Science.gov

Sample records for nonresponders hiv-coinfected patients

  1. HIV coinfection shortens the survival of patients with hepatitis C virus-related decompensated cirrhosis.

    PubMed

    Pineda, Juan A; Romero-Gómez, Manuel; Díaz-García, Fernando; Girón-González, José A; Montero, José L; Torre-Cisneros, Julián; Andrade, Raúl J; González-Serrano, Mercedes; Aguilar, José; Aguilar-Guisado, Manuela; Navarro, José M; Salmerón, Javier; Caballero-Granado, Francisco J; García-García, José A

    2005-04-01

    The impact of human immunodeficiency virus (HIV) coinfection on the survival of patients with hepatitis C virus (HCV)-related end-stage liver disease (ESLD) is unknown. Because HIV infection is no longer considered an absolute contraindication for liver transplantation in some countries, it has become a priority to address this topic. The objective of this study was to compare the survival of HIV-infected and HIV-uninfected patients with decompensated cirrhosis due to HCV. In a retrospective cohort study, the survival of 1,037 HCV monoinfected and 180 HCV/HIV-coinfected patients with cirrhosis after the first hepatic decompensation was analyzed. Of the group, 386 (37%) HCV-monoinfected and 100 (56%) HCV/HIV-coinfected subjects died during the follow-up. The median survival time of HIV-infected and HIV-uninfected patients was 16 and 48 months, respectively (P < .001). The relative risk (95% CI) of death for HIV-infected patients was 2.26 (1.51-3.38). Other independent predictors of survival were age older than 63 years (2.25 [1.53-3.31]); Child-Turcotte-Pugh class B versus class A (1.95 [1.41-2.68]) and class C versus class A (2.78 [1.66-4.70]); hepatitis D virus infection (1.56 [1.12-4.77]); model for end-stage liver disease score, (1.05 [1.01-1-11]); more than one simultaneous decompensation (1.23 [1.12-3.33]); and the type of the first hepatic decompensation, with a poorer prognosis associated with encephalopathy compared with portal hypertensive gastrointestinal bleeding (2.03 [1.26-3.10]). In conclusion, HIV coinfection reduces considerably the survival of patients with HCV-related ESLD independently of other markers of poor prognosis. This fact must be taken into account to establish the adequate timing of liver transplantation in HIV-coinfected subjects.

  2. Modulation of HCV Replication After Combination Antiretroviral Therapy in HCV/HIV Coinfected Patients

    PubMed Central

    Sherman, Kenneth E.; Guedj, Jeremie; Shata, Mohamed Tarek; Blackard, Jason T.; Rouster, Susan D.; Castro, Mario; Feinberg, Judith; Sterling, Richard K.; Goodman, Zachary; Aronow, Bruce J.; Perelson, Alan S.

    2015-01-01

    The hepatitis C virus (HCV) is an important contributor to morbidity and mortality in patients coinfected with human immunodeficiency virus (HIV). Coinfection results in increased HCV replication and more rapid rates of liver disease progression. The effect of HIV combination antiretroviral therapy (cART) on HCV replication has not been studied in depth. To address this issue, we enrolled a small cohort of HCV/HIV coinfected patients into a cART initiation trial, and used dynamic modeling combined with evaluation of immune responses and microarray profiles to determine how effective treatment of HIV affects HCV. Treatment with cART resulted in HCV flare and alanine aminotransferase (ALT) increase (2× or more increase from baseline) in a subset of treated patients. Subjects with evidence of hepatic injury (increased ALT) were more likely to have HCV-specific immune responses directed against HCV epitopes. Over time, HCV viral loads declined. Reproducible and biologically important gene expression changes occurred in patients who underwent successful cART, particularly with respect to downregulation of genes with known antiviral roles. Our findings suggest that the effective suppression of HIV by cART initiates a cascade of early and late events in treated patients with HCV. Early events involving downregulation of interferon-stimulated genes may lead to transiently increased viral replication and hepatic injury. At later time points, HCV viral load declines to levels comparable to those seen in the setting of HCV monoinfection. These findings support early antiretroviral therapy in those with HCV/HIV coinfection. PMID:25101888

  3. Granzyme B as a diagnostic marker of tuberculosis in patients with and without HIV coinfection.

    PubMed

    Sarkar, Pronoti; Mitra, Soumik; Pant, Priyannk; Kotwal, Aarti; Kakati, Barnali; Masih, Victor; Sindhwani, Girish; Biswas, Debasis

    2016-05-01

    Immunodiagnostic tests for tuberculosis (TB) are based on the estimation of interferon γ (IFN-γ) or IFN-γ-secreting CD4(+) T cells following ex vivo stimulation with ESAT6 and CFP-10. Sensitivity of these tests is likely to be compromised in CD4(+) T-cell-depleted situations, like HIV-TB coinfection. CD4(+) and CD8(+) T cells, isolated from 3 groups, viz., HIV-negative patients with active TB, HIV-TB coinfected patients, and healthy household contacts (HHCs) were cocultivated with autologous dendritic cells, and the cytokine response to rESAT6 stimulation was compared between groups in supernatants. While CD4(+) T-cell stimulation yielded significantly elevated levels of IFN-γ and interleukin 4 in HIV-negative TB patients, compared to HHCs, the levels of both these cytokines were nondiscriminatory between HIV-positive TB patients and HHCs. However, CD8(+) T-cell stimulation yielded significantly elevated granzyme B titers in both groups of patients, irrespective of HIV coinfection status. Hence, contrary to IFN-γ, granzyme B might be a useful diagnostic marker for Mycobacterium tuberculosis infection particularly in HIV coinfected patients.

  4. Intrahepatic CD4+ cell depletion in hepatitis C virus/HIV-coinfected patients.

    PubMed

    Canchis, P Wilfredo; Yee, Herman T; Fiel, M Isabel; Dieterich, Douglas T; Liu, Ruei-Che; Chiriboga, Luis; Jacobson, Ira M; Edlin, Brian R; Talal, Andrew H

    2004-09-01

    Coinfection with HIV and hepatitis C virus (HCV)-specific immune responses, increases hepatic inflammation, accelerates hepatic fibrosis, and is associated with deceased treatment responses. We quantified intrahepatic lymphocyte and hepatocyte phenotypes in HCV-infected patients with (n = 38) and without (n = 41) HIV infection. A single pathologist counted positive cells in 5 portal and 5 lobular areas. Coinfected patients had 6.81 +/- 1.9 fewer CD4 cells per portal field (10.58 +/- 1.12 vs. 4.97 +/- 1.09 cells/high-power field [HPF]; P < 0.001) and 0.48 +/- 0.15 more apoptotic lymphocytes per lobular field (0.16 +/- 0.06 vs. 0.64 +/- 0.15 cell/HPF; P = 0.002) than monoinfected patients. The number of portal CD4 cells was not associated with the peripheral CD4 cell number. Portal and lobular CD8 cells did not differ between the 2 groups. Portal proliferative hepatocytes were increased in coinfected patients with HIV RNA levels of >400 copies/mL (1.13 +/- 0.32 cells/HPF; P = 0.01) compared with those with undetectable HIV RNA (0.46 +/- 0.09 cell/HPF) and monoinfected patients (0.45 +/- 0.08 cell/HPF). In conclusion, HIV coinfection is associated with fewer portal CD4 cells and increased lobular lymphocyte apoptosis that may impact on the natural history of HCV infection.

