a proxy for therapeutic inertia. This group was older, had higher Framingham 10-year coronary risk than patients controlled on 1 to 2 medications (P<0.01), and comprised 34.4% of all uncontrolled and 72.0% of treated uncontrolled patients in 2005 to 2008. We found that aTRH increased from 15.9% (1998-2004) to 28.0% (2005-2008) of treated patients (P<0.001). Clinical characteristics associated with aTRH included ≥4 visits per year, obesity, chronic kidney disease, and Framingham 10-year coronary risk >20% (P<0.01). CONCLUSION: Untreated, undertreated, and aTRH patients have consistent characteristics that could inform strategies to improve blood pressure control by decreasing untreated hypertension, reducing therapeutic inertia in undertreated patients, and enhancing therapeutic efficiency in aTRH.

A comprehensive understanding of the neurobiology of alcohol cue reactivity is critical in identifying the neuropathology of alcohol use disorders (AUD) and developing treatments that may attenuate alcohol craving and reduce relapse risk. Functional neuroimaging studies have identified many brain areas in which alcohol cues elicit activation. However, extant studies have included relatively small numbers of cases, with AUD of varying severity, and have employed many different cue paradigms. We used activation likelihood estimation, a quantitative, coordinate-based meta-analytic method, to analyze the brain areas activated by alcohol-related cues across studies, and to examine whether these areas were differentially activated between cases and controls. Secondarily, we reviewed correlations between behavioral measures and cue-elicited activation, as well as treatment effects on such activation. Data analyzed were from 28 studies of 679 cases and 174 controls. Among cases, alcohol cues elicited robust activation of limbic and prefrontal regions, including ventral striatum, anterior cingulate and ventromedial prefrontal cortex. As compared to controls, cases demonstrated greater activation of parietal and temporal regions, including posterior cingulate, precuneus and superior temporal gyrus. Cue-elicited activation of ventral striatum was most frequently correlated with behavioral measures and most frequently reduced by treatment, but these results were often derived from region-of-interest analyses that interrogated only limbic regions. These findings support long-standing theories of mesolimbic involvement in alcohol cue processing, but suggest that cue-elicited activation of other brain areas may more clearly differentiate cases from controls. Prevention and treatment for AUD should consider interventions that may reduce cue-elicited activation of these areas.

UNLABELLED: The increased popularity and functionality of mobile devices has a number of implications for the delivery of mental health services. Effective use of mobile applications has the potential to (a) increase access to evidence-based care; (b) better inform consumers of care and more actively engage them in treatment; (c) increase the use of evidence-based practices; and (d) enhance care after formal treatment has concluded. The current paper presents an overview of the many potential uses of mobile applications as a means to facilitate ongoing care at various stages of treatment. Examples of current mobile applications in behavioural treatment and research are described, and the implications of such uses are discussed. Finally, we provide recommendations for methods to include mobile applications into current treatment and outline future directions for evaluation. KEY PRACTITIONER MESSAGE: Mobile devices are becoming increasingly common among the adult population and have tremendous potential to advance clinical care. Mobile applications have the potential to enhance clinical care at stages of treatment-from engaging patients in clinical care to facilitating adherence to practices and in maintaining treatment gains. Research is needed to validate the efficacy and effectiveness of mobile applications in clinical practice. Research on such devices must incorporate assessments of usability and adherence in addition to their incremental benefit to treatment.

Intensive research over the past 2 decades has implicated ceramide in the regulation of several cell responses. However, emerging evidence points to dramatic complexities in ceramide metabolism and structure that defy the prevailing unifying hypothesis on ceramide function that is based on the understanding of ceramide as a single entity. Here, we develop the concept that "ceramide" constitutes a family of closely related molecules, subject to metabolism by >28 enzymes and with >200 structurally distinct mammalian ceramides distinguished by specific structural modifications. These ceramides are synthesized in a combinatorial fashion with distinct enzymes responsible for the specific modifications. These multiple pathways of ceramide generation led to the hypothesis that individual ceramide molecular species are regulated by specific biochemical pathways in distinct subcellular compartments and execute distinct functions. In this minireview, we describe the "many ceramides" paradigm, along with the rationale, supporting evidence, and implications for our understanding of bioactive sphingolipids and approaches for unraveling these pathways.

