Science.gov

Sample records for prazosin treatment suppresses

  1. Prazosin for treatment of nightmares related to posttraumatic stress disorder.

    PubMed

    Taylor, Heather R; Freeman, Maisha Kelly; Cates, Marshall E

    2008-04-15

    The efficacy of prazosin for the treatment of posttraumatic stress disorder (PTSD)-related nightmares is reviewed. PTSD is an anxiety disorder that can occur after experiencing or witnessing a life-threatening event, such as military combat, natural disasters, terrorist attacks, serious accidents, or violent personal assaults. The event that induced PTSD is often relived through nightmares or flashbacks. Sleep disturbances affect approximately 70% of patients with PTSD. Several medications have been evaluated for reducing PTSD-related nightmares, with limited success. Prazosin is a centrally and peripherally acting alpha(1)-adrenergic antagonist whose mechanism of action, favorable adverse-effect profile, and low cost make it a promising agent for the treatment of PTSD. To date, two case reports, two chart reviews, three open-label trials, and two placebo-controlled trials have been published documenting the efficacy and safety of prazosin in the treatment of PTSD-related nightmares. Therapy with prazosin resulted in a reduction in nightmares in patients with both combat- and noncombat-related trauma. A therapeutic benefit occurred with prazosin dosages as low as 1 mg daily, and suppression of nightmare symptoms occurred within one week of prazosin initiation. The most frequently reported adverse event was orthostatic hypotension. The variability in the populations studied (e.g., combat, noncombat, recent traumatic experiences) leaves additional unanswered questions that must be addressed in large, randomized, controlled trials. Prazosin appears to be a promising and well-tolerated agent for the management of PTSD-related nightmares. Further well-designed trials are warranted to establish its place in the treatment of PTSD.

  2. High-dose prazosin for the treatment of post-traumatic stress disorder

    PubMed Central

    Koola, Maju Mathew; Fawcett, Jan A.

    2014-01-01

    Patients with post-traumatic stress disorder (PTSD) are frequently symptomatic despite being on medications currently approved by the US Food and Drug Administration for PTSD. There is evidence to support the notion that prazosin is effective for PTSD nightmares. However, PTSD-related nightmares often do not resolve completely on a low dose of prazosin. The capacity of prazosin to treat daytime symptoms of PTSD which are distressing to patients has not been well studied. Clinicians are reluctant to increase the dose of prazosin due to side effect concerns. To date, the highest reported dose of prazosin used for PTSD is 16 mg daily. We illustrate two case reports using high-dose (up to 30 and 45 mg) prazosin for PTSD with comorbid treatment-resistant mood disorders. We report that high-dose prazosin was safe, tolerable and effective for PTSD in adults. To our knowledge, this is the first case series to highlight the importance of using high-dose prazosin for the treatment of PTSD. In patients with partial response to currently available medications for PTSD, greater utilization of high-dose prazosin for the management of PTSD may lead to better outcomes. PMID:24490030

  3. Effect of adrenergic blockers, carvedilol, prazosin, metoprolol and combination of prazosin and metoprolol on paracetamol-induced hepatotoxicity in rabbits.

    PubMed

    Zubairi, Maysaa B; Ahmed, Jawad H; Al-Haroon, Sawsan S

    2014-01-01

    To evaluate hepatoprotective potential of carvedilol, prazosin, metoprolol and prazosin plus metoprolol in paracetamol-induced hepatotoxicity. Thirty-six male rabbits were divided into six groups, six in each, group 1 received distilled water, group 2 were treated with paracetamol (1 g/kg/day, orally), group 3, 4,5 and 6 were treated at a dose in (mg/kg/day) of the following: Carvedilol (10 mg), prazosin (0.5 mg), metoprolol (10 mg), and a combination of metoprolol (10 mg) and prazosin (0.5 mg) respectively 1 h before paracetamol treatment. All treatments were given for 9 days; animals were sacrificed at day 10. Liver function tests, malondialdehyde (MDA) and glutathione (GSH) in serum and liver homogenates were estimated. Histopathological examinations of liver were performed. Histopathological changes of hepatotoxicity were found in all paracetamol-treated rabbits. The histopathological findings of paracetamol toxicity disappeared in five rabbits on prazosin, very mild in one. In carvedilol group paracetamol toxicity completely disappeared in three, while mild in three rabbits. Paracetamol hepatotoxicity was not changed by metoprolol. In metoprolol plus prazosin treated rabbits, moderate histopathological changes were observed. Serum liver function tests and MDA in serum and in liver homogenate were elevated; GSH was depleted after paracetamol treatment and returned back to the control value on prior treatment with prazosin. MDA in serum and liver homogenate, alkaline phosphatase, total bilirubin were significantly decreased after carvedilol and prazosin plus metoprolol treatments. Carvedilol and prazosin are hepatoprotective in paracetamol hepatotoxicity, combination of prazosin and metoprolol have moderate, and metoprolol has a little hepatoprotection.

  4. Effect of adrenergic blockers, carvedilol, prazosin, metoprolol and combination of prazosin and metoprolol on paracetamol-induced hepatotoxicity in rabbits

    PubMed Central

    Zubairi, Maysaa B.; Ahmed, Jawad H.; Al-Haroon, Sawsan S.

    2014-01-01

    Objectives: To evaluate hepatoprotective potential of carvedilol, prazosin, metoprolol and prazosin plus metoprolol in paracetamol-induced hepatotoxicity. Materials and Methods: Thirty-six male rabbits were divided into six groups, six in each, group 1 received distilled water, group 2 were treated with paracetamol (1 g/kg/day, orally), group 3, 4,5 and 6 were treated at a dose in (mg/kg/day) of the following: Carvedilol (10 mg), prazosin (0.5 mg), metoprolol (10 mg), and a combination of metoprolol (10 mg) and prazosin (0.5 mg) respectively 1 h before paracetamol treatment. All treatments were given for 9 days; animals were sacrificed at day 10. Liver function tests, malondialdehyde (MDA) and glutathione (GSH) in serum and liver homogenates were estimated. Histopathological examinations of liver were performed. Results: Histopathological changes of hepatotoxicity were found in all paracetamol-treated rabbits. The histopathological findings of paracetamol toxicity disappeared in five rabbits on prazosin, very mild in one. In carvedilol group paracetamol toxicity completely disappeared in three, while mild in three rabbits. Paracetamol hepatotoxicity was not changed by metoprolol. In metoprolol plus prazosin treated rabbits, moderate histopathological changes were observed. Serum liver function tests and MDA in serum and in liver homogenate were elevated; GSH was depleted after paracetamol treatment and returned back to the control value on prior treatment with prazosin. MDA in serum and liver homogenate, alkaline phosphatase, total bilirubin were significantly decreased after carvedilol and prazosin plus metoprolol treatments. Conclusion: Carvedilol and prazosin are hepatoprotective in paracetamol hepatotoxicity, combination of prazosin and metoprolol have moderate, and metoprolol has a little hepatoprotection. PMID:25538338

  5. Treatment of Post-Traumatic Stress Disorders with the Alpha-1 Adrenergic Antagonist Prazosin.

    PubMed

    Simon, Philippe Yves Rémy; Rousseau, Pierre-François

    2017-03-01

    The present review aims to assess the clinical efficacy and safety of the α-1-adrenergic antagonist prazosin as primary pharmacologic treatment for post-traumatic stress disorder (PTSD). A systematic review was performed using keywords (i.e., prazosin, α-1-adrenergic antagonist, α-1-blocker, post-traumatic stress disorder) in the databases PubMed/Medline (1966-May 2016), Embase (1966-May 2016), ScienceDirect (1823-May 2016), OvidSP (1946-May 2016) and Nature (1845-May 2016). To be considered for inclusion, studies had to test the efficacy of prazosin either alone or added to ongoing treatment in adults with PTSD, use validated tools to assess and monitor the disorders, allow comparisons on the basis of univariate analyses (i.e., p-values of t-tests and effect sizes) and list the identified adverse reactions. 12 studies were included: 5 randomized controlled trials, 4 open-label prospective trials and 3 retrospective file reviews. The evaluation concerned 276 patients exposed to civilian trauma (19%) or war trauma (81%). Prazosin significantly decreases trauma nightmares, avoidance, hypervigilance and improves patient status in all studies. No significant difference of blood pressure was observed at the end of trials. Beyond the methodological and clinical biases of these studies, the present review not only confirms the effectiveness and good tolerability of prazosin, but also suggests its possible use as primary pharmacologic treatment for PTSD. Uncertainties remain, however, regarding the prescription modalities and dosages.

  6. The efficacy of prazosin for the treatment of posttraumatic stress disorder nightmares in U.S. military veterans.

    PubMed

    Breen, Annamarie; Blankley, Kory; Fine, Julie

    2017-02-01

    Nightmares associated with posttraumatic stress disorder (PTSD) are a hallmark symptom among U.S. military veterans who have seen combat. Management of combat-related nightmares can be difficult and current pharmacologic options are limited and tend to have adverse side effects. The aim of this review is to explore recent literature regarding the efficacy of prazosin for the treatment of nightmare disorder in the veteran population. Recent literature consisting of three systematic reviews was reviewed, as well as current clinical guidelines published by The Department of Veterans Affairs (VA) and The Department of Defense (DoD) and the American Academy of Sleep Medicine (AASM). Prazosin has been shown to be effective in the treatment of PTSD trauma-related nightmares. As a result of its low side effect profile and abilities to improve both sleep and reduce trauma nightmares, prazosin has been recommended as an adjunct therapy. Prazosin should be initiated as an adjunctive treatment to promote sleep in those suffering from PTSD nightmares. It should be initiated at 1 mg and then titrated upward until absence or desired reduction of nightmares is achieved, with a maximum dosage recommendation of 20 mg at bedtime and 5 mg midmorning. ©2016 American Association of Nurse Practitioners.

  7. Prazosin Augmentation of Outpatient Treatment of Alcohol Use Disorders in Active Duty Soldiers with and without PTSD

    DTIC Science & Technology

    2016-10-01

    and without PTSD PRINCIPAL INVESTIGATOR: Murray Raskind, MD CONTRACTING ORGANIZATION: Seattle Institute for Biomedical and Clinical Research...a 12-week randomized controlled trial (RCT) of prazosin for AUD in 200 OIF/OEF soldiers both with and without comorbid PTSD enrolled in the Alcohol...efficacy for AUD in OIF/OEF soldiers participating in outpatient AUD treatment and 2) to determine if the presence of PTSD affects prazosin efficacy for AUD

  8. Combining the α1-Adrenergic Receptor Antagonist, Prazosin, with the β-Adrenergic Receptor Antagonist, Propranolol, Reduces Alcohol Drinking More Effectively Than Either Drug Alone

    PubMed Central

    Rasmussen, Dennis D; Beckwith, Lauren E; Kincaid, Carrie L; Froehlich, Janice C

    2014-01-01

    Background Evidence suggests that activation of the noradrenergic system may contribute to alcohol drinking in animals and humans. Our previous studies demonstrated that blocking α1-adrenergic receptors with the antagonist, prazosin, decreased alcohol drinking in rats under various conditions. Since noradrenergic activation is also regulated by β-adrenergic receptors, we now examine the effects of the β-adrenergic receptor antagonist, propranolol, alone or in combination with prazosin, on alcohol drinking in rats selectively bred for high voluntary alcohol intake and alcohol preference (P line). Methods Two studies were conducted with male P rats. In study one, rats were allowed to become alcohol-dependent during 14 weeks of ad libitum access to food, water and 20% alcohol and the effect of propranolol (5–15 mg/kg, IP) and prazosin (1–2 mg/kg, IP) on alcohol intake during withdrawal were assessed. In study two, the effect of propranolol (5 mg/kg, IP) and prazosin (2 mg/kg, IP) on alcohol intake following prolonged imposed abstinence was assessed. Results Alcohol drinking following propranolol treatment was variable, but the combination of propranolol + prazosin consistently suppressed alcohol drinking during both alcohol withdrawal and following prolonged imposed abstinence, and the combination of these two drugs was more effective than was treatment with either drug alone. Conclusions Treatment with prazosin + propranolol, or a combination of other centrally active α1- and β-adrenergic receptor antagonists, may assist in preventing alcohol relapse in some individuals. PMID:24891220

  9. Two Case Reports on Use of Prazosin for Drug Dreams.

    PubMed

    Gopalakrishna, Ganesh; Popoola, Oluwole; Campbell, Austin; Nemetalla, Marina A

    2016-01-01

    Substance abuse and dependence is estimated to cost roughly $700 billion annually including direct and indirect care in the United States. Drug dreams (DD), or using dreams, are a reportedly common phenomenon among patients with substance abuse, and have been postulated as triggers for relapse. Prazosin is an alpha-1 receptor antagonist originally approved by the United States Food and Drug Administration for the treatment of hypertension. Prazosin passes the blood brain barrier easily, contributing to central and cognitive effects. Prazosin's efficacy has been demonstrated in the management of posttraumatic stress disorder (PTSD), and associated nightmares. We present the cases of two patients with substance use disorder experiencing DD which resolved after the addition of prazosin during an acute psychiatric hospitalization. To our knowledge, this is the first time treatment of DD with prazosin has been reported in the literature. Both patients reported an alleviation of their DD after the medication was initiated. The effect was immediate and results were seen on the same night of the initial dose. The precise mechanism of this effect is unclear, but we hypothesize it is related to the decrease in noradrenaline effects at α-1 adrenoreceptors in the brain, similar to the effect on nightmares in PTSD. The key limitation is the low number of patients and lack of follow up presented in this report. No causal relationship can be established between the use of prazosin and resolution of DD in our patients.

  10. Prazosin during Threat Discrimination Boosts Memory of the Safe Stimulus

    ERIC Educational Resources Information Center

    Homan, Philipp; Lin, Qi; Murrough, James W.; Soleimani, Laili; Bach, Dominik R.; Clem, Roger L.; Schiller, Daniela

    2017-01-01

    The alpha-1 adrenoreceptor antagonist prazosin has shown promise in the treatment of post-traumatic stress disorder (PTSD) symptoms, but its mechanisms are not well understood. Here we administered prazosin or placebo prior to threat conditioning (day 1) and tested subsequent extinction (day 2) and reextinction (day 3) in healthy human…

  11. Prazosin Prevents Increased Anxiety Behavior That Occurs in Response to Stress During Alcohol Deprivations.

    PubMed

    Rasmussen, Dennis D; Kincaid, Carrie L; Froehlich, Janice C

    2017-01-01

    Stress-induced anxiety is a risk factor for relapse to alcohol drinking. The aim of this study was to test the hypothesis that the central nervous system (CNS)-active α 1 -adrenergic receptor antagonist, prazosin, would block the stress-induced increase in anxiety that occurs during alcohol deprivations. Selectively bred male alcohol-preferring (P) rats were given three cycles of 5 days of ad libitum voluntary alcohol drinking interrupted by 2 days of alcohol deprivation, with or without 1 h of restraint stress 4 h after the start of each of the first two alcohol deprivation cycles. Prazosin (1.0 or 1.5 mg/kg, IP) or vehicle was administered before each restraint stress. Anxiety-like behavior during alcohol deprivation following the third 5-day cycle of alcohol drinking (7 days after the most recent restraint stress ± prazosin treatment) was measured by performance in an elevated plus-maze and in social approach/avoidance testing. Rats that received constant alcohol access, or alcohol access and deprivations without stress or prazosin treatments in the first two alcohol deprivations did not exhibit augmented anxiety-like behavior during the third deprivation. In contrast, rats that had been stressed during the first two alcohol deprivations exhibited increased anxiety-like behavior (compared with control rats) in both anxiety tests during the third deprivation. Prazosin given before stresses in the first two cycles of alcohol withdrawal prevented increased anxiety-like behavior during the third alcohol deprivation. Prazosin treatment before stresses experienced during alcohol deprivations may prevent the increased anxiety during subsequent deprivation/abstinence that is a risk factor for relapse to alcohol drinking. Administration of prazosin before stresses during repetitive alcohol deprivations in male alcohol-preferring (P) rats prevents increased anxiety during a subsequent deprivation without further prazosin treatment. Prazosin treatment during repeated

  12. Prazosin Prevents Increased Anxiety Behavior That Occurs in Response to Stress During Alcohol Deprivations

    PubMed Central

    Rasmussen, Dennis D.; Kincaid, Carrie L.; Froehlich, Janice C.

    2017-01-01

    Aims Stress-induced anxiety is a risk factor for relapse to alcohol drinking. The aim of this study was to test the hypothesis that the central nervous system (CNS)-active α1-adrenergic receptor antagonist, prazosin, would block the stress-induced increase in anxiety that occurs during alcohol deprivations. Methods Selectively bred male alcohol-preferring (P) rats were given three cycles of 5 days of ad libitum voluntary alcohol drinking interrupted by 2 days of alcohol deprivation, with or without 1 h of restraint stress 4 h after the start of each of the first two alcohol deprivation cycles. Prazosin (1.0 or 1.5 mg/kg, IP) or vehicle was administered before each restraint stress. Anxiety-like behavior during alcohol deprivation following the third 5-day cycle of alcohol drinking (7 days after the most recent restraint stress ± prazosin treatment) was measured by performance in an elevated plus-maze and in social approach/avoidance testing. Results Rats that received constant alcohol access, or alcohol access and deprivations without stress or prazosin treatments in the first two alcohol deprivations did not exhibit augmented anxiety-like behavior during the third deprivation. In contrast, rats that had been stressed during the first two alcohol deprivations exhibited increased anxiety-like behavior (compared with control rats) in both anxiety tests during the third deprivation. Prazosin given before stresses in the first two cycles of alcohol withdrawal prevented increased anxiety-like behavior during the third alcohol deprivation. Conclusion Prazosin treatment before stresses experienced during alcohol deprivations may prevent the increased anxiety during subsequent deprivation/abstinence that is a risk factor for relapse to alcohol drinking. Short summary Administration of prazosin before stresses during repetitive alcohol deprivations in male alcohol-preferring (P) rats prevents increased anxiety during a subsequent deprivation without further prazosin

  13. Use of prazosin in management of hypertension in patients with chronic renal failure and in renal transplant recipients.

    PubMed Central

    Curtis, J R; Bateman, F J

    1975-01-01

    Prazosin was used in combination with other antihypertensive drugs in the successful management of hypertension in seven patients with chronic renal failure and six renal transplant recipients, also with chronic renal failure. The addition of small doses of prazosin (mean 3 mg/day) to the antihypertensive regimen produced significant falls in systolic and diastolic blood pressures in both the lying and standing positions. The standing blood pressures were significantly lower than the lying blood pressures during prazosin treatment. Neither the mean blood urea concentrations nor the mean plasma creatinine concentrations changed significantly during prazosin administration. Chromium-51 edetic acid clearances did not change significantly during prazosin treatment in the seven patients in whom it was measured. Severe symptomatic postural hypotension occurred in one patient a week after starting prazosin 3 mg/day. This hypotensive episode was associated with a transient and reversible deterioration in renal function. Another patient developed a rash while on prazosin but it was probably related to propranolol rather than prazosin. Prazosin is thus an effective antihypertensive drug in patients with chronic renal failure, and it may be used with a variety of other drugs. It should be used cautiously, however, since patients with chronic renal failure may respond to small doses, and significant postural falls in blood pressure may result. There was no evidence that the use of prazosin resulted in progressive deterioration in the residual renal function of the patients with chronic renal failure. PMID:811312

  14. Use of prazosin in management of hypertension in patients with chronic renal failure and in renal transplant recipients.

    PubMed

    Curtis, J R; Bateman, F J

    1975-11-22

    Prazosin was used in combination with other antihypertensive drugs in the successful management of hypertension in seven patients with chronic renal failure and six renal transplant recipients, also with chronic renal failure. The addition of small doses of prazosin (mean 3 mg/day) to the antihypertensive regimen produced significant falls in systolic and diastolic blood pressures in both the lying and standing positions. The standing blood pressures were significantly lower than the lying blood pressures during prazosin treatment. Neither the mean blood urea concentrations nor the mean plasma creatinine concentrations changed significantly during prazosin administration. Chromium-51 edetic acid clearances did not change significantly during prazosin treatment in the seven patients in whom it was measured. Severe symptomatic postural hypotension occurred in one patient a week after starting prazosin 3 mg/day. This hypotensive episode was associated with a transient and reversible deterioration in renal function. Another patient developed a rash while on prazosin but it was probably related to propranolol rather than prazosin. Prazosin is thus an effective antihypertensive drug in patients with chronic renal failure, and it may be used with a variety of other drugs. It should be used cautiously, however, since patients with chronic renal failure may respond to small doses, and significant postural falls in blood pressure may result. There was no evidence that the use of prazosin resulted in progressive deterioration in the residual renal function of the patients with chronic renal failure.

  15. Investigation of the Atypical Glass Transition and Recrystallization Behavior of Amorphous Prazosin Salts

    PubMed Central

    Kumar, Lokesh; Popat, Dharmesh; Bansal, Arvind K.

    2011-01-01

    This manuscript studied the effect of counterion on the glass transition and recrystallization behavior of amorphous salts of prazosin. Three amorphous salts of prazosin, namely, prazosin hydrochloride, prazosin mesylate and prazosin tosylate were prepared by spray drying, and characterized by optical-polarized microscopy, differential scanning calorimetry and powder X-ray diffraction. Modulated differential scanning calorimetry was used to determine the glass transition and recrystallization temperature of amorphous salts. Glass transition of amorphous salts followed the order: prazosin mesylate > prazosin tosylate ∼ prazosin hydrochloride. Amorphous prazosin mesylate and prazosin tosylate showed glass transition, followed by recrystallization. In contrast, amorphous prazosin hydrochloride showed glass transition and recrystallization simultaneously. Density Functional Theory, however, suggested the expected order of glass transition as prazosin hydrochloride > prazosin mesylate > prazosin tosylate. The counterintuitive observation of amorphous prazosin hydrochloride having lower glass transition was explained in terms of its lower activation energy (206.1 kJ/mol) for molecular mobility at Tg, compared to that for amorphous prazosin mesylate (448.5 kJ/mol) and prazosin tosylate (490.7 kJ/mol), and was further correlated to a difference in hydrogen bonding strength of the amorphous and the corresponding recrystallized salts. This study has implications in selection of an optimal amorphous salt form for pharmaceutical development. PMID:24310595

  16. Investigation of the atypical glass transition and recrystallization behavior of amorphous prazosin salts.

    PubMed

    Kumar, Lokesh; Popat, Dharmesh; Bansal, Arvind K

    2011-08-25

    This manuscript studied the effect of counterion on the glass transition and recrystallization behavior of amorphous salts of prazosin. Three amorphous salts of prazosin, namely, prazosin hydrochloride, prazosin mesylate and prazosin tosylate were prepared by spray drying, and characterized by optical-polarized microscopy, differential scanning calorimetry and powder X-ray diffraction. Modulated differential scanning calorimetry was used to determine the glass transition and recrystallization temperature of amorphous salts. Glass transition of amorphous salts followed the order: prazosin mesylate > prazosin tosylate ~ prazosin hydrochloride. Amorphous prazosin mesylate and prazosin tosylate showed glass transition, followed by recrystallization. In contrast, amorphous prazosin hydrochloride showed glass transition and recrystallization simultaneously. Density Functional Theory, however, suggested the expected order of glass transition as prazosin hydrochloride > prazosin mesylate > prazosin tosylate. The counterintuitive observation of amorphous prazosin hydrochloride having lower glass transition was explained in terms of its lower activation energy (206.1 kJ/mol) for molecular mobility at Tg, compared to that for amorphous prazosin mesylate (448.5 kJ/mol) and prazosin tosylate (490.7 kJ/mol), and was further correlated to a difference in hydrogen bonding strength of the amorphous and the corresponding recrystallized salts. This study has implications in selection of an optimal amorphous salt form for pharmaceutical development.

  17. Combining naltrexone and prazosin in a single oral medication decreases alcohol drinking more effectively than does either drug alone.

    PubMed

    Froehlich, Janice C; Hausauer, Brett J; Rasmussen, Dennis D

    2013-10-01

    Naltrexone (NTX) is underutilized in clinical treatment settings because its efficacy is modest, and it is not effective for all alcoholics and, when it is effective, a significant number of alcoholics fail to maintain initial treatment gains and subsequently relapse to heavy drinking. This has slowed acceptance of NTX by the treatment community, and there is a clear need for additional treatments for alcoholism and alcohol use disorders. Given that NTX and prazosin can each reduce alcohol drinking in rats selectively bred for alcohol preference and high voluntary alcohol drinking (alcohol-preferring "P" rats), we tested whether a combination of NTX + prazosin is more effective in decreasing alcohol drinking than is either drug alone. P rats were given access to a 15% (v/v) alcohol solution for 2 hours daily. Rats were fed NTX and prazosin, alone or in combination, prior to onset of the daily 2-hour alcohol access period for 4 weeks and the effect of drug treatment on alcohol and water intake was assessed. During the first week of treatment, neither a low dose of NTX, nor prazosin, was effective in decreasing alcohol intake when each drug was administered alone, but combining the 2 drugs in a single medication significantly reduced alcohol intake. The combination was as effective as was a higher dose of NTX. Using a low dose of NTX in combination with prazosin may reduce the potential for undesirable side effects early in treatment which, in turn, may improve patient compliance and result in a more successful outcome when NTX is used for treating alcoholism and alcohol use disorders. Combining low-dose NTX and prazosin in a single medication may be more useful than is either drug alone for treating both inpatient and outpatient alcoholics and heavy drinkers early in the treatment process. Copyright © 2013 by the Research Society on Alcoholism.

  18. Sleep Disturbances and Nightmares in a Patient Treated with Prazosin.

    PubMed

    Kosari, Sam; Naunton, Mark

    2016-04-15

    Prazosin is increasingly being used off-label to treat nightmares in patients with posttraumatic stress disorder. The literature about the psychiatric adverse effects of prazosin is very limited. We present a case in which low-dose prazosin was associated with nightmares and sleep disturbances in an elderly patient without previously diagnosed mental illness or coexisting environmental risk factors for nightmares. Insomnia and hallucinations are listed as some of the rare side effects of prazosin by the manufacturer. Prazosin could be associated with rare psychiatric adverse effects and sleep disturbances. Particular attention is required in identifying these adverse effects, which can be difficult to distinguish from other drug-related side effects in the elderly particularly because they are often using multiple medications. © 2016 American Academy of Sleep Medicine.

  19. Prazosin Augmentation of Outpatient Treatment of Alcohol Use Disorders in Active Duty Soldiers with and without PTSD

    DTIC Science & Technology

    2014-10-01

    future combat deployments. It is also important to avoid sedation, weight gain, decreased libido, and other adverse effects of psychotropic drugs that...ated, and blood pressure changes did not differ between groups. Conclusions: Prazosin is effective for combat- related PTSD with trauma night- mares in...combat- related trauma nightmares, sleep quality, and global status. Prazosin was also effective for overall PTSD symptoms even after the CAPS

  20. Prazosin for Veterans with Posttraumatic Stress Disorder and Comorbid Alcohol Dependence: A Clinical Trial.

    PubMed

    Petrakis, Ismene L; Desai, Nitigna; Gueorguieva, Ralitza; Arias, Albert; O'Brien, Erin; Jane, J Serrita; Sevarino, Kevin; Southwick, Steven; Ralevski, Elizabeth

    2016-01-01

    Posttraumatic stress disorder (PTSD) is an important and timely clinical issue particularly for combat veterans. Few pharmacologic options are available to treat PTSD, particularly among military personnel, and they are not based on rational neurobiology. The evidence for noradrenergic dysregulation in PTSD is strong, and the alpha-adrenergic agonist prazosin is one of the most promising medications to treat sleep disturbances associated with PTSD as well as PTSD symptoms among both veterans and civilians. Evidence also implicates noradrenergic dysregulation in the pathophysiology of alcohol dependence (AD); prazosin also may have efficacy in treating this disorder. The use of prazosin represents a rational and compelling approach for the treatment of PTSD and comorbid AD. Given the high rates of comorbid AD in trauma survivors with PTSD, and the enormous impact that these comorbid disorders have on psychosocial function and well-being, finding effective treatments for this population is of high clinical importance. Ninety-six veterans with PTSD and comorbid AD were randomized to receive prazosin (16 mg) or placebo in an outpatient, randomized, double-blind, clinical trial for 13 weeks. Main outcomes included symptoms of PTSD, sleep disturbances, and alcohol use. Symptoms of PTSD improved over time, but contrary to the hypothesis, there was no medication effect on PTSD symptoms, or on sleep. Alcohol consumption also decreased over time, but there were no significant differences in outcomes between medication groups. Prazosin was not effective in treating PTSD symptoms, improving sleep, or reducing alcohol consumption overall in this dually diagnosed group. This does not support the use of prazosin in an actively drinking population and suggests that the presence of a comorbid condition affects the efficacy of this medication. This study highlights the importance of conducting clinical trials in "real-world" patients, as results may vary based on comorbid

  1. Chronic prazosin attenuates the natriuretic response to a modest saline load in anaesthetized rats.

    PubMed Central

    Penner, S. B.; Smyth, D. D.

    1988-01-01

    1. The effect of chronic prazosin pretreatment (3 days) on the ability to excrete a modest saline load (i.v. saline, 0.097 ml min-1) was studied in the anaesthetized rat. Three days before the experiment, the drinking water was replaced with 0.5% dextrose (control), 0.015 mg ml-1 prazosin in 0.5% dextrose (low dose) or 0.15 mg ml-1 prazosin in 0.5% dextrose (high dose). 2. The selectivity of the prazosin for alpha 1-adrenoceptors was evaluated in pithed rats. The pressor response to phenylephrine was partially attenuated by the low dose of prazosin and completely attenuated by the high dose of prazosin. The pressor response to clonidine was slightly decreased by the 3 day prazosin pretreatment indicating a selectivity for alpha 1-adrenoceptors. 3. In rats pretreated with the low dose of prazosin, there was a significant decrease in sodium and water, but not potassium excretion as compared to the control group. Captopril failed to alter these effects of the low dose of prazosin. Blood pressure and creatinine clearance were the same in both groups. In rats pretreated with the high dose of prazosin, there was a further decrease in sodium and water but not potassium excretion. However, this dose of prazosin also significantly decreased blood pressure and increased creatinine clearance. A decrease in renal perfusion pressure with an aortic clamp to the same level as that observed with the high prazosin dose also decreased sodium and water but not potassium excretion. The decrease in sodium and water excretion was not as great as that observed with the high dose of prazosin.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2896036

  2. Prazosin Augmentation of Outpatient Treatment of Alcohol Use Disorders in Active Duty Soldiers with and without PTSD

    DTIC Science & Technology

    2015-10-01

    Substance Abuse Program (ASAP) at Madigan Health Care System/Joint Base Lewis McChord. The aims of this trial are 1) to determine prazosin’s efficacy...Augmentation of Outpatient Treatment of AUD in Active Duty Soldiers with and without PTSD. Presented at Joint Army/NIH Substance Abuse IP – September 29...randomized controlled trial (RCT) of prazosin for AUD in active duty soldiers both with and without comorbid PTSD enrolled in the Alcohol and Substance

  3. A trial of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq and Afghanistan.

    PubMed

    Raskind, Murray A; Peterson, Kris; Williams, Tammy; Hoff, David J; Hart, Kimberly; Holmes, Hollie; Homas, Dallas; Hill, Jeffrey; Daniels, Colin; Calohan, Jess; Millard, Steven P; Rohde, Kirsten; O'Connell, James; Pritzl, Denise; Feiszli, Kevin; Petrie, Eric C; Gross, Christopher; Mayer, Cynthia L; Freed, Michael C; Engel, Charles; Peskind, Elaine R

    2013-09-01

    The authors conducted a 15-week randomized controlled trial of the alpha-1 adrenoreceptor antagonist prazosin for combat trauma nightmares, sleep quality, global function, and overall symptoms in active-duty soldiers with posttraumatic stress disorder (PTSD) returned from combat deployments to Iraq and Afghanistan. Sixty-seven soldiers were randomly assigned to treatment with prazosin or placebo for 15 weeks. Drug was titrated based on nightmare response over 6 weeks to a possible maximum dose of 5 mg midmorning and 20 mg at bedtime for men and 2 mg midmorning and 10 mg at bedtime for women. Mean achieved bedtime doses were 15.6 mg of prazosin (SD=6.0) and 18.8 mg of placebo (SD=3.3) for men and 7.0 mg of prazosin (SD=3.5) and 10.0 mg of placebo (SD=0.0) for women. Mean achieved midmorning doses were 4.0 mg of prazosin (SD=1.4) and 4.8 mg of placebo (SD=0.8) for men and 1.7 mg of prazosin (SD=0.5) and 2.0 mg of placebo (SD=0.0) mg for women. Primary outcome measures were the nightmare item of the Clinician-Administered PTSD Scale (CAPS), the Pittsburgh Sleep Quality Index, and the change item of the Clinical Global Impressions Scale anchored to functioning. Secondary outcome measures were the 17-item CAPS, the Hamilton Depression Rating Scale, the Patient Health Questionnaire-9, and the Quality of Life Index. Maintenance psychotropic medications and supportive psychotherapy were held constant. Prazosin was effective for trauma nightmares, sleep quality, global function, CAPS score, and the CAPS hyperarousal symptom cluster. Prazosin was well tolerated, and blood pressure changes did not differ between groups. Prazosin is effective for combat-related PTSD with trauma nightmares in active-duty soldiers, and benefits are clinically meaningful. Substantial residual symptoms suggest that studies combining prazosin with effective psychotherapies might demonstrate further benefit.

  4. A Placebo-Controlled Augmentation Trial of Prazosin for Combat Trauma PTSD

    DTIC Science & Technology

    2012-06-01

    controlled trial to evaluate the efficacy and tolerability of the alpha-1 adrenergic antagonist, prazosin, for reducing trauma nightmares and sleep...efficacy and tolerability of the alpha-1 adrenergic antagonist prazosin compared to placebo for combat stress- related nightmares, sleep disturbance

  5. Geographical diffusion of prazosin across Veterans Health Administration: Examination of regional variation in daily dosing and quality indicators among veterans with posttraumatic stress disorder.

    PubMed

    Abrams, Thad E; Lund, Brian C; Alexander, Bruce; Bernardy, Nancy C; Friedman, Matthew J

    2015-01-01

    Posttraumatic stress disorder (PTSD) is a high-priority treatment area for the Veterans Health Administration (VHA), and dissemination patterns of innovative, efficacious therapies can inform areas for potential improvement of diffusion efforts and quality prescribing. In this study, we replicated a prior examination of the period prevalence of prazosin use as a function of distance from Puget Sound, Washington, where prazosin was first tested as an effective treatment for PTSD and where prazosin use was previously shown to be much greater than in other parts of the United States. We tested the following three hypotheses related to prazosin geographic diffusion: (1) a positive geographical correlation exists between the distance from Puget Sound and the proportion of users treated according to a guideline recommended minimum therapeutic target dose (>/=6 mg/d), (2) an inverse geographic correlation exists between prazosin and benzodiazepine use, and (3) no geographical correlation exists between prazosin use and serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) use. Among a national sample of veterans with PTSD, overall prazosin utilization increased from 5.5 to 14.8% from 2006 to 2012. During this time period, rates at the Puget Sound VHA location declined from 34.4 to 29.9%, whereas utilization rates at locations a minimum of 2,500 miles away increased from 3.0 to 12.8%. Rates of minimum target dosing fell from 42.6 to 34.6% at the Puget Sound location. In contrast, at distances of at least 2,500 miles from Puget Sound, minimum threshold dosing rates remained stable (range, 18.6 to 17.7%). No discernible association was demonstrated between SSRI/SNRI or benzodiazepine utilization and the geographic distance from Puget Sound. Minimal threshold dosing of prazosin correlated positively with increased diffusion of prazosin use, but there was still a distance diffusion gradient. Although prazosin adoption has improved, geographic

  6. Prazosin, an adrenergic blocking agent inadequate as male contraceptive pill.

    PubMed

    Kjaergaard, N; Kjaergaard, B; Lauritsen, J G

    1988-06-01

    The purpose of this study was to investigate the efficacy and the acceptability of Prazosin as a male contraceptive pill. Acceptable antifertility drugs for men are proving difficult to produce, and the possibility of using pharmacological agents to block selectively or to inhibit normal sperm transport through the male genital tract is an interesting approach. Prazosin administered in doses up to 10 mg/day did not cause azoospermia following ejaculation. In conclusion, we have not been able to confirm either the efficacy or the acceptability of the alpha 1-adrenoceptor antagonist Prazosin as a male contraceptive drug. Homonnai et al. confirmed the fact that phenoxybenzamine blocks ejaculation, but it should be noted that although both drugs are alpha 1-adrenoceptor blocking agents, they are not chemically identical.

  7. The effect of prazosin on skin microcirculation as assessed by laser Doppler flowmetry.

    PubMed Central

    Khan, F; Struthers, A D; Spence, V A

    1988-01-01

    1. Laser Doppler flowmetry was used in six normal volunteers to record changes in fingertip skin blood flow after the administration of prazosin to block postsynaptic alpha 1-adrenoceptors. 2. Prazosin (0.5 mg orally) did not alter systolic or diastolic blood pressure or heart rate. 3. Prazosin did significantly increase basal skin blood flow 2 h after its administration but this effect was no longer evident after contralateral hand warming. Prazosin markedly reduced the skin vasoconstrictor response to deep inspiration and to contralateral hand cooling. 4. This study suggests that postsynaptic alpha 1-adrenoceptors are involved in maintaining skin vasoconstrictor tone at rest and are also involved in the rapid skin vasoconstriction seen in response to a deep inspiration and to contralateral hand cooling. PMID:2846022

  8. Trial of Prazosin for Post-Traumatic Stress Disorder in Military Veterans.

    PubMed

    Raskind, Murray A; Peskind, Elaine R; Chow, Bruce; Harris, Crystal; Davis-Karim, Anne; Holmes, Hollie A; Hart, Kimberly L; McFall, Miles; Mellman, Thomas A; Reist, Christopher; Romesser, Jennifer; Rosenheck, Robert; Shih, Mei-Chiung; Stein, Murray B; Swift, Robert; Gleason, Theresa; Lu, Ying; Huang, Grant D

    2018-02-08

    In randomized trials, prazosin, an α 1 -adrenoreceptor antagonist, has been effective in alleviating nightmares associated with post-traumatic stress disorder (PTSD) in military veterans. We recruited veterans from 13 Department of Veterans Affairs medical centers who had chronic PTSD and reported frequent nightmares. Participants were randomly assigned to receive prazosin or placebo for 26 weeks; the drug or placebo was administered in escalating divided doses over the course of 5 weeks to a daily maximum of 20 mg in men and 12 mg in women. After week 10, participants continued to receive prazosin or placebo in a double-blind fashion for an additional 16 weeks. The three primary outcome measures were the change in score from baseline to 10 weeks on the Clinician-Administered PTSD Scale (CAPS) item B2 ("recurrent distressing dreams"; scores range from 0 to 8, with higher scores indicating more frequent and more distressing dreams); the change in score from baseline to 10 weeks on the Pittsburgh Sleep Quality Index (PSQI; scores range from 0 to 21, with higher scores indicating worse sleep quality); and the Clinical Global Impression of Change (CGIC) score at 10 weeks (scores range from 1 to 7, with lower scores indicating greater improvement and a score of 4 indicating no change). A total of 304 participants underwent randomization; 152 were assigned to prazosin, and 152 to placebo. At 10 weeks, there were no significant differences between the prazosin group and the placebo group in the mean change from baseline in the CAPS item B2 score (between-group difference, 0.2; 95% confidence interval [CI], -0.3 to 0.8; P=0.38), in the mean change in PSQI score (between-group difference, 0.1; 95% CI, -0.9 to 1.1; P=0.80), or in the CGIC score (between-group difference, 0; 95% CI, -0.3 to 0.3; P=0.96). There were no significant differences in these measures at 26 weeks (a secondary outcome) or in other secondary outcomes. At 10 weeks, the mean difference between the

  9. The anti-hypertensive drug prazosin inhibits glioblastoma growth via the PKCδ-dependent inhibition of the AKT pathway.

    PubMed

    Assad Kahn, Suzana; Costa, Silvia Lima; Gholamin, Sharareh; Nitta, Ryan T; Dubois, Luiz Gustavo; Fève, Marie; Zeniou, Maria; Coelho, Paulo Lucas Cerqueira; El-Habr, Elias; Cadusseau, Josette; Varlet, Pascale; Mitra, Siddhartha S; Devaux, Bertrand; Kilhoffer, Marie-Claude; Cheshier, Samuel H; Moura-Neto, Vivaldo; Haiech, Jacques; Junier, Marie-Pierre; Chneiweiss, Hervé

    2016-05-01

    A variety of drugs targeting monoamine receptors are routinely used in human pharmacology. We assessed the effect of these drugs on the viability of tumor-initiating cells isolated from patients with glioblastoma. Among the drugs targeting monoamine receptors, we identified prazosin, an α1- and α2B-adrenergic receptor antagonist, as the most potent inducer of patient-derived glioblastoma-initiating cell death. Prazosin triggered apoptosis of glioblastoma-initiating cells and of their differentiated progeny, inhibited glioblastoma growth in orthotopic xenografts of patient-derived glioblastoma-initiating cells, and increased survival of glioblastoma-bearing mice. We found that prazosin acted in glioblastoma-initiating cells independently from adrenergic receptors. Its off-target activity occurred via a PKCδ-dependent inhibition of the AKT pathway, which resulted in caspase-3 activation. Blockade of PKCδ activation prevented all molecular changes observed in prazosin-treated glioblastoma-initiating cells, as well as prazosin-induced apoptosis. Based on these data, we conclude that prazosin, an FDA-approved drug for the control of hypertension, inhibits glioblastoma growth through a PKCδ-dependent mechanism. These findings open up promising prospects for the use of prazosin as an adjuvant therapy for glioblastoma patients. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

  10. Low-dose prazosin alone and in combination with propranolol or naltrexone: effects on ethanol and sucrose seeking and self-administration in the P rat.

    PubMed

    Verplaetse, Terril L; Czachowski, Cristine L

    2015-08-01

    Evidence suggests that the noradrenergic system mediates ethanol reinforcement. However, preclinical studies suggest that noradrenergic antagonists block other oral reinforcers indicating possible unwanted secondary medication effects. This study examined combinations of low-dose prazosin with propranolol or naltrexone using a behavioral paradigm that separately assesses reinforcer seeking and self-administration. Male alcohol-preferring (P) rats (n = 20/experiment) were trained to complete a response requirement (RR) resulting in access to 1 % sucrose (n = 10) or 10 % ethanol (n = 10) for 20 min. Rats received vehicle, prazosin alone (0.125, 0.25, 0.5, and 1.0 mg/kg, intraperitoneally (IP)), or prazosin in combination with propranolol (5 mg/kg (IP); Exp. 1) or in combination with naltrexone (0.03 mg/kg, subcutaneously (SC); Exp. 2). For Exp. 1, prazosin alone effectively decreased sucrose seeking more than ethanol seeking, but decreased ethanol self-administration only. Propranolol alone effectively decreased ethanol seeking more than sucrose seeking and decreased ethanol intake only. At some dose combinations, there was a greater attenuation of ethanol and sucrose intake relative to either drug alone. For Exp. 2, prazosin alone and naltrexone alone were effective in decreasing ethanol seeking and intake only. Combination treatment was more effective than either drug alone at decreasing ethanol seeking and consumption and sucrose intake, but not sucrose seeking. Propranolol and naltrexone alone were specific to ethanol indicating that low doses of either medication may be beneficial in treating alcohol use disorders. Prazosin in combination with propranolol or naltrexone was more effective than either drug alone and also reduced sucrose-reinforced behaviors. These data suggest that the noradrenergic system is a viable target for developing treatment approaches for problem drinkers.

  11. Low-Dose Prazosin Alone and in Combination with Propranolol or Naltrexone: Effects on Ethanol- and Sucrose-Seeking and Self-Administration in the P Rat

    PubMed Central

    Verplaetse, Terril L.; Czachowski, Cristine L.

    2015-01-01

    Rationale Evidence suggests that the noradrenergic system mediates ethanol-reinforcement. However, preclinical studies suggest that noradrenergic antagonists block other oral reinforcers indicating possible unwanted secondary medication effects. Methods This study examined combinations of low-dose prazosin with propranolol or naltrexone using a behavioral paradigm that separately assesses reinforcer-seeking and self-administration. Male alcohol-preferring (P) rats (n=20/experiment) were trained to complete a response requirement (RR) resulting in access to 1% sucrose (n=10) or 10% ethanol (n=10) for 20min. Rats received vehicle, prazosin alone (0.125, 0.25, 0.5, 1.0 mg/kg; intraperitoneally (IP)) or prazosin in combination with propranolol (5 mg/kg (IP); Exp1) or in combination with naltrexone (0.03 mg/kg (subcutaneously (SC); Exp2). Results For Exp1, prazosin alone effectively decreased sucrose-seeking more than ethanol-seeking, but decreased ethanol self-administration only. Propranolol alone effectively decreased ethanol-seeking more than sucrose-seeking and decreased ethanol intake only. At some dose combinations, there was a greater attenuation of ethanol and sucrose intake relative to either drug alone. For Exp2, prazosin alone and naltrexone alone were effective in decreasing ethanol-seeking and intake only. Combination treatment was more effective than either drug alone at decreasing ethanol-seeking and consumption and sucrose intake, but not sucrose-seeking. Conclusions Propranolol and naltrexone alone were specific to ethanol indicating that low doses of either medication may be beneficial in treating alcohol use disorders. Prazosin in combination with propranolol or naltrexone was more effective than either drug alone, but also reduced sucrose-reinforced behaviors. These data suggest that the noradrenergic system is a viable target for developing treatment approaches for problem drinkers. PMID:25743758

  12. Single Prazosin Infusion in Prelimbic Cortex Fosters Extinction of Amphetamine-Induced Conditioned Place Preference.

    PubMed

    Latagliata, Emanuele C; Lo Iacono, Luisa; Chiacchierini, Giulia; Sancandi, Marco; Rava, Alessandro; Oliva, Valeria; Puglisi-Allegra, Stefano

    2017-01-01

    Exposure to drug-associated cues to induce extinction is a useful strategy to contrast cue-induced drug seeking. Norepinephrine (NE) transmission in medial prefrontal cortex has a role in the acquisition and extinction of conditioned place preference induced by amphetamine. We have reported recently that NE in prelimbic cortex delays extinction of amphetamine-induced conditioned place preference (CPP). A potential involvement of α1-adrenergic receptors in the extinction of appetitive conditioned response has been also suggested, although their role in prelimbic cortex has not been yet fully investigated. Here, we investigated the effects of the α1-adrenergic receptor antagonist prazosin infusion in the prelimbic cortex of C57BL/6J mice on expression and extinction of amphetamine-induced CPP. Acute prelimbic prazosin did not affect expression of amphetamine-induced CPP on the day of infusion, while in subsequent days it produced a clear-cut advance of extinction of preference for the compartment previously paired with amphetamine (Conditioned stimulus, CS). Moreover, prazosin-treated mice that had extinguished CS preference showed increased mRNA expression of brain-derived neurotrophic factor ( BDNF ) and post-synaptic density 95 ( PSD-95 ) in the nucleus accumbens shell or core, respectively, thus suggesting that prelimbic α1-adrenergic receptor blockade triggers neural adaptations in subcortical areas that could contribute to the extinction of cue-induced drug-seeking behavior. These results show that the pharmacological blockade of α1-adrenergic receptors in prelimbic cortex by a single infusion is able to induce extinction of amphetamine-induced CPP long before control (vehicle) animals, an effect depending on contingent exposure to retrieval, since if infused far from or after reactivation it did not affect preference. Moreover, they suggest strongly that the behavioral effects depend on post-treatment neuroplasticity changes in corticolimbic network

  13. The alpha1-adrenergic antagonist prazosin ameliorates combat trauma nightmares in veterans with posttraumatic stress disorder: a report of 4 cases.

    PubMed

    Raskind, M A; Dobie, D J; Kanter, E D; Petrie, E C; Thompson, C E; Peskind, E R

    2000-02-01

    Central nervous system (CNS) adrenergic hyperresponsiveness may be involved in the pathophysiology of posttraumatic stress disorder (PTSD). Two Vietnam combat veterans with PTSD prescribed the centrally active alpha1-adrenergic antagonist prazosin for symptoms of benign prostatic hypertrophy unexpectedly reported elimination of combat trauma nightmares. This observation prompted an open-label feasibility trial of prazosin for combat trauma nightmares in chronic combat-induced PTSD. Four consecutively identified combat veterans with chronic DSM-IV PTSD and severe intractable combat trauma nightmares participated in an 8-week open trial of escalating-dose prazosin. Nightmare severity response was rated using the nightmare item of the Clinician Administered PTSD Scale and the Clinical Global Impressions-Change scale. The 2 patients who achieved a daily prazosin dose of at least 5 mg were markedly improved, with complete elimination of trauma nightmares and resumption of normal dreaming. The 2 subjects limited to 2 mg of prazosin to avoid excessive blood pressure reduction were moderately improved with at least 50% reduction in nightmare severity. These clinical observations, together with neurobiological evidence for alpha1-adrenergic regulation of CNS neurobiological systems relevant to PTSD, provide rationale for placebo-controlled trials of prazosin for PTSD combat trauma nightmares.

  14. Time-Dependent Effects of Prazosin on the Development of Methamphetamine Conditioned Hyperactivity and Context-Specific Sensitization in Mice

    PubMed Central

    White, André O.; Rauhut, Anthony S.

    2014-01-01

    The present experiments examined the effects of prazosin, a selective α1-adrenergic receptor antagonist, on the development of methamphetamine conditioned hyperactivity and context-specific sensitization. Mice received an injection of vehicle (distilled water) or prazosin (0.5, 1.0 or 2.0 mg/kg) 30 minutes prior to a second injection of vehicle (saline) or methamphetamine (1.0 mg/kg) during the conditioning sessions (Experiment 1). Following the conditioning sessions, mice were tested for conditioned hyperactivity and then tested for context-specific sensitization. In subsequent experiments, mice received an injection of vehicle (distilled water) or prazosin (2.0 mg/kg) immediately (Experiment 2) or 24 hours (Experiment 3) after the conditioning sessions and then tested for conditioned hyperactivity and context-specific sensitization. Prazosin dose-dependently blocked the development of methamphetamine conditioned hyperactivity and context-specific sensitization when administered prior to the methamphetamine during the conditioning phase; however nonspecific motor impairments also were observed (Experiment 1). Immediate (Experiment 2), but not the 24-hour delay (Experiment 3), post-session administration of prazosin attenuated the development of methamphetamine conditioned hyperactivity and context-specific sensitization. Nonspecific motor impairments were not observed in these latter experiments. Collectively, these results suggest that the α1-adrenergic receptor mediates the development of methamphetamine-conditioned hyperactivity and context-specific sensitization, perhaps by altering memory consolidation and/or reconsolidation processes. PMID:24487011

  15. Chronic treatment with prazosin or duloxetine lessens concurrent anxiety-like behavior and alcohol intake: evidence of disrupted noradrenergic signaling in anxiety-related alcohol use

    PubMed Central

    Skelly, Mary J; Weiner, Jeff L

    2014-01-01

    Background Alcohol use disorders have been linked to increased anxiety, and enhanced central noradrenergic signaling may partly explain this relationship. Pharmacological interventions believed to reduce the excitatory effects of norepinephrine have proven effective in attenuating ethanol intake in alcoholics as well as in rodent models of ethanol dependence. However, most preclinical investigations into the effectiveness of these drugs in decreasing ethanol intake have been limited to acute observations, and none have concurrently assessed their anxiolytic effects. The purpose of these studies was to examine the long-term effectiveness of pharmacological interventions presumed to decrease norepinephrine signaling on concomitant ethanol self-administration and anxiety-like behavior in adult rats with relatively high levels of antecedent anxiety-like behavior. Methods Adult male Long-Evans rats self-administered ethanol on an intermittent access schedule for eight to ten weeks prior to being implanted with osmotic minipumps containing either an a1-adrenoreceptor antagonist (prazosin, 1.5 mg/kg/day), a β1/2-adrenoreceptor antagonist (propranolol, 2.5 mg/kg/day), a serotonin/norepinephrine reuptake inhibitor (duloxetine, 1.5 mg/kg/day) or vehicle (10% dimethyl sulfoxide). These drugs were continuously delivered across four weeks, during which animals continued to have intermittent access to ethanol. Anxiety-like behavior was assessed on the elevated plus maze before treatment and again near the end of the drug delivery period. Results Our results indicate that chronic treatment with a low dose of prazosin or duloxetine significantly decreases ethanol self-administration (P < 0.05). Furthermore, this decrease in drinking is accompanied by significant reductions in the expression of anxiety-like behavior (P < 0.05). Conclusions These findings suggest that chronic treatment with putative inhibitors of central noradrenergic signaling may attenuate ethanol intake via a

  16. Chronic treatment with prazosin or duloxetine lessens concurrent anxiety-like behavior and alcohol intake: evidence of disrupted noradrenergic signaling in anxiety-related alcohol use.

    PubMed

    Skelly, Mary J; Weiner, Jeff L

    2014-07-01

    Alcohol use disorders have been linked to increased anxiety, and enhanced central noradrenergic signaling may partly explain this relationship. Pharmacological interventions believed to reduce the excitatory effects of norepinephrine have proven effective in attenuating ethanol intake in alcoholics as well as in rodent models of ethanol dependence. However, most preclinical investigations into the effectiveness of these drugs in decreasing ethanol intake have been limited to acute observations, and none have concurrently assessed their anxiolytic effects. The purpose of these studies was to examine the long-term effectiveness of pharmacological interventions presumed to decrease norepinephrine signaling on concomitant ethanol self-administration and anxiety-like behavior in adult rats with relatively high levels of antecedent anxiety-like behavior. Adult male Long-Evans rats self-administered ethanol on an intermittent access schedule for eight to ten weeks prior to being implanted with osmotic minipumps containing either an a1-adrenoreceptor antagonist (prazosin, 1.5 mg/kg/day), a β1/2-adrenoreceptor antagonist (propranolol, 2.5 mg/kg/day), a serotonin/norepinephrine reuptake inhibitor (duloxetine, 1.5 mg/kg/day) or vehicle (10% dimethyl sulfoxide). These drugs were continuously delivered across four weeks, during which animals continued to have intermittent access to ethanol. Anxiety-like behavior was assessed on the elevated plus maze before treatment and again near the end of the drug delivery period. Our results indicate that chronic treatment with a low dose of prazosin or duloxetine significantly decreases ethanol self-administration (P < 0.05). Furthermore, this decrease in drinking is accompanied by significant reductions in the expression of anxiety-like behavior (P < 0.05). These findings suggest that chronic treatment with putative inhibitors of central noradrenergic signaling may attenuate ethanol intake via a reduction in anxiety-like behavior.

  17. pKI values of prazosin and idazoxan for receptors stimulated by neuronally released transmitter in the epididymal portion of rat isolated vas deferens.

    PubMed

    Mackay, D; Kengatharan, M

    1994-01-01

    1. A new method has been used to measure pKI values of prazosin and idazoxan against neuronally-released transmitter in the epididymal portion of the rat isolated vas deferens. The most reproducible results were obtained with a prolonged antagonist equilibration time (1 h). 2. Under these conditions the pKI of prazosin was practically unaffected by addition of alpha, beta-methylene-adenosine-5'-triphosphate (10 microM) to desensitize purinoceptors. Addition of desmethylimipramine (DMI) (0.3 microM) produced a small, but statistically non-significant, reduction. 3. The same method has been used to measure the pKI of prazosin against exogenous noradrenaline. In the latter case addition of DMI (0.3 microM) and corticosterone (30 microM) together produced a statistically significant reduction in the apparent pKI of prazosin. 4. The new method for estimating pKI values shows that DMI itself acts either pseudo-irreversibly or non-competitively and may be reducing the apparent pKI of prazosin. 5. The pKI values obtained for prazosin and idazoxan against neuronally-released transmitter are in good agreement with those obtained by other workers for the actions of these drugs on alpha-adrenoceptors.

  18. Time-dependent effects of prazosin on the development of methamphetamine conditioned hyperactivity and context-specific sensitization in mice.

    PubMed

    White, André O; Rauhut, Anthony S

    2014-04-15

    The present experiments examined the effects of prazosin, a selective α₁-adrenergic receptor antagonist, on the development of methamphetamine conditioned hyperactivity and context-specific sensitization. Mice received an injection of vehicle (distilled water) or prazosin (0.5, 1.0 or 2.0 mg/kg) 30 min prior to a second injection of vehicle (saline) or methamphetamine (1.0 mg/kg) during the conditioning sessions (Experiment 1). Following the conditioning sessions, mice were tested for conditioned hyperactivity and then tested for context-specific sensitization. In subsequent experiments, mice received an injection of vehicle (distilled water) or prazosin (2.0 mg/kg) immediately (Experiment 2) or 24 h (Experiment 3) after the conditioning sessions and then tested for conditioned hyperactivity and context-specific sensitization. Prazosin dose-dependently blocked the development of methamphetamine conditioned hyperactivity and context-specific sensitization when administered prior to the methamphetamine during the conditioning phase; however nonspecific motor impairments also were observed (Experiment 1). Immediate (Experiment 2), but not the 24-h delay (Experiment 3), post-session administration of prazosin attenuated the development of methamphetamine conditioned hyperactivity and context-specific sensitization. Nonspecific motor impairments were not observed in these latter experiments. Collectively, these results suggest that the α₁-adrenergic receptor mediates the development of methamphetamine-conditioned hyperactivity and context-specific sensitization, perhaps by altering memory consolidation and/or reconsolidation processes. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Prazosin + naltrexone decreases alcohol drinking more effectively than does either drug alone in P rats with a protracted history of extensive voluntary alcohol drinking, dependence and multiple withdrawals

    PubMed Central

    Rasmussen, Dennis D; Kincaid, Carrie L; Froehlich, Janice C

    2015-01-01

    Background Prazosin (PRZ, an α1-adrenergic receptor antagonist) and naltrexone (NTX, a non-specific opioid receptor antagonist) each decrease alcohol drinking when administered to rats selectively-bred for high voluntary alcohol drinking (alcohol-preferring, or “P”), and the combination of PRZ+NTX decreases alcohol drinking more effectively than does either drug alone. Since drug responsiveness can depend on history of alcohol drinking and dependence, we investigated whether various schedules of PRZ and NTX administration, alone or in combination, are effective in decreasing alcohol drinking in male P rats with a history of protracted voluntary alcohol drinking, dependence and repeated withdrawals closely resembling human alcoholism. Methods Male P rats became alcohol-dependent during 1 year of ad libitum 24 h/day access to food, water and 20% alcohol with repetitive temporary alcohol withdrawals. Four sequential studies then addressed effects of oral PRZ (2 mg/kg) and NTX (10 mg/kg), alone or together, on alcohol drinking during: 1) daily alcohol access with daily drug treatment, 2) intermittent alcohol access with daily drug treatment, 3) intermittent alcohol access with occasional drug treatment, and 4) post-deprivation reinstatement of alcohol access. Results The combination of PRZ+NTX consistently suppressed alcohol drinking during daily or intermittent alcohol access conditions and when drug treatment was either daily or occasional. PRZ+NTX was consistently more effective than either drug alone. The reduction in alcohol drinking was not due to sedation, motor effects or malaise. Conclusions Both daily and “as-needed” treatment with PRZ+NTX are highly effective in suppressing daily, intermittent and post-deprivation alcohol drinking in male P rats with a protracted history of alcohol dependence and repeated withdrawals. This drug combination may be especially effective for treating individuals with long histories of heavy alcohol abuse, dependence and

  20. Antagonistic effects of atipamezole, yohimbine, and prazosin on xylazine-induced diuresis in clinically normal cats

    PubMed Central

    Murahata, Yusuke; Miki, Yuya; Hikasa, Yoshiaki

    2014-01-01

    This study aimed to investigate and compare the antagonistic effects of atipamezole, yohimbine, and prazosin on xylazine-induced diuresis in clinically normal cats. Five cats were repeatedly used in each of the 9 groups. One group was not medicated. Cats in the other groups received 2 mg/kg BW xylazine intramuscularly, and saline (as the control); 160 μg/kg BW prazosin; or 40, 160, or 480 μg/kg BW atipamezole or yohimbine intravenously 0.5 h later. Urine and blood samples were collected 10 times over 8 h. Urine volume, pH, and specific gravity; plasma arginine vasopressin (AVP) concentration; and creatinine, osmolality, and electrolyte values in both urine and plasma were measured. Both atipamezole and yohimbine antagonized xylazine-induced diuresis, but prazosin did not. The antidiuretic effect of atipamezole was more potent than that of yohimbine but not dose-dependent, in contrast to the effect of yohimbine at the tested doses. Both atipamezole and yohimbine reversed xylazine-induced decreases in both urine specific gravity and osmolality, and the increase in free water clearance. Glomerular filtration rate, osmolar clearance, and plasma electrolyte concentrations were not significantly altered. Antidiuresis of either atipamezole or yohimbine was not related to the area under the curve for AVP concentration, although the highest dose of both atipamezole and yohimbine increased plasma AVP concentration initially and temporarily, suggesting that this may in part influence antidiuretic effects of both agents. The diuretic effect of xylazine in cats may be mediated by α2-adrenoceptors but not α1-adrenoceptors. Atipamezole and yohimbine can be used as antagonistic agents against xylazine-induced diuresis in clinically normal cats. PMID:25356000

  1. Impairment of contextual conditioned fear extinction after microinjection of alpha-1-adrenergic blocker prazosin into the medial prefrontal cortex.

    PubMed

    Do-Monte, Fabrício H M; Allensworth, Melody; Carobrez, Antônio P

    2010-07-29

    Long-lasting memories of aversive or stressful events have been associated with the noradrenergic system activation. Alpha-1-adrenergic antagonist prazosin has successfully been used in the last years to treat anxiety disorders related to aversive memories recurrence in humans. Contextual conditioned fear extinction paradigm in rats has been used to better understand the mechanisms involved in the attenuation of defensive behaviour after a traumatic situation. Here we investigated the effects of systemic administration of prazosin in the fear extinction processes. Rats were previously paired in a contextual fear conditioning box (1 footshock, 1 mA, 2s duration), further returning to the same box during three consecutive days receiving an intraperitoneal injection of vehicle or prazosin 30 min before (acquisition of extinction; 0.1 or 0.5mg/kg) or immediately after (consolidation of extinction, 0.5 or 1.5mg/kg) each extinction session (10 min). On the last day, all animals were re-exposed undrugged to the apparatus. Since the medial prefrontal cortex (mPFC) has been described as a key structure in the modulation of conditioned fear extinction, the effects of intra-mPFC microinjection (0.2 microl per side) of vehicle (PBS) or prazosin (0.75 or 2.5 nmol) in the acquisition of fear extinction (10 min before extinction session 1) were further evaluated. Subjects were drug-free re-exposed to the same box in the next day (extinction session 2). The percentage of freezing time was used as the memory retention parameter. The results showed that either systemic or intra-mPFC-alpha-1-adrenergic blockade increased the freezing time in the last extinction sessions, suggesting impairment of the extinction of contextual conditioned fear in rats. Copyright 2010 Elsevier B.V. All rights reserved.

  2. Delivery of prazosin hydrochloride from osmotic pump system prepared by coating the core tablet with an indentation.

    PubMed

    Liu, Longxiao; Wang, Jinchao; Zhu, Suyan

    2007-04-01

    The preparation of an osmotic pump tablet was simplified by elimination of laser drilling using prazosin hydrochloride as the model drug. The osmotic pump system was obtained by coating the indented core tablet compressed by the punch with a needle. A multiple regression equation was achieved with the experimental data of core tablet formulations, and then the formulation was optimized. The influences of the indentation size of the core tablet, environmental media, and agitation rate on drug release profile were investigated. The optimal osmotic pump tablet was found to deliver prazosin hydrochloride at an approximately constant rate up to 24 hr, and independent on both release media and agitation rate. Indentation size of core tablet hardly affected drug release in the range of 0.80-1.15 mm. The method that is simplified by elimination of laser drilling may be promising for preparation of an osmotic pump tablet.

  3. Prazosin for Prophylaxis of Chronic Post Traumatic Headaches in OEF/OIF/OND Service Members and Veterans with Mild TBI

    DTIC Science & Technology

    2016-10-01

    compared to placebo on HA frequency, HA severity and duration, use of abortive /analgesic medications, and HA-related disability. Specific Aim 2: To...the effect of prazosin compared to placebo on post- traumatic HA frequency, severity, duration, use of abortive /analgesic medications, and HA-related

  4. Losartan Attenuates Myocardial Endothelial-To-Mesenchymal Transition in Spontaneous Hypertensive Rats via Inhibiting TGF-β/Smad Signaling.

    PubMed

    Wu, Miao; Peng, Zhenyu; Zu, Changhao; Ma, Jing; Lu, Shijuan; Zhong, Jianghua; Zhang, Saidan

    2016-01-01

    Losartan plays an important role in the inhibition of myocardial fibrosis. But the underlying mechanism is not entirely clear. Emerging evidences have indicated that endothelial-to-mesenchymal transition (EndMT) plays a crucial role in cardiac fibrosis. Here the present study aims to first investigated the effect of Losartan on EndMT in cardiac fibrosis of spontaneous hypertensive rats (SHRs). Male SHRs were randomly divided into three groups and fed for 12 weeks, namely the SHR group (Group S), the Losartan-treated group (Group L) and the Prazosin-treated group (Group P). Wistar-Kyoto rats served as controls (Group W). The histological changes were evaluated by Masson's trichrome. Co-expression of CD31 and fibroblast-specific protein 1 (FSP1) were used as the markers of EndMT through immunofluorescence. The expressions of FSP1, CD31, TGF-β, Smad were detected by Western blot analysis. It was identified that elevated blood pressure induced a significant increase in myocardial fibrosis and EndMT in SHRs, which was reversed by Losartan and Prazosin treatment. Furthermore, the activity of TGF-β/Smad signaling was detected in the four groups. TGF-β/Smad signaling was activated in SHRs and suppressed by Losartan or Prazosin treatment. Losartan exhibited more efficiently than Prazosin in inhibiting TGF-β/Smad signaling activation, EndMT and myocardial fibrosis. These results showed that EndMT played an important role in promoting hypertensive cardiac fibrosis, and that losartan could suppress cardiac fibrosis through the inhibition of EndMT via classical TGF-β/Smad pathway.

  5. Suppressed pituitary ACTH response after ACTH treatment of infantile spasms.

    PubMed

    Ross, D L

    1986-01-01

    Suppression of an adrenocorticotropic hormone (ACTH) response to insulin hypoglycemia has been reported in ACTH-treated adults. There are no guidelines for withdrawal of ACTH treatment in children. After observing suppressed morning cortisol in several children, insulin tolerance tests were performed in five children within 48 hours after tapered withdrawal of ACTH treatment for myoclonic seizures. ACTH response, as determined by cortisol and beta-endorphin radioimmunoassay, was adequate in four of the children. One child showed low basal levels and minimal elevation during hypoglycemia for both beta-endorphin (0 to 3 pg/ml) and cortisol (3.6 to 4.4 micrograms/dL) on initial testing, but normal responses six weeks later. Measurement of beta-endorphin response supported a central basis for suppression in the child, who had had an adrenal hemorrhage during gram-negative sepsis while on ACTH. ACTH release is transiently suppressed in some children after exogenous ACTH treatment. Tapered withdrawal and stress coverage is recommended.

  6. Long-term effect of prazosin and losartan administration on blood pressure, heart, carotid artery, and acetylcholine induced dilation of cardiovascular system of young Wistar rats and SHR.

    PubMed

    Kristek, Frantisek; Malekova, Magdalena; Cacanyiova, Sona

    2013-06-01

    The long-term effects of prazosin and losartan administration on blood pressure, trophicity of the heart and carotid arteries, and responses of the cardiovascular system to acetylcholine, were studied in Wistar rats and spontaneously hypertensive rats (SHRs). Four-week-old rats were treated with prazosin (10 mg/kg b.w./day in tap water) or losartan (20 mg/kg b.w./day in tap water) for 5-6 weeks. BP was measured by plethysmographic method. Ten animals of each group were subjected to in vivo studies and subsequent to morphological investigations. The right jugular vein was cannulated for administration of acetylcholine (0.1, 1, and 10 µg). After perfusion with a glutaraldehyde fixative (120 mmHg), the carotid arteries were embedded in Durcupan ACM, and the inner diameter (ID), wall thickness (WT) (tunica intima and media), cross sectional area (CSA) (tunica intima and media), and WT/ID ratio were calculated. In Wistar rats and SHRs, prazosin and losartan administration produced a decrease in the blood pressure and trophicity of the heart. In Wistar rats, both drugs decreased the WT, CSA, and the WT/ID ratio. In addition, these drugs increased the circumferential stress of the artery without affecting the ID. In contrast, in the SHRs, only losartan administration produced these effects. Importantly, both the drugs improved the responses to acetylcholine in SHRs.

  7. The measurement and treatment of suppression in amblyopia.

    PubMed

    Black, Joanna M; Hess, Robert F; Cooperstock, Jeremy R; To, Long; Thompson, Benjamin

    2012-12-14

    neither eye has a performance advantage is a measure of the "balance point" and is a direct measure of suppression. This technique has been validated psychophysically both in control(13,14) and patient(6,9,11) populations. In addition to measuring suppression this technique also forms the basis of a novel form of treatment to decrease suppression over time and improve binocular and often monocular function in adult patients with amblyopia(12,15,16) . This new treatment approach can be deployed either on the goggle system described above or on a specially modified iPod touch device(15).

  8. Effect of Prazosin and Naltrexone on Script Induced Alcohol Craving in Veterans with Alcohol Use Disorders with and without Co-occurring PTSD

    DTIC Science & Technology

    2015-01-01

    status, moderate medication response. 15. SUBJECT TERMS Alcohol Drinking, Drinking Behavior, Naltrexone, Prazosin, Adrenergic Agents, Adrenergice ...primates and humans express α1 adrenergic receptors. Given the interplay of the noradrenergic system with craving-related brain systems, blocking α1...Antagonists, Adrenergic alpha-1 receptor antagonists, Adrenergic alpha- antagonists, Antihypertensive agents, Narcotic antagonists, Therapeutic uses

  9. Prazosin for Prophylaxis of Chronic Post Traumatic Headaches in OEF/OIF/OND Service Members and Veterans with Mild TBI

    DTIC Science & Technology

    2017-10-01

    does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 1. REPORT DATE October 2017 2. REPORT TYPE...comes from a large open-label case series in Iraq and Afghanistan Veterans with mTBI and posttraumatic headaches and data from a placebo- controlled trial...will be accomplished by conducting a randomized placebo- controlled double blind trial of prazosin vs placebo in 160 Iraq/Afghanistan active-duty

  10. Effect of Prazosin and Naltrexone on Script Induced Alcohol Craving in Veterans with Alcohol Use Disorders with and without Co-occurring PTSD

    DTIC Science & Technology

    2017-01-01

    associated with continued problematic use and relapse is craving. Three different types of craving have been hypothesized, reward , relief, and obsessive...and each is postulated to be mediated by different neurological substrates. The neural networks postulated to subserve reward and relief craving...noradrenergic system with craving-related brain systems , blocking α1 receptors with the noradrenergic antagonist, prazosin, theoretically has the

  11. Effect of alpha-adrenoceptor antagonists (phentolamine, nicergoline and prazosin) on reperfusion arrhythmias and noradrenaline release in perfused rat heart.

    PubMed Central

    Bralet, J.; Didier, J.; Moreau, D.; Opie, L. H.; Rochette, L.

    1985-01-01

    Rat isolated hearts were perfused through the left atrium with a modified Krebs-Henseleit solution or mounted on a Langendorff perfusion system. The hearts were prelabelled with [3H]-noradrenaline [( 3H]-NA) and the left main coronary artery was ligated for 10 min after which reperfusion followed. The liberation of [3H]-NA and the development of ventricular tachycardia and fibrillation were monitored throughout. During the occlusion period, ventricular arrhythmias did not occur and heart rate was not significantly altered in the control series. In contrast, reperfusion was followed by ventricular fibrillation and ventricular tachycardia in all the hearts in the control series (Langendorff or 'working' models). The alpha-adrenoceptor antagonists phentolamine (7.1 X 10(-6) M and 7.1 X 10(-5) M) and nicergoline (3.1 X 10(-6) M) diminished or prevented reperfusion arrhythmias. However, prazosin (5.2 X 10(-6) M) was not effective. The lower concentration of phentolamine did not alter the pattern of [3H]-NA release, whereas, high doses of phentolamine and nicergoline increased the release of [3H]-NA. Prazosin (5.2 X 10(-6) M) caused a very marked increase in release of [3H]-NA but was not antiarrhythmic. A 'membrane-stabilizing' effect seems the most appropriate explanation for these antiarrhythmic effects of alpha-antagonist agents. PMID:2858234

  12. Hazardous fuel treatments, suppression cost impacts, and risk mitigation

    Treesearch

    Matthew P. Thompson; Michael S. Hand; Julie W. Gilbertson-Day; Nicole M. Vaillant; Darek J. Nalle

    2013-01-01

    Land management agencies face uncertain tradeoffs regarding investments in preparedness and fuels management versus future suppression costs and impacts to valued resources and assets. Prospective evaluation of fuel treatments allows for comparison of alternative treatment strategies in terms of socioeconomic and ecological impacts, and can facilitate tradeoff analysis...

  13. Impact of methamphetamine precursor chemical legislation, a suppression policy, on the demand for drug treatment.

    PubMed

    Cunningham, James K; Liu, Lon-Mu

    2008-04-01

    Research is needed to help treatment programs plan for the impacts of drug suppression efforts. Studies to date indicate that heroin suppression may increase treatment demand. This study examines whether treatment demand was impacted by a major US methamphetamine suppression policy -- legislation regulating precursor chemicals. The precursors ephedrine and pseudoephedrine, in forms used by large-scale methamphetamine producers, were regulated in August 1995 and October 1997, respectively. ARIMA-intervention time-series analysis was used to examine the impact of each precursor's regulation on monthly voluntary methamphetamine treatment admissions (a measure of treatment demand), including first-time admissions and re-admissions, in California (1992-2004). Cocaine, heroin, and alcohol treatment admissions were used as quasi-control series. The 1995 regulation of ephedrine was found to be associated with a significant reduction in methamphetamine treatment admissions that lasted approximately 2 years. The 1997 regulation of pseudoephedrine was associated with a significant reduction that lasted approximately 4 years. First-time admissions declined more than re-admissions. Cocaine, heroin, and alcohol admissions were generally unaffected. While heroin suppression may be associated with increased treatment demand as suggested by research to date, this study indicates that methamphetamine precursor regulation was associated with decreases in treatment demand. A possible explanation is that, during times of suppression, heroin users may seek treatment to obtain substitute drugs (e.g., methadone), while methamphetamine users have no comparable incentive. Methamphetamine suppression may particularly impact treatment demand among newer users, as indicated by larger declines in first-time admissions.

  14. The prednisolone suppression test in depression: Dose—response and changes with antidepressant treatment

    PubMed Central

    Juruena, Mario F.; Cleare, Anthony J.; Papadopoulos, Andrew S.; Poon, Lucia; Lightman, Stafford; Pariante, Carmine M.

    2010-01-01

    Summary Depressed patients have reduced glucocorticoid receptor (GR) function, as demonstrated by resistance to the suppressive effects of the synthetic glucocorticoid hormone, and GR agonist, dexamethasone. We have developed a suppressive test with prednisolone, a synthetic glucocorticoid that is similar to cortisol in its pharmacodynamics and pharmacokinetics, and binds to both the GR and the mineralocorticoid receptor (MR). We have found that depressed patients suppress normally to prednisolone, unless they are particularly non-responsive to treatment. In the present study, we evaluated 28 inpatients with treatment-resistant depression (TRD), and compared salivary cortisol secretion (at 0900 h, 1200 h and 1700 h) after placebo or after prednisolone (5 mg), before and after an inpatient treatment admission. Half of the patients (n = 14) reached treatment response. When comparing the assessment between admission and discharge, cortisol output after placebo fell (−26% of area under the curve; p = 0.024) while the output after prednisolone did not change. Moreover, there was no change in the response to prednisolone (percentage suppression) between admission at discharge, and this was not influenced by treatment response. Finally, we could confirm and extend our previously published data with prednisolone (5 mg), showing that depressed patients (n = 12) and controls (n = 12) suppressed equally to both 5 and 10 mg doses of prednisolone. This study suggests that the response to prednisolone is similar in depressed patients and controls at different doses of prednisolone, and does not change with symptomatic improvement. This is in contrast with findings, from us and others, using other measures of hypothalamic—pituitary—adrenal axis function, such as basal cortisol levels or the response to dexamethasone. Thus, we propose that the prednisolone suppression test may offer specific biological and clinical information, related to its action at both the GR and the MR

  15. Quiet engine program: Turbine noise suppression. -Volume 1: General treatment evaluation and measurement techniques

    NASA Technical Reports Server (NTRS)

    Clemons, A.; Hehmann, H.; Radecki, K.

    1973-01-01

    Acoustic treatment was developed for jet engine turbine noise suppression. Acoustic impedance and duct transmission loss measurements were made for various suppression systems. An environmental compatibility study on several material types having suppression characteristics is presented. Two sets of engine hardware were designed and are described along with engine test results which include probe, farfield, near field, and acoustic directional array data. Comparisons of the expected and the measured suppression levels are given as well as a discussion of test results and design techniques.

  16. The relation of weight suppression and body mass index to symptomatology and treatment response in anorexia nervosa

    PubMed Central

    Berner, Laura A.; Shaw, Jena A.; Witt, Ashley A.; Lowe, Michael R.

    2013-01-01

    Weight suppression, the difference between highest past weight and current weight, is a robust predictor of clinical characteristics of bulimia nervosa; however, the influence of weight suppression in anorexia nervosa (AN) has been little studied, and no study to date has investigated the ways in which the relevance of weight suppression in AN may depend upon an individual’s current body mass index (BMI). The present study investigated weight suppression, BMI, and their interaction as cross-sectional and prospective predictors of psychological symptoms and weight in AN. Women with AN completed depression (Beck Depression Inventory-II) and eating disorder symptomatology measures (Eating Disorder Examination Questionnaire and Eating Disorders Inventory-3) at residential treatment admission (N = 350) and discharge (N = 238). Weight suppression and BMI were weakly correlated (r = −.22). At admission, BMI was positively correlated with all symptom measures except Restraint and depression scores. Weight suppression was also independently positively correlated with all measures except Weight Concern and Body Dissatisfaction subscale scores. In analyses examining discharge scores (including admission values as covariates), the admission weight suppression X BMI interaction consistently predicted post-treatment psychopathology. Controlling for weight gain in treatment and age, higher admission weight suppression predicted lower discharge scores (less symptom endorsement) among those with lower BMIs; among those with higher BMIs, higher weight suppression predicted higher discharge scores. These results are the first to demonstrate that absolute and relative weight status are joint indicators of AN severity and prognosis. These findings may have major implications for conceptualization and treatment of AN. PMID:24016010

  17. Modeling fuel treatment leverage: Encounter rates, risk reduction, and suppression cost impacts

    Treesearch

    Matthew P. Thompson; Karin L. Riley; Dan Loeffler; Jessica R. Haas

    2017-01-01

    The primary theme of this study is the cost-effectiveness of fuel treatments at multiple scales of investment. We focused on the nexus of fuel management and suppression response planning, designing spatial fuel treatment strategies to incorporate landscape features that provide control opportunities that are relevant to fire operations. Our analysis explored the...