  5. Successful Treatment of Hepatitis C with Simeprevir, Sofosbuvir, and Ribavirin in an HIV Coinfected Liver Transplant Patient with Advanced Chronic Kidney Disease.

    PubMed

    Maruyama, Anna; Hussaini, Trana; Partovi, Nilufar; Erb, Siegfried R; Azalgara, Vladimir Marquez; Zalunardo, Nadia; Pick, Neora; Hull, Mark; Yoshida, Eric M

    2016-01-01

    Although major advances have occurred in treating patients with hepatitis C virus (HCV) with the development of new direct-acting antivirals (DAAs), treatment of liver transplant recipients with HCV, human immunodeficiency virus (HIV) coinfection, and renal disease is challenging due to the lack of efficacy and safety data in this population. We report a case of successful HCV therapy in a postliver transplant HIV coinfected patient, with stage 4 chronic kidney disease, using an all-oral regimen of simeprevir, sofosbuvir, and ribavirin. The 51-year-old male achieved SVR24, and no specific HIV-related or transplant-related adverse events were documented during the treatment period. The new DAAs show promise for HIV coinfected patients and those with severe to end-stage renal disease (ESRD); however, robust clinical trials or large cohort studies will need to be conducted to confirm the efficacy and safety of these newer agents in this setting.

  6. Liver Damage in Patients with HCV/HIV Coinfection Is Linked to HIV-Related Oxidative Stress

    PubMed Central

    Huang, Xiangbo; Liang, Hua; Fan, Xueying; Zhu, Liyan; Shen, Tao

    2016-01-01

    HIV infection aggravates the progression of liver damage in HCV-coinfected patients, with the underlying pathogenesis being multifactorial. Although high level of oxidative stress has been observed frequently in patients infected with HIV or HCV, the status of oxidative stress in HIV/HCV coinfection and its contribution to HCV liver damage have not been determined. This study involved 363 HBsAg-negative, anti-HCV-positive former blood donors recruited from a village in central China in July 2005; of these, 140 were positive for HIV. Of these 363 subjects, 282 were successfully followed up through July 2009. HIV/HCV-coinfected subjects had higher rates of end-stage liver disease-related death than those monoinfected with HCV. Liver ultrasound manifestations were poor in HIV-positive than in HIV-negative individuals, in both chronic HCV carriers and those with resolved HCV. Serum concentrations of total glutathione (tGSH), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), GSSG, and reduced GSH were higher in HIV-positive than HIV-negative subjects. GSSG concentrations were higher in HIV-infected subjects with abnormal ALT/AST levels than in those with normal ALT/AST levels and were associated with poorer liver ultrasound manifestations. These finding indicated that HIV infection accelerated HCV-associated liver damage in HIV/HCV-coinfected individuals. Increased oxidative stress, induced primarily by HIV coinfection, may contribute to aggravated liver damage. PMID:26881041

  7. Treatment Options for Visceral Leishmaniasis and HIV Coinfection.

    PubMed

    Monge-Maillo, Begoña; López-Vélez, Rogelio

    2016-01-01

    Leishmania and HIV coinfection is a major health problem in more than 35 countries worldwide. The impaired immune function of visceral leishmaniasis/HIV-coinfected patients may: (i) favor the reactivation of latent Leishmania infection; (ii) induce a more severe presentation of visceral leishmaniasis; (iii) cause a poorer therapeutic response; and (iv) increase the risk of relapse after treatment. One of the major challenges in the management of visceral leishmaniasis/HIV coinfection is developing an effective drug therapy that not only resolves the first episode of visceral leishmaniasis but also prevents relapse. However, scarce evidence and data are available on the optimal therapy for visceral leishmaniasis/HIV coinfection. In our study we reviewed the efficacy of several drugs currently employed for visceral leishmaniasis in HIV patients and current knowledge of secondary prophylaxis. Additionally, we reviewed a set of ongoing clinical trials that are being performed to evaluate the efficacy of new therapeutic regimens for visceral leishmaniasis in patients with and without HIV. Finally, other therapeutic strategies based on immunotherapy, vaccination, or screening for latent leishmaniasis infection in HIV patients are reviewed. Apart from being potentially useful in clinical practice, the results obtained in our study highlight the need for further research on the management of visceral leishmaniasis/HIV coinfection.

  8. Major Challenges in Clinical Management of TB/HIV Coinfected Patients in Eastern Europe Compared with Western Europe and Latin America

    PubMed Central

    Efsen, Anne Marie W.; Schultze, Anna; Post, Frank A.; Panteleev, Alexander; Furrer, Hansjakob; Miller, Robert F.; Losso, Marcelo H.; Toibaro, Javier; Skrahin, Aliaksandr; Miro, Jose M.; Caylà, Joan A.; Girardi, Enrico; Bruyand, Mathias; Obel, Niels; Podlekareva, Daria N.; Lundgren, Jens D.; Mocroft, Amanda; Kirk, Ole

    2015-01-01

    Objectives Rates of TB/HIV coinfection and multi-drug resistant (MDR)-TB are increasing in Eastern Europe (EE). We aimed to study clinical characteristics, factors associated with MDR-TB and predicted activity of empiric anti-TB treatment at time of TB diagnosis among TB/HIV coinfected patients in EE, Western Europe (WE) and Latin America (LA). Design and Methods Between January 1, 2011, and December 31, 2013, 1413 TB/HIV patients (62 clinics in 19 countries in EE, WE, Southern Europe (SE), and LA) were enrolled. Results Significant differences were observed between EE (N = 844), WE (N = 152), SE (N = 164), and LA (N = 253) in the proportion of patients with a definite TB diagnosis (47%, 71%, 72% and 40%, p<0.0001), MDR-TB (40%, 5%, 3% and 15%, p<0.0001), and use of combination antiretroviral therapy (cART) (17%, 40%, 44% and 35%, p<0.0001). Injecting drug use (adjusted OR (aOR) = 2.03 (95% CI 1.00–4.09), prior anti-TB treatment (3.42 (1.88–6.22)), and living in EE (7.19 (3.28–15.78)) were associated with MDR-TB. Among 585 patients with drug susceptibility test (DST) results, the empiric (i.e. without knowledge of the DST results) anti-TB treatment included ≥3 active drugs in 66% of participants in EE compared with 90–96% in other regions (p<0.0001). Conclusions In EE, TB/HIV patients were less likely to receive a definite TB diagnosis, more likely to house MDR-TB and commonly received empiric anti-TB treatment with reduced activity. Improved management of TB/HIV patients in EE requires better access to TB diagnostics including DSTs, empiric anti-TB therapy directed at both susceptible and MDR-TB, and more widespread use of cART. PMID:26716686

  9. Breaking down the barriers to hepatitis C virus (HCV) treatment among individuals with HCV/HIV coinfection: action required at the system, provider, and patient levels.