Background: While disease-modifying therapies exist for heart failure (HF) with reduced left ventricular ejection fraction (LVEF), few options are available for patients in the higher range of LVEF (&gt;40%). Sacubitril/valsartan has been compared with a renin-angiotensin-aldosterone–system inhibitor alone in 2 similarly designed clinical trials of patients with reduced and preserved LVEF, permitting examination of its effects across the full spectrum of LVEF. Methods: We combined data from PARADIGM-HF (LVEF eligibility≤40%; n=8399) and PARAGON-HF (LVEF eligibility≥45%; n=4796) in a prespecified pooled analysis. We divided randomized patients into LVEF categories: ≤22.5% (n=1269), &gt;22.5% to 32.5% (n=3987), &gt;32.5% to 42.5% (n=3143), &gt; 42.5% to 52.5% (n=1427), &gt; 52.5% to 62.5% (n=2166), and &gt;62.5% (n=1202). We assessed time to first cardiovascular death and HF hospitalization, its components, and total heart failure hospitlizations, all-cause mortality, and noncardiovascular mortality. Incidence rates and treatment effects were examined across categories of LVEF. Results: Among 13 195 randomized patients, we observed lower rates of cardiovascular death and HF hospitalization, but similar rates of noncardiovascular death, among patients in the highest versus the lowest groups. Overall sacubitril/valsartan was superior to renin-angiotensin-aldosterone–system inhibition for first cardiovascular death or heart failure hospitalization (Hazard Ratio [HR] 0.84 [95% CI, 0.78–0.90]), cardiovascular death (HR 0.84 [95% CI, 0.76–0.92]), heart failure hospitalization (HR 0.84 [95% CI, 0.77–0.91]), and all-cause mortality (HR 0.88 [95% CI, 0.81–0.96]). The effect of sacubitril/valsartan was modified by LVEF (treatment-by-continuous LVEF interaction P =0.02), and benefit appeared to be present for individuals with EF primarily below the normal range, although the treatment benefit for cardiovascular death diminished at a lower ejection fraction. We observed effect modification by LVEF on the efficacy of sacubitril/valsartan in both men and women with respect to composite total HF hospitalizations and cardiovascular death, although women derived benefit to higher ejection fractions. Conclusions: The therapeutic effects of sacubitril/valsartan, compared with a renin-angiotensin-aldosterone–system inhibitor alone, vary by LVEF with treatment benefits, particularly for heart failure hospitalization, that appear to extend to patients with heart failure and mildly reduced ejection fraction. These therapeutic benefits appeared to extend to a higher LVEF range in women compared with men. Clinical Trial Registration: https://www.clinicaltrials.gov . Unique identifiers: NCT01920711 (PARAGON-HF), NCT01035255 (PARADIGM-HF).

Therapeutic inertia (TI), defined as the providers' failure to increase therapy when treatment goals are unmet, contributes to the high prevalence of uncontrolled hypertension (> or =140/90 mm Hg), but the quantitative impact is unknown. To address this gap, a retrospective cohort study was conducted on 7253 hypertensives that had > or =4 visits and > or =1 elevated blood pressure (BP) in 2003. A 1-year TI score was calculated for each patient as the difference between expected and observed medication change rates with higher scores reflecting greater TI. Antihypertensive therapy was increased on 13.1% of visits with uncontrolled BP. Systolic BP decreased in patients in the lowest quintile of the TI score but increased in those in the highest quintile (-6.8+/-0.5 versus +1.8+/-0.6 mm Hg; P<0.001). Individuals in the lowest TI quintile were &33 times more likely to have their BP controlled at the last visit than those in highest quintile (odds ratio, 32.7; 95% CI, 25.1 to 42.6; P<0.0001). By multivariable analysis, TI accounted for &19% of the variance in BP control. If TI scores were decreased &50%, that is, increasing medication dosages on &30% of visits, BP control would increase from the observed 45.1% to a projected 65.9% in 1 year. This study confirms the high rate of TI in uncontrolled hypertensive subjects. TI has a major impact on BP control in hypertensive subjects receiving regular care. Reducing TI is critical in attaining the Healthy People 2010 goal of controlling hypertension in 50% of all patients.