  18. Prazosin for Treatment of Patients With PTSD and Comorbid Alcohol Dependence

    DTIC Science & Technology

    2013-07-01

    treat individuals with comorbid AD and TSD. The use of an alpha-! adrenergic receptor antagonist represents a novel approach to treatment that may... adrenergic ~ceptor antagonist that has been used successfully in the treatment of trauma nightmares and sleep disturbance in combat veterans with TSD, and...stressor, presented randomly. Outcome measures include self-reported measures of alcohol craving and anxiety . Subjects are subsequently randomized

  19. Ginger Treatment Ameliorates Alcohol-induced Myocardial Damage by Suppression of Hyperlipidemia and Cardiac Biomarkers in Rats.

    PubMed

    Subbaiah, Ganjikunta Venkata; Mallikarjuna, Korivi; Shanmugam, Bhasha; Ravi, Sahukari; Taj, Patan Usnan; Reddy, Kesireddy Sathyavelu

    2017-01-01

    Alcohol-induced hyperlipidemia is positively correlated with cardiovascular diseases. Several herbal extracts have been reported to protect the cardiac injury and suppress the hyperlipidemia. However, the effect of ginger extracts on alcohol-induced hyperlipidemia and associated myocardial damage remains unclear. This study investigated the cardio-protective properties of ginger ethanolic extract (Gt) against alcohol-induced myocardial damage, and further distinguished the association between hyperlipidemia and occurrence of myocardial damage in rats. Twenty four Wistar male albino rats (250 ± 20 g) were divided into four groups including, Normal control (NC) (0.9% NaCl), Ginger treated (Gt) (200 mg/Kg b.w.), Alcohol treated (At) (20% of 6g/kg b.w. alcohol), and Alcohol along with Ginger treatment (At+Gt). In this study, lipid profiles such as fatty acids, triglycerides, total cholesterol, phospholipids, low density lipoprotein and high density lipoproteins, and cardiac biomarkers, including LDH, AST, CK-MB, cTn-T and cTn-I were examined in rats. Furthermore, histopathological studies were also conducted. We found that alcohol-induced myocardial damage was associated with increased lipid profile except high density lipoprotein in alcohol treated (20%, 6g/kg b.w.) rats compared with control. Ginger treatment significantly reduced the alcohol-induced lipid profiles except high density lipoproteins. Furthermore, elevated cardiac biomarkers activity with alcohol intoxication was substantially suppressed by ginger treatment. In addition, ginger treatment for 7-weeks significantly minimized the alcohol-induced myocardial damage. Our results concluded that ginger could protect alcohol-induced myocardial damage by suppression of hyperlipidemia and cardiac biomarkers. Ginger extract could alleviate the myocardial injury partially due to the suppression of circulating FFAs and TG levels.Increased circulating cholesterol, LDL and phospholipids with alcohol intake were

  20. Examining the relative effects of fire weather, suppression and fuel treatment on fire behaviour--a simulation study.

    PubMed

    Penman, T D; Collins, L; Price, O F; Bradstock, R A; Metcalf, S; Chong, D M O

    2013-12-15

    Large budgets are spent on both suppression and fuel treatments in order to reduce the risk of wildfires. There is little evidence regarding the relative contribution of fire weather, suppression and fuel treatments in determining the risk posed from wildfires. Here we undertake a simulation study in the Sydney Basin, Australia, to examine this question using a fire behaviour model (Phoenix Rapidfire). Results of the study indicate that fire behaviour is most strongly influenced by fire weather. Suppression has a greater influence on whether a fire reaches 5 ha in size compared to fuel treatments. In contrast, fuel treatments have a stronger effect on the fire size and maximum distance the fire travels. The study suggests that fire management agencies will receive additional benefits from fuel treatment if they are located in areas which suppression resources can respond rapidly and attempt to contain the fires. No combination of treatments contained all fires, and the proportion of uncontained fires increased under more severe fire weather when the greatest number of properties are lost. Our study highlights the importance of alternative management strategies to reduce the risk of property loss. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

  1. Efficacy and Safety of Gonadotropin-Releasing Hormone Agonist Treatment to Suppress Puberty in Gender Dysphoric Adolescents.

    PubMed

    Schagen, Sebastian E E; Cohen-Kettenis, Peggy T; Delemarre-van de Waal, Henriette A; Hannema, Sabine E

    2016-07-01

    Puberty suppression using gonadotropin-releasing hormone agonists (GnRHas) is recommended by current guidelines as the treatment of choice for gender dysphoric adolescents. Although GnRHas have long been used to treat precocious puberty, there are few data on the efficacy and safety in gender dysphoric adolescents. Therefore, the Endocrine Society guideline recommends frequent monitoring of gonadotropins, sex steroids, and renal and liver function. To evaluate the efficacy and safety of GnRHa treatment to suppress puberty in gender dysphoric adolescents. Forty-nine male-to-female and 67 female-to-male gender dysphoric adolescents treated with triptorelin were included in the analysis. Physical examination, including assessment of Tanner stage, took place every 3 months and blood samples were drawn at 0, 3, and 6 months and then every 6 months. Body composition was evaluated using dual energy x-ray absorptiometry. GnRHa treatment caused a decrease in testicular volume in 43 of 49 male-to-female subjects. In one of four female-to-male subjects who presented at Tanner breast stage 2, breast development completely regressed. Gonadotropins and sex steroid levels were suppressed within 3 months. Treatment did not have to be adjusted because of insufficient suppression in any subject. No sustained abnormalities of liver enzymes or creatinine were encountered. Alkaline phosphatase decreased, probably related to a slower growth velocity, because height SD score decreased in boys and girls. Lean body mass percentage significantly decreased during the first year of treatment in girls and boys, whereas fat percentage significantly increased. Triptorelin effectively suppresses puberty in gender dysphoric adolescents. These data suggest routine monitoring of gonadotropins, sex steroids, creatinine, and liver function is not necessary during treatment with triptorelin. Further studies should evaluate the extent to which changes in height SD score and body composition that occur

  2. Suppression of phytohemagglutinin-induction of thymidine uptake in guinea pig lymphocytes by methylglyoxal bis(guanylhydrazone) treatment.

    PubMed

    Otani, S; Matsui, I; Morisawa, S

    1977-10-18

    Treatment with methylglyoxal bis(guanylhydrazone), a specific inhibitor of S-adenosylmethionine decarboxylase (EC 4.1.1.50), suppressed the phytohemagglutinin-induction of [3H]thymidine uptake by guinea pig lymphocytes. The kinetics of [3H]thymidine uptake revealed that the Km value for thymidine was not changed, but the V value was markedly lowered by the methylglyoxal bis(guanylhydrazone) treatment. The induction of ATP: thymidine 5'-phosphotransferase (EC 2.7.1.75) (thymidine kinase) activity by phytohemagglutinin was suppressed to about the same extent as the induction of thymidine uptake. These suppressions were dependent on the methylglyoxal bis(guanylhydrazone) doses and on duration of the methylglyoxal bis(guanylhydrazone) treatment. Analysis of [3H]thymidine labelled compounds of the acid-soluble fraction showed that conversion of thymidine to thymidine 5'-triphosphate was inhibited by the methylglyoxal bis(guanylhydrazone) treatment. DNA polymerase activity was less inhibited by the methylglyoxal bis(guanylhydrazone) treatment in comparison with the methylglyoxal bis(guanylhydrazone) inhibition of thymidine uptake by whole cells. These results strongly suggested that blocking of polyamine accumulation by the methylglyoxal bis(guanylhydrazone) treatment influenced phytohemagglutinin induction of thymidine phosphorylation, resulting in a decrease of thymidine incorporation into DNA.

  3. Combined aspirin and apatinib treatment suppresses gastric cancer cell proliferation.

    PubMed

    Zhang, Wei; Tan, Yongsheng; Ma, Heping

    2017-11-01

    Gastric cancer (GC), one of the types of tumor most prone to malignancy, is characterized by high lethality. Numerous molecular mediators of GC have been identified, including transcription factors, signaling molecules and non-coding RNAs. Recently, inhibition of angiogenesis has emerged as a potential strategy for GC therapy. In the present study, the levels of vascular endothelial growth factor (VEGF), peroxisome proliferator-activated receptor-α (PPARα) and miR-21 in GC patients and individuals without cancer, and the correlation between VEGF and miR-21, and PPARα and miR-21 expression were analyzed. In addition, the GC MKN45 cell line was treated with apatinib (a tyrosine kinase inhibitor) and aspirin (an activator of the transcription factor, PPARα) to investigate the effects of these compounds on tumorigenesis. Furthermore, the present study attempted to elucidate the molecular mechanisms of alteration of GC tumorigenesis by aspirin and apatinib. The results of the current study demonstrated that there was a higher expression of VEGF and miR-21 in GC tissues compared with that in morphologically adjacent normal tissues whereas PPARα expression was decreased. These results were confirmed in vitro , as treatment of MKN45 cells with VEGF resulted in a significant increase in miR-21 expression and a significant reduction in PPARα protein expression. Furthermore, the inhibitory effects of VEGF on PPARα mRNA and protein expression were demonstrated to be mediated by miR-21. Suppression of PPARα protein expression attenuated the inhibitory effects of miR-21 on the level of PPARα mRNA, thereby enhancing tumorigenesis in gastric cancer. Treatment of MKN45 cells with aspirin reduced the levels of phosphorylated AKT by activating PPARα, whereas treatment with apatinib inhibited the phosphorylation of vascular endothelial growth factor receptor 2 and phosphoinositide-3 kinase in MKN45 cells. Finally, treatment of MKN45 cells with apatinib and aspirin suppressed

  4. Photodynamic therapy with simultaneous suppression of multiple treatment escape pathways (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Spring, Bryan Q.; Sears, R. Bryan; Zheng, Lei Z.; Mai, Zhiming; Watanabe, Reika; Sherwood, Margaret E.; Schoenfeld, David A.; Pogue, Brian W.; Pereira, Stephen P.; Villa, Elizabeth; Hasan, Tayyaba

    2016-03-01

    We introduce photoactivatable multi-inhibitor nanoliposomes (PMILs) for photodynamic tumor cell and microvessel damage in synchrony with photo-initiation of tumor-confined, multikinase inhibitor release. The PMIL is a biodegradable delivery system comprised of a nanoliposome carrying a photoactivable chromophore (benzoporphyrin derivative monoacid A, BPD) in its bilayer. A multikinase inhibitor-loaded PEG-PLGA nanoparticle is encapsulated within the liposome, which acts a barrier to nanoparticle erosion and drug release. Following intravenous PMIL administration, near infrared irradiation of tumors triggers photodynamic therapy and initiates tumor-confined drug release from the nanoparticle. This talk presents promising preclinical data in mouse models of pancreatic cancer utilizing this concept to suppress the VEGF and MET signaling pathways—both critical to cancer progression, metastasis and treatment escape. A single PMIL treatment using low doses of a multikanse inhibitor (cabozantinib, XL184) achieves sustained tumor reduction and suppresses metastatic escape, whereas combination therapy by co-administration of the individual agents has significantly reduced efficacy. The PMIL concept is amenable to a number of molecular inhibitors and offers new prospects for spatiotemporal synchronization of combination therapies whilst reducing systemic drug exposure and associated toxicities.

  5. Specific binding of nicergoline on an alpha1-like adrenoreceptor in the rat retina.

    PubMed

    Lograno, M D; Tricarico, D; Masciopinto, V; Scuderl, A C

    2000-02-01

    Systemic treatment with nicergoline, an ergoline derivative showing alpha1-antagonist properties, causes vasodilatation in the eye without apparent untoward cardiovascular effects. In the present work we investigated the ability of nicergoline to inhibit the binding of radiolabelled prazosin in the rat retina and cortex. We found that nicergoline inhibited [3H]prazosin binding in both tissues, being more potent than unlabelled prazosin in the retinal tissue. The competition curves of the ergoline derivative were well fitted by a one-site model in the cortical tissue, with an IC50 (concentration of the drugs needed to inhibit the binding of labelled prazosin by 50%) of 2.54 x 10(-8) M, and by a two-site model in the retinal tissue, with IC50 values of 7.08 x 10(-12) M and 1.82 x 10(-5) M. 2-(2,6 dimetoxyphenoxyethyl) aminomethyl-1,4-benzodioxane hydrochloride (WB4101) and phentolamine, selective ligands for the high-affinity binding site for prazosin, in particular the alpha1A-site, fully inhibited prazosin binding in the cortex but only partially inhibited prazosin binding in the retina, being less potent in this tissue than either nicergoline or prazosin. Our results suggest that a binding component of alpha1-adrenoreceptors is expressed to a lesser extent in the retina than the cortex, leading to a reduced response of the retinal tissue to prazosin, and more particularly to WB4101 and phentolamine. The selective binding of the nicergoline on this retinal adrenoreceptor may explain the peculiar efficacy of the drug in ocular pathophysiology.

  6. The pressor effect of angiotensin-(1-7) in the rat rostral ventrolateral medulla involves multiple peripheral mechanisms.

    PubMed

    Oliveira, Rita C; Campagnole-Santos, Maria J; Santos, Robson A S

    2013-01-01

    In the present study, the peripheral mechanism that mediates the pressor effect of angiotensin-(1-7) in the rostral ventrolateral medulla was investigated. Angiotensin-(1-7) (25 pmol) was bilaterally microinjected in the rostral ventrolateral medulla near the ventral surface in urethane-anesthetized male Wistar rats that were untreated or treated (intravenously) with effective doses of selective autonomic receptor antagonists (atenolol, prazosin, methyl-atropine, and hexamethonium) or a vasopressin V1 receptor antagonist [d(CH2)5 -Tyr(Me)-AVP] given alone or in combination. Unexpectedly, the pressor response produced by angiotensin-(1-7) (16 ± 2 mmHg, n = 12), which was not associated with significant changes in heart rate, was not significantly altered by peripheral treatment with prazosin, the vasopressin V1 receptor antagonist, hexamethonium or methyl-atropine. Similar results were obtained in experiments that tested the association of prazosin and atenolol; methyl-atropine and the vasopressin V1 antagonist or methyl-atropine and prazosin. Peripheral treatment with the combination of prazosin, atenolol and the vasopressin V1 antagonist abolished the pressor effect of glutamate; however, this treatment produced only a small decrease in the pressor effect of angiotensin-(1-7) at the rostral ventrolateral medulla. The combination of hexamethonium with the vasopressin V1 receptor antagonist or the combination of prazosin, atenolol, the vasopressin V1 receptor antagonist and methyl-atropine was effective in blocking the effect of angiotensin-(1-7) at the rostral ventrolateral medulla. These results indicate that angiotensin-(1-7) triggers a complex pressor response at the rostral ventrolateral medulla that involves an increase in sympathetic tonus, release of vasopressin and possibly the inhibition of a vasodilatory mechanism.

  7. Synergistic suppression of autoimmune arthritis through concurrent treatment with tolerogenic DC and MSC

    PubMed Central

    Li, Rong; Zhang, Yujuan; Zheng, Xiufen; Peng, Shanshan; Yuan, Keng; Zhang, Xusheng; Min, Weiping

    2017-01-01

    Rheumatoid arthritis (RA) is an autoimmune disease characterized by progressive immune-mediated joint deterioration. Current treatments are not antigen specific and are associated with various adverse. We have previously demonstrated that tolerogenic dendritic cells (Tol-DC) are potent antigen-specific immune regulators, which hold great promise in immunotherapy of autoimmune diseases. In this study, we aimed to develop new immunotherapy by combining Tol-DC and mesenchymal stem cells (MSC). We demonstrated that RelB gene silencing resulted in generation of Tol-DC that suppressed T cell responses and selectively promoted Treg generation. The combination of MSC synergized the tolerogenic capacity of Tol-DC in inhibition of T cell responses. In murine collagen-induced arthritis (CIA) model, we demonstrated that progression of arthritis was inhibited with administration of RelB gene-silenced Tol-DC or MSC. This therapeutic effect was remarkably enhanced with concurrent treatment of combination Tol-DC and MSC as demonstrated by improved clinical symptoms, decreased clinical scores and attenuated joint damage. These therapeutic effects were associated with suppression of CII-specific T cell responses, polarization of Th and inhibition of proinflammatory cytokines, and reduced cartilage degeneration. This study for the first time demonstrates a new approach to treat autoimmune inflammatory joint disease with concurrent treatment of RelB gene-silenced Tol-DC and MSC. PMID:28230210

  8. Suppression of ongoing experimental myasthenia by oral treatment with an acetylcholine receptor recombinant fragment

    PubMed Central

    Im, Sin-Hyeog; Barchan, Dora; Fuchs, Sara; Souroujon, Miriam C.

    1999-01-01

    Myasthenia gravis (MG) is an autoimmune disorder in which the nicotinic acetylcholine receptor (AChR) is the major autoantigen. In an attempt to develop an antigen-specific therapy for MG, we administered a nonmyasthenogenic recombinant fragment of AChR orally to rats. This fragment, corresponding to the extracellular domain of the human AChR α-subunit (Hα1-205), protected rats from subsequently induced experimental autoimmune myasthenia gravis (EAMG) and suppressed ongoing EAMG when treatment was initiated during either the acute or chronic phases of disease. Prevention and suppression of EAMG were accompanied by a significant decrease in AChR-specific humoral and cellular responses. The underlying mechanism for the Hα1-205–induced oral tolerance seems to be active suppression, mediated by a shift from a T-helper 1 (Th1) to a Th2/Th3 response. This shift was assessed by changes in the cytokine profile, a deviation of anti-AChR IgG isotypes from IgG2 to IgG1, and a suppressed AChR-specific delayed-type hypersensitivity response. Our results in experimental myasthenia suggest that oral administration of AChR-specific recombinant fragments may be considered for antigen-specific immunotherapy of myasthenia gravis. J. Clin. Invest. 104:1723–1730 (1999). PMID:10606626

  9. Clinical study of Gene-Eden-VIR/Novirin in genital herpes: suppressive treatment safely decreases the duration of outbreaks in both severe and mild cases.

    PubMed

    Polansky, Hanan; Itzkovitz, Edan; Javaherian, Adrian

    2016-12-01

    We conducted a clinical study that tested the effect of suppressive treatment with the botanical product Gene-Eden-VIR/Novirin on genital herpes. Our previous paper showed that the treatment decreased the number of genital herpes outbreaks without any side effects. It also showed that the clinical effects of Gene-Eden-VIR/Novirin are mostly better than those reported in the studies that tested acyclovir, valacyclovir, and famciclovir. The current paper reports the effect of suppressive treatment with Gene-Eden-VIR/Novirin on the duration of outbreaks, in severe and mild genital herpes cases. The framework was a retrospective chart review. The population included 137 participants. The treatment was 1-4 capsules per day. The duration of treatment was 2-48 months. The study included three controls: baseline, no-treatment, and dose-response. The treatment decreased the duration of outbreaks in 87 % of participants and decreased the mean duration of outbreaks from 8.77 days and 6.7 days in the control groups to 2.87 days in the treatment group (P < 0.001, both groups). All participants reported no adverse experiences. This paper shows that suppressive treatment with Gene-Eden-VIR/Novirin decreased the duration of genital herpes outbreaks, in both severe and mild cases, without any side effects. Based on the results reported in this and our previous paper, we recommend suppressive treatment with Gene-Eden-VIR/Novirin as a natural alternative to both suppressive and episodic treatments with current drugs, in both severe and mild genital herpes cases. Trial registration ClinicalTrials.gov NCT02715752 Registered 17 March 2016 Retrospectively Registered.

  10. Suppressive Effects of Bee Venom Acupuncture on Paclitaxel-Induced Neuropathic Pain in Rats: Mediation by Spinal α2-Adrenergic Receptor

    PubMed Central

    Choi, Jiho; Jeon, Changhoon; Jang, Jo Ung; Quan, Fu Shi; Lee, Kyungjin; Kim, Woojin

    2017-01-01

    Paclitaxel, a chemotherapy drug for solid tumors, induces peripheral painful neuropathy. Bee venom acupuncture (BVA) has been reported to have potent analgesic effects, which are known to be mediated by activation of spinal α-adrenergic receptor. Here, we investigated the effect of BVA on mechanical hyperalgesia and spinal neuronal hyperexcitation induced by paclitaxel. The role of spinal α-adrenergic receptor subtypes in the analgesic effect of BVA was also observed. Administration of paclitaxel (total 8 mg/kg, intraperitoneal) on four alternate days (days 0, 2, 4, and 6) induced significant mechanical hyperalgesic signs, measured using a von Frey filament. BVA (1 mg/kg, ST36) relieved this mechanical hyperalgesia for at least two hours, and suppressed the hyperexcitation in spinal wide dynamic range neurons evoked by press or pinch stimulation. Both melittin (0.5 mg/kg, ST36) and phospholipase A2 (0.12 mg/kg, ST36) were shown to play an important part in this analgesic effect of the BVA, as they significantly attenuated the pain. Intrathecal pretreatment with the α2-adrenergic receptor antagonist (idazoxan, 50 µg), but not α1-adrenergic receptor antagonist (prazosin, 30 µg), blocked the analgesic effect of BVA. These results suggest that BVA has potent suppressive effects against paclitaxel-induced neuropathic pain, which were mediated by spinal α2-adrenergic receptor. PMID:29088102

  11. The role of suppression in amblyopia.

    PubMed

    Li, Jingrong; Thompson, Benjamin; Lam, Carly S Y; Deng, Daming; Chan, Lily Y L; Maehara, Goro; Woo, George C; Yu, Minbin; Hess, Robert F

    2011-06-13

    This study had three main goals: to assess the degree of suppression in patients with strabismic, anisometropic, and mixed amblyopia; to establish the relationship between suppression and the degree of amblyopia; and to compare the degree of suppression across the clinical subgroups within the sample. Using both standard measures of suppression (Bagolini lenses and neutral density [ND] filters, Worth 4-Dot test) and a new approach involving the measurement of dichoptic motion thresholds under conditions of variable interocular contrast, the degree of suppression in 43 amblyopic patients with strabismus, anisometropia, or a combination of both was quantified. There was good agreement between the quantitative measures of suppression made with the new dichoptic motion threshold technique and measurements made with standard clinical techniques (Bagolini lenses and ND filters, Worth 4-Dot test). The degree of suppression was found to correlate directly with the degree of amblyopia within our clinical sample, whereby stronger suppression was associated with a greater difference in interocular acuity and poorer stereoacuity. Suppression was not related to the type or angle of strabismus when this was present or the previous treatment history. These results suggest that suppression may have a primary role in the amblyopia syndrome and therefore have implications for the treatment of amblyopia.

  12. [Suppression of cycling activity in sheep using parenteral progestagen treatment].

    PubMed

    Janett, F; Camponovo, L; Lanker, U; Hässig, M; Thun, R

    2004-03-01

    The objective of this study was to evaluate the effect of two synthetic progestagen preparations Chlormadinone acetate (CAP, Chronosyn, Veterinaria AG Zürich) and Medroxyprogesterone acetate (MPA, Nadigest, G Streuli & Co. Uznach) on cycling activity and fertility in sheep. A flock of 28 non pregnant white alpine sheep was randomly divided into three groups, A (n = 10), B (n = 9) and C (n = 9). During a period of 4 weeks the cycling activity was confirmed by blood progesterone analysis. Thereafter, the animals of group A were treated with 50 mg CAP, those of group B with 140 mg MPA and those of group C with physiological saline solution. All injections were given intramuscularly. Suppression of endogenous progesterone secretion lasted from 28 to 49 days (mean = 39 days) in group A and from 42 to 70 days (mean = 50 days) in group B. The synchronization effect of both preparations was unsatisfactory as the occurrence of first estrus was distributed over a period of 3 weeks in group A and 4 weeks in group B. These findings could also be confirmed by the lambing period which lasted 52 days in group A and 36 days in group B. Control animals lambed within 9 days due to the synchronizing effect of the ram. The first fertile estrus was observed 36 days (group A) and 45 days (group B) after the treatment. In group A all 10 animals and in groups B and C 8 of 9 ewes each became pregnant. Parenteral progestagen application with CAP and MPA is a simple, safe and reversible method of estrus suppression in the sheep. The minimal suppressive duration of 4 (CAP) and 5 weeks (MPA) is not sufficient when a period of 3 months (alpine pasture period) is desired.

  13. Factor structure and clinical correlates of the Food Thought Suppression Inventory within treatment seeking obese women with binge eating disorder

    PubMed Central

    Barnes, Rachel D.; Sawaoka, Takuya; White, Marney A.; Masheb, Robin M.; Grilo, Carlos M.

    2013-01-01

    Prior research on the relations among eating behaviors and thought suppression is limited to a measure of general thought suppression, the White Bear Suppression Inventory. To address this limitation, researchers recently validated the Food Thought Suppression Inventory (FTSI). Analyses using this measure suggest that food thought suppression is distinct from and is more predictive of eating disorder psychopathology than is general thought suppression. The FTSI, however, has not yet been validated in clinical samples. The purpose of the current study is to examine the factor structure and clinical correlates of the FTSI within treatment seeking obese women with binge eating disorder (BED; N = 128). Analyses revealed a valid and reliable one-factor measure of food thought suppression that was related to higher levels of eating and general psychopathology. The findings provide evidence for the use of the FTSI with obese women with BED. Future research should examine the psychometric properties of the FTSI within larger and more diverse samples. PMID:23265399

  14. Stress and PTSD Mechanisms as Targets for Pharmacotherapy of Alcohol Abuse, Addiction and Relapse

    DTIC Science & Technology

    2017-10-01

    and due to the need for some methodology refinements. 15. SUBJECT TERMS PTSD, alcohol, ethanol, prazosin, noradrenergic, startle, anxiety, stress...behaviors in the differing experimental models used in these studies; we continue to evaluate whether prazosin treatment disproportionately decreases...intermittent alcohol access (IAA, 24 h/day free choice between 20% alcohol vs water on 3 non -consecutive days/week) to establish stable elevated

  15. Fire behavior, fuel treatments, and fire suppression on the Hayman Fire - Part 5: Fire suppression activities

    Treesearch

    Charles W. McHugh; Paul Gleason

    2003-01-01

    The purpose of this report is to document the suppression actions taken during the Hayman Fire. The long duration of suppression activities (June 8 through July 18), and multiple incident management teams assigned to the fire, makes this a challenging task. Original records and reports produced independently by the various teams assigned to different portions of the...

  16. Rapid Suppression of Onchocerca volvulus Transmission in Two Communities of the Southern Chiapas Focus, Mexico, Achieved by Quarterly Treatments with Mectizan

    PubMed Central

    Rodríguez-Pérez, Mario A.; Lutzow-Steiner, Miguel A.; Segura-Cabrera, Aldo; Lizarazo-Ortega, Cristian; Domínguez-Vázquez, Alfredo; Sauerbrey, Mauricio; Richards, Frank; Unnasch, Thomas R.; Hassan, Hassan K.; Hernández-Hernández, Raymundo

    2008-01-01

    The impact of quarterly Mectizan (ivermectin) treatments on transmission, microfiladermia, and ocular lesions was evaluated in two formerly hyperendemic communities (Las Golondrinas and Las Nubes II) located in the main endemic focus for onchocerciasis in Southern Chiapas, Mexico. The data suggest that Onchocerca volvulus transmission has been suppressed after elimination of microfiladermia in these two communities. Increasing the frequency of Mectizan treatment to four times per year appears to have resulted in the rapid suppression of transmission in communities with residual transmission. PMID:18689630

  17. Trehalose treatment suppresses inflammation, oxidative stress, and vasospasm induced by experimental subarachnoid hemorrhage

    PubMed Central

    2012-01-01

    Background Subarachnoid hemorrhage (SAH) frequently results in several complications, including cerebral vasospasm, associated with high mortality. Although cerebral vasospasm is a major cause of brain damages after SAH, other factors such as inflammatory responses and oxidative stress also contribute to high mortality after SAH. Trehalose is a non-reducing disaccharide in which two glucose units are linked by α,α-1,1-glycosidic bond, and has been shown to induce tolerance to a variety of stressors in numerous organisms. In the present study, we investigated the effect of trehalose on cerebral vasospasm, inflammatory responses, and oxidative stress induced by blood in vitro and in vivo. Methods Enzyme immunoassay for eicosanoids, pro-inflammatory cytokines, and endothelin-1, and western blotting analysis for cyclooxygenase-2, inducible nitric oxide synthase, and inhibitor of NF-κB were examined in macrophage-like cells treated with hemolysate. After treatment with hemolysate and hydrogen peroxide, the levels of lipid peroxide and amounts of arachidonic acid release were also analyzed. Three hours after the onset of experimental SAH, 18 Japanese White rabbits received an injection of saline, trehalose, or maltose into the cisterna magna. Angiographic and histological analyses of the basilar arteries were performed. In a separate study, the femoral arteries from 60 rats were exposed to fresh autologous blood. At 1, 3, 5, 7, 10, and 20 days after treatment, cryosections prepared from the femoral arteries were histologically analyzed. Results When cells were treated with hemolysate, trehalose inhibited the production of several inflammatory mediators and degradation of the inhibitor of NF-κB and also suppressed the lipid peroxidation, the reactive oxygen species-induced arachidonic acid release in vitro. In the rabbit model, trehalose produced an inhibitory effect on vasospasm after the onset of experimental SAH, while maltose had only a moderate effect. When the

  18. Week 4 viral load predicts long-term suppression of hepatitis B virus DNA during antiviral therapy: improving hepatitis B treatment in the real world.

    PubMed

    Truong, J; Shadbolt, B; Ooi, M; Chitturi, S; Kaye, G; Farrell, G C; Teoh, N C

    2017-01-01

    Entecavir and tenofovir potently suppress hepatitis B virus (HBV) replication so that serum HBV DNA levels <20 IU/mL can be achieved after 2 years. Despite this, inadequate suppression is reported in >20% of cases for unclear reasons. We tested whether 4-week viral load (VL) assessment could improve 96-week treatment outcome. Data on all chronic hepatitis B patients treated with entecavir or tenofovir between 2005 and 2014 were entered prospectively. Full data capture included pre-treatment, weeks 4, 24, 48 and 96 HBV DNA titre, HBeAg, age, gender, antiviral agent and dose escalation. Compliance data were compiled from pharmacy records, doctors' letters and clinic bookings/attendance. Time to achieve complete viral suppression (HBV DNA < 20 IU/mL) was graphed using Kaplan-Meier curves. Factors affecting this were examined using a multivariate Cox Proportional Hazard model. Among 156 patients treated, 72 received entecavir and 84 tenofovir. Pre-treatment HBV DNA titre, 4-week assessment and compliance impacted significantly on time to complete viral suppression. At 96 weeks, 90% of those assessed as compliant by 4-week HBV DNA had complete viral suppression versus 50% followed by 6-month VL estimation. Continuing care by the same physician was related to 4-week VL testing and optimal compliance. Medium-term outcomes of HBV antiviral therapy are improved by early on-treatment VL testing, facilitating patient engagement and improved compliance. The observation that 90% complete viral suppression after 2 years monotherapy is achievable in a routine clinic setting questions the need for combination therapy in HBV cases with suboptimal response. © 2016 Royal Australasian College of Physicians.

  19. Diurnal suppression of EGFR signalling by glucocorticoids and implications for tumour progression and treatment.

    PubMed

    Lauriola, Mattia; Enuka, Yehoshua; Zeisel, Amit; D'Uva, Gabriele; Roth, Lee; Sharon-Sevilla, Michal; Lindzen, Moshit; Sharma, Kirti; Nevo, Nava; Feldman, Morris; Carvalho, Silvia; Cohen-Dvashi, Hadas; Kedmi, Merav; Ben-Chetrit, Nir; Chen, Alon; Solmi, Rossella; Wiemann, Stefan; Schmitt, Fernando; Domany, Eytan; Yarden, Yosef

    2014-10-03

    Signal transduction by receptor tyrosine kinases (RTKs) and nuclear receptors for steroid hormones is essential for body homeostasis, but the cross-talk between these receptor families is poorly understood. We observed that glucocorticoids inhibit signalling downstream of EGFR, an RTK. The underlying mechanism entails suppression of EGFR's positive feedback loops and simultaneous triggering of negative feedback loops that normally restrain EGFR. Our studies in mice reveal that the regulation of EGFR's feedback loops by glucocorticoids translates to circadian control of EGFR signalling: EGFR signals are suppressed by high glucocorticoids during the active phase (night-time in rodents), while EGFR signals are enhanced during the resting phase. Consistent with this pattern, treatment of animals bearing EGFR-driven tumours with a specific kinase inhibitor was more effective if administered during the resting phase of the day, when glucocorticoids are low. These findings support a circadian clock-based paradigm in cancer therapy.

  20. Estrogen suppression in premenopausal women following 8 weeks of treatment with exemestane and triptorelin versus triptorelin alone.

    PubMed

    Jannuzzo, Maria Gabriella; Di Salle, Enrico; Spinelli, Riccardo; Pirotta, Nicoletta; Buchan, Peter; Bello, Akintunde

    2009-02-01

    Luteinizing hormone-releasing hormone (LHRH) agonists (e.g., triptorelin) reduce ovarian estrogen production in premenopausal women with hormone-sensitive breast cancer. Aromatase inhibitors (e.g., exemestane) inhibit extraovarian production of estrogen and may further reduce circulating estrogens when combined with an LHRH agonist. Healthy premenopausal women were randomized to receive 3.75 mg triptorelin (T) on days 1 and 29 with 25 mg exemestane (EX) or matched placebo once daily for 8 weeks, from day 1 to day 56. The primary objective was to evaluate the effect of T +/- EX on estradiol (E(2)) suppression by comparing the AUC(day 36-57 )for the 2 treatments. Secondary objectives included evaluation of estrone (E(1)), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) suppression; effects of EX on the T-induced gonadotrophin and estrogen flare; pharmacokinetics (PK); and safety. Twenty-eight (14 in each arm) were evaluable for efficacy and PK. Mean plasma estrogen levels (AUC(day 36-57)) were significantly lower for subjects who received T + EX than for subjects who received T alone (20.6 vs. 54.0 pg d/ml [-62%; P < 0.05], and 38.9 vs. 198.0 pg d/ml [-80%; P < 0.01] for E(2) and E(1), respectively). Coadministration of EX did not affect the initial flare or subsequent suppression of LH and FSH following the first dose of T, or the PK of T. Both treatments were well tolerated. Coadministration of T and EX resulted in greater estrogen suppression than when T was given alone. These findings could translate into improved clinical outcomes for premenopausal breast cancer patients receiving LHRH agonists.

  1. The relation of weight suppression and BMI to bulimic symptoms.

    PubMed

    Butryn, Meghan L; Juarascio, Adrienne; Lowe, Michael R

    2011-11-01

    High levels of weight suppression have been associated with greater binge eating and weight gain as well as poorer treatment outcome in bulimia nervosa. This study examined the relationship between weight suppression and bulimia nervosa symptoms and explored how weight suppression might interact with body mass index (BMI) in accounting for level of symptomatology at presentation for treatment. Participants were 64 women with threshold or sub-threshold bulimia nervosa. A clinical interview assessed binge eating and purging. Weight suppression and the interaction between BMI and weight suppression predicted frequency of binge eating such that participants with low BMI and high weight suppression engaged in the most binge eating. High levels of weight suppression also predicted more frequent purging. Additional research is warranted to examine mediators of these relationships. Copyright © 2010 Wiley Periodicals, Inc.

  2. Efficacy of alginate-based reflux suppressant and magnesium-aluminium antacid gel for treatment of heartburn in pregnancy: a randomized double-blind controlled trial

    PubMed Central

    Meteerattanapipat, Pontip; Phupong, Vorapong

    2017-01-01

    The aim of this study was to compare the therapeutic efficacy of alginate-based reflux suppressant and magnesium-aluminium antacid gel for treatment of heartburn in pregnancy. A double-blinded, randomized, controlled trial was conducted. One hundred pregnant women at less than 36 weeks gestation with heartburn at least twice per week were randomized to either alginate-based reflux suppressant or to magnesium-aluminium antacid gel. Details of heartburn were recorded before beginning the treatment and the second week of study. Primary outcome measure was the improvement of heartburn frequency after treatment and secondary outcome were the improvement of heartburn intensity, quality of life, maternal satisfaction, maternal side effects, pregnancy and neonatal outcomes. There was no difference between treatment and control groups in improvement of heartburn frequency (80% vs 88%, p = 0.275), 50% reduction of frequency of heartburn (56% vs 52%, p = 0.688), improvement of heartburn intensity (92% vs 92%, p = 1.000) and 50% reduction of heartburn intensity (68% vs 80% cases, p = 0.075). There were also no significant differences in quality of life, maternal satisfaction, maternal side effects, pregnancy and neonatal outcomes. Alginate-based reflux suppressant was not different from magnesium-aluminium antacid gel in the treatment of heartburn in pregnancy. PMID:28317885

  3. ACTIVE SUPPRESSION OF IMMUNOGLOBULIN ALLOTYPE SYNTHESIS

    PubMed Central

    Herzenberg, Leonore A.; Chan, Eva L.; Ravitch, Myrnice M.; Riblet, Roy J.; Herzenberg, Leonard A.

    1973-01-01

    Thymus-derived cells (T cells) that actively suppress production of IgG2a immunoglobulins carrying the Ig-1b allotype have been found in adult (SJL x BALB/c)F1 mice exposed to anti-Ig-1b early in life. The suppression is specific for Ig-1b. The allelic product, Ig-1a, is unaffected. Spleen, lymph node, bone marrow, or thymus cells from suppressed mice suppress production of Ig-1b by syngeneic spleen cells from normal F1 mice. When a mixture of suppressed and normal cells is transferred into lethally irradiated BALB/c mice, there is a short burst of Ig-1b production after which Ig-1b levels in the recipient fall rapidly below detectability. Pretreatment of the cells from the suppressed mice with antiserum specific for T cells (anti-Thy-1b) plus complement before mixture destroys the suppressing activity. Similar results with suppressor cells were obtained in vitro using Mishell-Dutton cultures. Mixture of spleen cells from suppressed animals with sheep erythrocyte (SRBC)-primed syngeneic normal spleen before culture suppresses Ig-1b plaque-forming cell (PFC) formation while leaving Ig-1a PFC unaffected. Treatment of the suppressed spleen with anti-Thy-1b before transfer removes the suppressing activity. PMID:4541122

  4. Enzalutamide and CXCR7 inhibitor combination treatment suppresses cell growth and angiogenic signaling in castration‐resistant prostate cancer models

    PubMed Central

    Luo, Yong; Azad, Abul Kalam; Karanika, Styliani; Basourakos, Spyridon P.; Zuo, Xuemei; Wang, Jianxiang; Yang, Luan; Yang, Guang; Korentzelos, Dimitrios; Yin, Jianhua; Park, Sanghee; Zhang, Penglie; Campbell, James J.; Schall, Thomas J.; Cao, Guangwen; Li, Likun

    2018-01-01

    Previous studies have shown that increased levels of chemokine receptor CXCR7 are associated with the increased invasiveness of prostate cancer cells. We now show that CXCR7 expression is upregulated in VCaP and C4‐2B cells after enzalutamide (ENZ) treatment. ENZ treatment induced apoptosis (sub‐G1) in VCaP and C4‐2B cells, and this effect was further increased after combination treatment with ENZ and CCX771, a specific CXCR7 inhibitor. The levels of p‐EGFR (Y1068), p‐AKT (T308) and VEGFR2 were reduced after ENZ and CCX771 combination treatment compared to single agent treatment. In addition, significantly greater reductions in migration were shown after combination treatment compared to those of single agents or vehicle controls, and importantly, similar reductions in the levels of secreted VEGF were also demonstrated. Orthotopic VCaP xenograft growth and subcutaneous MDA133‐4 patient‐derived xenograft (PDX) tumor growth was reduced by single agent treatment, but significantly greater suppression was observed in the combination treatment group. Although overall microvessel densities in the tumor tissues were not different among the different treatment groups, a significant reduction in large blood vessels (>100 μm2) was observed in tumors following combination treatment. Apoptotic indices in tumor tissues were significantly increased following combination treatment compared with vehicle control‐treated tumor tissues. Our results demonstrate that significant tumor suppression mediated by ENZ and CXCR7 combination treatment may be due, in part, to reductions in proangiogenic signaling and in the formation of large blood vessels in prostate cancer tumors. PMID:29277895

  5. Molecular cloning and functional expression of the guinea pig alpha(1a)-adrenoceptor.

    PubMed

    González-Espinosa, C; Romero-Avila, M T; Mora-Rodríguez, D M; González-Espinosa, D; García-Sáinz, J A

    2001-08-31

    In the present paper, the cloning and expression of the guinea pig alpha(1A)-adrenoceptor is presented. The nucleotide sequence had an open reading frame of 1401 bp that encoded a 466 amino-acid protein with an estimated molecular mass of approximately 51.5 kDa. When the clone was expressed in Cos-1 cells, specific high-affinity binding of [(3)H]prazosin and [(3)H]tamsulosin was observed. Chloroethylclonidine treatment of membranes slightly decreased the total binding with both radioligands. Binding competition experiments using [(3)H]tamsulosin showed the following potency order: (a) for agonists: oxymetazoline >epinephrine>norepinephrine>methoxamine, and (b) for antagonists: prazosin> or 5-methyl-urapidil=benoxathian>phentolamine>BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]decane-7,9-dione). Photoaffinity labeling using [(125)I-aryl]azido-prazosin revealed a major broad band with a molecular mass between 70 and 80 kDa. The receptor was functional, as evidenced by an epinephrine-increased production of [(3)H]inositol phosphates that was blocked by prazosin.

  6. [Herbs for calming liver and suppressing yang in treatment of hyperthyroidism with hyperactive liver yang: herbal effects on lymphocyte protein expression].

    PubMed

    Li, Xiangping; Yin, Tao; Zhong, Guangwei; Li, Wei; Luo, Yanhong; Xiang, Lingli; Liu, Zhehao

    2011-07-01

    To observe the herbal effects on hyperthyroidism patients with syndrome of hyperactivity of liver-Yang by method for calming the liver and suppressing Yang and investigate its effects on the lymphocyte protein expression. This approach may lay a foundation for the further investigation of the curative mechanisms of calming the liver and suppressing Yang treatment. A total of 48 hyperthyroidism patients with syndrome of hyperactivity of liver-Yang were randomly divided into treatment group and control group. The treatment group was treated by method for calming the liver and suppressing Yang in accordance with traditional Chinese medicine (TCM) and the control group with thiamazole tablets for three periods of treatment The therapeutic effects, the score of TCM symptom, electrocardiogram (P wave), thyroid hormones and ultrasound were observed in both groups before and after the treatment. The side effects in the treatment course were observed in both groups. The level of differential protein expression was analyzed by two-dimensional electrphoresis and matrix assisted laser desorption/ionizaton time-of-flight mass spectrometry. The treatment group has the effect on stepping down the heart rate, cutting down the P wave amplitude changes, regulating the level of thyroid hormones and decreasing the volume of thyromegaly. There are not statistically significant between the treatment group and control group. However, the treatment group has obviously better effect on regulating TCM symptom and decreasing the side reaction than the control group (P<0.05). There are not statistically significant on the total effective between the treatment group and control group. The average spots in lymphocyte for normal people, before and after treating hyperthyroidism patients with syndrome of hyperactivity of liver-Yang were (429 +/- 31), (452 +/- 28) and (437 +/- 36) spots respectively. Eight down-regulated protein expressions and 11 up-regulated protein expressions were obtained in

  7. Perillyl alcohol suppresses antigen-induced immune responses in the lung

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Imamura, Mitsuru; Sasaki, Oh; Okunishi, Katsuhide

    Highlights: •Perillyl alcohol (POH) is an isoprenoid which inhibits the mevalonate pathway. •We examined whether POH suppresses immune responses with a mouse model of asthma. •POH treatment during sensitization suppressed Ag-induced priming of CD4{sup +} T cells. •POH suppressed airway eosinophila and cytokine production in thoracic lymph nodes. -- Abstract: Perillyl alcohol (POH) is an isoprenoid which inhibits farnesyl transferase and geranylgeranyl transferase, key enzymes that induce conformational and functional changes in small G proteins to conduct signal production for cell proliferation. Thus, it has been tried for the treatment of cancers. However, although it affects the proliferation of immunocytes,more » its influence on immune responses has been examined in only a few studies. Notably, its effect on antigen-induced immune responses has not been studied. In this study, we examined whether POH suppresses Ag-induced immune responses with a mouse model of allergic airway inflammation. POH treatment of sensitized mice suppressed proliferation and cytokine production in Ag-stimulated spleen cells or CD4{sup +} T cells. Further, sensitized mice received aerosolized OVA to induce allergic airway inflammation, and some mice received POH treatment. POH significantly suppressed indicators of allergic airway inflammation such as airway eosinophilia. Cytokine production in thoracic lymph nodes was also significantly suppressed. These results demonstrate that POH suppresses antigen-induced immune responses in the lung. Considering that it exists naturally, POH could be a novel preventive or therapeutic option for immunologic lung disorders such as asthma with minimal side effects.« less

  8. [The advances of suppression in research of amblyopia].

    PubMed

    Liu, S; Liu, H

    2016-04-11

    Suppression that is the result of interocular competition is an important machanism of amblyopia. The imbalance of suppression may lead the consequence to amblyopia. In the early study, researchers had raised the theory of II. Quadratic Summation which had revealed the relationship of interocular interaction and suppression. In some basic researches, other studies had showed the most possible anatomic location of suppression. Recently, researchers found a new method to quantify the interocular suppression named the noise model. Further studies found a novel disinhibition therapy to treat amblyopia. We summarized the research advances in suppression and disinhibition treatment in amblyopia. (Chin J Ophthalmol, 2016, 52: 305-308).

  9. Family-based intervention in adolescent restrictive eating disorders: early treatment response and low weight suppression is associated with favourable one-year outcome.

    PubMed

    Swenne, Ingemar; Parling, Thomas; Salonen Ros, Helena

    2017-09-15

    Family-based treatments are first-line treatments for adolescents with restrictive eating disorders (ED) but have to be improved since outcome is poor for some. We have investigated the one-year outcome of a family-based intervention programme with defined and decisive interventions at the start of treatment. Data pertaining 201 adolescents with restrictive ED with features of anorexia nervosa but not fulfilling the weight criterion starting treatment 2010-2015, had a wide range of body mass index (BMI) and of weight loss at presentation, and completed a one-year follow-up was analysed. Recovery from the ED was defined as an Eating Disorder Examination-questionnaire (EDE-Q) score < 2.0 or as not fulfilling criteria for an ED at a clinical interview. By EDE-Q 130 (65%) had recovered at 1 year and by clinical interview 106 (53%). According to the EDE-Q criterion recovery was independently associated with lower EDE-Q score at presentation, higher weight gain after 3 months of treatment and lower weight suppression at follow-up, weight suppression being defined as the difference between premorbid and current BMI. Not fulfilling criteria for an ED was associated with the same factors and also by higher BMI at presentation. The observations that low weight and high ED cognitions confer a poor prognosis but that rapid weight gain at the start of treatment predicts a better prognosis are presently extended to adolescents with restrictive ED with a wide range of BMI at presentation. High weight suppression at follow-up is associated with a poor prognosis and indicates the importance of taking premorbid BMI into account when setting weight targets for treatment.

  10. Chronic agomelatine treatment prevents comorbid depression in the post-status epilepticus model of acquired epilepsy through suppression of inflammatory signaling.

    PubMed

    Tchekalarova, Jana; Atanasova, Dimitrinka; Kortenska, Lidia; Atanasova, Milena; Lazarov, Nikolai

    2018-07-01

    Inflammatory signal molecules are suggested to be involved in the mechanism underlying comorbid depression in epilepsy. In the present study, we tested the hypothesis that the novel antidepressant agomelatine, a potent melatonin MT 1 and MT 2 receptor agonist and serotonin 5HT 2C receptor antagonist, can prevent depressive symptoms developed during the chronic epileptic phase by suppressing an inflammatory response. Chronic treatment with agomelatine (40 mg/kg, i.p.) was initiated an hour after the kainate acid (KA)-induced status epilepticus (SE) and maintained for a period of 10 weeks in Wistar rats. Registration of spontaneous motor seizures was performed through a video (24 h/day) and EEG monitoring. Antidepressant activity of agomelatine was explored in the splash test, sucrose preference test (SPT) and forced swimming test (FST) while anxiolytic effect was observed through the novelty suppression-feeding test (NSFT) during chronic phase in epileptic rats. The frequency of motor seizures detected by video and EEG recording did not differ between vehicle and Ago group. Rats with registered spontaneous motor seizures showed symptoms typical for depressive behavior that included decreased grooming, anhedonia during the dark period and hopeless-like behavior. Epileptic rats exhibited also anxiety with novelty-induced hypophagia. This behavioral deficit correlated with increased signal markers of inflammation (plasma levels of interleukin (IL)-1β and activated glia in brain), while plasma corticosterone levels were not changed. Agomelatine treatment during epileptogenesis exerted a clear antidepressant effect by suppressing all behavioral hallmarks, reducing plasma IL-1β levels and preventing microgliosis and astrogliosis in specific limbic regions. The present results suggest that agomelatine treatment starting after SE can provide an effective therapy of comorbid depression in chronic epileptic condition through suppression of inflammatory signaling

  11. Suppression of NLRP3 inflammasome by oral treatment with sulforaphane alleviates acute gouty inflammation.

    PubMed

    Yang, Gabsik; Yeon, Sang Hyeon; Lee, Hye Eun; Kang, Han Chang; Cho, Yong Yeon; Lee, Hye Suk; Lee, Joo Young

    2018-04-01

    The aetiology of gout is closely linked to the deposition of monosodium uric acid (MSU) crystals and the consequent activation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome. In this study, we investigated whether oral administration of an NLRP3 inhibitor would be effective to attenuate the symptoms of gout. The effects of oral administration with sulforaphane (SFN) were examined in two mouse models of acute gout induced by injection of MSU crystals into footpads or air pouch. The production of caspase-1 (p10) and IL-1β was examined by immunoblotting and ELISA as hallmarks of NLRP3 inflammasome activation. Oral administration of SFN attenuated MSU crystal-induced swelling and neutrophil recruitment in a mouse foot acute gout model, correlating with the suppression of the NLRP3 inflammasome activation in foot tissues. Consistently, oral administration of SFN blocked MSU-crystal-induced activation of the NLRP3 inflammasome in a mouse air pouch gout model. SFN suppressed NLRP3 inflammasome activation induced by MSU crystals, adenosine triphosphate and nigericin but not by poly(dA:dT) in primary mouse macrophages, independent of the reactive oxygen species pathway. SFN inhibited ligand-independent activation of the NLRP3 inflammasome, suggesting that SFN may act directly on the NLRP3 inflammasome complex. Oral administration of SFN effectively alleviated acute gouty inflammation by suppression of the NLRP3 inflammasome. Our results provide a novel strategy in which oral treatment with SFN may be beneficial in preventing acute attacks of gout.

  12. Molecular Modulation of Prefrontal Cortex: Rational Development of Treatments for Psychiatric Disorders

    PubMed Central

    Gamo, Nao J.; Arnsten, Amy F.T.

    2011-01-01

    Dysfunction of the prefrontal cortex (PFC) is a central feature of many psychiatric disorders, such as attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), schizophrenia and bipolar disorder. Thus, understanding molecular influences on PFC function through basic research in animals is essential to rational drug development. In this review, we discuss the molecular signaling events initiated by norepinephrine and dopamine that strengthen working memory function mediated by the dorsolateral PFC under optimal conditions, and weaken working memory function during uncontrollable stress. We also discuss how these intracellular mechanisms can be compromised in psychiatric disorders, and how novel treatments based on these findings may restore a molecular environment conducive to PFC regulation of behavior, thought and emotion. Examples of successful translation from animals to humans include guanfacine for the treatment of ADHD and related PFC disorders, and prazosin for the treatment of PTSD. PMID:21480691

  13. Thought-action fusion and thought suppression in obsessive-compulsive disorder.

    PubMed

    Rassin, E; Diepstraten, P; Merckelbach, H; Muris, P

    2001-07-01

    To examine the significance of thought-action fusion (TAF) and thought suppression tendencies, the present study obtained pre- and post-treatment questionnaire data on these constructs in a sample of OCD patients (n=24) and non-OCD anxiety patients (n=20). Results indicate that TAF and suppression are correlated with severity of psychopathology. Yet, the associations between TAF and psychopathology are not typical for OCD, but do also occur in other anxiety disorders (e.g., panic disorder, post traumatic stress disorder, and social phobia). As well, mean scores on the TAF and thought suppression measures dropped significantly from pre- to post-treatment, indicating that TAF and thought suppression are susceptible to change during psychotherapy.

  14. Abnormal Grain Growth Suppression in Aluminum Alloys

    NASA Technical Reports Server (NTRS)

    Hales, Stephen J. (Inventor); Claytor, Harold Dale (Inventor); Alexa, Joel A. (Inventor)

    2015-01-01

    The present invention provides a process for suppressing abnormal grain growth in friction stir welded aluminum alloys by inserting an intermediate annealing treatment ("IAT") after the welding step on the article. The IAT may be followed by a solution heat treatment (SHT) on the article under effectively high solution heat treatment conditions. In at least some embodiments, a deformation step is conducted on the article under effective spin-forming deformation conditions or under effective superplastic deformation conditions. The invention further provides a welded article having suppressed abnormal grain growth, prepared by the process above. Preferably the article is characterized with greater than about 90% reduction in area fraction abnormal grain growth in any friction-stir-welded nugget.

  15. Prazosin

    MedlinePlus

    ... and other problems. In addition to taking medication, making lifestyle changes will also help to control your ... This branded product is no longer on the market. Generic alternatives may be available.

  16. Weight Suppression But Not Symptom Improvement Predicts Weight Gain During Inpatient Treatment for Bulimia Nervosa.

    PubMed

    Hessler, Johannes Baltasar; Diedrich, Alice; Greetfeld, Martin; Schlegl, Sandra; Schwartz, Caroline; Voderholzer, Ulrich

    2018-03-01

    Fear of gaining weight is a common obstacle to seeking treatment for bulimia nervosa (BN). We investigated changes in body mass index (BMI) during inpatient treatment for BN in relation to treatment outcome and weight suppression (WS). Female inpatients of a specialized eating disorders clinic were grouped as deteriorated/unchanged, reliably improved, and clinically significantly improved based on Eating Disorder Inventory-2 scores. Repeated measures ANOVA was employed to examine changes in BMI between admission and discharge depending on treatment outcome and WS. One-hundred seventy-nine patients were included. Overall, the average BMI significantly increased by 0.54 kg/m 2 (SD = 1.24). Repeated measures ANOVA revealed no association of change in BMI with treatment outcome [F(df) = 1.13 (2166), p = 0.327] but with WS [F(df) = 2.76 (3166), p < 0.044]. Bulimia nervosa can be successfully treated without causing excessive weight gain. Patients with higher WS might expect somewhat more weight gain. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.

  17. Selective activation of cannabinoid CB2 receptors suppresses neuropathic nociception induced by treatment with the chemotherapeutic agent paclitaxel in rats.

    PubMed

    Rahn, Elizabeth J; Zvonok, Alexander M; Thakur, Ganesh A; Khanolkar, Atmaram D; Makriyannis, Alexandros; Hohmann, Andrea G

    2008-11-01

    Activation of cannabinoid CB(2) receptors suppresses neuropathic pain induced by traumatic nerve injury. The present studies were conducted to evaluate the efficacy of cannabinoid CB(2) receptor activation in suppressing painful peripheral neuropathy evoked by chemotherapeutic treatment with the antitumor agent paclitaxel. Rats received paclitaxel (2 mg/kg i.p./day) on 4 alternate days to induce mechanical hypersensitivity (mechanical allodynia). Mechanical allodynia was defined as a lowering of the threshold for paw withdrawal to stimulation of the plantar hind paw surface with an electronic von Frey stimulator. Mechanical allodynia developed in paclitaxel-treated animals relative to groups receiving the Cremophor EL/ethanol/saline vehicle at the same times. Two structurally distinct cannabinoid CB(2) agonists, the aminoalkylindole (R,S)-AM1241 [(R,S)-(2-iodo-5-nitrophenyl)-[1-((1-methyl-piperidin-2-yl)methyl)-1H-indol-3-yl]-methanone] and the cannabilactone AM1714 (1,9-dihydroxy-3-(1',1'-dimethylheptyl)-6H-benzo[c]chromene-6-one), produced a dose-related suppression of established paclitaxel-evoked mechanical allodynia after systemic administration. Pretreatment with the CB(2) antagonist SR144528 [5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)-1H-pyrazole-3-carboxamide], but not the CB(1) antagonist SR141716 [5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide], blocked the antiallodynic effects of both (R,S)-AM1241 and AM1714. Moreover, (R)-AM1241, but not (S)-AM1241, suppressed paclitaxel-evoked mechanical allodynia relative to either vehicle treatment or preinjection thresholds, consistent with mediation by CB(2). Administration of either the CB(1) or CB(2) antagonist alone failed to alter paclitaxel-evoked mechanical allodynia. Moreover, (R,S)-AM1241 did not alter paw withdrawal thresholds in rats that received the Cremophor EL vehicle in lieu of paclitaxel, whereas AM

  18. Suppression of bacterial infection in rice by treatment with a sulfated peptide.

    PubMed

    Wei, Tong; Chern, Mawsheng; Liu, Furong; Ronald, Pamela C

    2016-12-01

    The rice XA21 receptor kinase confers robust resistance to bacterial blight disease caused by Xanthomonas oryzae pv. oryzae (Xoo). A tyrosine-sulfated peptide from Xoo, called RaxX, triggers XA21-mediated immune responses, including the production of ethylene and reactive oxygen species and the induction of defence gene expression. It has not been tested previously whether these responses confer effective resistance to Xoo. Here, we describe a newly established post-inoculation treatment assay that facilitates investigations into the effect of the sulfated RaxX peptide in planta. In this assay, rice plants were inoculated with a virulent strain of Xoo and then treated with the RaxX peptide 2 days after inoculation. We found that post-inoculation treatment of XA21 plants with the sulfated RaxX peptide suppresses the development of Xoo infection in XA21 rice plants. The treated plants display restricted lesion development and reduced bacterial growth. Our findings demonstrate that exogenous application of sulfated RaxX activates XA21-mediated immunity in planta, and provides a potential strategy for the control of bacterial disease in the field. © 2016 BSPP and John Wiley & Sons Ltd.

  19. Treatment with selective estrogen receptor modulators regulates myelin specific T-cells and suppresses experimental autoimmune encephalomyelitis.

    PubMed

    Bebo, Bruce F; Dehghani, Babak; Foster, Scott; Kurniawan, Astrid; Lopez, Francisco J; Sherman, Larry S

    2009-05-01

    Steroidal estrogens can regulate inflammatory immune responses and may be involved in the suppression of multiple sclerosis (MS) during pregnancy. However, the risks and side effects associated with steroidal estrogens may limit their usefulness for long-term MS therapy. Selective estrogen receptor modulators (SERMs) could provide an alternative therapeutic strategy, because they behave as estrogen agonists in some tissues, but are either inert or behave like estrogen antagonists in other tissues. In this study, we investigated the ability of two commercially available SERMs (tamoxifen and raloxifene) to regulate myelin specific immunity and experimental autoimmune encephalomyelitis (EAE) in mice. Both tamoxifen and raloxifene suppressed myelin antigen specific T-cell proliferation. However, tamoxifen was more effective in this regard. Tamoxifen treatment reduced the induction of major histocompatibility complex II by lipopolysaccharide stimulated dendritic cells and decreased their ability to activate myelin specific T-cells. At lower doses, tamoxifen was found to increase the levels of Th2 transcription factors and induce a Th2 bias in cultures of myelin-specific splenocytes. EAE symptoms and the degree of demyelination were less severe in mice treated with tamoxifen than in control mice. These findings support the notion that tamoxifen or related SERMs are potential agents that could be used in the treatment of inflammatory autoimmune disorders that affect the central nervous system.

  20. Binocular Therapy for Childhood Amblyopia Improves Vision Without Breaking Interocular Suppression.

    PubMed

    Bossi, Manuela; Tailor, Vijay K; Anderson, Elaine J; Bex, Peter J; Greenwood, John A; Dahlmann-Noor, Annegret; Dakin, Steven C

    2017-06-01

    Amblyopia is a common developmental visual impairment characterized by a substantial difference in acuity between the two eyes. Current monocular treatments, which promote use of the affected eye by occluding or blurring the fellow eye, improve acuity, but are hindered by poor compliance. Recently developed binocular treatments can produce rapid gains in visual function, thought to be as a result of reduced interocular suppression. We set out to develop an effective home-based binocular treatment system for amblyopia that would engage high levels of compliance but that would also allow us to assess the role of suppression in children's response to binocular treatment. Balanced binocular viewing therapy (BBV) involves daily viewing of dichoptic movies (with "visibility" matched across the two eyes) and gameplay (to monitor compliance and suppression). Twenty-two children (3-11 years) with anisometropic (n = 7; group 1) and strabismic or combined mechanism amblyopia (group 2; n = 6 and 9, respectively) completed the study. Groups 1 and 2 were treated for a maximum of 8 or 24 weeks, respectively. The treatment elicited high levels of compliance (on average, 89.4% ± 24.2% of daily dose in 68.23% ± 12.2% of days on treatment) and led to a mean improvement in acuity of 0.27 logMAR (SD 0.22) for the amblyopic eye. Importantly, acuity gains were not correlated with a reduction in suppression. BBV is a binocular treatment for amblyopia that can be self-administered at home (with remote monitoring), producing rapid and substantial benefits that cannot be solely mediated by a reduction in interocular suppression.

  1. Trek2a regulates gnrh3 expression under control of melatonin receptor Mt1 and α2-adrenoceptor.

    PubMed

    Loganathan, Kavinash; Moriya, Shogo; Parhar, Ishwar S

    2018-02-12

    Gonadotrophin-releasing hormone (GnRH) expression is associated with the two-pore domain potassium ion (K + ) channel-related K + (TREK) channel trek2a expression and melatonin levels. We aimed to investigate correlation of trek2a expression with gnrh3 expression, and regulatory mechanisms of trek2a expression by the melatonin receptor Mt1 and α 2 -adrenoceptor which are regulated by melatonin. trek2a specific siRNA, Mt1 antagonist luzindole and α 2 -adrenoceptor antagonist prazosin were administered into the adult zebrafish brain and gene expressions were examined by real-time PCR. trek2a specific siRNA administration significantly reduced expression levels of trek2a, gnrh3 and mt1. Luzindole administration suppressed trek2a and gnrh3 expressions. Prazosin administration reduced trek2a and gnrh3 expressions. It is suggested that Trek2a regulates gnrh3 expression under the control of Mt1 and α 2 -adrenoceptor. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. Prazosin induced lysosomal tubulation interferes with cytokinesis and the endocytic sorting of the tumour antigen CD98hc.

    PubMed

    Fuchs, Robert; Stracke, Anika; Holzmann, Viktoria; Luschin-Ebengreuth, Gerfried; Meier-Allard, Nathalie; Ebner, Nadine; Lassacher, Teresa Maria; Absenger-Novak, Markus; Fröhlich, Eleonore; Schittmayer, Matthias; Cano Crespo, Sara; Palacin, Manuel; Rinner, Beate; Birner-Gruenberger, Ruth

    2018-06-15

    The quinazoline based drug prazosin (PRZ) is a potent inducer of apoptosis in human cancer cells. We recently reported that PRZ enters cells via endocytosis and induces tubulation of the endolysosomal system. In a proteomics approach aimed at identifying potential membrane proteins with binding affinity to quinazolines, we detected the oncoprotein CD98hc. We confirmed shuttling of CD98hc towards lysosomes and upregulation of CD98hc expression in PRZ treated cells. Gene knockout (KO) experiments revealed that endocytosis of PRZ still occurs in the absence of CD98hc - suggesting that PRZ does not enter the cell via CD98hc but misroutes the protein towards tubular lysosomes. Lysosomal tubulation interfered with completion of cytokinesis and provoked endoreplication. CD98hc KO cells showed reduced endoreplication capacity and lower sensitivity towards PRZ induced apoptosis than wild type cells. Thus, loss of CD98hc does not affect endocytosis of PRZ and lysosomal tubulation, but the ability for endoreplication and survival of cells. Furthermore, we found that glutamine, lysomototropic agents - namely chloroquine and NH 4 Cl - as well as inhibition of v-ATPase, interfere with the intracellular transport of CD98hc. In summary, our study further emphasizes lysosomes as target organelles to inhibit proliferation and to induce cell death in cancer. Most importantly, we demonstrate for the first time that the intracellular trafficking of CD98hc can be modulated by small molecules. Since CD98hc is considered as a potential drug target in several types of human malignancies, our study possesses translational significance suggesting, that old drugs are able to act on a novel target. Copyright © 2018 Elsevier B.V. All rights reserved.

  3. Proton Radiotherapy for Prostate Cancer Is Not Associated With Post-Treatment Testosterone Suppression

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Nichols, R. Charles, E-mail: rnichols@floridaproton.org; University of Florida Proton Therapy Institute, Jacksonville, FL; Morris, Christopher G.

    Purpose: Three independent studies of photon (x-ray) radiotherapy (RT) for prostate cancer have demonstrated evidence of testosterone suppression after treatment. The present study was undertaken to determine whether this would also be the case with conformal protons. Methods and Materials: Between August 2006 and October 2007, 171 patients with low- and intermediate-risk prostate cancer were enrolled and underwent treatment according to University of Florida Proton Therapy Institute institutional review board-approved PR01 and PR02 protocols. Of the 171 patients, 18 were excluded because they had received androgen deprivation therapy either before (n = 17) or after (n = 1) RT. Themore » pretreatment serum testosterone level was available for 150 of the remaining 153 patients. These 150 patients were included in the present study. The post-treatment levels were compared with the pretreatment levels. Results: The median baseline pretreatment serum testosterone level was 357.9 ng/dL. The median post-treatment testosterone value was 375.5 ng/dL at treatment completion (p = .1935) and 369.9 ng/dL (p = .1336), 348.7 ng/dL (p = .7317), 353.4 ng/dL (p = .6996), and 340.9 ng/dL (p = .1669) at 6, 12, 18, and 24 months after proton therapy, respectively. Conclusions: Conformal proton therapy to the prostate, as delivered using University of Florida Proton Therapy Institute PR01 and PR02 protocols, did not appear to significantly affect the serum testosterone levels within 24 months after RT.« less

  4. Prevention and treatment of breast cancer by suppressing aromatase activity and expression.

    PubMed

    Chen, Shiuan; Zhou, Dujin; Okubo, Tomoharu; Kao, Yeh-Chih; Eng, Elizabeth T; Grube, Baiba; Kwon, Annette; Yang, Chun; Yu, Bin

    2002-06-01

    Estrogen promotes the proliferation of breast cancer cells. Aromatase is the enzyme that converts androgen to estrogen. In tumors, expression of aromatase is upregulated compared to that of surrounding noncancerous tissue. Tumor aromatase is thought to stimulate breast cancer growth in both an autocrine and a paracrine manner. A treatment strategy for breast cancer is to abolish in situ estrogen formation with aromatase inhibitors. In addition, aromatase suppression in postmenapausal women is being evaluated as a potential chemopreventive modality against breast cancer. One area of aromatase research in this laboratory is the identification of foods and dietary compounds that can suppress aromatase activity. In vitro and in vivo studies have found that grapes and mushrooms contain chemicals that can inhibit aromatase. Therefore, a diet that includes grapes and mushrooms would be considered preventative against breast cancer. Another area of our aromatase research is the elucidation of the regulatory mechanism of aromatase expression in breast cancer tissue. Increased aromatase expression in breast tumors is attributed to changes in the transcriptional control of aromatase expression. Whereas promoter I.4 is the main promoter that controls aromatase expression in noncancerous breast tissue, promoters II and I.3 are the dominant promoters that drive aromatase expression in breast cancer tissue. Our recent gene regulation studies revealed that in cancerous versus normal tissue, several positive regulatory proteins (e.g., nuclear receptors and CREB1) are present at higher levels and several negative regulatory proteins (e.g., snail and slug proteins) are present at lower levels. This may explain why the activity of promoters II and I.3 is upregulated in cancerous tissue. In addition, our in vitro transcription/translation analysis using plasmids containing T7 promoter and the human snail gene as a reporter capped with different untranslated exon Is revealed that exon

  5. Symptom Presentation and Prescription of Sleep Medications for Veterans With Posttraumatic Stress Disorder.

    PubMed

    Greenbaum, Mark A; Neylan, Thomas C; Rosen, Craig S

    2017-02-01

    This study tested whether sleep medications prescribed to veterans diagnosed with posttraumatic stress disorder (PTSD) are being targeted to patients who report more severe insomnia or nightmares. Secondary analysis of survey and pharmacy data was conducted in samples of veterans from two periods: from 2006 to 2008 and from 2009 to 2013. Logistic regression tested associations between self-reported insomnia and nightmare severity, and being prescribed trazodone, prazosin, zolpidem, and benzodiazepines, controlling for PTSD severity and other covariates. In both samples, insomnia severity independently predicted trazodone receipt, and nightmare severity independently predicted prazosin receipt. In the later study, insomnia severity predicted receipt of zolpidem. Veterans in the later sample were more likely to receive trazodone, prazosin, and non-benzodiazepine hypnotics, and less likely to receive benzodiazepines than those in the earlier sample. Further research is needed to evaluate and optimize pharmacological and psychosocial treatments for sleep problems among veterans with PTSD.

  6. Dynamics of Interocular Suppression in Amblyopic Children during Electronically Monitored Occlusion Therapy: First Insight.

    PubMed

    Kehrein, Stephan; Kohnen, Thomas; Fronius, Maria

    2016-06-01

    Interocular suppression is assumed to be the mechanism leading to impaired visual acuity, especially in strabismic amblyopia. Little is known about the dynamics of suppression during treatment. The aim of our study was to assess the development of the depth of suppression and its relation to changes in visual acuity during electronically monitored occlusion treatment. In a prospective pilot study, 15 amblyopes (8 with and 7 without strabismus) aged 5 to 16 years (mean 10.24 years) were examined before initiation of patching and then every 3 to 6 weeks for 4 months. To quantify suppression, a red filter ladder (Sbisa bar) was used, attenuating the image of the dominant eye until the patients reported a binocular perception (diplopia, rivalry, color mixture) or a change in eye dominance. Acuity was assessed with crowded Landolt rings. Daily occlusion was recorded using occlusion dose monitors. The depth of interocular suppression showed a biphasic change: it increased significantly during the first month (P=0.02), while visual acuity improved (mean 0.14 log units ±0.13; P<0.01). During the following 3 months, median suppression decreased back to the initial values. This reduction in suppression was more pronounced in anisometropic patients without strabismus than in amblyopes with strabismus. The average visual acuity steadily improved (P<0.01) during the 4 months of treatment. Mean recorded patching dose rate was 3.91 h/d. The correlation between mean daily occlusion and suppression changes was not statistically significant. This first insight into the functional changes during electronically monitored patching suggests a complex relationship between visual acuity and interocular suppression that seems to be influenced by the presence of strabismus. Knowledge of the dynamics of interocular suppression is crucial for enhancing the outcome of occlusion treatment and also for the evaluation of its future role compared to emerging dichoptic treatments.

  7. The advantages of subtotal thyroidectomy and suppression of TSH in the primary treatment of papillary carcinoma of the thyroid

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Crile, G. Jr.; Antunez, A.R.; Esselstyn, C.B. Jr.

    1985-06-01

    Patients between the ages of 6 and 45 years with distant metastases from papillary carcinoma of the thyroid can be treated as effectively by subtotal thyroidectomy and suppressive doses of thyroid hormone as by total thyroidectomy followed by treatment with iodine 131 (/sup 131/I). Moreover, distant metastases can be treated by either /sup 131/I or suppression as effectively after they are apparent on x-ray as they can be when treated in a subclinical stage. Therefore, in patients younger than 45 years old it is rarely necessary to perform a total thyroidectomy or to do frequent postoperative scans. In patients oldermore » than 44 or younger than 7 who have distant metastases or extensive involvement of both lobes, total or almost total thyroidectomy is justified if it can be done with minimal morbidity. In patients of this age group whose tumors fail to respond to suppressive doses of thyroid, /sup 131/I should be used. In view of the importance of diagnostic related groups (DRG) to the economy of hospitals, we note that the cost of total thyroidectomy, ablation by /sup 131/I, and intermittent body scans is at least three times that of less radical procedures which, in conjunction with suppression by thyroid feeding, give the same survival with less morbidity.« less

  8. Glechoma hederacea Suppresses RANKL-mediated Osteoclastogenesis.

    PubMed

    Hwang, J K; Erkhembaatar, M; Gu, D R; Lee, S H; Lee, C H; Shin, D M; Lee, Y R; Kim, M S

    2014-07-01

    Glechoma hederacea (GH), commonly known as ground-ivy or gill-over-the-ground, has been extensively used in folk remedies for relieving symptoms of inflammatory disorders. However, the molecular mechanisms underlying the therapeutic action of GH are poorly understood. Here, we demonstrate that GH constituents inhibit osteoclastogenesis by abrogating receptor activator of nuclear κ-B ligand (RANKL)-induced free cytosolic Ca(2+) ([Ca(2+)]i) oscillations. To evaluate the effect of GH on osteoclastogenesis, we assessed the formation of multi-nucleated cells (MNCs), enzymatic activity of tartrate-resistant acidic phosphatase (TRAP), expression of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), and [Ca(2+)]i alterations in response to treatment with GH ethanol extract (GHE) in primarily cultured bone marrow-derived macrophages (BMMs). Treatment of RANKL-stimulated or non-stimulated BMMs with GHE markedly suppressed MNC formation, TRAP activity, and NFATc1 expression in a dose-dependent manner. Additionally, GHE treatment induced a large transient elevation in [Ca(2+)]i while suppressing RANKL-induced [Ca(2+)]i oscillations, which are essential for NFATc1 activation. GHE-evoked increase in [Ca(2+)]i was dependent on extracellular Ca(2+) and was inhibited by 1,4-dihydropyridine (DHP), inhibitor of voltage-gated Ca(2+) channels (VGCCs), but was independent of store-operated Ca(2+) channels. Notably, after transient [Ca(2+)] elevation, treatment with GHE desensitized the VGCCs, resulting in an abrogation of RANKL-induced [Ca(2+)]i oscillations and MNC formation. These findings demonstrate that treatment of BMMs with GHE suppresses RANKL-mediated osteoclastogenesis by activating and then desensitizing DHP-sensitive VGCCs, suggesting potential applications of GH in the treatment of bone disorders, such as periodontitis, osteoporosis, and rheumatoid arthritis. © International & American Associations for Dental Research.

  9. Binocular vision in amblyopia: structure, suppression and plasticity.

    PubMed

    Hess, Robert F; Thompson, Benjamin; Baker, Daniel H

    2014-03-01

    The amblyopic visual system was once considered to be structurally monocular. However, it now evident that the capacity for binocular vision is present in many observers with amblyopia. This has led to new techniques for quantifying suppression that have provided insights into the relationship between suppression and the monocular and binocular visual deficits experienced by amblyopes. Furthermore, new treatments are emerging that directly target suppressive interactions within the visual cortex and, on the basis of initial data, appear to improve both binocular and monocular visual function, even in adults with amblyopia. The aim of this review is to provide an overview of recent studies that have investigated the structure, measurement and treatment of binocular vision in observers with strabismic, anisometropic and mixed amblyopia. © 2014 The Authors Ophthalmic & Physiological Optics © 2014 The College of Optometrists.

  10. Selective Activation of Cannabinoid CB2 Receptors Suppresses Neuropathic Nociception Induced by Treatment with the Chemotherapeutic Agent Paclitaxel in Rats

    PubMed Central

    Rahn, Elizabeth J.; Zvonok, Alexander M.; Thakur, Ganesh A.; Khanolkar, Atmaram D.; Makriyannis, Alexandros; Hohmann, Andrea G.

    2009-01-01

    Activation of cannabinoid CB2 receptors suppresses neuropathic pain induced by traumatic nerve injury. The present studies were conducted to evaluate the efficacy of cannabinoid CB2 receptor activation in suppressing painful peripheral neuropathy evoked by chemotherapeutic treatment with the anti-tumor agent paclitaxel. Rats received paclitaxel (2 mg/kg i.p. per day) on four alternate days to induce mechanical hypersensitivity (mechanical allodynia). Mechanical allodynia was defined as a lowering of the threshold for paw withdrawal to stimulation of the plantar hind paw surface with an electronic von Frey stimulator. Mechanical allodynia developed in paclitaxel-treated animals relative to groups receiving the cremophor: ethanol: saline vehicle at the same times. Two structurally distinct cannabinoid CB2 agonists—the aminoalkylindole (R,S)-AM1241 ((R,S)-(2-iodo-5-nitrophenyl)-[1-((1-methyl-piperidin-2-yl)methyl)-1H-indol-3-yl]-methanone) and the cannabilactone AM1714 (1,9-dihydroxy-3-(1′,1′-dimethylheptyl)-6H-benzo[c]chromene-6-one)—produced a dose-related suppression of established paclitaxel-evoked mechanical allodynia following systemic administration. Pretreatment with the CB2 antagonist SR144528 (5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-N-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)-1H-pyrazole-3-carboxamide), but not the CB1 antagonist SR141716 (5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide), blocked the anti-allodynic effects of both (R,S)-AM1241 and AM1714. Moreover, (R)-AM1241, but not (S)-AM1241, suppressed paclitaxel-evoked mechanical allodynia relative to either vehicle treatment or pre-injection thresholds, consistent with mediation by CB2. Administration of either the CB1 or CB2 antagonist alone failed to alter paclitaxel-evoked mechanical allodynia. Moreover, (R,S)-AM1241 did not alter paw withdrawal thresholds in rats that received the cremophor vehicle in lieu of paclitaxel whereas AM1714

  11. Best practice guide for the treatment of nightmare disorder in adults.

    PubMed

    Aurora, R Nisha; Zak, Rochelle S; Auerbach, Sanford H; Casey, Kenneth R; Chowdhuri, Susmita; Karippot, Anoop; Maganti, Rama K; Ramar, Kannan; Kristo, David A; Bista, Sabin R; Lamm, Carin I; Morgenthaler, Timothy I

    2010-08-15

    Prazosin is recommended for treatment of Posttraumatic Stress Disorder (PTSD)-associated nightmares. Level A. Image Rehearsal Therapy (IRT) is recommended for treatment of nightmare disorder. Level A. Systematic Desensitization and Progressive Deep Muscle Relaxation training are suggested for treatment of idiopathic nightmares. Level B. Venlafaxine is not suggested for treatment of PTSD-associated nightmares. Level B. Clonidine may be considered for treatment of PTSD-associated nightmares. Level C. The following medications may be considered for treatment of PTSD-associated nightmares, but the data are low grade and sparse: trazodone, atypical antipsychotic medications, topiramate, low dose cortisol, fluvoxamine, triazolam and nitrazepam, phenelzine, gabapentin, cyproheptadine, and tricyclic antidepressants. Nefazodone is not recommended as first line therapy for nightmare disorder because of the increased risk of hepatotoxicity. Level C. The following behavioral therapies may be considered for treatment of PTSD-associated nightmares based on low-grade evidence: Exposure, Relaxation, and Rescripting Therapy (ERRT); Sleep Dynamic Therapy; Hypnosis; Eye-Movement Desensitization and Reprocessing (EMDR); and the Testimony Method. Level C. The following behavioral therapies may be considered for treatment of nightmare disorder based on low-grade evidence: Lucid Dreaming Therapy and Self-Exposure Therapy. Level C No recommendation is made regarding clonazepam and individual psychotherapy because of sparse data.

  12. A Comparison of Urge Intensity and the Probability of Tic Completion During Tic Freely and Tic Suppression Conditions.