    PubMed

    Grebely, Jason; Oser, Megan; Taylor, Lynn E; Dore, Gregory J

    2013-03-01

    The majority of hepatitis C virus (HCV) and human immunodeficiency virus (HIV) coinfection occurs among persons who inject drugs. Rapid improvements in responses to HCV therapy have been observed, but liver-related morbidity rates remain high, given notoriously low uptake of HCV treatment. Advances in HCV therapy will have a limited impact on the burden of HCV-related disease at the population-level unless barriers to HCV education, screening, evaluation, and treatment are addressed and treatment uptake increases. This review will outline barriers to HCV care in HCV/HIV coinfection, with a particular emphasis on persons who inject drugs, proposing strategies to enhance HCV treatment uptake and outcomes.

  10. Influence of IL28B Polymorphisms on Response to a Lower-Than-Standard Dose peg-IFN-α 2a for Genotype 3 Chronic Hepatitis C in HIV-Coinfected Patients

    PubMed Central

    López-Cortés, Luis F.; Ruiz-Valderas, Rosa; Jimenez-Jimenez, Luis; González-Escribano, María F.; Torres-Cornejo, Almudena; Mata, Rosario; Rivero, Antonio; Pineda, Juan A.; Marquez-Solero, Manuel; Viciana, Pompeyo

    2012-01-01

    Background Data on which to base definitive recommendations on the doses and duration of therapy for genotype 3 HCV/HIV-coinfected patients are scarce. We evaluated the efficacy of a lower peginterferon-α 2a dose and a shorter duration of therapy than the current standard of care in genotype 3 HCV/HIV-coinfected patients. Methods and Findings Pilot, open-label, single arm clinical trial which involved 58 Caucasian HCV/HIV-coinfected patients who received weekly 135 µg peginterferon-α 2a plus ribavirin 400 mg twice daily during 20 weeks after attaining undetectable viremia. The relationships between baseline patient-related variables, including IL28B genotype, plasma HCV-RNA, ribavirin dose/kg, peginterferon-α 2a and ribavirin levels with virological responses were analyzed. Only 4 patients showed lack of response and 5 patients dropped out due to adverse events related to the study medication. Overall, sustained virologic response (SVR) rates were 58.3% by intention-to-treat and 71.4% by per protocol analysis, respectively. Among patients with rapid virologic response (RVR), SVR and relapses rates were 92.6% and 7.4%, respectively. No relationships were observed between viral responses and ribavirin dose/kg, peginterferon-α 2a concentrations, ribavirin levels or rs129679860 genotype. Conclusions Weekly 135 µg pegIFN-α 2a could be as effective as the standard 180 µg dose, with a very low incidence of severe adverse events. A 24-week treatment duration appears to be appropriate in patients achieving RVR, but extending treatment up to just 20 weeks beyond negativization of viremia is associated with a high relapse rate in those patients not achieving RVR. There was no influence of IL28B genotype on the virological responses. Trial Registration: ClinicalTrials.gov NCT00553930 PMID:22235243

  11. Visceral Leishmaniasis and HIV Coinfection in the Mediterranean Region

    PubMed Central

    Monge-Maillo, Begoña; Norman, Francesca F.; Cruz, Israel; Alvar, Jorge; López-Vélez, Rogelio

    2014-01-01

    Visceral leishmaniasis is hypoendemic in Mediterranean countries, where it is caused by the flagellate protozoan Leishmania infantum. VL cases in this area account for 5%–6% of the global burden. Cases of Leishmania/HIV coinfection have been reported in the Mediterranean region, mainly in France, Italy, Portugal, and Spain. Since highly active antiretroviral therapy was introduced in 1997, a marked decrease in the number of coinfected cases in this region has been reported. The development of new diagnostic methods to accurately identify level of parasitemia and the risk of relapse is one of the main challenges in improving the treatment of coinfected patients. Clinical trials in the Mediterranean region are needed to determine the most adequate therapeutic options for Leishmania/HIV patients as well as the indications and regimes for secondary prophylaxis. This article reviews the epidemiological, diagnostic, clinical, and therapeutic aspects of Leishmania/HIV coinfection in the Mediterranean region. PMID:25144380

  12. The Need to Reevaluate Nonresponding Ergonomic Patients

    NASA Technical Reports Server (NTRS)

    Scarpa, Philip J.; Field, Steven A.

    1999-01-01

    The Kennedy Space Center (KSC) Environmental Health (EH) contractor performs ergonomic evaluations under its Ergonomic Program. Any KSC employee may request one or the reviewing physician may request one for a patient during a visit to an onsite medical facility. As part of the ergonomic evaluation, recommendations are given to the patient to help reduce any ergonomic problems they experience. The recommendations, if implemented, are successful in the majority of KSC patients; however, a group of patients do not seem to improve. Those who don't improve may be identified by reevaluations, which are performed to implement maximum resolution of ergonomic problems.

  13. Visceral Leishmaniasis and HIV coinfection in East Africa.

    PubMed

    Diro, Ermias; Lynen, Lutgarde; Ritmeijer, Koert; Boelaert, Marleen; Hailu, Asrat; van Griensven, Johan

    2014-06-01

    Visceral Leishmaniasis (VL) is an important protozoan opportunistic disease in HIV patients in endemic areas. East Africa is second to the Indian subcontinent in the global VL caseload and first in VL-HIV coinfection rate. Because of the alteration in the disease course, the diagnostic challenges, and the poor treatment responses, VL with HIV coinfection has become a very serious challenge in East Africa today. Field experience with the use of liposomal amphotericin B in combination with miltefosine, followed by secondary prophylaxis and antiretroviral drugs, looks promising. However, this needs to be confirmed through clinical trials. Better diagnostic and follow-up methods for relapse and prediction of relapse should also be looked for. Basic research to understand the immunological interaction of the two infections may ultimately help to improve the management of the coinfection.

  14. Visceral Leishmaniasis and HIV Coinfection in Latin America

    PubMed Central

    Lindoso, José Angelo; Cota, Gláucia Fernandes; da Cruz, Alda Maria; Goto, Hiro; Maia-Elkhoury, Ana Nilce Silveira; Romero, Gustavo Adolfo Sierra; de Sousa-Gomes, Márcia Leite; Santos-Oliveira, Joanna Reis; Rabello, Ana

    2014-01-01

    Visceral leishmaniasis (VL) is an endemic zoonotic disease in Latin America caused by Leishmania (Leishmania) infantum, which is transmitted by sand flies from the genus Lutzomyia. VL occurs in 12 countries of Latin America, with 96% of cases reported in Brazil. Recently, an increase in VL, primarily affecting children and young adults, has been observed in urban areas of Latin America. The area in which this spread of VL is occurring overlaps regions with individuals living with HIV, the number of whom is estimated to be 1.4 million people by the World Health Organization. This overlap is suggested to be a leading cause of the increased number of reported VL-HIV coinfections. The clinical progression of HIV and L. infantum infections are both highly dependent on the specific immune response of an individual. Furthermore, the impact on the immune system caused by either pathogen and by VL-HIV coinfection can contribute to an accelerated progression of the diseases. Clinical presentation of VL in HIV positive patients is similar to patients without HIV, with symptoms characterized by fever, splenomegaly, and hepatomegaly, but diarrhea appears to be more common in coinfected patients. In addition, VL relapses are higher in coinfected patients, affecting 10% to 56.5% of cases and with a lethality ranging from 8.7% to 23.5% in Latin America, depending on the study. With regards to the diagnosis of VL, parasitological tests of bone marrow aspirates have proven to be the most sensitive test in HIV-infected patients. Serologic tests have demonstrated a variable sensitivity according to the method and antigens used, with the standard tests used for diagnosing VL in Latin America displaying lower sensitivity. For this review, few articles were identified that related to VL-HIV coinfections and originated from Latin America, highlighting the need for improving research within the regions most greatly affected. We strongly support the formation of a Latin American network for

  15. Visceral leishmaniasis and HIV coinfection in Latin America.

    PubMed

    Lindoso, José Angelo; Cota, Gláucia Fernandes; da Cruz, Alda Maria; Goto, Hiro; Maia-Elkhoury, Ana Nilce Silveira; Romero, Gustavo Adolfo Sierra; de Sousa-Gomes, Márcia Leite; Santos-Oliveira, Joanna Reis; Rabello, Ana

    2014-09-01

    Visceral leishmaniasis (VL) is an endemic zoonotic disease in Latin America caused by Leishmania (Leishmania) infantum, which is transmitted by sand flies from the genus Lutzomyia. VL occurs in 12 countries of Latin America, with 96% of cases reported in Brazil. Recently, an increase in VL, primarily affecting children and young adults, has been observed in urban areas of Latin America. The area in which this spread of VL is occurring overlaps regions with individuals living with HIV, the number of whom is estimated to be 1.4 million people by the World Health Organization. This overlap is suggested to be a leading cause of the increased number of reported VL-HIV coinfections. The clinical progression of HIV and L. infantum infections are both highly dependent on the specific immune response of an individual. Furthermore, the impact on the immune system caused by either pathogen and by VL-HIV coinfection can contribute to an accelerated progression of the diseases. Clinical presentation of VL in HIV positive patients is similar to patients without HIV, with symptoms characterized by fever, splenomegaly, and hepatomegaly, but diarrhea appears to be more common in coinfected patients. In addition, VL relapses are higher in coinfected patients, affecting 10% to 56.5% of cases and with a lethality ranging from 8.7% to 23.5% in Latin America, depending on the study. With regards to the diagnosis of VL, parasitological tests of bone marrow aspirates have proven to be the most sensitive test in HIV-infected patients. Serologic tests have demonstrated a variable sensitivity according to the method and antigens used, with the standard tests used for diagnosing VL in Latin America displaying lower sensitivity. For this review, few articles were identified that related to VL-HIV coinfections and originated from Latin America, highlighting the need for improving research within the regions most greatly affected. We strongly support the formation of a Latin American network for

  16. Leishmaniasis–HIV coinfection: current challenges

    PubMed Central

    Lindoso, José Angelo Lauletta; Cunha, Mirella Alves; Queiroz, Igor Thiago; Moreira, Carlos Henrique Valente

    2016-01-01

    Leishmaniasis – human immunodeficiency virus (HIV) coinfection can manifest itself as tegumentary or visceral leishmaniasis. Almost 35 countries have reported autochthonous coinfections. Visceral leishmaniasis is more frequently described. However, usual and unusual manifestations of tegumentary leishmaniasis have been reported mainly in the Americas, but the real prevalence of Leishmania infection in HIV-infected patients is not clear. Regarding the clinical manifestations, there are some reports showing unusual manifestations in visceral leishmaniasis and tegumentary leishmaniasis in HIV-infected patients; yet, the usual manifestations are more frequent. Leishmaniasis diagnosis relies on clinical methods, but serological tests are used to diagnose visceral leishmaniasis despite them having a low sensitivity to tegumentary leishmaniasis. The search for the parasite is used to diagnose both visceral leishmaniasis and tegumentary leishmaniasis. Nevertheless, in HIV-infected patients, the sensitivity of serology is very low. Drugs available to treat leishmaniasis are more restricted and cause severe side effects. Furthermore, in HIV-infected patients, these side effects are more prominent and relapses and lethality are more recurrent. In this article, we discuss the current challenges of tegumentary leishmaniasis and visceral leishmaniasis–HIV infection, focusing mainly on the clinical manifestations, diagnosis, and treatment of leishmaniasis. PMID:27785103

  17. Pharmacokinetics of rifampin and isoniazid in tuberculosis-HIV-coinfected patients receiving nevirapine- or efavirenz-based antiretroviral treatment.

    PubMed

    Bhatt, N B; Barau, C; Amin, A; Baudin, E; Meggi, B; Silva, C; Furlan, V; Grinsztejn, B; Barrail-Tran, A; Bonnet, M; Taburet, A M

    2014-06-01

    This is a substudy of the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS) Comparison of Nevirapine and Efavirenz for the Treatment of HIV-TB Co-infected Patients (ANRS 12146-CARINEMO) trial, which assessed the pharmacokinetics of rifampin or isoniazid with or without the coadministration of nonnucleoside reverse transcriptase inhibitor-based HIV antiretroviral therapy in HIV-tuberculosis-coinfected patients in Mozambique. Thirty-eight patients on antituberculosis therapy based on rifampin and isoniazid participated in the substudy (57.9% males; median age, 33 years; median weight, 51.9 kg; median CD4(+) T cell count, 104 cells/μl; median HIV-1 RNA load, 5.5 log copies/ml). The daily doses of rifampin and isoniazid were 10 and 5 mg/kg of body weight, respectively. Twenty-one patients received 200 mg of nevirapine twice a day (b.i.d.), and 17 patients received 600 mg of efavirenz once a day (q.d.) in combination with lamivudine and stavudine from day 1 until the end of the study. Blood samples were collected at regular time-dosing intervals after morning administration of a fixed-dose combination of rifampin and isoniazid. When rifampin was administered alone, the median maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve (AUC) at steady state were 6.59 mg/liter (range, 2.70 to 14.07 mg/liter) and 27.69 mg · h/liter (range, 11.41 to 109.75 mg · h/liter), respectively. Concentrations remained unchanged when rifampin was coadministered with nevirapine or efavirenz. When isoniazid was administered alone, the median isoniazid Cmax and AUC at steady state were 5.08 mg/liter (range, 1.26 to 11.51 mg/liter) and 20.92 mg · h/liter (range, 7.73 to 56.95 mg · h/liter), respectively. Concentrations remained unchanged when isoniazid was coadministered with nevirapine; however, a 29% decrease in the isoniazid AUC was observed when isoniazid was combined with efavirenz. The pharmacokinetic parameters of

  18. Pharmacokinetics of Rifampin and Isoniazid in Tuberculosis-HIV-Coinfected Patients Receiving Nevirapine- or Efavirenz-Based Antiretroviral Treatment

    PubMed Central

    Bhatt, N. B.; Barau, C.; Amin, A.; Baudin, E.; Meggi, B.; Silva, C.; Furlan, V.; Grinsztejn, B.; Barrail-Tran, A.; Bonnet, M.