    PubMed

    Specht, Matt W; Nicotra, Cassandra M; Kelly, Laura M; Woods, Douglas W; Ricketts, Emily J; Perry-Parrish, Carisa; Reynolds, Elizabeth; Hankinson, Jessica; Grados, Marco A; Ostrander, Rick S; Walkup, John T

    2014-03-01

    Tic-suppression-based treatments (TSBTs) represent a safe and effective treatment option for Chronic Tic Disorders (CTDs). Prior research has demonstrated that treatment naive youths with CTDs have the capacity to safely and effectively suppress tics for prolonged periods. It remains unclear how tic suppression is achieved. The current study principally examines how effective suppression is achieved and preliminary correlates of the ability to suppress tics. Twelve youths, ages 10 to 17 years, with moderate-to-marked CTDs participated in an alternating sequence of tic freely and reinforced tic suppression conditions during which urge intensity and tic frequency were frequently assessed. Probability of tics occurring was half as likely following high-intensity urges during tic suppression (31%) in contrast to low-intensity urges during tic freely conditions (60%). Age was not associated with ability to suppress. Intelligence indices were associated with or trended toward greater ability to suppress tics. Attention difficulties were not associated with ability to suppress but were associated with tic severity. In contrast to our "selective suppression" hypothesis, we found participants equally capable of suppressing their tics regardless of urge intensity during reinforced tic suppression. Tic suppression was achieved with an "across-the-board" effort to resist urges. Preliminary data suggest that ability to suppress may be associated with general cognitive variables rather than age, tic severity, urge severity, and attention. Treatment naive youths appear to possess a capacity for robust tic suppression. TSBTs may bolster these capacities and/or enable their broader implementation, resulting in symptom improvement. © The Author(s) 2014.

  13. A limited CpG-containing oligodeoxynucleotide therapy regimen induces sustained suppression of allergic airway inflammation in mice

    PubMed Central

    Kozy, Heather M.; Lum, Jeremy A.; Sweetwood, Rosemary; Chu, Mabel; Cunningham, Cameron R.; Salamon, Hugh; Lloyd, Clare M.; Coffman, Robert L.; Hessel, Edith M.

    2015-01-01

    Background CpG-containing oligodeoxynucleotides (CpG-ODN) are potent inhibitors of Th2-mediated allergic airway disease in sensitized mice challenged with allergen. A single treatment has transient effects but a limited series of treatments has potential to achieve clinically meaningful sustained inhibition of allergic airway disease. Objective To optimize the treatment regimen and determine the mechanisms of action in mice of an inhaled form of CpG-ODN being developed for human asthma treatment. Methods A limited series of weekly intranasal 1018 ISS (CpG-ODN; B-class) treatments were given to ragweed allergen-sensitized mice chronically exposed to allergen during and after the 1018 ISS treatment regimen. Treatment effects were evaluated by measuring effect on lung Th2 cytokines and eosinophilia as well as lung dendritic cell function and T cell responses. Results Twelve intranasal 1018 ISS treatments induced significant suppression of BAL eosinophilia and IL-4, IL-5, and IL-13 levels and suppression was maintained through 13 weekly ragweed exposures administered after treatment cessation. At least 5 treatments were required for lasting Th2 suppression. CpG-ODN induced moderate Th1 responses but Th2 suppression did not require IFN-γ. Th2 suppression was associated with induction of a regulatory T cell response. Conclusion A short series of CpG-ODN treatments results in sustained suppression of allergic lung inflammation induced by a clinically relevant allergen. PMID:24464743

  14. Pharmacological treatment of comorbid PTSD and substance use disorder: recent progress.

    PubMed

    Sofuoglu, Mehmet; Rosenheck, Robert; Petrakis, Ismene

    2014-02-01

    Previous research has identified a strong association between posttraumatic stress disorder (PTSD) and substance use disorder (SUD), necessitating the development of treatments that address both conditions. Some pharmacotherapies are effective for the treatment of PTSD and SUD alone, however; no medications have been proven to be effective for the combination of these conditions. We review the recent advances in pharmacological treatment of comorbid PTSD and SUD. A randomized clinical trial of sertraline, a serotonin reuptake inhibitor (SSRI), did not show overall efficacy for comorbid PTSD and alcohol dependence (AD), although it may have efficacy among light drinkers. Another clinical trial demonstrated the efficacy of both disulfiram and naltrexone for the treatment of AD in individuals with PTSD. A more recent clinical trial suggested that norepinephrine uptake inhibitors may also have efficacy for the treatment of comorbid PTSD and AD. In animal and preliminary human studies, brain norepinephrine and glutamate/GABA have emerged as potential treatment targets for comorbid PTSD and SUD. Noradrenergic medications that are promising for comorbid PTSD and SUD include prazosin, guanfacine, and atomoxetine. Promising glutamate/GABA medications include topiramate, memantine, acamprosate, N-acetylcysteine (NAC), and ketamine. The safety and efficacy of these medications for the treatment of PTSD and SUD need to be tested in controlled clinical trials. Published by Elsevier Ltd.

  15. The regional extent of suppression: strabismics versus nonstrabismics.

    PubMed

    Babu, Raiju Jacob; Clavagnier, Simon R; Bobier, William; Thompson, Benjamin; Hess, Robert F

    2013-10-09

    Evidence is accumulating that suppression may be the cause of amblyopia rather than a secondary consequence of mismatched retinal images. For example, treatment interventions that target suppression may lead to better binocular and monocular outcomes. Furthermore, it has recently been demonstrated that the measurement of suppression may have prognostic value for patching therapy. For these reasons, the measurement of suppression in the clinic needs to be improved beyond the methods that are currently available, which provide a binary outcome. We describe a novel quantitative method for measuring the regional extent of suppression that is suitable for clinical use. The method involves a dichoptic perceptual matching procedure at multiple visual field locations. We compare a group of normal controls (mean age: 28 ± 5 years); a group with strabismic amblyopia (four with microesotropia, five with esotropia, and one with exotropia; mean age: 35 ± 10 years); and a group with nonstrabismic anisometropic amblyopia (mean age: 33 ± 12 years). The extent and magnitude of suppression was similar for observers with strabismic and nonstrabismic amblyopia. Suppression was strongest within the central field and extended throughout the 20° field that we measured. Suppression extends throughout the central visual field in both strabismic and anisometropic forms of amblyopia. The strongest suppression occurs within the region of the visual field corresponding to the fovea of the fixing eye.

  16. Patterns and Predictors of Tic Suppressibility in Youth With Tic Disorders

    PubMed Central

    Conelea, Christine A.; Wellen, Brianna; Woods, Douglas W.; Greene, Deanna J.; Black, Kevin J.; Specht, Matthew; Himle, Michael B.; Lee, Han-Joo; Capriotti, Matthew

    2018-01-01

    Tic suppression is the primary target of tic disorder treatment, but factors that influence voluntary tic inhibition are not well understood. Several studies using the Tic Suppression Task have demonstrated significant inter-individual variability in tic suppressibility but have individually been underpowered to address correlates of tic suppression. The present study explored patterns and clinical correlates of reward-enhanced tic suppression in youth with tic disorders using a large, pooled dataset. Individual-level data from nine studies using the Tic Suppression Task were pooled, yielding a sample of 99 youth with tic disorders. Analyses examined patterns of tic suppressibility and the relationship between tic suppressibility and demographic and clinical characteristics. A large majority of youth demonstrated a high degree of tic suppression, but heterogeneous patterns of tic suppressibility were also observed. Better tic suppressibility was related to older age and more frequent tics but unrelated to other clinical variables, including presence of psychiatric comorbidity, psychotropic medication status, tic and premonitory urge severity, and self-rated tic suppressibility. The mechanisms underlying the observed heterogeneity in reward-enhanced tic suppressibility warrant further investigation. The Tic Suppression Task is a promising method for testing mechanistic hypotheses related to tic suppression. PMID:29875706

  17. Patterns and Predictors of Tic Suppressibility in Youth With Tic Disorders.

    PubMed

    Conelea, Christine A; Wellen, Brianna; Woods, Douglas W; Greene, Deanna J; Black, Kevin J; Specht, Matthew; Himle, Michael B; Lee, Han-Joo; Capriotti, Matthew

    2018-01-01

    Tic suppression is the primary target of tic disorder treatment, but factors that influence voluntary tic inhibition are not well understood. Several studies using the Tic Suppression Task have demonstrated significant inter-individual variability in tic suppressibility but have individually been underpowered to address correlates of tic suppression. The present study explored patterns and clinical correlates of reward-enhanced tic suppression in youth with tic disorders using a large, pooled dataset. Individual-level data from nine studies using the Tic Suppression Task were pooled, yielding a sample of 99 youth with tic disorders. Analyses examined patterns of tic suppressibility and the relationship between tic suppressibility and demographic and clinical characteristics. A large majority of youth demonstrated a high degree of tic suppression, but heterogeneous patterns of tic suppressibility were also observed. Better tic suppressibility was related to older age and more frequent tics but unrelated to other clinical variables, including presence of psychiatric comorbidity, psychotropic medication status, tic and premonitory urge severity, and self-rated tic suppressibility. The mechanisms underlying the observed heterogeneity in reward-enhanced tic suppressibility warrant further investigation. The Tic Suppression Task is a promising method for testing mechanistic hypotheses related to tic suppression.

  18. HIV-1 Viral Escape in Cerebrospinal Fluid of Subjects on Suppressive Antiretroviral Treatment

    PubMed Central

    Edén, Arvid; Fuchs, Dietmar; Hagberg, Lars; Nilsson, Staffan; Spudich, Serena; Svennerholm, Bo; Price, Richard W.; Gisslén, Magnus

    2010-01-01

    Background. Occasional cases of viral escape in cerebrospinal fluid (CSF) despite suppression of plasma human immunodeficiency virus type 1 (HIV-1) RNA have been reported. We investigated CSF viral escape in subjects treated with commonly used antiretroviral therapy regimens in relation to intrathecal immune activation and central nervous system penetration effectiveness (CPE) rank. Methods. Sixty-nine neurologically asymptomatic subjects treated with antiretroviral therapy >6 months and plasma HIV-1 RNA <50 copies/mL were cross-sectionally included in the analysis. Antiretroviral therapy regimens included efavirenz, lopinavir/ritonavir or atazanavir/ritonavir combined with tenofovir, abacavir, or zidovudine and emtricitabine or lamivudine. HIV-1 RNA was analyzed with real-time polymerase chain reaction assays. Neopterin was analyzed by enzyme-linked immunosorbent assay. Results. Seven (10%) of the 69 subjects had detectable CSF HIV-1 RNA, in median 121 copies/mL (interquartile range, 54–213 copies/mL). Subjects with detectable CSF virus had significantly higher CSF neopterin and longer duration of treatment. Previous treatment interruptions were more common in subjects with CSF escape. Central nervous system penetration effectiveness rank was not a significant predictor of detectable CSF virus or CSF neopterin levels. Conclusions. Viral escape in CSF is more common than previously reported, suggesting that low-grade central nervous system infection may continue in treated patients. Although these findings need extension in longitudinal studies, they suggest the utility of monitoring CSF responses, as new treatment combinations and strategies modify clinical practice. PMID:21050119

  19. HIV-1 viral escape in cerebrospinal fluid of subjects on suppressive antiretroviral treatment.

    PubMed

    Edén, Arvid; Fuchs, Dietmar; Hagberg, Lars; Nilsson, Staffan; Spudich, Serena; Svennerholm, Bo; Price, Richard W; Gisslén, Magnus

    2010-12-15

    Occasional cases of viral escape in cerebrospinal fluid (CSF) despite suppression of plasma human immunodeficiency virus type 1 (HIV-1) RNA have been reported. We investigated CSF viral escape in subjects treated with commonly used antiretroviral therapy regimens in relation to intrathecal immune activation and central nervous system penetration effectiveness (CPE) rank. Sixty-nine neurologically asymptomatic subjects treated with antiretroviral therapy >6 months and plasma HIV-1 RNA <50 copies/mL were cross-sectionally included in the analysis. Antiretroviral therapy regimens included efavirenz, lopinavir/ritonavir or atazanavir/ritonavir combined with tenofovir, abacavir, or zidovudine and emtricitabine or lamivudine. HIV-1 RNA was analyzed with real-time polymerase chain reaction assays. Neopterin was analyzed by enzyme-linked immunosorbent assay. Seven (10%) of the 69 subjects had detectable CSF HIV-1 RNA, in median 121 copies/mL (interquartile range, 54-213 copies/mL). Subjects with detectable CSF virus had significantly higher CSF neopterin and longer duration of treatment. Previous treatment interruptions were more common in subjects with CSF escape. Central nervous system penetration effectiveness rank was not a significant predictor of detectable CSF virus or CSF neopterin levels. Viral escape in CSF is more common than previously reported, suggesting that low-grade central nervous system infection may continue in treated patients. Although these findings need extension in longitudinal studies, they suggest the utility of monitoring CSF responses, as new treatment combinations and strategies modify clinical practice.

  20. Novel Americium Treatment Process for Surface Water and Dust Suppression Water

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tiepel, E.W.; Pigeon, P.; Nesta, S.

    2006-07-01

    treat Am-241 contaminated pond water, surface run-off and D and D dust suppression water during the later stages of the D and D effort at Rocky Flats. This novel chemical treatment system allowed for highly efficient, high-volume treatment of all contaminated waste waters to the very low stream standard of 0.15 pCi/1 with strict compliance to the RFCA discharge criteria for release to off-site surface waters. The rapid development and implementation of the treatment system avoided water management issues that would have had to be addressed if contaminated water had remained in Pond A-4 into the Spring of 2005. Implementation of this treatment system for the Pond A-4 waters and the D and D waters from Buildings 776 and 371 enabled the site to achieve cost-effective treatment that minimized secondary waste generation, avoiding the need for expensive off-site water disposal. Water treatment was conducted for a cost of less than $0.20/gal which included all development costs, capital costs and operational costs. This innovative and rapid response effort saved the RFETS cleanup program well in excess of $30 million for the potential cost of off-site transportation and treatment of radioactive liquid waste. (authors)« less

  1. Shikonin Suppresses Skin Carcinogenesis via Inhibiting Cell Proliferation

    PubMed Central

    Ren, Amy; Li, Teena; Jin, Rong; Li, Guohong; Gu, Xin; Shi, Runhua; Zhao, Yunfeng

    2015-01-01

    The M2 isoform of pyruvate kinase M2 (PKM2) has been shown to be up-regulated in human skin cancers. To test whether PKM2 may be a target for chemoprevention, shikonin, a natural product from the root of Lithospermum erythrorhizon and a specific inhibitor of PKM2, was used in a chemically-induced mouse skin carcinogenesis study. The results revealed that shikonin treatment suppressed skin tumor formation. Morphological examinations and immunohistochemical staining of the skin epidermal tissues suggested that shikonin inhibited cell proliferation without inducing apoptosis. Although shikonin alone suppressed PKM2 activity, it did not suppress tumor promoter-induced PKM2 activation in the skin epidermal tissues at the end of the skin carcinogenesis study. To reveal the potential chemopreventive mechanism of shikonin, an antibody microarray analysis was performed, and the results showed that the transcription factor ATF2 and its downstream target Cdk4 were up-regulated by chemical carcinogen treatment; whereas these up-regulations were suppressed by shikonin. In a promotable skin cell model, the nuclear levels of ATF2 were increased during tumor promotion, whereas this increase was inhibited by shikonin. Furthermore, knockdown of ATF2 decreased the expression levels of Cdk4 and Fra-1 (a key subunit of the activator protein 1. In summary, these results suggest that shikonin, rather than inhibiting PKM2 in vivo, suppresses the ATF2 pathway in skin carcinogenesis. PMID:25961580

  2. Mindfulness-based cognitive therapy for depressed individuals improves suppression of irrelevant mental-sets.

    PubMed

    Greenberg, Jonathan; Shapero, Benjamin G; Mischoulon, David; Lazar, Sara W

    2017-04-01

    An impaired ability to suppress currently irrelevant mental-sets is a key cognitive deficit in depression. Mindfulness-based cognitive therapy (MBCT) was specifically designed to help depressed individuals avoid getting caught in such irrelevant mental-sets. In the current study, a group assigned to MBCT plus treatment-as-usual (n = 22) exhibited significantly lower depression scores and greater improvements in irrelevant mental-set suppression compared to a wait-list plus treatment-as-usual (n = 18) group. Improvements in mental-set-suppression were associated with improvements in depression scores. Results provide the first evidence that MBCT can improve suppression of irrelevant mental-sets and that such improvements are associated with depressive alleviation.

  3. Mindfulness-based cognitive therapy may reduce thought suppression in previously suicidal participants: findings from a preliminary study.

    PubMed

    Hepburn, Silvia R; Crane, Catherine; Barnhofer, Thorsten; Duggan, Danielle S; Fennell, Melanie J V; Williams, J Mark G

    2009-06-01

    Thought suppression is a strategy aimed at mental control that may paradoxically increase the frequency of unwanted thoughts. This preliminary study examined effects of mindfulness-based cognitive therapy (MBCT) on thought suppression and depression in individuals with past depression and suicidality. In a randomized controlled trial design, 68 participants were allocated to an MBCT group or a treatment-as-usual waitlist control. Measures of thought suppression and depression were taken pre- and post-treatment. MBCT did not reduce thought suppression as measured by the White Bear Suppression Inventory, but significantly reduced self-reported attempts to suppress in the previous week. Preliminary evidence suggests that MBCT for suicidality may reduce thought suppression, but differential effects on thought suppression measures warrant further studies.

  4. Adverse events in IBD: to stop or continue immune suppressant and biologic treatment.

    PubMed

    McLean, Leon P; Cross, Raymond K

    2014-03-01

    Crohn's disease and ulcerative colitis affect an increasing number of patients. A variety of medical options exist for the treatment of these diseases including immune suppressants and biologic therapies. Unfortunately, these agents are associated with adverse events ranging from mild nuisance symptoms to potentially life-threatening complications including infections and malignancies. This review discusses adverse events associated with azathioprine, mercaptopurine, and methotrexate as well as anti-TNF-α and anti-integrin antibodies. In addition, adverse events associated with combination therapy are discussed as are clinical scenarios in which it may be reasonable to discontinue or de-escalate drug therapy. It is the responsibility of the treating gastroenterologist to effectively communicate the benefits and risks of therapy with patients; this review offers strategies that may assist providers in communicating risk with patients in addition to offering our perspective on whether modification or cessation of therapy can be considered.

  5. Adverse events in IBD: to stop or continue immune suppressant and biologic treatment

    PubMed Central

    McLean, Leon P; Cross, Raymond K

    2014-01-01

    Crohn’s disease and ulcerative colitis affect an increasing number of patients. A variety of medical options exist for the treatment of these diseases including immune suppressants and biologic therapies. Unfortunately, these agents are associated with adverse events ranging from mild nuisance symptoms to potentially life-threatening complications including infections and malignancies. This review discusses adverse events associated with azathioprine, mercaptopurine, and methotrexate as well as anti-TNF-α and anti-integrin antibodies. In addition, adverse events associated with combination therapy are discussed as are clinical scenarios in which it may be reasonable to discontinue or de-escalate drug therapy. It is the responsibility of the treating gastroenterologist to effectively communicate the benefits and risks of therapy with patients; this review offers strategies that may assist providers in communicating risk with patients in addition to offering our perspective on whether modification or cessation of therapy can be considered. PMID:24490595

  6. Regional Extent of Peripheral Suppression in Amblyopia.

    PubMed

    Babu, Raiju J; Clavagnier, Simon; Bobier, William R; Thompson, Benjamin; Hess, Robert F

    2017-04-01

    Previously, we have mapped amblyopic eye suppression within the central 20° of the visual field and observed a gradient of suppression that is strongest in central vision and weakens with increasing eccentricity. In this study, using a large dichoptic display, we extend our novel suppression mapping approach further into the periphery (from 20°-60°) to assess whether suppression continues to decline with eccentricity or plateaus. Sixteen participants with amblyopia (10 with strabismus, 6 with anisometropia without strabismus; mean age: 37.9 ± 11 years) and six normal observers (mean age: 28.3 ± 5 years) took part. The visual stimulus (60° diameter), viewed from 57 cm, was composed of four concentric annuli (5° radius) with alternate contrast polarities starting from an eccentricity of 10°. Each annulus was divided into eight sectors subtending 45° of visual angle. Participants adjusted the contrast of a single sector presented to the fellow eye to match the perceived contrast of the remaining stimulus elements that were presented to the amblyopic eye. A matching contrast that was lower in the fellow eye than the amblyopic eye indicated suppression. Patients with strabismus exhibited significantly stronger interocular suppression than controls across all eccentricities (P = 0.01). Patients with anisometropia did not differ from controls (P = 0.58). Suppression varied significantly with eccentricity (P = 0.005) but this effect did not differ between patient groups (P = 0.217). In amblyopia, suppression is present beyond the central 10° in patients with strabismus. Suppression becomes weaker at greater eccentricities and this may enable peripheral fusion that could be used by binocular treatment methods.

  7. Alpha 1-adrenergic blockade does not alter control of skin blood flow during exercise.

    PubMed

    Kenney, W L; Tankersley, C G; Newswanger, D L; Puhl, S M

    1991-03-01

    Human skin blood flow (SkBF) is controlled by both an alpha-adrenergic vasoconstrictor system and an active vasodilator system. During upright dynamic exercise, SkBF increases linearly with increasing body core temperature (Tc) until higher (i.e., greater than 38 degrees C) Tcs, beyond which little further increase in SkBF occurs. To examine the role of the two efferent control arms in this attenuated SkBF rise, we tested nine men (aged 25-53 yr) with and without (placebo) orally administered prazosin HCl (an alpha 1-adrenergic antagonist) during 1 h of moderate cycle exercise (100 W) in a warm (36 degrees C, 45% relative humidity) environment. Blockade of reflex vasoconstriction was verified via a cold challenge. During exercise, mean arterial pressure (MAP, brachial auscultation) was significantly lower (P less than 0.03) and heart rate significantly higher (P less than 0.02) during the prazosin trials; plasma catecholamine concentrations were unaffected. Neither esophageal temperature (Tes) nor mean skin temperature was affected by the drug during exercise. Forearm vascular conductance (FVC) was calculated from forearm blood flow (FBF, venous occlusion plethysmography) and MAP (FVC = FBF/MAP). FVC plotted as a function of time or Tes resulted in coincident response patterns for the placebo and prazosin treatments, reaching a plateau at a Tes of about 38 degrees C. The responses of the older men were not selectively altered by prazosin treatment, indicating that the lower FBF responses previously seen in older subjects during exercise in the heat does not appear to be the result of an increased alpha 1-adrenergic tone.(ABSTRACT TRUNCATED AT 250 WORDS)

  8. Suppression of bovine lymphocyte function by treatment with physiologic concentrations of cortisone

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ojo-Amaize, E.A.; Paape, M.J.; Guidry, A.J.

    1986-03-01

    The blastogenic response of peripheral blood lymphocytes (PBL) (8 cows) to capsular antigen extract of Staphylococcus aureus, PHA and LPS was measured in vitro using /sup 5/H-thymidine pulse labelling. isolated PBL were treated in vitro for 6-8 days with 10, 25 and 45 ng/ml cortisone. These concentrations simulate serum corticosteroid levels during environmental stress, acute clinical mastitis and ACTH therapy, respectively. To determine the minimal concentration of cortisone that would induce suppression, PBL were also incubated with increasing concentrations of cortisone starting at 10 pg/ml. All concentrations of cortisone caused a significant (P<0.01) depression of lymphocyte blastogenic response to S.more » aureus, PHA and LPS. Macrophage depletion experiments showed no macrophage suppressor effects. Both the blastogenic response of untreated peripheral blood lymphocytes to S. aureus, PHA and LPS and the degree to which that response was suppressed by cortisone differed significantly among cows. Results indicate that cortisone levels found during physiological stress and after therapeutic administration of ACTH can suppress lymphocyte function.« less

  9. Advancements in the treatment of agitation in Alzheimer's disease.

    PubMed

    Antonsdottir, Inga M; Smith, Jessica; Keltz, Melanie; Porsteinsson, Anton P

    2015-01-01

    Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are associated with significant negative outcomes for patients and their caregivers. Agitation, one of the most distressing NPS, lacks well-established long-term interventions that are both effective and safe. While non-pharmacological interventions are the suggested first-line treatment, it isn't effective in managing symptoms for every patient. In such cases, clinicians turn to the use of pharmacological interventions. Traditionally, these interventions consist of off-label use of antipsychotics, sedative/hypnotics, anxiolytics, acetylcholinesterase inhibitors, memantine and antidepressants, where the efficacy doesn't necessarily outweigh the associated risks. Gains made in understanding the neurobiological mechanisms underlying agitation have fueled several recent clinical trials. A comprehensive literature search for published articles evaluating pharmacologic interventions for agitation in AD was done. A review of some of these clinical trials was completed: dextromethorphan/quinidine, scyllo-inositol, brexpiprazole, prazosin, cannabinoids, dronabinol and citalopram show promise in treating agitation. Neurobiological findings and enhanced trial designs have re-ignited the area of pharmacological treatment of NPS. Although further research is needed to fully determine the safety, tolerability and efficacy of these treatments, the mission to finding effective treatments for NPS such as agitation in patients with dementia is well underway.

  10. Bird assemblage response to restoration of fire-suppressed longleaf pine sandhills.

    PubMed

    Steen, David A; Conner, L M; Smith, Lora L; Provencher, Louis; Hiers, J Kevin; Pokswinski, Scott; Helms, Brian S; Guyer, Craig

    2013-01-01

    The ecological restoration of fire-suppressed habitats may require a multifaceted approach. Removal of hardwood trees together with reintroduction of fire has been suggested as a method of restoring fire-suppressed longleaf pine (Pinus palustris) forests; however, this strategy, although widespread, has not been evaluated on large spatial and temporal scales. We used a landscape-scale experimental design to examine how bird assemblages in fire-suppressed longleaf pine sandhills responded to fire alone or fire following mechanical removal or herbicide application to reduce hardwood levels. Individual treatments were compared to fire-suppressed controls and reference sites. After initial treatment, all sites were managed with prescribed fire, on an approximately two- to three-year interval, for over a decade. Nonmetric multidimensional scaling ordinations suggested that avian assemblages on sites that experienced any form of hardwood removal differed from assemblages on both fire-suppressed sites and reference sites 3-4 years after treatment (i.e., early posttreatment). After >10 years of prescribed burning on all sites (i.e., late posttreatment), only assemblages at sites treated with herbicide were indistinguishable from assemblages at reference sites. By the end of the study, individual species that were once indicators of reference sites no longer contributed to making reference sites unique. Occupancy modeling of these indicator species also demonstrated increasing similarity across treatments over time. Overall, although we documented long-term and variable assemblage-level change, our results indicate occupancy for birds considered longleaf pine specialists was similar at treatment and reference sites after over a decade of prescribed burning, regardless of initial method of hardwood removal. In other words, based on the response of species highly associated with the habitat, we found no justification for the added cost and effort of fire surrogates; fire

  11. Interocular suppression in children with deprivation amblyopia.

    PubMed

    Hamm, Lisa; Chen, Zidong; Li, Jinrong; Black, Joanna; Dai, Shuan; Yuan, Junpeng; Yu, Minbin; Thompson, Benjamin

    2017-04-01

    In patients with anisometropic or strabismic amblyopia, interocular suppression can be minimized by presenting high contrast stimulus elements to the amblyopic eye and lower contrast elements to the fellow eye. This suggests a structurally intact binocular visual system that is functionally suppressed. We investigated whether suppression can also be overcome by contrast balancing in children with deprivation amblyopia due to childhood cataracts. To quantify interocular contrast balance, contrast interference thresholds were measured using an established dichoptic global motion technique for 21 children with deprivation amblyopia, 14 with anisometropic or mixed strabismic/anisometropic amblyopia and 10 visually normal children (mean age mean=9.9years, range 5-16years). We found that interocular suppression could be overcome by contrast balancing in most children with deprivation amblyopia, at least intermittently, and all children with anisometropic or mixed anisometropic/strabismic amblyopia. However, children with deprivation amblyopia due to early unilateral or bilateral cataracts could tolerate only very low contrast levels to the stronger eye indicating strong suppression. Our results suggest that treatment options reliant on contrast balanced dichoptic presentation could be attempted in a subset of children with deprivation amblyopia. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Adjuvant ovarian suppression in premenopausal breast cancer.

    PubMed

    Francis, Prudence A; Regan, Meredith M; Fleming, Gini F; Láng, István; Ciruelos, Eva; Bellet, Meritxell; Bonnefoi, Hervé R; Climent, Miguel A; Da Prada, Gian Antonio; Burstein, Harold J; Martino, Silvana; Davidson, Nancy E; Geyer, Charles E; Walley, Barbara A; Coleman, Robert; Kerbrat, Pierre; Buchholz, Stefan; Ingle, James N; Winer, Eric P; Rabaglio-Poretti, Manuela; Maibach, Rudolf; Ruepp, Barbara; Giobbie-Hurder, Anita; Price, Karen N; Colleoni, Marco; Viale, Giuseppe; Coates, Alan S; Goldhirsch, Aron; Gelber, Richard D

    2015-01-29

    Suppression of ovarian estrogen production reduces the recurrence of hormone-receptor-positive early breast cancer in premenopausal women, but its value when added to tamoxifen is uncertain. We randomly assigned 3066 premenopausal women, stratified according to prior receipt or nonreceipt of chemotherapy, to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. The primary analysis tested the hypothesis that tamoxifen plus ovarian suppression would improve disease-free survival, as compared with tamoxifen alone. In the primary analysis, 46.7% of the patients had not received chemotherapy previously, and 53.3% had received chemotherapy and remained premenopausal. After a median follow-up of 67 months, the estimated disease-free survival rate at 5 years was 86.6% in the tamoxifen-ovarian suppression group and 84.7% in the tamoxifen group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.83; 95% confidence interval [CI], 0.66 to 1.04; P=0.10). Multivariable allowance for prognostic factors suggested a greater treatment effect with tamoxifen plus ovarian suppression than with tamoxifen alone (hazard ratio, 0.78; 95% CI, 0.62 to 0.98). Most recurrences occurred in patients who had received prior chemotherapy, among whom the rate of freedom from breast cancer at 5 years was 82.5% in the tamoxifen-ovarian suppression group and 78.0% in the tamoxifen group (hazard ratio for recurrence, 0.78; 95% CI, 0.60 to 1.02). At 5 years, the rate of freedom from breast cancer was 85.7% in the exemestane-ovarian suppression group (hazard ratio for recurrence vs. tamoxifen, 0.65; 95% CI, 0.49 to 0.87). Adding ovarian suppression to tamoxifen did not provide a significant benefit in the overall study population. However, for women who were at sufficient risk for recurrence to warrant adjuvant chemotherapy and who remained premenopausal, the addition of ovarian suppression improved disease outcomes. Further

  13. Arsenite suppression of BMP signaling in human keratinocytes

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Phillips, Marjorie A.; Qin, Qin; Hu, Qin

    2013-06-15

    Arsenic, a human skin carcinogen, suppresses differentiation of cultured keratinocytes. Exploring the mechanism of this suppression revealed that BMP-6 greatly increased levels of mRNA for keratins 1 and 10, two of the earliest differentiation markers expressed, a process prevented by co-treatment with arsenite. BMP also stimulated, and arsenite suppressed, mRNA for FOXN1, an important transcription factor driving early keratinocyte differentiation. Keratin mRNAs increased slowly after BMP-6 addition, suggesting they are indirect transcriptional targets. Inhibition of Notch1 activation blocked BMP induction of keratins 1 and 10, while FOXN1 induction was largely unaffected. Supporting a requirement for Notch1 signaling in keratin induction,more » BMP increased levels of activated Notch1, which was blocked by arsenite. BMP also greatly decreased active ERK, while co-treatment with arsenite maintained active ERK. Inhibition of ERK signaling mimicked BMP by inducing keratin and FOXN1 mRNAs and by increasing active Notch1, effects blocked by arsenite. Of 6 dual-specificity phosphatases (DUSPs) targeting ERK, two were induced by BMP unless prevented by simultaneous exposure to arsenite and EGF. Knockdown of DUSP2 or DUSP14 using shRNAs greatly reduced FOXN1 and keratins 1 and 10 mRNA levels and their induction by BMP. Knockdown also decreased activated Notch1, keratin 1 and keratin 10 protein levels, both in the presence and absence of BMP. Thus, one of the earliest effects of BMP is induction of DUSPs, which increases FOXN1 transcription factor and activates Notch1, both required for keratin gene expression. Arsenite prevents this cascade by maintaining ERK signaling, at least in part by suppressing DUSP expression. - Highlights: • BMP induces FOXN1 transcription. • BMP induces DUSP2 and DUSP14, suppressing ERK activation. • Arsenite suppresses levels of phosphorylated Smad1/5 and FOXN1 and DUSP mRNA. • These actions rationalize arsenite suppression of

  14. Allowing a wildfire to burn: estimating the effect on future fire suppression costs

    Treesearch

    Rachel M. Houtman; Claire A. Montgomery; Aaron R. Gagnon; David E. Calkin; Thomas G. Dietterich; Sean McGregor; Mark Crowley

    2013-01-01

    Where a legacy of aggressive wildland fire suppression has left forests in need of fuel reduction, allowing wildland fire to burn may provide fuel treatment benefits, thereby reducing suppression costs from subsequent fires. The least-cost-plus-net-value-change model of wildland fire economics includes benefits of wildfire in a framework for evaluating suppression...

  15. Suppression of nonsense mutations as a therapeutic approach to treat genetic diseases.

    PubMed

    Keeling, Kim M; Bedwell, David M

    2011-01-01

    Suppression therapy is a treatment strategy for genetic diseases caused by nonsense mutations. This therapeutic approach utilizes pharmacological agents that suppress translation termination at in-frame premature termination codons (PTCs) to restore translation of a full-length, functional polypeptide. The efficiency of various classes of compounds to suppress PTCs in mammalian cells is discussed along with the current limitations of this therapy. We also elaborate on approaches to improve the efficiency of suppression that include methods to enhance the effectiveness of current suppression drugs and the design or discovery of new, more effective suppression agents. Finally, we discuss the role of nonsense-mediated mRNA decay (NMD) in limiting the effectiveness of suppression therapy, and describe tactics that may allow the efficiency of NMD to be modulated in order to enhance suppression therapy. Copyright © 2011 John Wiley & Sons, Ltd.

  16. The Analysis of the Adverse Reaction of Traditional Chinese Medicine Tumor Bone Marrow Suppression

    NASA Astrophysics Data System (ADS)

    Wei, Zhenzhen; Fang, Xiaoyan; Miao, Mingsan

    2018-01-01

    With the rapid increase of cancer patients, chemotherapy is the main method for the clinical treatment of cancer, but also in the treatment of the adverse reactions--bone marrow suppression is often a serious infection caused by patients after chemotherapy and the important cause of mortality. Chinese medicine has obvious advantages in the prevention and treatment of bone marrow depression after chemotherapy. According to tumor bone marrow suppression after chemotherapy of etiology and pathogenesis of traditional Chinese medicine and China national knowledge internet nearly 10 years of traditional Chinese medicine in the prevention and control of the status of clinical and laboratory research of tumor bone marrow suppression, the author analyzed and summarized its characteristics, so as to provide the basis for treating bone marrow suppression of drug research and development, and promote small adverse reactions of the development and utilization of natural medicine and its preparations.

  17. Visual Blocking: Suppression of Excessive Verbalizations.

    ERIC Educational Resources Information Center

    Zlomke, Lee; And Others

    1986-01-01

    Visual blocking procedures (briefly holding a paper screen in front of a subject's face contingent upon inappropriate behavior) were effective in decreasing inappropriate verbalizations in a moderately retarded 32-year-old male. Followup 4 months later indicated that suppression was maintained in treatment settings but failed to generalize to…

  18. Thyrotropin suppression and disease progression in patients with differentiated thyroid cancer: results from the National Thyroid Cancer Treatment Cooperative Registry.

    PubMed

    Cooper, D S; Specker, B; Ho, M; Sperling, M; Ladenson, P W; Ross, D S; Ain, K B; Bigos, S T; Brierley, J D; Haugen, B R; Klein, I; Robbins, J; Sherman, S I; Taylor, T; Maxon, H R

    1998-09-01

    The ideal therapy for differentiated thyroid cancer is uncertain. Although thyroid hormone treatment is pivotal, the degree of thyrotropin (TSH) suppression that is required to prevent recurrences has not been studied in detail. We have examined the relation of TSH suppression to baseline disease characteristics and to the likelihood of disease progression in a cohort of thyroid cancer patients who have been followed in a multicenter thyroid cancer registry that was established in 1986. The present study describes 617 patients with papillary and 66 patients with follicular thyroid cancer followed annually for a median of 4.5 years (range 1-8.6 years). Cancer staging was assessed using a staging scheme developed and validated by the registry. Cancer status was defined as no residual disease; progressive disease at any follow-up time; or death from thyroid cancer. A mean TSH score was calculated for each patient by averaging all available TSH determinations, where 1 = undetectable TSH; 2 = subnormal TSH; 3 = normal TSH; and 4 = elevated TSH. Patients were also grouped by their TSH scores: group 1: mean TSH score 1.0-1.99; group 2: mean TSH score 2.0-2.99; group 3: mean TSH score 3.0-4.0. The degree of TSH suppression did not differ between papillary and follicular thyroid cancer patients. However, TSH suppression was greater in papillary cancer patients who were initially classified as being at higher risk for recurrence. This was not the case for follicular cancer patients, where TSH suppression was similar for all patients. For all stages of papillary cancer, a Cox proportional hazards model showed that disease stage, patient age, and radioiodine therapy all predicted disease progression, but TSH score category did not. However, TSH score category was an independent predictor of disease progression in high risk patients (p = 0.03), but was no longer significant when radioiodine therapy was included in the model (p = 0.09). There were too few patients with

  19. Denervation suppresses gastric tumorigenesis

    PubMed Central

    Kodama, Yosuke; Muthupalani, Sureshkumar; Westphalen, Christoph B.; Andersen, Gøran T.; Flatberg, Arnar; Johannessen, Helene; Friedman, Richard A.; Renz, Bernhard W.; Sandvik, Arne K.; Beisvag, Vidar; Tomita, Hiroyuki; Hara, Akira; Quante, Michael; Li, Zhishan; Gershon, Michael D.; Kaneko, Kazuhiro; Fox, James G.; Wang, Timothy C.; Chen, Duan

    2015-01-01

    The nervous system plays an important role in the regulation of epithelial homeostasis and has also been postulated to play a role in tumorigenesis. We provide evidence that proper innervation is critical at all stages of gastric tumorigenesis. In three separate mouse models of gastric cancer, surgical or pharmacological denervation of the stomach (bilateral or unilateral truncal vagotomy, or local injection of botulinum toxin type A) markedly reduced tumor incidence and progression, but only in the denervated portion of the stomach. Vagotomy or botulinum toxin type A treatment also enhanced the therapeutic effects of systemic chemotherapy and prolonged survival. Denervation-induced suppression of tumorigenesis was associated with inhibition of Wnt signaling and suppression of stem cell expansion. In gastric organoid cultures, neurons stimulated growth in a Wnt-mediated fashion through cholinergic signaling. Furthermore, pharmacological inhibition or genetic knockout of the muscarinic acetylcholine M3 receptor suppressed gastric tumorigenesis. In gastric cancer patients, tumor stage correlated with neural density and activated Wnt signaling, whereas vagotomy reduced the risk of gastric cancer. Together, our findings suggest that vagal innervation contributes to gastric tumorigenesis via M3 receptor–mediated Wnt signaling in the stem cells, and that denervation might represent a feasible strategy for the control of gastric cancer. PMID:25143365

  20. Characteristics associated with suppression of spermatogenesis in a male hormonal contraceptive trial using testosterone and Nestorone(®) gels.

    PubMed

    Roth, M Y; Ilani, N; Wang, C; Page, S T; Bremner, W J; Swerdloff, R S; Dart, C; Sitruk-Ware, R; Kumar, N; Blithe, D; Amory, J K

    2013-11-01

    Development of a male hormonal contraceptive has been challenging ascribable to the failure to adequately suppress spermatogenesis in 5-10% of men. Methods to identify incomplete suppressors early in treatment might identify men most responsive to male hormonal contraceptives. We hypothesized that serum hormone and gonadotropin concentrations after 4 weeks of transdermal treatment with testosterone and Nestorone in a contraceptive trial would be associated with suppression of sperm concentrations to <1 million/mL after 24 weeks. Indeed, luteinizing hormone or follicle-stimulating hormone concentrations greater than 1 IU/L after 4 weeks of transdermal testosterone/nestorone treatment were 97% sensitive for predicting failure to suppress spermatogenesis after 24 weeks of treatment. Serum nestorone concentrations were significantly associated with suppression, but serum testosterone concentrations were not. Early suppression of gonadotropins is associated with, but does not ensure, adequate suppression of spermatogenesis. This information may allow for rapid identification of non-responders in male hormonal contraceptive trials. © 2013 American Society of Andrology and European Academy of Andrology.

  1. SUPPRESSION OF ALLERGIC UVEITIS BY 6-MERCAPTOPURINE

    PubMed Central

    Wirostko, E.; Halbert, S. P.

    1962-01-01

    Experimental uveitis in rabbits was induced by single intraocular antigen injection. Treatment with 6-MP for 14 days suppressed the allergic inflammation and antibody response. A good correlation was demonstrated between the degree of uveitis and the antibody titer. PMID:14001284

  2. Social Mimicry Enhances Mu-Suppression During Action Observation.

    PubMed

    Hogeveen, Jeremy; Chartrand, Tanya L; Obhi, Sukhvinder S

    2015-08-01

    During social interactions, there is a tendency for people to mimic the gestures and mannerisms of others, which increases liking and rapport. Psychologists have extensively studied the antecedents and consequences of mimicry at the social level, but the neural basis of this behavior remains unclear. Many researchers have speculated that mimicry is related to activity in the human mirror system (HMS), a network of parietofrontal regions that are involved in both action execution and observation. However, activity of the HMS during reciprocal social interactions involving mimicry has not been demonstrated. Here, we took an electroencephalographic (EEG) index of mirror activity-mu-suppression during action observation-in a pretest/post-test design with 1 of 3 intervening treatments: 1) social interaction in which the participant was mimicked, 2) social interaction without mimicry, or 3) an innocuous computer task, not involving another human agent. The change in mu-suppression from pre- to post-test varied as a function of the intervening treatment, with participants who had been mimicked showing an increase in mu-suppression during the post-treatment action observation session. We propose that this specific modulation of HMS activity as a function of mimicry constitutes the first direct evidence for mirror system involvement in real social mimicry. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  3. Increased CD8 T-cell granzyme B in COPD is suppressed by treatment with low-dose azithromycin.

    PubMed

    Hodge, Sandra; Hodge, Greg; Holmes, Mark; Jersmann, Hubertus; Reynolds, Paul N

    2015-01-01

    Corticosteroid resistance in chronic obstructive pulmonary disease (COPD) is a major challenge. We have reported increased bronchial epithelial cell apoptosis and increased airway CD8 T-cell numbers in COPD. Apoptosis can be induced via the serine protease, granzyme B. However, glucocorticosteroids fail to adequately suppress granzyme B production by CD8 T cells. We previously showed that low-dose azithromycin reduced airways inflammation in COPD subjects and we hypothesized that it would also reduce granzyme B production by CD8 T cells. We administered 250 mg azithromycin daily for 5 days then twice weekly (total 12 weeks) to 11 COPD subjects (five current smokers; six ex-smokers) and assessed granzyme B in the airway (bronchoalveolar lavage), intra-epithelial compartment and peripheral blood, collected before and following administration of azithromycin. To then dissect the effects of on CD4 and CD8 T-cell subsets, we applied an in vitro assay and physiologically relevant concentrations of azithromycin (and, for comparison, n-acetyl cysteine) and stimulation of peripheral blood mononuclear cells from five healthy subjects with CD3/CD28 T-cell expander. T-cell granzyme B production in both airway and intra-epithelial compartments was reduced in COPD patients following 12 weeks of azithromycin treatment, with no significant effect in blood. Both azithromycin and n-acetyl cysteine suppressed CD4 T-cell granzyme B production, but only azithromycin was effective at reducing CD8+ T-cell granzyme B production in vitro. We provide further evidence for the application of low-dose azithromycin as an attractive adjunct treatment option for controlling epithelial cell apoptosis, abnormal airway repair and chronic inflammation in COPD. © 2014 Asian Pacific Society of Respirology.

  4. Examining the relationship between food thought suppression and binge eating disorder.

    PubMed

    Barnes, Rachel D; Masheb, Robin M; White, Marney A; Grilo, Carlos M

    2013-10-01

    Food thought suppression, or purposely attempting to avoid thoughts of food, is related to a number of unwanted eating- and weight-related consequences, particularly in dieting and obese individuals. Little is known about the possible significance of food thought suppression in clinical samples, particularly obese patients who binge eat. This study examined food thought suppression in 150 obese patients seeking treatment for binge eating disorder (BED). Food thought suppression was not associated with binge eating frequency or body mass index but was significantly associated with higher current levels of eating disorder psychopathology and variables pertaining to obesity, dieting, and binge eating. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Long-term valacyclovir suppressive treatment after herpes simplex virus type 2 meningitis: a double-blind, randomized controlled trial.

    PubMed

    Aurelius, E; Franzen-Röhl, E; Glimåker, M; Akre, O; Grillner, L; Jorup-Rönström, C; Studahl, M

    2012-05-01

    Herpes simplex virus type 2 (HSV-2) is a common cause of acute and recurrent aseptic meningitis. Our aim was to determine the impact of antiviral suppression on recurrence of meningitis and to delineate the full spectrum of neurological complications. One hundred and one patients with acute primary or recurrent HSV-2 meningitis were assigned to placebo (n = 51) or 0.5 g of valacyclovir twice daily (n = 50) for 1 year after initial treatment with 1 g of valacyclovir 3 times daily for 1 week in a prospective, placebo-controlled, multicenter trial. The primary outcome was time until recurrence of meningitis. The patients were followed up for 2 years. The first year, no significant difference was found between the valacyclovir and placebo groups. The second year, without study drugs, the risk of recurrence of verified and probable HSV-2 meningitis was significantly higher among patients exposed to valacyclovir (hazard ratio, 3.29 [95% confidence interval, 10.06-10.21]). One-third of the patients experienced 1-4 meningitis episodes during the study period. A considerable morbidity rate, comprising symptoms from the central, peripheral, and autonomous nervous system, was found in both groups. Suppressive treatment with 0.5 g of valacyclovir twice daily was not shown to prohibit recurrent meningitis and cannot be recommended for this purpose after HSV meningitis in general. Protection against mucocutaneous lesions was observed, but the dosage was probably inappropriate for the prevention of HSV activation in the central nervous system. The higher frequency of meningitis, after cessation of active drug, could be interpreted as a rebound phenomenon.

  6. Dosimetric impact of a CT metal artefact suppression algorithm for proton, electron and photon therapies

    NASA Astrophysics Data System (ADS)

    Wei, Jikun; Sandison, George A.; Hsi, Wen-Chien; Ringor, Michael; Lu, Xiaoyi

    2006-10-01

    Accurate dose calculation is essential to precision radiation treatment planning and this accuracy depends upon anatomic and tissue electron density information. Modern treatment planning inhomogeneity corrections use x-ray CT images and calibrated scales of tissue CT number to electron density to provide this information. The presence of metal in the volume scanned by an x-ray CT scanner causes metal induced image artefacts that influence CT numbers and thereby introduce errors in the radiation dose distribution calculated. This paper investigates the dosimetric improvement achieved by a previously proposed x-ray CT metal artefact suppression technique when the suppressed images of a patient with bilateral hip prostheses are used in commercial treatment planning systems for proton, electron or photon therapies. For all these beam types, this clinical image and treatment planning study reveals that the target may be severely underdosed if a metal artefact-contaminated image is used for dose calculations instead of the artefact suppressed one. Of the three beam types studied, the metal artefact suppression is most important for proton therapy dose calculations, intermediate for electron therapy and least important for x-ray therapy but still significant. The study of a water phantom having a metal rod simulating a hip prosthesis indicates that CT numbers generated after image processing for metal artefact suppression are accurate and thus dose calculations based on the metal artefact suppressed images will be of high fidelity.

  7. Persistence and Suppressiveness of Pasteuria penetrans to Meloidogyne arenaria Race.

    PubMed

    Cetintas, R; Dickson, D W

    2004-12-01

    The long-term persistence and suppressiveness of Pasteuria penetrans against Meloidogyne arenaria race 1 were investigated in a formerly root-knot nematode suppressive site following 9 years of continuous cultivation of three treatments and 4 years of continuous peanut. The three treatments were two M. arenaria race 1 nonhost crops, bahiagrass (Paspalum notatum cv. Pensacola var. Tifton 9), rhizomal peanut (Arachis glabrata cv. Florigraze), and weed fallow. Two root-knot nematode susceptible weeds commonly observed in weed fallow plots were hairy indigo (Indigofera hirsuta) and alyce clover (Alysicarpus vaginalis). The percentage of J2 with endospores attached reached the highest level of 87% in 2000 in weed fallow, and 63% and 53% in 2002 in bahiagrass and rhizomal peanut, respectively. The percentage of endospore-filled females extracted from peanut roots grown in weed fallow plots increased from nondetectable in 1999 to 56% in 2002, whereas the percentages in bahiagrass and rhizomal peanut plots were 41% and 16%, respectively. Over 4 years, however, there was no strong evidence that endospores densities reached suppressive levels because peanut roots, pods, and pegs were heavily galled, and yields were suppressed. This might be attributed to the discovery of M. javanica infecting peanut in this field in early autumn 2001. A laboratory test confirmed that although the P. penetrans isolate specific to M. arenaria attached to M. javanica J2, no development occurred. In summary, P. penetrans increased on M. arenaria over a 4-year period, but apparently because of infection of M. javanica on peanut at the field site root-knot disease was not suppressed. This was confirmed by a suppressive soil test that showed a higher level of soil suppressiveness than occurred in the field (P

  8. Suppression of umami aftertaste by polysaccharides in soy sauce.

    PubMed

    Imamura, Miho; Matsushima, Kenichiro

    2013-08-01

    Umami is one of 5 basic tastes that make foods savory and palatable. The umami aftertaste is a long-lasting taste sensation that is important for Japanese broth (dashi) utilized for various Japanese foods. Soy sauce is usually added when making dashi-based dishes; however, different soy sauces produce distinct effects on the umami aftertaste. In this study, we attempted to identify the substances that cause the suppression of the umami aftertaste in soy sauce by combining sensory analysis, size fractionation, chemical analysis, and enzymatic treatment. The suppressive substance was revealed to be polysaccharides with molecular weights between 44900 and 49700. The results of acid hydrolysis and enzymatic treatment suggested that the polysaccharides were cellulose. These results indicate that a type of water-soluble cellulose derived from soybean, wheat, or microorganisms has a suppressive effect on the umami aftertaste of soy sauce. Future studies should focus on developing a strategy that regulates the amount of these polysaccharides generated during soy sauce production, to maintain or enhance the umami aftertaste. © 2013 Institute of Food Technologists®

  9. Does alpha 1-acid glycoprotein act as a non-functional receptor for alpha 1-adrenergic antagonists?

    PubMed

    Qin, M; Oie, S

    1994-11-01

    The ability of a variety of alpha 1-acid glycoproteins (AAG) to affect the intrinsic activity of the alpha 1-adrenergic antagonist prazosin was studied in rabbit aortic strip preparations. From these studies, the activity of AAG appears to be linked to their ability to bind the antagonist. However, a capability to bind prazosin was not the only requirement for this effect. The removal of sialic acid and partial removal of the galactose and mannose residues by periodate oxidation of human AAG all but eliminated the ability of AAG to affect the intrinsic pharmacologic activity of prazosin, although the binding of prazosin was not significantly affected. The presence of bovine AAG, a protein that has a low ability to bind prazosin, reduced the effect of human AAG on prazosin activity. Based upon these results, we propose that AAG is able to bind in the vicinity of the alpha 1-adrenoceptors, therefore extending the binding region for antagonists in such a way as to decrease the ability of the antagonist to interact with the receptor. The carbohydrate side-chains are important for the binding of AAG in the region of the adrenoceptor.

  10. Combined treatment with dipeptidyl peptidase-4 inhibitor (sitagliptin) and angiotensin-II type 1 receptor blocker (losartan) suppresses progression in a non-diabetic rat model of steatohepatitis.

    PubMed

    Okura, Yasushi; Namisaki, Tadashi; Moriya, Kei; Kitade, Mitsuteru; Takeda, Kosuke; Kaji, Kosuke; Noguchi, Ryuichi; Nishimura, Norihisa; Seki, Kenichiro; Kawaratani, Hideto; Takaya, Hiroaki; Sato, Shinya; Sawada, Yasuhiko; Shimozato, Naotaka; Furukawa, Masanori; Nakanishi, Keisuke; Saikawa, Soichiro; Kubo, Takuya; Asada, Kiyoshi; Yoshiji, Hitoshi

    2017-11-01

    Dipeptidyl peptidase-4 (DPP4) inhibitors (DPP4-I) are oral glucose-lowering drugs for type 2 diabetes mellitus. Previously, we reported that DPP4-I (sitagliptin) exerted suppressive effects on experimental liver fibrosis in rats. Blockade of the renin-angiotensin system by angiotensin-II type 1 receptor blocker (losartan), commonly used in the management of hypertension, has been shown to significantly alleviate hepatic fibrogenesis and carcinogenesis. We aimed to elucidate the effects and possible mechanisms of a sitagliptin + losartan combination on the progression of non-diabetic non-alcoholic steatohepatitis (NASH) in a rat model. To induce NASH, Fischer 344 rats were fed a choline-deficient L-amino acid-defined diet for 12 weeks. We elucidated the chemopreventive effects of sitagliptin + losartan, especially in conjunction with hepatic stellate cell (HSC) activation, angiogenesis, and oxidative stress, all known to play important roles in the progression of NASH. Sitagliptin + losartan suppressed choline-deficient L-amino acid-defined diet-induced hepatic fibrogenesis and carcinogenesis. The combination treatment exerted a greater inhibitory effect than monotherapy. These inhibitory effects occurred almost concurrently with the suppression of HSC activation, neovascularization, and oxidative stress. In vitro studies showed that sitagliptin + losartan inhibited angiotensin II-induced proliferation and expression of transforming growth factor-β1 and α1 (I)-procollagen mRNA of activated HSC and in vitro angiogenesis, in parallel with the suppression observed in in vivo studies. The widely and safely used sitagliptin + losartan combination treatment in clinical practice could be an effective strategy against NASH. © 2016 The Japan Society of Hepatology.

  11. Hypothalamic-pituitary-adrenal (HPA) axis suppression after treatment with glucocorticoid therapy for childhood acute lymphoblastic leukaemia.

    PubMed

    Rensen, Niki; Gemke, Reinoud Jbj; van Dalen, Elvira C; Rotteveel, Joost; Kaspers, Gertjan Jl

    2017-11-06

    Glucocorticoids play a major role in the treatment of acute lymphoblastic leukaemia (ALL). However, supraphysiological doses can suppress the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis suppression resulting in reduced cortisol response may cause an impaired stress response and an inadequate host defence against infection, which remain a cause of morbidity and death. Suppression commonly occurs in the first days after cessation of glucocorticoid therapy, but the exact duration is unclear. This review is the second update of a previously published Cochrane review. To examine the occurrence and duration of HPA axis suppression after (each cycle of) glucocorticoid therapy for childhood ALL. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 11), MEDLINE/PubMed (from 1945 to December 2016), and Embase/Ovid (from 1980 to December 2016). In addition, we searched reference lists of relevant articles, conference proceedings (the International Society for Paediatric Oncology and the American Society of Clinical Oncology from 2005 up to and including 2016, and the American Society of Pediatric Hematology/Oncology from 2014 up to and including 2016), and ongoing trial databases (the International Standard Registered Clinical/Social Study Number (ISRCTN) register via http://www.controlled-trials.com, the National Institutes of Health (NIH) register via www.clinicaltrials.gov, and the International Clinical Trials Registry Platform (ICTRP) of the World Health Organization (WHO) via apps.who.int/trialsearch) on 27 December 2016. All study designs, except case reports and patient series with fewer than 10 children, examining effects of glucocorticoid therapy for childhood ALL on HPA axis function. Two review authors independently performed study selection. One review author extracted data and assessed 'Risk of bias'; another review author checked this information. We identified 10 studies (total of 298 children; we identified two studies

  12. Suppression of coenzyme Q₁₀ levels and the induction of multiple PDSS and COQ genes in human cells following oligomycin treatment.

    PubMed

    Yen, H-C; Liu, C-C; Kan, C-C; Chen, C-S; Wei, H-R

    2014-09-01

    Endogenous coenzyme Q10 (CoQ10) is a lipid-soluble antioxidant and essential for the electron transport chain. We previously demonstrated that hydrogen peroxide enhanced CoQ10 levels, whereas disruption of mitochondrial membrane potential by a chemical uncoupler suppressed CoQ10 levels, in human 143B cells. In this study, we investigated how CoQ10 levels and expression of two PDSS and eight COQ genes were affected by oligomycin, which inhibited ATP synthesis at Complex V without uncoupling the mitochondria. We confirmed that oligomycin increased the production of reactive oxygen species (ROS) and decreased mitochondria-dependent ATP production in 143B cells. We also demonstrated that CoQ10 levels were decreased by oligomycin after 42 or 48 h of treatment, but not at earlier time points. Expression of PDSS2 and COQ2-COQ9 were up-regulated after 18-hour oligomycin treatment, and the expression of PPARGC1A (PGC1-1α) elevated concurrently. Knockdown of PPARGC1A down-regulated the basal mRNA levels of PDSS2 and five COQ genes and suppressed the induction of COQ8 and COQ9 genes by oligomycin, but did not affect CoQ10 levels under these conditions. N-acetylcysteine suppressed the augmentation of ROS levels and the enhanced expression of COQ2, COQ4, COQ7, and COQ9 induced by oligomycin, but did not modulate the changes in CoQ10 levels. These results suggested that the condition of mitochondrial dysfunction induced by oligomycin decreased CoQ10 levels independent of oxidative stress. Up-regulation of PDSS2 and several COQ genes by oligomycin might be regulated by multiple mechanisms, including the signaling pathways mediated by PGC-1α and ROS, but it would not restore CoQ10 levels.

  13. Spatial variation in automated burst suppression detection in pharmacologically induced coma.

    PubMed

    An, Jingzhi; Jonnalagadda, Durga; Moura, Valdery; Purdon, Patrick L; Brown, Emery N; Westover, M Brandon

    2015-01-01

    Burst suppression is actively studied as a control signal to guide anesthetic dosing in patients undergoing medically induced coma. The ability to automatically identify periods of EEG suppression and compactly summarize the depth of coma using the burst suppression probability (BSP) is crucial to effective and safe monitoring and control of medical coma. Current literature however does not explicitly account for the potential variation in burst suppression parameters across different scalp locations. In this study we analyzed standard 19-channel EEG recordings from 8 patients with refractory status epilepticus who underwent pharmacologically induced burst suppression as medical treatment for refractory seizures. We found that although burst suppression is generally considered a global phenomenon, BSP obtained using a previously validated algorithm varies systematically across different channels. A global representation of information from individual channels is proposed that takes into account the burst suppression characteristics recorded at multiple electrodes. BSP computed from this representative burst suppression pattern may be more resilient to noise and a better representation of the brain state of patients. Multichannel data integration may enhance the reliability of estimates of the depth of medical coma.

  14. Oral progestin induces rapid, reversible suppression of ovarian activity in the cat

    PubMed Central

    Stewart, R.A.; Pelican, K.M.; Brown, J.L.; Wildt, D.E.; Ottinger, M.A.; Howard, J.G.

    2010-01-01

    The influence of oral progestin (altrenogest; ALT) on cat ovarian activity was studied using non-invasive fecal steroid monitoring. Queens were assigned to various ALT dosages: 1) 0 mg/kg (control; n = 5 cats); 2) 0.044 mg/kg (LOW; n = 5); 3) 0.088 mg/kg (MID; n = 6); or 4) 0.352 mg/kg (HIGH; n = 6). Fecal estrogen and progestagen concentrations were quantified using enzyme immunoassays for 60 days before, 38 days during and 60 days after ALT treatment. Initiation of follicular activity was suppressed in all cats during progestin treatment, whereas controls continued to cycle normally. Females (n = 6) with elevated fecal estrogens at treatment onset completed a normal follicular phase before returning to baseline and remained suppressed until treatment withdrawal. All cats receiving oral progestin reinitiated follicular activity after treatment, although MID cats experienced the most synchronized return (within 10-16 days). Mean baseline fecal estrogens and progestagens were higher (P < 0.05) after treatment in HIGH, but not LOW or MID cats compared to pre-treatment values. Results demonstrate that: 1) oral progestin rapidly suppresses initiation of follicular activity in the cat, but does not influence a follicular phase that exists before treatment initiation; and 2) queens return to normal follicular activity after progestin withdrawal. This study provides foundational information for research aimed at using progestin priming to improve ovarian response in felids scheduled for ovulation induction and assisted breeding. PMID:20051246

  15. The current use of estrogens for growth-suppressant therapy in adolescent girls.

    PubMed

    Barnard, Neal D; Scialli, Anthony R; Bobela, Suzanne

    2002-02-01

    To assess the current prevalence of growth-suppressant therapy using oral estrogens for tall adolescent girls among U.S. pediatric endocrinologists. A questionnaire was mailed to pediatric endocrinologists practicing in the United States, asking how many patients each clinician had recently treated for tall stature using oral estrogens, whether he/she continued to offer such treatment, reasons for offering or declining to offer it, criteria for initiating and terminating treatment, choice of estrogen, and typical doses, durations, and effects. Of 411 respondents, 92 (22%) reported having treated 1-5 girls for tall stature during the preceding five years. Only 4 (1%) had treated more than 5 cases during this period. Growth-suppression treatment was currently offered by 137 respondents (33.3%). Reasons for doing so included parents' and patients' concerns about stature and the adverse social effects of unusually tall stature. Reasons for not offering such treatments were that its long-term risks are unknown, that tall stature is not a disease, and a lack of referrals. Few clinicians initiated treatment if predicted mature height was below 183 cm. Treatment was typically terminated based on evidence of epiphyseal fusion, usually within less than two years, although extended treatments were common. Frequently reported adverse effects included weight gain, nausea/vomiting, areolar or nipple pigmentation, headache, and irregular menses. Although treatment is less commonly initiated than in the past, many pediatric endocrinologists continue to offer oral estrogens to suppress growth for tall adolescent girls.

  16. β₂ adrenergic receptor activation suppresses bone morphogenetic protein (BMP)-induced alkaline phosphatase expression in osteoblast-like MC3T3E1 cells.

    PubMed

    Yamada, Takayuki; Ezura, Yoichi; Hayata, Tadayoshi; Moriya, Shuichi; Shirakawa, Jumpei; Notomi, Takuya; Arayal, Smriti; Kawasaki, Makiri; Izu, Yayoi; Harada, Kiyoshi; Noda, Masaki

    2015-06-01

    β adrenergic stimulation suppresses bone formation in vivo while its actions in osteoblastic differentiation are still incompletely understood. We therefore examined the effects of β2 adrenergic stimulation on osteoblast-like MC3T3-E1 cells focusing on BMP-induced alkaline phosphatase expression. Morphologically, isoproterenol treatment suppresses BMP-induced increase in the numbers of alkaline phosphatase-positive small foci in the cultures of MC3T3-E1 cells. Biochemically, isoproterenol treatment suppresses BMP-induced enzymatic activity of alkaline phosphatase in a dose-dependent manner. Isoproterenol suppression of alkaline phosphatase activity is observed even when the cells are treated with high concentrations of BMP. With respect to cell density, isoproterenol treatment tends to suppress BMP-induced increase in alkaline phosphatase expression more in osteoblasts cultured at higher cell density. In terms of treatment protocol, continuous isoproterenol treatment is compared to cyclic treatment. Continuous isoproterenol treatment is more suppressive against BMP-induced increase in alkaline phosphatase expression than cyclic regimen. At molecular level, isoproterenol treatment suppresses BMP-induced enhancement of alkaline phosphatase mRNA expression. Regarding the mode of isoproterenol action, isoproterenol suppresses BMP-induced BRE-luciferase activity. These data indicate that isoproterenol regulates BMP-induced alkaline phosphatase expression in osteoblast-like MC3T3E1 cells. © 2014 Wiley Periodicals, Inc.

  17. Gain media edge treatment to suppress amplified spontaneous emission in a high power laser

    DOEpatents

    Hackel, Lloyd A [Livermore, CA; Soules, Thomas F [Livermore, CA; Fochs, Scott N [Livermore, CA; Rotter, Mark D [San Ramon, CA; Letts, Stephan A [San Ramon, CA

    2011-02-22

    A novel method and apparatus for suppressing ASE and/or parasitic oscillation modes in a laser is introduced. By roughening one or more peripheral edges of a solid-state crystal or ceramic laser gain media and by bonding such edges to a predetermined electromagnetic absorbing material arranged adjacent to the entire outer surface of the peripheral edges of the roughened laser gain media, ASE, parasitic oscillation modes and/or residual pump energy can be effectively suppressed.

  18. Fuel Treatment Effects on Water Use Efficiency in Western Pine Forests Under Fire Suppression Evaluated Using Tree Ring Carbon Isotopes

    NASA Astrophysics Data System (ADS)

    Taylor, A. H.; Belmecheri, S.; Harris, L. B.

    2016-12-01

    We identified variation on water use efficiency interpreted from carbon 13 in tree ring cellulose in dense ponderosa pines forests in Washington and Arizona. Historically, these forests burned every decade until fires were suppressed beginning in the early twentieth century. The reduction in fire caused large increases in forest density and forest biomass and potential for intense fire. Forests with hazardous fuels are common in the western United States and these types of forests are treated with mechanical thinning and mechanical thinning and burning to reduce hazardous fuels and fire intensity. At each site we extracted tree ring samples from five trees in each treatment type and a control to identify the effects of fuel treatment of concentration of carbon 13 in tree ring cellulose. Water use efficiency as measured by carbon 13 increased after fuel treatments. Treatment effects were larger for the mechanical plus burn treatment than for the mechanical treatment in each study area compared to the control stands Our results suggest that fuel treatments reduce sensitivity of tree growth to climate and increase water use efficiency. Since tree ring carbon 13 is related to plant productivity, carbon 13 in tree rings can be used as a metric of change in ecosystem function for evaluating fuel treatments.

  19. Predominant Suppression of FSHβ-immunoreactivity after Long-Term Treatment of Intact and Castrate Adult Male Rats with the GnRH Agonist Deslorelin

    PubMed Central

    Smith, Arik W.; Asa, Cheryl S.; Edwards, Brian S.; Murdoch, William J.; Skinner, Donal C.

    2017-01-01

    GnRH agonists are used to treat gonadal steroid-dependent disorders in humans and contracept animals. These agonists are thought to work by desensitizing gonadotropes to GnRH, thereby suppressing FSH and LH secretion. It is not known whether changes occur in the cellular composition of the pituitary gland following chronic GnRH agonist exposure. Adult male Sprague-Dawley rats were treated with a sham, deslorelin, or deslorelin plus testosterone implant for 41.0±0.6 days. In a second experiment, rats were castrated and treated with deslorelin and/or testosterone. Pituitary sections were labeled immunocytochemically for FSHβ and LHβ, or αGSU. Deslorelin suppressed testis weight by two thirds and reduced plasma FSH and LH in intact rats. Deslorelin decreased the percentage of gonadotropes but the effect was specific to the FSHβ-ir cells. Testosterone did not reverse the deslorelin-induced reduction in the overall gonadotrope population. However, in the presence of testosterone, the proportion of gonadotropes that was FSHβ-ir increased in the remaining gonadotropes. There was no effect of treatment on the total LHβ-ir cell population although the loss of FSHβ in bi-hormonal cells increased the proportion of mono-hormonal LHβ-ir gonadotropes. The castration-induced plasma LH and FSH increases were suppressed by deslorelin, testosterone or both. Castration increased both LH-ir and FSH-ir without increasing the overall gonadotrope population; thus increasing the proportion of bi-hormonal cells. Deslorelin suppressed these increases. Testosterone increased FSH-ir in deslorelin-treated castrate rats. Deslorelin did not affect αGSU immunoreactivity, suggesting that the gonadotrope population per se is not eliminated by deslorelin but the ability of gonadotropes to synthesize FSHβ is compromised. We hypothesize that the FSH dominant suppression may be central to the long-term contraceptive efficacy of deslorelin in the male. PMID:22172059

  20. A compact clinical instrument for quantifying suppression.

    PubMed

    Black, Joanne M; Thompson, Benjamin; Maehara, Goro; Hess, Robert F

    2011-02-01

    We describe a compact and convenient clinical apparatus for the measurement of suppression based on a previously reported laboratory-based approach. In addition, we report and validate a novel, rapid psychophysical method for measuring suppression using this apparatus, which makes the technique more applicable to clinical practice. By using a Z800 dual pro head-mounted display driven by a MAC laptop, we provide dichoptic stimulation. Global motion stimuli composed of arrays of moving dots are presented to each eye. One set of dots move in a coherent direction (termed signal) whereas another set of dots move in a random direction (termed noise). To quantify performance, we measure the signal/noise ratio corresponding to a direction-discrimination threshold. Suppression is quantified by assessing the extent to which it matters which eye sees the signal and which eye sees the noise. A space-saving, head-mounted display using current video technology offers an ideal solution for clinical practice. In addition, our optimized psychophysical method provided results that were in agreement with those produced using the original technique. We made measures of suppression on a group of nine adult amblyopic participants using this apparatus with both the original and new psychophysical paradigms. All participants had measurable suppression ranging from mild to severe. The two different psychophysical methods gave a strong correlation for the strength of suppression (rho = -0.83, p = 0.006). Combining the new apparatus and new psychophysical method creates a convenient and rapid technique for parametric measurement of interocular suppression. In addition, this apparatus constitutes the ideal platform for suppressors to combine information between their eyes in a similar way to binocularly normal people. This provides a convenient way for clinicians to implement the newly proposed binocular treatment of amblyopia that is based on antisuppression training.

  1. Unloading-induced bone loss was suppressed in gold-thioglucose treated mice.

    PubMed

    Hino, K; Nifuji, A; Morinobu, M; Tsuji, K; Ezura, Y; Nakashima, K; Yamamoto, H; Noda, M

    2006-10-15

    Loss of mechanical stress causes bone loss. However, the mechanisms underlying the unloading-induced bone loss are largely unknown. Here, we examined the effects of gold-thioglucose (GTG) treatment, which destroys ventromedial hypothalamus (VMH), on unloading-induced bone loss. Unloading reduced bone volume in control (saline-treated) mice. Treatment with GTG-reduced bone mass and in these GTG-treated mice, unloading-induced reduction in bone mass levels was not observed. Unloading reduced the levels of bone formation rate (BFR) and mineral apposition rate (MAR). GTG treatment also reduced these parameters and under this condition, unloading did not further reduce the levels of BFR and MAR. Unloading increased the levels of osteoclast number (Oc.N/BS) and osteoclast surface (Oc.S/BS). GTG treatment did not alter the basal levels of these bone resorption parameters. In contrast to control, GTG treatment suppressed unloading-induced increase in the levels of Oc.N/BS and Oc.S/BS. Unloading reduced the levels of mRNA expression of the genes encoding osteocalcin, type I collagen and Cbfa1 in bone. In contrast, GTG treatment suppressed such unloading-induced reduction of mRNA expression. Unloading also enhanced the levels of fat mass in bone marrow and mRNA expression of the genes encoding PPARgamma2, C/EBPalpha, and C/EBPbeta in bone. In GTG-treated mice, unloading did not increase fat mass and the levels of fat-related mRNA expression. These results indicated that GTG treatment suppressed unloading-induced alteration in bone loss. 2006 Wiley-Liss, Inc.

  2. Gain media edge treatment to suppress amplified spontaneous emission in a high power laser

    DOEpatents

    Hackel, Lloyd A.; Soules, Thomas F.; Fochs, Scott N.; Rotter, Mark D.; Letts, Stephan A.

    2008-12-09

    A novel method and apparatus for suppressing ASE and parasitic oscillation modes in a high average power laser is introduced. By roughening one or more peripheral edges of a solid-state crystal or ceramic laser gain media and by bonding such edges using a substantially high index bonding elastomer or epoxy to a predetermined electromagnetic absorbing arranged adjacent to the entire outer surface of the peripheral edges of the roughened laser gain media, ASE and parasitic oscillation modes can be effectively suppressed.

  3. The sigma-1 antagonist BMY-14802 inhibits L-DOPA-induced abnormal involuntary movements by a WAY-100635-sensitive mechanism

    PubMed Central

    Paquette, Melanie A.; Foley, Katherine; Brudney, Elizabeth G.; Meshul, Charles K.; Johnson, Steven W.; Berger, S. Paul

    2010-01-01

    Rationale Levodopa (L-DOPA), the gold standard treatment for Parkinson's disease (PD), eventually causes L-DOPA-induced dyskinesia (LID) in up to 80% of patients. In the 6-hydroxydopamine (6-OHDA) rat model of PD, L-DOPA induces a similar phenomenon, which has been termed abnormal involuntary movement (AIM). We previously demonstrated that BMY-14802 suppresses AIM expression in this model. Objectives Although BMY-14802 is widely used as a sigma-1 antagonist, it is also an agonist at serotonin (5-HT) 1A and adrenergic α-1 receptors. The current study was conducted to determine which of these mechanisms underlies BMY-14802's AIM-suppressing effect. This characterization included testing the 5-HT1A agonist buspirone and multiple sigma agents. When these studies implicated a 5-HT1A mechanism, we subsequently undertook a pharmacological reversal study, evaluating whether the 5-HT1A antagonist WAY-100635 counteracted BMY-14802's AIM-suppressing effects. Results Buspirone dose-dependently suppressed AIM, supporting past findings. However, no AIM-suppressing effects were produced by drugs with effects at sigma receptors, including BD-1047, finasteride, SM-21, DTG, trans-dehydroandrosterone (DHEA), carbetapentane, and opipramol. Finally, we show for the first time that the AIM-suppressing effect of BMY-14802 was dose-dependently prevented by WAY-100635 but not by the α-1 antagonist prazosin. Conclusions BMY-14802 exerts its AIM-suppressing effects via a 5-HT1A agonist mechanism, similar to buspirone. Other 5-HT1A agonists have failed clinical trials, possibly due to submicromolar affinity at other receptors, including D2, which may exacerbate PD symptoms. BMY-14802 is a promising candidate for clinical trials due to its extremely low affinity for the D2 receptor and lack of extrapyramidal effects during prior clinical trials for schizophrenia. PMID:19283364

  4. Adjuvant Exemestane with Ovarian Suppression in Premenopausal Breast Cancer

    PubMed Central

    Pagani, Olivia; Regan, Meredith M.; Walley, Barbara A.; Fleming, Gini F.; Colleoni, Marco; Láng, István; Gomez, Henry L.; Tondini, Carlo; Burstein, Harold J.; Perez, Edith A.; Ciruelos, Eva; Stearns, Vered; Bonnefoi, Hervé R.; Martino, Silvana; Geyer, Charles E.; Pinotti, Graziella; Puglisi, Fabio; Crivellari, Diana; Ruhstaller, Thomas; Winer, Eric P.; Rabaglio-Poretti, Manuela; Maibach, Rudolf; Ruepp, Barbara; Giobbie-Hurder, Anita; Price, Karen N.; Bernhard, Jürg; Luo, Weixiu; Ribi, Karin; Viale, Giuseppe; Coates, Alan S.; Gelber, Richard D.; Goldhirsch, Aron; Francis, Prudence A.

    2014-01-01

    BACKGROUND Adjuvant therapy with an aromatase inhibitor improves outcomes, as compared with tamoxifen, in postmenopausal women with hormone-receptor–positive breast cancer. METHODS In two phase 3 trials, we randomly assigned premenopausal women with hormone-receptor–positive early breast cancer to the aromatase inhibitor exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The primary analysis combined data from 4690 patients in the two trials. RESULTS After a median follow-up of 68 months, disease-free survival at 5 years was 91.1% in the exemestane–ovarian suppression group and 87.3% in the tamoxifen–ovarian suppression group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.72; 95% confidence interval [CI], 0.60 to 0.85; P<0.001). The rate of freedom from breast cancer at 5 years was 92.8% in the exemestane–ovarian suppression group, as compared with 88.8% in the tamoxifen–ovarian suppression group (hazard ratio for recurrence, 0.66; 95% CI, 0.55 to 0.80; P<0.001). With 194 deaths (4.1% of the patients), overall survival did not differ significantly between the two groups (hazard ratio for death in the exemestane–ovarian suppression group, 1.14; 95% CI, 0.86 to 1.51; P = 0.37). Selected adverse events of grade 3 or 4 were reported for 30.6% of the patients in the exemestane–ovarian suppression group and 29.4% of those in the tamoxifen–ovarian suppression group, with profiles similar to those for postmenopausal women. CONCLUSIONS In premenopausal women with hormone-receptor–positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. (Funded by Pfizer and others; TEXT and SOFT Clinical

  5. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer.

    PubMed

    Pagani, Olivia; Regan, Meredith M; Walley, Barbara A; Fleming, Gini F; Colleoni, Marco; Láng, István; Gomez, Henry L; Tondini, Carlo; Burstein, Harold J; Perez, Edith A; Ciruelos, Eva; Stearns, Vered; Bonnefoi, Hervé R; Martino, Silvana; Geyer, Charles E; Pinotti, Graziella; Puglisi, Fabio; Crivellari, Diana; Ruhstaller, Thomas; Winer, Eric P; Rabaglio-Poretti, Manuela; Maibach, Rudolf; Ruepp, Barbara; Giobbie-Hurder, Anita; Price, Karen N; Bernhard, Jürg; Luo, Weixiu; Ribi, Karin; Viale, Giuseppe; Coates, Alan S; Gelber, Richard D; Goldhirsch, Aron; Francis, Prudence A

    2014-07-10

    Adjuvant therapy with an aromatase inhibitor improves outcomes, as compared with tamoxifen, in postmenopausal women with hormone-receptor-positive breast cancer. In two phase 3 trials, we randomly assigned premenopausal women with hormone-receptor-positive early breast cancer to the aromatase inhibitor exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The primary analysis combined data from 4690 patients in the two trials. After a median follow-up of 68 months, disease-free survival at 5 years was 91.1% in the exemestane-ovarian suppression group and 87.3% in the tamoxifen-ovarian suppression group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.72; 95% confidence interval [CI], 0.60 to 0.85; P<0.001). The rate of freedom from breast cancer at 5 years was 92.8% in the exemestane-ovarian suppression group, as compared with 88.8% in the tamoxifen-ovarian suppression group (hazard ratio for recurrence, 0.66; 95% CI, 0.55 to 0.80; P<0.001). With 194 deaths (4.1% of the patients), overall survival did not differ significantly between the two groups (hazard ratio for death in the exemestane-ovarian suppression group, 1.14; 95% CI, 0.86 to 1.51; P=0.37). Selected adverse events of grade 3 or 4 were reported for 30.6% of the patients in the exemestane-ovarian suppression group and 29.4% of those in the tamoxifen-ovarian suppression group, with profiles similar to those for postmenopausal women. In premenopausal women with hormone-receptor-positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. (Funded by Pfizer and others; TEXT and SOFT ClinicalTrials.gov numbers, NCT00066703 and NCT00066690, respectively.).

  6. Brain Maturation, Cognition and Voice Pattern in a Gender Dysphoria Case under Pubertal Suppression.

    PubMed

    Schneider, Maiko A; Spritzer, Poli M; Soll, Bianca Machado Borba; Fontanari, Anna M V; Carneiro, Marina; Tovar-Moll, Fernanda; Costa, Angelo B; da Silva, Dhiordan C; Schwarz, Karine; Anes, Maurício; Tramontina, Silza; Lobato, Maria I R

    2017-01-01

    Introduction: Gender dysphoria (GD) (DMS-5) is a condition marked by increasing psychological suffering that accompanies the incongruence between one's experienced or expressed gender and one's assigned gender. Manifestation of GD can be seen early on during childhood and adolescence. During this period, the development of undesirable sexual characteristics marks an acute suffering of being opposite to the sex of birth. Pubertal suppression with gonadotropin releasing hormone analogs (GnRHa) has been proposed for these individuals as a reversible treatment for postponing the pubertal development and attenuating psychological suffering. Recently, increased interest has been observed on the impact of this treatment on brain maturation, cognition and psychological performance. Objectives: The aim of this clinical report is to review the effects of puberty suppression on the brain white matter (WM) during adolescence. WM Fractional anisotropy, voice and cognitive functions were assessed before and during the treatment. MRI scans were acquired before, and after 22 and 28 months of hormonal suppression. Methods: We performed a longitudinal evaluation of a pubertal transgender girl undergoing hormonal treatment with GnRH analog. Three longitudinal magnetic resonance imaging (MRI) scans were performed for diffusion tensor imaging (DTI), regarding Fractional Anisotropy (FA) for regions of interest analysis. In parallel, voice samples for acoustic analysis as well as executive functioning with the Wechsler Intelligence Scale (WISC-IV) were performed. Results: During the follow-up, white matter fractional anisotropy did not increase, compared to normal male puberty effects on the brain. After 22 months of pubertal suppression, operational memory dropped 9 points and remained stable after 28 months of follow-up. The fundamental frequency of voice varied during the first year; however, it remained in the female range. Conclusion: Brain white matter fractional anisotropy

  7. Brain Maturation, Cognition and Voice Pattern in a Gender Dysphoria Case under Pubertal Suppression

    PubMed Central

    Schneider, Maiko A.; Spritzer, Poli M.; Soll, Bianca Machado Borba; Fontanari, Anna M. V.; Carneiro, Marina; Tovar-Moll, Fernanda; Costa, Angelo B.; da Silva, Dhiordan C.; Schwarz, Karine; Anes, Maurício; Tramontina, Silza; Lobato, Maria I. R.

    2017-01-01

    Introduction: Gender dysphoria (GD) (DMS-5) is a condition marked by increasing psychological suffering that accompanies the incongruence between one's experienced or expressed gender and one's assigned gender. Manifestation of GD can be seen early on during childhood and adolescence. During this period, the development of undesirable sexual characteristics marks an acute suffering of being opposite to the sex of birth. Pubertal suppression with gonadotropin releasing hormone analogs (GnRHa) has been proposed for these individuals as a reversible treatment for postponing the pubertal development and attenuating psychological suffering. Recently, increased interest has been observed on the impact of this treatment on brain maturation, cognition and psychological performance. Objectives: The aim of this clinical report is to review the effects of puberty suppression on the brain white matter (WM) during adolescence. WM Fractional anisotropy, voice and cognitive functions were assessed before and during the treatment. MRI scans were acquired before, and after 22 and 28 months of hormonal suppression. Methods: We performed a longitudinal evaluation of a pubertal transgender girl undergoing hormonal treatment with GnRH analog. Three longitudinal magnetic resonance imaging (MRI) scans were performed for diffusion tensor imaging (DTI), regarding Fractional Anisotropy (FA) for regions of interest analysis. In parallel, voice samples for acoustic analysis as well as executive functioning with the Wechsler Intelligence Scale (WISC-IV) were performed. Results: During the follow-up, white matter fractional anisotropy did not increase, compared to normal male puberty effects on the brain. After 22 months of pubertal suppression, operational memory dropped 9 points and remained stable after 28 months of follow-up. The fundamental frequency of voice varied during the first year; however, it remained in the female range. Conclusion: Brain white matter fractional anisotropy

  8. BMP suppresses PTEN expression via RAS/ERK signaling.

    PubMed

    Beck, Stayce E; Carethers, John M

    2007-08-01

    Bone morphogenetic protein (BMP), a member of the transforming growth factor beta family, classically utilizes the SMAD signaling pathway for its growth suppressive effects,and loss of this signaling cascade may accelerate cell growth. In the colon cancer predisposition syndrome Juvenile Polyposis, as well as in the late progression stages of nonsyndromic colorectal cancers, SMAD4 function is typically abrogated. Here, we utilized the SMAD4-null SW480 colon cancer cell line to examine BMPs effect on a potential target gene, PTEN, and how its expression might be regulated. Initial treatment of the SMAD4-null cells with BMP resulted in mild growth suppression, but with prolonged exposure to BMP, the cells become growth stimulatory, which coincided with observed decreases in transcription and translation of PTEN, and with corresponding increases in phospho-AKT protein levels. BMP-induced PTEN suppression was mediated via the RAS/ERK pathway, as pharmacologic inhibition of RAS/ERK, or interference with protein function in the cytosol by DN-RAS prevented BMP-induced growth promotion and changes in PTEN levels, as did treatment with noggin, a BMP ligand inhibitor. Thus, BMP downregulates PTEN via RAS/ERK in a SMAD4-null environment that contributes to cell growth, and constitutes a SMAD4-independent but BMP-responsive signaling pathway.

  9. Effect of Thyrotropin Suppression Therapy on Bone in Thyroid Cancer Patients

    PubMed Central

    Hawley, Sarah T.; Haymart, Megan R.

    2016-01-01

    Background. The thyroid cancer incidence is rising. Despite current guidelines, controversy exists regarding the degree and duration of thyrotropin suppression therapy. Also, its potential skeletal effects remain a concern to physicians caring for thyroid cancer patients. We conducted a review of published data to evaluate existing studies focusing on the skeletal effects of thyrotropin suppression therapy in thyroid cancer patients. Materials and Methods. A systematic search of the PubMed, Ovid/Medline, and Cochrane Central Register of Controlled Trials databases was conducted. The retained studies were evaluated for methodological quality, and the study populations were categorized into premenopausal women, postmenopausal women, and men. Results. Twenty-five pertinent studies were included. Seven studies were longitudinal and 18 were cross-sectional. Of the 25 included studies, 13 were assigned an excellent methodological quality score. Three of 5 longitudinal studies and 3 of 13 cross-sectional studies reported decreased bone mineral density (BMD) in premenopausal women; 2 of 4 longitudinal studies and 5 of 13 cross-sectional studies reported decreased BMD in postmenopausal women. The remaining studies showed no effect on BMD. The only longitudinal study of men showed bone mass loss; however, cross-sectional studies of men did not demonstrate a similar effect. Conclusion. Studies to date have yielded conflicting results on the skeletal effects of thyrotropin suppression therapy and a knowledge gap remains, especially for older adults and men. Existing data should be cautiously interpreted because of the variable quality and heterogeneity. Identifying groups at risk of adverse effects from thyrotropin suppression therapy will be instrumental to providing focused and tailored thyroid cancer treatment. Implications for Practice: The standard treatment for thyroid cancer includes total thyroidectomy with or without radioactive iodine ablation, often followed by

  10. Effect of Thyrotropin Suppression Therapy on Bone in Thyroid Cancer Patients.

    PubMed

    Papaleontiou, Maria; Hawley, Sarah T; Haymart, Megan R

    2016-02-01

    The thyroid cancer incidence is rising. Despite current guidelines, controversy exists regarding the degree and duration of thyrotropin suppression therapy. Also, its potential skeletal effects remain a concern to physicians caring for thyroid cancer patients. We conducted a review of published data to evaluate existing studies focusing on the skeletal effects of thyrotropin suppression therapy in thyroid cancer patients. A systematic search of the PubMed, Ovid/Medline, and Cochrane Central Register of Controlled Trials databases was conducted. The retained studies were evaluated for methodological quality, and the study populations were categorized into premenopausal women, postmenopausal women, and men. Twenty-five pertinent studies were included. Seven studies were longitudinal and 18 were cross-sectional. Of the 25 included studies, 13 were assigned an excellent methodological quality score. Three of 5 longitudinal studies and 3 of 13 cross-sectional studies reported decreased bone mineral density (BMD) in premenopausal women; 2 of 4 longitudinal studies and 5 of 13 cross-sectional studies reported decreased BMD in postmenopausal women. The remaining studies showed no effect on BMD. The only longitudinal study of men showed bone mass loss; however, cross-sectional studies of men did not demonstrate a similar effect. Studies to date have yielded conflicting results on the skeletal effects of thyrotropin suppression therapy and a knowledge gap remains, especially for older adults and men. Existing data should be cautiously interpreted because of the variable quality and heterogeneity. Identifying groups at risk of adverse effects from thyrotropin suppression therapy will be instrumental to providing focused and tailored thyroid cancer treatment. The standard treatment for thyroid cancer includes total thyroidectomy with or without radioactive iodine ablation, often followed by thyrotropin suppression therapy. Despite current guidelines, controversy exists

  11. Burst suppression probability algorithms: state-space methods for tracking EEG burst suppression

    NASA Astrophysics Data System (ADS)

    Chemali, Jessica; Ching, ShiNung; Purdon, Patrick L.; Solt, Ken; Brown, Emery N.

    2013-10-01

    Objective. Burst suppression is an electroencephalogram pattern in which bursts of electrical activity alternate with an isoelectric state. This pattern is commonly seen in states of severely reduced brain activity such as profound general anesthesia, anoxic brain injuries, hypothermia and certain developmental disorders. Devising accurate, reliable ways to quantify burst suppression is an important clinical and research problem. Although thresholding and segmentation algorithms readily identify burst suppression periods, analysis algorithms require long intervals of data to characterize burst suppression at a given time and provide no framework for statistical inference. Approach. We introduce the concept of the burst suppression probability (BSP) to define the brain's instantaneous propensity of being in the suppressed state. To conduct dynamic analyses of burst suppression we propose a state-space model in which the observation process is a binomial model and the state equation is a Gaussian random walk. We estimate the model using an approximate expectation maximization algorithm and illustrate its application in the analysis of rodent burst suppression recordings under general anesthesia and a patient during induction of controlled hypothermia. Main result. The BSP algorithms track burst suppression on a second-to-second time scale, and make possible formal statistical comparisons of burst suppression at different times. Significance. The state-space approach suggests a principled and informative way to analyze burst suppression that can be used to monitor, and eventually to control, the brain states of patients in the operating room and in the intensive care unit.

  12. Influence of mianserin on the activity of some hypotensive drugs in spontaneously hypertensive rats.

    PubMed

    Górska, Dorota; Andrzejczak, Dariusz

    2003-01-01

    Mianserin might be an alternative drug in patients with depression accompanied by hypertension because of its effectiveness and lack of side effects in the circulatory system. However, a few studies reported in literature show influence of the drug on blood pressure. We investigate interactions between mianserin and commonly used hypotensive drugs (propranolol, enalapril and prazosin) in spontaneously hypertensive rats (SHR). The experiments were performed in two experimental designs: a single administration of both mianserin and a hypotensive drug, and repeated administration of mianserin with a single administration of a hypotensive drug. Arterial blood pressure was measured by bloodless method with manometer made by LETICA. A single administration of mianserin caused a statistically significant decrease in systolic, diastolic and mean blood pressure in the 60th minute of observation and intensified hypotensive effect of prazosin. However, long-term administration of mianserin in SHR rats had no significant influence on arterial blood pressure. Chronic and single administration of mianserin with propranolol or enalapril did not influence the circulatory system. A long-term administration of mianserin intensified the hypotensive effect of prazosin. This interaction might suggest possibility of dangerous complications in the treatment of humans with this drug combination.

  13. Full Viral Suppression, Low-Level Viremia, and Quantifiable Plasma HIV-RNA at the End of Pregnancy in HIV-Infected Women on Antiretroviral Treatment.

    PubMed

    Baroncelli, Silvia; Pirillo, Maria F; Tamburrini, Enrica; Guaraldi, Giovanni; Pinnetti, Carmela; Degli Antoni, Anna; Galluzzo, Clementina M; Stentarelli, Chiara; Amici, Roberta; Floridia, Marco

    2015-07-01

    There is limited information on full viral suppression and low-level HIV-RNA viremia in HIV-infected women at the end of pregnancy. We investigated HIV-RNA levels close to delivery in women on antiretroviral treatment in order to define rates of complete suppression, low-level viremia, and quantifiable HIV-RNA, exploring as potential determinants some clinical and viroimmunological variables. Plasma samples from a national study in Italy, collected between 2003 and 2012, were used. According to plasma HIV-RNA levels, three groups were defined: full suppression (target not detected), low-level viremia (target detected but <37 copies/ml), and quantifiable HIV-RNA (≥37 copies/ml). Multivariable logistic regression was used to define determinants of full viral suppression and of quantifiable HIV-RNA. Among 107 women evaluated at a median gestational age of 35 weeks, 90 (84.1%) had HIV-RNA <37 copies/ml. Most of them (59/90, 65.6%) had full suppression, with the remaining (31/90, 34.4%) showing low-level viremia (median: 11.9 copies/ml; IQR 7.4-16.3). Among the 17 women with quantifiable viral load, median HIV-RNA was 109 copies/ml (IQR 46-251), with only one case showing resistance (mutation M184V; rate: 9.1%). In multivariable analyses, women with higher baseline HIV-RNA levels and with hepatitis C virus (HCV) coinfection were significantly more likely to have quantifiable HIV-RNA in late pregnancy. Full viral suppression was significantly more likely with nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens and significantly less likely with higher HIV-RNA in early pregnancy. No cases of HIV transmission occurred. In conclusion, HIV-infected pregnant women showed a high rate of viral suppression and a low resistance rate before delivery. In most cases no target HIV-RNA was detected in plasma, suggesting a low risk of subsequent virological rebound and development of resistance. Women with high levels of HIV-RNA in early pregnancy and those who have

  14. Assessing Suppression in Amblyopic Children With a Dichoptic Eye Chart.

    PubMed

    Birch, Eileen E; Morale, Sarah E; Jost, Reed M; De La Cruz, Angie; Kelly, Krista R; Wang, Yi-Zhong; Bex, Peter J

    2016-10-01

    Suppression has a key role in the etiology of amblyopia, and contrast-balanced binocular treatment can overcome suppression and improve visual acuity. Quantitative assessment of suppression could have a role in managing amblyopia. We describe a novel eye chart to assess suppression in children. We enrolled 100 children (7-12 years; 63 amblyopic, 25 nonamblyopic with strabismus or anisometropia, 12 controls) in the primary cohort and 22 children (3-6 years; 13 amblyopic, 9 nonamblyopic) in a secondary cohort. Letters were presented on a dichoptic display (5 letters per line). Children wore polarized glasses so that each eye saw a different letter chart. At each position, the identity of the letter and its contrast on each eye's chart differed. Children read 8 lines of letters for each of 3 letter sizes. The contrast balance ratio was the ratio at which 50% of letters seen by the amblyopic eye were reported. Amblyopic children had significantly higher contrast balance ratios for all letter sizes compared to nonamblyopic children and controls, requiring 4.6 to 5.6 times more contrast in the amblyopic eye compared to the fellow eye (P < 0.0001). Amblyopic eye visual acuity was correlated with contrast balance ratio (r ranged from 0.49-0.57 for the 3 letter sizes). Change in visual acuity with amblyopia treatment was correlated with change in contrast balance ratio (r ranged from 0.43-0.62 for the 3 letter sizes). Severity of suppression can be monitored as part of a routine clinical exam in the management of amblyopia in children.

  15. Effective treatment for suppression of acrylamide formation in fried potato chips using L-asparaginase from Bacillus subtilis.

    PubMed

    Onishi, Yohei; Prihanto, Asep A; Yano, Shigekazu; Takagi, Kazuyoshi; Umekawa, Midori; Wakayama, Mamoru

    2015-10-01

    It has been reported that acrylamide, a potential carcinogen, is formed from the reaction of L-asparagine (L-Asn) and reducing sugars contained in foods during heating processes and free asparagine is a limiting factor for acrylamide formation. It has been reported that potato products such as potato chips, which are made through heating processes, contain high levels of acrylamide. To decrease the amount of L-Asn in potatoes using L-asparaginase, effective treatment conditions of sliced potatoes with the enzyme have been investigated. By treating sliced potatoes with Bacillus subtilis L-asparaginase II (BAsnase; 4 U/g potato), appriximately 40 % of L-Asn in the sliced potatoes was converted into L-aspartic acid (L-Asp). To make this enzyme more effective, prior to enzymatic treatment, sliced potatoes were freeze-thawed, dried at 90 °C for 20 min, and vacuum treated for 10 min under decompressed condition, resulting in the hydrolysis of approximately 90 % of L-Asn to L-Asp. The acrylamide content of BAsnase-treated fried potato chips decreased to below 20 % of that of BAsnase-untreated fried potato chips. Treatment conditions examined in this study were found to be effective to suppress the formation of acrylamide in fried potato chips.

  16. The Potent Humanin Analogue (HNG) Protects Germ Cells and Leucocytes While Enhancing Chemotherapy-Induced Suppression of Cancer Metastases in Male Mice.

    PubMed

    Lue, YanHe; Swerdloff, Ronald; Wan, Junxiang; Xiao, Jialin; French, Samuel; Atienza, Vince; Canela, Victor; Bruhn, Kevin W; Stone, Brian; Jia, Yue; Cohen, Pinchas; Wang, Christina

    2015-12-01

    Humanin is a peptide that is cytoprotective against stresses in many cell types. We investigated whether a potent humanin analogue S14G-humanin (HNG) would protect against chemotherapy-induced damage to normal cells without interfering with the chemotherapy-induced suppression of cancer cells. Young adult male mice were inoculated iv with murine melanoma cells. After 1 week, cancer-bearing mice were randomized to receive either: no treatment, daily ip injection of HNG, a single ip injection of cyclophosphamide (CP), or CP+HNG and killed at the end of 3 weeks. HNG rescued the CP-induced suppression of leucocytes and protected germ cell from CP-induced apoptosis. Lung metastases were suppressed by HNG or CP alone, and further suppressed by CP+HNG treatment. Plasma IGF-1 levels were suppressed by HNG with or without CP treatment. To investigate whether HNG maintains its protective effects on spermatogonial stem cells, sperm output, and peripheral leucocytes after repeated doses of CP, normal adult male mice received: no treatment, daily sc injection of HNG, 6 ip injections of CP at 5-day intervals, and the same regimens of CP+HNG and killed at the end of 4 weeks of treatment. Cauda epididymal sperm counts were elevated by HNG and suppressed by CP. HNG rescued the CP-induced suppression of spermatogonial stem cells, sperm count and peripheral leucocytes. We conclude that HNG 1) protects CP-induced loss of male germ cells and leucocytes, 2) enhances CP-induced suppression of cancer metastases, and 3) acts as a caloric-restriction mimetic by suppressing IGF-1 levels. Our findings suggest that humanin analogues may be promising adjuvants to chemotherapy.

  17. The Potent Humanin Analogue (HNG) Protects Germ Cells and Leucocytes While Enhancing Chemotherapy-Induced Suppression of Cancer Metastases in Male Mice

    PubMed Central

    Lue, YanHe; Swerdloff, Ronald; Wan, Junxiang; Xiao, Jialin; French, Samuel; Atienza, Vince; Canela, Victor; Bruhn, Kevin W.; Stone, Brian; Jia, Yue; Cohen, Pinchas

    2015-01-01

    Humanin is a peptide that is cytoprotective against stresses in many cell types. We investigated whether a potent humanin analogue S14G-humanin (HNG) would protect against chemotherapy-induced damage to normal cells without interfering with the chemotherapy-induced suppression of cancer cells. Young adult male mice were inoculated iv with murine melanoma cells. After 1 week, cancer-bearing mice were randomized to receive either: no treatment, daily ip injection of HNG, a single ip injection of cyclophosphamide (CP), or CP+HNG and killed at the end of 3 weeks. HNG rescued the CP-induced suppression of leucocytes and protected germ cell from CP-induced apoptosis. Lung metastases were suppressed by HNG or CP alone, and further suppressed by CP+HNG treatment. Plasma IGF-1 levels were suppressed by HNG with or without CP treatment. To investigate whether HNG maintains its protective effects on spermatogonial stem cells, sperm output, and peripheral leucocytes after repeated doses of CP, normal adult male mice received: no treatment, daily sc injection of HNG, 6 ip injections of CP at 5-day intervals, and the same regimens of CP+HNG and killed at the end of 4 weeks of treatment. Cauda epididymal sperm counts were elevated by HNG and suppressed by CP. HNG rescued the CP-induced suppression of spermatogonial stem cells, sperm count and peripheral leucocytes. We conclude that HNG 1) protects CP-induced loss of male germ cells and leucocytes, 2) enhances CP-induced suppression of cancer metastases, and 3) acts as a caloric-restriction mimetic by suppressing IGF-1 levels. Our findings suggest that humanin analogues may be promising adjuvants to chemotherapy. PMID:26384090

  18. Suppression of Striatal Prediction Errors by the Prefrontal Cortex in Placebo Hypoalgesia.

    PubMed

    Schenk, Lieven A; Sprenger, Christian; Onat, Selim; Colloca, Luana; Büchel, Christian

    2017-10-04

    Classical learning theories predict extinction after the discontinuation of reinforcement through prediction errors. However, placebo hypoalgesia, although mediated by associative learning, has been shown to be resistant to extinction. We tested the hypothesis that this is mediated by the suppression of prediction error processing through the prefrontal cortex (PFC). We compared pain modulation through treatment cues (placebo hypoalgesia, treatment context) with pain modulation through stimulus intensity cues (stimulus context) during functional magnetic resonance imaging in 48 male and female healthy volunteers. During acquisition, our data show that expectations are correctly learned and that this is associated with prediction error signals in the ventral striatum (VS) in both contexts. However, in the nonreinforced test phase, pain modulation and expectations of pain relief persisted to a larger degree in the treatment context, indicating that the expectations were not correctly updated in the treatment context. Consistently, we observed significantly stronger neural prediction error signals in the VS in the stimulus context compared with the treatment context. A connectivity analysis revealed negative coupling between the anterior PFC and the VS in the treatment context, suggesting that the PFC can suppress the expression of prediction errors in the VS. Consistent with this, a participant's conceptual views and beliefs about treatments influenced the pain modulation only in the treatment context. Our results indicate that in placebo hypoalgesia contextual treatment information engages prefrontal conceptual processes, which can suppress prediction error processing in the VS and lead to reduced updating of treatment expectancies, resulting in less extinction of placebo hypoalgesia. SIGNIFICANCE STATEMENT In aversive and appetitive reinforcement learning, learned effects show extinction when reinforcement is discontinued. This is thought to be mediated by

  19. Best Practice Guide for the Treatment of Nightmare Disorder in Adults

    PubMed Central

    Aurora, R. Nisha; Zak, Rochelle S.; Auerbach, Sanford H.; Casey, Kenneth R.; Chowdhuri, Susmita; Karippot, Anoop; Maganti, Rama K.; Ramar, Kannan; Kristo, David A.; Bista, Sabin R.; Lamm, Carin I.; Morgenthaler, Timothy I.

    2010-01-01

    Summary of Recommendations: Prazosin is recommended for treatment of Posttraumatic Stress Disorder (PTSD)-associated nightmares. Level A Image Rehearsal Therapy (IRT) is recommended for treatment of nightmare disorder. Level A Systematic Desensitization and Progressive Deep Muscle Relaxation training are suggested for treatment of idiopathic nightmares. Level B Venlafaxine is not suggested for treatment of PTSD-associated nightmares. Level B Clonidine may be considered for treatment of PTSD-associated nightmares. Level C The following medications may be considered for treatment of PTSD-associated nightmares, but the data are low grade and sparse: trazodone, atypical antipsychotic medications, topiramate, low dose cortisol, fluvoxamine, triazolam and nitrazepam, phenelzine, gabapentin, cyproheptadine, and tricyclic antidepressants. Nefazodone is not recommended as first line therapy for nightmare disorder because of the increased risk of hepatotoxicity. Level C The following behavioral therapies may be considered for treatment of PTSD-associated nightmares based on low-grade evidence: Exposure, Relaxation, and Rescripting Therapy (ERRT); Sleep Dynamic Therapy; Hypnosis; Eye-Movement Desensitization and Reprocessing (EMDR); and the Testimony Method. Level C The following behavioral therapies may be considered for treatment of nightmare disorder based on low-grade evidence: Lucid Dreaming Therapy and Self-Exposure Therapy. Level C No recommendation is made regarding clonazepam and individual psychotherapy because of sparse data. Citation: Aurora RN; Zak RS; Auerbach SH; Casey KR; Chowduri S; Krippot A; Maganti RK; Ramar K; Kristo DA; Bista SR; Lamm CI; Morgenthaler TI. Best practice guide for the treatment of nightmare disorder in adults. J Clin Sleep Med 2010;6(4):389-401. PMID:20726290

  20. Efficacy of Testosterone Suppression with Sustained-Release Triptorelin in Advanced Prostate Cancer.

    PubMed

    Breul, Jürgen; Lundström, Eija; Purcea, Daniela; Venetz, Werner P; Cabri, Patrick; Dutailly, Pascale; Goldfischer, Evan R

    2017-02-01

    Androgen deprivation therapy (ADT) is a mainstay of treatment against advanced prostate cancer (PC). As a treatment goal, suppression of plasma testosterone levels to <50 ng/dl has been established over decades. Evidence is growing though that suppression to even lower levels may add further clinical benefit. Therefore, we undertook a pooled retrospective analysis on the efficacy of 1-, 3-, and 6-month sustained-release (SR) formulations of the gonadotropin-releasing hormone (GnRH) agonist triptorelin to suppress serum testosterone concentrations beyond current standards. Data of 920 male patients with PC enrolled in 9 prospective studies using testosterone serum concentrations as primary endpoint were pooled. Patients aged 42-96 years had to be eligible for ADT and to be either naïve to hormonal treatment or have undergone appropriate washout prior to enrolment. Patients were treated with triptorelin SR formulations for 2-12 months. Primary endpoints of this analysis were serum testosterone concentrations under treatment and success rates overall and per formulation, based on a testosterone target threshold of 20 ng/dl. After 1, 3, 6, 9, and 12 months of treatment, 79%, 92%, 93%, 90%, and 91% of patients reached testosterone levels <20 ng/dl, respectively. For the 1-, 3-, and 6-month formulations success rates ranged from 80-92%, from 83-93%, and from 65-97% with median (interquartile range) serum testosterone values of 2.9 (2.9-6.5), 5.0 (2.9-8.7), and 8.7 (5.8-14.1) ng/dl at study end, respectively. In the large majority of patients, triptorelin SR formulations suppressed serum testosterone concentrations to even <20 ng/dl. Testosterone should be routinely monitored in PC patients on ADT although further studies on the clinical benefit of very low testosterone levels and the target concentrations are still warranted.

  1. Design and performance of duct acoustic treatment

    NASA Technical Reports Server (NTRS)

    Motsinger, R. E.; Kraft, R. E.

    1991-01-01

    The procedure for designing acoustic treatment panels used to line the walls of aircraft engine ducts and for estimating the resulting suppression of turbofan engine duct noise is discussed. This procedure is intended to be used for estimating noise suppression of existing designs or for designing new acoustic treatment panels and duct configurations to achieve desired suppression levels.

  2. Thought Suppression, Impaired Regulation of Urges, and Addiction-Stroop Predict Affect-Modulated Cue-Reactivity among Alcohol Dependent Adults

    PubMed Central

    Garland, Eric L.; Carter, Kristin; Ropes, Katie; Howard, Matthew O.

    2011-01-01

    Abstinent alcohol dependent individuals commonly employ thought suppression to cope with stress and intrusive cognitions about alcohol. This strategy may inadvertently bias attention toward alcohol-related stimuli while depleting neurocognitive resources needed to regulate urges, manifested as decreased heart rate variability (HRV) responsivity to alcohol cues. The present study tested the hypothesis that trait and state thought suppression, impaired regulation of urges, and alcohol attentional bias as measured by the Addiction-Stroop would have significant effects on the HRV responsivity of 58 adults in residential treatment for alcohol dependence (mean age = 39.6 ± 9.4, 81% female) who participated in an affect-modulated cue-reactivity protocol. Regression analyses controlling for age, level of pre-treatment alcohol consumption, and baseline HRV indicated that higher levels of trait thought suppression, impaired regulation of alcohol urges, and attentional fixation on alcohol cues were associated with lower HRV responsivity during stress-primed alcohol cue-exposure. Moreover, there was a significant state X trait suppression interaction on HRV cue-responsivity, such that alcohol dependent persons reporting high levels of state and trait suppression exhibited less HRV during cue-exposure than persons reporting low levels of state and trait suppression. Results suggest that chronic thought suppression taxes regulatory resources reflected in reduced HRV responsivity, an effect that is particularly evident when high trait suppressors engage in intensive suppression of drinking-related thoughts under conditions of stress. Treatment approaches that offer effective alternatives to the maladaptive strategy of suppressing alcohol urges may be crucial for relapse prevention. PMID:21967855

  3. Thought suppression, impaired regulation of urges, and Addiction-Stroop predict affect-modulated cue-reactivity among alcohol dependent adults.

    PubMed

    Garland, Eric L; Carter, Kristin; Ropes, Katie; Howard, Matthew O

    2012-01-01

    Abstinent alcohol dependent individuals commonly employ thought suppression to cope with stress and intrusive cognitions about alcohol. This strategy may inadvertently bias attention towards alcohol-related stimuli while depleting neurocognitive resources needed to regulate urges, manifested as decreased heart rate variability (HRV) responsivity to alcohol cues. The present study tested the hypothesis that trait and state thought suppression, impaired regulation of urges, and alcohol attentional bias as measured by the Addiction-Stroop would have significant effects on the HRV responsivity of 58 adults in residential treatment for alcohol dependence (mean age=39.6 ± 9.4, 81% female) who participated in an affect-modulated cue-reactivity protocol. Regression analyses controlling for age, level of pre-treatment alcohol consumption, and baseline HRV indicated that higher levels of trait thought suppression, impaired regulation of alcohol urges, and attentional fixation on alcohol cues were associated with lower HRV responsivity during stress-primed alcohol cue-exposure. Moreover, there was a significant state × trait suppression interaction on HRV cue-responsivity, such that alcohol dependent persons reporting high levels of state and trait suppression exhibited less HRV during cue-exposure than persons reporting low levels of state and trait suppression. Results suggest that chronic thought suppression taxes regulatory resources reflected in reduced HRV responsivity, an effect that is particularly evident when high trait suppressors engage in intensive suppression of drinking-related thoughts under conditions of stress. Treatment approaches that offer effective alternatives to the maladaptive strategy of suppressing alcohol urges may be crucial for relapse prevention. Copyright © 2011 Elsevier B.V. All rights reserved.

  4. Sulfasalazine Treatment Suppresses the Formation of HLA-B27 Heavy Chain Homodimer in Patients with Ankylosing Spondylitis.

    PubMed

    Yu, Hui-Chun; Lu, Ming-Chi; Huang, Kuang-Yung; Huang, Hsien-Lu; Liu, Su-Qin; Huang, Hsien-Bin; Lai, Ning-Sheng

    2015-12-29

    Human leukocytic antigen-B27 heavy chain (HLA-B27 HC) has the tendency to fold slowly, in turn gradually forming a homodimer, (B27-HC)₂ via a disulfide linkage to activate killer cells and T-helper 17 cells and inducing endoplasmic reticulum (ER) stress to trigger the IL-23/IL-17 axis for pro-inflammatory reactions. All these consequences lead to the pathogenesis of ankylosing spondylitis (AS). Sulfasalazine (SSA) is a common medication used for treatment of patients with AS. However, the effects of SSA treatment on (B27-HC)₂ formation and on suppression of IL-23/IL-17 axis of AS patients remain to be determined. In the current study, we examine the (B27-HC)₂ of peripheral blood mononuclear cells (PBMC), the mean grade of sarcoiliitis and lumbar spine Bath Ankylosing Spondylitis Radiology Index (BASRI) scores of 23 AS patients. The results indicated that AS patients without (B27-HC)₂ on PBMC showed the lower levels of mean grade of sarcoiliitis and the lumbar spine BASRI scores. In addition, after treatment with SSA for four months, the levels of (B27-HC)₂ on PBMCs were significantly reduced. Cytokines mRNA levels, including TNFα, IL-17A, IL-17F and IFNγ, were also significantly down-regulated in PBMCs. However, SSA treatment did not affect the levels of IL-23 and IL-23R mRNAs.

  5. Food for thought: examining the relationship between food thought suppression and weight-related outcomes.

    PubMed

    Barnes, Rachel D; Tantleff-Dunn, Stacey

    2010-08-01

    The current study sought to extend previous eating behaviors and thought suppression literature by assessing the relationship between food thought suppression and weight-related outcomes. Three hundred and twelve overweight/obese community men and women completed self-report measures of thought suppression, weight history, and eating behaviors. Women were more likely than men to endorse food thought suppression, as were individuals who currently were dieting, when compared with those nondieters. Food thought suppression also predicted binge eating, food cravings, and other eating disordered symptoms. Results have implications for obesity and support further exploration of third wave interventions, such as Acceptance and Commitment Therapy and Mindfulness, in the treatment of obesity. 2010 Elsevier Ltd. All rights reserved.

  6. Fatty Acids Suppress Autophagic Turnover in β-Cells*

    PubMed Central

    Las, Guy; Serada, Sam B.; Wikstrom, Jakob D.; Twig, Gilad; Shirihai, Orian S.

    2011-01-01

    Recent studies have shown that autophagy is essential for proper β-cell function and survival. However, it is yet unclear under what pathogenic conditions autophagy is inhibited in β-cells. Here, we report that long term exposure to fatty acids and glucose block autophagic flux in β-cells, contributing to their toxic effect. INS1 cells expressing GFP-LC3 (an autophagosome marker) were treated with 0.4 mm palmitate, 0.4 mm oleate, and various concentrations of glucose for 22 h. Kinetics of the effect of fatty acids on autophagy showed a biphasic response. During the second phase of autophagy, the size of autophagosomes and the content of autophagosome substrates (GFP-LC3, p62) and endogenous LC3 was increased. During the same phase, fatty acids suppressed autophagic degradation of long lived protein in both INS1 cells and islets. In INS1 cells, palmitate induced a 3-fold decrease in the number and the acidity of Acidic Vesicular Organelles. This decrease was associated with a suppression of hydrolase activity, suppression of endocytosis, and suppression of oxidative phosphorylation. The combination of fatty acids with glucose synergistically suppressed autophagic turnover, concomitantly suppressing insulin secretion. Rapamycin treatment resulted in partial reversal of the inhibition of autophagic flux, the inhibition of insulin secretion, and the increase in cell death. Our results indicate that excess nutrient could impair autophagy in the long term, hence contributing to nutrient-induced β-cell dysfunction. This may provide a novel mechanism that connects diet-induced obesity and diabetes. PMID:21859708

  7. DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gaba, D.M.; Metz, S.; Maze, M.

    Transthoracic electric countershock can cause necrotic myocardial lesions in humans as well as experimental animals. The authors investigated the effect on postcountershock myocardial damage of pretreatment with prazosin, an alpha-1 antagonist; L-metoprolol, a beta-1 antagonist, and verapamil, a calcium channel-blocking agent. Twenty dogs were anesthetized with halothane and given two transthoracic countershocks of 295 delivered joules each after drug or vehicle treatment. Myocardial injury was quantitated 24 h following countershock by measuring the uptake of technetium-99m pyrophosphate in the myocardium. Elevated technetium-99m pyrophosphate uptake occurred in visible lesions in most dogs regardless of drug treatment. For each of four parametersmore » of myocardial damage there was no statistically significant difference between control animals and those treated with prazosin, metoprolol, or verapamil. These data suggest that adrenergic or calcium channel-mediated mechanisms are not involved in the pathogenesis of postcountershock myocardial damage.« less

  8. α1-Adrenergic receptor downregulates hepatic FGF21 production and circulating FGF21 levels in mice.

    PubMed

    Nonogaki, Katsunori; Kaji, Takao

    2017-01-18

    Fibroblast growth factor 21 (FGF21) is primarily secreted by the liver as an endocrine hormone and is suggested as a promising target for the treatment of metabolic diseases. FGF21 acts centrally to exert its effects on energy expenditure and body weight via the sympathetic nervous system in mice. Here we show that intraperitoneal injection of phentolamine (an α-adrenergic receptor antagonist, 5mg/kg) significantly increased plasma FGF21 levels compared with the saline controls in C57BL6J mice, whereas alprenolol (a β-adrenergic receptor antagonist, 6mg/kg) had no effect. In addition, intraperitoneal injection of prazosin (an α1-adrenergic receptor antagonist, 5mg/kg) significantly increased plasma FGF21 levels compared with the controls, whereas yohimbine (an α2-adrenergic receptor antagonist, 5mg/kg) had no effect. Moreover, the treatment with prazosin significantly increased the expression of hepatic FGF21, while having no effect on the expression of hepatic PPARα and PPARγ. After a 5-h fast, intraperitoneal injection of prazosin significantly increased plasma FGF21 levels and impaired glucose tolerance compared with controls. These findings suggest that α1-adrenergic receptor downregulates the expression of hepatic FGF21 and plasma FGF21 levels independently of feeding and hepatic PPARα and PPARγ expression in mice, and that the increases in circulating FGF21 levels might be related to impaired glucose tolerance. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. Carvedilol suppresses cartilage matrix destruction

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Li, Zhigang; Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning; Liu, Baoyi

    Collagen type Ⅱ (col Ⅱ) and aggrecan, the main components of the extracellular matrix (ECM) in human joint cartilage, have been reported to be reduced by chronic production of inflammatory cytokine interleukin (IL)-1β in arthritic joints. Carvedilol, a licensed medicine, has been used for treatment of hypertension, congestive heart failure and coronary disease in clinics. In this study, we investigated the effects of Carvedilol on the expression of col Ⅱ and aggrecan. Our results demonstrate that treatment with Carvedilol didn't change the expression of aggrecan or col Ⅱ at mRNA levels in SW1353 chondrocytes. However, the expression of aggrecan andmore » Col II at protein levels were significantly reduced by IL-1β treatment, which were reversed by Carvedilol in a dose dependent manner, suggesting the inhibitory effects of Carvedilol on the expression of aggrecan and Col II are at post-translational modification levels. In addition, it was shown that IL-1β treatment highly induced MMP-1 and MMP-13 expression in SW1353 chondrocytes at both gene and protein expression levels, which were restored by Carvedilol in a dose dependent manner. Mechanistically, exposure to IL-1β increased phosphorylation of IKK-α/β and degradation of IκB-α in SW1353 chondrocytes, which were suppressed by pretreatment with Carvedilol. Administration of Carvedilol inhibited IL-1β-induced translocation of NF-κB p65 from cytosol to nucleus manner. Notably, a luciferase reporter assay showed that IL-1β severely increased NF-κB luciferase activity, which was markedly suppressed by Carvedilol treatment. Our results suggest that Carvedilol might be a potential therapeutic agent for chondro-protective therapy. - Highlights: • Carvedilol abolishes IL-1β induced degradation of col Ⅱ and aggrecan. • Carvedilol inhibits the expression of MMP-1 and MMP-3 induced by IL-1β. • Carvedilol attenuates phosphorylation of IKK-α/β and degradation of IκB-α. • Carvedilol inhibits

  10. Jet noise suppression

    NASA Astrophysics Data System (ADS)

    Gliebe, P. R.; Brausch, J. F.; Majjigi, R. K.; Lee, R.

    1991-08-01

    The objectives of this chapter are to review and summarize the jet noise suppression technology, to provide a physical and theoretical model to explain the measured jet noise suppression characteristics of different concepts, and to provide a set of guidelines for evolving jet noise suppression designs. The underlying principle for all jet noise suppression devices is to enhance rapid mixing (i.e., diffusion) of the jet plume by geometric and aerothermodynamic means. In the case of supersonic jets, the shock-cell broadband noise reduction is effectively accomplished by the elimination or mitigation of the shock-cell structure. So far, the diffusion concepts have predominantly concentrated on jet momentum and energy (kinetic and thermal) diffusion, in that order, and have yielded better noise reduction than the simple conical nozzles. A critical technology issue that needs resolution is the effect of flight on the noise suppression potential of mechanical suppressor nozzles. A more thorough investigation of this mechanism is necessary for the successful development and design of an acceptable noise suppression device for future high-speed civil transports.

  11. Platelet activating factor receptor binding plays a critical role in jet fuel-induced immune suppression.

    PubMed

    Ramos, Gerardo; Kazimi, Nasser; Nghiem, Dat X; Walterscheid, Jeffrey P; Ullrich, Stephen E

    2004-03-15

    Applying military jet fuel (JP-8) or commercial jet fuel (Jet-A) to the skin of mice suppresses the immune response in a dose-dependent manner. The release of biological response modifiers, particularly prostaglandin E2 (PGE2), is a critical step in activating immune suppression. Previous studies have shown that injecting selective cyclooxygenase-2 inhibitors into jet fuel-treated mice blocks immune suppression. Because the inflammatory phospholipid mediator, platelet-activating factor (PAF), up-regulates cyclooxygenase-2 production and PGE2 synthesis by keratinocytes, we tested the hypothesis that PAF-receptor binding plays a role in jet fuel-induced immune suppression. Treating keratinocyte cultures with PAF and/or jet fuel (JP-8 and Jet-A) stimulates PGE2 secretion. Jet fuel-induced PGE2 production was suppressed by treating the keratinocytes with specific PAF-receptor antagonists. Injecting mice with PAF, or treating the skin of the mice with JP-8, or Jet-A, induced immune suppression. Jet fuel-induced immune suppression was blocked when the jet fuel-treated mice were injected with PAF-receptor antagonists before treatment. Jet fuel treatment has been reported to activate oxidative stress and treating the mice with anti-oxidants (Vitamins C, or E or beta-hydroxy toluene), before jet fuel application, interfered with immune suppression. These findings confirm previous studies showing that PAF-receptor binding can modulate immune function. Furthermore, they suggest that PAF-receptor binding may be an early event in the induction of immune suppression by immunotoxic environmental agents that target the skin.

  12. Electrical Stimulation of Afferent Pathways for the Suppression of Pathological Tremor

    PubMed Central

    Dideriksen, Jakob L.; Laine, Christopher M.; Dosen, Strahinja; Muceli, Silvia; Rocon, Eduardo; Pons, José L.; Benito-Leon, Julian; Farina, Dario

    2017-01-01

    Pathological tremors are involuntary oscillatory movements which cannot be fully attenuated using conventional treatments. For this reason, several studies have investigated the use of neuromuscular electrical stimulation for tremor suppression. In a recent study, however, we found that electrical stimulation below the motor threshold also suppressed tremor, indicating involvement of afferent pathways. In this study, we further explored this possibility by systematically investigating how tremor suppression by afferent stimulation depends on the stimulation settings. In this way, we aimed at identifying the optimal stimulation strategy, as well as to elucidate the underlying physiological mechanisms of tremor suppression. Stimulation strategies varying the stimulation intensity and pulse timing were tested in nine tremor patients using either intramuscular or surface stimulation. Significant tremor suppression was observed in six patients (tremor suppression > 75% was observed in three patients) and the average optimal suppression level observed across all subjects was 52%. The efficiency for each stimulation setting, however, varied substantially across patients and it was not possible to identify a single set of stimulation parameters that yielded positive results in all patients. For example, tremor suppression was achieved both with stimulation delivered in an out-of-phase pattern with respect to the tremor, and with random timing of the stimulation. Overall, these results indicate that low-current stimulation of afferent fibers is a promising approach for tremor suppression, but that further research is required to identify how the effect can be maximized in the individual patient. PMID:28420958

  13. A comparison of the suppression of human transferrin synthesis by lead and lipopolysaccharide.

    PubMed

    Barnum-Huckins, K M; Martinez, A O; Rivera, E V; Adrian, E K; Herbert, D C; Weaker, F J; Walter, C A; Adrian, G S

    1997-03-14

    Transferrin, as the major iron-transport protein in serum and other body fluids, has a central role in managing iron the body receives. Liver is a major site of transferrin synthesis, and in this study we present evidence that liver synthesis of human transferrin is suppressed by both the toxic metal lead and bacterial lipopolysaccharide, an inducer of the hepatic acute phase response. The responses of intact endogenous transferrin in the human hepatoma cell line HepG2 and chimeric human transferrin-chloramphenicol acetyltransferase genes in transgenic mice were examined. In HepG2 cells, 35S-transferrin protein synthesis and mRNA levels were suppressed by 100 microM and 10 microM lead acetate as early as 24 h after the initial treatment. Yet, synthesis of two proteins known to respond in the hepatic acute phase reaction, complement C3 and albumin, was not altered by the lead treatment. In transgenic mouse liver, lead suppressed expression of chimeric human transferrin genes at both the protein and mRNA levels, but LPS only suppressed at the protein level. The study indicates that lead suppresses human transferrin synthesis by a mechanism that differs from the hepatic acute phase response and that lead may also affect iron metabolism in humans by interfering with transferrin levels.

  14. Ubenimex enhances Brd4 inhibition by suppressing HEXIM1 autophagic degradation and suppressing the Akt pathway in glioma cells.

    PubMed

    Han, Liping; Zhao, Qingwei; Liang, Xianhong; Wang, Xiaoqing; Zhang, Zhen; Ma, Zhiguo; Zhao, Miaoqing; Wang, Aihua; Liu, Shuai

    2017-07-11

    Inhibition of Brd4 by JQ1 treatment showed potential in the treatment of glioma, however, some cases showed low sensitivity of JQ1. In addition, the pre-clinical analysis showed its limitation by demonstrating that transient treatment with JQ1 leads to aggressive tumor development. Thus, an improved understanding of the mechanisms underlying JQ1 is urgently required to design strategies to improve its efficiency, as well as overcome its limitation. HEXIM1 has been confirmed to have an important role in regulating JQ1 sensitivity. In our study, ubenimex, a classical anti-cancer drug showed potential in regulating the JQ1 sensitivity of glioma cells using the WST-1 proliferation assay. Further studies demonstrated that ubenimex inhibited autophagy and downregulated the autophagic degradation of HEXIM1. The role of HEXIM1 in regulating JQ1 sensitivity was verified by the HEXIM1 knockdown. Since ubenimex was verified as an Akt inhibitor, we further studied the role of Akt inhibition in regulating JQ1 sensitivity and migration of glioma cells. Data showed that ubenimex improved the efficiency of JQ1 treatment and suppressed migration both in the in vitro and in vivo xenografts models. The Akt agonist attenuated these effects, pointing to the role of Akt inhibition in JQ1 sensitivity and suppressed migration. Our findings suggest the potential of ubenimex adjuvant treatment to enhance JQ1 efficiency and attenuate parts of its side effect (enhancing tumor aggressive) by regulating the autophagic degradation of HEXIM1 and Akt inhibition.

  15. Resolution of abnormal cardiac MRI T2 signal following immune suppression for cardiac sarcoidosis.

    PubMed

    Crouser, Elliott D; Ruden, Emily; Julian, Mark W; Raman, Subha V

    2016-08-01

    Cardiac MR (CMR) with late gadolinium enhancement is commonly used to detect cardiac damage in the setting of cardiac sarcoidosis. The addition of T2 mapping to CMR was recently shown to enhance cardiac sarcoidosis detection and correlates with increased cardiac arrhythmia risk. This study was conducted to determine if CMR T2 abnormalities and related arrhythmias are reversible following immune suppression therapy. A retrospective study of subjects with cardiac sarcoidosis with abnormal T2 signal on baseline CMR and a follow-up CMR study at least 4 months later was conducted at The Ohio State University from 2011 to 2015. Immune suppression treated participants had a significant reduction in peak myocardial T2 value (70.0±5.5 vs 59.2±6.1 ms, pretreatment vs post-treatment; p=0.017), and 83% of immune suppression treated subjects had objective improvement in cardiac arrhythmias. Two subjects who had received inadequate immune suppression treatment experienced progression of cardiac sarcoidosis. This report indicates that abnormal CMR T2 signal represents an acute inflammatory manifestation of cardiac sarcoidosis that is potentially reversible with adequate immune suppression therapy. Copyright © 2016 American Federation for Medical Research.

  16. Glucose Suppresses Biological Ferroelectricity in Aortic Elastin

    PubMed Central

    Liu, Yuanming; Wang, Yunjie; Chow, Ming-Jay; Chen, Nataly Q.; Ma, Feiyue; Zhang, Yanhang; Li, Jiangyu

    2013-01-01

    Elastin is an intriguing extracellular matrix protein present in all connective tissues of vertebrates, rendering essential elasticity to connective tissues subjected to repeated physiological stresses. Using piezoresponse force microscopy, we show that the polarity of aortic elastin is switchable by an electrical field, which may be associated with the recently discovered biological ferroelectricity in the aorta. More interestingly, it is discovered that the switching in aortic elastin is largely suppressed by glucose treatment, which appears to freeze the internal asymmetric polar structures of elastin, making it much harder to switch, or suppressing the switching completely. Such loss of ferroelectricity could have important physiological and pathological implications from aging to arteriosclerosis that are closely related to glycation of elastin. PMID:23679639

  17. Assessing Suppression in Amblyopic Children With a Dichoptic Eye Chart

    PubMed Central

    Birch, Eileen E.; Morale, Sarah E.; Jost, Reed M.; De La Cruz, Angie; Kelly, Krista R.; Wang, Yi-Zhong; Bex, Peter J.

    2016-01-01

    Purpose Suppression has a key role in the etiology of amblyopia, and contrast-balanced binocular treatment can overcome suppression and improve visual acuity. Quantitative assessment of suppression could have a role in managing amblyopia. We describe a novel eye chart to assess suppression in children. Methods We enrolled 100 children (7–12 years; 63 amblyopic, 25 nonamblyopic with strabismus or anisometropia, 12 controls) in the primary cohort and 22 children (3–6 years; 13 amblyopic, 9 nonamblyopic) in a secondary cohort. Letters were presented on a dichoptic display (5 letters per line). Children wore polarized glasses so that each eye saw a different letter chart. At each position, the identity of the letter and its contrast on each eye's chart differed. Children read 8 lines of letters for each of 3 letter sizes. The contrast balance ratio was the ratio at which 50% of letters seen by the amblyopic eye were reported. Results Amblyopic children had significantly higher contrast balance ratios for all letter sizes compared to nonamblyopic children and controls, requiring 4.6 to 5.6 times more contrast in the amblyopic eye compared to the fellow eye (P < 0.0001). Amblyopic eye visual acuity was correlated with contrast balance ratio (r ranged from 0.49–0.57 for the 3 letter sizes). Change in visual acuity with amblyopia treatment was correlated with change in contrast balance ratio (r ranged from 0.43–0.62 for the 3 letter sizes). Conclusions Severity of suppression can be monitored as part of a routine clinical exam in the management of amblyopia in children. PMID:27784068

  18. Sequential drug treatment algorithm for agitation and aggression in Alzheimer's and mixed dementia.

    PubMed

    Davies, Simon Jc; Burhan, Amer M; Kim, Donna; Gerretsen, Philip; Graff-Guerrero, Ariel; Woo, Vincent L; Kumar, Sanjeev; Colman, Sarah; Pollock, Bruce G; Mulsant, Benoit H; Rajji, Tarek K

    2018-05-01

    Behavioural and psychological symptoms of dementia (BPSD) include agitation and aggression in people with dementia. BPSD is common on inpatient psychogeriatric units and may prevent individuals from living at home or in residential/nursing home settings. Several drugs and non-pharmacological treatments have been shown to be effective in reducing behavioural and psychological symptoms of dementia. Algorithmic treatment may address the challenge of synthesizing this evidence-based knowledge. A multidisciplinary team created evidence-based algorithms for the treatment of behavioural and psychological symptoms of dementia. We present drug treatment algorithms for agitation and aggression associated with Alzheimer's and mixed Alzheimer's/vascular dementia. Drugs were appraised by psychiatrists based on strength of evidence of efficacy, time to onset of clinical effect, tolerability, ease of use, and efficacy for indications other than behavioural and psychological symptoms of dementia. After baseline assessment and discontinuation of potentially exacerbating medications, sequential trials are recommended with risperidone, aripiprazole or quetiapine, carbamazepine, citalopram, gabapentin, and prazosin. Titration schedules are proposed, with adjustments for frailty. Additional guidance is given on use of electroconvulsive therapy, optimization of existing cholinesterase inhibitors/memantine, and use of pro re nata medications. This algorithm-based approach for drug treatment of agitation/aggression in Alzheimer's/mixed dementia has been implemented in several Canadian Hospital Inpatient Units. Impact should be assessed in future research.

  19. Improved Binocular Outcomes Following Binocular Treatment for Childhood Amblyopia

    PubMed Central

    Kelly, Krista R.; Jost, Reed M.; Wang, Yi-Zhong; Dao, Lori; Beauchamp, Cynthia L.; Leffler, Joel N.; Birch, Eileen E.

    2018-01-01

    Purpose Childhood amblyopia can be treated with binocular games or movies that rebalance contrast between the eyes, which is thought to reduce depth of interocular suppression so the child can experience binocular vision. While visual acuity gains have been reported following binocular treatment, studies rarely report gains in binocular outcomes (i.e., stereoacuity, suppression) in amblyopic children. Here, we evaluated binocular outcomes in children who had received binocular treatment for childhood amblyopia. Methods Data for amblyopic children enrolled in two ongoing studies were pooled. The sample included 41 amblyopic children (6 strabismic, 21 anisometropic, 14 combined; age 4–10 years; ≤4 prism diopters [PD]) who received binocular treatment (20 game, 21 movies; prescribed 9–10 hours treatment). Amblyopic eye visual acuity and binocular outcomes (Randot Preschool Stereoacuity, extent of suppression, and depth of suppression) were assessed at baseline and at 2 weeks. Results Mean amblyopic eye visual acuity (P < 0.001) and mean stereoacuity improved (P = 0.045), and mean extent (P = 0.005) and depth of suppression (P = 0.003) were reduced from baseline at the 2-week visit (87% game adherence, 100% movie adherence). Depth of suppression was reduced more in children aged <8 years than in those aged ≥8 years (P = 0.004). Worse baseline depth of suppression was correlated with a larger depth of suppression reduction at 2 weeks (P = 0.001). Conclusions After 2 weeks, binocular treatment in amblyopic children improved visual acuity and binocular outcomes, reducing the extent and depth of suppression and improving stereoacuity. Binocular treatments that rebalance contrast to overcome suppression are a promising additional option for treating amblyopia. PMID:29625442

  20. Improved Binocular Outcomes Following Binocular Treatment for Childhood Amblyopia.

    PubMed

    Kelly, Krista R; Jost, Reed M; Wang, Yi-Zhong; Dao, Lori; Beauchamp, Cynthia L; Leffler, Joel N; Birch, Eileen E

    2018-03-01

    Childhood amblyopia can be treated with binocular games or movies that rebalance contrast between the eyes, which is thought to reduce depth of interocular suppression so the child can experience binocular vision. While visual acuity gains have been reported following binocular treatment, studies rarely report gains in binocular outcomes (i.e., stereoacuity, suppression) in amblyopic children. Here, we evaluated binocular outcomes in children who had received binocular treatment for childhood amblyopia. Data for amblyopic children enrolled in two ongoing studies were pooled. The sample included 41 amblyopic children (6 strabismic, 21 anisometropic, 14 combined; age 4-10 years; ≤4 prism diopters [PD]) who received binocular treatment (20 game, 21 movies; prescribed 9-10 hours treatment). Amblyopic eye visual acuity and binocular outcomes (Randot Preschool Stereoacuity, extent of suppression, and depth of suppression) were assessed at baseline and at 2 weeks. Mean amblyopic eye visual acuity (P < 0.001) and mean stereoacuity improved (P = 0.045), and mean extent (P = 0.005) and depth of suppression (P = 0.003) were reduced from baseline at the 2-week visit (87% game adherence, 100% movie adherence). Depth of suppression was reduced more in children aged <8 years than in those aged ≥8 years (P = 0.004). Worse baseline depth of suppression was correlated with a larger depth of suppression reduction at 2 weeks (P = 0.001). After 2 weeks, binocular treatment in amblyopic children improved visual acuity and binocular outcomes, reducing the extent and depth of suppression and improving stereoacuity. Binocular treatments that rebalance contrast to overcome suppression are a promising additional option for treating amblyopia.

  1. Two faces of Hippo: activate or suppress the Hippo pathway in cancer.

    PubMed

    Cao, Jingwen; Huang, Wenlong

    2017-11-01

    The Hippo pathway has generated considerable interest in recent years because of its involvement in several key hallmarks of cancer progression and metastasis. Research on the Hippo signaling pathway in cancer has been used to determine the activity of yes-associated protein (YAP) in tumorigenesis and disease progression. Previous studies have shown that the Hippo pathway can be used as a target to inhibit YAP activity and is a viable treatment for cancer. However, more studies are required to further advance our understanding of the Hippo signaling pathway in cancer. It has been shown that knockout of serine/threonine-kinases LATS1/2 in the Hippo pathway suppresses cancer immunity in mice. In addition, suppression of the oncogene YAP could contribute toward cancer immune therapy. Therefore, regulation of Hippo signaling can be an attractive alternative strategy for cancer treatment. This review will provide a summary of currently known compounds that activate or suppress the Hippo pathway.

  2. A Mathematical Model of Intermittent Androgen Suppression for Prostate Cancer

    NASA Astrophysics Data System (ADS)

    Ideta, Aiko Miyamura; Tanaka, Gouhei; Takeuchi, Takumi; Aihara, Kazuyuki

    2008-12-01

    For several decades, androgen suppression has been the principal modality for treatment of advanced prostate cancer. Although the androgen deprivation is initially effective, most patients experience a relapse within several years due to the proliferation of so-called androgen-independent tumor cells. Bruchovsky et al. suggested in animal models that intermittent androgen suppression (IAS) can prolong the time to relapse when compared with continuous androgen suppression (CAS). Therefore, IAS has been expected to enhance clinical efficacy in conjunction with reduction in adverse effects and improvement in quality of life of patients during off-treatment periods. This paper presents a mathematical model that describes the growth of a prostate tumor under IAS therapy based on monitoring of the serum prostate-specific antigen (PSA). By treating the cancer tumor as a mixed assembly of androgen-dependent and androgen-independent cells, we investigate the difference between CAS and IAS with respect to factors affecting an androgen-independent relapse. Numerical and bifurcation analyses show how the tumor growth and the relapse time are influenced by the net growth rate of the androgen-independent cells, a protocol of the IAS therapy, and the mutation rate from androgen-dependent cells to androgen-independent ones.

  3. Raltegravir Treatment Intensification Does Not Alter Cerebrospinal Fluid HIV-1 Infection or Immunoactivation in Subjects on Suppressive Therapy

    PubMed Central

    Dahl, Viktor; Lee, Evelyn; Peterson, Julia; Spudich, Serena S.; Leppla, Idris; Sinclair, Elizabeth; Fuchs, Dietmar; Palmer, Sarah

    2011-01-01

    Background. Despite suppression of plasma human immunodeficiency virus type 1 (HIV-1) RNA by antiretroviral therapy to levels below clinical assay detection, infection and immune activation may persist within the central nervous system and possibly lead to continued brain injury. We hypothesized that intensifying therapy would decrease cerebrospinal fluid (CSF) infection and immune activation. Methods. This was a 12-week, randomized, open-label pilot study comparing addition of the integrase inhibitor raltegravir to no treatment augmentation, with an option for rollover to raltegravir. CSF and plasma were analyzed for HIV-1 RNA using a single-copy assay. CSF and blood immune activation was assessed by neopterin concentrations and CD4+ and CD8+ T-cell surface antigen expression. Results. Primary analysis compared 14 intensified (including rollovers) to 9 nonintensified subject experiences. Median HIV-1 RNA levels in all samples were lower in CSF (<.3 copies/mL) than in plasma (<.9 copies/mL; P < .0001), and raltegravir did not reduce HIV-1 RNA, CSF neopterin, or CD4+ and CD8+ T-cell activation. Conclusions. Raltegravir intensification did not reduce intrathecal immunoactivation or alter CSF HIV-1 RNA levels in subjects with baseline viral suppression. With and without raltegravir intensification, HIV RNA levels in CSF were very low in the enrolled subjects. Clinical Trials Registration. NCT00672932. PMID:22021620

  4. Fumagillin Prodrug Nanotherapy Suppresses Macrophage Inflammatory Response via Endothelial Nitric Oxide

    PubMed Central

    2015-01-01

    Antiangiogenesis has been extensively explored for the treatment of a variety of cancers and certain inflammatory processes. Fumagillin, a mycotoxin produced by Aspergillus fumigatus that binds methionine aminopeptidase 2 (MetAP-2), is a potent antiangiogenic agent. Native fumagillin, however, is poorly soluble and extremely unstable. We have developed a lipase-labile fumagillin prodrug (Fum-PD) that eliminated the photoinstability of the compound. Using αvβ3-integrin-targeted perfluorocarbon nanocarriers to deliver Fum-PD specifically to angiogenic vessels, we effectively suppressed clinical disease in an experimental model of rheumatoid arthritis (RA). The exact mechanism by which Fum-PD-loaded targeted nanoparticles suppressed inflammation in experimental RA, however, remained unexplained. We herein present evidence that Fum-PD nanotherapy indirectly suppresses inflammation in experimental RA through the local production of endothelial nitric oxide (NO). Fum-PD-induced NO activates AMP-activated protein kinase (AMPK), which subsequently modulates macrophage inflammatory response. In vivo, NO-induced AMPK activation inhibits mammalian target of rapamycin (mTOR) activity and enhances autophagic flux, as evidenced by p62 depletion and increased autolysosome formation. Autophagy in turn mediates the degradation of IkappaB kinase (IKK), suppressing the NF-κB p65 signaling pathway and inflammatory cytokine release. Inhibition of NO production by NG-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase inhibitor, reverses the suppression of NF-κB-mediated inflammatory response induced by Fum-PD nanotherapy. These unexpected results uncover an activity of Fum-PD nanotherapy that may be further explored in the treatment of angiogenesis-dependent diseases. PMID:24941020

  5. Mechanism of microbial flotation using Thiobacillus ferrooxidans for pyrite suppression.

    PubMed

    Ohmura, N; Kitamura, K; Saiki, H

    1993-03-15

    Microbial desulfurization might be developed as a new process for the removal of pyrite sulfur from coal sluries such as coal-water mixture (CWM). An application of iron-oxidizing bacterium Thiobacillus ferrooxidans to flotation would shorten the periods of the microbial removal of pyrite from some weeks by leaching methods to a few minutes. The floatability of pyrite in flotation was mainly reduced by T. ferrooxidans itself rather than by other microbial substances in bacterial culture as additive of flotation liquor. Floatability was suppressed within a few seconds by bacterial contact. The suppression was proportional to increasing the number of cells observed between bacterial adhesion and the suppression of floatability. If 25% of the total pyrite surface area covered with the bacteria, pyrite floatability would be completely depressed. Bacteria that lost their iron-oxidizing activities by sodium cyanide treatment were also able to adhere to pyrite and reduced pyrite floatability as much as normal bacteria did. Thiobacillus ferrooxidans ATCC 23270, T-1, 9, and 11, which had different iron-oxidizing abilities, suppressed floatability to similar-levels. The oxidizing ability of bacteria did not influence the suppressing effect. These results showed the mechanism of the suppression of pyrite floatability by bacteria. Quick bacterial adhesion to pyrite induced floatability suppression by changing the surface property from hydrophobic. The quick adhesion of the bacterium was the novel function which worked to change the surface property of pyrite to remove it from coal. (c) 1993 John Wiley & Sons, Inc.

  6. Tetrathiomolybdate Treatment Leads to the Suppression of Inflammatory Responses through the TRAF6/NFκB Pathway in LPS-Stimulated BV-2 Microglia

    PubMed Central

    Wang, Zhuo; Zhang, Ya-Hong; Guo, Chuang; Gao, Hui-Ling; Zhong, Man-Li; Huang, Ting-Ting; Liu, Na-Na; Guo, Rui-Fang; Lan, Tian; Zhang, Wei; Wang, Zhan-You; Zhao, Pu

    2018-01-01

    Although the positive relationship between copper and Alzheimer's disease (AD) was reported by a lot of epidemiological data, the mechanism is not completely known. Copper is a redox metal and serves as a mediator of inflammation. Because the homeostasis of copper is altered in Aβ precursor protein (APP) and presenilin 1 (PS1) transgenic (Tg) mice, the using of copper chelators is a potential therapeutic strategy for AD. Here we report that a copper chelator, tetrathiomolybdate (TM), is a potential therapeutic drug of AD. We investigated whether TM treatment led to a decrease of pro-inflammatory cytokines in vivo and in vitro, and found that TM treatment reduced the expression of iNOS and TNF-α in APP/PS1 Tg mice through up-regulating superoxide dismutase 1 (SOD1) activity. In vitro, once stimulated, microglia secretes a variety of proinflammatory cytokines, so we utilized LPS-stimulated BV-2 cells as the inflammatory cell model to detect the anti-inflammatory effects of TM. Our results indicated that TM-pretreatment suppressed the ubiquitination of TRAF6 and the activation of NFκB without affecting the expression of TLR4 and Myd88 in vitro. By detecting the activity of SOD1 and the production of reactive oxygen species (ROS), we found that the anti-inflammatory effects of TM could be attributed to its ability to reduce the amount of intracellular bioavailable copper, and the production of ROS which is an activator of the TRAF6 auto-ubiquitination. Hence, our results revealed that TM-treatment could reduce the production of inflammatory cytokines by the suppression of ROS/TRAF6/AKT/NFκB signaling pathway. PMID:29535623

  7. Suppressing bullfrog larvae with carbon dioxide

    USGS Publications Warehouse

    Gross, Jackson A.; Ray, Andrew; Sepulveda, Adam J.; Watten, Barnaby J.; Densmore, Christine L.; Layhee, Megan J.; Mark Abbey-Lambert,; ,

    2014-01-01

    Current management strategies for the control and suppression of the American Bullfrog (Lithobates catesbeianus = Rana catesbeiana Shaw) and other invasive amphibians have had minimal effect on their abundance and distribution. This study evaluates the effects of carbon dioxide (CO2) on pre- and prometamorphic Bullfrog larvae. Bullfrogs are a model organism for evaluating potential suppression agents because they are a successful invader worldwide. From experimental trials we estimated that the 24-h 50% and 99% lethal concentration (LC50 and LC99) values for Bullfrog larvae were 371 and 549 mg CO2/L, respectively. Overall, larvae that succumbed to experimental conditions had a lower body condition index than those that survived. We also documented sublethal changes in blood chemistry during prolonged exposure to elevated CO2. Specifically, blood pH decreased by more than 0.5 pH units after 9 h of exposure and both blood partial pressure of CO2 (pCO2) and blood glucose increased. These findings suggest that CO2 treatments can be lethal to Bullfrog larvae under controlled laboratory conditions. We believe this work represents the necessary foundation for further consideration of CO2 as a potential suppression agent for one of the most harmful invaders to freshwater ecosystems.

  8. CBP501 suppresses macrophage induced cancer stem cell like features and metastases

    PubMed Central

    Mine, Naoki; Yamamoto, Sayaka; Saito, Naoya; Sato, Takuji; Sakakibara, Keiichi; Kufe, Donald W.; VonHoff, Daniel D.; Kawabe, Takumi

    2017-01-01

    CBP501 is an anti-cancer drug candidate which has been shown to increase cis-diamminedichloro-platinum (II) (CDDP) uptake into cancer cell through calmodulin (CaM) inhibition. However, the effects of CBP501 on the cells in the tumor microenvironment have not been addressed. Here, we investigated new aspects of the potential anti-tumor mechanism of action of CBP501 by examining its effects on the macrophages. Macrophages contribute to cancer-related inflammation and sequential production of cytokines such as IL-6 and TNF-α which cause various biological processes that promote tumor initiation, growth and metastasis (1). These processes include the epithelial to mesenchymal transition (EMT) and cancer stem cell (CSC) formation, which are well-known, key events for metastasis. The present work demonstrates that CBP501 suppresses lipopolysaccharide (LPS)-induced production of IL-6, IL-10 and TNF-α by macrophages. CBP501 also suppressed formation of the tumor spheroids by culturing with conditioned medium from the LPS-stimulated macrophage cell line RAW264.7. Moreover, CBP501 suppressed expression of ABCG2, a marker for CSCs, by inhibiting the interaction between cancer cells expressing VCAM-1 and macrophages expressing VLA-4. Consistently with these results, CBP501 in vivo suppressed metastases of a tumor cell line, 4T1, one which is insensitive to combination treatment of CBP501 and CDDP in vitro. Taken together, these results offer potential new, unanticipated advantages of CBP501 treatment in anti-tumor therapy through a mechanism that entails the suppression of interactions between macrophages and cancer cells with suppression of sequential CSC-like cell formation in the tumor microenvironment. PMID:28969049

  9. Personalizing Androgen Suppression for Prostate Cancer Using Mathematical Modeling.

    PubMed

    Hirata, Yoshito; Morino, Kai; Akakura, Koichiro; Higano, Celestia S; Aihara, Kazuyuki

    2018-02-08

    Using a dataset of 150 patients treated with intermittent androgen suppression (IAS) through a fixed treatment schedule, we retrospectively designed a personalized treatment schedule mathematically for each patient. We estimated 100 sets of parameter values for each patient by randomly resampling each patient's time points to take into account the uncertainty for observations of prostate specific antigen (PSA). Then, we identified 3 types and classified patients accordingly: in type (i), the relapse, namely the divergence of PSA, can be prevented by IAS; in type (ii), the relapse can be delayed by IAS later than by continuous androgen suppression (CAS); in type (iii) IAS was not beneficial and therefore CAS would have been more appropriate in the long run. Moreover, we obtained a treatment schedule of hormone therapy by minimizing the PSA of 3 years later in the worst case scenario among the 100 parameter sets by searching exhaustively all over the possible treatment schedules. If the most frequent type among 100 sets was type (i), the maximal PSA tended to be kept less than 100 ng/ml longer in IAS than in CAS, while there was no statistical difference for the other cases. Thus, mathematically personalized IAS should be studied prospectively.

  10. Deconstructing continuous flash suppression

    PubMed Central

    Yang, Eunice; Blake, Randolph

    2012-01-01

    In this paper, we asked to what extent the depth of interocular suppression engendered by continuous flash suppression (CFS) varies depending on spatiotemporal properties of the suppressed stimulus and CFS suppressor. An answer to this question could have implications for interpreting the results in which CFS influences the processing of different categories of stimuli to different extents. In a series of experiments, we measured the selectivity and depth of suppression (i.e., elevation in contrast detection thresholds) as a function of the visual features of the stimulus being suppressed and the stimulus evoking suppression, namely, the popular “Mondrian” CFS stimulus (N. Tsuchiya & C. Koch, 2005). First, we found that CFS differentially suppresses the spatial components of the suppressed stimulus: Observers' sensitivity for stimuli of relatively low spatial frequency or cardinally oriented features was more strongly impaired in comparison to high spatial frequency or obliquely oriented stimuli. Second, we discovered that this feature-selective bias primarily arises from the spatiotemporal structure of the CFS stimulus, particularly within information residing in the low spatial frequency range and within the smooth rather than abrupt luminance changes over time. These results imply that this CFS stimulus operates by selectively attenuating certain classes of low-level signals while leaving others to be potentially encoded during suppression. These findings underscore the importance of considering the contribution of low-level features in stimulus-driven effects that are reported under CFS. PMID:22408039

  11. Deconstructing continuous flash suppression.

    PubMed

    Yang, Eunice; Blake, Randolph

    2012-03-08

    In this paper, we asked to what extent the depth of interocular suppression engendered by continuous flash suppression (CFS) varies depending on spatiotemporal properties of the suppressed stimulus and CFS suppressor. An answer to this question could have implications for interpreting the results in which CFS influences the processing of different categories of stimuli to different extents. In a series of experiments, we measured the selectivity and depth of suppression (i.e., elevation in contrast detection thresholds) as a function of the visual features of the stimulus being suppressed and the stimulus evoking suppression, namely, the popular "Mondrian" CFS stimulus (N. Tsuchiya & C. Koch, 2005). First, we found that CFS differentially suppresses the spatial components of the suppressed stimulus: Observers' sensitivity for stimuli of relatively low spatial frequency or cardinally oriented features was more strongly impaired in comparison to high spatial frequency or obliquely oriented stimuli. Second, we discovered that this feature-selective bias primarily arises from the spatiotemporal structure of the CFS stimulus, particularly within information residing in the low spatial frequency range and within the smooth rather than abrupt luminance changes over time. These results imply that this CFS stimulus operates by selectively attenuating certain classes of low-level signals while leaving others to be potentially encoded during suppression. These findings underscore the importance of considering the contribution of low-level features in stimulus-driven effects that are reported under CFS.

  12. Suppression on your own terms: internally generated displays of craving suppression predict rebound effects.

    PubMed

    Sayers, W Michael; Sayette, Michael A

    2013-09-01

    Research on emotion suppression has shown a rebound effect, in which expression of the targeted emotion increases following a suppression attempt. In prior investigations, participants have been explicitly instructed to suppress their responses, which has drawn the act of suppression into metaconsciousness. Yet emerging research emphasizes the importance of nonconscious approaches to emotion regulation. This study is the first in which a craving rebound effect was evaluated without simultaneously raising awareness about suppression. We aimed to link spontaneously occurring attempts to suppress cigarette craving to increased smoking motivation assessed immediately thereafter. Smokers (n = 66) received a robust cued smoking-craving manipulation while their facial responses were videotaped and coded using the Facial Action Coding System. Following smoking-cue exposure, participants completed a behavioral choice task previously found to index smoking motivation. Participants evincing suppression-related facial expressions during cue exposure subsequently valued smoking more than did those not displaying these expressions, which suggests that internally generated suppression can exert powerful rebound effects.

  13. Fire Suppression and Response

    NASA Technical Reports Server (NTRS)

    Ruff, Gary A.

    2004-01-01

    This report is concerned with the following topics regarding fire suppression:What is the relative effectiveness of candidate suppressants to extinguish a representative fire in reduced gravity, including high-O2 mole fraction, low -pressure environments? What are the relative advantages and disadvantages of physically acting and chemically-acting agents in spacecraft fire suppression? What are the O2 mole fraction and absolute pressure below which a fire cannot exist? What effect does gas-phase radiation play in the overall fire and post-fire environments? Are the candidate suppressants effective to extinguish fires on practical solid fuels? What is required to suppress non-flaming fires (smoldering and deep seated fires) in reduced gravity? How can idealized space experiment results be applied to a practical fire scenario? What is the optimal agent deployment strategy for space fire suppression?

  14. Experiential avoidance mediates the association between thought suppression and mindfulness with problem gambling.

    PubMed

    Riley, Ben

    2014-03-01

    Experiential avoidance (EA) has been shown to be an important etiological and maintenance factor in a wide range psychopathology that includes addictive, anxiety, depressive and impulse control disorders. One common form of EA is thought suppression. Problem gambling causes enormous problems for afflicted individuals and has major social costs for their families and the community. Despite increasing interest in the contribution of EA to a broad range of psychological problems, its association with problem gambling has not previously been empirically investigated. The purpose of this cross-sectional study was to investigate the relationship between EA, thought suppression, and mindfulness among a group of 103 treatment seeking problem gamblers. Of particular interest was the extent to which EA accounted for the relationships between problem gambling and the two theoretically opposing constructs: thought suppression and mindfulness. Results showed EA was predictive of problem gambling. Thought suppression was positively associated and mindfulness negatively associated with problem gambling, and these relationships were mediated by EA. Directions for future research are suggested which include the application of treatments for problem gambling that undermine EA, such as acceptance and mindfulness based therapies.

  15. Dexamethasone suppression test

    MedlinePlus

    DST; ACTH suppression test; Cortisol suppression test ... During this test, you will receive dexamethasone. This is a strong man-made (synthetic) glucocorticoid medicine. Afterward, your blood is drawn ...

  16. Emerging science, emerging ethical issues: who should fund innate alloimmunity-suppressing drugs?

    PubMed

    Land, W G; Gutmann, Th; Daar, A S

    2008-01-01

    An emerging body of evidence suggests that the innate immune system plays a critical role in allograft rejection. Any injury to the donor organ, e.g. the reperfusion injury, induces an inflammatory milieu in the allograft which appears to be the initial event for activation of the innate immune system. Injury-induced intragraft damage- associated molecular patterns (DAMPs) are recognized by donor-derived and recipient-derived, TLR4/2-bearing immature dendritic cells (iDCs). After recognition, these cells mature and initiate allorecognition/alloactivation in the lymphoid system of the recipient. Indeed, the key "innate" event, leading to activation of the adaptive alloimmune response, is the injury-induced, TLR4-triggered, and NFkappaB-mediated maturation of DCs ("innate alloimmunity"). Time-restricted treatment of innate immune events would include 1) treatment of the donor during organ removal, 2) in-situ/ex-vivo treatment of the donor organs alone, and 3) treatment of the recipient during allograft reperfusion and immediately postoperatively. Treatment modalities would include 1) minimization of the oxidative allograft injury with the use of antioxidants; 2) prevention of the TLR4-triggered maturation of DCs with the use of TLR4-antagonists; 3) inhibition of complement activation with the use of complement inhibiting agents. According to data from clinical and experimental studies it can be assumed that successful suppression of innate alloimmune events results in either subsequent significant reduction in, or even complete avoidance of the currently applied adaptive alloimmunity-suppressing drugs. However, in view of the time-restricted period of treatment, and the fear to potentially destroy its own business with currently applied alloimmunity-suppressing drugs, the pharmaceutical industry is still, but quite legitimately, reluctant to invest in the high cost of clinical development of those drugs for transplant patients because there are no marketing interests

  17. Perceptions of Sex, Gender, and Puberty Suppression: A Qualitative Analysis of Transgender Youth.

    PubMed

    Vrouenraets, Lieke Josephina Jeanne Johanna; Fredriks, A Miranda; Hannema, Sabine E; Cohen-Kettenis, Peggy T; de Vries, Martine C

    2016-10-01

    International guidelines recommend the use of Gonadotropin-Releasing Hormone (GnRH) agonists in adolescents with gender dysphoria (GD) to suppress puberty. Little is known about the way gender dysphoric adolescents themselves think about this early medical intervention. The purpose of the present study was (1) to explicate the considerations of gender dysphoric adolescents in the Netherlands concerning the use of puberty suppression; (2) to explore whether the considerations of gender dysphoric adolescents differ from those of professionals working in treatment teams, and if so in what sense. This was a qualitative study designed to identify considerations of gender dysphoric adolescents regarding early treatment. All 13 adolescents, except for one, were treated with puberty suppression; five adolescents were trans girls and eight were trans boys. Their ages ranged between 13 and 18 years, with an average age of 16 years and 11 months, and a median age of 17 years and 4 months. Subsequently, the considerations of the adolescents were compared with views of clinicians treating youth with GD. From the interviews with the gender dysphoric adolescents, three themes emerged: (1) the difficulty of determining what is an appropriate lower age limit for starting puberty suppression. Most adolescents found it difficult to define an appropriate age limit and saw it as a dilemma; (2) the lack of data on the long-term effects of puberty suppression. Most adolescents stated that the lack of long-term data did not and would not stop them from wanting puberty suppression; (3) the role of the social context, for which there were two subthemes: (a) increased media-attention, on television, and on the Internet; (b) an imposed stereotype. Some adolescents were positive about the role of the social context, but others raised doubts about it. Compared to clinicians, adolescents were often more cautious in their treatment views. It is important to give voice to gender dysphoric

  18. Tumor suppressive action of indomethacin is NK-cell-independent.

    PubMed

    Cvetkovska, E; Asea, A; Hellstrand, K; Edström, S

    1997-01-01

    This study was undertaken to determine whether NK-cells constitute a necessary mediator for the suppression of tumor growth by indomethacin. C57Bl mice with a methylcholantrene (MCG 101) tumor were studied. Indomethacin treatment was provided by daily subcutaneous injections (1 microgram/g body weight). NK-cells were depleted by treatment with a monoclonal antibody to NK1.1. Consecutive indomethacin injections prolonged survival in tumor bearing animals. Indomethacin was equally effective in animals with intact NK-cells as in NK-cell-depleted animals. Further, the MCG cells were apparently insensitive to the lytic activity of NK-cells in vivo. Thus, the clearance of intravenously injected MCG cells from lungs was not affected by depletion of NK-cells in vivo; in contrast, the corresponding clearance of NK-cell-sensitive YAC-1 lymphoma cells was strikingly reduced by the depletion of NK-cells. Our data suggest that NK cells are not a necessary mediator for the suppression of tumor growth by indomethacin.