    2014-01-01

    This is a substudy of the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS) Comparison of Nevirapine and Efavirenz for the Treatment of HIV-TB Co-infected Patients (ANRS 12146-CARINEMO) trial, which assessed the pharmacokinetics of rifampin or isoniazid with or without the coadministration of nonnucleoside reverse transcriptase inhibitor-based HIV antiretroviral therapy in HIV-tuberculosis-coinfected patients in Mozambique. Thirty-eight patients on antituberculosis therapy based on rifampin and isoniazid participated in the substudy (57.9% males; median age, 33 years; median weight, 51.9 kg; median CD4+ T cell count, 104 cells/μl; median HIV-1 RNA load, 5.5 log copies/ml). The daily doses of rifampin and isoniazid were 10 and 5 mg/kg of body weight, respectively. Twenty-one patients received 200 mg of nevirapine twice a day (b.i.d.), and 17 patients received 600 mg of efavirenz once a day (q.d.) in combination with lamivudine and stavudine from day 1 until the end of the study. Blood samples were collected at regular time-dosing intervals after morning administration of a fixed-dose combination of rifampin and isoniazid. When rifampin was administered alone, the median maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve (AUC) at steady state were 6.59 mg/liter (range, 2.70 to 14.07 mg/liter) and 27.69 mg · h/liter (range, 11.41 to 109.75 mg · h/liter), respectively. Concentrations remained unchanged when rifampin was coadministered with nevirapine or efavirenz. When isoniazid was administered alone, the median isoniazid Cmax and AUC at steady state were 5.08 mg/liter (range, 1.26 to 11.51 mg/liter) and 20.92 mg · h/liter (range, 7.73 to 56.95 mg · h/liter), respectively. Concentrations remained unchanged when isoniazid was coadministered with nevirapine; however, a 29% decrease in the isoniazid AUC was observed when isoniazid was combined with efavirenz. The pharmacokinetic parameters of

  19. Deconvoluting the Composition of Low-Frequency Hepatitis C Viral Quasispecies: Comparison of Genotypes and NS3 Resistance-Associated Variants between HCV/HIV Coinfected Hemophiliacs and HCV Monoinfected Patients in Japan

    PubMed Central

    Ogishi, Masato; Yotsuyanagi, Hiroshi; Tsutsumi, Takeya; Gatanaga, Hiroyuki; Ode, Hirotaka; Sugiura, Wataru; Moriya, Kyoji; Oka, Shinichi; Kimura, Satoshi; Koike, Kazuhiko

    2015-01-01

    Pre-existing low-frequency resistance-associated variants (RAVs) may jeopardize successful sustained virological responses (SVR) to HCV treatment with direct-acting antivirals (DAAs). However, the potential impact of low-frequency (∼0.1%) mutations, concatenated mutations (haplotypes), and their association with genotypes (Gts) on the treatment outcome has not yet been elucidated, most probably owing to the difficulty in detecting pre-existing minor haplotypes with sufficient length and accuracy. Herein, we characterize a methodological framework based on Illumina MiSeq next-generation sequencing (NGS) coupled with bioinformatics of quasispecies reconstruction (QSR) to realize highly accurate variant calling and genotype-haplotype detection. The core-to-NS3 protease coding sequences in 10 HCV monoinfected patients, 5 of whom had a history of blood transfusion, and 11 HCV/HIV coinfected patients with hemophilia, were studied. Simulation experiments showed that, for minor variants constituting more than 1%, our framework achieved a positive predictive value (PPV) of 100% and sensitivities of 91.7–100% for genotyping and 80.6% for RAV screening. Genotyping analysis indicated the prevalence of dominant Gt1a infection in coinfected patients (6/11 vs 0/10, p = 0.01). For clinical samples, minor genotype overlapping infection was prevalent in HCV/HIV coinfected hemophiliacs (10/11) and patients who experienced whole-blood transfusion (4/5) but none in patients without exposure to blood (0/5). As for RAV screening, the Q80K/R and S122K/R variants were particularly prevalent among minor RAVs observed, detected in 12/21 and 6/21 cases, respectively. Q80K was detected only in coinfected patients, whereas Q80R was predominantly detected in monoinfected patients (1/11 vs 7/10, p < 0.01). Multivariate interdependence analysis revealed the previously unrecognized prevalence of Gt1b-Q80K, in HCV/HIV coinfected hemophiliacs [Odds ratio = 13.4 (3.48–51.9), p < 0.01]. Our study

  20. Impact of lopinavir-ritonavir or nevirapine on bedaquiline exposures and potential implications for patients with tuberculosis-HIV coinfection.

    PubMed

    Svensson, Elin M; Dooley, Kelly E; Karlsson, Mats O

    2014-11-01

    Concomitant treatment of tuberculosis (TB) and HIV is recommended and improves outcomes. Bedaquiline is a novel drug for the treatment of multidrug-resistant (MDR) TB; combined use with antiretroviral drugs, nevirapine, or ritonavir-boosted lopinavir (LPV/r) is anticipated, but no clinical data from coinfected patients are available. Plasma concentrations of bedaquiline and its M2 metabolite after single doses were obtained from interaction studies with nevirapine or LPV/r in healthy volunteers. The antiretrovirals' effects on bedaquiline and M2 pharmacokinetics were assessed by nonlinear mixed-effects modeling. Potential dose adjustments were evaluated with simulations. No significant effects of nevirapine on bedaquiline pharmacokinetics were identified. LPV/r decreased bedaquiline and M2 clearances to 35% (relative standard error [RSE], 9.2%) and 58% (RSE, 8.4%), respectively, of those without comedication. As almost 3-fold (bedaquiline) and 2-fold (M2) increases in exposures during chronic treatment with LPV/r are expected, dose adjustments are suggested for evaluation. Efficacious, safe bedaquiline dosing for MDR-TB patients receiving antiretrovirals is important. Modeling results suggest that bedaquiline can be coadministered with nevirapine without dose adjustments. The predicted elevation of bedaquiline and M2 levels during LPV/r coadministration may be a safety concern, and careful monitoring is recommended. Further data are being collected in coinfected patients to determine whether dose adjustments are needed. (These studies have been registered at ClinicalTrials.gov under registration numbers NCT00828529 [study C110] and NCT00910806 [study C117].).

  1. Tax gene characterization of human T-lymphotropic virus type 1 strains from Brazilian HIV-coinfected patients.

    PubMed

    Magri, Mariana Cavalheiro; Brigido, Luis Fernando de Macedo; Rodrigues, Rosangela; Morimoto, Helena Kaminami; Caterino-de-Araujo, Adele

    2012-12-01

    The tax gene of human T-lymphotropic virus type 1 (HTLV-1) diverges among isolates according to geographic regions and has been classified into two genotypes: taxA and taxB. In Brazil, taxA is the most prevalent genotype in symptomatic and asymptomatic carriers. Few studies have been conducted in HIV-infected patients. The present study characterized the tax gene (1059 bp) in 13 Brazilian HIV-1/HTLV-1-coinfected patients from the south and southeast regions. The results confirmed the transcontinental HTLV-1 subgroup A of the Cosmopolitan subtype and showed high nucleotide similarity both among Brazilian sequences and in relation to the ATK prototype (99.5% and 99.2%, respectively). Six nucleotide substitutions were highly conserved among isolates, ranging from 76.9% to 100%: C7401T, T7914C, C7920T, C7982T, G8231A, and A8367C. The presence of the Brazilian molecular signature of genotype taxA was confirmed in all of the isolates, and they clustered into two Latin American clusters, which confirms the double introduction of HTLV-1 in Brazil.