  19. Effect of Soil Moisture and a Surfactant on Entomopathogenic Nematode Suppression of the Pecan Weevil, Curculio caryae

    PubMed Central

    Shapiro-Ilan, David I.; Cottrell, Ted E.; Brown, Ian; Gardner, Wayne A.; Hubbard, Robert K.; Wood, Bruce W.

    2006-01-01

    Our overall goal was to investigate several aspects of pecan weevil, Curculio caryae, suppression with entomopathogenic nematodes. Specifically, our objectives were to: 1) determine optimum moisture levels for larval suppression, 2) determine suppression of adult C. caryae under field conditions, and 3) measure the effects of a surfactant on nematode efficacy. In the laboratory, virulence of Heterorhabditis megidis (UK211) and Steinernema carpocapsae (All) were tested in a loamy sand at gravimetric water contents of negative 0.01, 0.06, 0.3, 1.0, and 15 bars. Curculio caryae larval survival decreased as moisture levels increased. The nematode effect was most pronounced at –0.06 bars. At –0.01 bars, larval survival was ≤5% regardless of nematode presence, thus indicating that intense irrigation alone might reduce C. caryae populations. Overall, our results indicated no effect of a surfactant (Kinetic) on C. caryae suppression with entomopathogenic nematodes. In a greenhouse test, C. caryae larval survival was lower in all nematode treatments compared with the control, yet survival was lower in S. carpocapsae (Italian) and S. riobrave (7–12) treatments than in S. carpocapsae (Agriotos), S. carpocapsae (Mexican), and S. riobrave (355) treatments (survival was reduced to approximately 20% in the S. riobrave [7–12] treatment). A mixture of S. riobrave strains resulted in intermediate larval survival. In field experiments conducted over two consecutive years, S. riobrave (7–12) applications resulted in no observable control, and, although S. carpocapsae (Italian) provided some suppression, treatment effects were generally only detectable one day after treatment. Nematode strains possessing both high levels of virulence and a greater ability to withstand environmental conditions in the field need to be developed and tested. PMID:19259466

  20. Glycolipids from spinach suppress LPS-induced vascular inflammation through eNOS and NK-κB signaling.

    PubMed

    Ishii, Masakazu; Nakahara, Tatsuo; Araho, Daisuke; Murakami, Juri; Nishimura, Masahiro

    2017-07-01

    Glycolipids are the major constituent of the thylakoid membrane of higher plants and have a variety of biological and pharmacological activities. However, anti-inflammatory effects of glycolipids on vascular endothelial cells have not been elucidated. Here, we investigated the effect of glycolipids extracted from spinach on lipopolysaccharides (LPS)-induced endothelial inflammation and evaluated the underlying molecular mechanisms. Treatment with glycolipids from spinach had no cytotoxic effects on cultured human umbilical vein endothelial cells (HUVECs) and significantly blocked the expression of LPS-induced interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), and intracellular adhesion molecule-1 (ICAM-1) in them. Glycolipids treatment also effectively suppressed monocyte adhesion to HUVECs. Treatment with glycolipids inhibited LPS-induced NF-κB phosphorylation and nuclear translocation. In addition, glycolipids treatment significantly promoted endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) production in HUVECs. Furthermore, glycolipids treatment blocked LPS-induced inducible NOS (iNOS) expression in HUVECs. Pretreatment with a NOS inhibitor attenuated glycolipids-induced suppression of NF-κB activation and adhesion molecule expression, and abolished the glycolipids-mediated suppression of monocyte adhesion to HUVECs. These results indicate that glycolipids suppress LPS-induced vascular inflammation through attenuation of the NF-κB pathway by increasing NO production in endothelial cells. These findings suggest that glycolipids from spinach may have a potential therapeutic use for inflammatory vascular diseases. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  1. A pilot study examining density of suppression measurement in strabismus.

    PubMed

    Piano, Marianne; Newsham, David

    2015-01-01

    Establish whether the Sbisa bar, Bagolini filter (BF) bar, and neutral density filter (NDF) bar, used to measure density of suppression, are equivalent and possess test-retest reliability. Determine whether density of suppression is altered when measurement equipment/testing conditions are changed. Our pilot study had 10 subjects aged ≥18 years with childhood-onset strabismus, no ocular pathologies, and no binocular vision when manifest. Density of suppression upon repeated testing, with clinic lights on/off, and using a full/reduced intensity light source, was investigated. Results were analysed for test-retest reliability, equivalence, and changes with alteration of testing conditions. Test-retest reliability issues were present for the BF bar (median 6 filter change from first to final test, p = 0.021) and NDF bar (median 5 filter change from first to final test, p = 0.002). Density of suppression was unaffected by environmental illumination or fixation light intensity variations. Density of suppression measurements were higher when measured with the NDF bar (e.g. NDF bar = 1.5, medium suppression, vs BF bar = 6.5, light suppression). Test-retest reliability issues may be present for the two filter bars currently still under manufacture. Changes in testing conditions do not significantly affect test results, provided the same filter bar is used consistently for testing. Further studies in children with strabismus having active amblyopia treatment would be of benefit. Despite extensive use of these tests in the UK, this is to our knowledge the first study evaluating filter bar equivalence/reliability.

  2. Progranulin Protects Hippocampal Neurogenesis via Suppression of Neuroinflammatory Responses Under Acute Immune Stress.

    PubMed

    Ma, Yanbo; Matsuwaki, Takashi; Yamanouchi, Keitaro; Nishihara, Masugi

    2017-07-01

    Immune stress is well known to suppress adult neurogenesis in the hippocampus. We have demonstrated that progranulin (PGRN) has a mitogenic effect on neurogenesis under several experimental conditions. We have also shown that PGRN suppresses excessive neuroinflammatory responses after traumatic brain injury. However, the role of PGRN in modulating neurogenesis under acute immune stress is yet to be elucidated. In the present study, we evaluated the involvement of PGRN in neurogenesis and inflammatory responses in the hippocampus using a lipopolysaccharide (LPS)-induced immune stress model. Treatment of mice with LPS significantly increased the expression of PGRN in activated microglia and decreased neurogenesis in the dentate gyrus of the hippocampus. PGRN deficiency increased CD68-immunoreactive area and exacerbated suppression of neurogenesis following LPS treatment. The expression levels of lysosomal genes including lysozyme M, macrophage expressed gene 1, and cathepsin Z were higher in PGRN-deficient than in wild-type mice, while PGRN deficiency decreased mammalian target of rapamycin (mTOR) mRNA levels, suggesting that PGRN suppresses excessive lysosomal biogenesis by promoting mTOR signaling. LPS treatment also increased the expression of proinflammatory genes such as interleukin (IL)-1β, tumor necrosis factor-α, and microsomal prostaglandin E synthase-1 (mPGES-1) in the hippocampus, and PGRN deficiency further enhanced gene expression of IL-6 and mPGES-1. These results suggest that PGRN plays a protecting role in hippocampal neurogenesis at least partially by attenuating neuroinflammatory responses during LPS-induced acute immune stress.

  3. Puberty suppression in adolescents with gender identity disorder: a prospective follow-up study.

    PubMed

    de Vries, Annelou L C; Steensma, Thomas D; Doreleijers, Theo A H; Cohen-Kettenis, Peggy T

    2011-08-01

    Puberty suppression by means of gonadotropin-releasing hormone analogues (GnRHa) is used for young transsexuals between 12 and 16 years of age. The purpose of this intervention is to relieve the suffering caused by the development of secondary sex characteristics and to provide time to make a balanced decision regarding actual gender reassignment. To compare psychological functioning and gender dysphoria before and after puberty suppression in gender dysphoric adolescents. Of the first 70 eligible candidates who received puberty suppression between 2000 and 2008, psychological functioning and gender dysphoria were assessed twice: at T0, when attending the gender identity clinic, before the start of GnRHa; and at T1, shortly before the start of cross-sex hormone treatment. Behavioral and emotional problems (Child Behavior Checklist and the Youth-Self Report), depressive symptoms (Beck Depression Inventory), anxiety and anger (the Spielberger Trait Anxiety and Anger Scales), general functioning (the clinician's rated Children's Global Assessment Scale), gender dysphoria (the Utrecht Gender Dysphoria Scale), and body satisfaction (the Body Image Scale) were assessed. Behavioral and emotional problems and depressive symptoms decreased, while general functioning improved significantly during puberty suppression. Feelings of anxiety and anger did not change between T0 and T1. While changes over time were equal for both sexes, compared with natal males, natal females were older when they started puberty suppression and showed more problem behavior at both T0 and T1. Gender dysphoria and body satisfaction did not change between T0 and T1. No adolescent withdrew from puberty suppression, and all started cross-sex hormone treatment, the first step of actual gender reassignment. Puberty suppression may be considered a valuable contribution in the clinical management of gender dysphoria in adolescents. © 2010 International Society for Sexual Medicine.

  4. Penfluridol suppresses glioblastoma tumor growth by Akt-mediated inhibition of GLI1

    PubMed Central

    Ranjan, Alok; Srivastava, Sanjay K.

    2017-01-01

    Glioblastoma (GBM) is the most common brain tumor with poor survival rate. Our results show that penfluridol, an antipsychotic drug significantly reduced the survival of ten adult and pediatric glioblastoma cell lines with IC50 ranging 2–5 μM after 72 hours of treatment and induced apoptosis. Penfluridol treatment suppressed the phosphorylation of Akt at Ser473 and reduced the expression of GLI1, OCT4, Nanog and Sox2 in several glioblastoma cell lines in a concentration-dependent manner. Inhibiting Akt with LY294002 and siRNA, or inhibiting GLI1 using GANT61, cyclopamine, siRNA and CRISPR/Cas9 resulted in enhanced cell growth suppressive effects of penfluridol. On the other hand, overexpression of GLI1 significantly attenuated the effects of penfluridol. Our results further demonstrated that penfluridol treatment inhibited the growth of U87MG tumors by 65% and 72% in subcutaneous and intracranial in vivo glioblastoma tumor models respectively. Immunohistochemical and western blot analysis of tumors revealed reduced pAkt (Ser 473), GLI1, OCT4 and increase in caspase-3 cleavage and TUNEL staining, confirming in vitro findings. Taken together, our results indicate that overall glioblastoma tumor growth suppression by penfluridol was associated with Akt-mediated inhibition of GLI1. PMID:28380428

  5. Active suppression induced by repetitive self-epitopes protects against EAE development.

    PubMed

    Puentes, Fabiola; Dickhaut, Katharina; Hofstätter, Maria; Falk, Kirsten; Rötzschke, Olaf

    2013-01-01

    Autoimmune diseases result from a breakdown in self-tolerance to autoantigens. Self-tolerance is induced and sustained by central and peripheral mechanisms intended to deviate harmful immune responses and to maintain homeostasis, where regulatory T cells play a crucial role. The use of self-antigens in the study and treatment of a range of autoimmune diseases has been widely described; however, the mechanisms underlying the induced protection by these means are unclear. This study shows that protection of experimental autoimmune disease induced by T cell self-epitopes in a multimerized form (oligomers) is mediated by the induction of active suppression. The experimental autoimmune encephalomyelitis (EAE) animal model for multiple sclerosis was used to study the mechanisms of protection induced by the treatment of oligomerized T cell epitope of myelin proteolipid protein (PLP139-151). Disease protection attained by the administration of oligomers was shown to be antigen specific and effective in both prevention and treatment of ongoing EAE. Oligomer mediated tolerance was actively transferred by cells from treated mice into adoptive hosts. The induction of active suppression was correlated with the recruitment of cells in the periphery associated with increased production of IL-10 and reduction of the pro-inflammatory cytokine TNF-α. The role of suppressive cytokines was demonstrated by the reversion of oligomer-induced protection after in vivo blocking of either IL-10 or TGF-β cytokines. This study strongly supports an immunosuppressive role of repeat auto-antigens to control the development of EAE with potential applications in vaccination and antigen specific treatment of autoimmune diseases.

  6. Detection of burst suppression patterns in EEG using recurrence rate.

    PubMed

    Liang, Zhenhu; Wang, Yinghua; Ren, Yongshao; Li, Duan; Voss, Logan; Sleigh, Jamie; Li, Xiaoli

    2014-01-01

    Burst suppression is a unique electroencephalogram (EEG) pattern commonly seen in cases of severely reduced brain activity such as overdose of general anesthesia. It is important to detect burst suppression reliably during the administration of anesthetic or sedative agents, especially for cerebral-protective treatments in various neurosurgical diseases. This study investigates recurrent plot (RP) analysis for the detection of the burst suppression pattern (BSP) in EEG. The RP analysis is applied to EEG data containing BSPs collected from 14 patients. Firstly we obtain the best selection of parameters for RP analysis. Then, the recurrence rate (RR), determinism (DET), and entropy (ENTR) are calculated. Then RR was selected as the best BSP index one-way analysis of variance (ANOVA) and multiple comparison tests. Finally, the performance of RR analysis is compared with spectral analysis, bispectral analysis, approximate entropy, and the nonlinear energy operator (NLEO). ANOVA and multiple comparison tests showed that the RR could detect BSP and that it was superior to other measures with the highest sensitivity of suppression detection (96.49%, P = 0.03). Tracking BSP patterns is essential for clinical monitoring in critically ill and anesthetized patients. The purposed RR may provide an effective burst suppression detector for developing new patient monitoring systems.

  7. Suppression sours sacrifice: emotional and relational costs of suppressing emotions in romantic relationships.

    PubMed

    Impett, Emily A; Kogan, Aleksandr; English, Tammy; John, Oliver; Oveis, Christopher; Gordon, Amie M; Keltner, Dacher

    2012-06-01

    What happens when people suppress their emotions when they sacrifice for a romantic partner? This multimethod study investigates how suppressing emotions during sacrifice shapes affective and relationship outcomes. In Part 1, dating couples came into the laboratory to discuss important romantic relationship sacrifices. Suppressing emotions was associated with emotional costs for the partner discussing his or her sacrifice. In Part 2, couples participated in a 14-day daily experience study. Within-person increases in emotional suppression during daily sacrifice were associated with decreases in emotional well-being and relationship quality as reported by both members of romantic dyads. In Part 3, suppression predicted decreases in relationship satisfaction and increases in thoughts about breaking up with a romantic partner 3 months later. In the first two parts of the study, authenticity mediated the costly effects of suppression. Implications for research on close relationships and emotion regulation are discussed.

  8. Legacy effects of anaerobic soil disinfestation on soil bacterial community composition and production of pathogen-suppressing volatiles

    PubMed Central

    van Agtmaal, Maaike; van Os, Gera J.; Hol, W.H. Gera; Hundscheid, Maria P.J.; Runia, Willemien T.; Hordijk, Cornelis A.; de Boer, Wietse

    2015-01-01

    There is increasing evidence that microbial volatiles (VOCs) play an important role in natural suppression of soil-borne diseases, but little is known on the factors that influence production of suppressing VOCs. In the current study we examined whether a stress-induced change in soil microbial community composition would affect the production by soils of VOCs suppressing the plant-pathogenic oomycete Pythium. Using pyrosequencing of 16S ribosomal gene fragments we compared the composition of bacterial communities in sandy soils that had been exposed to anaerobic disinfestation (AD), a treatment used to kill harmful soil organisms, with the composition in untreated soils. Three months after the AD treatment had been finished, there was still a clear legacy effect of the former anaerobic stress on bacterial community composition with a strong increase in relative abundance of the phylum Bacteroidetes and a significant decrease of the phyla Acidobacteria, Planctomycetes, Nitrospirae, Chloroflexi, and Chlorobi. This change in bacterial community composition coincided with loss of production of Pythium suppressing soil volatiles (VOCs) and of suppression of Pythium impacts on Hyacinth root development. One year later, the composition of the bacterial community in the AD soils was reflecting that of the untreated soils. In addition, both production of Pythium-suppressing VOCs and suppression of Pythium in Hyacinth bioassays had returned to the levels of the untreated soil. GC/MS analysis identified several VOCs, among which compounds known to be antifungal, that were produced in the untreated soils but not in the AD soils. These compounds were again produced 15 months after the AD treatment. Our data indicate that soils exposed to a drastic stress can temporarily lose pathogen suppressive characteristics and that both loss and return of these suppressive characteristics coincides with shifts in the soil bacterial community composition. Our data are supporting the

  9. Quantitative measurement of interocular suppression in anisometropic amblyopia: a case-control study.

    PubMed

    Li, Jinrong; Hess, Robert F; Chan, Lily Y L; Deng, Daming; Yang, Xiao; Chen, Xiang; Yu, Minbin; Thompson, Benjamin

    2013-08-01

    The aims of this study were to assess (1) the relationship between interocular suppression and visual function in patients with anisometropic amblyopia, (2) whether suppression can be simulated in matched controls using monocular defocus or neutral density filters, (3) the effects of spectacle or rigid gas-permeable contact lens correction on suppression in patients with anisometropic amblyopia, and (4) the relationship between interocular suppression and outcomes of occlusion therapy. Case-control study (aims 1-3) and cohort study (aim 4). Forty-five participants with anisometropic amblyopia and 45 matched controls (mean age, 8.8 years for both groups). Interocular suppression was assessed using Bagolini striated lenses, neutral density filters, and an objective psychophysical technique that measures the amount of contrast imbalance between the 2 eyes that is required to overcome suppression (dichoptic motion coherence thresholds). Visual acuity was assessed using a logarithm minimum angle of resolution tumbling E chart and stereopsis using the Randot preschool test. Interocular suppression assessed using dichoptic motion coherence thresholds. Patients exhibited significantly stronger suppression than controls, and stronger suppression was correlated significantly with poorer visual acuity in amblyopic eyes. Reducing monocular acuity in controls to match that of cases using neutral density filters (luminance reduction) resulted in levels of interocular suppression comparable with that in patients. This was not the case for monocular defocus (optical blur). Rigid gas-permeable contact lens correction resulted in less suppression than spectacle correction, and stronger suppression was associated with poorer outcomes after occlusion therapy. Interocular suppression plays a key role in the visual deficits associated with anisometropic amblyopia and can be simulated in controls by inducing a luminance difference between the eyes. Accurate quantification of suppression

  10. Suppression of Experimental Choroidal Neovascularization by Curcumin in Mice

    PubMed Central

    Xie, Ping; Zhang, WeiWei; Yuan, Songtao; Chen, Zhiqiang; Yang, Qin; Yuan, DongQing; Wang, Feng; Liu, QingHuai

    2012-01-01

    Purpose To investigate the effects of curcumin on the development of experimental choroidal neovascularization (CNV) with underlying cellular and molecular mechanisms. Methods C57BL/6N mice were pretreated with intraperitoneal injections of curcumin daily for 3 days prior to laser-induced CNV, and the drug treatments were continued until the end of the study. The CNV area was analyzed by fluorescein-labeled dextran angiography of retinal pigment epithelium (RPE)-choroid flat mounts on day 7 and 14, and CNV leakage was evaluated by fluorescein angiography (FA) on day 14 after laser photocoagulation. The infiltration of F4/80 positive macrophages and GR-1 positive granulocytes were evaluated by immunohistochemistry on RPE-choroid flat mounts on day 3. Their expression in RPE-choroid complex was quantified by real-time PCR (F4/80) and Western blotting (GR-1) on day 3. RPE-choroid levels of vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1, and intercellular adhesion molecule (ICAM)-1 were examined by ELISA on day 3. Double immunostaining of F4/80 and VEGF was performed on cryo-sections of CNV lesions on day 3. The expression of nuclear factor (NF)-κB and hypoxia-inducible factor (HIF)−1α in the RPE-choroid was determined by Western blotting. Results Curcumin-treated mice had significantly less CNV area (P<0.05) and CNV leakage (P<0.001) than vehicle-treated mice. Curcumin treatment led to significant inhibition of F4/80 positive macrophages (P<0.05) and GR-1 positive granulocytes infiltration (P<0.05). VEGF mainly expressed in F4/80 positive macrophages in laser injury sites, which was suppressed by curcumin treatment (P<0.01). Curcumin inhibited the RPE-choroid levels of TNF-α (P<0.05), MCP-1 (P<0.05) and ICAM-1 (P<0.05), and suppressed the activation of NF-κB in nuclear extracts (P<0.05) and the activation of HIF−1α (P<0.05). Conclusion Curcumin treatment led to the suppression of CNV development

  11. Brain Injury-Induced Synaptic Reorganization in Hilar Inhibitory Neurons Is Differentially Suppressed by Rapamycin

    PubMed Central

    2017-01-01

    Abstract Following traumatic brain injury (TBI), treatment with rapamycin suppresses mammalian (mechanistic) target of rapamycin (mTOR) activity and specific components of hippocampal synaptic reorganization associated with altered cortical excitability and seizure susceptibility. Reemergence of seizures after cessation of rapamycin treatment suggests, however, an incomplete suppression of epileptogenesis. Hilar inhibitory interneurons regulate dentate granule cell (DGC) activity, and de novo synaptic input from both DGCs and CA3 pyramidal cells after TBI increases their excitability but effects of rapamycin treatment on the injury-induced plasticity of interneurons is only partially described. Using transgenic mice in which enhanced green fluorescent protein (eGFP) is expressed in the somatostatinergic subset of hilar inhibitory interneurons, we tested the effect of daily systemic rapamycin treatment (3 mg/kg) on the excitability of hilar inhibitory interneurons after controlled cortical impact (CCI)-induced focal brain injury. Rapamycin treatment reduced, but did not normalize, the injury-induced increase in excitability of surviving eGFP+ hilar interneurons. The injury-induced increase in response to selective glutamate photostimulation of DGCs was reduced to normal levels after mTOR inhibition, but the postinjury increase in synaptic excitation arising from CA3 pyramidal cell activity was unaffected by rapamycin treatment. The incomplete suppression of synaptic reorganization in inhibitory circuits after brain injury could contribute to hippocampal hyperexcitability and the eventual reemergence of the epileptogenic process upon cessation of mTOR inhibition. Further, the cell-selective effect of mTOR inhibition on synaptic reorganization after CCI suggests possible mechanisms by which rapamycin treatment modifies epileptogenesis in some models but not others. PMID:29085896

  12. Brain Injury-Induced Synaptic Reorganization in Hilar Inhibitory Neurons Is Differentially Suppressed by Rapamycin.

    PubMed

    Butler, Corwin R; Boychuk, Jeffery A; Smith, Bret N

    2017-01-01

    Following traumatic brain injury (TBI), treatment with rapamycin suppresses mammalian (mechanistic) target of rapamycin (mTOR) activity and specific components of hippocampal synaptic reorganization associated with altered cortical excitability and seizure susceptibility. Reemergence of seizures after cessation of rapamycin treatment suggests, however, an incomplete suppression of epileptogenesis. Hilar inhibitory interneurons regulate dentate granule cell (DGC) activity, and de novo synaptic input from both DGCs and CA3 pyramidal cells after TBI increases their excitability but effects of rapamycin treatment on the injury-induced plasticity of interneurons is only partially described. Using transgenic mice in which enhanced green fluorescent protein (eGFP) is expressed in the somatostatinergic subset of hilar inhibitory interneurons, we tested the effect of daily systemic rapamycin treatment (3 mg/kg) on the excitability of hilar inhibitory interneurons after controlled cortical impact (CCI)-induced focal brain injury. Rapamycin treatment reduced, but did not normalize, the injury-induced increase in excitability of surviving eGFP+ hilar interneurons. The injury-induced increase in response to selective glutamate photostimulation of DGCs was reduced to normal levels after mTOR inhibition, but the postinjury increase in synaptic excitation arising from CA3 pyramidal cell activity was unaffected by rapamycin treatment. The incomplete suppression of synaptic reorganization in inhibitory circuits after brain injury could contribute to hippocampal hyperexcitability and the eventual reemergence of the epileptogenic process upon cessation of mTOR inhibition. Further, the cell-selective effect of mTOR inhibition on synaptic reorganization after CCI suggests possible mechanisms by which rapamycin treatment modifies epileptogenesis in some models but not others.

  13. Effects of treatment with suppressive combination antiretroviral drug therapy and the histone deacetylase inhibitor suberoylanilide hydroxamic acid; (SAHA) on SIV-infected Chinese rhesus macaques.

    PubMed

    Ling, Binhua; Piatak, Michael; Rogers, Linda; Johnson, Ann-Marie; Russell-Lodrigue, Kasi; Hazuda, Daria J; Lifson, Jeffrey D; Veazey, Ronald S

    2014-01-01

    Viral reservoirs-persistent residual virus despite combination antiretroviral therapy (cART)-remain an obstacle to cure of HIV-1 infection. Difficulty studying reservoirs in patients underscores the need for animal models that mimics HIV infected humans on cART. We studied SIV-infected Chinese-origin rhesus macaques (Ch-RM) treated with intensive combination antiretroviral therapy (cART) and 3 weeks of treatment with the histone deacetyalse inhibitor, suberoylanilide hydroxamic acid (SAHA). SIVmac251 infected Ch-RM received reverse transcriptase inhibitors PMPA and FTC and integrase inhibitor L-870812 beginning 7 weeks post infection. Integrase inhibitor L-900564 and boosted protease inhibitor treatment with Darunavir and Ritonavir were added later. cART was continued for 45 weeks, with daily SAHA administered for the last 3 weeks, followed by euthanasia/necropsy. Plasma viral RNA and cell/tissue-associated SIV gag RNA and DNA were quantified by qRT-PCR/qPCR, with flow cytometry monitoring changes in immune cell populations. Upon cART initiation, plasma viremia declined, remaining <30 SIV RNA copy Eq/ml during cART, with occasional blips. Decreased viral replication was associated with decreased immune activation and partial restoration of intestinal CD4+ T cells. SAHA was well tolerated but did not result in demonstrable treatment-associated changes in plasma or cell associated viral parameters. The ability to achieve and sustain virological suppression makes cART-suppressed, SIV-infected Ch-RM a potentially useful model to evaluate interventions targeting residual virus. However, despite intensive cART over one year, persistent viral DNA and RNA remained in tissues of all three animals. While well tolerated, three weeks of SAHA treatment did not demonstrably impact viral RNA levels in plasma or tissues; perhaps reflecting dosing, sampling and assay limitations.

  14. Using Unplanned Fires to Help Suppressing Future Large Fires in Mediterranean Forests

    PubMed Central

    Regos, Adrián; Aquilué, Núria; Retana, Javier; De Cáceres, Miquel; Brotons, Lluís

    2014-01-01

    Despite the huge resources invested in fire suppression, the impact of wildfires has considerably increased across the Mediterranean region since the second half of the 20th century. Modulating fire suppression efforts in mild weather conditions is an appealing but hotly-debated strategy to use unplanned fires and associated fuel reduction to create opportunities for suppression of large fires in future adverse weather conditions. Using a spatially-explicit fire–succession model developed for Catalonia (Spain), we assessed this opportunistic policy by using two fire suppression strategies that reproduce how firefighters in extreme weather conditions exploit previous fire scars as firefighting opportunities. We designed scenarios by combining different levels of fire suppression efficiency and climatic severity for a 50-year period (2000–2050). An opportunistic fire suppression policy induced large-scale changes in fire regimes and decreased the area burnt under extreme climate conditions, but only accounted for up to 18–22% of the area to be burnt in reference scenarios. The area suppressed in adverse years tended to increase in scenarios with increasing amounts of area burnt during years dominated by mild weather. Climate change had counterintuitive effects on opportunistic fire suppression strategies. Climate warming increased the incidence of large fires under uncontrolled conditions but also indirectly increased opportunities for enhanced fire suppression. Therefore, to shift fire suppression opportunities from adverse to mild years, we would require a disproportionately large amount of area burnt in mild years. We conclude that the strategic planning of fire suppression resources has the potential to become an important cost-effective fuel-reduction strategy at large spatial scale. We do however suggest that this strategy should probably be accompanied by other fuel-reduction treatments applied at broad scales if large-scale changes in fire regimes are

  15. Using unplanned fires to help suppressing future large fires in Mediterranean forests.

    PubMed

    Regos, Adrián; Aquilué, Núria; Retana, Javier; De Cáceres, Miquel; Brotons, Lluís

    2014-01-01

    Despite the huge resources invested in fire suppression, the impact of wildfires has considerably increased across the Mediterranean region since the second half of the 20th century. Modulating fire suppression efforts in mild weather conditions is an appealing but hotly-debated strategy to use unplanned fires and associated fuel reduction to create opportunities for suppression of large fires in future adverse weather conditions. Using a spatially-explicit fire-succession model developed for Catalonia (Spain), we assessed this opportunistic policy by using two fire suppression strategies that reproduce how firefighters in extreme weather conditions exploit previous fire scars as firefighting opportunities. We designed scenarios by combining different levels of fire suppression efficiency and climatic severity for a 50-year period (2000-2050). An opportunistic fire suppression policy induced large-scale changes in fire regimes and decreased the area burnt under extreme climate conditions, but only accounted for up to 18-22% of the area to be burnt in reference scenarios. The area suppressed in adverse years tended to increase in scenarios with increasing amounts of area burnt during years dominated by mild weather. Climate change had counterintuitive effects on opportunistic fire suppression strategies. Climate warming increased the incidence of large fires under uncontrolled conditions but also indirectly increased opportunities for enhanced fire suppression. Therefore, to shift fire suppression opportunities from adverse to mild years, we would require a disproportionately large amount of area burnt in mild years. We conclude that the strategic planning of fire suppression resources has the potential to become an important cost-effective fuel-reduction strategy at large spatial scale. We do however suggest that this strategy should probably be accompanied by other fuel-reduction treatments applied at broad scales if large-scale changes in fire regimes are to be

  16. Peptide immunotherapy in allergic asthma generates IL-10–dependent immunological tolerance associated with linked epitope suppression

    PubMed Central

    Campbell, John D.; Buckland, Karen F.; McMillan, Sarah J.; Kearley, Jennifer; Oldfield, William L.G.; Stern, Lawrence J.; Grönlund, Hans; van Hage, Marianne; Reynolds, Catherine J.; Boyton, Rosemary J.; Cobbold, Stephen P.; Kay, A. Barry; Altmann, Daniel M.; Larché, Mark

    2009-01-01

    Treatment of patients with allergic asthma using low doses of peptides containing T cell epitopes from Fel d 1, the major cat allergen, reduces allergic sensitization and improves surrogate markers of disease. Here, we demonstrate a key immunological mechanism, linked epitope suppression, associated with this therapeutic effect. Treatment with selected epitopes from a single allergen resulted in suppression of responses to other (“linked”) epitopes within the same molecule. This phenomenon was induced after peptide immunotherapy in human asthmatic subjects and in a novel HLA-DR1 transgenic mouse model of asthma. Tracking of allergen-specific T cells using DR1 tetramers determined that suppression was associated with the induction of interleukin (IL)-10+ T cells that were more abundant than T cells specific for the single-treatment peptide and was reversed by anti–IL-10 receptor administration. Resolution of airway pathophysiology in this model was associated with reduced recruitment, proliferation, and effector function of allergen-specific Th2 cells. Our results provide, for the first time, in vivo evidence of linked epitope suppression and IL-10 induction in both human allergic disease and a mouse model designed to closely mimic peptide therapy in humans. PMID:19528258

  17. Local cortical dynamics of burst suppression in the anaesthetized brain.

    PubMed

    Lewis, Laura D; Ching, Shinung; Weiner, Veronica S; Peterfreund, Robert A; Eskandar, Emad N; Cash, Sydney S; Brown, Emery N; Purdon, Patrick L

    2013-09-01

    , subcortical circuits express seemingly different sensitivities to high doses of anaesthetics that suggest a hierarchy governing how the brain enters burst suppression, and emphasize the role of local dynamics in what has previously been regarded as a global state. These findings suggest a conceptual shift in how neurologists could assess the brain function of patients undergoing burst suppression. First, analysing spatial variation in burst suppression could provide insight into the circuit dysfunction underlying a given pathology, and could improve monitoring of medically-induced coma. Second, analysing the temporal dynamics within a burst could help assess the underlying brain state. This approach could be explored as a prognostic tool for recovery from coma, and for guiding treatment of status epilepticus. Overall, these results suggest new research directions and methods that could improve patient monitoring in clinical practice.

  18. Thyroid stimulating hormone suppression post-therapy in patients with Graves' disease: a systematic review of pathophysiology and clinical data.

    PubMed

    Yu, Huan; Farahani, Pendar

    2015-04-08

    Post-treatment hypothyroidism is common in Graves' disease, and clinical guidelines recommend monitoring for it; however, thyroid stimulating hormone (TSH) can remain suppressed in these patients following treatment. The objectives of this study were to explore the proposed pathophysiology behind the phenomenon of post-therapy TSH suppression and to systematically review existing clinical data on post-therapy TSH suppression in patients with Graves' disease. A systematic literature search was performed using EMBASE and PubMed databases, with several combinations of MeSH terms. Bibliography mining was also done on relevant articles to be as inclusive as possible. A total of 18 articles described possible mechanisms for post-therapy TSH suppression. Several of the studies demonstrate evidence of thyrotroph atrophy and hypothesize that this contributes to the ongoing suppression. TSH receptors have been identified in folliculo-stellate cells of the pituitary as well as astroglial cells of the hypothalamus, mediating paracrine feedback. A few studies have demonstrated inverse correlation between autoantibody titres and TSH levels, suggestive of their role in mediating ongoing TSH suppression in patients with Graves' disease. In addition, five studies were identified that provided clinical data on the duration of TSH suppression. Combined data show that 45.5% of patients recover TSH by 3 months after treatment, increasing to 69.3% by 6 months, and plateauing to 73.8% by 12 months (p>0.0001). Sub-analysis also shows that for patients who are TBII negative, 80.7% recover their TSH by 6 months compared with only 58.7% in those who are TBII positive (p= 0.003). Clinical data suggests that TSH recovery is most likely to occur within the first 6 months after treatment, with recovery plateauing at approximately 70% of patients, suggesting that reliance on this assay for monitoring can be very misleading. Furthermore, TBII positivity is associated with lower likelihood of TSH

  19. Nicotinamide Cofactors Suppress Active-Site Labeling of Aldehyde Dehydrogenases.

    PubMed

    Stiti, Naim; Chandrasekar, Balakumaran; Strubl, Laura; Mohammed, Shabaz; Bartels, Dorothea; van der Hoorn, Renier A L

    2016-06-17

    Active site labeling by (re)activity-based probes is a powerful chemical proteomic tool to globally map active sites in native proteomes without using substrates. Active site labeling is usually taken as a readout for the active state of the enzyme because labeling reflects the availability and reactivity of active sites, which are hallmarks for enzyme activities. Here, we show that this relationship holds tightly, but we also reveal an important exception to this rule. Labeling of Arabidopsis ALDH3H1 with a chloroacetamide probe occurs at the catalytic Cys, and labeling is suppressed upon nitrosylation and oxidation, and upon treatment with other Cys modifiers. These experiments display a consistent and strong correlation between active site labeling and enzymatic activity. Surprisingly, however, labeling is suppressed by the cofactor NAD(+), and this property is shared with other members of the ALDH superfamily and also detected for unrelated GAPDH enzymes with an unrelated hydantoin-based probe in crude extracts of plant cell cultures. Suppression requires cofactor binding to its binding pocket. Labeling is also suppressed by ALDH modulators that bind at the substrate entrance tunnel, confirming that labeling occurs through the substrate-binding cavity. Our data indicate that cofactor binding adjusts the catalytic Cys into a conformation that reduces the reactivity toward chloroacetamide probes.

  20. The Temporal Relationship Between Intrafamilial Violence, Deployment, and Serious Mental Illness in US Army Service Members

    DTIC Science & Technology

    2013-03-01

    PROPOXYPHENE (DARVON) - TRAMADOL (ULTRAM) ANTI SEIZURE MEDICATION (USED FOR CHRONIC PAIN ) - PHENYTOIN (DILANTIN) NSAIDS - ASPIRIN - IBUPROFEN...ESZOPICLONE) g. Prazosin - PRAZOSIN HCL (MINIPRESS) h. Other relevant Medications: Pain medications OPIODS - CODEINE - FENTANYL... pain : - AMITRIPTYLINE HCL/CHLORDIAZEPOXIDE (LIMBITROL) - AMITRIPTYLINE HCL/PERPHENAZINE (TRIAVIL, ETRAFON) - DESIPRAMINE HCL (PERTOFRANE, NORPRAMIN

  1. Metformin alleviated endotoxemia-induced acute lung injury via restoring AMPK-dependent suppression of mTOR.

    PubMed

    Wu, Kejia; Tian, Rui; Huang, Jing; Yang, Yongqiang; Dai, Jie; Jiang, Rong; Zhang, Li

    2018-05-31

    Inflammation requires intensive metabolic support and modulation of the metabolic pathways might become a novel strategy to limit inflammatory injury. Recent studies have revealed the anti-inflammatory effects of the anti-diabetic reagent metformin, but the underlying mechanisms remain unclear. In the present study, the potential effects of metformin on endotoxemia-induced acute lung injury (ALI) and their relationship with the representative metabolic regulator, including AMPK, sirtuin 1 and mTOR, were investigated. The results indicated that treatment with metformin suppressed LPS-induced upregulation of IL-6 and TNF-α, alleviated pulmonary histological abnormalities, improved the survival rate of LPS-challenged mice. Treatment with metformin reversed LPS-induced decline of AMPK phosphorylation. Co-administration of the AMPK inhibitor compound C abolished the stimulatory effects of metformin on AMPK phosphorylation, the suppressive effects of metformin on IL-6 induction and pulmonary lesions. In addition, co-administration of the mTOR activator 3BDO but not the sirtuin 1 inhibitor EX-527 abolished the effects of metformin on IL-6 induction and pulmonary lesions. Finally, treatment with metformin suppressed LPS-induced p70S6K1 phosphorylation, which was abolished by the AMPK inhibitor. These data suggest that metformin might provide anti-inflammatory benefits in endotoxemia-induced inflammatory lung injury via restoring AMPK-dependent suppression of mTOR. Copyright © 2018. Published by Elsevier B.V.

  2. Correcting intermittent central suppression improves binocular marksmanship.

    PubMed

    Hussey, Eric S

    2007-04-01

    Intermittent central suppression (ICS) is a defect in normal binocular (two-eyed) vision that causes confusion in visual detail. ICS is a repetitive intermittent loss of visual sensation in the central area of vision. As the central vision of either eye "turns on and off", aiming errors in sight can occur that must be corrected when both eyes are seeing again. Any aiming errors in sight might be expected to interfere with marksmanship during two-eyed seeing. We compared monocular (one-eyed, patched) and binocular (two-eyed) marksmanship with pistol shooting with an Army ROTC cadet before and after successful therapy for diagnosed ICS. Pretreatment, monocular marksmanship was significantly better than binocular marksmanship, suggesting defective binocularity reduced accuracy. After treatment for ICS, binocular and monocular marksmanship were essentially the same. Results confirmed predictions that with increased visual stability from correcting the suppression, binocular and monocular marksmanship accuracies should merge.

  3. Puberty suppression in gender identity disorder: the Amsterdam experience.

    PubMed

    Kreukels, Baudewijntje P C; Cohen-Kettenis, Peggy T

    2011-05-17

    The use of gonadotropin-releasing hormone analogs (GnRHa) to suppress puberty in adolescents with gender dysphoria is a fairly new intervention in the field of gender identity disorders or transsexualism. GnRHa are used to give adolescents time to make balanced decisions on any further treatment steps, and to obtain improved results in the physical appearance of those who opt to continue with sex reassignment. The effects of GnRHa are reversible. However, concerns have been raised about the risk of making the wrong treatment decisions, as gender identity could fluctuate during adolescence, adolescents in general might have poor decision-making abilities, and there are potential adverse effects on health and on psychological and psychosexual functioning. Proponents of puberty suppression emphasize the beneficial effects of GnRHa on the adolescents' mental health, quality of life and of having a physical appearance that makes it possible for the patients to live unobtrusively in their desired gender role. In this Review, we discuss the evidence pertaining to the debate on the effects of GnRHa treatment. From the studies that have been published thus far, it seems that the benefits outweigh the risks. However, more systematic research in this area is needed to determine the safety of this approach.

  4. Using topography to meet wildlife and fuels treatment objectives in fire-suppressed landscapes

    Treesearch

    Emma C. Underwood; Joshua H. Viers; James F. Quinn; Malcolm North

    2010-01-01

    Past forest management practices, fire suppression, and climate change are increasing the need to actively manage California Sierra Nevada forests for multiple environmental amenities. Here we present a relatively low-cost, repeatable method for spatially parsing the landscape to help the U.S. Forest Service manage for different forest and fuel conditions to meet...

  5. Transient Suppression of TGFβ Receptor Signaling Facilitates Human Islet Transplantation

    PubMed Central

    Fischbach, Shane; Song, Zewen; Gaffar, Iljana; Zimmerman, Ray; Wiersch, John; Prasadan, Krishna; Shiota, Chiyo; Guo, Ping; Ramachandran, Sabarinathan; Witkowski, Piotr

    2016-01-01

    Although islet transplantation is an effective treatment for severe diabetes, its broad application is greatly limited due to a shortage of donor islets. Suppression of TGFβ receptor signaling in β-cells has been shown to increase β-cell proliferation in mice, but has not been rigorously examined in humans. Here, treatment of human islets with a TGFβ receptor I inhibitor, SB-431542 (SB), significantly improved C-peptide secretion by β-cells, and significantly increased β-cell number by increasing β-cell proliferation. In addition, SB increased cell-cycle activators and decreased cell-cycle suppressors in human β-cells. Transplantation of SB-treated human islets into diabetic immune-deficient mice resulted in significant improvement in blood glucose control, significantly higher serum and graft insulin content, and significantly greater increases in β-cell proliferation in the graft, compared with controls. Thus, our data suggest that transient suppression of TGFβ receptor signaling may improve the outcome of human islet transplantation, seemingly through increasing β-cell number and function. PMID:26872091

  6. Tenofovir alafenamide plus emtricitabine versus abacavir plus lamivudine for treatment of virologically suppressed HIV-1-infected adults: a randomised, double-blind, active-controlled, non-inferiority phase 3 trial.

    PubMed

    Winston, Alan; Post, Frank A; DeJesus, Edwin; Podzamczer, Daniel; Di Perri, Giovanni; Estrada, Vicente; Raffi, François; Ruane, Peter; Peyrani, Paula; Crofoot, Gordon; Mallon, Patrick W G; Castelli, Francesco; Yan, Mingjin; Cox, Stephanie; Das, Moupali; Cheng, Andrew; Rhee, Martin S

    2018-04-01

    Abacavir and tenofovir alafenamide offer reduced bone toxicity compared with tenofovir disoproxil fumarate. We aimed to compare safety and efficacy of tenofovir alafenamide plus emtricitabine with that of abacavir plus lamivudine. In this randomised, double-blind, active-controlled, non-inferiority phase 3 trial, HIV-1-positive adults (≥18 years) were screened at 79 sites in 11 countries in North America and Europe. Eligible participants were virologically suppressed (HIV-1 RNA <50 copies per mL) and on a stable three-drug regimen containing abacavir plus lamivudine. Participants were randomly assigned (1:1) by a computer-generated allocation sequence (block size 4) to switch to fixed-dose tablets of tenofovir alafenamide (10 mg or 25 mg) plus emtricitabine (200 mg) or remain on abacavir (600 mg) plus lamivudine (300 mg), with matching placebo, while continuing to take the third drug. Randomisation was stratified by the third drug (boosted protease inhibitor vs other drug) at screening. Investigators, participants, and study staff giving treatment, assessing outcomes, and collecting data were masked to treatment group. The primary endpoint was the proportion of participants with virological suppression (HIV-1 RNA <50 copies per mL) at week 48 (assessed by snapshot algorithm), with a 10% non-inferiority margin. We analysed the primary endpoint in participants enrolled before May 23, 2016 (when target sample size was reached), and we analysed safety in all enrolled participants who received at least one dose of study drug (including patients enrolled after these dates). This study was registered with ClinicalTrials.gov, number NCT02469246. Study enrolment began on June 29, 2015, and the cutoff enrolment date for the week 48 primary endpoint analysis was May 23, 2016. 501 participants were randomly assigned and treated. At week 48, virological suppression was maintained in 227 (90%) of 253 participants receiving tenofovir alafenamide plus emtricitabine compared with

  7. Kinetic suppression of microtubule dynamic instability by griseofulvin: Implications for its possible use in the treatment of cancer

    PubMed Central

    Panda, Dulal; Rathinasamy, K.; Santra, Manas K.; Wilson, Leslie

    2005-01-01

    The antifungal drug griseofulvin inhibits mitosis strongly in fungal cells and weakly in mammalian cells by affecting mitotic spindle microtubule (MT) function. Griseofulvin also blocks cell-cycle progression at G2/M and induces apoptosis in human tumor cell lines. Despite extensive study, the mechanism by which the drug inhibits mitosis in human cells remains unclear. Here, we analyzed the ability of griseofulvin to inhibit cell proliferation and mitosis and to affect MT polymerization and organization in HeLa cells together with its ability to affect MT polymerization and dynamic instability in vitro. Griseofulvin inhibited cell-cycle progression at prometaphase/anaphase of mitosis in parallel with its ability to inhibit cell proliferation. At its mitotic IC50 of 20 μM, spindles in blocked cells displayed nearly normal quantities of MTs and MT organization similar to spindles blocked by more powerful MT-targeted drugs. Similar to previously published data, we found that very high concentrations of griseofulvin (>100 μM) were required to inhibit MT polymerization in vitro. However, much lower drug concentrations (1–20 μM) strongly suppressed the dynamic instability behavior of the MTs. We suggest that the primary mechanism by which griseofulvin inhibits mitosis in human cells is by suppressing spindle MT dynamics in a manner qualitatively similar to that of much more powerful antimitotic drugs, including the vinca alkaloids and the taxanes. In view of griseofulvin's lack of significant toxicity in humans, we further suggest that it could be useful as an adjuvant in combination with more powerful drugs for the treatment of cancer. PMID:15985553

  8. A clinical data validated mathematical model of prostate cancer growth under intermittent androgen suppression therapy

    NASA Astrophysics Data System (ADS)

    Portz, Travis; Kuang, Yang; Nagy, John D.

    2012-03-01

    Prostate cancer is commonly treated by a form of hormone therapy called androgen suppression. This form of treatment, while successful at reducing the cancer cell population, adversely affects quality of life and typically leads to a recurrence of the cancer in an androgen-independent form. Intermittent androgen suppression aims to alleviate some of these adverse affects by cycling the patient on and off treatment. Clinical studies have suggested that intermittent therapy is capable of maintaining androgen dependence over multiple treatment cycles while increasing quality of life during off-treatment periods. This paper presents a mathematical model of prostate cancer to study the dynamics of androgen suppression therapy and the production of prostate-specific antigen (PSA), a clinical marker for prostate cancer. Preliminary models were based on the assumption of an androgen-independent (AI) cell population with constant net growth rate. These models gave poor accuracy when fitting clinical data during simulation. The final model presented hypothesizes an AI population with increased sensitivity to low levels of androgen. It also hypothesizes that PSA production is heavily dependent on androgen. The high level of accuracy in fitting clinical data with this model appears to confirm these hypotheses, which are also consistent with biological evidence.

  9. Interaction Between 2 Nutraceutical Treatments and Host Immune Status in the Pediatric Critical Illness Stress-Induced Immune Suppression Comparative Effectiveness Trial.

    PubMed

    Carcillo, Joseph A; Dean, J Michael; Holubkov, Richard; Berger, John; Meert, Kathleen L; Anand, Kanwaljeet J S; Zimmerman, Jerry J; Newth, Christopher J L; Harrison, Rick; Burr, Jeri; Willson, Douglas F; Nicholson, Carol; Bell, Michael J; Berg, Robert A; Shanley, Thomas P; Heidemann, Sabrina M; Dalton, Heidi; Jenkins, Tammara L; Doctor, Allan; Webster, Angie; Tamburro, Robert F

    2017-11-01

    The pediatric Critical Illness Stress-induced Immune Suppression (CRISIS) trial compared the effectiveness of 2 nutraceutical supplementation strategies and found no difference in the development of nosocomial infection and sepsis in the overall population. We performed an exploratory post hoc analysis of interaction between nutraceutical treatments and host immune status related to the development of nosocomial infection/sepsis. Children from the CRISIS trial were analyzed according to 3 admission immune status categories marked by decreasing immune competence: immune competent without lymphopenia, immune competent with lymphopenia, and previously immunocompromised. The comparative effectiveness of the 2 treatments was analyzed for interaction with immune status category. There were 134 immune-competent children without lymphopenia, 79 previously immune-competent children with lymphopenia, and 27 immunocompromised children who received 1 of the 2 treatments. A significant interaction was found between treatment arms and immune status on the time to development of nosocomial infection and sepsis ( P < .05) and on the rate of nosocomial infection and sepsis per 100 patient days ( P < .05). Whey protein treatment protected immune-competent patients without lymphopenia from infection and sepsis, both nutraceutical strategies were equivalent in immune-competent patients with lymphopenia, and zinc, selenium, glutamine, and metoclopramide treatment protected immunocompromised patients from infection and sepsis. The science of immune nutrition is more complex than previously thought. Future trial design should consider immune status at the time of trial entry because differential effects of nutraceuticals may be related to this patient characteristic.

  10. Allele-specific suppression as a tool to study protein-protein interactions in bacteria.

    PubMed

    Manson, M D

    2000-01-01

    Suppression analysis is well suited to study the interactions of gene products. It offers the advantage of simplicity for any organism for which a convenient genetic system has been developed, which holds for a wide spectrum of bacteria and an ever-increasing number of unicellular as well as complex eukaryotes. No other method provides as much information about the functional relationships of biological macromolecules. The intrinsic value of suppression analysis is enhanced by advances in genomics and in biophysical techniques for investigating the properties of nucleic acids and proteins, such as X-ray crystallography, liquid and solid-state nuclear magnetic resonance, electron spin labeling, and isothermal calorimetry. These approaches confirm and complement whatever is revealed by genetics. Despite these sterling qualities, suppression analysis has its dangers, less in execution than in conceptualization of experiments and interpretation of data. A consistent nomenclature is essential for a uniform and widespread understanding of the results. Familiarity with the genetic background and idiosyncracies of the organism studied is critical in avoiding extraneous phenomena that can affect the outcome. Finally, it is imperative not to underestimate potentially bizarre and improbable consequences that can transpire when rigorous genetic selection is maintained for an appreciable length of time. The article begins with a somewhat pedagogical discussion of genetic terminology. It then moves on to the necessary precautions to observe while planning and conducting suppression analysis. The remainder of the article considers different manifestations of suppression: bypass suppression; gradients of suppression; suppression by relaxed specificity; allele-specific "suppression at a distance"; and true conformational suppression. The treatment is not exhaustive, but representative examples have been gleaned from the recent bacterial literature. Copyright 2000 Academic Press.

  11. MicroRNA-214 Suppresses Gluconeogenesis by Targeting Activating Transcriptional Factor 4*

    PubMed Central

    Li, Kai; Zhang, Jin; Yu, Junjie; Liu, Bin; Guo, Yajie; Deng, Jiali; Chen, Shanghai; Wang, Chunxia; Guo, Feifan

    2015-01-01

    Although the gluconeogenesis pathway is already a target for the treatment of type 2 diabetes, the potential role of microRNAs (miRNAs) in gluconeogenesis remains unclear. Here, we investigated the physiological functions of miR-214 in gluconeogenesis. The expression of miR-214 was suppressed by glucagon via protein kinase A signaling in primary hepatocytes, and miR-214 was down-regulated in the livers of fasted, high fat diet-induced diabetic and leptin receptor-mutated (db/db) mice. The overexpression of miR-214 in primary hepatocytes suppressed glucose production, and silencing miR-214 reversed this effect. Gluconeogenesis was suppressed in the livers of mice injected with an adenovirus expressing miR-214 (Ad-miR-214). Additionally, Ad-miR-214 alleviated high fat diet-induced elevation of gluconeogenesis and hyperglycemia. Furthermore, we found that activating transcription factor 4 (ATF4), a reported target of miR-214, can reverse the suppressive effect of miR-214 on gluconeogenesis in primary hepatocytes, and this suppressive effect was blocked in liver-specific ATF4 knock-out mice. ATF4 regulated gluconeogenesis via affecting forkhead box protein O1 (FOXO1) transcriptional activity. Finally, liver-specific miR-214 transgenic mice exhibited suppressed gluconeogenesis and reduced expression of ATF4, phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase in liver. Taken together, our results suggest that the miR-214-ATF4 axis is a novel pathway for the regulation of hepatic gluconeogenesis. PMID:25657009

  12. Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression

    PubMed Central

    Westerlund, Isabelle; Shi, Yao; Toskas, Konstantinos; Fell, Stuart M.; Li, Shuijie; Surova, Olga; Södersten, Erik; Kogner, Per; Nyman, Ulrika; Schlisio, Susanne; Holmberg, Johan

    2017-01-01

    Neuroblastoma is a pediatric cancer characterized by variable outcomes ranging from spontaneous regression to life-threatening progression. High-risk neuroblastoma patients receive myeloablative chemotherapy with hematopoietic stem-cell transplant followed by adjuvant retinoid differentiation treatment. However, the overall survival remains low; hence, there is an urgent need for alternative therapeutic approaches. One feature of high-risk neuroblastoma is the high level of DNA methylation of putative tumor suppressors. Combining the reversibility of DNA methylation with the differentiation-promoting activity of retinoic acid (RA) could provide an alternative strategy to treat high-risk neuroblastoma. Here we show that treatment with the DNA-demethylating drug 5-Aza-deoxycytidine (AZA) restores high-risk neuroblastoma sensitivity to RA. Combined systemic distribution of AZA and RA impedes tumor growth and prolongs survival. Genome-wide analysis of treated tumors reveals that this combined treatment rapidly induces a HIF2α-associated hypoxia-like transcriptional response followed by an increase in neuronal gene expression and a decrease in cell-cycle gene expression. A small-molecule inhibitor of HIF2α activity diminishes the tumor response to AZA+RA treatment, indicating that the increase in HIF2α levels is a key component in tumor response to AZA+RA. The link between increased HIF2α levels and inhibited tumor growth is reflected in large neuroblastoma patient datasets. Therein, high levels of HIF2α, but not HIF1α, significantly correlate with expression of neuronal differentiation genes and better prognosis but negatively correlate with key features of high-risk tumors, such as MYCN amplification. Thus, contrary to previous studies, our findings indicate an unanticipated tumor-suppressive role for HIF2α in neuroblastoma. PMID:28696319

  13. Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression.

    PubMed

    Westerlund, Isabelle; Shi, Yao; Toskas, Konstantinos; Fell, Stuart M; Li, Shuijie; Surova, Olga; Södersten, Erik; Kogner, Per; Nyman, Ulrika; Schlisio, Susanne; Holmberg, Johan

    2017-07-25

    Neuroblastoma is a pediatric cancer characterized by variable outcomes ranging from spontaneous regression to life-threatening progression. High-risk neuroblastoma patients receive myeloablative chemotherapy with hematopoietic stem-cell transplant followed by adjuvant retinoid differentiation treatment. However, the overall survival remains low; hence, there is an urgent need for alternative therapeutic approaches. One feature of high-risk neuroblastoma is the high level of DNA methylation of putative tumor suppressors. Combining the reversibility of DNA methylation with the differentiation-promoting activity of retinoic acid (RA) could provide an alternative strategy to treat high-risk neuroblastoma. Here we show that treatment with the DNA-demethylating drug 5-Aza-deoxycytidine (AZA) restores high-risk neuroblastoma sensitivity to RA. Combined systemic distribution of AZA and RA impedes tumor growth and prolongs survival. Genome-wide analysis of treated tumors reveals that this combined treatment rapidly induces a HIF2α-associated hypoxia-like transcriptional response followed by an increase in neuronal gene expression and a decrease in cell-cycle gene expression. A small-molecule inhibitor of HIF2α activity diminishes the tumor response to AZA+RA treatment, indicating that the increase in HIF2α levels is a key component in tumor response to AZA+RA. The link between increased HIF2α levels and inhibited tumor growth is reflected in large neuroblastoma patient datasets. Therein, high levels of HIF2α, but not HIF1α, significantly correlate with expression of neuronal differentiation genes and better prognosis but negatively correlate with key features of high-risk tumors, such as MYCN amplification. Thus, contrary to previous studies, our findings indicate an unanticipated tumor-suppressive role for HIF2α in neuroblastoma.

  14. Selective blockade by nicergoline of vascular responses elicited by stimulation of alpha 1A-adrenoceptor subtype in the rat.

    PubMed

    Alvarez-Guerra, M; Bertholom, N; Garay, R P

    1999-01-01

    The alpha 1-adrenergic blocking activity of nicergoline was re-examined in rats, with a particular emphasis on alpha 1-adrenoceptor subtypes. In pithed rats, nicergoline and prazosin infused at a single small dose (0.5 microgram/kg/min i.v.) produced a substantial and identical shift to the right of the control dose pressor response curve to the specific alpha 1-agonist cirazoline (ED50 = 4.0 +/- 0.1, 4.0 +/- 0.1 and 0.9 +/- 0.01 microgram/kg i.v. for nicergoline, prazosin and vehicle respectively). In the isolated perfused mesenteric vascular bed, nicergoline strongly inhibited the pressor responses elicited by cirazoline, with approximately 40-fold higher potency (pA2 = 11.1 +/- 0.3) than prazosin (pA2 = 9.5 +/- 0.3). Conversely, nicergoline was 20-fold less potent than prazosin to antagonize the contractile effects of cirazoline in isolated endothelium-denuded aorta (pA2 = 8.6 +/- 0.2 and 9.9 +/- 0.2 for nicergoline and prazosin respectively). Pretreatment of mesenteric vascular beds with chloroethylclonidine did not significantly modify nicergoline antagonistic potency (pA2 = 10.6 +/- 0.2). Nicergoline displaced [3H]-prazosin bound to rat forebrain membranes pretreated with chloroethylclonidine (pKi = 9.9 +/- 0.2) at concentrations 60-fold lower than in rat liver membranes (pKi = 8.1 +/- 0.2). Finally, of the nicergoline metabolites studied, lumilysergol acted as a modest alpha 1 antagonist (bromonicotinic acid was devoid of alpha 1 antagonist activity). In conclusion, nicergoline is a potent and selective alpha 1A-adrenoceptor subtype antagonist, an alpha 1-adrenoceptor subtype which is mainly represented in resistance arteries.

  15. Chemical peeling by SA-PEG remodels photo-damaged skin: suppressing p53 expression and normalizing keratinocyte differentiation.

    PubMed

    Dainichi, Teruki; Amano, Satoshi; Matsunaga, Yukiko; Iriyama, Shunsuke; Hirao, Tetsuji; Hariya, Takeshi; Hibino, Toshihiko; Katagiri, Chika; Takahashi, Motoji; Ueda, Setsuko; Furue, Masutaka

    2006-02-01

    Chemical peeling with salicylic acid in polyethylene glycol vehicle (SA-PEG), which specifically acts on the stratum corneum, suppresses the development of skin tumors in UVB-irradiated hairless mice. To elucidate the mechanism through which chemical peeling with SA-PEG suppresses skin tumor development, the effects of chemical peeling on photodamaged keratinocytes and cornified envelopes (CEs) were evaluated in vivo. Among UVB-irradiated hairless mice, the structural atypia and expression of p53 protein in keratinocytes induced by UVB irradiation were intensely suppressed in the SA-PEG-treated mice 28 days after the start of weekly SA-PEG treatments when compared to that in the control UVB-irradiated mice. Incomplete expression of filaggrin and loricrin in keratinocytes from the control mice was also improved in keratinocytes from the SA-PEG-treated mice. In photo-exposed human facial skin, immature CEs were replaced with mature CEs 4 weeks after treatment with SA-PEG. Restoration of photodamaged stratum corneum by treatment with SA-PEG, which may affect remodeling of the structural environment of the keratinocytes, involved the normalization of keratinocyte differentiation and suppression of skin tumor development. These results suggest that the stratum corneum plays a protective role against carcinogenesis, and provide a novel strategy for the prevention of photo-induced skin tumors.

  16. Silymarin Suppresses Cellular Inflammation By Inducing Reparative Stress Signaling.

    PubMed

    Lovelace, Erica S; Wagoner, Jessica; MacDonald, James; Bammler, Theo; Bruckner, Jacob; Brownell, Jessica; Beyer, Richard P; Zink, Erika M; Kim, Young-Mo; Kyle, Jennifer E; Webb-Robertson, Bobbie-Jo M; Waters, Katrina M; Metz, Thomas O; Farin, Federico; Oberlies, Nicholas H; Polyak, Stephen J

    2015-08-28

    Silymarin, a characterized extract of the seeds of milk thistle (Silybum marianum), suppresses cellular inflammation. To define how this occurs, transcriptional profiling, metabolomics, and signaling studies were performed in human liver and T cell lines. Cellular stress and metabolic pathways were modulated within 4 h of silymarin treatment: activation of Activating Transcription Factor 4 (ATF-4) and adenosine monophosphate protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) signaling, the latter being associated with induction of DNA-damage-inducible transcript 4 (DDIT4). Metabolomics analyses revealed silymarin suppression of glycolytic, tricarboxylic acid (TCA) cycle, and amino acid metabolism. Anti-inflammatory effects arose with prolonged (i.e., 24 h) silymarin exposure, with suppression of multiple pro-inflammatory mRNAs and signaling pathways including nuclear factor kappa B (NF-κB) and forkhead box O (FOXO). Studies with murine knock out cells revealed that silymarin inhibition of both mTOR and NF-κB was partially AMPK dependent, whereas silymarin inhibition of mTOR required DDIT4. Other natural products induced similar stress responses, which correlated with their ability to suppress inflammation. Thus, natural products activate stress and repair responses that culminate in an anti-inflammatory cellular phenotype. Natural products like silymarin may be useful as tools to define how metabolic, stress, and repair pathways regulate cellular inflammation.

  17. Silymarin Suppresses Cellular Inflammation By Inducing Reparative Stress Signaling

    PubMed Central

    Lovelace, Erica S.; Wagoner, Jessica; MacDonald, James; Bammler, Theo; Bruckner, Jacob; Brownell, Jessica; Beyer, Richard; Zink, Erika M.; Kim, Young-Mo; Kyle, Jennifer E.; Webb-Robertson, Bobbie-Jo; Waters, Katrina M.; Metz, Thomas O.; Farin, Federico; Oberlies, Nicholas H.; Polyak, Stephen J.

    2016-01-01

    Silymarin, a characterized extract of the seeds of milk thistle (Silybum marianum), suppresses cellular inflammation. To define how this occurs, transcriptional profiling, metabolomics, and signaling studies were performed in human liver and T cell lines. Cellular stress and metabolic pathways were modulated within 4 h of silymarin treatment: activation of Activating Transcription Factor 4 (ATF-4) and adenosine monophosphate protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) signaling, the latter being associated with induction of DNA-damage-inducible transcript 4 (DDIT4). Metabolomics analyses revealed silymarin suppression of glycolytic, tricarboxylic acid (TCA) cycle, and amino acid metabolism. Anti-inflammatory effects arose with prolonged (i.e. 24 h) silymarin exposure, with suppression of multiple pro-inflammatory mRNAs and signaling pathways including nuclear factor kappa B (NF-κB) and forkhead box O (FOXO). Studies with murine knock out cells revealed that silymarin inhibition of both mTOR and NF-κB was partially AMPK dependent, while silymarin inhibition of mTOR required DDIT4. Other natural products induced similar stress responses, which correlated with their ability to suppress inflammation. Thus, natural products activate stress and repair responses that culminate in an anti-inflammatory cellular phenotype. Natural products like silymarin may be useful as tools to define how metabolic, stress, and repair pathways regulate cellular inflammation. PMID:26186142

  18. Histidine augments the suppression of hepatic glucose production by central insulin action.

    PubMed

    Kimura, Kumi; Nakamura, Yusuke; Inaba, Yuka; Matsumoto, Michihiro; Kido, Yoshiaki; Asahara, Shun-Ichiro; Matsuda, Tomokazu; Watanabe, Hiroshi; Maeda, Akifumi; Inagaki, Fuyuhiko; Mukai, Chisato; Takeda, Kiyoshi; Akira, Shizuo; Ota, Tsuguhito; Nakabayashi, Hajime; Kaneko, Shuichi; Kasuga, Masato; Inoue, Hiroshi

    2013-07-01

    Glucose intolerance in type 2 diabetes is related to enhanced hepatic glucose production (HGP) due to the increased expression of hepatic gluconeogenic enzymes. Previously, we revealed that hepatic STAT3 decreases the expression of hepatic gluconeogenic enzymes and suppresses HGP. Here, we show that increased plasma histidine results in hepatic STAT3 activation. Intravenous and intracerebroventricular (ICV) administration of histidine-activated hepatic STAT3 reduced G6Pase protein and mRNA levels and augmented HGP suppression by insulin. This suppression of hepatic gluconeogenesis by histidine was abolished by hepatic STAT3 deficiency or hepatic Kupffer cell depletion. Inhibition of HGP by histidine was also blocked by ICV administration of a histamine H1 receptor antagonist. Therefore, histidine activates hepatic STAT3 and suppresses HGP via central histamine action. Hepatic STAT3 phosphorylation after histidine ICV administration was attenuated in histamine H1 receptor knockout (Hrh1KO) mice but not in neuron-specific insulin receptor knockout (NIRKO) mice. Conversely, hepatic STAT3 phosphorylation after insulin ICV administration was attenuated in NIRKO but not in Hrh1KO mice. These findings suggest that central histidine action is independent of central insulin action, while both have additive effects on HGP suppression. Our results indicate that central histidine/histamine-mediated suppression of HGP is a potential target for the treatment of type 2 diabetes.

  19. Histidine Augments the Suppression of Hepatic Glucose Production by Central Insulin Action

    PubMed Central

    Kimura, Kumi; Nakamura, Yusuke; Inaba, Yuka; Matsumoto, Michihiro; Kido, Yoshiaki; Asahara, Shun-ichiro; Matsuda, Tomokazu; Watanabe, Hiroshi; Maeda, Akifumi; Inagaki, Fuyuhiko; Mukai, Chisato; Takeda, Kiyoshi; Akira, Shizuo; Ota, Tsuguhito; Nakabayashi, Hajime; Kaneko, Shuichi; Kasuga, Masato; Inoue, Hiroshi

    2013-01-01

    Glucose intolerance in type 2 diabetes is related to enhanced hepatic glucose production (HGP) due to the increased expression of hepatic gluconeogenic enzymes. Previously, we revealed that hepatic STAT3 decreases the expression of hepatic gluconeogenic enzymes and suppresses HGP. Here, we show that increased plasma histidine results in hepatic STAT3 activation. Intravenous and intracerebroventricular (ICV) administration of histidine-activated hepatic STAT3 reduced G6Pase protein and mRNA levels and augmented HGP suppression by insulin. This suppression of hepatic gluconeogenesis by histidine was abolished by hepatic STAT3 deficiency or hepatic Kupffer cell depletion. Inhibition of HGP by histidine was also blocked by ICV administration of a histamine H1 receptor antagonist. Therefore, histidine activates hepatic STAT3 and suppresses HGP via central histamine action. Hepatic STAT3 phosphorylation after histidine ICV administration was attenuated in histamine H1 receptor knockout (Hrh1KO) mice but not in neuron-specific insulin receptor knockout (NIRKO) mice. Conversely, hepatic STAT3 phosphorylation after insulin ICV administration was attenuated in NIRKO but not in Hrh1KO mice. These findings suggest that central histidine action is independent of central insulin action, while both have additive effects on HGP suppression. Our results indicate that central histidine/histamine-mediated suppression of HGP is a potential target for the treatment of type 2 diabetes. PMID:23474485

  20. Distinguishing among potential mechanisms of singleton suppression.

    PubMed

    Gaspelin, Nicholas; Luck, Steven J

    2018-04-01

    Previous research has revealed that people can suppress salient stimuli that might otherwise capture visual attention. The present study tests between 3 possible mechanisms of visual suppression. According to first-order feature suppression models , items are suppressed on the basis of simple feature values. According to second-order feature suppression models , items are suppressed on the basis of local discontinuities within a given feature dimension. According to global-salience suppression models , items are suppressed on the basis of their dimension-independent salience levels. The current study distinguished among these models by varying the predictability of the singleton color value. If items are suppressed by virtue of salience alone, then it should not matter whether the singleton color is predictable. However, evidence from probe processing and eye movements indicated that suppression is possible only when the color values are predictable. Moreover, the ability to suppress salient items developed gradually as participants gained experience with the feature that defined the salient distractor. These results are consistent with first-order feature suppression models, and are inconsistent with the other models of suppression. In other words, people primarily suppress salient distractors on the basis of their simple features and not on the basis of salience per se. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

  1. Withaferin A suppresses the growth of myelodysplasia and leukemia cell lines by inhibiting cell cycle progression.

    PubMed

    Okamoto, Shuichiro; Tsujioka, Takayuki; Suemori, Shin-Ichiro; Kida, Jun-Ichiro; Kondo, Toshinori; Tohyama, Yumi; Tohyama, Kaoru

    2016-09-01

    Treatment outcomes for acute myeloid leukemia and myelodysplastic syndromes (MDS) remain unsatisfactory despite progress in various types of chemotherapy and hematopoietic stem cell transplantation. Therefore, there is a need for the development of new treatment options. We investigated the growth-suppressive effects of withaferin A (WA), a natural plant steroidal lactone, on myelodysplasia and leukemia cell lines. WA exhibited growth-suppressive effects on the cell lines, MDS-L, HL-60, THP-1, Jurkat and Ramos, and induction of cell cycle arrest at G2/M phase at relatively low doses. Evaluation by annexin V/PI also confirmed the induction of partial apoptosis. Gene expression profiling and subsequent gene set enrichment analysis revealed increased expression of heme oxygenase-1 (HMOX1). HMOX1 is known to induce autophagy during anticancer chemotherapy and is considered to be involved in the treatment resistance. Our study indicated increased HMOX1 protein levels and simultaneous increases in the autophagy-related protein LC3A/B in MDS-L cells treated with WA, suggesting increased autophagy. Combined use of WA with chloroquine, an autophagy inhibitor, enhanced early apoptosis and growth suppression. Together with the knowledge that WA had no apparent suppressive effect on the growth of human normal bone marrow CD34-positive cells in the short-term culture, this drug may have a potential for a novel therapeutic approach to the treatment of leukemia or MDS. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  2. Multivariate analysis of covariates of adherence among HIV-positive mothers with low viral suppression.

    PubMed

    Nsubuga-Nyombi, Tamara; Sensalire, Simon; Karamagi, Esther; Aloyo, Judith; Byabagambi, John; Rahimzai, Mirwais; Nabitaka, Linda Kisaakye; Calnan, Jacqueline

    2018-03-31

    As part of efforts to improve the prevention of mother-to-child transmission in Northern Uganda, we explored reasons for poor viral suppression among 122 pregnant and lactating women who were in care, received viral load tests, but had not achieved viral suppression and had more than 1000 copies/mL. Understanding the patient factors associated with low viral suppression was of interest to the Ministry of Health to guide the development of tools and interventions to achieve viral suppression for pregnant and lactating women newly initiating on ART as well as those on ART with unsuppressed viral load. A facility-based cross-sectional and mixed methods study design was used, with retrospective medical record review. We assessed 122 HIV-positive mothers with known low viral suppression across 31 health facilities in Northern Uganda. Adjusted odds ratios were used to determine the covariates of adherence among HIV positive mothers using logistic regression. A study among health care providers shed further light on predictors of low viral suppression and a history of low early retention. This study was part of a larger national evaluation of the performance of integrated care services for mothers. Adherence defined as taking antiretroviral medications correctly everyday was low at 67.2%. The covariates of low adherence are: taking other medications in addition to ART, missed appointments in the past 6 months, experienced violence in the past 6 months, and faces obstacles to treatment. Mothers who were experiencing each of these covariates were less likely to adhere to treatment. These covariates were triangulated with perspectives of health providers as covariates of low adherence and included: long distances to health facility, missed appointments, running out of pills, sharing antiretroviral drugs, violence, and social lifestyles such as multiple sexual partners coupled with non-disclosure to partners. Inadequate counseling, stigma, and lack of client identity are

  3. Pharmaceuticals suppress algal growth and microbial respiration and alter bacterial communities in stream biofilms.

    PubMed

    Rosi-Marshall, Emma J; Kincaid, Dustin W; Bechtold, Heather A; Royer, Todd V; Rojas, Miguel; Kelly, John J

    2013-04-01

    Pharmaceutical and personal care products are ubiquitous in surface waters but their effects on aquatic biofilms and associated ecosystem properties are not well understood. We measured in situ responses of stream biofilms to six common pharmaceutical compounds (caffeine, cimetidine, ciprofloxacin, diphenhydramine, metformin, ranitidine, and a mixture of each) by deploying pharmaceutical-diffusing substrates in streams in Indiana, Maryland, and New York. Results were consistent across seasons and geographic locations. On average, algal biomass was suppressed by 22%, 4%, 22%, and 18% relative to controls by caffeine, ciprofloxacin, diphenhydramine, and the mixed treatment, respectively. Biofilm respiration was significantly suppressed by caffeine (53%), cimetidine (51%), ciprofloxacin (91%), diphenhydramine (63%), and the mixed treatment (40%). In autumn in New York, photosynthesis was also significantly suppressed by diphenhydramine (99%) and the mixed treatment (88%). Pyrosequencing of 16S rRNA genes was used to examine the effects of caffeine and diphenhydramine on biofilm bacterial community composition at the three sites. Relative to the controls, diphenhydramine exposure significantly altered bacterial community composition and resulted in significant relative increases in Pseudomonas sp. and decreases in Flavobacterium sp. in all three streams. These ubiquitous pharmaceuticals, alone or in combination, influenced stream biofilms, which could have consequences for higher trophic levels and important ecosystem processes.

  4. Correlates of HIV-1 viral suppression in a cohort of HIV-positive drug users receiving antiretroviral therapy in Hanoi, Vietnam

    PubMed Central

    Jordan, Michael R; La, Hanh; Nguyen, Hien Duc; Sheehan, Heidi; Lien, Trinh Thi Minh; Van Dang, Duong; Hellinger, James; Wanke, Christine; Tang, Alice M

    2009-01-01

    Summary Injection drug users bear the burden of HIV in Vietnam and are a focus of national treatment programs. To date, determinants of successful therapy in this population are unknown. Substance use and clinical correlates of viral suppression were studied in 100 HIV-1 infected drug users receiving antiretroviral therapy (ART) for at least 6 months in Hanoi, Vietnam. Mean age of the cohort was 29.9 + 4.9 years; all were men. A majority of patients (73%) achieved viral suppression (HIV-RNA < 1000 copies/ml). Correlates of viral suppression include self-reported >95% adherence (p<0.01) and current use of trimethoprim/sulfamethoxazole (p<0.01); current or ever diagnosed with tuberculosis was associated with viral non-suppression (p=0.006). Tobacco use was prevalent (84%), and surprisingly 48% of patients reported active drug use; neither was associated with viral non-suppression. This is the first study to document successful ART treatment in a population of Vietnamese drug users; rates of viral suppression are comparable to other international populations. The 28% of patients without HIV-1 suppression highlights the need for adherence promotion, risk reduction programs, and population based surveillance strategies for assessing the emergence of HIV drug resistance in settings where access to viral load and drug resistance testing is limited. PMID:19451329

  5. Correlates of HIV-1 viral suppression in a cohort of HIV-positive drug users receiving antiretroviral therapy in Hanoi, Vietnam.

    PubMed

    Jordan, M R; La, H; Nguyen, H D; Sheehan, H; Lien, T T M; Duong, D V; Hellinger, J; Wanke, C; Tang, A M

    2009-06-01

    Injection drug users bear the burden of HIV in Vietnam and are a focus of national treatment programmes. To date, determinants of successful therapy in this population are unknown. Substance use and clinical correlates of viral suppression were studied in 100 HIV-1-infected drug users receiving antiretroviral therapy (ART) for at least six months in Hanoi, Vietnam. The mean age of the cohort was 29.9 + 4.9 years; all were men. A majority of patients (73%) achieved viral suppression (HIV-RNA <1000 copies/mL). Correlates of viral suppression include self-reported > or = 95% adherence (P < 0.01) and current use of trimethoprim/sulphamethoxazole (P < 0.01); current or ever diagnosed with tuberculosis was associated with viral non-suppression (P = 0.006). Tobacco use was prevalent (84%), and surprisingly 48% of patients reported active drug use; neither was associated with viral non-suppression. This is the first study to document successful ART treatment in a population of Vietnamese drug users; rates of viral suppression are comparable to other international populations. The 28% of patients without HIV-1 suppression highlight the need for adherence promotion, risk reduction programmes, and population-based surveillance strategies for assessing the emergence of HIV drug resistance in settings where access to viral load and drug resistance testing is limited.

  6. Food thought suppression: a matched comparison of obese individuals with and without binge eating disorder.

    PubMed

    Barnes, Rachel D; Masheb, Robin M; Grilo, Carlos M

    2011-12-01

    Preliminary studies of non-clinical samples suggest that purposely attempting to avoid thoughts of food, referred to as food thought suppression, is related to a number of unwanted eating- and weight-related consequences, particularly in obese individuals. Despite possible implications for the treatment of obesity and eating disorders, little research has examined food thought suppression in obese individuals with binge eating disorder (BED). This study compared food thought suppression in 60 obese patients with BED to an age-, gender-, and body mass index (BMI)-matched group of 59 obese persons who do not binge eat (NBO). In addition, this study examined the associations between food thought suppression and eating disorder psychopathology within the BED and NBO groups and separately by gender. Participants with BED and women endorsed the highest levels of food thought suppression. Food thought suppression was significantly and positively associated with many features of ED psychopathology in NBO women and with eating concerns in men with BED. Among women with BED, higher levels of food thought suppression were associated with higher frequency of binge eating, whereas among men with BED, higher levels of food thought suppression were associated with lower frequency of binge eating. Our findings suggest gender differences in the potential significance of food thought suppression in obese groups with and without co-existing binge eating problems. Copyright © 2011 Elsevier Ltd. All rights reserved.

  7. Resveratrol promotes regression of renal carcinoma cells via a renin-angiotensin system suppression-dependent mechanism.

    PubMed

    Li, Jianchang; Qiu, Mingning; Chen, Lieqian; Liu, Lei; Tan, Guobin; Liu, Jianjun

    2017-02-01

    The aim of the present study was to investigate the effect of resveratrol on renal carcinoma cells and explore possible renin-angiotensin system-associated mechanisms. Subsequent to resveratrol treatment, the cell viability, apoptosis rate, cytotoxicity levels, caspase 3/7 activity and the levels of angiotensin II (AngII), AngII type 1 receptor (AT1R), vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) were evaluated in renal carcinoma cells. The effects of AngII, AT1R, VEGF and COX-2 on resveratrol-induced cell growth inhibition and apoptosis were also examined. The results indicated that resveratrol treatment may suppress growth, induce apoptosis, and decrease AngII, AT1R, VEGF and COX-2 levels in renal carcinoma ACHN and A498 cells. In addition, resveratrol-induced cell growth suppression and apoptosis were reversed when co-culturing with AT1R or VEGF. Thus, resveratrol may suppress renal carcinoma cell proliferation and induce apoptosis via an AT1R/VEGF pathway.

  8. Pharmacological activation of estrogen receptor beta augments innate immunity to suppress cancer metastasis.

    PubMed

    Zhao, Linjie; Huang, Shuang; Mei, Shenglin; Yang, Zhengnan; Xu, Lian; Zhou, Nianxin; Yang, Qilian; Shen, Qiuhong; Wang, Wei; Le, Xiaobing; Lau, Wayne Bond; Lau, Bonnie; Wang, Xin; Yi, Tao; Zhao, Xia; Wei, Yuquan; Warner, Margaret; Gustafsson, Jan-Åke; Zhou, Shengtao

    2018-04-17

    Metastases constitute the greatest causes of deaths from cancer. However, no effective therapeutic options currently exist for cancer patients with metastasis. Estrogen receptor β (ERβ), as a member of the nuclear receptor superfamily, shows potent tumor-suppressive activities in many cancers. To investigate whether modulation of ERβ could serve as a therapeutic strategy for cancer metastasis, we examined whether the selective ERβ agonist LY500307 could suppress lung metastasis of triple-negative breast cancer (TNBC) and melanoma. Mechanistically, while we observed that LY500307 potently induced cell death of cancer cells metastasized to lung in vivo, it does not mediate apoptosis of cancer cells in vitro, indicating that the cell death-inducing effects of LY500307 might be mediated by the tumor microenvironment. Pathological examination combined with flow cytometry assays indicated that LY500307 treatment induced significant infiltration of neutrophils in the metastatic niche. Functional experiments demonstrated that LY500307-treated cancer cells show chemotactic effects for neutrophils and that in vivo neutrophil depletion by Ly6G antibody administration could reverse the effects of LY500307-mediated metastasis suppression. RNA sequencing analysis showed that LY500307 could induce up-regulation of IL-1β in TNBC and melanoma cells, which further triggered antitumor neutrophil chemotaxis. However, the therapeutic effects of LY500307 treatment for suppression of lung metastasis was attenuated in IL1B -/- murine models, due to failure to induce antitumor neutrophil infiltration in the metastatic niche. Collectively, our study demonstrated that pharmacological activation of ERβ could augment innate immunity to suppress cancer metastatic colonization to lung, thus providing alternative therapeutic options for cancer patients with metastasis.

  9. A budesonide prodrug accelerates treatment of colitis in rats.

    PubMed Central

    Cui, N; Friend, D R; Fedorak, R N

    1994-01-01

    Although oral glucocorticoids are the treatment of choice for moderate to severe ulcerative pancolitis, their systemic side effects and adrenal suppression account for considerable morbidity. An oral glucocorticoid-conjugate (prodrug), budesonide-beta-D-glucuronide, which is not absorbed in the small intestine but is hydrolysed by colonic bacterial and mucosal beta-glucuronidase to release free budesonide into the colon was synthesised. The objective of this study was to compare treatment with budesonide-beta-D-glucuronide with treatment with free budesonide by examining: (1) the healing of experimental colitis and (2) the extent of adrenal suppression. Pancolitis was induced with 4% acetic acid. Animals were then randomised to receive oral therapy for 72 hours with (1) budesonide-beta-D-glucuronide, (2) free budesonide, or (3) vehicle. Drug efficacy and colitic healing was determined by measuring gross colonic ulceration, myeloperoxidase activity, and in vivo colonic fluid absorption. Adrenal suppression was determined by measuring plasma adrenocorticotrophic hormone and serum corticosterone. Vehicle-treated colitis animals had gross ulceration, increased myeloperoxidase activity, and net colonic fluid secretion. Treatment with oral budesonide-beta-D-glucuronide accelerated all measures of colitis healing at a fourfold lower dose than did free budesonide. Furthermore, treatment with budesonide-beta-D-glucuronide did not result in adrenal suppression whereas free budesonide treatment did. A newly synthesised orally administered glucocorticoid-conjugate accelerates colitis healing with limited adrenal suppression. Development of an orally administered colon-specific steroid delivery system represents a novel approach to inflammatory bowel disease treatment. PMID:7959202

  10. Morton neuroma: evaluation with MR imaging performed with contrast enhancement and fat suppression.

    PubMed

    Terk, M R; Kwong, P K; Suthar, M; Horvath, B C; Colletti, P M

    1993-10-01

    To evaluate clinically suspected Morton neuroma with contrast material-enhanced magnetic resonance (MR) images. Fifteen patients with clinically suspected Morton neuroma underwent examination with conventional T1- and T2-weighted MR imaging and a combination of fat suppression and administration of gadopentetate dimeglumine. A T1-weighted spectral presaturation with inversion recovery sequence was used for fat suppression. In six patients, a tumor that conformed to the clinical findings was seen in the interdigital space; surgical findings in these patients correlated closely with the imaging findings in all patients. Patients without positive findings on MR images tended to have less typical clinical findings and received nonsurgical treatment. In all patients, the lesions were best depicted with the combination of contrast-enhanced imaging and fat suppression; conventional MR images either entirely failed to demonstrate the lesions or demonstrated the lesions less clearly. In patients who need imaging confirmation of a clinically suspected Morton neuroma, the combination of fat suppression and contrast enhancement provides reliable high-contrast images.

  11. Vitamin K3 suppressed inflammatory and immune responses in a redox-dependent manner.

    PubMed

    Checker, Rahul; Sharma, Deepak; Sandur, Santosh K; Khan, Nazir M; Patwardhan, Raghavendra S; Kohli, Vineet; Sainis, Krishna B

    2011-08-01

    Recent investigations suggest that cellular redox status may play a key role in the regulation of several immune functions. Treatment of lymphocytes with vitamin K3 (menadione) resulted in a significant decrease in cellular GSH/GSSG ratio and concomitant increase in the ROS levels. It also suppressed Concanavalin A (Con A)-induced proliferation and cytokine production in lymphocytes and CD4 + T cells in vitro. Immunosuppressive effects of menadione were abrogated only by thiol containing antioxidants. Mass spectrometric analysis showed that menadione directly interacted with thiol antioxidant GSH. Menadione completely suppressed Con A-induced activation of ERK, JNK and NF-κB in lymphocytes. It also significantly decreased the homeostasis driven proliferation of syngeneic CD4 + T cells. Further, menadione significantly delayed graft-vs-host disease morbidity and mortality in mice. Menadione suppressed phytohemagglutinin-induced cytokine production in human peripheral blood mononuclear cells. These results reveal that cellular redox perturbation by menadione is responsible for significant suppression of lymphocyte responses.

  12. Synthetic triterpenoid induces 15-PGDH expression and suppresses inflammation-driven colon carcinogenesis.

    PubMed

    Choi, Sung Hee; Kim, Byung-Gyu; Robinson, Janet; Fink, Steve; Yan, Min; Sporn, Michael B; Markowitz, Sanford D; Letterio, John J

    2014-06-01

    Colitis-associated colon cancer (CAC) develops as a result of inflammation-induced epithelial transformation, which occurs in response to inflammatory cytokine-dependent downregulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and subsequent suppression of prostaglandin metabolism. Agents that both enhance 15-PGDH expression and suppress cyclooxygenase-2 (COX-2) production may more effectively prevent CAC. Synthetic triterpenoids are a class of small molecules that suppress COX-2 as well as inflammatory cytokine signaling. Here, we found that administration of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-C28-methyl ester (CDDO-Me) suppresses CAC in mice. In a spontaneous, inflammation-driven intestinal neoplasia model, deletion of Smad4 specifically in T cells led to progressive production of inflammatory cytokines, including TNF-α, IFN-γ, iNOS, IL-6, IL-1β; as well as activation of STAT1 and STAT3; along with suppression of 15-PGDH expression. Oral administration of CDDO-Me to mice with SMAD4-deficient T cells increased survival and suppressed intestinal epithelial neoplasia by decreasing production of inflammatory mediators and increasing expression of 15-PGDH. Induction of 15-PGDH by CDDO-Me was dose dependent in epithelial cells and was abrogated following treatment with TGF-β signaling inhibitors in vitro. Furthermore, CDDO-Me-dependent 15-PGDH induction was not observed in Smad3-/- mice. Similarly, CDDO-Me suppressed azoxymethane plus dextran sodium sulfate-induced carcinogenesis in wild-type animals, highlighting the potential of small molecules of the triterpenoid family as effective agents for the chemoprevention of CAC in humans.

  13. Synthetic Oligodeoxynucleotides (ODN) Containing Suppressive TTAGGG Motifs Inhibit AIM2 Inflammasome Activation

    PubMed Central

    Kaminski, John J.; Schattgen, Stefan A.; Tzeng, Te-Chen; Bode, Christian; Klinman, Dennis M.; Fitzgerald, Katherine A.

    2013-01-01

    Synthetic oligodeoxynucleotides comprised of the immunosuppressive motif TTAGGG block TLR9 signaling, prevent STAT1 and STAT4 phosphorylation and attenuate a variety of inflammatory responses in vivo. Here, we demonstrate that such suppressive oligodeoxynucleotides (sup ODN) abrogate activation of cytosolic nucleic acid sensing pathways. Pretreatment of dendritic cells and macrophages with the suppressive ODN-A151 abrogated type I IFN, TNFα and ISG induction in response to cytosolic dsDNA. In addition, A151 abrogated caspase-1-dependent IL-1β and IL-18 maturation in dendritic cells stimulated with dsDNA and murine cytomegalovirus (MCMV). Inhibition was dependent on A151’s phosphorothioate backbone while substitution of the guanosine residues for adenosine negatively affected potency. A151 mediates these effects by binding to AIM2 in a manner that is competitive with immune-stimulatory DNA and as a consequence prevents AIM2 inflammasome complex formation. Collectively, these findings reveal a new route by which suppressive ODNs modulate the immune system and unveil novel applications for suppressive ODNs in the treatment of infectious and autoimmune diseases. PMID:23986531

  14. MicroRNA-214 suppresses gluconeogenesis by targeting activating transcriptional factor 4.

    PubMed

    Li, Kai; Zhang, Jin; Yu, Junjie; Liu, Bin; Guo, Yajie; Deng, Jiali; Chen, Shanghai; Wang, Chunxia; Guo, Feifan

    2015-03-27

    Although the gluconeogenesis pathway is already a target for the treatment of type 2 diabetes, the potential role of microRNAs (miRNAs) in gluconeogenesis remains unclear. Here, we investigated the physiological functions of miR-214 in gluconeogenesis. The expression of miR-214 was suppressed by glucagon via protein kinase A signaling in primary hepatocytes, and miR-214 was down-regulated in the livers of fasted, high fat diet-induced diabetic and leptin receptor-mutated (db/db) mice. The overexpression of miR-214 in primary hepatocytes suppressed glucose production, and silencing miR-214 reversed this effect. Gluconeogenesis was suppressed in the livers of mice injected with an adenovirus expressing miR-214 (Ad-miR-214). Additionally, Ad-miR-214 alleviated high fat diet-induced elevation of gluconeogenesis and hyperglycemia. Furthermore, we found that activating transcription factor 4 (ATF4), a reported target of miR-214, can reverse the suppressive effect of miR-214 on gluconeogenesis in primary hepatocytes, and this suppressive effect was blocked in liver-specific ATF4 knock-out mice. ATF4 regulated gluconeogenesis via affecting forkhead box protein O1 (FOXO1) transcriptional activity. Finally, liver-specific miR-214 transgenic mice exhibited suppressed gluconeogenesis and reduced expression of ATF4, phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase in liver. Taken together, our results suggest that the miR-214-ATF4 axis is a novel pathway for the regulation of hepatic gluconeogenesis. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  15. Suppressive effects of 3-methylcholanthrene on the in vitro antitumor activity of naturally cytotoxic cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lill, P.H.; Gangemi, D.

    1986-01-01

    Transient suppression of splenic natural killer (NK), natural cytotoxic (NC) and peritoneal macrophage cytotoxicity was observed following a single injection of 3-methylcholanthrene (3-MC) into C3H/HeN mice. Natural killer cell activity was depressed by 30-60% 4-6 d after injection of 1.0 mg 3-MC. Levels of NK reactivity returned to normal 8 d post 3-MC injection, and no suppression of natural killing was seen when tested 6 wk after 3-MC treatment. 3-MC did not affect propionibacterium acnes augmentation of NK cell activity when tested both 6 d and 6 wk after carcinogen injection. The results indicate that the observed suppression of naturallymore » cytotoxic cells may not be important in allowing 3-MC-induced tumors to grow, since suppression is not long-lasting. Therefore, any effect on tumor growth mediated by a suppression of naturally cytotoxic cells would have to be exerted at the earliest stages of tumor development.« less

  16. Lufenuron suppresses the resistance of Formosan subterranean termites (Isoptera: Rhinotermitidae) to entomopathogenic bacteria.

    PubMed

    Wang, Cai; Henderson, Gregg; Gautam, Bal K

    2013-08-01

    Pesticides can negatively affect insect immunity. Although studies show that Formosan subterranean termites, Coptotermes formosanus Shiraki, are resistant to microbial infections, the effects of pesticides on disease resistance is not well studied. In this study, C. formosanus previously fed lufenuron was exposed to each of the three entomopathogenic bacteria, Pseudomonas aeruginosa (Schroeter) Migula, Serratia marcescens Bizio, and Bacillus thuringiensis Berliner subsp. israelensis. We found that termite mortality was significantly higher and synergistic in the combination of lufenuron and P. aeruginosa compared with treatment of lufenuron or P. aeruginosa alone. Other bacteria and lufenuron combinations were not quite as effective. Interestingly, only in treatments without lufenuron did termites show carcass-burying behavior. The results indicate that lufenuron, a chitin synthesis inhibitor, can suppress Formosan subterranean termite resistance to P. aeruginosa. Possible suppression mechanisms are discussed.

  17. Dual treatment with lopinavir-ritonavir plus lamivudine versus triple treatment with lopinavir-ritonavir plus lamivudine or emtricitabine and a second nucleos(t)ide reverse transcriptase inhibitor for maintenance of HIV-1 viral suppression (OLE): a randomised, open-label, non-inferiority trial.

    PubMed

    Arribas, José R; Girard, Pierre-Marie; Landman, Roland; Pich, Judit; Mallolas, Josep; Martínez-Rebollar, María; Zamora, Francisco X; Estrada, Vicente; Crespo, Manuel; Podzamczer, Daniel; Portilla, Joaquín; Dronda, Fernando; Iribarren, José A; Domingo, Pere; Pulido, Federico; Montero, Marta; Knobel, Hernando; Cabié, André; Weiss, Laurence; Gatell, José M

    2015-07-01

    Our objective was to assess therapeutic non-inferiority of dual treatment with lopinavir-ritonavir and lamivudine to triple treatment with lopinavir-ritonavir plus two nucleos(t)ides for maintenance of HIV-1 viral suppression. In this randomised, open-label, non-inferiority trial, we recruited patients from 32 HIV units in hospitals in Spain and France. Eligible patients were HIV-infected adults (aged ≥18 years) with HIV-1 RNA of less than 50 copies per mL, for at least 6 months on triple treatment with lopinavir-ritonavir (twice daily) plus lamivudine or emtricitabine and a second nucleos(t)ide, with no resistance or virological failure to these drugs, and no positive hepatitis B serum surface antigen. Investigators at each centre randomly assigned patients (1:1; block size of four; stratified by time to suppression [<1 year or >1 year] and nadir CD4 cell count [<100 cells per μL or >100 cells per μL]; computer-generated random sequence) to continue triple treatment or switch to dual treatment (oral lopinavir 400 mg and oral ritonavir 100 mg twice daily plus oral lamivudine 300 mg once daily). The primary endpoint was response to treatment in the intention-to-treat population (all randomised patients) at 48 weeks. The non-inferiority margin was 12%. This study is registered with ClinicalTrials.gov, number NCT01471821. Between Oct 1, 2011, and April 1, 2013, we randomly assigned 250 participants to continue triple treatment (127 [51%] patients) or switch to dual treatment (123 [49%] patients). In the intention-to-treat population, 110 (86·6%) of 127 patients in the triple-treatment group responded to treatment versus 108 (87·8%) of 123 in the dual-treatment group (difference -1·2% [95% CI -9·6 to 7·3]; p=0·92), meeting the criteria for non-inferiority. Serious adverse events occurred in eight (7%) patients in the triple-treatment group and five (4%) in the dual-treatment group (p=0·515), and study drug discontinuations due to adverse events occurred in

  18. Msx-1 is suppressed in bisphosphonate-exposed jaw bone analysis of bone turnover-related cell signalling after bisphosphonate treatment.

    PubMed

    Wehrhan, F; Hyckel, P; Amann, K; Ries, J; Stockmann, P; Schlegel, Ka; Neukam, Fw; Nkenke, E

    2011-05-01

    Bone-destructive disease treatments include bisphosphonates and antibodies against receptor activator for nuclear factor κB ligand (aRANKL). Osteonecrosis of the jaw (ONJ) is a side-effect. Aetiopathology models failed to explain their restriction to the jaw. The osteoproliferative transcription factor Msx-1 is expressed constitutively only in mature jaw bone. Msx-1 expression might be impaired in bisphosphonate-related ONJ. This study compared the expression of Msx-1, Bone Morphogenetic Protein (BMP)-2 and RANKL, in ONJ-affected and healthy jaw bone. An automated immunohistochemistry-based alkaline phosphatase-anti-alkaline phosphatase method was used on ONJ-affected and healthy jaw bone samples (n = 20 each): cell-number ratio (labelling index, Bonferroni adjustment). Real-time RT-PCR was performed to quantitatively compare Msx-1, BMP-2, RANKL and GAPDH mRNA levels. Labelling indices were significantly lower for Msx-1 (P < 0.03) and RANKL (P < 0.003) and significantly higher (P < 0.02) for BMP-2 in ONJ compared with healthy bone. Expression was sevenfold lower (P < 0.03) for Msx-1, 22-fold lower (P < 0.001) for RANKL and eightfold higher (P < 0.02) for BMP-2 in ONJ bone. Msx-1, RANKL suppression and BMP-2 induction were consistent with the bisphosphonate-associated osteopetrosis and impaired bone remodelling in BP- and aRANKL-induced ONJ. Msx-1 suppression suggested a possible explanation of the exclusivity of ONJ in jaw bone. Functional analyses of Msx-1- RANKL interaction during bone remodelling should be performed in the future. © 2011 John Wiley & Sons A/S.

  19. Hybrid optimal scheduling for intermittent androgen suppression of prostate cancer

    NASA Astrophysics Data System (ADS)

    Hirata, Yoshito; di Bernardo, Mario; Bruchovsky, Nicholas; Aihara, Kazuyuki

    2010-12-01

    We propose a method for achieving an optimal protocol of intermittent androgen suppression for the treatment of prostate cancer. Since the model that reproduces the dynamical behavior of the surrogate tumor marker, prostate specific antigen, is piecewise linear, we can obtain an analytical solution for the model. Based on this, we derive conditions for either stopping or delaying recurrent disease. The solution also provides a design principle for the most favorable schedule of treatment that minimizes the rate of expansion of the malignant cell population.

  20. Rituximab selectively suppresses specific islet antibodies.

    PubMed

    Yu, Liping; Herold, Kevan; Krause-Steinrauf, Heidi; McGee, Paula L; Bundy, Brian; Pugliese, Alberto; Krischer, Jeff; Eisenbarth, George S

    2011-10-01

    The TrialNet Study Group evaluated rituximab, a B-cell-depleting monoclonal antibody, for its effect in new-onset patients with type 1A diabetes. Rituximab decreased the loss of C-peptide over the first year of follow-up and markedly depleted B lymphocytes for 6 months after administration. This article analyzes the specific effect of rituximab on multiple islet autoantibodies. A total of 87 patients between the ages of 8 and 40 years received either rituximab or a placebo infusion weekly for four doses close to the onset of diabetes. Autoantibodies to insulin (IAAs), GAD65 (GADAs), insulinoma-associated protein 2 (IA2As), and ZnT8 (ZnT8As) were measured with radioimmunoassays. The primary outcome for this autoantibody analysis was the mean level of autoantibodies during follow-up. Rituximab markedly suppressed IAAs compared with the placebo injection but had a much smaller effect on GADAs, IA2As, and ZnT8As. A total of 40% (19 of 48) of rituximab-treated patients who were IAA positive became IAA negative versus 0 of 29 placebo-treated patients (P < 0.0001). In the subgroup (n = 6) treated within 50 days of diabetes, IAAs were markedly suppressed by rituximab in all patients for 1 year and for four patients as long as 3 years despite continuing insulin therapy. Independent of rituximab treatment, the mean level of IAAs at study entry was markedly lower (P = 0.035) for patients who maintained C-peptide levels during the first year of follow-up in both rituximab-treated and placebo groups. A single course of rituximab differentially suppresses IAAs, clearly blocking IAAs for >1 year in insulin-treated patients. For the patients receiving insulin for >2 weeks prior to rituximab administration, we cannot assess whether rituximab not only blocks the acquisition of insulin antibodies induced by insulin administration and/or also suppresses preformed insulin autoantibodies. Studies in prediabetic non-insulin-treated patients will likely be needed to evaluate the specific

  1. Using Topography to Meet Wildlife and Fuels Treatment Objectives in Fire-Suppressed Landscapes

    PubMed Central

    Viers, Joshua H.; Quinn, James F.; North, Malcolm

    2010-01-01

    Past forest management practices, fire suppression, and climate change are increasing the need to actively manage California Sierra Nevada forests for multiple environmental amenities. Here we present a relatively low-cost, repeatable method for spatially parsing the landscape to help the U.S. Forest Service manage for different forest and fuel conditions to meet multiple goals relating to sensitive species, fuels reduction, forest products, water, carbon storage, and ecosystem restoration. Using the Kings River area of the Sierra Nevada as a case study, we create areas of topographically-based units, Landscape Management Units (LMUs) using a three by three matrix (canyon, mid-slope, ridge-top and northerly, southerly, and neutral aspects). We describe their size, elevation, slope, aspect, and their difference in inherent wetness and solar radiation. We assess the predictive value and field applicability of LMUs by using existing data on stand conditions and two sensitive wildlife species. Stand conditions varied significantly between LMUs, with canyons consistently having the greatest stem and snag densities. Pacific fisher (Martes pennanti) activity points (from radio telemetry) and California spotted owl (Strix occidentalis occidentalis) nests, roosts, and sightings were both significantly different from uniform, with a disproportionate number of observations in canyons, and fewer than expected on ridge-tops. Given the distinct characteristics of the LMUs, these units provide a relatively simple but ecologically meaningful template for managers to spatially allocate forest treatments, thereby meeting multiple National Forest objectives. These LMUs provide a framework that can potentially be applied to other fire-dependent western forests with steep topographic relief. PMID:20872142

  2. Identifying the educative and suppressive effects of positive practice and restitutional overcorrection.

    PubMed Central

    Carey, R G; Bucher, B

    1981-01-01

    Two major features of the overcorrection procedure, restitution and positive practice, were analyzed for their educative and suppressive properties in the treatment of profoundly retarded adults. Positive practice techniques that were topographically similar and dissimilar to the target behavior were studied. Eating behavior and puzzle performance were observed. Restitutional overcorrection and both forms of positive practice were effective for suppressing inappropriate behaviors. Even when appropriate behaviors had been acquired by positive practice, restitution and dissimilar positive practice were generally ineffective for increasing their rate of occurrence. However, topographically similar positive practice was successful as a means of teaching new appropriate behaviors. PMID:7216933

  3. Identifying the educative and suppressive effects of positive practice and restitutional overcorrection.

    PubMed

    Carey, R G; Bucher, B

    1981-01-01

    Two major features of the overcorrection procedure, restitution and positive practice, were analyzed for their educative and suppressive properties in the treatment of profoundly retarded adults. Positive practice techniques that were topographically similar and dissimilar to the target behavior were studied. Eating behavior and puzzle performance were observed. Restitutional overcorrection and both forms of positive practice were effective for suppressing inappropriate behaviors. Even when appropriate behaviors had been acquired by positive practice, restitution and dissimilar positive practice were generally ineffective for increasing their rate of occurrence. However, topographically similar positive practice was successful as a means of teaching new appropriate behaviors.

  4. Immune suppressive effects of Helicobacter pylori on human peripheral blood mononuclear cells.

    PubMed

    Knipp, U; Birkholz, S; Kaup, W; Opferkuch, W

    1993-05-01

    Helicobacter pylori, the causative agent of type-B gastritis and duodenal ulcer in man is described as a bacterium able to stimulate the human immune system. This study demonstrates that H. pylori besides this property possesses an immune suppressive activity. The in vitro proliferation of human peripheral blood mononuclear cells to purified protein derivative of tuberculin (PPD), phytohemagglutinin, and concanavalin A was reduced in a dose-dependent manner by bacteria which had been inactivated by incubation at 56 degrees C as well as by a soluble cytoplasmic fraction of H. pylori. The immune suppressive effect on the mitogen-induced proliferation could be increased by preincubation of the mononuclear cells with H. pylori. The observed effect does not seem to be a specific phenomenon depending on prior exposure of the blood donors to H. pylori, since suppression occurred with mononuclear cells of H. pylori-infected patients as well as of antibody-negative healthy control individuals. The suppressive activity was non-dialyzable, heat-labile (100 degrees C, 30 min) and sensitive to trypsin. Furthermore, the treatment at 100 degrees C caused an increase in the capability of H. pylori to induce lymphoproliferation. This fact indicates that the suppressive factor is also effective on H. pylori antigens. While exogenous interleukin-2, could to a certain extent, restore the responsiveness of the lymphocytes after PPD-stimulation in the presence of H. pylori, the addition of interleukin-1 had no effect on the suppressed lymphoproliferation. Cell-separation and cell-mixing experiments indicated that an influence on monocytes rather than on T cells is the major cause of the observed suppressive effect. Although the immunological mechanisms involved in H. pylori-associated gastritis are not clearly defined, it is reasonable to presume that suppression of host defense mechanisms may contribute to the pathogenesis of this disease.

  5. The Alternaria alternata Mycotoxin Alternariol Suppresses Lipopolysaccharide-Induced Inflammation

    PubMed Central

    Grover, Shivani; Lawrence, Christopher B.

    2017-01-01

    The Alternaria mycotoxins alternariol (AOH) and alternariol monomethyl ether (AME) have been shown to possess genotoxic and cytotoxic properties. In this study, the ability of AOH and AME to modulate innate immunity in the human bronchial epithelial cell line (BEAS-2B) and mouse macrophage cell line (RAW264.7) were investigated. During these studies, it was discovered that AOH and to a lesser extent AME potently suppressed lipopolysaccharide (LPS)-induced innate immune responses in a dose-dependent manner. Treatment of BEAS-2B cells with AOH resulted in morphological changes including a detached pattern of growth as well as elongated arms. AOH/AME-related immune suppression and morphological changes were linked to the ability of these mycotoxins to cause cell cycle arrest at the G2/M phase. This model was also used to investigate the AOH/AME mechanism of immune suppression in relation to aryl hydrocarbon receptor (AhR). AhR was not found to be important for the immunosuppressive properties of AOH/AME, but appeared important for the low levels of cell death observed in BEAS-2B cells. PMID:28726766

  6. Fire behavior, fuel treatments, and fire suppression on the Hayman Fire - Part 4: Relation of roads to burn severity

    Treesearch

    Charles W. McHugh; Mark A. Finney

    2003-01-01

    Effects of roads on fire behavior intensity and severity can be studied directly or indirectly. A direct study of road effects would include uses by fire suppression, burnout operations, and delay of fire progress at the roadside. Interpretations after the fire burns are easily confounded by the unknown nature of suppression activities and fire arrival time, and fire...

  7. Interocular suppression

    NASA Astrophysics Data System (ADS)

    Tuna, Ana Rita; Almeida Neves Carrega, Filipa; Nunes, Amélia Fernandes

    2017-08-01

    The objective of this work is to quantify the suppressive imbalance, based on the manipulation of ocular luminance, between a group of subjects with normal binocular vision and a group of subjects with amblyopia. The result reveals that there are statistically significant differences in interocular dominance between two groups, evidencing a greater suppressive imbalance in amblyopic subjects. The technique used, proved to be a simple, easy to apply and economic method, for quantified ocular dominance. It is presented as a technique with the potential to accompany subjects with a marked dominance in one of the eyes that makes fusion difficult.

  8. RORγt antagonist suppresses M3 muscarinic acetylcholine receptor-induced Sjögren's syndrome-like sialadenitis.

    PubMed

    Tahara, M; Tsuboi, H; Segawa, S; Asashima, H; Iizuka-Koga, M; Hirota, T; Takahashi, H; Kondo, Y; Matsui, M; Matsumoto, I; Sumida, T

    2017-02-01

    We showed recently that M3 muscarinic acetylcholine receptor (M3R)-reactive CD3 + T cells play a pathogenic role in the development of murine autoimmune sialadenitis (MIS), which mimics Sjögren's syndrome (SS). The aim of this study was to determine the effectiveness and mechanism of action of retinoic acid-related orphan receptor-gamma t (RORγt) antagonist (A213) in MIS. Splenocytes from M3R knockout (M3R -/- ) mice immunized with murine M3R peptide mixture were inoculated into recombination-activating gene 1 knockout (Rag-1 -/- ) mice (M3R -/- →Rag-1 -/- ) with MIS. Immunized M3R -/- mice (pretransfer treatment) and M3R -/- →Rag-1 -/- mice (post-transfer treatment) were treated with A213 every 3 days. Salivary volume, severity of sialadenitis and cytokine production from M3R peptide-stimulated splenocytes and lymph node cells were examined. Effects of A213 on cytokine production were analysed by enzyme-linked immunosorbent assay (ELISA) and on T helper type 1 (Th1), Th17 and Th2 differentiation from CD4 + T cells by flow cytometry. Pretransfer A213 treatment maintained salivary volume, improved MIS and reduced interferon (IFN)-γ and interleukin (IL)-17 production significantly compared with phosphate-buffered saline (PBS) (P < 0·05). These suppressive effects involved CD4 + T cells rather than CD11c + cells. Post-transfer treatment with A213 increased salivary volume (P < 0·05), suppressed MIS (P < 0·005) and reduced IFN-γ and IL-17 production (P < 0·05). In vitro, A213 suppressed IFN-γ and IL-17 production from M3R-stimulated splenocytes and CD4 + T cells of immunized M3R -/- mice (P < 0·05). In contrast with M3R specific responses, A213 suppressed only IL-17 production from Th17 differentiated CD4 + T cells without any effect on Th1 and Th2 differentiation in vitro. Our findings suggested that RORγt antagonism is potentially suitable treatment strategy for SS-like sialadenitis through suppression of IL-17 and IFN-γ production

  9. The Main Suppressing Factors of Dry Forage Intake in Large-type Goats

    PubMed Central

    Van Thang, Tran; Sunagawa, Katsunori; Nagamine, Itsuki; Kishi, Tetsuya; Ogura, Go

    2012-01-01

    In large-type goats that were fed on dry forage twice daily, dry forage intake was markedly suppressed after 40 min of feeding had elapsed. The objective of this study was to determine whether or not marked decreases in dry forage intake after 40 min of feeding are mainly caused by the two factors, that is, ruminal distension and increased plasma osmolality induced thirst produced by dry forage feeding. Six large-type male esophageal- and ruminal-fistulated goats (crossbred Japanese Saanen/Nubian, aged 2 to 6 years, weighing 85.1±4.89 kg) were used in two experiments. The animals were fed ad libitum a diet of roughly crushed alfalfa hay cubes for 2 h from 10:00 to 12:00 am during two experiments. Water was withheld during feeding in both experiments but was available for a period of 30 min after completion of the 2 h feeding period. In experiment 1, saliva lost via the esophageal fistula was replenished by an intraruminal infusion of artificial parotid saliva (RIAPS) in sham feeding conditions (SFC) control, and the treatment was maintained under normal feeding conditions (NFC). In experiment 2, a RIAPS and non-insertion of a balloon (RIAPS-NB) control was conducted in the same manner as the SFC control of experiment 1. The intraruminal infusion of hypertonic solution and insertion of a balloon (RIHS-IB) treatment was carried out simultaneously to reproduce the effects of changing salt content and ruminal distension due to feed entering the rumen. The results of experiment 1 showed that due to the effects of multiple dry forage suppressing factors when feed boluses entered the rumen, eating rates in the NFC treatment decreased (p<0.05) after 40 min of feeding and cumulative dry forage intake for the 2 h feeding period reduced to 43.8% of the SFC control (p<0.01). The results of experiment 2 indicated that due to the two suppressing factors of ruminal distension and increased plasma osmolality induced thirst, eating rates in the RIHS-IB treatment were, as observed

  10. Tocotrienols inhibit AKT and ERK activation and suppress pancreatic cancer cell proliferation by suppressing the ErbB2 pathway.

    PubMed

    Shin-Kang, Sonyo; Ramsauer, Victoria P; Lightner, Janet; Chakraborty, Kanishka; Stone, William; Campbell, Sharon; Reddy, Shrikanth A G; Krishnan, Koyamangalath

    2011-09-15

    Tocotrienols are members of the vitamin E family but, unlike tocopherols, possess an unsaturated isoprenoid side chain that confers superior anti-cancer properties. The ability of tocotrienols to selectively inhibit the HMG-CoA reductase pathway through posttranslational degradation and to suppress the activity of transcription factor NF-κB could be the basis for some of these properties. Our studies indicate that γ- and δ-tocotrienols have potent antiproliferative activity in pancreatic cancer cells (Panc-28, MIA PaCa-2, Panc-1, and BxPC-3). Indeed both tocotrienols induced cell death (>50%) by the MTT cell viability assay in all four pancreatic cancer cell lines. We also examined the effects of the tocotrienols on the AKT and the Ras/Raf/MEK/ERK signaling pathways by Western blotting analysis. γ- and δ-tocotrienol treatment of cells reduced the activation of ERK MAP kinase and that of its downstream mediator RSK (ribosomal protein S6 kinase) in addition to suppressing the activation of protein kinase AKT. Suppression of activation of AKT by γ-tocotrienol led to downregulation of p-GSK-3β and upregulation accompanied by nuclear translocation of Foxo3. These effects were mediated by the downregulation of Her2/ErbB2 at the messenger level. Tocotrienols but not tocopherols were able to induce the observed effects. Our results suggest that the tocotrienol isoforms of vitamin E can induce apoptosis in pancreatic cancer cells through the suppression of vital cell survival and proliferative signaling pathways such as those mediated by the PI3-kinase/AKT and ERK/MAP kinases via downregulation of Her2/ErbB2 expression. The molecular components for this mechanism are not completely elucidated and need further investigation. Copyright © 2011 Elsevier Inc. All rights reserved.

  11. MEK5 suppresses osteoblastic differentiation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kaneshiro, Shoichi; Department of Orthopaedic Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871; Otsuki, Dai

    Extracellular signal-regulated kinase 5 (ERK5) is a member of the mitogen-activated protein kinase (MAPK) family and is activated by its upstream kinase, MAPK kinase 5 (MEK5), which is a member of the MEK family. Although the role of MEK5 has been investigated in several fields, little is known about its role in osteoblastic differentiation. In this study, we have demonstrated the role of MEK5 in osteoblastic differentiation in mouse preosteoblastic MC3T3-E1 cells and bone marrow stromal ST2 cells. We found that treatment with BIX02189, an inhibitor of MEK5, increased alkaline phosphatase (ALP) activity and the gene expression of ALP, osteocalcinmore » (OCN) and osterix, as well as it enhanced the calcification of the extracellular matrix. Moreover, osteoblastic cell proliferation decreased at a concentration of greater than 0.5 μM. In addition, knockdown of MEK5 using siRNA induced an increase in ALP activity and in the gene expression of ALP, OCN, and osterix. In contrast, overexpression of wild-type MEK5 decreased ALP activity and attenuated osteoblastic differentiation markers including ALP, OCN and osterix, but promoted cell proliferation. In summary, our results indicated that MEK5 suppressed the osteoblastic differentiation, but promoted osteoblastic cell proliferation. These results implied that MEK5 may play a pivotal role in cell signaling to modulate the differentiation and proliferation of osteoblasts. Thus, inhibition of MEK5 signaling in osteoblasts may be of potential use in the treatment of osteoporosis. - Highlights: • MEK5 inhibitor BIX02189 suppresses proliferation of osteoblasts. • MEK5 knockdown and MEK5 inhibitor promote differentiation of osteoblasts. • MEK5 overexpression inhibits differentiation of osteoblasts.« less

  12. Bone suppression technique for chest radiographs

    NASA Astrophysics Data System (ADS)

    Huo, Zhimin; Xu, Fan; Zhang, Jane; Zhao, Hui; Hobbs, Susan K.; Wandtke, John C.; Sykes, Anne-Marie; Paul, Narinder; Foos, David

    2014-03-01

    High-contrast bone structures are a major noise contributor in chest radiographic images. A signal of interest in a chest radiograph could be either partially or completely obscured or "overshadowed" by the highly contrasted bone structures in its surrounding. Thus, removing the bone structures, especially the posterior rib and clavicle structures, is highly desirable to increase the visibility of soft tissue density. We developed an innovative technology that offers a solution to suppress bone structures, including posterior ribs and clavicles, on conventional and portable chest X-ray images. The bone-suppression image processing technology includes five major steps: 1) lung segmentation, 2) rib and clavicle structure detection, 3) rib and clavicle edge detection, 4) rib and clavicle profile estimation, and 5) suppression based on the estimated profiles. The bone-suppression software outputs an image with both the rib and clavicle structures suppressed. The rib suppression performance was evaluated on 491 images. On average, 83.06% (±6.59%) of the rib structures on a standard chest image were suppressed based on the comparison of computer-identified rib areas against hand-drawn rib areas, which is equivalent to about an average of one rib that is still visible on a rib-suppressed image based on a visual assessment. Reader studies were performed to evaluate reader performance in detecting lung nodules and pneumothoraces with and without a bone-suppression companion view. Results from reader studies indicated that the bone-suppression technology significantly improved radiologists' performance in the detection of CT-confirmed possible nodules and pneumothoraces on chest radiographs. The results also showed that radiologists were more confident in making diagnoses regarding the presence or absence of an abnormality after rib-suppressed companion views were presented

  13. Caffeic acid phenethyl ester suppresses melanoma tumor growth by inhibiting PI3K/AKT/XIAP pathway.

    PubMed

    Pramanik, Kartick C; Kudugunti, Shashi K; Fofaria, Neel M; Moridani, Majid Y; Srivastava, Sanjay K

    2013-09-01

    Melanoma is highly metastatic and resistant to chemotherapeutic drugs. Our previous studies have demonstrated that caffeic acid phenethyl ester (CAPE) suppresses the growth of melanoma cells and induces reactive oxygen species generation. However, the exact mechanism of the growth suppressive effects of CAPE was not clear. Here, we determined the potential mechanism of CAPE against melanoma in vivo and in vitro. Administration of 10 mg/kg/day CAPE substantially suppressed the growth of B16F0 tumor xenografts in C57BL/6 mice. Tumors from CAPE-treated mice showed reduced phosphorylation of phosphoinositide 3-kinase, AKT, mammalian target of rapamycin and protein level of X-linked inhibitor of apoptosis protein (XIAP) and enhanced the cleavage of caspase-3 and poly (ADP ribose) polymerase. In order to confirm the in vivo observations, melanoma cells were treated with CAPE. CAPE treatment suppressed the activating phosphorylation of phosphoinositide 3-kinase at Tyr 458, phosphoinositide-dependent kinase-1 at Ser 241, mammalian target of rapamycin at Ser 2448 and AKT at Ser 473 in B16F0 and SK-MEL-28 cells in a concentration and time-dependent study. Furthermore, the expression of XIAP, survivin and BCL-2 was downregulated by CAPE treatment in both cell lines. Significant apoptosis was observed by CAPE treatment as indicated by cleavage of caspase-3 and poly (ADP ribose) polymerase. AKT kinase activity was inhibited by CAPE in a concentration-dependent manner. CAPE treatment increased the nuclear translocation of XIAP, indicating increased apoptosis in melanoma cells. To confirm the involvement of reactive oxygen species in the inhibition of AKT/XIAP pathway, cells were treated with antioxidant N-acetyl-cysteine (NAC) prior to CAPE treatment. Our results indicate that NAC blocked CAPE-mediated AKT/XIAP inhibition and protected the cells from apoptosis. Because AKT regulates XIAP, their interaction was examined by immunoprecipitation studies. Our results show that CAPE

  14. Caffeic acid phenethyl ester suppresses melanoma tumor growth by inhibiting PI3K/AKT/XIAP pathway

    PubMed Central

    Srivastava, Sanjay K.

    2013-01-01

    Melanoma is highly metastatic and resistant to chemotherapeutic drugs. Our previous studies have demonstrated that caffeic acid phenethyl ester (CAPE) suppresses the growth of melanoma cells and induces reactive oxygen species generation. However, the exact mechanism of the growth suppressive effects of CAPE was not clear. Here, we determined the potential mechanism of CAPE against melanoma in vivo and in vitro. Administration of 10 mg/kg/day CAPE substantially suppressed the growth of B16F0 tumor xenografts in C57BL/6 mice. Tumors from CAPE-treated mice showed reduced phosphorylation of phosphoinositide 3-kinase, AKT, mammalian target of rapamycin and protein level of X-linked inhibitor of apoptosis protein (XIAP) and enhanced the cleavage of caspase-3 and poly (ADP ribose) polymerase. In order to confirm the in vivo observations, melanoma cells were treated with CAPE. CAPE treatment suppressed the activating phosphorylation of phosphoinositide 3-kinase at Tyr 458, phosphoinositide-dependent kinase-1 at Ser 241, mammalian target of rapamycin at Ser 2448 and AKT at Ser 473 in B16F0 and SK-MEL-28 cells in a concentration and time-dependent study. Furthermore, the expression of XIAP, survivin and BCL-2 was downregulated by CAPE treatment in both cell lines. Significant apoptosis was observed by CAPE treatment as indicated by cleavage of caspase-3 and poly (ADP ribose) polymerase. AKT kinase activity was inhibited by CAPE in a concentration-dependent manner. CAPE treatment increased the nuclear translocation of XIAP, indicating increased apoptosis in melanoma cells. To confirm the involvement of reactive oxygen species in the inhibition of AKT/XIAP pathway, cells were treated with antioxidant N-acetyl-cysteine (NAC) prior to CAPE treatment. Our results indicate that NAC blocked CAPE-mediated AKT/XIAP inhibition and protected the cells from apoptosis. Because AKT regulates XIAP, their interaction was examined by immunoprecipitation studies. Our results show that CAPE

  15. Repeated landscape-scale treatments following fire suppress a non-native annual grass and promote recovery of native perennial vegetation

    USGS Publications Warehouse

    Munson, Seth M.; Long, A. Lexine; Decker, Cheryl E.; Johnson, Katie A.; Walsh, Kathleen; Miller, Mark E.

    2015-01-01

    Invasive non-native species pose a large threat to restoration efforts following large-scale disturbances. Bromus tectorum (cheatgrass) is a non-native annual grass in the western U.S. that both spreads quickly following fire and accelerates the fire cycle. Herbicide and seeding applications are common restoration practices to break the positive fire-invasion feedback loop and recover native perennial species, but their interactive effects have infrequently been tested at the landscape-scale and repeated in time to encourage long-lasting effects. We determined the efficacy of repeated post-fire application of the herbicide imazapic and seeding treatments to suppressBromus abundance and promote perennial vegetation recovery. We found that the selective herbicide reduced Bromus cover by ~30 % and density by >50 % across our study sites, but had a strong initial negative effect on seeded species. The most effective treatment to promote perennial seeded species cover was seeding them alone followed by herbicide application 3 years later when the seeded species had established. The efficacy of the treatments was strongly influenced by water availability, as precipitation positively affected the density and cover of Bromus; soil texture and aspect secondarily influenced Bromus abundance and seeded species cover by modifying water retention in this semi-arid region. Warmer temperatures positively affected the non-native annual grass in the cool-season, but negatively affected seeded perennial species in the warm-season, suggesting an important role of seasonality in a region projected to experience large increases in warming in the future. Our results highlight the importance of environmental interactions and repeated treatments in influencing restoration outcomes at the landscape-scale.

  16. Combined transdermal testosterone gel and the progestin nestorone suppresses serum gonadotropins in men.

    PubMed

    Mahabadi, Vahid; Amory, John K; Swerdloff, Ronald S; Bremner, William J; Page, Stephanie T; Sitruk-Ware, Regine; Christensen, Peter D; Kumar, Narender; Tsong, Yun-Yen; Blithe, Diana; Wang, Christina

    2009-07-01

    Testosterone (T) plus progestin combinations are the most promising hormonal male contraceptives. Nestorone (NES), a progestin without estrogenic or androgenic activity, when combined with T may be an excellent candidate for male contraception. Our objective was to determine the effect of transdermal NES gel alone or with T gel on gonadotropin suppression. The randomized, unblinded clinical trial was conducted at two academic medical centers. A total of 140 healthy male volunteers participated. One hundred subjects were randomized initially (20 per group) to apply NES gel 2 or 4 mg, T gel 10 g, or T gel 10 g plus NES gel 2 or 4 mg daily for 20 d. Because only about half of the subjects in T plus NES 4 mg group suppressed serum gonadotropins to 0.5 IU/liter or less (suboptimal suppression), two additional groups of 20 men were randomized to apply daily T gel 10 g plus NES gel 6 or 8 mg. Suppression of serum LH and FSH concentrations to 0.5 IU/liter or less after treatment was the main outcome variable. A total of 119 subjects were compliant with gel applications with few study-related adverse events. NES alone reduced gonadotropins significantly but less than T gel alone. Combined T gel 10g plus NES gel 6 or 8 mg suppressed both serum gonadotropins to 0.5 IU/liter or less in significantly more men than either gel alone. Transdermal NES gel alone had gonadotropin suppression activity. Combined transdermal NES (6 or 8 mg) plus T gel demonstrated safe and effective suppression of gonadotropins, justifying a longer-term study of this combination for suppression of spermatogenesis.

  17. Curcumin Suppresses the Colon Cancer Proliferation by Inhibiting Wnt/β-Catenin Pathways via miR-130a.

    PubMed

    Dou, Huiqiang; Shen, Renhui; Tao, Jianxin; Huang, Longchang; Shi, Haoze; Chen, Hang; Wang, Yixin; Wang, Tong

    2017-01-01

    Curcumin exhibits anti-tumor effects in several cancers, including colorectal carcinoma (CRC), but the detailed mechanisms are still unclear. Here we studied the mechanisms underlying the anti-tumor effect of curcumin in colon cancer cells. SW480 cells were injected into mice to establish the xenograft tumor model, followed by evaluation of survival rate with the treatment of curcumin. The expression levels of β-catenin, Axin and TCF4 were measured in the SW480 cells in the absence or presence of curcumin. Moreover, miRNAs related to the curcumin treatment were also detected in vitro . Curcumin could suppress the growth of colon cancer cells in the mouse model. This anti-tumor activity of curcumin was exerted by inhibiting cell proliferation rather than promoting cell apoptosis. Further study suggested that curcumin inhibited cell proliferation by suppressing the Wnt/β-catenin pathway. MiR-130a was down-regulated by curcumin treatment, and overexpressing miR-130a could abolish the anti-tumor activity of curcumin. Our study confirms that curcumin is able to inhibit colon cancer by suppressing the Wnt/β-catenin pathways via miR-130a. MiR-130a may serve as a new target of curcumin for CRC treatment.

  18. Yeast-derived Particulate β-Glucan Treatment Subverts the Suppression of Myeloid-derived Suppressor Cells by Inducing PMN-MDSC Apoptosis and M-MDSC Differentiation to APC in Cancer

    PubMed Central

    Albeituni, Sabrin H.; Ding, Chuanlin; Liu, Min; Hu, Xiaoling; Luo, Fengling; Kloecker, Goetz; Bousamra, Micahel; Zhang, Huang-ge; Yan, Jun

    2016-01-01

    Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that promote tumor progression. Herein, we demonstrated that activation of a C-type lectin receptor, dectin-1, in MDSC differentially modulates the function of different MDSC subsets. Yeast-derived whole β-glucan particles (WGP), a ligand to engage and activate dectin-1, oral treatment in vivo significantly decreased tumor weight and splenomegaly in tumor-bearing mice with reduced accumulation of PMN-MDSC but not M-MDSC, and decreased PMN-MDSC suppression in vitro through the induction of respiratory burst and apoptosis. On a different axis, WGP-treated M-MDSC differentiated into F4/80+CD11c+ cells in vitro that served as potent antigen-presenting cells (APC) to induce Ag-specific CD4+ and CD8+ T cell responses in a dectin-1 dependent manner. In addition, ERK1/2 phosphorylation was required for the acquisition of APC properties in M-MDSC. Moreover, WGP-treated M-MDSC differentiated into CD11c+ cells in vivo with high MHC class II expression and induced decreased tumor burden when inoculated subcutaneously with LLC cells. This effect was dependent of the dectin-1 receptor. Strikingly, patients with non-small cell lung cancer (NSCLC) that had received WGP treatment for 10–14 days prior to any other treatment had a decreased frequency of CD14−HLA-DR−CD11b+CD33+ MDSC in the peripheral blood. Overall, these data indicate that WGP may be a potent immune modulator of MDSC suppressive function and differentiation in cancer. PMID:26810222

  19. New therapy with ASC-J9® to suppress the prostatitis via altering the cytokine CCL2 signals

    PubMed Central

    Lin, Shin-Jen; Chou, Fu-Ju; Lin, Chang-Yi; Chang, Hong-Chiang; Yeh, Shuyuan; Chang, Chawnshang

    2016-01-01

    Prostatitis is a common disease contributing to 8% of all urologist visits. Yet the etiology and effective treatment remain to be further elucidated. Using a non-obese diabetes mouse model that can be induced by autoimmune response for the spontaneous development of prostatitis, we found that injection of the ASC-J9® at 75 mg/Kg body weight/48 hours led to significantly suppressed prostatitis that was accompanied with reduction of lymphocyte infiltration with reduced CD4+ T cells in prostate. In vitro studies with a co-culture system also confirmed that ASC-J9® treatment could suppress the CD4+ T cell migration to prostate stromal cells. Mechanisms dissection indicated that ASC-J9® can suppress CD4+ T cell migration via decreasing the cytokine CCL2 in vitro and in vivo, and restoring CCL2 could interrupt the ASC-J9® suppressed CD4+ T cell migration. Together, results from in vivo and in vitro studies suggest that ASC-J9® can suppress prostatitis by altering the autoimmune response induced by CD4+ T cell recruitment, and using ASC-J9® may help us to develop a potential new therapy to battle the prostatitis with little side effects. PMID:27564257

  20. New therapy with ASC-J9® to suppress the prostatitis via altering the cytokine CCL2 signals.

    PubMed

    Lin, Shin-Jen; Chou, Fu-Ju; Lin, Chang-Yi; Chang, Hong-Chiang; Yeh, Shuyuan; Chang, Chawnshang

    2016-10-11

    Prostatitis is a common disease contributing to 8% of all urologist visits. Yet the etiology and effective treatment remain to be further elucidated. Using a non-obese diabetes mouse model that can be induced by autoimmune response for the spontaneous development of prostatitis, we found that injection of the ASC-J9® at 75 mg/Kg body weight/48 hours led to significantly suppressed prostatitis that was accompanied with reduction of lymphocyte infiltration with reduced CD4+ T cells in prostate. In vitro studies with a co-culture system also confirmed that ASC-J9® treatment could suppress the CD4+ T cell migration to prostate stromal cells. Mechanisms dissection indicated that ASC-J9® can suppress CD4+ T cell migration via decreasing the cytokine CCL2 in vitro and in vivo, and restoring CCL2 could interrupt the ASC-J9® suppressed CD4+ T cell migration. Together, results from in vivo and in vitro studies suggest that ASC-J9® can suppress prostatitis by altering the autoimmune response induced by CD4+ T cell recruitment, and using ASC-J9® may help us to develop a potential new therapy to battle the prostatitis with little side effects.

  1. Inducing amnesia through systemic suppression

    PubMed Central

    Hulbert, Justin C.; Henson, Richard N.; Anderson, Michael C.

    2016-01-01

    Hippocampal damage profoundly disrupts the ability to store new memories of life events. Amnesic windows might also occur in healthy people due to disturbed hippocampal function arising during mental processes that systemically reduce hippocampal activity. Intentionally suppressing memory retrieval (retrieval stopping) reduces hippocampal activity via control mechanisms mediated by the lateral prefrontal cortex. Here we show that when people suppress retrieval given a reminder of an unwanted memory, they are considerably more likely to forget unrelated experiences from periods surrounding suppression. This amnesic shadow follows a dose-response function, becomes more pronounced after practice suppressing retrieval, exhibits characteristics indicating disturbed hippocampal function, and is predicted by reduced hippocampal activity. These findings indicate that stopping retrieval engages a suppression mechanism that broadly compromises hippocampal processes and that hippocampal stabilization processes can be interrupted strategically. Cognitively triggered amnesia constitutes an unrecognized forgetting process that may account for otherwise unexplained memory lapses following trauma. PMID:26977589

  2. Lead suppresses chimeric human transferrin gene expression in transgenic mouse liver.

    PubMed

    Adrian, G S; Rivera, E V; Adrian, E K; Lu, Y; Buchanan, J; Herbert, D C; Weaker, F J; Walter, C A; Bowman, B H

    1993-01-01

    The major iron-transport protein in serum is transferrin (TF) which also has the capacity to transport other metals. This report presents evidence that synthesis of human TF can be regulated by the metal lead. Transgenic mice carrying chimeric human TF-chloramphenicol acetyl transferase (CAT) genes received lead or sodium salts by intraperitoneal injections or in drinking water. Transgene expression in liver was suppressed 31 to 50% by the lead treatment. Lead regulates human TF transgenes at the mRNA level since liver CAT enzyme activity, CAT protein, and TF-CAT mRNA levels were all suppressed. The dosages of lead did not alter synthesis of the other liver proteins, mouse TF and albumin, as measured by Northern blot analysis of total liver RNA and rocket immunoelectrophoresis of mouse sera. Moderate levels of lead exposure were sufficient to evoke the human TF transgene response; blood lead levels in mice that received lead acetate in drinking water ranged from 30 micrograms/dl to 56 micrograms/dl. In addition to suppressing expression of TF-CAT genes in transgenic mice, lead also suppressed synthesis of TF protein in cultured human hepatoma HepG2 cells. The regulation of human TF apparently differs from the regulation of mouse TF which is unresponsive to lead exposure.

  3. Dose-Dependent Suppression of Gonadotropins and Ovarian Hormones by Elagolix in Healthy Premenopausal Women.

    PubMed

    Ng, Juki; Chwalisz, Kristof; Carter, David C; Klein, Cheri E

    2017-05-01

    Elagolix is a nonpeptide, oral gonadotropin-releasing hormone (GnRH) antagonist being developed for sex-hormone-dependent diseases in women. We evaluated the pharmacokinetics and pharmacodynamics of elagolix. This study was a randomized, double-blind, placebo-controlled, multiple-ascending dose study in 45 healthy premenopausal women at a research unit. Elagolix [150 mg once daily or 100, 200, 300, or 400 mg twice daily (BID)] or placebo was administered for 21 days. Main outcome measures were elagolix pharmacokinetics, suppression of gonadotropics [follicle-stimulating hormone (FSH), luteinizing hormone (LH)] and ovarian hormones [estradiol (E2), progesterone (P)], and adverse events. Elagolix was rapidly absorbed after oral dosing, reaching maximum concentrations at 1.0 to 1.5 hours, with a half-life of 4 to 6 hours. FSH, LH, and E2 were suppressed within hours of elagolix administration on day 1. Dose-dependent suppression of E2 was observed, with maximum suppression achieved with elagolix 200 mg BID. Dose-dependent suppression of FSH and LH was also observed, with maximal or near-maximal suppression achieved at 300 mg BID and 200 mg BID, respectively. At elagolix doses ≥100 mg BID, P concentrations remained at anovulatory levels throughout 21 days of dosing. The most frequently reported adverse events were headache and hot flush. Elagolix administration allows for modulation of gonadotropin and ovarian hormone concentrations, from partial suppression at lower doses to nearly full suppression at higher doses. The results of this study provide a rationale for elagolix dose selection for treatment of sex hormone-dependent diseases in women. Copyright © 2017 Endocrine Society

  4. Explosion suppression system

    DOEpatents

    Sapko, Michael J.; Cortese, Robert A.

    1992-01-01

    An explosion suppression system and triggering apparatus therefor are provided for quenching gas and dust explosions. An electrically actuated suppression mechanism which dispenses an extinguishing agent into the path ahead of the propagating flame is actuated by a triggering device which is light powered. This triggering device is located upstream of the propagating flame and converts light from the flame to an electrical actuation signal. A pressure arming device electrically connects the triggering device to the suppression device only when the explosion is sensed by a further characteristic thereof beside the flame such as the pioneer pressure wave. The light powered triggering device includes a solar panel which is disposed in the path of the explosion and oriented between horizontally downward and vertical. Testing mechanisms are also preferably provided to test the operation of the solar panel and detonator as well as the pressure arming mechanism.

  5. Fire Suppression, District 5

    Treesearch

    Roy Headley

    1916-01-01

    The increasing effectiveness of suppression practice is shown by the fact that in 1915 fire suppression cost one-third as much as in 1914, and damage to Government property was kept down to one-fourth the 1914 figure. The seasons were approximately equal in danger. Is further progress to be expected?

  6. Treatment of Post-Traumatic Stress Disorder Nightmares at a Veterans Affairs Medical Center

    PubMed Central

    Detweiler, Mark B.; Pagadala, Bhuvaneshwar; Candelario, Joseph; Boyle, Jennifer S.; Detweiler, Jonna G.; Lutgens, Brian W.

    2016-01-01

    The effectiveness of medications for PTSD in general has been well studied, but the effectiveness of medicatio.ns prescribed specifically for post-traumatic stress disorder (PTSD) nightmares is less well known. This retrospective chart review examined the efficacy of various medications used in actual treatment of PTSD nightmares at one Veteran Affairs Hospital. Records at the Salem, VA Veterans Affairs Medical Center (VAMC) were examined from 2009 to 2013 to check for the efficacy of actual treatments used in comparis.on with treatments suggested in three main review articles. The final sample consisted of 327 patients and 478 separate medication trials involving 21 individual medications plus 13 different medication combinations. The three most frequently utilized medications were prazosin (107 trials), risperidone (81 trials), and quetiapine (72 trials). Five medications had 20 or more trials with successful results (partial to full nightmare cessation) in >50% of trials: risperidone (77%, 1.0–6.0 mg), clonidine (63%, 0.1–2.0 mg), quetiapine (50%, 12.5–800.0 mg), mirtazapine (50%; 7.5–30.0 mg), and terazosin (64%, 50.0–300.0 mg). Notably, olanzapine (2.5–10.0) was successful (full remission) in all five prescription trials in five separate patients. Based on the clinical results, the use of risperidone, clonidine, terazosin, and olanzapine warrants additional investigation in clinically controlled trials as medications prescribed specifically for PTSD nightmares. PMID:27999253

  7. Relaxin suppresses atrial fibrillation in aged rats by reversing fibrosis and upregulating Na+ channels.

    PubMed

    Henry, Brian L; Gabris, Beth; Li, Qiao; Martin, Brian; Giannini, Marianna; Parikh, Ashish; Patel, Divyang; Haney, Jamie; Schwartzman, David S; Shroff, Sanjeev G; Salama, Guy

    2016-04-01

    Atrial fibrillation (AF) contributes significantly to morbidity and mortality in elderly patients and has been correlated with enhanced age-dependent atrial fibrosis. Reversal of atrial fibrosis has been proposed as therapeutic strategy to suppress AF. To test the ability of relaxin to reverse age-dependent atrial fibrosis and suppress AF. Aged F-344 rats (24 months old) were treated with subcutaneous infusion of vehicle or relaxin (0.4 mg/kg/day) for 2 weeks. Rat hearts were excised, perfused on a Langendorff apparatus, and stained with voltage and Ca(2+) indicator dyes. Optical mapping and programmed electrical stimulation was used to test arrhythmia vulnerability and changes in electrophysiological characteristics. Changes in protein expression and Na(+) current density (INa) were measured by tissue immunofluorescence and whole-cell patch clamp technique. In aged rats, sustained AF was readily induced with a premature pulse (n = 7/8) and relaxin treatment suppressed sustained AF by a premature impulse or burst pacing (n = 1/6) (P < .01). Relaxin significantly increased atrial action potential conduction velocity and decreased atrial fibrosis. Relaxin treatment increased Nav1.5 expression (n = 6; 36% ± 10%) and decreased total collagen and collagen I (n = 5-6; 55%-66% ± 15%) in aged atria (P < .05) and decreased collagen I and III and TGF-β1 mRNA (P < .05). Voltage-clamp experiments demonstrated that relaxin treatment (100 nM for 2 days) increased atrial INa by 46% ± 4% (n = 12-13/group, P < .02). Relaxin suppresses AF through an increase in atrial conduction velocity by decreasing atrial fibrosis and increasing INa. These data provide compelling evidence that relaxin may serve as an effective therapy to manage AF in geriatric patients by reversing fibrosis and modulating cardiac ionic currents. Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

  8. Rebamipide suppresses TNF-α production and macrophage infiltration in the conjunctiva.

    PubMed

    Tajima, Kazuki; Hattori, Takaaki; Takahashi, Hiroki; Katahira, Haruki; Narimatsu, Akitomo; Kumakura, Shigeto; Goto, Hiroshi

    2017-12-18

    To evaluate the anti-inflammatory effect of rebamipide during corneal epithelial wound healing using a mouse wound repair model. A 2-mm circular disc of the central cornea was demarcated in the right eye of C57BL/6 mice and the epithelium removed. Rebamipide 2% eyedrop was instilled onto the wounded eye 5 times a day (n = 26). Phosphate-buffered saline (PBS) was used in the control group (n = 26). Corneal and conjunctival IL-1β and TNF-α levels were measured at 6 h and 24 h postinjury by ELISA. The wounded area was evaluated by fluorescein staining at 24 h postinjury. Macrophage infiltration was assessed immunohistochemically, and TNF-α secretion from macrophages was examined in vitro. Conjunctival IL-1β and corneal IL-1β levels were not significantly different between PBS-treated and rebamipide-treated groups. However, conjunctival TNF-α level was significantly lower in the rebamipide-treated group compared with the PBS-treated group. Macrophage migration into the conjunctiva, but not into the cornea, was suppressed by rebamipide treatment. In addition, TNF-α secretion from cultured macrophages was suppressed by rebamipide in a concentration-dependent manner. Rebamipide treatment significantly accelerated corneal epithelial wound healing at 24 h postinjury. In a mouse corneal epithelial wound model, rebamipide suppressed TNF-α secretion and macrophage infiltration in the conjunctiva, which might have contributed to accelerated corneal epithelial wound healing in the first 24 h following injury. © 2017 American College of Veterinary Ophthalmologists.

  9. Differential Roles of Thought Suppression and Dispositional Mindfulness in Posttraumatic Stress Symptoms and Craving

    PubMed Central

    Garland, Eric; Roberts-Lewis, Amelia

    2012-01-01

    Exposure to traumatic events often results in severe distress which may elicit self-medication behaviors. Yet, some individuals exposed to trauma do not develop post-traumatic stress symptoms and comorbid addictive impulses. In the wake of traumatic events, psychological processes like thought suppression and mindfulness may modulate post-traumatic stress and craving for substances. We examined the differential roles of mindfulness and suppression in comorbid post-traumatic stress and craving in a sample of 125 persons with extensive trauma histories and psychiatric symptoms in residential treatment for substance dependence. Results indicated that thought suppression, rather than extent of trauma history, significantly predicted post-traumatic stress symptom severity while dispositional mindfulness significantly predicted both post-traumatic stress symptoms and craving. In multiple regression models, mindfulness and thought suppression combined explained nearly half of the variance in post-traumatic stress symptoms and one-quarter of the variance in substance craving. Moreover, multivariate path analysis indicated that prior traumatic experience was associated with greater thought suppression, which in turn was correlated with increased post-traumatic stress symptoms and drug craving, whereas dispositional mindfulness was associated with decreased suppression, post-traumatic stress, and craving. The maladaptive strategy of thought suppression appears to be linked with adverse psychological consequences of traumatic life events. In contrast, dispositional mindfulness appears to be a protective factor that buffers individuals from experiencing more severe post-traumatic stress symptoms and craving. PMID:22385734

  10. Therapeutic burst-suppression coma in pediatric febrile refractory status epilepticus.

    PubMed

    Lin, Jainn-Jim; Chou, Cheng-Che; Lan, Shih-Yun; Hsiao, Hsiang-Ju; Wang, Yu; Chan, Oi-Wa; Hsia, Shao-Hsuan; Wang, Huei-Shyong; Lin, Kuang-Lin

    2017-09-01

    Evidence for the beneficial effect of therapeutic burst-suppression coma in pediatric patients with febrile refractory status epilepticus is limited, and the clinical outcomes of this treatment strategy are largely unknown. Therefore, the aim of this study was to explore the outcomes of therapeutic burst-suppression coma in a series of children with febrile refractory status epilepticus. We retrospectively reviewed consecutive pediatric patients with febrile refractory status epilepticus admitted to our pediatric intensive care unit between January 2000 and December 2013. The clinical characteristics were analyzed. Thirty-five patients (23 boys; age range: 1-18years) were enrolled, of whom 28 (80%) developed super-refractory status epilepticus. All of the patients received the continuous administration of intravenous antiepileptic drugs for febrile refractory status epilepticus, and 26 (74.3%) achieved therapeutic burst-suppression coma. All of the patients received mechanical ventilatory support, and 26 (74.3%) received inotropic agents. Eight (22.9%) patients died within 1month. The neurologically functional outcomes at 6months were good in six (27.3%) of the 22 survivors, of whom two returned to clinical baseline. The patients with therapeutic burst-suppression coma were significantly associated with hemodynamic support than the patients with electrographic seizures control (p=0.03), and had a trend of higher 1-month mortality rate, worse 6months outcomes, and a longer duration of hospitalization. Our results suggest that therapeutic burst-suppression coma to treat febrile refractory status epilepticus may lead to an increased risk of hemodynamic instability and a trend of worse outcomes. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  11. Suboptimal Viral Suppression Rates Among HIV-Infected Children in Low- and Middle-Income Countries: A Meta-analysis.

    PubMed

    Boerma, Ragna S; Boender, T Sonia; Bussink, Anton P; Calis, Job C J; Bertagnolio, Silvia; Rinke de Wit, Tobias F; Boele van Hensbroek, Michael; Sigaloff, Kim C E

    2016-12-15

     The 90-90-90 goal to achieve viral suppression in 90% of all human immunodeficiency virus (HIV)-infected people on antiretroviral treatment (ART) is especially challenging in children. Global estimates of viral suppression among children in low- and middle-income countries (LMICs) are lacking.  We searched for randomized controlled trials and observational studies and analyzed viral suppression rates among children started on ART during 3 time periods: early (2000-2005), intermediate (2006-2009), and current (2010 and later), using random effects meta-analysis.  Seventy-two studies, reporting on 51 347 children (aged <18 years), were included. After 12 months on first-line ART, viral suppression was achieved by 64.7% (95% confidence interval [CI], 57.5-71.8) in the early, 74.2% (95% CI, 70.2-78.2) in the intermediate, and 72.7% (95% 62.6-82.8) in the current time period. Rates were similar after 6 and 24 months of ART. Using an intention-to-treat analysis, 42.7% (95% CI, 33.7-51.7) in the early, 45.7% (95% CI, 33.2-58.3) in the intermediate, and 62.5% (95% CI, 53.3-72.6) in the current period were suppressed. Long-term follow-up data were scarce.  Viral suppression rates among children on ART in LMICs were low and considerably poorer than those previously found in adults in LMICs and children in high-income countries. Little progress has been made in improving viral suppression rates over the past years. Without increased efforts to improve pediatric HIV treatment, the 90-90-90 goal for children in LMIC will not be reached. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  12. Enhanced suppression of tumor growth by concomitant treatment of human lung cancer cells with suberoylanilide hydroxamic acid and arsenic trioxide

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Chien, Chia-Wen; Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11490, Taiwan; Yao, Ju-Hsien

    2011-11-15

    The efficacy of arsenic trioxide (ATO) against acute promyelocytic leukemia (APL) and relapsed APL has been well documented. ATO may cause DNA damage by generating reactive oxygen intermediates. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, modulates gene and protein expression via histone-dependent or -independent pathways that may result in chromatin decondensation, cell cycle arrest, differentiation, and apoptosis. We investigated whether ATO and SAHA act synergistically to enhance the death of cancer cells. Our current findings showed that combined treatment with ATO and SAHA resulted in enhanced suppression of non-small-cell lung carcinoma in vitro in H1299 cells and in vivomore » in a xenograft mouse model. Flow cytometric analysis of annexin V+ cells showed that apoptotic cell death was significantly enhanced after combined treatment with ATO and SAHA. At the doses used, ATO did not interfere with cell cycle progression, but SAHA induced p21 expression and led to G1 arrest. A Comet assay demonstrated that ATO, but not SAHA, induced DNA strand breaks in H1299 cells; however, co-treatment with SAHA significantly increased ATO-induced DNA damage. Moreover, SAHA enhanced acetylation of histone H3 and sensitized genomic DNA to DNase I digestion. Our results suggest that SAHA may cause chromatin relaxation and increase cellular susceptibility to ATO-induced DNA damage. Combined administration of SAHA and ATO may be an effective approach to the treatment of lung cancer. -- Highlights: Black-Right-Pointing-Pointer ATO and SAHA are therapeutic agents with different action modes. Black-Right-Pointing-Pointer Combination of ATO and SAHA synergistically inhibits tumor cell growth. Black-Right-Pointing-Pointer SAHA loosens chromatin structure resulting in increased sensitivity to DNase I. Black-Right-Pointing-Pointer ATO-induced DNA damage and apoptosis are enhanced by co-treatment with SAHA.« less

  13. Suppression of methylmercury-induced MIP-2 expression by N-acetyl-L-cysteine in murine RAW264.7 macrophage cell line.

    PubMed

    David, Juliet; Nandakumar, Athira; Muniroh, Muflihatul; Akiba, Suminori; Yamamoto, Megumi; Koriyama, Chihaya

    2017-11-09

    The aim of this study is to examine the inflammatory-cytokine expressions in the presence of non-cytotoxic dose of methylmercury (MeHg) in murine macrophages, which is suspected to play an important role in brain damage caused by MeHg exposure. We focused on murine macrophage inflammatory protein-2 (MIP-2), keratinocyte chemoattractant (KC), and monocyte chemoattractant protein-5 (MCP-5). MIP-2 and KC are murine functional homologues of human IL-8 and MCP-5 for human MCP-1. Furthermore, we examined the suppressive effect of N-acetyl-L-cysteine (NAC) on the MeHg-induced inflammatory cytokines. In a murine RAW264.7 macrophage cell line, MeHg-induced cytokine expressions were measured using real-time PCR. The suppressive effect of NAC was examined by putting it into the culture medium together with MeHg (co-treatment). In addition, pre- and post-treatment experiments were conducted, in which the cells were treated with NAC before and after MeHg exposure, respectively. Exposure to a non-cytotoxic dose of MeHg up-regulated the mRNA expression of MIP-2 and MCP-5. On the other hand, KC expression was not induced in the presence of MeHg. Effect of MeHg on MIP-2 expressions was suppressed by pre-, co-, and post-treatment with NAC. However, the suppressive effect of pre-treatment was less than the post-treatment, which was as effective as co-treatment. In functional homologues of human IL-8, only MIP-2 expression, not KC, was activated in the presence of non-cytotoxic dose of MeHg in murine RAW264.7 macrophage cell line. The more evident inhibitory effect of NAC observed in post-treatment experiments suggests a possible involvement of intracellular activities such as antioxidant effects.

  14. Rebamipide suppresses PolyI:C-stimulated cytokine production in human conjunctival epithelial cells.

    PubMed

    Ueta, Mayumi; Sotozono, Chie; Yokoi, Norihiko; Kinoshita, Shigeru

    2013-09-01

    We previously documented that ocular surface epithelial cells could regulate ocular surface inflammation and suggested that, while Toll-like receptor 3 upregulates, EP3, one of the prostaglandin E2 receptors, downregulates ocular surface inflammation. Others reported that rebamipide, a gastroprotective drug, could not only increase the gastric mucus production, but also suppressed gastric mucosal inflammation and that it was dominantly distributed in mucosal tissues. The eyedrop form of rebamipide, approved in Japan for use in the treatment of dry eye diseases, upregulates mucin secretion and production, thereby suppressing superficial punctate keratopathy on the ocular surface of patients with this disease. In the current study, we investigated whether rebamipide has anti- inflammatory effects on the ocular surface. To examine the effects of rebamipide on polyI:C-induced cytokine expression by primary human conjunctival epithelial cells, we used enzyme-linked immunosorbent assay and quantitative reverse transcription-polymerase chain reaction assay. We studied the effects of rebamipide on ocular surface inflammation in our murine experimental allergic conjunctivitis (EAC) model. Rebamipide could suppress polyI:C-induced cytokine production and the expression of mRNAs for CXCL10, CXCL11, RANTES, MCP-1, and IL-6 in human conjunctival epithelial cells. In our EAC model, the topical administration of rebamipide suppressed conjunctival allergic eosinophil infiltration. The topical application of rebamipide on the ocular surface might suppress ocular surface inflammation by suppressing the production of cytokines by ocular surface epithelial cells.

  15. Stable Caloric Intake and Continued Virologic Suppression for HIV-Positive Antiretroviral Treatment-Experienced Women After Switching to a Single-Tablet Regimen of Emtricitabine, Rilpivirine, and Tenofovir Disoproxil Fumarate.

    PubMed

    Menezes, Prema; Mollan, Katie; Hoffman, Erin; Xie, Zimeng; Wills, Jennifer; Marcus, Cheryl; Rublein, John; Hudgens, Michael; Eron, Joseph J

    2018-05-02

    Benefits of switching to a single-tablet regimen (STR) of emtricitabine/rilpivirine/tenofovir (FTC/RPV/TDF) in virologically suppressed antiretroviral treatment (ART) experienced HIV-positive women include pregnancy category B rating and lack of clinically significant drug interactions between RPV and oral contraceptives. Unfortunately, studies involving switching to FTC/RPV/TDF enrolled fewer than 25% women. We undertook this 48-week study to assess the ability of virologically suppressed HIV-positive women switching to RPV STR to remain virologically suppressed and comply with the caloric intake requirement. HIV-positive women on ART with viral load <50 c/mL for 6 months before study entry and no known resistance to FTC, TDF, or RPV were enrolled and switched to STR RPV/FTC/TDF. Caloric intake (≥400 kcal) compliance and concurrency with oral STR RPV/FTC/TDF were evaluated with a 3-day food diary, which was validated by obtaining participant's caloric consumption through phone calls on randomly chosen dates. For each 3-day food diary, the daily median caloric intake and median value for each macronutrient consumed concurrent with FTC/RPV/TDF were computed. Medication adherence was measured using a visual analog scale. We enrolled 33 women, 73% of whom were African American. At week 48, virologic suppression (HIV RNA <40 c/mL) was maintained in 96% of women, including those (n = 4) who reported imperfect ART adherence. The daily median caloric intake concurrent with FTC/RPV/TDF was 820 kcal by food diary and 677 kcal by random phone call. Median kcal intake (food diary) did not change significantly from baseline (684 kcal) to week 48 (820 kcal); median change 102 kcal, p = .15. Women who reported noncompliance with a ≥400 kcal meal did not experience virologic failure. Significant concordance between caloric adherence and virologic suppression was not detected. Our study demonstrated that HIV-positive women who switched to STR FTC

  16. hTERT peptide fragment GV1001 demonstrates radioprotective and antifibrotic effects through suppression of TGF‑β signaling.

    PubMed

    Chen, Wei; Shin, Ki-Hyuk; Kim, Sangjae; Shon, Won-Jun; Kim, Reuben H; Park, No-Hee; Kang, Mo K

    2018-06-01

    GV1001 is a 16‑amino acid peptide derived from the human telomerase reverse transcriptase (hTERT) protein (616‑626; EARPALLTSRLRFIPK), which lies within the reverse transcriptase domain. Originally developed as an anticancer vaccine, GV1001 demonstrates diverse cellular effects, including anti‑inflammatory, tumor suppressive and antiviral effects. In the present study, the radioprotective and antifibrotic effects of GV1001 were demonstrated through suppressing transforming growth factor‑β (TGF‑β) signaling. Proliferating human keratinocytes underwent premature senescence upon exposure to ionizing radiation (IR), however, treatment of cells with GV1001 allowed the cells to proliferate and showed a reduction in senescent phenotype. GV1001 treatment notably increased the levels of Grainyhead‑like 2 and phosphorylated (p‑)Akt (Ser473), and reduced the activation of p53 and the level of p21/WAF1 in irradiated keratinocytes. It also markedly suppressed the level of TGF‑β signaling molecules, including p‑small mothers against decapentaplegic (Smad)2/3 and Smad4, and TGF‑β target genes, including zinc finger E‑box binding homeobox 1, fibronectin, N‑cadharin and Snail, in irradiated keratinocytes. Furthermore, GV1001 suppressed TGF‑β signaling in primary human fibroblasts and inhibited myofibroblast differentiation. Chromatin immunoprecipitation revealed that GV1001 suppressed the binding of Smad2 on the promoter regions of collagen type III α1 chain (Col3a1) and Col1a1. In a dermal fibrosis model in vivo, GV1001 treatment notably reduced the thickness of fibrotic lesions and the synthesis of Col3a1. These data indicated that GV1001 ameliorated the IR‑induced senescence phenotype and tissue fibrosis by inhibiting TGF‑β signaling and may have therapeutic effects on radiation‑induced tissue damage.

  17. Comparative Metatranscriptomics of Wheat Rhizosphere Microbiomes in Disease Suppressive and Non-suppressive Soils for Rhizoctonia solani AG8

    PubMed Central

    Hayden, Helen L.; Savin, Keith W.; Wadeson, Jenny; Gupta, Vadakattu V. S. R.; Mele, Pauline M.