  2. Frequent injection cocaine use increases the risk of renal impairment among hepatitis C and HIV coinfected patients

    PubMed Central

    Rossi, Carmine; Cox, Joseph; Cooper, Curtis; Martel-Laferrière, Valérie; Walmsley, Sharon; Gill, John; Sapir-Pichhadze, Ruth; Moodie, Erica E.M.; Klein, Marina B.

    2016-01-01

    Objective: To examine the association between injection cocaine use, hepatitis C virus (HCV) infection, and chronic renal impairment (CRI). Design: Prospective observational cohort study of HIV–HCV coinfected patients. Methods: Data from 1129 participants in the Canadian Co-Infection Cohort with baseline and follow-up serum creatinine measurements between 2003 and 2014 were analyzed. Prevalent and incident cohorts were created to examine the association between self-reported past, current, and cumulative cocaine use and chronic HCV with CRI. CRI was defined as an estimated glomerular filtration rate below 70 ml/min per 1.73 m2. Multivariate logistic regression was used to calculate odds ratios, and discrete-time proportional-hazards models were used to calculate hazard ratios for cocaine use, in the two respective cohorts, adjusted for HCV RNA and important demographic, HIV disease stage, and comorbidity confounders. Results: Eighty-seven participants (8%) had prevalent CRI. Past injection cocaine use was associated with a two-fold greater risk of prevalent CRI [odds ratio 2.03, 95% confidence interval (CI) 0.96, 4.32]. During follow-up, 126 of 1061 participants (12%) developed incident CRI (31 per 1000 person-years). Compared to nonusers, heavy (≥ 3 days/week) and frequent injection cocaine users (≥75% of follow-up time) experienced more rapid progression to CRI (hazard ratio 2.65, 95% CI 1.35, 5.21; and hazard ratio 1.82, 95% CI 1.07, 3.07, respectively). There was no association between chronic HCV and CRI in either cohort. Conclusion: After accounting for HCV RNA, frequent and cumulative injection cocaine abuse was associated with CRI progression and should be taken into consideration when evaluating impaired renal function in HIV–HCV coinfection. PMID:26859371

  3. Prevalence of malaria and HIV coinfection and influence of HIV infection on malaria disease severity in population residing in malaria endemic area along the Thai-Myanmar border.

    PubMed

    Rattanapunya, Siwalee; Kuesap, Jiraporn; Chaijaroenkul, Wanna; Rueangweerayut, Ronnatrai; Na-Bangchang, Kesara

    2015-05-01

    The objective of the study is to investigate the prevalence of malaria and HIV coinfection and assess the effect of HIV coinfection on malaria disease severity in malaria patients from the endemic area of Thailand along the Thai-Myanmar border. Blood samples were collected from a total of 867 patients with malaria (all species and severity) who attended Mae Tao clinic for migrant workers, Tak Province during 2005-2007 (439 samples), 2008-2010 (273 samples), and 2011-2013 (155 samples). The average prevalence rate of malaria and HIV coinfected cases in this malaria endemic area of the country during the three periods was 1.85%. HIV coinfection was observed only in samples with mono-infection of Plasmodium falciparum or Plasmodium vivax, with similar proportions (0.81 vs. 1.04%). Patients' admission parasite density, an indicator of disease severity, was significantly higher in cases with HIV coinfection observed during 2008-2010. Anemia was found at a significantly higher frequency in patients coinfected with malaria and HIV observed during 2005-2007 compared with those infected with malaria alone. No association was observed between malaria and HIV coinfection and gender, and infected malaria species during the three observation periods. Patients with malaria and HIV coinfection had a significantly lower hemoglobin level than those with malaria infection alone. In conclusion, the prevalence of malaria and HIV coinfection in population of the malaria endemic area along the Thai-Myanmar border is low. HIV coinfection tended to increase parasite density, an indicator of malaria disease severity.

  4. Pharmacokinetics of para-Aminosalicylic Acid in HIV-Uninfected and HIV-Coinfected Tuberculosis Patients Receiving Antiretroviral Therapy, Managed for Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis

    PubMed Central

    de Kock, Lizanne; Sy, Sherwin K. B.; Diacon, Andreas H.; Prescott, Kim; Hernandez, Kenneth R.; Yu, Mingming; Derendorf, Hartmut; Donald, Peter R.

    2014-01-01

    The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis prompted the reintroduction of para-aminosalicylic acid (PAS) to protect companion anti-tuberculosis drugs from additional acquired resistance. In sub-Saharan Africa, MDR/XDR tuberculosis with HIV coinfection is common, and concurrent treatment of HIV infection and MDR/XDR tuberculosis is required. Out of necessity, patients receive multiple drugs, and PAS therapy is frequent; however, neither potential drug interactions nor the effects of HIV infection are known. Potential drug-drug interaction with PAS and the effect of HIV infection was examined in 73 pulmonary tuberculosis patients; 22 (30.1%) were HIV coinfected. Forty-one pulmonary MDR or XDR tuberculosis patients received 4 g PAS twice daily, and in a second crossover study, another 32 patients were randomized, receiving 4 g PAS twice daily or 8 g PAS once daily. A PAS population pharmacokinetic model in two dosing regimens was developed; potential covariates affecting its pharmacokinetics were examined, and Monte Carlo simulations were conducted evaluating the pharmacokinetic-pharmacodynamic index. The probability of target attainment (PTA) to maintain PAS levels above MIC during the dosing interval was estimated by simulation of once-, twice-, and thrice-daily dosing regimens not exceeding 12 g daily. Concurrent efavirenz (EFV) medication resulted in a 52% increase in PAS clearance and a corresponding >30% reduction in mean PAS area under the concentration curve in 19 of 22 HIV-M. tuberculosis-coinfected patients. Current practice recommends maintenance of PAS concentrations at ≥1 μg/ml (the MIC of M. tuberculosis), but the model predicts that at only a minimum dose of 4 g twice daily can this PTA be achieved in at least 90% of the population, whether or not EFV is concomitantly administered. Once-daily dosing of 12 g PAS will not provide PAS concentrations exceeding the MIC over the entire dosing

  5. Diagnosis, Clinical Presentation, and In-Hospital Mortality of Severe Malaria in HIV-Coinfected Children and Adults in Mozambique

    PubMed Central

    Hendriksen, Ilse C. E.; Ferro, Josefo; Montoya, Pablo; Chhaganlal, Kajal D.; Seni, Amir; Gomes, Ermelinda; Silamut, Kamolrat; Lee, Sue J.; Lucas, Marcelino; Chotivanich, Kesinee; Fanello, Caterina I.; Day, Nicholas P. J.; White, Nicholas J.; von Seidlein, Lorenz; Dondorp, Arjen M.