    2018-01-01

    The soilborne fungus Rhizoctonia solani anastomosis group (AG) 8 is a major pathogen of grain crops resulting in substantial production losses. In the absence of resistant cultivars of wheat or barley, a sustainable and enduring method for disease control may lie in the enhancement of biological disease suppression. Evidence of effective biological control of R. solani AG8 through disease suppression has been well documented at our study site in Avon, South Australia. A comparative metatranscriptomic approach was applied to assess the taxonomic and functional characteristics of the rhizosphere microbiome of wheat plants grown in adjacent fields which are suppressive and non-suppressive to the plant pathogen R. solani AG8. Analysis of 12 rhizosphere metatranscriptomes (six per field) was undertaken using two bioinformatic approaches involving unassembled and assembled reads. Differential expression analysis showed the dominant taxa in the rhizosphere based on mRNA annotation were Arthrobacter spp. and Pseudomonas spp. for non-suppressive samples and Stenotrophomonas spp. and Buttiauxella spp. for the suppressive samples. The assembled metatranscriptome analysis identified more differentially expressed genes than the unassembled analysis in the comparison of suppressive and non-suppressive samples. Suppressive samples showed greater expression of a polyketide cyclase, a terpenoid biosynthesis backbone gene (dxs) and many cold shock proteins (csp). Non-suppressive samples were characterised by greater expression of antibiotic genes such as non-heme chloroperoxidase (cpo) which is involved in pyrrolnitrin synthesis, and phenazine biosynthesis family protein F (phzF) and its transcriptional activator protein (phzR). A large number of genes involved in detoxifying reactive oxygen species (ROS) and superoxide radicals (sod, cat, ahp, bcp, gpx1, trx) were also expressed in the non-suppressive rhizosphere samples most likely in response to the infection of wheat roots by R

  18. Hyperglycemia Suppresses Calcium Phosphate-Induced Aneurysm Formation Through Inhibition of Macrophage Activation.

    PubMed

    Tanaka, Teruyoshi; Takei, Yuichiro; Yamanouchi, Dai

    2016-03-28

    The aim of this study was to elucidate aspects of diabetes mellitus-induced suppression of aneurysm. We hypothesized that high glucose suppresses aneurysm by inhibiting macrophage activation via activation of Nr1h2 (also known as liver X receptor β), recently characterized as a glucose-sensing nuclear receptor. Calcium phosphate (CaPO4)-induced aneurysm formation was significantly suppressed in the arterial wall in type 1 and 2 diabetic mice. A murine macrophage cell line, RAW264.7, was treated with tumor necrosis factor α (TNF-α) plus CaPO4 and showed a significant increase in matrix metalloproteinase 9 (Mmp9) mRNA and secreted protein expression compared with TNF-α alone. Elevated Mmp9 expression was significantly suppressed by hyperglycemic conditions (15.5 mmol/L glucose) compared with normoglycemic conditions (5.5 mmol/L glucose) or normoglycemic conditions with high osmotic pressure (5.5 mmol/L glucose +10.0 mmol/L mannitol). Nr1h2 mRNA and protein expression were suppressed by treatment with TNF-α plus CaPO4 but were restored by hyperglycemic conditions. Activation of Nr1h2 by the antagonist GW3965 during stimulation with TNF-α plus CaPO4 mimicked hyperglycemic conditions and inhibited Mmp9 upregulation, whereas the deactivation of Nr1h2 by small interfering RNA (siRNA) under hyperglycemic conditions canceled the suppressive effect and restored Mmp9 expression induced by TNF-α plus CaPO4. Moreover, Nr1h2 activation with GW3965 significantly suppressed CaPO4-induced aneurysm in mice compared with vehicle-injected control mice. Our results show that hyperglycemia suppresses macrophage activation and aneurysmal degeneration through the activation of Nr1h2. Although further validation of the underlying pathway is necessary, targeting Nr1h2 is a potential therapeutic approach to treating aneurysm. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  19. Mechanism and evidence of nonsense suppression therapy for genetic eye disorders.

    PubMed

    Richardson, Rose; Smart, Matthew; Tracey-White, Dhani; Webster, Andrew R; Moosajee, Mariya

    2017-02-01

    Between 5 and 70% of genetic disease is caused by in-frame nonsense mutations, which introduce a premature termination codon (PTC) within the disease-causing gene. Consequently, during translation, non-functional or gain-of-function truncated proteins of pathological significance, are formed. Approximately 50% of all inherited retinal disorders have been associated with PTCs, highlighting the importance of novel pharmacological or gene correction therapies in ocular disease. Pharmacological nonsense suppression of PTCs could delineate a therapeutic strategy that treats the mutation in a gene- and disease-independent manner. This approach aims to suppress the fidelity of the ribosome during protein synthesis so that a near-cognate aminoacyl-tRNA, which shares two of the three nucleotides of the PTC, can be inserted into the peptide chain, allowing translation to continue, and a full-length functional protein to be produced. Here we discuss the mechanisms and evidence of nonsense suppression agents, including the small molecule drug ataluren (or PTC124) and next generation 'designer' aminoglycosides, for the treatment of genetic eye disease. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Human Gut-Derived Commensal Bacteria Suppress CNS Inflammatory and Demyelinating Disease.

    PubMed

    Mangalam, Ashutosh; Shahi, Shailesh K; Luckey, David; Karau, Melissa; Marietta, Eric; Luo, Ningling; Choung, Rok Seon; Ju, Josephine; Sompallae, Ramakrishna; Gibson-Corley, Katherine; Patel, Robin; Rodriguez, Moses; David, Chella; Taneja, Veena; Murray, Joseph

    2017-08-08

    The human gut is colonized by a large number of microorganisms (∼10 13 bacteria) that support various physiologic functions. A perturbation in the healthy gut microbiome might lead to the development of inflammatory diseases, such as multiple sclerosis (MS). Therefore, gut commensals might provide promising therapeutic options for treating MS and other diseases. We report the identification of human gut-derived commensal bacteria, Prevotella histicola, which can suppress experimental autoimmune encephalomyelitis (EAE) in a human leukocyte antigen (HLA) class II transgenic mouse model. P. histicola suppresses disease through the modulation of systemic immune responses. P. histicola challenge led to a decrease in pro-inflammatory Th1 and Th17 cells and an increase in the frequencies of CD4 + FoxP3 + regulatory T cells, tolerogenic dendritic cells, and suppressive macrophages. Our study provides evidence that the administration of gut commensals may regulate a systemic immune response and may, therefore, have a possible role in treatment strategies for MS. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  1. Eckol suppresses maintenance of stemness and malignancies in glioma stem-like cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hyun, Kyung-Hwan; Yoon, Chang-Hwan; Kim, Rae-Kwon

    A subpopulation of cancer cells with stem cell properties is responsible for tumor maintenance and progression, and may contribute to resistance to anticancer treatments. Thus, compounds that target cancer stem-like cells could be usefully applied to destroy cancer. In this study, we investigated the effect of Eckol, a phlorotannin compound, on stemness and malignancies in glioma stem-like cells. To determine whether Eckol targets glioma stem-like cells, we examined whether Eckol treatment could change the expression levels of glioma stem-like cell markers and self-renewal-related proteins as well as the sphere forming ability, and the sensitivity to anticancer treatments. Alterations in themore » malignant properties of sphere-derived cells by Eckol were also investigated by soft-agar colony forming assay, by xenograft assay in nude mice, and by cell invasion assay. Treatment of sphere-forming glioma cells with Eckol effectively decreased the sphere formation as well as the CD133{sup +} cell population. Eckol treatment suppressed expression of the glioma stem-like cell markers and the self-renewal-related proteins without cell death. Moreover, treatment of glioma stem-like cells with Eckol significantly attenuated anchorage-independent growth on soft agar and tumor formation in xenograft mice. Importantly, Eckol treatment effectively reduced the resistance of glioma stem-like cells to ionizing radiation and temozolomide. Treatment of glioma stem-like cells with Eckol markedly blocked both phosphoinositide 3-kinase-Akt and Ras-Raf-1-Erk signaling pathways. These results indicate that the natural phlorotannin Eckol suppresses stemness and malignancies in glioma stem-like cells, and thereby makes glioma stem-like cells more sensitive to anticancer treatments, providing novel therapeutic strategies targeting specifically cancer stem-like cells.« less

  2. Time from HIV infection to virological suppression: dramatic fall from 2007 to 2016.

    PubMed

    Medland, Nicholas A; Nicholson, Suellen; Chow, Eric P F; Read, Timothy R H; Bradshaw, Catriona S; Denham, Ian; Fairley, Christopher K

    2017-11-13

    Time from HIV infection to virological suppression: dramatic fall from 2007 to 2016. We examined the time from HIV infection to virological suppression in MSM who were first diagnosed at Melbourne Sexual Health Centre between 2007 and 2016. Retrospective cohort. Date of infection was imputed from the testing history or serological evidence of recent infection (negative or indeterminate western blot) or baseline CD4 cell count. Date of virological suppression was determined using clinical viral load data. We analysed predictors of diagnosis with serological evidence of recent infection (logistic regression) and time from diagnosis to suppression and from infection to suppression (Cox regression) using demographic, clinical, and behavioral covariates. Between 2007 and 2016, the median time from HIV infection to diagnosis fell from 6.8 to 4.3 months (P = 0.001), from diagnosis to suppression fell from 22.7 to 3.2 months (P < 0.0001), and from infection to suppression fell from 49.0 to 9.6 months (P < 0.0001). Serological evidence of recent infection increased from 15.6 to 34.3% (P < 0.0001) of diagnoses. In the multivariate analyses, age, being recently arrived from a non-English speaking country, history of IDU, other sexually transmitted infections, and sexual risk were not associated with any of these measures. The duration of infectiousness in MSM diagnosed with HIV infection at Melbourne Sexual Health Centre in Victoria has fallen dramatically between 2007 and 2016 and the proportion diagnosed with serological evidence of recent infection has increased. This effect is observed across all population subgroups and marks a positive milestone for the treatment as prevention paradigm.

  3. DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lee, H.B.; Wexler, J.P.; Scharf, S.C.

    The effect of two antihypertensive agents (captopril and prazosin) and of digoxin on the efficiency of Tc-99m binding to RBCs was evaluated in the rat. RBCs were labeled with Tc-99m in vivo in six groups of rats: I-normotensive controls Wistar rat (WR), II-prazosin treated WR, III-spontaneously hypertensive rat (SHR), IV-prazosin-treated SHR, V-digoxin-treated WR, and VI-captopril-treated WR. The percentage of intravascular Tc-99m bound to RBC (%T) and the percentage of injected dose remaining intravascular 5 min after injection (%i.v.) were determined. Mean %T was 94.2, 83.8, 94.9, 86.1, 79.7, and 93.3 for groups I-VI respectively. Mean %I.V. was 96.4, 74.6, 94.9,more » 79.0, 74.4, and 87.4 for groups I-VI respectively. The findings demonstrate a significant reduction of RBC tagging with Tc-99m in rats treated with prazosin and digoxin but not with captopril. The data suggest a potential interference by patient medication with the performance of blood-pool studies.« less

  4. Choline attenuates immune inflammation and suppresses oxidative stress in patients with asthma.

    PubMed

    Mehta, Amit K; Singh, Bhanu P; Arora, Naveen; Gaur, Shailendra N

    2010-07-01

    Asthma is a chronic immune inflammatory disease characterized by variable airflow obstruction and increased bronchial hyperreactivity (BHR). Therapeutic interventions reduce airway inflammation and relieve symptoms but associated with potential side effects that limit their usefulness. The present study was undertaken to assess the effect of choline on immune inflammation and BHR in asthma subjects. The patients of asthma (n=76) were recruited and treated with choline supplement (1500 mg twice) or standard pharmacotherapy for 6 months in two groups. The patients were evaluated by clinical, immunologic and biochemical parameters. The treatment with choline showed significant reduction in symptom/drug score and improvement in PC(20) FEV1 compared to baseline or standard pharmacotherapy (p<0.01). Choline therapy significantly reduced IL-4, IL-5 and TNF-alpha level as compared to baseline or standard pharmacotherapy after 6 months (p<0.01). Blood eosinophil count and total IgE levels were reduced in both the treatment groups. Cysteinyl leukotriene and leukotriene B4 were suppressed significantly by choline treatment (p<0.01). This was accompanied by decreased 8-isoprostanes, a biomarker for oxidative stress after choline treatment (p<0.01). Choline therapy modulates immune inflammation and suppresses oxidative stress in asthma patients. It can be used as an adjunct therapy for asthma patients. Copyright 2009 Elsevier GmbH. All rights reserved.

  5. Mast cells mediate the immune suppression induced by dermal exposure to JP-8 jet fuel.

    PubMed

    Limón-Flores, Alberto Y; Chacón-Salinas, Rommel; Ramos, Gerardo; Ullrich, Stephen E

    2009-11-01

    Applying jet propulsion-8 (JP-8) jet fuel to the skin of mice induces immune suppression. Applying JP-8 to the skin of mice suppresses T-cell-mediated immune reactions including, contact hypersensitivity (CHS) delayed-type hypersensitivity and T-cell proliferation. Because dermal mast cells play an important immune regulatory role in vivo, we tested the hypothesis that mast cells mediate jet fuel-induced immune suppression. When we applied JP-8 to the skin of mast cell deficient mice CHS was not suppressed. Reconstituting mast cell deficient mice with wild-type bone marrow derived mast cells (mast cell "knock-in mice") restored JP-8-induced immune suppression. When, however, mast cells from prostaglandin E(2) (PGE(2))-deficient mice were used, the ability of JP-8 to suppress CHS was not restored, indicating that mast cell-derived PGE(2) was activating immune suppression. Examining the density of mast cells in the skin and lymph nodes of JP-8-treated mice indicated that jet fuel treatment caused an initial increase in mast cell density in the skin, followed by increased numbers of mast cells in the subcutaneous space and then in draining lymph nodes. Applying JP-8 to the skin increased mast cell expression of CXCR4, and increased the expression of CXCL12 by draining lymph node cells. Because CXCL12 is a chemoattractant for CXCR4+ mast cells, we treated JP-8-treated mice with AMD3100, a CXCR4 antagonist. AMD3100 blocked the mobilization of mast cells to the draining lymph node and inhibited JP-8-induced immune suppression. Our findings demonstrate the importance of mast cells in mediating jet fuel-induced immune suppression.

  6. SIRT1 Suppresses Human T-Cell Leukemia Virus Type 1 Transcription

    PubMed Central

    Tang, Hei-Man Vincent; Gao, Wei-Wei; Chan, Chi-Ping; Cheng, Yun; Deng, Jian-Jun; Yuen, Kit-San; Iha, Hidekatsu

    2015-01-01

    ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1)-associated diseases are poorly treatable, and HTLV-1 vaccines are not available. High proviral load is one major risk factor for disease development. HTLV-1 encodes Tax oncoprotein, which activates transcription from viral long terminal repeats (LTR) and various types of cellular promoters. Counteracting Tax function might have prophylactic and therapeutic benefits. In this work, we report on the suppression of Tax activation of HTLV-1 LTR by SIRT1 deacetylase. The transcriptional activity of Tax on the LTR was largely ablated when SIRT1 was overexpressed, but Tax activation of NF-κB was unaffected. On the contrary, the activation of the LTR by Tax was boosted when SIRT1 was depleted. Treatment of cells with resveratrol shunted Tax activity in a SIRT1-dependent manner. The activation of SIRT1 in HTLV-1-transformed T cells by resveratrol potently inhibited HTLV-1 proviral transcription and Tax expression, whereas compromising SIRT1 by specific inhibitors augmented HTLV-1 mRNA expression. The administration of resveratrol also decreased the production of cell-free HTLV-1 virions from MT2 cells and the transmission of HTLV-1 from MT2 cells to uninfected Jurkat cells in coculture. SIRT1 associated with Tax in HTLV-1-transformed T cells. Treatment with resveratrol prevented the interaction of Tax with CREB and the recruitment of CREB, CRTC1, and p300 to Tax-responsive elements in the LTR. Our work demonstrates the negative regulatory function of SIRT1 in Tax activation of HTLV-1 transcription. Small-molecule activators of SIRT1 such as resveratrol might be considered new prophylactic and therapeutic agents in HTLV-1-associated diseases. IMPORTANCE Human T-cell leukemia virus type 1 (HTLV-1) causes a highly lethal blood cancer or a chronic debilitating disease of the spinal cord. Treatments are unsatisfactory, and vaccines are not available. Disease progression is associated with robust expression of HTLV-1 genes

  7. Statins suppress apolipoprotein CIII-induced vascular endothelial cell activation and monocyte adhesion.

    PubMed

    Zheng, Chunyu; Azcutia, Veronica; Aikawa, Elena; Figueiredo, Jose-Luiz; Croce, Kevin; Sonoki, Hiroyuki; Sacks, Frank M; Luscinskas, Francis W; Aikawa, Masanori

    2013-02-01

    Activation of vascular endothelial cells (ECs) contributes importantly to inflammation and atherogenesis. We previously reported that apolipoprotein CIII (apoCIII), found abundantly on circulating triglyceride-rich lipoproteins, enhances adhesion of human monocytes to ECs in vitro. Statins may exert lipid-independent anti-inflammatory effects. The present study examined whether statins suppress apoCIII-induced EC activation in vitro and in vivo. Physiologically relevant concentrations of purified human apoCIII enhanced attachment of the monocyte-like cell line THP-1 to human saphenous vein ECs (HSVECs) or human coronary artery ECs (HCAECs) under both static and laminar shear stress conditions. This process mainly depends on vascular cell adhesion molecule-1 (VCAM-1), as a blocking VCAM-1 antibody abolished apoCIII-induced monocyte adhesion. ApoCIII significantly increased VCAM-1 expression in HSVECs and HCAECs. Pre-treatment with statins suppressed apoCIII-induced VCAM-1 expression and monocyte adhesion, with two lipophilic statins (pitavastatin and atorvastatin) exhibiting inhibitory effects at lower concentration than those of hydrophilic pravastatin. Nuclear factor κB (NF-κB) mediated apoCIII-induced VCAM-1 expression, as demonstrated via loss-of-function experiments, and pitavastatin treatment suppressed NF-κB activation. Furthermore, in the aorta of hypercholesterolaemic Ldlr(-/-) mice, pitavastatin administration in vivo suppressed VCAM-1 mRNA and protein, induced by apoCIII bolus injection. Similarly, in a subcutaneous dorsal air pouch mouse model of leucocyte recruitment, apoCIII injection induced F4/80+ monocyte and macrophage accumulation, whereas pitavastatin administration reduced this effect. These findings further establish the direct role of apoCIII in atherogenesis and suggest that anti-inflammatory effects of statins could improve vascular disease in the population with elevated plasma apoCIII.

  8. Suppressive effect of delta 9-tetrahydrocannabinol in vitro on phagocytosis by murine macrophages.

    PubMed

    Friedman, M; Cepero, M L; Klein, T; Friedman, H

    1986-06-01

    Incubation of normal mouse peritoneal cells consisting of over 90% phagocytizing macrophages with delta 9-tetrahydrocannabinol (THC) resulted in a inhibition of phagocytic function. The THC in a dose-related manner suppressed the percentage of macrophages per culture which ingested yeast and the average number of yeast particles ingested by the phagocytizing macrophages. The vehicle used to suspend the THC in vitro, i.e., DMSO, had no detectable effect on macrophage function. Suppression of phagocytosis with no effects on viability or cell number occurred with doses of 10 micrograms or less THC per milliliter culture medium. Measurable suppression also occurred after 24- to 48-hr treatment of the macrophages with the THC. This compound had little if any detectable effect on phagocytosis when added directly to the cultures shortly before testing for phagocytosis. Further studies concerning the effects of THC on macrophage function appear warranted.

  9. Acupuncture suppresses intravenous methamphetamine self-administration through GABA receptor's mediation.

    PubMed

    Choi, Yi Jeong; Kim, Nam Jun; Zhao, Rong Jie; Kim, Da Hye; Yang, Chae Ha; Kim, Hee Young; Gwak, Young S; Jang, Eun Young; Kim, Jae Su; Lee, Yun Kyu; Lee, Hyun Jong; Lee, Sang Nam; Lim, Sung Chul; Lee, Bong Hyo

    2018-01-01

    Methamphetamine is one of the widely abused drugs. In spite of a number of studies, there is still little successful therapy to suppress the methamphetamine abuse. Acupuncture has shown to attenuate the reinforcing effects of psychostimulant. Based on, the present study investigated if acupuncture could suppress intravenous methamphetamine self-administration behavior. In addition, a possible neuronal mechanism was investigated. Male Sprague-Dawley rats weighing 270-300g were trained to intake food pellet. After catheter implantation, animal was trained to self-administer methamphetamine (0.05mg/kg) intravenously using fixed ratio 1 schedule in daily 2h session during 3 weeks. After training, rats who established baseline (infusion variation less than 20% of the mean for 3 consecutive days) received acupuncture treatment on the next day. Acupuncture was performed at each acupoint manually. In the second experiment, the selective antagonists of GABA A or GABA B receptor were given before acupuncture to investigate the possible neuronal involvement of GABA receptor pathway in the acupuncture effects. C-Fos expression was examined in the nucleus accumbens to support behavioral data. Acupuncture at HT7, but not at control acupoint LI5, reduced the self-administration behavior significantly. Also, the effects of acupuncture were blocked by the GABA receptor antagonists. C-Fos expression was shown to be parallel with the behavioral data. Results of this study have shown that acupuncture at HT7 suppressed methamphetamine self-administration through GABA receptor system, suggesting that acupuncture at HT7 can be a useful therapy for the treatment of methamphetamine abuse. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Online Adaptive Hyperthermia Treatment Planning During Locoregional Heating to Suppress Treatment-Limiting Hot Spots.

    PubMed

    Kok, H Petra; Korshuize-van Straten, Linda; Bakker, Akke; de Kroon-Oldenhof, Rianne; Geijsen, Elisabeth D; Stalpers, Lukas J A; Crezee, Johannes

    2017-11-15

    Adequate tumor temperatures during hyperthermia are essential for good clinical response, but excessive heating of normal tissue should be avoided. This makes locoregional heating using phased array systems technically challenging. Online application of hyperthermia treatment planning could help to improve the heating quality. The aim of this study was to evaluate the clinical benefit of online treatment planning during treatment of pelvic tumors heated with the AMC-8 locoregional hyperthermia system. For online adaptive hyperthermia treatment planning, a graphical user interface was developed. Electric fields were calculated in a preprocessing step using our in-house-developed finite-difference-based treatment planning system. This allows instant calculation of the temperature distribution for user-selected phase-amplitude settings during treatment and projection onto the patient's computed tomographic scan for online visualization. Online treatment planning was used for 14 treatment sessions in 8 patients to reduce the patients' reports of hot spots while maintaining the same level of tumor heating. The predicted decrease in hot spot temperature should be at least 0.5°C, and the tumor temperature should decrease less than 0.2°C. These predictions were compared with clinical data: patient feedback about the hot spot and temperature measurements in the tumor region. In total, 17 hot spot reports occurred during the 14 sessions, and the alternative settings predicted the hot spot temperature to decrease by at least 0.5°C, which was confirmed by the disappearance of all 17 hot spot reports. At the same time, the average tumor temperature was predicted to change on average -0.01°C (range, -0.19°C to 0.34°C). The measured tumor temperature change was on average only -0.02°C (range, -0.26°C to 0.31°C). In only 2 cases the temperature decrease was slightly larger than 0.2°C, but at most it was 0.26°C. Online application of hyperthermia treatment planning is

  11. Antidepressant suppression of non-REM sleep spindles and REM sleep impairs hippocampus-dependent learning while augmenting striatum-dependent learning.

    PubMed

    Watts, Alain; Gritton, Howard J; Sweigart, Jamie; Poe, Gina R

    2012-09-26

    Rapid eye movement (REM) sleep enhances hippocampus-dependent associative memory, but REM deprivation has little impact on striatum-dependent procedural learning. Antidepressant medications are known to inhibit REM sleep, but it is not well understood if antidepressant treatments impact learning and memory. We explored antidepressant REM suppression effects on learning by training animals daily on a spatial task under familiar and novel conditions, followed by training on a procedural memory task. Daily treatment with the antidepressant and norepinephrine reuptake inhibitor desipramine (DMI) strongly suppressed REM sleep in rats for several hours, as has been described in humans. We also found that DMI treatment reduced the spindle-rich transition-to-REM sleep state (TR), which has not been previously reported. DMI REM suppression gradually weakened performance on a once familiar hippocampus-dependent maze (reconsolidation error). DMI also impaired learning of the novel maze (consolidation error). Unexpectedly, learning of novel reward positions and memory of familiar positions were equally and oppositely correlated with amounts of TR sleep. Conversely, DMI treatment enhanced performance on a separate striatum-dependent, procedural T-maze task that was positively correlated with the amounts of slow-wave sleep (SWS). Our results suggest that learning strategy switches in patients taking REM sleep-suppressing antidepressants might serve to offset sleep-dependent hippocampal impairments to partially preserve performance. State-performance correlations support a model wherein reconsolidation of hippocampus-dependent familiar memories occurs during REM sleep, novel information is incorporated and consolidated during TR, and dorsal striatum-dependent procedural learning is augmented during SWS.

  12. Antidepressant Suppression of Non-REM Sleep Spindles and REM Sleep Impairs Hippocampus-Dependent Learning While Augmenting Striatum-Dependent Learning

    PubMed Central

    Watts, Alain; Gritton, Howard J.; Sweigart, Jamie

    2012-01-01

    Rapid eye movement (REM) sleep enhances hippocampus-dependent associative memory, but REM deprivation has little impact on striatum-dependent procedural learning. Antidepressant medications are known to inhibit REM sleep, but it is not well understood if antidepressant treatments impact learning and memory. We explored antidepressant REM suppression effects on learning by training animals daily on a spatial task under familiar and novel conditions, followed by training on a procedural memory task. Daily treatment with the antidepressant and norepinephrine reuptake inhibitor desipramine (DMI) strongly suppressed REM sleep in rats for several hours, as has been described in humans. We also found that DMI treatment reduced the spindle-rich transition-to-REM sleep state (TR), which has not been previously reported. DMI REM suppression gradually weakened performance on a once familiar hippocampus-dependent maze (reconsolidation error). DMI also impaired learning of the novel maze (consolidation error). Unexpectedly, learning of novel reward positions and memory of familiar positions were equally and oppositely correlated with amounts of TR sleep. Conversely, DMI treatment enhanced performance on a separate striatum-dependent, procedural T-maze task that was positively correlated with the amounts of slow-wave sleep (SWS). Our results suggest that learning strategy switches in patients taking REM sleep-suppressing antidepressants might serve to offset sleep-dependent hippocampal impairments to partially preserve performance. State–performance correlations support a model wherein reconsolidation of hippocampus-dependent familiar memories occurs during REM sleep, novel information is incorporated and consolidated during TR, and dorsal striatum-dependent procedural learning is augmented during SWS. PMID:23015432

  13. Choline+ is a low-affinity ligand for alpha 1-adrenoceptors.

    PubMed

    Unelius, L; Cannon, B; Nedergaard, J

    1994-10-07

    The effect of choline+, a commonly used Na+ substitute, on ligand binding to alpha 1-adrenoceptors was investigated. It was found that replacement of 25% of the Na+ in a Krebs-Ringer bicarbonate buffer with choline+ led to a 3-fold decrease in the apparent affinity of [3H]prazosin for its binding site (i.e. the alpha 1-receptor) in a membrane preparation from brown adipose tissue, while no decrease in the total number of binding sites was observed. Similar effects were seen in membrane preparations from liver and brain. In competition experiments, it was found that choline+ could inhibit [3H]prazosin binding; from the inhibition curve, an affinity (Ki) of 31 mM choline+ for the [3H]prazosin-binding site could be calculated. In fully choline(+)-substituted buffers, where the level of [3H]prazosin binding was substantially reduced, both phentolamine and norepinephrine could still compete with [3H]prazosin for its binding site, with virtually unaltered affinity; thus choline+ did not substantially affect the characteristics of those receptors to which it did not bind. Choline+ did not affect the binding characteristics of the beta 1/beta 2 radioligand [3H]CGP-12177; thus, the effect on alpha 1-receptors was not due to general, unspecific effects on the membrane preparations. It is concluded that choline+ possesses characteristics similar to those of a competitive ligand for the alpha 1-adrenoceptor; it has a low affinity but the competitive type of interaction of choline may nonetheless under experimental conditions interfere with agonist interaction with the alpha 1-receptor.

  14. Novel Combined Ato-C Treatment Synergistically Suppresses Proliferation of Bcr-Abl-Positive Leukemic Cells In Vitro and In Vivo.

    PubMed

    Wahiduzzaman, Md; Ota, Akinobu; Karnan, Sivasundaram; Hanamura, Ichiro; Mizuno, Shohei; Kanasugi, Jo; Rahman, Md Lutfur; Hyodo, Toshinori; Konishi, Hiroyuki; Tsuzuki, Shinobu; Takami, Akiyoshi; Hosokawa, Yoshitaka

    2018-06-23

    Chronic myelogenous leukemia (CML) accounts for 15-20% of all leukemias affecting adults. Despite recent advances in the development of specific Bcr-Abl tyrosine kinase inhibitors (TKIs), some CML patients suffer from relapse due to TKI resistance. Here, we assessed the efficacy of a novel combinatorial arsenic trioxide (ATO) and cisplatin (CDDP) treatment (Ato-C) in human Bcr-Abl-positive leukemic cells. Combination index analyses revealed that a synergistic interaction of ATO and CDDP elicits a wide range of effects in K562, KU-812, MEG-A2, and KCL-22 cells. Notably, Ato-C synergistically enhanced apoptosis and decreased the survival of both acquired TKI-resistant CML cells and the cells expressing mutant Bcr-Abl T315I . In addition, Ato-C dramatically decreased the phosphorylation level of forkhead transcription factor FOXO1/3a and STAT5 as well as c-Myc protein level. Interestingly, results of gene set enrichment analysis showed that Ato-C significantly downregulates the expression of MYC- and/or E2F1-targets genes. Furthermore, Ato-C significantly suppressed the proliferation of MEG-A2-derived tumor when compared with that following monotherapy in vivo. Collectively, these results suggest that combined Ato-C treatment could be a promising alternative to the current therapeutic regime in CML. Copyright © 2018. Published by Elsevier B.V.

  15. Desipramine Inhibits Histamine H1 Receptor-Induced Ca2+ Signaling in Rat Hypothalamic Cells

    PubMed Central

    Lee, Kwang Min; Cho, Sukhee; Seo, Jinsoo; Hur, Eun-Mi; Park, Chul-Seung; Baik, Ja-Hyun; Choi, Se-Young

    2012-01-01

    The hypothalamus in the brain is the main center for appetite control and integrates signals from adipose tissue and the gastrointestinal tract. Antidepressants are known to modulate the activities of hypothalamic neurons and affect food intake, but the cellular and molecular mechanisms by which antidepressants modulate hypothalamic function remain unclear. Here we have investigated how hypothalamic neurons respond to treatment with antidepressants, including desipramine and sibutramine. In primary cultured rat hypothalamic cells, desipramine markedly suppressed the elevation of intracellular Ca2+ evoked by histamine H1 receptor activation. Desipramine also inhibited the histamine-induced Ca2+ increase and the expression of corticotrophin-releasing hormone in hypothalamic GT1-1 cells. The effect of desipramine was not affected by pretreatment with prazosin or propranolol, excluding catecholamine reuptake activity of desipramine as an underlying mechanism. Sibutramine which is also an antidepressant but decreases food intake, had little effect on the histamine-induced Ca2+ increase or AMP-activated protein kinase activity. Our results reveal that desipramine and sibutramine have different effects on histamine H1 receptor signaling in hypothalamic cells and suggest that distinct regulation of hypothalamic histamine signaling might underlie the differential regulation of food intake between antidepressants. PMID:22563449

  16. Immune suppression with supraoptimal doses of antigen in contact sensitivity. I. Demonstration of suppressor cells and their sensitivity to cyclophosphamide.

    PubMed

    Sy, M S; Miller, S D; Claman, H N

    1977-07-01

    Immunologic suppression was induced in a mouse model of contact sensitization to DNFB by using supraoptimal doses of antigen. In these studies, in vivo measurement of ear swelling as an indication of immunologic responsiveness correlated well with measurement of in vitro antigen-induced cell proliferation. This unresponsiveness was specific, since supraoptimal doses of DNFB did not interfere with the development of contact sensitivity to another contactant, oxazolone. The decrease in responsiveness is a form of active suppression, as lymphoid cells from supraoptimally sensitized donors transferred suppression to normal recipients. Furthermore, pretreatment with cyclophosphamide (Cy) reversed the suppression seen in supraoptimally sensitized animals but had no effect on the optimal sensitization regimen. These results indicate that supraoptimal doses of contactants can activate suppressor cells and that precursors of these cells are sensitive to Cy. Such suppressors regenerate within 7 to 14 days after Cy treatment. The ability of Cy pretreatment to affect supraoptimal sensitization without affecting optimal sensitization confirms other reports indicating that the observed results of Cy treatment depend critically upon the dose of antigen used.

  17. The role of thought suppression in the relation between mindfulness meditation and alcohol use

    PubMed Central

    Bowen, Sarah; Witkiewitz, Katie; Dillworth, Tiara M.; Marlatt, G. Alan

    2007-01-01

    Previous studies have demonstrated that attempts to suppress thoughts about using substances may actually lead to increases in substance use. Vipassana, a mindfulness meditation practice, emphasizes acceptance, rather than suppression, of unwanted thoughts. Bowen and colleagues (2006) studied the effects of a Vipassana course on substance use and in an incarcerated population, showing significant reductions in substance use among the Vipassana group as compared to a treatment as usual control condition (Bowen, Witkiewitz, Dillworth, Chawla, Simpson, Ostafin, et al., 2006). The current study further examines the mediating effects of thought suppression in the relationship between participation in the course and subsequent alcohol use in an incarcerated population. Those who participated in the course reported significant decreases in avoidance of thoughts when compared to controls. The decrease in avoidance partially mediated effects of the course on post-release alcohol use and consequences. PMID:17300875

  18. CAPE suppresses migration and invasion of prostate cancer cells via activation of non-canonical Wnt signaling.

    PubMed

    Tseng, Jen-Chih; Lin, Ching-Yu; Su, Liang-Chen; Fu, Hsiao-Hui; Yang, Shiaw-Der; Chuu, Chih-Pin

    2016-06-21

    Prostate cancer (PCa) was the fifth most common cancer overall in the world. More than 80% of patients died from PCa developed bone metastases. Caffeic acid phenethyl ester (CAPE) is a main bioactive component of honeybee hive propolis. Transwell and wound healing assays demonstrated that CAPE treatment suppressed the migration and invasion of PC-3 and DU-145 PCa cells. Gelatin zymography and Western blotting indicated that CAPE treatment reduced the abundance and activity of MMP-9 and MMP-2. Analysis using Micro-Western Array (MWA), a high-throughput antibody-based proteomics platform with 264 antibodies detecting signaling proteins involved in important pathways indicated that CAPE treatment induced receptor tyrosine kinase-like orphan receptor 2 (ROR2) in non-canonical Wnt signaling pathway but suppressed abundance of β-catenin, NF-κB activity, PI3K-Akt signaling, and epithelial-mesenchymal transition (EMT). Overexpression or knockdown of ROR2 suppressed or enhanced cell migration of PC-3 cells, respectively. TCF-LEF promoter binding assay revealed that CAPE treatment reduced canonical Wnt signaling. Intraperitoneal injection of CAPE reduced the metastasis of PC-3 xenografts in tail vein injection nude mice model. Immunohistochemical staining demonstrated that CAPE treatment increased abundance of ROR2 and Wnt5a but decreased protein expression of Ki67, Frizzle 4, NF-κB p65, MMP-9, Snail, β-catenin, and phosphorylation of IκBα. Clinical evidences suggested that genes affected by CAPE treatment (CTNNB1, RELA, FZD5, DVL3, MAPK9, SNAl1, ROR2, SMAD4, NFKBIA, DUSP6, and PLCB3) correlate with the aggressiveness of PCa. Our study suggested that CAPE may be a potential therapeutic agent for patients with advanced PCa.

  19. Intravesical application of rebamipide suppresses bladder inflammation in a rat cystitis model.

    PubMed

    Funahashi, Yasuhito; Yoshida, Masaki; Yamamoto, Tokunori; Majima, Tsuyoshi; Takai, Shun; Gotoh, Momokazu

    2014-04-01

    We examined the effects of intravesical application of rebamipide (Otsuka Pharmaceutical, Tokyo, Japan) on bladder inflammation and overactivity in a chemically induced cystitis model. Female Sprague Dawley® rats under isoflurane anesthesia were injected with 150 mg/kg cyclophosphamide in the peritoneum, and 1 mM or 10 mM rebamipide or vehicle was administered in the bladder and remained for 1 hour. Control rats were injected with saline in the peritoneum and vehicle was administered in the bladder. The bladder was harvested at 48 hours. Hematoxylin and eosin staining was performed and the inflammation grade was assessed. The amount of myeloperoxidase was measured using enzyme-linked immunosorbent assay. Proinflammatory cytokines were quantified using reverse transcriptase-polymerase chain reaction. Cystometrogram was done in awake rats 48 hours after cyclophosphamide treatment to measure voiding reflex parameters. Histological evaluation revealed that bladder inflammation in cyclophosphamide treated rats was suppressed by rebamipide in a dose dependent manner. Up-regulated myeloperoxidase, IL-1β, IL-6 and TNF-α expression in cyclophosphamide treated rats was also suppressed in rebamipide treated rats. Cystometrogram demonstrated that the intercontraction interval decreased in cyclophosphamide treated rats but was prolonged by rebamipide. Intravesical application of rebamipide suppressed bladder inflammation and overactivity in a dose dependent manner. This may provide a new treatment strategy for chemotherapy associated cystitis. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  20. Noise suppression in surface microseismic data

    USGS Publications Warehouse

    Forghani-Arani, Farnoush; Batzle, Mike; Behura, Jyoti; Willis, Mark; Haines, Seth S.; Davidson, Michael

    2012-01-01

    We introduce a passive noise suppression technique, based on the τ − p transform. In the τ − p domain, one can separate microseismic events from surface noise based on distinct characteristics that are not visible in the time-offset domain. By applying the inverse τ − p transform to the separated microseismic event, we suppress the surface noise in the data. Our technique significantly improves the signal-to-noise ratios of the microseismic events and is superior to existing techniques for passive noise suppression in the sense that it preserves the waveform. We introduce a passive noise suppression technique, based on the τ − p transform. In the τ − p domain, one can separate microseismic events from surface noise based on distinct characteristics that are not visible in the time-offset domain. By applying the inverse τ − p transform to the separated microseismic event, we suppress the surface noise in the data. Our technique significantly improves the signal-to-noise ratios of the microseismic events and is superior to existing techniques for passive noise suppression in the sense that it preserves the waveform.

  1. Lactobacillus gasseri OLL2809 and its RNA suppress proliferation of CD4(+) T cells through a MyD88-dependent signalling pathway.

    PubMed

    Yoshida, Ayako; Yamada, Kiyoshi; Yamazaki, Yasumasa; Sashihara, Toshihiro; Ikegami, Shuuji; Shimizu, Makoto; Totsuka, Mamoru

    2011-08-01

    Recent studies have shown that probiotics are beneficial in prevention and improvement of inflammatory diseases. Accumulating evidence indicates that probiotics can modulate immune cell responses, although the specific molecular mechanism by which probiotics work remains elusive. Because T cells express receptors for microbial components, we examined whether the probiotic strain Lactobacillus gasseri OLL2809 (LG2809) and its components regulate murine CD4(+) T-cell activation. LG2809, as well as two other Lactobacillus strains, inhibited proliferation of CD4(+) T cells; LG2809 had the strongest suppressive activity among them. RNA isolated from LG2809 was also shown to have suppressive activity. We observed this suppressive effect in the culture of CD4(+) T cells stimulated with anti-CD3/CD28 treatment, suggesting a direct effect on CD4(+) T cells. In contrast, the suppressive effect was not observed for CD4(+) T cells from myeloid differentiation primary response gene 88 (MyD88) protein-deficient mice, and was abrogated in the presence of an anti-oxidant reagent, N-acetyl-cysteine (NAC). These results demonstrate that the suppressive effect of LG2809 and its RNA occurred through a MyD88-dependent signalling pathway and suggest involvement of a reactive oxygen species-dependent mechanism. LG2809 RNA injected subcutaneously suppressed delayed-type-hypersensitivity response in DO11.10 mice, and the suppression was abrogated by treatment with NAC. Collectively, these results suggest that suppression of T-cell proliferation by RNA may be one of the mechanisms when a probiotic bacterial strain exerts suppressive effects on inflammatory responses. © 2011 The Authors. Immunology © 2011 Blackwell Publishing Ltd.

  2. Jasmonic acid-mediated defense suppresses brassinosteroid-mediated susceptibility to Rice black streaked dwarf virus infection in rice.

    PubMed

    He, Yuqing; Zhang, Hehong; Sun, Zongtao; Li, Junmin; Hong, Gaojie; Zhu, Qisong; Zhou, Xuebiao; MacFarlane, Stuart; Yan, Fei; Chen, Jianping

    2017-04-01

    Plant hormones play a vital role in plant immune responses. However, in contrast to the relative wealth of information on hormone-mediated immunity in dicot plants, little information is available on monocot-virus defense systems. We used a high-throughput-sequencing approach to compare the global gene expression of Rice black-streaked dwarf virus (RBSDV)-infected rice plants with that of healthy plants. Exogenous hormone applications and transgenic rice were used to test RBSDV infectivity and pathogenicity. Our results revealed that the jasmonic acid (JA) pathway was induced while the brassinosteroid (BR) pathway was suppressed in infected plants. Foliar application of methyl jasmonate (MeJA) or brassinazole (BRZ) resulted in a significant reduction in RBSDV incidence, while epibrassinolide (BL) treatment increased RBSDV infection. Infection studies using coi1-13 and Go mutants demonstrated JA-mediated resistance and BR-mediated susceptibility to RBSDV infection. A mixture of MeJA and BL treatment resulted in a significant reduction in RBSDV infection compared with a single BL treatment. MeJA application efficiently suppressed the expression of BR pathway genes, and this inhibition depended on the JA coreceptor OsCOI1. Collectively, our results reveal that JA-mediated defense can suppress the BR-mediated susceptibility to RBSDV infection. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

  3. 18β-glycyrrhetinic acid suppresses experimental autoimmune encephalomyelitis through inhibition of microglia activation and promotion of remyelination.

    PubMed

    Zhou, Jieru; Cai, Wei; Jin, Min; Xu, Jingwei; Wang, Yanan; Xiao, Yichuan; Hao, Li; Wang, Bei; Zhang, Yanyun; Han, Jie; Huang, Rui

    2015-09-02

    Microglia are intrinsic immune cells in the central nervous system (CNS). The under controlled microglia activation plays important roles in inflammatory demyelination diseases, such as multiple sclerosis (MS). However, the means to modulate microglia activation as a therapeutic modality and the underlying mechanisms remain elusive. Here we show that administration of 18β-glycyrrhetinic acid (GRA), by using both preventive and therapeutic treatment protocols, significantly suppresses disease severity of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. The treatment effect of GRA on EAE is attributed to its regulatory effect on microglia. GRA-modulated microglia significantly decreased pro-inflammatory profile in the CNS through suppression of MAPK signal pathway. The ameliorated CNS pro-inflammatory profile prevented the recruitment of encephalitogenic T cells into the CNS, which alleviated inflammation-induced demyelination. In addition, GRA treatment promoted remyelination in the CNS of EAE mice. The induced remyelination can be mediated by the overcome of inflammation-induced blockade of brain-derived neurotrophic factor expression in microglia, as well as enhancing oligodendrocyte precursor cell proliferation. Collectively, our results demonstrate that GRA-modulated microglia suppresses EAE through inhibiting microglia activation-mediated CNS inflammation, and promoting neuroprotective effect of microglia, which represents a potential therapeutic strategy for MS and maybe other neuroinflammatory diseases associated with microglia activation.

  4. Letrozole is superior to anastrozole in suppressing breast cancer tissue and plasma estrogen levels.

    PubMed

    Geisler, Jürgen; Helle, Hilgegunn; Ekse, Dagfinn; Duong, Nhat K; Evans, Dean B; Nordbø, Yngve; Aas, Turid; Lønning, Per E

    2008-10-01

    To evaluate the influence of the third-generation aromatase inhibitor letrozole (Femara) on breast cancer tissue levels of estrone (E(1)), estradiol (E(2)), and estrone sulfate (E(1)S) in postmenopausal women undergoing primary treatment for locally advanced estrogen receptor/progesterone receptor-positive breast cancers. Breast cancer tissue samples were collected before and following 4 months of neoadjuvant therapy with letrozole (2.5 mg o.d.), and tissue estrogen levels measured using a highly sensitive RIA after high-pressure liquid chromatography purification. Letrozole suppressed pretreatment tumor levels of E(2), E(1), and E(1)S by 97.6%, 90.7%, and 90.1%, respectively. These data reveal that letrozole suppresses tissue estrogen levels significantly below what has previously been recorded with anastrozole (89.0%, 83.4%, and 72.9% suppression, respectively) using the same methods. To confirm the differential effect of letrozole and anastrozole on each plasma estrogen fraction, we re-analyzed plasma samples obtained from a previous intrapatient cross-over study comparing letrozole and anastrozole using an improved RIA (detection limits of 0.67, 1.14, and 0.55 pmol/L for E(2), E(1), and E(1)S, respectively). Letrozole consistently suppressed each plasma estrogen fraction below the levels recorded for anastrozole: E(2) (average suppression by 95.2% versus 92.8%; P = 0.018), E(1) (98.8% suppression versus 96.3%; P = 0.003), and E(1)S (98.9% suppression versus 95.3%; P = 0.003). Our data reveals that letrozole (2.5 mg o.d.) is more effective compared with anastrozole (1.0 mg o.d.) with respect to tissue as well as plasma estrogen suppression in patients with postmenopausal breast cancer.

  5. Deconstructing Interocular Suppression: Attention and Divisive Normalization.

    PubMed

    Li, Hsin-Hung; Carrasco, Marisa; Heeger, David J

    2015-10-01

    In interocular suppression, a suprathreshold monocular target can be rendered invisible by a salient competitor stimulus presented in the other eye. Despite decades of research on interocular suppression and related phenomena (e.g., binocular rivalry, flash suppression, continuous flash suppression), the neural processing underlying interocular suppression is still unknown. We developed and tested a computational model of interocular suppression. The model included two processes that contributed to the strength of interocular suppression: divisive normalization and attentional modulation. According to the model, the salient competitor induced a stimulus-driven attentional modulation selective for the location and orientation of the competitor, thereby increasing the gain of neural responses to the competitor and reducing the gain of neural responses to the target. Additional suppression was induced by divisive normalization in the model, similar to other forms of visual masking. To test the model, we conducted psychophysics experiments in which both the size and the eye-of-origin of the competitor were manipulated. For small and medium competitors, behavioral performance was consonant with a change in the response gain of neurons that responded to the target. But large competitors induced a contrast-gain change, even when the competitor was split between the two eyes. The model correctly predicted these results and outperformed an alternative model in which the attentional modulation was eye specific. We conclude that both stimulus-driven attention (selective for location and feature) and divisive normalization contribute to interocular suppression.

  6. Deconstructing Interocular Suppression: Attention and Divisive Normalization

    PubMed Central

    Li, Hsin-Hung; Carrasco, Marisa; Heeger, David J.

    2015-01-01

    In interocular suppression, a suprathreshold monocular target can be rendered invisible by a salient competitor stimulus presented in the other eye. Despite decades of research on interocular suppression and related phenomena (e.g., binocular rivalry, flash suppression, continuous flash suppression), the neural processing underlying interocular suppression is still unknown. We developed and tested a computational model of interocular suppression. The model included two processes that contributed to the strength of interocular suppression: divisive normalization and attentional modulation. According to the model, the salient competitor induced a stimulus-driven attentional modulation selective for the location and orientation of the competitor, thereby increasing the gain of neural responses to the competitor and reducing the gain of neural responses to the target. Additional suppression was induced by divisive normalization in the model, similar to other forms of visual masking. To test the model, we conducted psychophysics experiments in which both the size and the eye-of-origin of the competitor were manipulated. For small and medium competitors, behavioral performance was consonant with a change in the response gain of neurons that responded to the target. But large competitors induced a contrast-gain change, even when the competitor was split between the two eyes. The model correctly predicted these results and outperformed an alternative model in which the attentional modulation was eye specific. We conclude that both stimulus-driven attention (selective for location and feature) and divisive normalization contribute to interocular suppression. PMID:26517321

  7. Psychopathology and Thought Suppression: A Quantitative Review

    PubMed Central

    Magee, Joshua C.; Harden, K. Paige; Teachman, Bethany A.

    2012-01-01

    Recent theories of psychopathology have suggested that thought suppression intensifies the persistence of intrusive thoughts, and proposed that difficulty with thought suppression may differ between groups with and without psychopathology. The current meta-analytic review evaluates empirical evidence for difficulty with thought suppression as a function of the presence and specific type of psychopathology. Based on theoretical proposals from the psychopathology literature, diagnosed and analogue samples were expected to show greater recurrence of intrusive thoughts during thought suppression attempts than non-clinical samples. However, results showed no overall differences in the recurrence of thoughts due to thought suppression between groups with and without psychopathology. There was, nevertheless, variation in the recurrence of thoughts across different forms of psychopathology, including relatively less recurrence during thought suppression for samples with symptoms of Obsessive-Compulsive Disorder, compared to non-clinical samples. However, these differences were typically small and provided only mixed support for existing theories. Implications for cognitive theories of intrusive thoughts are discussed, including proposed mechanisms underlying thought suppression. PMID:22388007

  8. Acoustic Suppression Systems and Related Methods

    NASA Technical Reports Server (NTRS)

    Kolaini, Ali R. (Inventor); Kern, Dennis L. (Inventor)

    2013-01-01

    An acoustic suppression system for absorbing and/or scattering acoustic energy comprising a plurality of acoustic targets in a containment is described, the acoustic targets configured to have resonance frequencies allowing the targets to be excited by incoming acoustic waves, the resonance frequencies being adjustable to suppress acoustic energy in a set frequency range. Methods for fabricating and implementing the acoustic suppression system are also provided.

  9. Mast Cells Mediate the Immune Suppression Induced by Dermal Exposure to JP-8 Jet Fuel

    PubMed Central

    Limón-Flores, Alberto Y.; Chacón-Salinas, Rommel; Ramos, Gerardo; Ullrich, Stephen E.

    2009-01-01

    Applying jet propulsion-8 (JP-8) jet fuel to the skin of mice induces immune suppression. Applying JP-8 to the skin of mice suppresses T-cell–mediated immune reactions including, contact hypersensitivity (CHS) delayed-type hypersensitivity and T-cell proliferation. Because dermal mast cells play an important immune regulatory role in vivo, we tested the hypothesis that mast cells mediate jet fuel–induced immune suppression. When we applied JP-8 to the skin of mast cell deficient mice CHS was not suppressed. Reconstituting mast cell deficient mice with wild-type bone marrow derived mast cells (mast cell “knock-in mice”) restored JP-8–induced immune suppression. When, however, mast cells from prostaglandin E2 (PGE2)–deficient mice were used, the ability of JP-8 to suppress CHS was not restored, indicating that mast cell–derived PGE2 was activating immune suppression. Examining the density of mast cells in the skin and lymph nodes of JP-8-treated mice indicated that jet fuel treatment caused an initial increase in mast cell density in the skin, followed by increased numbers of mast cells in the subcutaneous space and then in draining lymph nodes. Applying JP-8 to the skin increased mast cell expression of CXCR4, and increased the expression of CXCL12 by draining lymph node cells. Because CXCL12 is a chemoattractant for CXCR4+ mast cells, we treated JP-8-treated mice with AMD3100, a CXCR4 antagonist. AMD3100 blocked the mobilization of mast cells to the draining lymph node and inhibited JP-8–induced immune suppression. Our findings demonstrate the importance of mast cells in mediating jet fuel–induced immune suppression. PMID:19726579

  10. Exogenous regucalcin suppresses the growth of human liver cancer HepG2 cells in vitro.

    PubMed

    Yamaguchi, Masayoshi; Murata, Tomiyasu

    2018-04-05

    Regucalcin, which its gene is localized on the X chromosome, plays a pivotal role as a suppressor protein in signal transduction in various types of cells and tissues. Regucalcin gene expression has been demonstrated to be suppressed in various tumor tissues of animal and human subjects, suggesting a potential role of regucalcin in carcinogenesis. Regucalcin, which is produced from the tissues including liver, is found to be present in the serum of human subjects and animals. This study was undertaken to determine the effects of exogenous regucalcin on the proliferation in cloned human hepatoma HepG2 cells in vitro. Proliferation of HepG2 cells was suppressed after culture with addition of regucalcin (0.01 – 10 nM) into culture medium. Exogenous regucalcin did not reveal apoptotic cell death in HepG2 cells in vitro. Suppressive effects of regucalcin on cell proliferation were not enhanced in the presence of various signaling inhibitors including tumor necrosis factor-α (TNF-α), Bay K 8644, PD98059, staurosporine, worthomannin, 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) or gemcitabine, which were found to suppress the proliferation. In addition, exogenous regucalcin suppressed the formation of colonies of cultured hepatoma cells in vitro. These findings demonstrated that exogenous regucalcin exhibits a suppressive effect on the growth of human hepatoma HepG2 cells, proposing a strategy with the gene therapy for cancer treatment.

  11. Suppression effects in feature-based attention

    PubMed Central

    Wang, Yixue; Miller, James; Liu, Taosheng

    2015-01-01

    Attending to a feature enhances visual processing of that feature, but it is less clear what occurs to unattended features. Single-unit recording studies in middle temporal (MT) have shown that neuronal modulation is a monotonic function of the difference between the attended and neuron's preferred direction. Such a relationship should predict a monotonic suppressive effect in psychophysical performance. However, past research on suppressive effects of feature-based attention has remained inconclusive. We investigated the suppressive effect for motion direction, orientation, and color in three experiments. We asked participants to detect a weak signal among noise and provided a partially valid feature cue to manipulate attention. We measured performance as a function of the offset between the cued and signal feature. We also included neutral trials where no feature cues were presented to provide a baseline measure of performance. Across three experiments, we consistently observed enhancement effects when the target feature and cued feature coincided and suppression effects when the target feature deviated from the cued feature. The exact profile of suppression was different across feature dimensions: Whereas the profile for direction exhibited a “rebound” effect, the profiles for orientation and color were monotonic. These results demonstrate that unattended features are suppressed during feature-based attention, but the exact suppression profile depends on the specific feature. Overall, the results are largely consistent with neurophysiological data and support the feature-similarity gain model of attention. PMID:26067533

  12. Role of Cyclic Nucleotide-Dependent Actin Cytoskeletal Dynamics: [Ca2+]i and Force Suppression in Forskolin-Pretreated Porcine Coronary Arteries

    PubMed Central

    Hocking, Kyle M.; Baudenbacher, Franz J.; Putumbaka, Gowthami; Venkatraman, Sneha; Cheung-Flynn, Joyce; Brophy, Colleen M.; Komalavilas, Padmini

    2013-01-01

    Initiation of force generation during vascular smooth muscle contraction involves a rise in intracellular calcium ([Ca2+]i) and phosphorylation of myosin light chains (MLC). However, reversal of these two processes alone does not account for the force inhibition that occurs during relaxation or inhibition of contraction, implicating that other mechanisms, such as actin cytoskeletal rearrangement, play a role in the suppression of force. In this study, we hypothesize that forskolin-induced force suppression is dependent upon changes in actin cytoskeletal dynamics. To focus on the actin cytoskeletal changes, a physiological model was developed in which forskolin treatment of intact porcine coronary arteries (PCA) prior to treatment with a contractile agonist resulted in complete suppression of force. Pretreatment of PCA with forskolin suppressed histamine-induced force generation but did not abolish [Ca2+]i rise or MLC phosphorylation. Additionally, forskolin pretreatment reduced filamentous actin in histamine-treated tissues, and prevented histamine-induced changes in the phosphorylation of the actin-regulatory proteins HSP20, VASP, cofilin, and paxillin. Taken together, these results suggest that forskolin-induced complete force suppression is dependent upon the actin cytoskeletal regulation initiated by the phosphorylation changes of the actin regulatory proteins and not on the MLC dephosphorylation. This model of complete force suppression can be employed to further elucidate the mechanisms responsible for smooth muscle tone, and may offer cues to pathological situations, such as hypertension and vasospasm. PMID:23593369

  13. Role of cyclic nucleotide-dependent actin cytoskeletal dynamics:Ca(2+)](i) and force suppression in forskolin-pretreated porcine coronary arteries.

    PubMed

    Hocking, Kyle M; Baudenbacher, Franz J; Putumbaka, Gowthami; Venkatraman, Sneha; Cheung-Flynn, Joyce; Brophy, Colleen M; Komalavilas, Padmini

    2013-01-01

    Initiation of force generation during vascular smooth muscle contraction involves a rise in intracellular calcium ([Ca(2+)]i) and phosphorylation of myosin light chains (MLC). However, reversal of these two processes alone does not account for the force inhibition that occurs during relaxation or inhibition of contraction, implicating that other mechanisms, such as actin cytoskeletal rearrangement, play a role in the suppression of force. In this study, we hypothesize that forskolin-induced force suppression is dependent upon changes in actin cytoskeletal dynamics. To focus on the actin cytoskeletal changes, a physiological model was developed in which forskolin treatment of intact porcine coronary arteries (PCA) prior to treatment with a contractile agonist resulted in complete suppression of force. Pretreatment of PCA with forskolin suppressed histamine-induced force generation but did not abolish [Ca(2+)]i rise or MLC phosphorylation. Additionally, forskolin pretreatment reduced filamentous actin in histamine-treated tissues, and prevented histamine-induced changes in the phosphorylation of the actin-regulatory proteins HSP20, VASP, cofilin, and paxillin. Taken together, these results suggest that forskolin-induced complete force suppression is dependent upon the actin cytoskeletal regulation initiated by the phosphorylation changes of the actin regulatory proteins and not on the MLC dephosphorylation. This model of complete force suppression can be employed to further elucidate the mechanisms responsible for smooth muscle tone, and may offer cues to pathological situations, such as hypertension and vasospasm.

  14. Myricetin suppresses UVB-induced wrinkle formation and MMP-9 expression by inhibiting Raf

    PubMed Central

    Jung, Sung Keun; Lee, Ki Won; Kim, Ho Young; Oh, Mi Hyun; Byun, Sanguine; Lim, Sung Hwan; Heo, Yong-Seok; Kang, Nam Joo; Bode, Ann M.; Dong, Zigang; Lee, Hyong Joo

    2010-01-01

    Chronic exposure to solar ultraviolet (UV) light causes skin photoaging. Many studies have shown that naturally occurring phytochemicals have anti-photoaging effects, but their direct target molecule(s) and mechanism(s) remain unclear. We found that myricetin, a major flavonoid in berries and red wine, inhibited wrinkle formation in mouse skin induced by chronic UVB irradiation (0.18 J/cm2, 3 days/wk for 15 wk). Myricetin treatment reduced UVB-induced epidermal thickening of mouse skin and also suppressed UVB-induced matrix metalloproteinase-9 (MMP-9) protein expression and enzyme activity. Myricetin appeared to exert its anti-aging effects by suppressing UVB-induced Raf kinase activity and subsequent attenuation of UVB-induced phosphorylation of MEK and ERK in mouse skin. In vitro and in vivo pull-down assays revealed that myricetin bound with Raf in an ATP-noncompetitive manner. Overall, these results indicate that myricetin exerts potent anti-photoaging activity by regulating MMP-9 expression through the suppression of Raf kinase activity. PMID:20093107

  15. 10 Hz Amplitude Modulated Sounds Induce Short-Term Tinnitus Suppression

    PubMed Central

    Neff, Patrick; Michels, Jakob; Meyer, Martin; Schecklmann, Martin; Langguth, Berthold; Schlee, Winfried

    2017-01-01

    Objectives: Acoustic stimulation or sound therapy is proposed as a main treatment option for chronic subjective tinnitus. To further probe the field of acoustic stimulations for tinnitus therapy, this exploratory study compared 10 Hz amplitude modulated (AM) sounds (two pure tones, noise, music, and frequency modulated (FM) sounds) and unmodulated sounds (pure tone, noise) regarding their temporary suppression of tinnitus loudness. First, it was hypothesized that modulated sounds elicit larger temporary loudness suppression (residual inhibition) than unmodulated sounds. Second, with manipulation of stimulus loudness and duration of the modulated sounds weaker or stronger effects of loudness suppression were expected, respectively. Methods: We recruited 29 participants with chronic tonal tinnitus from the multidisciplinary Tinnitus Clinic of the University of Regensburg. Participants underwent audiometric, psychometric and tinnitus pitch matching assessments followed by an acoustic stimulation experiment with a tinnitus loudness growth paradigm. In a first block participants were stimulated with all of the sounds for 3 min each and rated their subjective tinnitus loudness to the pre-stimulus loudness every 30 s after stimulus offset. The same procedure was deployed in the second block with the pure tone AM stimuli matched to the tinnitus frequency, manipulated in length (6 min), and loudness (reduced by 30 dB and linear fade out). Repeated measures mixed model analyses of variance (ANOVA) were calculated to assess differences in loudness growth between the stimuli for each block separately. Results: First, we found that all sounds elicit a short-term suppression of tinnitus loudness (seconds to minutes) with strongest suppression right after stimulus offset [F(6, 1331) = 3.74, p < 0.01]. Second, similar to previous findings we found that AM sounds near the tinnitus frequency produce significantly stronger tinnitus loudness suppression than noise [vs. Pink noise: t

  16. Contribution of Ruminal Fungi, Archaea, Protozoa, and Bacteria to the Methane Suppression Caused by Oilseed Supplemented Diets

    PubMed Central

    Wang, Shaopu; Giller, Katrin; Kreuzer, Michael; Ulbrich, Susanne E.; Braun, Ueli; Schwarm, Angela

    2017-01-01

    Dietary lipids can suppress methane emission from ruminants, but effects are variable. Especially the role of bacteria, archaea, fungi and protozoa in mediating the lipid effects is unclear. In the present in vitro study, archaea, fungi and protozoa were selectively inhibited by specific agents. This was fully or almost fully successful for fungi and protozoa as well as archaeal activity as determined by the methyl-coenzyme M reductase alpha subunit gene. Five different microbial treatments were generated: rumen fluid being intact (I), without archaea (–A), without fungi (–F), without protozoa (–P) and with bacteria only (–AFP). A forage-concentrate diet given alone or supplemented with crushed full-fat oilseeds of either safflower (Carthamus tinctorius) or poppy (Papaver somniferum) or camelina (Camelina sativa) at 70 g oil kg−1 diet dry matter was incubated. This added up to 20 treatments with six incubation runs per treatment. All oilseeds suppressed methane emission compared to the non-supplemented control. Compared to the non-supplemented control, –F decreased organic matter (OM) degradation, and short-chain fatty acid concentration was greater with camelina and safflower seeds. Methane suppression per OM digested in –F was greater with camelina seeds (−12 vs.−7% with I, P = 0.06), but smaller with poppy seeds (−4 vs. −8% with I, P = 0.03), and not affected with safflower seeds. With –P, camelina seeds decreased the acetate-to-propionate ratio and enhanced the methane suppression per gram dry matter (18 vs. 10% with I, P = 0.08). Hydrogen recovery was improved with –P in any oilseeds compared to non-supplemented control. No methane emission was detected with the –A and –AFP treatments. In conclusion, concerning methanogenesis, camelina seeds seem to exert effects only on archaea and bacteria. By contrast, with safflower and poppy seeds methane was obviously reduced mainly through the interaction with protozoa or archaea associated

  17. Contribution of Ruminal Fungi, Archaea, Protozoa, and Bacteria to the Methane Suppression Caused by Oilseed Supplemented Diets.

    PubMed

    Wang, Shaopu; Giller, Katrin; Kreuzer, Michael; Ulbrich, Susanne E; Braun, Ueli; Schwarm, Angela

    2017-01-01

    Dietary lipids can suppress methane emission from ruminants, but effects are variable. Especially the role of bacteria, archaea, fungi and protozoa in mediating the lipid effects is unclear. In the present in vitro study, archaea, fungi and protozoa were selectively inhibited by specific agents. This was fully or almost fully successful for fungi and protozoa as well as archaeal activity as determined by the methyl-coenzyme M reductase alpha subunit gene. Five different microbial treatments were generated: rumen fluid being intact (I), without archaea (-A), without fungi (-F), without protozoa (-P) and with bacteria only (-AFP). A forage-concentrate diet given alone or supplemented with crushed full-fat oilseeds of either safflower ( Carthamus tinctorius ) or poppy ( Papaver somniferum ) or camelina ( Camelina sativa ) at 70 g oil kg -1 diet dry matter was incubated. This added up to 20 treatments with six incubation runs per treatment. All oilseeds suppressed methane emission compared to the non-supplemented control. Compared to the non-supplemented control, -F decreased organic matter (OM) degradation, and short-chain fatty acid concentration was greater with camelina and safflower seeds. Methane suppression per OM digested in -F was greater with camelina seeds (-12 vs.-7% with I, P = 0.06), but smaller with poppy seeds (-4 vs. -8% with I, P = 0.03), and not affected with safflower seeds. With -P, camelina seeds decreased the acetate-to-propionate ratio and enhanced the methane suppression per gram dry matter (18 vs. 10% with I, P = 0.08). Hydrogen recovery was improved with -P in any oilseeds compared to non-supplemented control. No methane emission was detected with the -A and -AFP treatments. In conclusion, concerning methanogenesis, camelina seeds seem to exert effects only on archaea and bacteria. By contrast, with safflower and poppy seeds methane was obviously reduced mainly through the interaction with protozoa or archaea associated with protozoa. This

  18. Large-Scale Identification and Analysis of Suppressive Drug Interactions

    PubMed Central

    Cokol, Murat; Weinstein, Zohar B.; Yilancioglu, Kaan; Tasan, Murat; Doak, Allison; Cansever, Dilay; Mutlu, Beste; Li, Siyang; Rodriguez-Esteban, Raul; Akhmedov, Murodzhon; Guvenek, Aysegul; Cokol, Melike; Cetiner, Selim; Giaever, Guri; Iossifov, Ivan; Nislow, Corey; Shoichet, Brian; Roth, Frederick P.

    2014-01-01

    SUMMARY One drug may suppress the effects of another. Although knowledge of drug suppression is vital to avoid efficacy-reducing drug interactions or discover countermeasures for chemical toxins, drug-drug suppression relationships have not been systematically mapped. Here, we analyze the growth response of Saccharomyces cerevisiae to anti-fungal compound (“drug”) pairs. Among 440 ordered drug pairs, we identified 94 suppressive drug interactions. Using only pairs not selected on the basis of their suppression behavior, we provide an estimate of the prevalence of suppressive interactions between anti-fungal compounds as 17%. Analysis of the drug suppression network suggested that Bromopyruvate is a frequently suppressive drug and Staurosporine is a frequently suppressed drug. We investigated potential explanations for suppressive drug interactions, including chemogenomic analysis, coaggregation, and pH effects, allowing us to explain the interaction tendencies of Bromopyruvate. PMID:24704506

  19. Genistein and resveratrol, alone and in combination, suppress prostate cancer in SV-40 tag rats.

    PubMed

    Harper, Curt E; Cook, Leah M; Patel, Brijesh B; Wang, Jun; Eltoum, Isam A; Arabshahi, Ali; Shirai, Tomoyuki; Lamartiniere, Coral A

    2009-11-01

    Chemoprevention utilizing dietary agents is an effective means to slow the development of prostate cancer. We evaluated the potential additive and synergistic effects of genistein and resveratrol for suppressing prostate cancer in the Simian Virus-40 T-antigen (SV-40 Tag) targeted probasin promoter rat model, a transgenic model of spontaneously developing prostate cancer. Rats were fed genistein or resveratrol (250 mg/kg AIN-76A diet) alone and in combination, and a low-dose combination (83 mg genistein + 83 mg resveratrol/kg diet). Histopathology and mechanisms of action studies were conducted at 30 and 12 weeks of age, respectively. Genistein, resveratrol, and the high-dose combination treatments suppressed prostate cancer. The low-dose combination did not elicit protection against prostate cancer and was most likely below the effective dose for causing significant histopathological changes. Total genistein and resveratrol concentrations in the blood reached 2,160 and 211 nM, respectively in rats exposed to the single treatments. Polyphenol treatments decreased cell proliferation and insulin-like growth factor-1 (IGF-1) protein expression in the prostate. In addition, genistein as a single agent induced apoptosis and decreased steroid receptor coactivator-3 (SRC-3) in the ventral prostate (VP). Genistein and resveratrol, alone and in combination, suppress prostate cancer development in the SV-40 Tag model. Regulation of SRC-3 and growth factor signaling proteins are consistent with these nutritional polyphenols reducing cell proliferation and increasing apoptosis in the prostate.

  20. Wind Noise Suppression for Infrasound Sensors

    DTIC Science & Technology

    2014-03-01

    Wind Noise Suppression for Infrasound Sensors by John M. Noble, W.C. Kirkpatrick Alberts, II, Sandra L. Collier, Richard Raspet, and Mark A...Laboratory Adelphi, MD 20783-1197 ARL-TR-6873 March 2014 Wind Noise Suppression for Infrasound Sensors John M. Noble, Sandra L. Collier, and...DATES COVERED (From - To) October 2012 to September 2013 4. TITLE AND SUBTITLE Wind Noise Suppression for Infrasound Sensors 5a. CONTRACT NUMBER 5b

  1. Purulent pericarditis in a dog administered immune-suppressing drugs.

    PubMed

    Mohri, Takashi; Takashima, Kazuaki; Yamane, Tsuyoshi; Sato, Hideki; Yamane, Yoshihisa

    2009-05-01

    A 5-year-old castrated mongrel dog was brought to our hospital with anorexia and vomiting. Laboratory testing revealed immune-mediated hemolytic anemia (IMHA), and so treatment was initiated with multiple immune-suppressing drugs, achieving partial remission from IMHA. However, cardiac tamponade due to purulent pericarditis was identified as a secondary disease. Culture of pericardial fluid yielded numerous Candida albicans and multidrug-resistant Acinetobacter sp. Pericardiocentesis was performed, and the condition of the dog improved. However, the dog died the next day.

  2. Components of Streptococcus pneumoniae suppress allergic airways disease and NKT cells by inducing regulatory T cells.

    PubMed

    Thorburn, Alison N; Foster, Paul S; Gibson, Peter G; Hansbro, Philip M

    2012-05-01

    Asthma is an allergic airways disease (AAD) caused by dysregulated immune responses and characterized by eosinophilic inflammation, mucus hypersecretion, and airway hyperresponsiveness (AHR). NKT cells have been shown to contribute to AHR in some mouse models. Conversely, regulatory T cells (Tregs) control aberrant immune responses and maintain homeostasis. Recent evidence suggests that Streptococcus pneumoniae induces Tregs that have potential to be harnessed therapeutically for asthma. In this study, mouse models of AAD were used to identify the S. pneumoniae components that have suppressive properties, and the mechanisms underlying suppression were investigated. We tested the suppressive capacity of type-3-polysaccharide (T3P), isolated cell walls, pneumolysoid (Ply) and CpG. When coadministered, T3P + Ply suppressed the development of: eosinophilic inflammation, Th2 cytokine release, mucus hypersecretion, and AHR. Importantly, T3P + Ply also attenuated features of AAD when administered during established disease. We show that NKT cells contributed to the development of AAD and also were suppressed by T3P + Ply treatment. Furthermore, adoptive transfer of NKT cells induced AHR, which also could be reversed by T3P + Ply. T3P + Ply-induced Tregs were essential for the suppression of NKT cells and AAD, which was demonstrated by Treg depletion. Collectively, our results show that the S. pneumoniae components T3P + Ply suppress AAD through the induction of Tregs that blocked the activity of NKT cells. These data suggest that S. pneumoniae components may have potential as a therapeutic strategy for the suppression of allergic asthma through the induction of Tregs and suppression of NKT cells.

  3. HSP90 Inhibition Suppresses Lipopolysaccharide-Induced Lung Inflammation In Vivo

    PubMed Central

    Lilja, Andrew; Weeden, Clare E.; McArthur, Kate; Nguyen, Thao; Donald, Alastair; Wong, Zi Xin; Dousha, Lovisa; Bozinovski, Steve; Vlahos, Ross; Burns, Christopher J.; Asselin-Labat, Marie-Liesse; Anderson, Gary P.

    2015-01-01

    Inflammation is an important component of cancer diathesis and treatment-refractory inflammation is a feature of many chronic degenerative lung diseases. HSP90 is a 90kDa protein which functions as an ATP-dependent molecular chaperone that regulates the signalling conformation and expression of multiple protein client proteins especially oncogenic mediators. HSP90 inhibitors are in clinical development as cancer therapies but the myeleosuppressive and neutropenic effect of first generation geldanamycin-class inhibitors has confounded studies on the effects on HSP90 inhibitors on inflammation. To address this we assessed the ability of Ganetespib, a non-geldanamycin HSP90 blocker, to suppress lipopolysaccharide (LPS)-induced cellular infiltrates, proteases and inflammatory mediator and transcriptional profiles. Ganetespib (10–100mg/kg, i.v.) did not directly cause myelosuppression, as assessed by video micrography and basal blood cell count, but it strongly and dose-dependently suppressed LPS-induced neutrophil mobilization into blood and neutrophil- and mononuclear cell-rich steroid-refractory lung inflammation. Ganetespib also suppressed B cell and NK cell accumulation, inflammatory cytokine and chemokine induction and MMP9 levels. These data identify non-myelosuppresssive HSP90 inhibitors as potential therapies for inflammatory diseases refractory to conventional therapy, in particular those of the lung. PMID:25615645

  4. Probiotics-mediated suppression of cancer.

    PubMed

    So, Stephanie S Y; Wan, Murphy L Y; El-Nezami, Hani

    2017-01-01

    Probiotics can be used as an adjuvant for cancer prevention or/and treatment through their abilities to modulate intestinal microbiota and host immune response. Although most of the recent reviews have focused on the potential role of probiotics against colon cancer, only few of them include the probiotic effect on extraintestinal cancers. The present review covers the most important findings from the literature published during the past 20 months (from January 2015 to August 2016) regarding the probiotics-mediated suppression of both gastrointestinal and extraintestinal cancers and the underlying mechanisms. A comprehensive literature search in Pubmed, Science direct and Google scholar databases was conducted to locate all relevant articles that investigated the effect of probiotics on prevention/treatment of both gastrointestinal and extraintestinal cancers. Different mechanisms for the beneficial effects of probiotics against cancer were also discussed, mainly via modulation of gut microbiota which thereby influences host metabolism and immunity. Despite laboratory-based studies having demonstrated encouraging outcomes that probiotics possess antitumor effects, the benefits should not be exaggerated before we get more results from human clinical trials. These are very important before the medical community can accept the use of probiotics as an alternative therapy for cancer control.

  5. Alpha1-adrenergic drugs affect the development and expression of ethanol-induced behavioral sensitization.

    PubMed

    Kim, Andrezza Kyunmi; Souza-Formigoni, Maria Lucia Oliveira

    2013-11-01

    According to the incentive sensitization theory, addiction is caused primarily by drug-induced sensitization in the brain mesocorticolimbic systems. After repeated ethanol administration, some animals develop psychomotor sensitization, a phenomenon which occurs simultaneously with the incentive sensitization. Recent evidence suggests the involvement of norepinephrine (NE) in drug addiction, with a critical role in the ethanol reinforcing properties. In this study we evaluated the influence of an agonist (phenylephrine) and an antagonist (prazosin) of alpha1-adrenergic receptors on the development and expression of behavioral sensitization to ethanol. Male Swiss mice, previously treated with ethanol or saline, were challenged with the combined administration of ethanol (or saline) with alpha1-adrenergic drugs. Prazosin (0.1; 0.5 and 1.0 mg/kg) and phenylephrine (1.0 and 2.0 mg/kg) administration blocked the expression of behavioral sensitization to ethanol. In another set of experiments, mice treated with 0.5mg/kg of prazosin+ethanol did not present the development of behavioral sensitization. However, when challenged with ethanol alone, they showed the same sensitized levels of locomotor activity of those presented by mice previously treated with ethanol and saline. Phenylephrine (1.0 mg/kg) treatment did not affect the development of behavioral sensitization. Based on this data, we concluded that the alteration of alpha1-adrenergic receptors functioning, by the administration agonists or antagonists, affected the locomotor sensitization to the stimulant effect of ethanol, suggesting that the normal functioning of the noradrenergic system is essential to its development and expression. Copyright © 2013 Elsevier B.V. All rights reserved.

  6. Controlled suppression of the photoluminescence superlinear dependence on excitation density in quantum dots

    PubMed Central

    2012-01-01

    We have shown that it is possible to tune, up to complete suppression, the photoluminescence superlinear dependence on the excitation density in quantum dot samples at high temperatures by annealing treatments. The effect has been attributed to the reduction of the defectivity of the material induced by annealing. PMID:23033918

  7. Triple antimicrobial therapy and acid suppression in dogs with chronic vomiting and gastric Helicobacter spp.

    PubMed

    Leib, Michael S; Duncan, Robert B; Ward, Daniel L

    2007-01-01

    Helicobacter pylori is a common cause of gastritis and peptic ulcers in humans. Many dogs, including those with gastritis and chronic vomiting, are infected with Helicobacter spp. Triple antimicrobial therapy will eradicate Helicobacter infection, improve gastritis, and reduce clinical signs. The addition of acid suppression medication will not improve results. Twenty-four pet dogs with chronic vomiting and gastric Helicobacter spp. Dogs were randomly assigned to triple antimicrobial therapy with or without famotidine. Gastroduodenoscopy was performed 4 weeks and 6 months after therapy. Helicobacter spp status was determined by histologic assessment of gastric mucosal biopsy specimens. Eradication rates for each treatment were not significantly different and combined were 75 and 42.9% at 4 weeks and 6 months, respectively. A greater improvement in gastritis scores occurred in dogs that became Helicobacter spp negative. Overall, the frequency of vomiting was reduced by 86.4%, but there were no differences between treatments. Eradication rates of Helicobacter spp with both treatments were not significantly different. Eradication rates at 6 months were modest, and more effective treatments should be developed. Acid suppression is not a necessary component of treatment protocols for dogs. Eradication of gastric Helicobacter spp was associated with improvement in gastritis scores. Dramatic reduction of the vomiting frequency occurred with both treatment protocols. Gastric Helicobacter spp may cause or contribute to chronic vomiting and gastritis in some dogs.

  8. Sigma Receptor Ligand, (+)-Pentazocine, Suppresses Inflammatory Responses of Retinal Microglia

    PubMed Central

    Zhao, Jing; Ha, Yonju; Liou, Gregory I.; Gonsalvez, Graydon B.; Smith, Sylvia B.; Bollinger, Kathryn E.

    2014-01-01

    Purpose. To evaluate the effects of the σ 1 receptor (σR1) agonist, (+)-pentazocine, on lipopolysaccharide (LPS)–induced inflammatory changes in retinal microglia cells. Methods. Retinal microglia cells were isolated from Sprague-Dawley rat pups. Cells were treated with LPS with or without (+)-pentazocine and with or without the σR1 antagonist BD1063. Morphologic changes were assayed. Cell viability was assessed by using MTT assay. Supernatant levels of tumor necrosis factor α (TNF-α), interleukin 10, (IL-10), monocyte chemoattractant protein-1 (MCP-1), and nitric oxide (NO) were determined. Reactive oxygen species (ROS) formation was assayed, and levels of mitogen-activated protein kinases (MAPKs) were analyzed by using Western blot. Results. The σR1 protein was expressed in retinal microglia. Incubation with LPS and/or (+)-pentazocine did not alter cell viability or σR1 protein levels. Incubation with LPS for 24 hours induced a marked change in microglial morphology and a significant increase in secreted levels of TNF-α, IL-10, MCP-1, and NO. Pretreatment with (+)-pentazocine inhibited the LPS-induced morphologic changes. Release of TNF-α, IL-10, MCP-1, and NO was reduced with (+)-pentazocine. Intracellular ROS formation was suppressed with (+)-pentazocine. Phosphorylation of extracellular signal–regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) was reduced in the presence of (+)-pentazocine. The σR1 antagonist BD1063 blocked the (+)-pentazocine–mediated inhibition of LPS-induced morphologic changes. In addition, BD1063 treatment blocked (+)-pentazocine–mediated suppression of LPS-induced TNF-α, IL-10, MCP-1, NO, and intracellular ROS release. Conclusions. Treatment with (+)-pentazocine suppressed inflammatory responses of retinal microglia and inhibited LPS-induced activation of ERK/JNK MAPK. In neurodegenerative disease, (+)-pentazocine may exert neuroprotective effects through manipulation of microglia. PMID:24812552

  9. Poppers: more evidence of suppressed immunity.

    PubMed

    James, J S

    1999-08-20

    Evidence from studies in mice shows that exposure to isobutyl nitrite suppresses the immune system. This immune suppression allows for bacterial growth in the lungs and livers of infected mice and can inhibit the ability of mediastinal lymph nodes to respond to antigen-specific stimulation. The mechanism for immune suppression may be a reduction in CD4+ and CD8+ T cell populations in the mediastinal lymph nodes following pulmonary infection with Listeria monocytogenes.