    2012-01-01

    Background. Severe falciparum malaria with human immunodeficiency virus (HIV) coinfection is common in settings with a high prevalence of both diseases, but there is little information on whether HIV affects the clinical presentation and outcome of severe malaria. Methods. HIV status was assessed prospectively in hospitalized parasitemic adults and children with severe malaria in Beira, Mozambique, as part of a clinical trial comparing parenteral artesunate versus quinine (ISRCTN50258054). Clinical signs, comorbidity, complications, and disease outcome were compared according to HIV status. Results. HIV-1 seroprevalence was 11% (74/655) in children under 15 years and 72% (49/68) in adults with severe malaria. Children with HIV coinfection presented with more severe acidosis, anemia, and respiratory distress, and higher peripheral blood parasitemia and plasma Plasmodium falciparum histidine-rich protein-2 (PfHRP2). During hospitalization, deterioration in coma score, convulsions, respiratory distress, and pneumonia were more common in HIV-coinfected children, and mortality was 26% (19/74) versus 9% (53/581) in uninfected children (P < .001). In an age- and antimalarial treatment–adjusted logistic regression model, significant, independent predictors for death were renal impairment, acidosis, parasitemia, and plasma PfHRP2 concentration. Conclusions. Severe malaria in HIV-coinfected patients presents with higher parasite burden, more complications, and comorbidity, and carries a higher case fatality rate. Early identification of HIV coinfection is important for the clinical management of severe malaria. PMID:22752514

  6. Risk of Hip Fracture Associated with Hepatitis C Virus Infection and Hepatitis C/HIV Coinfection

    PubMed Central

    Re, Vincent Lo; Volk, Jessica; Newcomb, Craig W.; Yang, Yu-Xiao; Freeman, Cristin P.; Hennessy, Sean; Kostman, Jay R.; Tebas, Pablo; Leonard, Mary B.; Localio, A. Russell

    2012-01-01

    Hepatitis C virus (HCV) infection has been associated with reduced bone mineral density, but its association with fracture rates is unknown, particularly in the setting of human immunodeficiency virus (HIV) coinfection. Our objectives were to determine whether persons with HCV infection alone are at increased risk for hip fracture compared to uninfected individuals and to examine if the risk of hip fracture is higher among HCV/HIV-coinfected persons compared to those with HCV alone, those with HIV alone, and those uninfected with either virus. We conducted a cohort study in 36,950 HCV/HIV-coinfected, 276,901HCV-monoinfected, 95,827 HIV-monoinfected, and 3,110,904 HCV/HIV-uninfected persons within the U.S. Medicaid populations of California, Florida, New York, Ohio, and Pennsylvania (1999–2005). Incidence rates of hip fracture were lowest among uninfected persons (1.29 events/1000 person-years), increased with the presence of either HIV infection (1.95 events/1000 person-years) or HCV infection (2.69 events/1000 person-years), and were highest among HCV/HIV-coinfected individuals (3.06 events/1000 person-years). HCV/HIV coinfection was associated with an increased relative hazard (adjusted hazard ratio [95% confidence interval]) of hip fracture compared to HCV-monoinfected (1.38 [1.25–1.53]), HIV-monoinfected (females: 1.76 [1.44–2.16]; males: 1.36 [1.20–1.55]), and uninfected persons (females: 2.65 [2.21–3.17]; males: 2.20 [1.97–2.47]). HCV monoinfection was associated with an increased risk of hip fracture compared to uninfected individuals, and the relative increase was highest in the youngest age groups (females, 18–39 years: 3.56 [2.93–4.32]; males, 18–39 years: 2.40 [2.02–2.84]). Conclusion Among Medicaid enrollees, HCV/HIV coinfection was associated with increased rates of hip fracture compared to HCV-monoinfected, HIV-monoinfected, and HCV/HIV-uninfected persons. HCV-monoinfected patients had an increased risk of hip fracture compared to

  7. Regression of liver fibrosis is progressive after sustained virological response to HCV therapy in patients with hepatitis C and HIV coinfection.

    PubMed

    Casado, J L; Quereda, C; Moreno, A; Pérez-Elías, M J; Martí-Belda, P; Moreno, S

    2013-12-01

    There are few data about the long-term histological outcome of HIV-/HCV-coinfected patients after therapy with interferon and ribavirin. We performed an observational study of 216 patients who received therapy against HCV and who had at least three successive transient elastographies (TE) during the follow-up. The primary endpoint was confirmed fibrosis regression, defined as a reduction of at least 1 point in Metavir fibrosis score, confirmed and without worsening in successive TE. At baseline, 23% had fibrosis stage 4 or cirrhosis. Overall, 82 (38%) achieved sustained virological response (SVR), without differences in baseline fibrosis or time of follow-up. Confirmed fibrosis regression was observed in 55% of patients, higher for SVR (71% vs 44%; P < 0.01), and the likelihood of achieving fibrosis regression at 3, 5 and 7 years was 0.17, 0.51 and 0.67, respectively, for SVR patients, in comparison with 0.02, 0.23 and 0.41 for no SVR patients (P < 0.01, log-rank test at any time point). Progressive regression, defined as continuous improvement in successive TE, was observed in 62% of patients with advanced liver fibrosis or cirrhosis who achieved SVR. In a Cox regression model, only SVR (HR, 4.01; 95% CI, 2.33-7.57; P < 0.01) and a younger age (HR, 1.14; 95% CI, 1.05-1.25; P < 0.01; per year) were associated with fibrosis regression. This study confirms that the rate of liver fibrosis regression increases during the follow-up after SVR to interferon therapy in HIV-/HCV-coinfected patients.

  8. Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode

    PubMed Central

    Belzeaux, R; Bergon, A; Jeanjean, V; Loriod, B; Formisano-Tréziny, C; Verrier, L; Loundou, A; Baumstarck-Barrau, K; Boyer, L; Gall, V; Gabert, J; Nguyen, C; Azorin, J-M; Naudin, J; Ibrahim, E C

    2012-01-01

    To date, it remains impossible to guarantee that short-term treatment given to a patient suffering from a major depressive episode (MDE) will improve long-term efficacy. Objective biological measurements and biomarkers that could help in predicting the clinical evolution of MDE are still warranted. To better understand the reason nearly half of MDE patients respond poorly to current antidepressive treatments, we examined the gene expression profile of peripheral blood samples collected from 16 severe MDE patients and 13 matched controls. Using a naturalistic and longitudinal design, we ascertained mRNA and microRNA (miRNA) expression at baseline, 2 and 8 weeks later. On a genome-wide scale, we detected transcripts with roles in various biological processes as significantly dysregulated between MDE patients and controls, notably those involved in nucleotide binding and chromatin assembly. We also established putative interactions between dysregulated mRNAs and miRNAs that may contribute to MDE physiopathology. We selected a set of mRNA candidates for quantitative reverse transcriptase PCR (RT-qPCR) to validate that the transcriptional signatures observed in responders is different from nonresponders. Furthermore, we identified a combination of four mRNAs (PPT1, TNF, IL1B and HIST1H1E) that could be predictive of treatment response. Altogether, these results highlight the importance of studies investigating the tight relationship between peripheral transcriptional changes and the dynamic clinical progression of MDE patients to provide biomarkers of MDE evolution and prognosis. PMID:23149449