  10. 30 CFR 75.1107 - Fire suppression devices.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Provisions] On and after March 30, 1971, fire-suppression devices meeting specifications prescribed by the... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Fire suppression devices. 75.1107 Section 75... HEALTH MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Fire Protection Fire Suppression Devices and...

  11. 30 CFR 75.1107 - Fire suppression devices.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Provisions] On and after March 30, 1971, fire-suppression devices meeting specifications prescribed by the... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Fire suppression devices. 75.1107 Section 75... HEALTH MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Fire Protection Fire Suppression Devices and...

  12. 30 CFR 75.1107 - Fire suppression devices.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Provisions] On and after March 30, 1971, fire-suppression devices meeting specifications prescribed by the... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Fire suppression devices. 75.1107 Section 75... HEALTH MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Fire Protection Fire Suppression Devices and...

  13. 30 CFR 75.1107 - Fire suppression devices.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Provisions] On and after March 30, 1971, fire-suppression devices meeting specifications prescribed by the... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Fire suppression devices. 75.1107 Section 75... HEALTH MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Fire Protection Fire Suppression Devices and...

  14. 30 CFR 75.1107 - Fire suppression devices.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Provisions] On and after March 30, 1971, fire-suppression devices meeting specifications prescribed by the... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Fire suppression devices. 75.1107 Section 75... HEALTH MANDATORY SAFETY STANDARDS-UNDERGROUND COAL MINES Fire Protection Fire Suppression Devices and...

  15. Downregulation of β-arrestin 1 suppresses glioblastoma cell malignant progression vis inhibition of Src signaling.

    PubMed

    Lan, Tian; Wang, Haoran; Zhang, Zhihua; Zhang, Mingshan; Qu, Yanming; Zhao, Zitong; Fan, Xinyi; Zhan, Qimin; Song, Yongmei; Yu, Chunjiang

    2017-08-01

    Glioblastoma multiforme (GBM) is one of the most common brain malignancies worldwide and is typically associated with a dismal prognosis, yet the mechanisms underlying its aggressiveness remain unclear. Here, we revealed that β-arrestin 1 was overexpressed in GBM and contributed to poorer outcome. Knockdown of β-arrestin 1 suppressed the proliferation, invasiveness and glycolysis of GBM cells, and also enhanced temozolomide efficacy. Further, we discovered that knockdown of β-arrestin 1 decreased the activity of Src, and suppression of Src signaling was critically involved in β-arrestin 1 silencing-mediated suppression of GBM malignancies. Finally, we investigated the effect of β-arrestin 1 knockdown on the tumor growth and survival of xenograft models, and found that shβ-arrestin 1 apparently inhibited GBM growth in vivo and resulted in better survival of mice. Taken together, our findings suggest that knockdown of β-arrestin 1 can suppress GBM cell proliferation, invasion and glycolysis by inhibiting Src signaling. Thus, targeting β-arrestin 1 may be a potential therapeutic strategy for GBM treatment. Copyright © 2017. Published by Elsevier Inc.

  16. Pharmacologic suppression of target cell recognition by engineered T cells expressing chimeric T-cell receptors.

    PubMed

    Alvarez-Vallina, L; Yañez, R; Blanco, B; Gil, M; Russell, S J

    2000-04-01

    Adoptive therapy with autologous T cells expressing chimeric T-cell receptors (chTCRs) is of potential interest for the treatment of malignancy. To limit possible T-cell-mediated damage to normal tissues that weakly express the targeted tumor antigen (Ag), we have tested a strategy for the suppression of target cell recognition by engineered T cells. Jurkat T cells were transduced with an anti-hapten chTCR tinder the control of a tetracycline-suppressible promoter and were shown to respond to Ag-positive (hapten-coated) but not to Ag-negative target cells. The engineered T cells were then reacted with hapten-coated target cells at different effector to target cell ratios before and after exposure to tetracycline. When the engineered T cells were treated with tetracycline, expression of the chTCR was greatly decreased and recognition of the hapten-coated target cells was completely suppressed. Tetracycline-mediated suppression of target cell recognition by engineered T cells may be a useful strategy to limit the toxicity of the approach to cancer gene therapy.

  17. An Example of Genetically Distinct HIV Type 1 Variants in Cerebrospinal Fluid and Plasma During Suppressive Therapy

    PubMed Central

    Dahl, Viktor; Gisslen, Magnus; Hagberg, Lars; Peterson, Julia; Shao, Wei; Spudich, Serena; Price, Richard W.; Palmer, Sarah

    2014-01-01

    We sequenced the genome of human immunodeficiency virus type 1 (HIV-1) recovered from 70 cerebrospinal fluid (CSF) specimens and 29 plasma samples and corresponding samples obtained before treatment initiation from 17 subjects receiving suppressive therapy. More CSF sequences than plasma sequences were hypermutants. We determined CSF sequences and plasma sequences in specimens obtained from 2 subjects after treatment initiation. In one subject, we found genetically distinct CSF and plasma sequences, indicating that they came from HIV-1 from 2 different compartments, one potentially the central nervous system, during suppressive therapy. In addition, there was little evidence of viral evolution in the CSF during therapy, suggesting that continuous virus replication is not the major cause of viral persistence in the central nervous system. PMID:24338353

  18. An example of genetically distinct HIV type 1 variants in cerebrospinal fluid and plasma during suppressive therapy.

    PubMed

    Dahl, Viktor; Gisslen, Magnus; Hagberg, Lars; Peterson, Julia; Shao, Wei; Spudich, Serena; Price, Richard W; Palmer, Sarah

    2014-05-15

    We sequenced the genome of human immunodeficiency virus type 1 (HIV-1) recovered from 70 cerebrospinal fluid (CSF) specimens and 29 plasma samples and corresponding samples obtained before treatment initiation from 17 subjects receiving suppressive therapy. More CSF sequences than plasma sequences were hypermutants. We determined CSF sequences and plasma sequences in specimens obtained from 2 subjects after treatment initiation. In one subject, we found genetically distinct CSF and plasma sequences, indicating that they came from HIV-1 from 2 different compartments, one potentially the central nervous system, during suppressive therapy. In addition, there was little evidence of viral evolution in the CSF during therapy, suggesting that continuous virus replication is not the major cause of viral persistence in the central nervous system.

  19. α-Lipoic acid suppresses the development of DNFB-induced atopic dermatitis-like symptoms in NC/Nga mice.

    PubMed

    Kim, Gun-Dong; Kim, Tae-Ho; Jang, An-Hee; Ahn, Hyun-Jong; Park, Yong Seek; Park, Cheung-Seog

    2011-02-01

    Atopic dermatitis (AD) is a common skin disease that has complex pathogenic mechanisms. Under specific pathogen-free conditions, repeated epicutaneous treatment of 2-4-dinitrofluorobenzene (DNFB) evokes AD-like clinical symptoms in NC/Nga mice. α-Lipoic acid (α-LA; 1, 2-dithiolane-3-pentanoic acid) is a dietary component that is synthesized in bacteria, yeast, plants, and mammals. α-LA and its reduced form, dihydrolipoic acid, are powerful antioxidants that have many physiological functions, including free radical scavenging of reactive oxygen species, generation of cellular antioxidants, chelation of metal ions, and inflammatory suppression. In this study, we investigated whether α-LA suppresses AD-like skin lesions induced by repeated DNFB application in NC/Nga mice. α-LA significantly suppressed production of interferon (IFN)-γ and interleukin (IL)-4 by activated CD4(+) T cells. We found that the oral administration of α-LA reduced AD-like clinical symptoms and inhibited increases of epidermal thickness in DNFB-induced AD-like skin lesions of NC/Nga mice. Furthermore, total serum IgE levels were dramatically reduced by topical α-LA treatment. Our findings suggest that oral administration of α-LA suppresses the development of AD in DNFB-treated NC/Nga mice and reduces IFN-γ and IL-4 production from activated CD4(+) T cells as well as total serum IgE levels. © 2011 John Wiley & Sons A/S.

  20. Animal and pasture responses to grazing management of chemically suppressed tall fescue in mixed pastures

    USDA-ARS?s Scientific Manuscript database

    Treatment of toxic endophyte-infected tall fescue [Lolium arundinaceum (Schreb.) Darbysh] with metsulfuran-methyl can mitigate fescue toxicosis and enhance forage nutritive value by suppressing seedhead emergence. A grazing experiment was conducted with steers (2013) and heifers (2014) to evaluate a...

  1. Apatinib Inhibits Angiogenesis Via Suppressing Akt/GSK3β/ANG Signaling Pathway in Anaplastic Thyroid Cancer.

    PubMed

    Jin, Zhijian; Cheng, Xi; Feng, Haoran; Kuang, Jie; Yang, Weiping; Peng, Chenghong; Shen, Baiyong; Qiu, Weihua

    2017-01-01

    Anaplastic thyroid carcinoma (ATC) is one of the most lethal human malignancies, and there is no efficient method to slow its process. Apatinib, a novel tyrosine kinase inhibitor (TKI), has been confirmed for its efficacy and safety in the treatment of advanced gastric carcinoma patients. However, the effects of Apatinib in ATC are still unknown. In this study, we explored the effects and mechanisms of Apatinib on tumor growth and angiogenesis in vitro and in vitro in ATC cells. Angiogenesis antibodies array was utilized to detect the expression of angiogenesis-related genes after Apatinib treatment in ATC cells. In addition, we used Akt activator, Akt inhibitor and GSK3β inhibitor to further study the mechanism for how Apatinib suppressed angiogenesis. Apatinib treatment could suppress the growth of ATC cells in a dose- and time-dependent manner via inducing apoptosis and blocking cell cycle progression at G0/G1 phase. Moreover, Apatinib treatment decreased the expression of angiogenin (ANG) and inhibited angiogenesis of ATC cells in vitro and in vitro. We further confirmed that recombinant human ANG (rhANG) significantly abrogated Apatinib-mediated anti-angiogenic ability in ATC cells. Additionally, Apatinib treatment decreased the level of p-Akt and p-GSK3β. Moreover, the Apatinib-mediated decrease of ANG and anti-angiogenic ability were partly reversed when an Akt activator, SC79, was administered. Furthermore, the anti-angiogenic ability of Apatinib can be enhanced in the presence of Akt inhibitor, and the inhibition of GSK3β attenuated the anti-angiogenic ability of Apatinib. Our results demonstrated that Apatinib treatment inhibited tumor growth, and Apatinib-induced suppression of Akt/GSK3β/ANG signaling pathway may play an important role in the inhibition of angiogenesis in ATC, supporting a potential therapeutic approach for using Apatinib in the treatment of ATC. © 2017 The Author(s). Published by S. Karger AG, Basel.

  2. Growth characteristics of a weed-suppressive indica x non-suppressive tropical japonica rice mapping population

    USDA-ARS?s Scientific Manuscript database

    The indica rice cultivar, PI 312777, can be highly productive as well as suppressive to C4 grass species such as barnyardgrass (Echinochloa crus-galli). A recombinant inbred line (RIL) mapping population was developed using single seed descent from a cross between ‘Katy’ (non-weed-suppressive) and ...

  3. Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir

    PubMed Central

    Avalos, Claudia R.; Abreu, Celina M.; Queen, Suzanne E.; Li, Ming; Price, Sarah; Shirk, Erin N.; Engle, Elizabeth L.; Forsyth, Ellen; Bullock, Brandon T.; Mac Gabhann, Feilim; Wietgrefe, Stephen W.; Haase, Ashley T.; Zink, M. Christine; Mankowski, Joseph L.; Clements, Janice E.

    2017-01-01

    ABSTRACT A human immunodeficiency virus (HIV) infection cure requires an understanding of the cellular and anatomical sites harboring virus that contribute to viral rebound upon treatment interruption. Despite antiretroviral therapy (ART), HIV-associated neurocognitive disorders (HAND) are reported in HIV-infected individuals on ART. Biomarkers for macrophage activation and neuronal damage in cerebrospinal fluid (CSF) of HIV-infected individuals demonstrate continued effects of HIV in brain and suggest that the central nervous system (CNS) may serve as a viral reservoir. Using a simian immunodeficiency virus (SIV)/macaque model for HIV encephalitis and AIDS, we evaluated whether infected cells persist in brain despite ART. Eight SIV-infected pig-tailed macaques were virally suppressed with ART, and plasma and CSF viremia levels were analyzed longitudinally. To assess whether virus persisted in brain macrophages (BrMΦ) in these macaques, we used a macrophage quantitative viral outgrowth assay (MΦ-QVOA), PCR, and in situ hybridization (ISH) to measure the frequency of infected cells and the levels of viral RNA and DNA in brain. Viral RNA in brain tissue of suppressed macaques was undetectable, although viral DNA was detected in all animals. The MΦ-QVOA demonstrated that the majority of suppressed animals contained latently infected BrMΦ. We also showed that virus produced in the MΦ-QVOAs was replication competent, suggesting that latently infected BrMΦ are capable of reestablishing productive infection upon treatment interruption. This report provides the first confirmation of the presence of replication-competent SIV in BrMΦ of ART-suppressed macaques and suggests that the highly debated issue of viral latency in macrophages, at least in brain, has been addressed in SIV-infected macaques treated with ART. PMID:28811349

  4. Berberine attenuates depressive-like behaviors by suppressing neuro-inflammation in stressed mice.

    PubMed

    Liu, Ya-Min; Niu, Le; Wang, Lin-Lin; Bai, Li; Fang, Xiao-Yan; Li, Yu-Cheng; Yi, Li-Tao

    2017-09-01

    Berberine, the major constituent alkaloid originally from the famous Chinese herb Huanglian (Coptis chinensis), has been shown to exert antidepressant-like effects in rodents. However, it is still not clear the involvement of neuro-inflammation suppression in the effects of berberine. The purpose of this study was to determine whether berberine affects the neuro-inflammation system in mice induced by chronic unpredictable mild stress (CUMS). Berberine was orally administrated in normal or CUMS mice for successive four weeks. Behavioral evaluation showed that berberine prevented the depressive deficits both in sucrose preference test and novelty-suppressed feeding test. The elevation of hippocampal pro-inflammatory cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), as well as the activation of microglia were decreased by berberine. In addition, chronic berberine treatment inhibited nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway as the phosphorylated proteins of NF-κB, IκB kinase (IKK)α and IKKβ in the hippocampus were suppressed after berberine administration. Furthermore, inducible nitric oxide synthase (iNOS), one downstream target of NF-κB signaling pathway was also inhibited by berberine. In conclusion, these findings suggest that administration of berberine could prevent depressive-like behaviors in CUMS mice by suppressing neuro-inflammation in the hippocampus. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Resveratrol Treatment after Status Epilepticus Restrains Neurodegeneration and Abnormal Neurogenesis with Suppression of Oxidative Stress and Inflammation.

    PubMed

    Mishra, Vikas; Shuai, Bing; Kodali, Maheedhar; Shetty, Geetha A; Hattiangady, Bharathi; Rao, Xiaolan; Shetty, Ashok K

    2015-12-07

    Antiepileptic drug therapy, though beneficial for restraining seizures, cannot thwart status epilepticus (SE) induced neurodegeneration or down-stream detrimental changes. We investigated the efficacy of resveratrol (RESV) for preventing SE-induced neurodegeneration, abnormal neurogenesis, oxidative stress and inflammation in the hippocampus. We induced SE in young rats and treated with either vehicle or RESV, commencing an hour after SE induction and continuing every hour for three-hours on SE day and twice daily thereafter for 3 days. Seizures were terminated in both groups two-hours after SE with a diazepam injection. In contrast to the vehicle-treated group, the hippocampus of animals receiving RESV during and after SE presented no loss of glutamatergic neurons in hippocampal cell layers, diminished loss of inhibitory interneurons expressing parvalbumin, somatostatin and neuropeptide Y in the dentate gyrus, reduced aberrant neurogenesis with preservation of reelin + interneurons, lowered concentration of oxidative stress byproduct malondialdehyde and pro-inflammatory cytokine tumor necrosis factor-alpha, normalized expression of oxidative stress responsive genes and diminished numbers of activated microglia. Thus, 4 days of RESV treatment after SE is efficacious for thwarting glutamatergic neuron degeneration, alleviating interneuron loss and abnormal neurogenesis, and suppressing oxidative stress and inflammation. These results have implications for restraining SE-induced chronic temporal lobe epilepsy.

  6. Combination Kinase Inhibitor Treatment Suppresses Rift Valley Fever Virus Replication.

    PubMed

    Bell, Todd M; Espina, Virginia; Lundberg, Lindsay; Pinkham, Chelsea; Brahms, Ashwini; Carey, Brian D; Lin, Shih-Chao; Dahal, Bibha; Woodson, Caitlin; de la Fuente, Cynthia; Liotta, Lance A; Bailey, Charles L; Kehn-Hall, Kylene

    2018-04-13

    Viruses must parasitize host cell translational machinery in order to make proteins for viral progeny. In this study, we sought to use this signal transduction conduit against them by inhibiting multiple kinases that influence translation. Previous work indicated that several kinases involved in translation, including p70 S6K, p90RSK, ERK, and p38 MAPK, are phosphorylated following Rift Valley fever virus (RVFV) infection. Furthermore, inhibiting p70 S6K through treatment with the FDA approved drug rapamycin prevents RVFV pathogenesis in a mouse model of infection. We hypothesized that inhibiting either p70 S6K, p90RSK, or p90RSK’s upstream kinases, ERK and p38 MAPK, would decrease translation and subsequent viral replication. Treatment with the p70 S6K inhibitor PF-4708671 resulted in decreased phosphorylation of translational proteins and reduced RVFV titers. In contrast, treatment with the p90RSK inhibitor BI-D1870, p38MAPK inhibitor SB203580, or the ERK inhibitor PD0325901 alone had minimal influence on RVFV titers. The combination of PF-4708671 and BI-D1870 treatment resulted in robust inhibition of RVFV replication. Likewise, a synergistic inhibition of RVFV replication was observed with p38MAPK inhibitor SB203580 or the ERK inhibitor PD0325901 combined with rapamycin treatment. These findings serve as a proof of concept regarding combination kinase inhibitor treatment for RVFV infection.

  7. Combination Kinase Inhibitor Treatment Suppresses Rift Valley Fever Virus Replication

    PubMed Central

    Bell, Todd M.; Espina, Virginia; Lundberg, Lindsay; Pinkham, Chelsea; Brahms, Ashwini; Dahal, Bibha; Woodson, Caitlin; de la Fuente, Cynthia; Liotta, Lance A.; Bailey, Charles L.

    2018-01-01

    Viruses must parasitize host cell translational machinery in order to make proteins for viral progeny. In this study, we sought to use this signal transduction conduit against them by inhibiting multiple kinases that influence translation. Previous work indicated that several kinases involved in translation, including p70 S6K, p90RSK, ERK, and p38 MAPK, are phosphorylated following Rift Valley fever virus (RVFV) infection. Furthermore, inhibiting p70 S6K through treatment with the FDA approved drug rapamycin prevents RVFV pathogenesis in a mouse model of infection. We hypothesized that inhibiting either p70 S6K, p90RSK, or p90RSK’s upstream kinases, ERK and p38 MAPK, would decrease translation and subsequent viral replication. Treatment with the p70 S6K inhibitor PF-4708671 resulted in decreased phosphorylation of translational proteins and reduced RVFV titers. In contrast, treatment with the p90RSK inhibitor BI-D1870, p38MAPK inhibitor SB203580, or the ERK inhibitor PD0325901 alone had minimal influence on RVFV titers. The combination of PF-4708671 and BI-D1870 treatment resulted in robust inhibition of RVFV replication. Likewise, a synergistic inhibition of RVFV replication was observed with p38MAPK inhibitor SB203580 or the ERK inhibitor PD0325901 combined with rapamycin treatment. These findings serve as a proof of concept regarding combination kinase inhibitor treatment for RVFV infection. PMID:29652799

  8. Bilirubin treatment suppresses pulmonary inflammation in a rat model of smoke-induced emphysema.

    PubMed

    Wei, Jingjing; Zhao, Hui; Fan, Guoquan; Li, Jianqiang

    2015-09-18

    Cigarette smoking is a significant risk factor for emphysema, which is characterized by airway inflammation and oxidative damage. To assess the capacity of bilirubin to protect against smoke-induced emphysema. Smoking status and bilirubin levels were recorded in 58 patients with chronic obstructive pulmonary diseases (COPD) and 71 non-COPD participants. The impact of smoking on serum bilirubin levels and exogenous bilirubin (20 mg/kg/day) on pulmonary injury was assessed in a rat model of smoking-induced emphysema. At sacrifice lung histology, airway leukocyte accumulation and cytokine and chemokine levels in serum, bronchoalveolar lavage fluid (BALF) and lung were analyzed. Oxidative lipid damage and anti-oxidative components was assessed by measuring malondialdehyde, superoxide dismutase (SOD) activity and glutathione. Total serum bilirubin levels were lower in smokers with or without COPD than non-smoking patients without COPD (P < 0.05). Indirect serum bilirubin levels were lower in COPD patients than patients without COPD (P < 0.05). In rats, cigarette smoke reduced serum total and indirect bilirubin levels. Administration of bilirubin reduced mean linear intercept and mean alveoli area, increased mean alveoli number, reduced macrophage, neutrophil and TNF-α content of BALF, and increased BALF and serum IL-10 level, but lowered local and systemic CCL2, CXCL2, CXCL8 and IL-17 levels. Bilirubin suppressed the smoke-induced systemic and regional oxidative lipid damage associated with increased SOD activity. Bilirubin attenuated smoking-induced pulmonary injury by suppressing inflammatory cell recruitment and pro-inflammatory cytokine secretion, increasing anti-inflammatory cytokine levels, and anti-oxidant SOD activity in a rat model of smoke-induced emphysema. Copyright © 2015. Published by Elsevier Inc.

  9. CONDITIONS FOR CSR MICROBUNCHING GAIN SUPPRESSION

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tsai, Cheng Ying; Douglas, David R.; Li, Rui

    The coherent synchrotron radiation (CSR) of a high brightness electron beam traversing a series of dipoles, such as transport arcs, may result in phase space degradation. On one hand, the CSR can perturb electron transverse motion in dispersive regions along the beamline, causing emittance growth. On the other hand, the CSR effect on the longitudinal beam dynamics could result in microbunching gain enhancement. For transport arcs, several schemes have been proposed* to suppress the CSR-induced emittance growth. Similarly, several scenarios have been introduced** to suppress CSR-induced microbunching gain, which however mostly aim for linac-based machines. In this paper we trymore » to provide sufficient conditions for suppression of CSR-induced microbunching gain along a transport arc, analogous to*. Several example lattices are presented, with the relevant microbunching analyses carried out by our semi-analytical Vlasov solver***. The simulation results show that lattices satisfying the proposed conditions indeed have microbunching gain suppressed. We expect this analysis can shed light on lattice design approach that could suppress the CSR-induced microbunching gain.« less

  10. Nematode suppression and growth stimulation in corn plants (Zea mays L.) irrigated with domestic effluent.

    PubMed

    Barros, Kenia Kelly; do Nascimento, Clístenes Williams Araújo; Florencio, Lourdinha

    2012-01-01

    Treated wastewater has great potential for agricultural use due to its concentrations of nutrients and organic matter, which are capable of improving soil characteristics. Additionally, effluents can induce suppression of plant diseases caused by soil pathogens. This study evaluates the effect of irrigation with effluent in a UASB reactor on maize (Zea mays L.) development and on suppression of the diseases caused by nematodes of the genus Meloidogyne. Twelve lysimeters of 1 m(3) each were arranged in a completely randomized design, with four treatments and three replicates. The following treatments were used: T1 (W+I), irrigation with water and infestation with nematodes; T2 (W+I+NPK), irrigation with water, infestation with nematodes and fertilization with nitrogen (N), phosphorus (P) and potassium (K); T3 (E+I), irrigation with effluent and infestation with nematodes; and T4 (E+I+P), irrigation with effluent, infestation with nematodes and fertilization with phosphorus. The plants irrigated with the effluent plus the phosphorus fertilizer had better growth and productivity and were more resistant to the disease symptoms caused by the nematodes. The suppression levels may have been due to the higher levels of Zn and NO(3)(-) found in the leaf tissue of the plants irrigated with the effluent and phosphorus fertilizer.

  11. Carvacrol suppresses high pressure high temperature inactivation of Bacillus cereus spores.

    PubMed

    Luu-Thi, Hue; Corthouts, Jorinde; Passaris, Ioannis; Grauwet, Tara; Aertsen, Abram; Hendrickx, Marc; Michiels, Chris W

    2015-03-16

    The inactivation of bacterial spores generally proceeds faster and at lower temperatures when heat treatments are conducted under high pressure, and high pressure high temperature (HPHT) processing is, therefore, receiving an increased interest from food processors. However, the mechanisms of spore inactivation by HPHT treatment are poorly understood, particularly at moderately elevated temperature. In the current work, we studied inactivation of the spores of Bacillus cereus F4430/73 by HPHT treatment for 5 min at 600MPa in the temperature range of 50-100°C, using temperature increments of 5°C. Additionally, we investigated the effect of the natural antimicrobial carvacrol on spore germination and inactivation under these conditions. Spore inactivation by HPHT was less than about 1 log unit at 50 to 70°C, but gradually increased at higher temperatures up to about 5 log units at 100°C. DPA release and loss of spore refractility in the spore population were higher at moderate (≤65°C) than at high (≥70°C) treatment temperatures, and we propose that moderate conditions induced the normal physiological pathway of spore germination resulting in fully hydrated spores, while at higher temperatures this pathway was suppressed and replaced by another mechanism of pressure-induced dipicolinic acid (DPA) release that results only in partial spore rehydration, probably because spore cortex hydrolysis is inhibited. Carvacrol strongly suppressed DPA release and spore rehydration during HPHT treatment at ≤65°C and also partly inhibited DPA release at ≥65°C. Concomitantly, HPHT spore inactivation was reduced by carvacrol at 65-90°C but unaffected at 95-100°C. Copyright © 2014 Elsevier B.V. All rights reserved.

  12. Tumor-suppressive effects of natural-type interferon-β through CXCL10 in melanoma

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kobayashi, Hikaru; Nobeyama, Yoshimasa, E-mail: nobederm@jikei.ac.jp; Nakagawa, Hidemi

    2015-08-21

    Introduction: Type 1 interferon is in widespread use as adjuvant therapy to inhibit melanoma progression. Considering the tumor-suppressive effects of local administration of interferon-β (IFN-β) on lymphatic metastasis, the present study was conducted to identify melanoma-suppressive molecules that are up-regulated by IFN-β treatment of lymphatic endothelial cells. Materials and methods: Lymphatic endothelial cells, fibroblasts, and melanoma cells were treated with natural-type IFN-β, and melanoma cells were treated with CXCL10. Genome-wide oligonucleotide microarray analysis was performed using lymphatic endothelial cells with or without IFN-β treatment. Quantitative real-time reverse transcription-PCR and an enzyme-linked immunosorbent assay were performed to examine CXCL10 expression. Amore » proliferation assay was performed to examine the effects of IFN-β and CXCL10 in melanoma cells. Results: Genome-wide microarray analyses detected CXCL10 as a gene encoding a secretory protein that was up-regulated by IFN-β in lymphatic endothelial cells. IFN-β treatment significantly induced CXCL10 in dermal lymphatic endothelial cells and melanoma cells that are highly sensitive to IFN-β. CXCL10 reduced melanoma cell proliferation in IFN-β-sensitive cells as well as resistant cells. Melanoma cells in which CXCL10 was knocked down were sensitive to IFN-β. CXCR3-B, which encodes the CXCL10 receptor, was up-regulated in melanoma cells with high sensitivity to IFN-β and down-regulated in melanoma cells with medium to low sensitivity. Conclusions: Our data suggest that IFN-β suppresses proliferation and metastasis from the local lymphatic system and melanoma cells via CXCL10. Down-regulation of CXCR3-B by IFN-β may be associated with resistance to IFN-β. - Highlights: • We search melanoma-suppressive molecules induced by IFN-β. • IFN-β induces a high amount of CXCL10 from lymphatic endothelial cells. • CXCL10 induction level in melanoma cells is

  13. The nucleus raphe magnus suppresses vomiting, and the solitary nucleus and 5-HT are not involved in this suppression.

    PubMed

    Hattori, Yuka; Hamaguchi, Chie; Yamada, Yuko; Urayama, Yukiko; Nakamura, Emi; Koga, Tomoshige; Fukuda, Hiroyuki

    2010-01-15

    In previous paper, we reported that stimulation of the nucleus raphe magnus (stim-NRM) inhibits the induction of retching by afferent vagal fibers (VAs). We performed the present study to identity the transmitter of inhibition and then the site. The following results were obtained in decerebrated and paralyzed dogs. 1) The induction of fictive retching was suppressed by i.v. injection of 5-HT, and by 4th ventricular administration of 5-HT or a 5-HT3-receptor (R) agonist, 1-(m-chlorophenyl)-biguanade hydrochloride (m-CPBG). 2) Both forms of suppression were antagonized by i.v. injection of ondansetron, a 5-HT3-R antagonist. 3) Administration of the antagonist into the 4th ventricle did not affect the induction or its suppression by stim-NRM. These results suggest that the transmission from VAs to neurons in the nucleus solitarius (NTS) is suppressed by 5-HT via 5-HT3-R. However, these results also suggest that both the transmitter and receptor are not involved in the induction of retching by VAs or in its suppression by the NRM. Next, we examined the site of suppression. Unitary firings of NTS neurons in response to pulse-train stimulation of VAs were not inhibited by NRM stimulation. Moreover, the firing of NTS neurons during the induction of retching by vagal stimulation did not significantly decrease with the superimposition of stim-NRM, although the induction of retching was completely suppressed. These results suggest that suppression of the induction of retching by the descending inhibitory system of pain did not occur in the synapse between afferent vagal fibers and NTS neurons. The site of suppression is discussed.

  14. An Alternative to Thought Suppression?

    ERIC Educational Resources Information Center

    Boice, Robert

    2012-01-01

    Comments on the original article, "Setting free the bears: Escape from thought suppression," by D. M. Wegner (see record 2011-25622-008). While Wegner supposed that we might have to learn to live with bad thoughts, the present author discusses the use of imagination and guided imagery as an alternative to forced thought suppression.

  15. Suppressing explosive synchronization by contrarians

    NASA Astrophysics Data System (ADS)

    Zhang, Xiyun; Guan, Shuguang; Zou, Yong; Chen, Xiaosong; Liu, Zonghua

    2016-01-01

    Explosive synchronization (ES) has recently received increasing attention and studies have mainly focused on the conditions of its onset so far. However, its inverse problem, i.e. the suppression of ES, has not been systematically studied so far. As ES is usually considered to be harmful in certain circumstances such as the cascading failure of power grids and epileptic seizure, etc., its suppression is definitely important and deserves to be studied. We here study this inverse problem by presenting an efficient approach to suppress ES from a first-order to second-order transition, without changing the intrinsic network structure. We find that ES can be suppressed by only changing a small fraction of oscillators into contrarians with negative couplings and the critical fraction for the transition from the first order to the second order increases with both the network size and the average degree. A brief theory is presented to explain the underlying mechanism. This finding underlines the importance of our method to improve the understanding of neural interactions underlying cognitive processes.

  16. An integrated genomic approach identifies persistent tumor suppressive effects of transforming growth factor-β in human breast cancer

    PubMed Central

    2014-01-01

    Introduction Transforming growth factor-βs (TGF-βs) play a dual role in breast cancer, with context-dependent tumor-suppressive or pro-oncogenic effects. TGF-β antagonists are showing promise in early-phase clinical oncology trials to neutralize the pro-oncogenic effects. However, there is currently no way to determine whether the tumor-suppressive effects of TGF-β are still active in human breast tumors at the time of surgery and treatment, a situation that could lead to adverse therapeutic responses. Methods Using a breast cancer progression model that exemplifies the dual role of TGF-β, promoter-wide chromatin immunoprecipitation and transcriptomic approaches were applied to identify a core set of TGF-β-regulated genes that specifically reflect only the tumor-suppressor arm of the pathway. The clinical significance of this signature and the underlying biology were investigated using bioinformatic analyses in clinical breast cancer datasets, and knockdown validation approaches in tumor xenografts. Results TGF-β-driven tumor suppression was highly dependent on Smad3, and Smad3 target genes that were specifically enriched for involvement in tumor suppression were identified. Patterns of Smad3 binding reflected the preexisting active chromatin landscape, and target genes were frequently regulated in opposite directions in vitro and in vivo, highlighting the strong contextuality of TGF-β action. An in vivo-weighted TGF-β/Smad3 tumor-suppressor signature was associated with good outcome in estrogen receptor-positive breast cancer cohorts. TGF-β/Smad3 effects on cell proliferation, differentiation and ephrin signaling contributed to the observed tumor suppression. Conclusions Tumor-suppressive effects of TGF-β persist in some breast cancer patients at the time of surgery and affect clinical outcome. Carefully tailored in vitro/in vivo genomic approaches can identify such patients for exclusion from treatment with TGF-β antagonists. PMID:24890385

  17. Nitrogen enrichment suppresses other environmental drivers and homogenizes salt marsh leaf microbiome.

    PubMed

    Daleo, Pedro; Alberti, Juan; Jumpponen, Ari; Veach, Allison; Ialonardi, Florencia; Iribarne, Oscar; Silliman, Brian

    2018-06-01

    Microbial community assembly is affected by a combination of forces that act simultaneously, but the mechanisms underpinning their relative influences remain elusive. This gap strongly limits our ability to predict human impacts on microbial communities and the processes they regulate. Here, we experimentally demonstrate that increased salinity stress, food web alteration and nutrient loading interact to drive outcomes in salt marsh fungal leaf communities. Both salinity stress and food web alterations drove communities to deterministically diverge, resulting in distinct fungal communities. Increased nutrient loads, nevertheless, partially suppressed the influence of other factors as determinants of fungal assembly. Using a null model approach, we found that increased nutrient loads enhanced the relative importance of stochastic over deterministic divergent processes; without increased nutrient loads, samples from different treatments showed a relatively (deterministic) divergent community assembly whereas increased nutrient loads drove the system to more stochastic assemblies, suppressing the effect of other treatments. These results demonstrate that common anthropogenic modifications can interact to control fungal community assembly. Furthermore, our results suggest that when the environmental conditions are spatially heterogeneous (as in our case, caused by specific combinations of experimental treatments), increased stochasticity caused by greater nutrient inputs can reduce the importance of deterministic filters that otherwise caused divergence, thus driving to microbial community homogenization. © 2018 by the Ecological Society of America.

  18. Nitrogen enrichment suppresses other environmental drivers and homogenizes salt marsh leaf microbiome

    DOE PAGES

    Daleo, Pedro; Alberti, Juan; Jumpponen, Ari; ...

    2018-04-12

    Microbial community assembly is affected by a combination of forces that act simultaneously, but the mechanisms underpinning their relative influences remain elusive. This gap strongly limits our ability to predict human impacts on microbial communities and the processes they regulate. Here, we experimentally demonstrate that increased salinity stress, food web alteration and nutrient loading interact to drive outcomes in salt marsh fungal leaf communities. Both salinity stress and food web alterations drove communities to deterministically diverge, resulting in distinct fungal communities. Increased nutrient loads, nevertheless, partially suppressed the influence of other factors as determinants of fungal assembly. Using a nullmore » model approach, we found that increased nutrient loads enhanced the relative importance of stochastic over deterministic divergent processes; without increased nutrient loads, samples from different treatments showed a relatively (deterministic) divergent community assembly whereas increased nutrient loads drove the system to more stochastic assemblies, suppressing the effect of other treatments. These results demonstrate that common anthropogenic modifications can interact to control fungal community assembly. As a result, our results suggest that when the environmental conditions are spatially heterogeneous (as in our case, caused by specific combinations of experimental treatments), increased stochasticity caused by greater nutrient inputs can reduce the importance of deterministic filters that otherwise caused divergence, thus driving to microbial community homogenization.« less

  19. Nitrogen enrichment suppresses other environmental drivers and homogenizes salt marsh leaf microbiome

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Daleo, Pedro; Alberti, Juan; Jumpponen, Ari

    Microbial community assembly is affected by a combination of forces that act simultaneously, but the mechanisms underpinning their relative influences remain elusive. This gap strongly limits our ability to predict human impacts on microbial communities and the processes they regulate. Here, we experimentally demonstrate that increased salinity stress, food web alteration and nutrient loading interact to drive outcomes in salt marsh fungal leaf communities. Both salinity stress and food web alterations drove communities to deterministically diverge, resulting in distinct fungal communities. Increased nutrient loads, nevertheless, partially suppressed the influence of other factors as determinants of fungal assembly. Using a nullmore » model approach, we found that increased nutrient loads enhanced the relative importance of stochastic over deterministic divergent processes; without increased nutrient loads, samples from different treatments showed a relatively (deterministic) divergent community assembly whereas increased nutrient loads drove the system to more stochastic assemblies, suppressing the effect of other treatments. These results demonstrate that common anthropogenic modifications can interact to control fungal community assembly. As a result, our results suggest that when the environmental conditions are spatially heterogeneous (as in our case, caused by specific combinations of experimental treatments), increased stochasticity caused by greater nutrient inputs can reduce the importance of deterministic filters that otherwise caused divergence, thus driving to microbial community homogenization.« less

  20. Chronic treatment with fluoxetine modulates vascular adrenergic responses by inhibition of pre- and post-synaptic mechanisms.

    PubMed

    Pereira, Camila A; Rodrigues, Fernanda L; Ruginsk, Silvia G; Zanotto, Camila Z; Rodrigues, José A; Duarte, Diego A; Costa-Neto, Claudio M; Resstel, Leonardo B; Carneiro, Fernando S; Tostes, Rita C

    2017-04-05

    Fluoxetine, a serotonin reuptake inhibitor (SSRI), has other effects in addition to blocking serotonin reuptake, including changes in the vasomotor tone. Whereas many studies focused on the acute effects of fluoxetine in the vasculature, its chronic effects are still limited. In the present study, we tested the hypothesis that chronic fluoxetine treatment modulates adrenergic vascular responses by interfering with post- and pre-synaptic mechanisms. Wistar rats were treated with vehicle (water) or chronic fluoxetine (10mg/kg/day) for 21 days. Blood pressure (BP) and heart rate were measured. Vascular reactivity was evaluated in perfused mesenteric arterial beds (MAB) and in mesenteric resistance arteries. Protein expression by western blot analysis or immunohistochemistry, β-arrestin recruitment by BRET and calcium influx by FLIPR assay. Fluoxetine treatment decreased phenylephrine (PE)-induced, but not electrical-field stimulation (EFS)-induced vasoconstriction. Fluoxetine-treated rats exhibited increased KCl-induced vasoconstriction, which was abolished by prazosin. Desipramine, an inhibitor of norepinephrine (NA) reuptake, increased EFS-induced vasoconstrictor response in vehicle-treated, but not in fluoxetine-treated rats. Chronic treatment did not alter vascular expression of α 1 adrenoceptor, phosphorylation of PKCα or ERK 1/2 and RhoA. On the other hand, vascular contractions to calcium (Ca 2+ ) as well as Ca 2+ influx in mesenteric arteries were increased, while intracellular Ca 2+ storage was decreased by the chronic treatment with fluoxetine. In vitro, fluoxetine decreased vascular contractions to PE, EFS and Ca 2+ , but did not change β-arrestin activity. In conclusion, chronic treatment with fluoxetine decreases sympathetic-mediated vascular responses by mechanisms that involve inhibition of NA release/reuptake and decreased Ca 2+ stores. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Suppression of Calpain Expression by NSAIDs is Associated with Inhibition of Cell Migration in Rat Duodenum

    PubMed Central

    Silver, Kristopher; Littlejohn, A.; Thomas, Laurel; Bawa, Bhupinder; Lillich, James D.

    2017-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for the alleviation of pain and inflammation, but these drugs are also associated with a suite of negative side effects. Gastrointestinal (GI) toxicity is particularly concerning since it affects an estimated 70% of individuals taking NSAIDs routinely, and evidence suggests the majority of toxicity is occurring in the small intestine. Traditionally, NSAID-induced GI toxicity has been associated with indiscriminate inhibition of cyclooxygenase isoforms, but other mechanisms, including inhibition of cell migration, intestinal restitution, and wound healing, are likely to contribute to toxicity. Previous efforts demonstrated that treatment of cultured intestinal epithelial cells (IEC) with NSAIDs inhibits expression and activity of calpain proteases, but the effects of specific inhibition of calpain expression in vitro or the effects of NSAIDs on intestinal cell migration in vivo remain to be determined. Accordingly, we examined the effect of suppression of calpain protease expression with siRNA on cell migration in cultured IECs and evaluated the effects of NSAID treatment on epithelial cell migration and calpain protease expression in rat duodenum. Our results show that calpain siRNA inhibits protease expression and slows migration in cultured IECs. Additionally, NSAID treatment of rats slowed migration up the villus axis and suppressed calpain expression in duodenal epithelial cells. Our results are supportive of the hypothesis that suppression of calpain expression leading to slowing of cell migration is a potential mechanism through which NSAIDs cause GI toxicity. PMID:28342779

  2. Acute inhibition of neurosteroid estrogen synthesis suppresses status epilepticus in an animal model

    PubMed Central

    Sato, Satoru M; Woolley, Catherine S

    2016-01-01

    Status epilepticus (SE) is a common neurological emergency for which new treatments are needed. In vitro studies suggest a novel approach to controlling seizures in SE: acute inhibition of estrogen synthesis in the brain. Here, we show in rats that systemic administration of an aromatase (estrogen synthase) inhibitor after seizure onset strongly suppresses both electrographic and behavioral seizures induced by kainic acid (KA). We found that KA-induced SE stimulates synthesis of estradiol (E2) in the hippocampus, a brain region commonly involved in seizures and where E2 is known to acutely promote neural activity. Hippocampal E2 levels were higher in rats experiencing more severe seizures. Consistent with a seizure-promoting effect of hippocampal estrogen synthesis, intra-hippocampal aromatase inhibition also suppressed seizures. These results reveal neurosteroid estrogen synthesis as a previously unknown factor in the escalation of seizures and suggest that acute administration of aromatase inhibitors may be an effective treatment for SE. DOI: http://dx.doi.org/10.7554/eLife.12917.001 PMID:27083045

  3. Considerations in choosing a primary endpoint that measures durability of virological suppression in an antiretroviral trial.

    PubMed

    Gilbert, P B; Ribaudo, H J; Greenberg, L; Yu, G; Bosch, R J; Tierney, C; Kuritzkes, D R

    2000-09-08

    At present, many clinical trials of anti-HIV-1 therapies compare treatments by a primary endpoint that measures the durability of suppression of HIV-1 replication. Several durability endpoints are compared. Endpoints are compared by their implicit assumptions regarding surrogacy for clinical outcomes, sample size requirements, and accommodations for inter-patient differences in baseline plasma HIV-1-RNA levels and in initial treatment response. Virological failure is defined by the non-suppression of virus levels at a prespecified follow-up time T(early virological failure), or by relapse. A binary virological failure endpoint is compared with three time-to-virological failure endpoints: time from (i) randomization that assigns early failures a failure time of T weeks; (ii) randomization that extends the early failure time T for slowly responding subjects; and (iii) virological response that assigns non-responders a failure time of 0 weeks. Endpoint differences are illustrated with Agouron's trial 511. In comparing high with low-dose nelfinavir (NFV) regimens in Agouron 511, the difference in Kaplan-Meier estimates of the proportion not failing by 24 weeks is 16.7% (P = 0.048), 6.5% (P = 0.29) and 22.9% (P = 0.0030) for endpoints (i), (ii) and (iii), respectively. The results differ because NFV suppresses virus more quickly at the higher dose, and the endpoints weigh this treatment difference differently. This illustrates that careful consideration needs to be given to choosing a primary endpoint that will detect treatment differences of interest. A time from randomization endpoint is usually recommended because of its advantages in flexibility and sample size, especially at interim analyses, and for its interpretation for patient management.

  4. Viral blips during suppressive antiretroviral treatment are associated with high baseline HIV-1 RNA levels.

    PubMed

    Sörstedt, Erik; Nilsson, Staffan; Blaxhult, Anders; Gisslén, Magnus; Flamholc, Leo; Sönnerborg, Anders; Yilmaz, Aylin

    2016-06-21

    Many HIV-1-infected patients on suppressive antiretroviral therapy (ART) have transiently elevated HIV RNA levels. The clinical significance of these viral blips is uncertain. We have determined the incidence of blips and investigated important associations in the Swedish HIV-cohort. HIV-1-infected ART naïve adults who commenced ART 2007-2013 were retrospectively included. Viral blips were defined as a transient viral load between 50 and 500 copies/mL Subjects not suppressed after six months on ART were excluded. Viral blips were found in 76/735 included subjects (10.3 %) and in 90/4449 samples (2.0 %). Median blip viral load was 76 copies/mL (range 56-138). Median follow-up time was 170 weeks (range 97-240). Baseline viral load was higher in subjects with viral blips (median log10 4.85 copies/mL) compared with subjects without blips (median log10 4.55 copies/mL) (p < 0.01). There was a significant association between viral blips and risk for subsequent virological failure (p < 0.001). The Swedish national HIV-cohort has a low incidence of viral blips (10 %). Blips were associated with high baseline viral load and an increased risk of subsequent virological failure.

  5. Impacts of suppressing guide on information spreading

    NASA Astrophysics Data System (ADS)

    Xu, Jinghong; Zhang, Lin; Ma, Baojun; Wu, Ye

    2016-02-01

    It is quite common that guides are introduced to suppress the information spreading in modern society for different purposes. In this paper, an agent-based model is established to quantitatively analyze the impacts of suppressing guides on information spreading. We find that the spreading threshold depends on the attractiveness of the information and the topology of the social network with no suppressing guides at all. Usually, one would expect that the existence of suppressing guides in the spreading procedure may result in less diffusion of information within the overall network. However, we find that sometimes the opposite is true: the manipulating nodes of suppressing guides may lead to more extensive information spreading when there are audiences with the reversal mind. These results can provide valuable theoretical references to public opinion guidance on various information, e.g., rumor or news spreading.

  6. Sevoflurane suppresses proliferation by upregulating microRNA-203 in breast cancer cells.

    PubMed

    Liu, Jiaying; Yang, Longqiu; Guo, Xia; Jin, Guangli; Wang, Qimin; Lv, Dongdong; Liu, Junli; Chen, Qiu; Song, Qiong; Li, Baolin

    2018-05-03

    Rapid proliferation is one of the critical characteristics of breast cancer. However, the underlying regulatory mechanism of breast cancer cell proliferation is largely unclear. The present study indicated that sevoflurane, one of inhalational anesthetics, could significantly suppress breast cancer cell proliferation by arresting cell cycle at G1 phase. Notably, the rescue experiment indicated that miR-203 was upregulated by sevoflurane and mediated the function of sevoflurane on suppressing the breast cancer cell proliferation. The present study indicated the function of the sevoflurane/miR-203 signaling pathway on regulating breast cancer cell proliferation. These results provide mechanistic insight into how the sevoflurane/miR-203 signaling pathway supresses proliferation of breast cancer cells, suggesting the sevoflurane/miR-203 pathway may be a potential target in the treatment of breast cancer.

  7. Tranexamic acid suppresses ultraviolet B eye irradiation-induced melanocyte activation by decreasing the levels of prohormone convertase 2 and alpha-melanocyte-stimulating hormone.

    PubMed

    Hiramoto, Keiichi; Yamate, Yurika; Sugiyama, Daijiro; Takahashi, Yumi; Mafune, Eiichi

    2014-12-01

    Tranexamic acid (trans-4-aminomethylcyclohexanecarboxylic acid) is a medicinal amino acid used in skin whitening care. This study examined the effects of tranexamic acid on the melanocyte activation of the skin induced by an ultraviolet (UV) B eye irradiation. The eye or ear was locally exposed to UVB at a dose of 1.0 kJ/m(2) using a 20SE sunlamp after covering the remaining body surface with aluminum foil. UVB eye irradiation induced melanocyte activation of the skin, similar to that observed following UVB ear irradiation, which was suppressed by the administration of tranexamic acid treatment. The plasma α-melanocyte-stimulating hormone (α-MSH) content was increased by UVB irradiation of the eye; however, the increase in α-MSH was suppressed by tranexamic acid treatment. In addition, UVB eye irradiation induced the up-regulation of prohormone convertase (PC) 2 in the pituitary gland. Meanwhile, the increase in PC2 induced by UVB eye irradiation was suppressed by tranexamic acid treatment. These results clearly indicate that tranexamic acid decreases the expression of PC2, which cleavages from proopiomelanocortin to α-MSH in the pituitary gland, thereby suppressing melanocyte activation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. The SIRT1 inhibitor EX-527 suppresses mTOR activation and alleviates acute lung injury in mice with endotoxiemia.

    PubMed

    Huang, Jing; Tian, Rui; Yang, Yongqiang; Jiang, Rong; Dai, Jie; Tang, Li; Zhang, Li

    2017-11-01

    It is generally regarded that Sirtuin 1 (SIRT1), a longevity factor in mammals, acts as a negative regulator of inflammation. However, recent studies also found that SIRT1 might be a detrimental factor under certain inflammatory circumstance. In this study, the potential pathophysiological roles and the underlying mechanisms of SIRT1 in a mouse model with endotoxemia-associated acute lung injury were investigated. The results indicated that treatment with the selective SIRT1 inhibitor EX-527 suppressed LPS-induced elevation of TNF-α and IL-6 in plasma. Treatment with EX-527 attenuated LPS-induced histological abnormalities in lung tissue, which was accompanied with decreased myeloperoxidase level and suppressed induction of tissue factor and plasminogen activator inhibitor-1. Treatment with EX-527 also suppressed LPS-induced phosphorylation of eukaryotic translation initiation factor-binding protein 1 (4E-BP1). Co-administration of a mammalian target of rapamycin (mTOR) activator 3-benzyl-5-[(2-nitrophenoxy) methyl]-dihydrofuran-2 (3H)-one (3BDO) abolished the inhibitory effects of EX-527 on 4E-BP1 phosphorylation. Meanwhile, the inhibitory effects of EX-527 on IL-6 induction and the beneficial effects of EX-527 on lung injury were partially reversed by 3BDO. This study suggests that selective inhibition of SIRT1 by EX-527 might alleviate endotoxemia-associated acute lung injury partially via suppression of mTOR, which implies that SIRT1 selective inhibitors might have potential value for the pharmacological intervention of inflammatory lung injury.

  9. Suppressive effects of ketamine on macrophage functions

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Chang Yi; Department of Anesthesiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan; Chen, T.-L.

    2005-04-01

    Ketamine is an intravenous anesthetic agent. Clinically, induction of anesthesia with ketamine can cause immunosuppression. Macrophages play important roles in host defense. In this study, we attempted to evaluate the effects of ketamine on macrophage functions and its possible mechanism using mouse macrophage-like Raw 264.7 cells as the experimental model. Exposure of macrophages to 10 and 100 {mu}M ketamine, which correspond to 0.1 and 1 times the clinically relevant concentration, for 1, 6, and 24 h had no effect on cell viability or lactate dehydrogenase release. When the administered concentration reached 1000 {mu}M, ketamine caused a release of lactate dehydrogenasemore » and cell death. Ketamine, at 10 and 100 {mu}M, did not affect the chemotactic activity of macrophages. Administration of 1000 {mu}M ketamine in macrophages resulted in a decrease in cell migration. Treatment of macrophages with ketamine reduced phagocytic activities. The oxidative ability of macrophages was suppressed by ketamine. Treatment with lipopolysaccharide induced TNF-{alpha}, IL-1{beta}, and IL-6 mRNA in macrophages. Administration of ketamine alone did not influence TNF-{alpha}, IL-1{beta}, or IL-6 mRNA production. Meanwhile, cotreatment with ketamine and lipopolysaccharide significantly inhibited lipopolysaccharide-induced TNF-{alpha}, IL-1{beta}, and IL-6 mRNA levels. Exposure to ketamine led to a decrease in the mitochondrial membrane potential. However, the activity of mitochondrial complex I NADH dehydrogenase was not affected by ketamine. This study shows that a clinically relevant concentration of ketamine (100 {mu}M) can suppress macrophage function of phagocytosis, its oxidative ability, and inflammatory cytokine production possibly via reduction of the mitochondrial membrane potential instead of direct cellular toxicity.« less

  10. Nifekalant hydrochloride suppresses severe electrical storm in patients with malignant ventricular tachyarrhythmias.

    PubMed

    Washizuka, Takashi; Chinushi, Masaomi; Watanabe, Hiroshi; Hosaka, Yukio; Komura, Satoru; Sugiura, Hirotaka; Hirono, Takashi; Furushima, Hiroshi; Tanabe, Yasutaka; Aizawa, Yoshifusa

    2005-12-01

    Some patients with an implantable cardioverter-defibrillator (ICD) suffer from burst of inappropriate multiple discharges (severe electrical storm), and because the current therapeutic options are limited, the effect of nifekalant hydrochloride, a new class III drug, on severe electrical storm was investigated in the present study. Ninety-one consecutive patients treated with ICD were included in the study (M 70; mean age 58 years; left ventricular ejection fraction 45+/-15%). Severe electrical storm was defined as more than 10 ICD discharges within 1 h. During a mean follow-up period of 30+/-13 months, 41/91 (45%) patients had appropriate ICD therapy for arrhythmias and severe electrical storm occurred in 11 of them (12%) at 20+/-18 months after ICD implantation. The mean number of ICD discharges/h during severe electrical storm was 18+/-12. In 4 of 10 patients, severe electrical storm was successfully suppressed by a combination of deep sedation and beta-blocking agent; 6 other patients were refractory to this treatment, but severe electrical storm was successfully suppressed by intravenous administration of nifekalant hydrochloride with no adverse effects. Nifekalant hydrochloride is an effective and safe treatment for severe electrical storm.

  11. An Artesunate-Containing Antimalarial Treatment Regimen Did Not Suppress Cytomegalovirus Viremia

    PubMed Central

    Gantt, Soren; Huang, Meei-Li; Magaret, Amalia; Bunts, Lisa; Selke, Stacy; Wald, Anna; Rosenthal, Philip J.; Dorsey, Grant; Casper, Corey

    2014-01-01

    Background Additional drugs are needed for the treatment of cytomegalovirus (CMV) infection. Artesunate is an antimalarial drug that has activity against CMV in vitro and in a rodent model. Only a small number of case reports are available describing the clinical effects of artesunate on CMV infection, and these yielded inconsistent results. Objective To evaluate the effect of artesunate on CMV infection, using blood samples collected from children who participated in malaria treatment trials. Study design Quantitative CMV DNA PCR was performed on dried blood spots collected from 494 Ugandan children, who were randomized either to artesunate plus amodiaquine or sulfadoxine-pyrimethamine plus amodiaquine for acute malaria infection. Poisson regression was used to compare treatment regimens with respect to the change in the frequency and quantity of CMV detected that occurred before and after treatment. Results CMV was detected in 11.4% of children immediately prior to treatment and 10.7% 3 days later (p=0.70). The average quantity of CMV was 0.30 log10 copies per million cells higher on day 3 than at treatment initiation (95% CI 0.01 to 0.58, p=0.041). There was no measurable difference in either the frequency or quantity of CMV detected in blood between children randomized to the two treatment arms. Conclusions A standard 3-day artesunate-containing antimalarial regimen had no detectable effect on CMV viremia in children with malaria. Longer treatment courses and/or higher doses of artesunate than those routinely used for malaria may be required for effective treatment of CMV infection. PMID:23827788

  12. Chondromalacia patellae: fat-suppressed MR imaging.

    PubMed

    Rose, P M; Demlow, T A; Szumowski, J; Quinn, S F

    1994-11-01

    To evaluate the accuracy of fat-suppressed magnetic resonance (MR) imaging in diagnosing chondromalacia patellae. Seventy-one patients underwent fat-suppressed MR imaging and arthroscopy of the patellofemoral compartment. Findings were classified as early or advanced chondromalacia or as normal and were correlated with arthroscopic findings. Early and advanced stages of chondromalacia patellae were reliably detected, with positive predictive values of 85% and 92%, respectively. Specificity in early stages was 94% and in late stages was 98%. However, the overall accuracies did not differ substantially from those reported in studies that did not use fat-suppressed imaging. Axial, fat-suppressed MR imaging accurately depicts changes caused by chondromalacia patellae. Early stages can be seen as intrasubstance changes of increased signal intensity. Results of this study suggest a high degree of specificity in excluding both early and advanced changes.

  13. Interleukin-35 induces regulatory B cells that suppress autoimmune disease.

    PubMed

    Wang, Ren-Xi; Yu, Cheng-Rong; Dambuza, Ivy M; Mahdi, Rashid M; Dolinska, Monika B; Sergeev, Yuri V; Wingfield, Paul T; Kim, Sung-Hye; Egwuagu, Charles E

    2014-06-01

    Interleukin-10 (IL-10)-producing regulatory B (Breg) cells suppress autoimmune disease, and increased numbers of Breg cells prevent host defense to infection and promote tumor growth and metastasis by converting resting CD4(+) T cells to regulatory T (Treg) cells. The mechanisms mediating the induction and development of Breg cells remain unclear. Here we show that IL-35 induces Breg cells and promotes their conversion to a Breg subset that produces IL-35 as well as IL-10. Treatment of mice with IL-35 conferred protection from experimental autoimmune uveitis (EAU), and mice lacking IL-35 (p35 knockout (KO) mice) or defective in IL-35 signaling (IL-12Rβ2 KO mice) produced less Breg cells endogenously or after treatment with IL-35 and developed severe uveitis. Adoptive transfer of Breg cells induced by recombinant IL-35 suppressed EAU when transferred to mice with established disease, inhibiting pathogenic T helper type 17 (TH17) and TH1 cells while promoting Treg cell expansion. In B cells, IL-35 activates STAT1 and STAT3 through the IL-35 receptor comprising the IL-12Rβ2 and IL-27Rα subunits. As IL-35 also induced the conversion of human B cells into Breg cells, these findings suggest that IL-35 may be used to induce autologous Breg and IL-35(+) Breg cells and treat autoimmune and inflammatory disease.

  14. Oral contraceptive therapy for polycystic ovary disease after chronic gonadotropin-releasing agonist administration. Predictors of continued ovarian suppression.

    PubMed

    Elkind-Hirsch, K E; Anania, C; Malinak, R

    1996-09-01

    To study the beneficial effects of oral contraceptive (OC) therapy following gonadotropin-releasing hormone agonist (GnRH-a) administration in women with polycystic ovary disease (PCOD). Twenty-three hyperandrogenic women (aged 15-39) were randomized into two groups; GnRH-a (depot every 28 days) for six months or combination therapy (GnRH-a plus OC "addback") for six months. Following six months of treatment with either therapy, all patients received OC therapy for at least six months. The hormonal state was evaluated at three-month intervals. Hormone levels of luteinizing hormone (LH), testosterone (T) and free T remained suppressed within the normal range in 11 of 17 patients (65%) during the six months of OC only therapy, while the other six patients showed "escape" from suppression, with the LH, T and free T concentrations rising to pre-GnRH-a treatment levels. Use of OC addback therapy did not potentiate the long-acting therapeutic effect of GnRH-a pretreatment; three of six patients in the escape group were pretreated with combination therapy and three with GnRH-a only. In the majority of women with PCOD, OC therapy following GnRH-a administration was effective in maintaining ovarian androgen suppression. Failure to maintain ovarian suppression in this patient population was associated with higher elevations of baseline free T concentrations.

  15. Evaluation of Hypothalamic-Pituitary-Adrenal Axis Suppression following Cutaneous Use of Topical Corticosteroids in Children: A Meta-Analysis.

    PubMed

    Wood Heickman, Lauren K; Davallow Ghajar, Ladan; Conaway, Mark; Rogol, Alan D

    2018-06-13

    A meta-analysis was performed to determine the likelihood of hypothalamic-pituitary-adrenal (HPA) axis suppression following short-term cutaneous treatment of atopic dermatitis with topical corticosteroids (TCS) in pediatric patients. All published pediatric clinical trials evaluating TCS use with pre- and post-treatment HPA axis assessment by cosyntropin stimulation testing were included. Of 128 eligible trials, 12 were selected for meta-analysis with a total of 522 participants. There were 20 observed cases of HPA axis suppression (3.8%, 95% CI 2.4-5.8). The percentage of HPA axis suppression with low- (classes 6-7), medium- (classes 3-5) and high-potency (classes 1-2) TCS use was 2% (3 of 148 patients, 95% CI 0.7-5.8), 3.1% (7 of 223 patients, 95% CI 1.5-6.3), and 6.6% (10 of 151 patients, 95% CI 3.6-11.8), respectively. There is a low rate of reversible HPA axis suppression with the use of mid- to low-potency TCS compared to more potent formulations. In pediatric clinical practice, the limited use of mid- to low-potency TCS is rarely associated with clinically significant adrenal insufficiency or adrenal crisis. In the absence of signs and symptoms of adrenal insufficiency, there is little need to test the HPA axis of these patients. © 2018 S. Karger AG, Basel.

  16. Suppressed visual looming stimuli are not integrated with auditory looming signals: Evidence from continuous flash suppression.

    PubMed

    Moors, Pieter; Huygelier, Hanne; Wagemans, Johan; de-Wit, Lee; van Ee, Raymond

    2015-01-01

    Previous studies using binocular rivalry have shown that signals in a modality other than the visual can bias dominance durations depending on their congruency with the rivaling stimuli. More recently, studies using continuous flash suppression (CFS) have reported that multisensory integration influences how long visual stimuli remain suppressed. In this study, using CFS, we examined whether the contrast thresholds for detecting visual looming stimuli are influenced by a congruent auditory stimulus. In Experiment 1, we show that a looming visual stimulus can result in lower detection thresholds compared to a static concentric grating, but that auditory tone pips congruent with the looming stimulus did not lower suppression thresholds any further. In Experiments 2, 3, and 4, we again observed no advantage for congruent multisensory stimuli. These results add to our understanding of the conditions under which multisensory integration is possible, and suggest that certain forms of multisensory integration are not evident when the visual stimulus is suppressed from awareness using CFS.

  17. U1 Adaptor Oligonucleotides Targeting BCL2 and GRM1 Suppress Growth of Human Melanoma Xenografts In Vivo

    PubMed Central

    Goraczniak, Rafal; Wall, Brian A; Behlke, Mark A; Lennox, Kim A; Ho, Eric S; Zaphiros, Nikolas H; Jakubowski, Christopher; Patel, Neil R; Zhao, Steven; Magaway, Carlo; Subbie, Stacey A; Jenny Yu, Lumeng; LaCava, Stephanie; Reuhl, Kenneth R; Chen, Suzie; Gunderson, Samuel I

    2013-01-01

    U1 Adaptor is a recently discovered oligonucleotide-based gene-silencing technology with a unique mechanism of action that targets nuclear pre-mRNA processing. U1 Adaptors have two distinct functional domains, both of which must be present on the same oligonucleotide to exert their gene-silencing function. Here, we present the first in vivo use of U1 Adaptors by targeting two different human genes implicated in melanomagenesis, B-cell lymphoma 2 (BCL2) and metabotropic glutamate receptor 1 (GRM1), in a human melanoma cell xenograft mouse model system. Using a newly developed dendrimer delivery system, anti-BCL2 U1 Adaptors were very potent and suppressed tumor growth at doses as low as 34 µg/kg with twice weekly intravenous (iv) administration. Anti-GRM1 U1 Adaptors suppressed tumor xenograft growth with similar potency. Mechanism of action was demonstrated by showing target gene suppression in tumors and by observing that negative control U1 Adaptors with just one functional domain show no tumor suppression activity. The anti-BCL2 and anti-GRM1 treatments were equally effective against cell lines harboring either wild-type or a mutant V600E B-RAF allele, the most common mutation in melanoma. Treatment of normal immune-competent mice (C57BL6) indicated no organ toxicity or immune stimulation. These proof-of-concept studies represent an in-depth (over 800 mice in ~108 treatment groups) validation that U1 Adaptors are a highly potent gene-silencing therapeutic and open the way for their further development to treat other human diseases. PMID:23673539

  18. Familiarity-Based Stimulus Generalization of Conditioned Suppression

    PubMed Central

    2017-01-01

    We report that stimulus novelty/familiarity is able to modulate stimulus generalization and discuss the theoretical implications of novelty/familiarity coding. Rats in Skinner boxes received clicker → shock pairings before generalization testing to a tone. Before clicker training, different groups of rats received preexposure treatments designed to systematically modulate the clicker and the tone’s novelty and familiarity. Rats whose preexposure matched novelty/familiarity (i.e., either both or neither clicker and tone were preexposed) showed enhanced suppression to the tone relative to rats whose preexposure mixed novelty/familiarity (i.e., only clicker or tone was preexposed). This was not the result of sensory preconditioning to clicker and tone. PMID:28383938

  19. Quantifying the potential impacts of fuel treatments on wildfire suppression costs

    Treesearch

    Matthew P. Thompson; Nicole M. Vaillant; Jessica R. Haas; Krista M. Gebert; Keith D. Stockmann

    2013-01-01

    Modeling the impacts and effects of hazardous fuel reduction treatments is a pressing issue within the wildfire management community. Prospective evaluation of fuel treatment effectiveness allows for comparison of alternative treatment strategies in terms of socioeconomic and ecological impacts and facilitates analysis of tradeoffs across land-management objectives....

  20. Suppression of compensating native defect formation during semiconductor processing via excess carriers

    NASA Astrophysics Data System (ADS)

    Alberi, K.; Scarpulla, M. A.

    2016-06-01

    In many semiconductors, compensating defects set doping limits, decrease carrier mobility, and reduce minority carrier lifetime thus limiting their utility in devices. Native defects are often responsible. Suppressing the concentrations of compensating defects during processing close to thermal equilibrium is difficult because formation enthalpies are lowered as the Fermi level moves towards the majority band edge. Excess carriers, introduced for example by photogeneration, modify the formation enthalpy of semiconductor defects and thus can be harnessed during crystal growth or annealing to suppress defect populations. Herein we develop a rigorous and general model for defect formation in the presence of steady-state excess carrier concentrations by combining the standard quasi-chemical formalism with a detailed-balance description that is applicable for any defect state in the bandgap. Considering the quasi-Fermi levels as chemical potentials, we demonstrate that increasing the minority carrier concentration increases the formation enthalpy for typical compensating centers, thus suppressing their formation. This effect is illustrated for the specific example of GaSb. While our treatment is generalized for excess carrier injection or generation in semiconductors by any means, we provide a set of guidelines for applying the concept in photoassisted physical vapor deposition.

  1. Development of damage suppression system using embedded SMA foil sensor and actuator

    NASA Astrophysics Data System (ADS)

    Ogisu, Toshimichi; Nomura, Masato; Ando, Norio; Takaki, Junji; Song, Dong Y.; Takeda, Nobuo

    2000-06-01

    The recent studies suggest possible applications of shape memory alloy (SMA) for a smart health monitoring and suppression of damage growth. The authors have been conducting research and development studies on applications of embedded SMA foil sensors and actuators in CFRP laminates. The goal of this research is suppression of damage growth in CFRP laminates. At first, the authors proposed a concept of damage suppression in CFRP laminates. Then, the development studies are conducted in three phases. The first phase is the improvement of interlaminar shear strength between SMA and CFRP laminates. Some surface treatments were investigated for the improvement of bonding property by peel resistance test and single lap shear strength test. The second phase is the investigation of fabrication technique for producing a CFRP panel with embedded SMA foils. Fixture jigs were devised to introduce tensile loads during the fabrication process. The third phase is the strength demonstration of CFRP laminates with embedded SMA foils. Some strength test were conducted to obtain the design data for aircraft structures. It is confirmed that the shrinking force of pre-strained SMA influences to the strength and the crack density of CFRP panel.

  2. Suppressive effects of 3-bromopyruvate on the proliferation and the motility of hepatocellular carcinoma cells.

    PubMed

    Tomizawa, Minoru; Shinozaki, Fuminobu; Motoyoshi, Yasufumi; Sugiyama, Takao; Yamamoto, Shigenori; Ishige, Naoki

    2016-01-01

    The compound 3-bromopyruvate (3BP) is an analogue of pyruvate, which is the final product of glycolysis that enters the citric acid cycle. The present study aimed to investigate the suppressive effects of 3BP on the proliferation and motility of hepatocellular carcinoma (HCC) cells. HLF and PLC/PRF/5 cells were cultured with 3BP and subjected to an MTS assay. Apoptosis was analyzed by hematoxylin and eosin staining. Cell motility was analyzed using a scratch assay. Real-time quantitative polymerase chain reaction (PCR) was performed to determine the expression levels of cyclin D1 and matrix metalloproteinase (MMP)9. Proliferation of both cell lines was significantly suppressed by 3BP at 100 µM (P<0.05). The expression level of cyclin D1 was decreased after 3BP treatment at 100 µM in both cell lines (P<0.05). Pyknotic nuclei were observed in the cells cultured with 3BP at 100 µM. These results revealed that 3BP suppressed cell proliferation, decreased the expression of cyclin D1, and induced apoptosis in HCC cells. 3BP significantly suppressed motility in both cell lines (P<0.05). The expression level of MMP9 was significantly decreased (P<0.05). 3BP suppressed the proliferation and motility of HCC cells by decreasing the expression of cyclin D1 and MMP9.

  3. Ethylene signaling renders the jasmonate response of Arabidopsis insensitive to future suppression by salicylic Acid.

    PubMed

    Leon-Reyes, Antonio; Du, Yujuan; Koornneef, Annemart; Proietti, Silvia; Körbes, Ana P; Memelink, Johan; Pieterse, Corné M J; Ritsema, Tita

    2010-02-01

    Cross-talk between jasmonate (JA), ethylene (ET), and Salicylic acid (SA) signaling is thought to operate as a mechanism to fine-tune induced defenses that are activated in response to multiple attackers. Here, 43 Arabidopsis genotypes impaired in hormone signaling or defense-related processes were screened for their ability to express SA-mediated suppression of JA-responsive gene expression. Mutant cev1, which displays constitutive expression of JA and ET responses, appeared to be insensitive to SA-mediated suppression of the JA-responsive marker genes PDF1.2 and VSP2. Accordingly, strong activation of JA and ET responses by the necrotrophic pathogens Botrytis cinerea and Alternaria brassicicola prior to SA treatment counteracted the ability of SA to suppress the JA response. Pharmacological assays, mutant analysis, and studies with the ET-signaling inhibitor 1-methylcyclopropene revealed that ET signaling renders the JA response insensitive to subsequent suppression by SA. The APETALA2/ETHYLENE RESPONSE FACTOR transcription factor ORA59, which regulates JA/ET-responsive genes such as PDF1.2, emerged as a potential mediator in this process. Collectively, our results point to a model in which simultaneous induction of the JA and ET pathway renders the plant insensitive to future SA-mediated suppression of JA-dependent defenses, which may prioritize the JA/ET pathway over the SA pathway during multi-attacker interactions.

  4. Effect of Patient Navigation With or Without Financial Incentives on Viral Suppression Among Hospitalized Patients With HIV Infection and Substance Use

    PubMed Central

    Metsch, Lisa R.; Feaster, Daniel J.; Gooden, Lauren; Matheson, Tim; Stitzer, Maxine; Das, Moupali; Jain, Mamta K.; Rodriguez, Allan E.; Armstrong, Wendy S.; Lucas, Gregory M.; Nijhawan, Ank E.; Drainoni, Mari-Lynn; Herrera, Patricia; Vergara-Rodriguez, Pamela; Jacobson, Jeffrey M.; Mugavero, Michael J.; Sullivan, Meg; Daar, Eric S.; McMahon, Deborah K.; Ferris, David C.; Lindblad, Robert; VanVeldhuisen, Paul; Oden, Neal; Castellón, Pedro C.; Tross, Susan; Haynes, Louise F.; Douaihy, Antoine; Sorensen, James L.; Metzger, David S.; Mandler, Raul N.; Colfax, Grant N.; del Rio, Carlos

    2017-01-01

    IMPORTANCE Substance use is a major driver of the HIV epidemic and is associated with poor HIV care outcomes. Patient navigation (care coordination with case management) and the use of financial incentives for achieving predetermined outcomes are interventions increasingly promoted to engage patients in substance use disorders treatment and HIV care, but there is little evidence for their efficacy in improving HIV-1 viral suppression rates. OBJECTIVE To assess the effect of a structured patient navigation intervention with or without financial incentives to improve HIV-1 viral suppression rates among patients with elevated HIV-1 viral loads and substance use recruited as hospital inpatients. DESIGN, SETTING, AND PARTICIPANTS From July 2012 through January 2014, 801 patients with HIV infection and substance use from 11 hospitals across the United States were randomly assigned to receive patient navigation alone (n = 266), patient navigation plus financial incentives (n = 271), or treatment as usual (n = 264). HIV-1 plasma viral load was measured at baseline and at 6 and 12 months. INTERVENTIONS Patient navigation included up to 11 sessions of care coordination with case management and motivational interviewing techniques over 6 months. Financial incentives (up to $1160) were provided for achieving targeted behaviors aimed at reducing substance use, increasing engagement in HIV care, and improving HIV outcomes. Treatment as usual was the standard practice at each hospital for linking hospitalized patients to outpatient HIV care and substance use disorders treatment. MAIN OUTCOMES AND MEASURES The primary outcome was HIV viral suppression (≤200 copies/mL) relative to viral nonsuppression or death at the 12-month follow-up. RESULTS Of 801 patients randomized, 261 (32.6%) were women (mean [SD] age, 44.6 years [10.0 years]). There were no differences in rates of HIV viral suppression versus nonsuppression or death among the 3 groups at 12 months. Eighty-five of 249

  5. Ferromagnetic resonance probe liftoff suppression apparatus

    DOEpatents

    Davis, Thomas J.; Tomeraasen, Paul L.

    1985-01-01

    A liftoff suppression apparatus utilizing a liftoff sensing coil to sense the amount a ferromagnetic resonance probe lifts off the test surface during flaw detection and utilizing the liftoff signal to modulate the probe's field modulating coil to suppress the liftoff effects.

  6. Suppression of Iron-Regulatory Hepcidin by Vitamin D

    PubMed Central

    Bacchetta, Justine; Zaritsky, Joshua J.; Sea, Jessica L.; Chun, Rene F.; Lisse, Thomas S.; Zavala, Kathryn; Nayak, Anjali; Wesseling-Perry, Katherine; Westerman, Mark; Hollis, Bruce W.; Salusky, Isidro B.

    2014-01-01

    The antibacterial protein hepcidin regulates the absorption, tissue distribution, and extracellular concentration of iron by suppressing ferroportin-mediated export of cellular iron. In CKD, elevated hepcidin and vitamin D deficiency are associated with anemia. Therefore, we explored a possible role for vitamin D in iron homeostasis. Treatment of cultured hepatocytes or monocytes with prohormone 25-hydroxyvitamin D or active 1,25-dihydroxyvitamin D decreased expression of hepcidin mRNA by 0.5-fold, contrasting the stimulatory effect of 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D on related antibacterial proteins such as cathelicidin. Promoter-reporter and chromatin immunoprecipitation analyses indicated that direct transcriptional suppression of hepcidin gene (HAMP) expression mediated by 1,25-dihydroxyvitamin D binding to the vitamin D receptor caused the decrease in hepcidin mRNA levels. Suppression of HAMP expression was associated with a concomitant increase in expression of the cellular target for hepcidin, ferroportin protein, and decreased expression of the intracellular iron marker ferritin. In a pilot study with healthy volunteers, supplementation with a single oral dose of vitamin D (100,000 IU vitamin D2) increased serum levels of 25D-hydroxyvitamin D from 27±2 ng/ml before supplementation to 44±3 ng/ml after supplementation (P<0.001). This response was associated with a 34% decrease in circulating levels of hepcidin within 24 hours of vitamin D supplementation (P<0.05). These data show that vitamin D is a potent regulator of the hepcidin-ferroportin axis in humans and highlight a potential new strategy for the management of anemia in patients with low vitamin D and/or CKD. PMID:24204002

  7. Aging and the depth of binocular rivalry suppression.

    PubMed

    Norman, J Farley; Norman, Hideko F; Pattison, Kristina; Taylor, M Jett; Goforth, Katherine E

    2007-09-01

    Two experiments were designed to examine the effect of aging on the strength of binocular rivalry suppression. To produce rivalry, orthogonally oriented sine-wave luminance gratings were presented dichoptically. The observers were then required either to discriminate the spatial location of a probe spot presented to the dominant or suppressed eye's view or to detect the presence or absence of the probe. The observers in the younger and older age groups exhibited typical rivalry suppression for both tasks (i.e., the probe was more difficult to detect or discriminate when presented to the suppressed eye), but the magnitude of the suppression was significantly larger in the older observers. This increased suppression that accompanies aging can be explained by a reduction in the inhibition produced by the binocular matching circuitry of S. R. Lehky and R. Blake's (1991) model. (PsycINFO Database Record (c) 2007 APA, all rights reserved).

  8. Punishment in human choice: direct or competitive suppression?

    PubMed Central

    Critchfield, Thomas S; Paletz, Elliott M; MacAleese, Kenneth R; Newland, M Christopher

    2003-01-01

    This investigation compared the predictions of two models describing the integration of reinforcement and punishment effects in operant choice. Deluty's (1976) competitive-suppression model (conceptually related to two-factor punishment theories) and de Villiers' (1980) direct-suppression model (conceptually related to one-factor punishment theories) have been tested previously in nonhumans but not at the individual level in humans. Mouse clicking by college students was maintained in a two-alternative concurrent schedule of variable-interval money reinforcement. Punishment consisted of variable-interval money losses. Experiment 1 verified that money loss was an effective punisher in this context. Experiment 2 consisted of qualitative model comparisons similar to those used in previous studies involving nonhumans. Following a no-punishment baseline, punishment was superimposed upon both response alternatives. Under schedule values for which the direct-suppression model, but not the competitive-suppression model, predicted distinct shifts from baseline performance, or vice versa, 12 of 14 individual-subject functions, generated by 7 subjects, supported the direct-suppression model. When the punishment models were converted to the form of the generalized matching law, least-squares linear regression fits for a direct-suppression model were superior to those of a competitive-suppression model for 6 of 7 subjects. In Experiment 3, a more thorough quantitative test of the modified models, fits for a direct-suppression model were superior in 11 of 13 cases. These results correspond well to those of investigations conducted with nonhumans and provide the first individual-subject evidence that a direct-suppression model, evaluated both qualitatively and quantitatively, describes human punishment better than a competitive-suppression model. We discuss implications for developing better punishment models and future investigations of punishment in human choice. PMID:13677606

  9. A Review of the Suppression of Secondary Electron Emission from the Electrodes of Multistage Collectors

    NASA Technical Reports Server (NTRS)

    Dayton, James A., Jr.

    1998-01-01

    A review is presented of more than 20 years of research conducted at NASA Lewis Research Center on the suppression of secondary electron emission (SEE) for the enhancement of the efficiency of vacuum electron devices with multistage depressed collectors. This paper will include a description of measurement techniques, data from measurements of SEE on a variety of materials of engineering interest and methods of surface treatment for the suppression of SEE. In the course of this work the lowest secondary electron yield ever reported was achieved for ion textured graphite, and, in a parallel line of research, the highest yield was obtained for chemical vapor deposited thin diamond films.