  9. Stronger hepatitis C virus-specific CD8+ T-cell responses in HIV coinfection.

    PubMed

    Barrett, L; Gallant, M; Howley, C; Ian Bowmer, M; Hirsch, G; Peltekian, K; Grant, M

    2011-03-01

    Hepatitis C virus (HCV) is a widespread chronic infection that shares routes of transmission with human immunodeficiency virus (HIV). Thus, coinfection with these viruses is a relatively common and growing problem. In general, liver disease develops over years with HIV coinfection, when compared to decades in HCV monoinfection. The role of the immune system in the accelerated pathogenesis of liver disease in HIV/HCV coinfection is not clear. In this study, we compared the frequency, magnitude, breadth and specificity of peripheral blood CD4+ and CD8+ T-cell responses between HCV-monoinfected and HCV/HIV-coinfected individuals and between HIV/HCV-coinfected subgroups distinguished by anti-HCV antibody and HCV RNA status. While HIV coinfection tended to reduce the frequency and breadth of anti-HCV CD8+ T-cell responses in general, responses that were present were substantially stronger than in monoinfection. In all groups, HCV-specific CD4+ T-cell responses were rare and weak, independent of either nadir or concurrent CD4+ T-cell counts of HIV-infected individuals. Subgroup analysis demonstrated restricted breadth of CD8+ HCV-specific T-cell responses and lower B-cell counts in HIV/HCV-coinfected individuals without anti-HCV antibodies. The greatest difference between HIV/HCV-coinfected and HCV-monoinfected groups was substantially stronger HCV-specific CD8+ T-cell responses in the HIV-coinfected group, which may relate to accelerated liver disease in this setting.

  10. Nonresponder anorectic patients after 6 months of multimodal treatment: predictors of outcome.

    PubMed

    Fassino, S; Abbate Daga, G; Amianto, F; Leombruni, P; Garzaro, L; Rovera, G G

    2001-12-01

    Currently the therapy of anorexia nervosa is a relevant clinical problem. The percentage of patients who respond to short-term pharmacotherapy and psychotherapy is still low and the condition often leads to chronic pathology or death. The present study aims to determine outcome predictors beyond personality traits, eating psychopathology, or particular clinical features. Forty patients with restricter type anorexia nervosa were tested, at T0 and after 180 days, with psychometric tests and clinical evaluation instruments. Patients were then divided into two groups. One group included patients who showed relevant clinical improvement; the other included not-yet-improved patients. A lower Novelty Seeking, higher levels of Ascetism and Maturity Fears characterised the not-yet-improved group. Correlation showed evidence of diverse bonds between personality and psychopathology in the improved and not-yet-improved groups. The psychopathology of non-yet-improved patients seemed to be more linked to their temperamental features, whereas improved patients seemed to be more influenced by their character. Different levels of psychological functioning can be expressed. The present data suggest focusing pharmacotherapy and psychotherapy, even family counseling, with a progression more strictly related to the current personality functioning level and psychopathology of each patient.

  11. Consensus interferon and ribavirin in patients with chronic hepatitis C who were nonresponders to pegylated interferon alfa-2b and ribavirin.

    PubMed

    Leevy, Carroll B

    2008-07-01

    Recent studies suggest that consensus interferon and ribavirin is effective in retreating patients with chronic hepatitis C who failed therapy with interferon alfa and ribavirin. The objective of the present study was to assess the efficacy, safety, and tolerability of consensus interferon and ribavirin in patients who did not respond to pegylated interferon alfa-2b and ribavirin. We retrospectively identified 137 consecutive nonresponders to pegylated interferon alfa-2b and ribavirin and initiated patients on daily treatment with consensus interferon 15 mug subcutaneously and weight-based ribavirin for 48 weeks. If patients were HCV RNA negative at 12 weeks, the dose was reduced to 15 mug three times weekly for the remaining 36 weeks. The sustained virologic response rate was 37%. Daily consensus interferon therapy was safe and well tolerated in all patients. No dose reductions were required, and no patient discontinued therapy. Further studies of consensus interferon and ribavirin in nonresponders are warranted.

  12. Stroke and aspirin non-responder patients: relation with hypertension and platelet response to adenosine diphosphate.

    PubMed

    Godeneche, G; Sorel, N; Ragot, S; Chomel, J C; Neau, J P; Macchi, L

    2009-11-01

    Despite its widespread use, there are many concerns about the efficacy of aspirin in the secondary prevention of cardiovascular events after stroke, leading to the concept of aspirin non-response (ANR). Although the mechanisms of ANR remain uncertain, it is expected to be due to a combination of clinical, biological and genetic characteristics affecting platelet function. In this study, we investigated whether clinical and/or biological factors such as hypertension and platelet response to ADP could contribute to the ANR. As a secondary objective, we determine whether ANR and collagen/ADP closure time (CADP-CT) could be related to platelet glycoprotein single nucleotide polymorphisms (SNPs). One hundred patients on aspirin (160 mg/day) were enrolled. ANR was measured with a platelet function analyzer (PFA-100); genotyping of four SNPs (GP IIIa, GP Ia, P2Y12 and GP VI) was performed using a tetra-primer amplification refractory mutation system. Using a collagen/epinephrine-coated cartridge on the PFA-100, the prevalence of ANR was 15% (n = 15). In the ANR group, (i) CADP-CT was significantly shorter and (ii) hypertension was an independent clinical predictive factor of ANR (OR = 4.25; 95%CI: 1.06-17.11). No clear relation was found between CADT-CT and platelet gene polymorphism as well as ANR status and SNPs. In conclusion our study confirms the independent relationship between hypertension, platelet hypersensitivity to ADP and aspirin (160 mg/day) non-response. The differential sensitivity to aspirin may have potential clinical implications, where adaptation of antiplatelet therapy is necessary according to a patient's clinical and genetic characteristics.

  13. Tuberculosis and HIV coinfection in Europe: looking at one reality from two angles

    PubMed Central

    van der Werf, Marieke J.; Ködmön, Csaba; Zucs, Phillip; Hollo, Vahur; Amato-Gauci, Andrew J.; Pharris, Anastasia

    2016-01-01

    Objective: To better understand the epidemiology of tuberculosis (TB)/HIV coinfection in the European Union (EU) and European Economic Area (EEA) for planning of prevention and control measures. Design: Analysis of surveillance data. Methods: We performed an analysis of the 2014 TB and AIDS data to assess the burden of TB/HIV coinfection and we applied multivariable logistic regression to evaluate predictors for coinfection. Results: Twenty-one of 31 EU/EEA countries reported HIV testing results for 64.6% of the 32 892 notified TB cases. Of those, 1051 (4.9%) were reported as HIV-positive. Males [adjusted odds ratio (aOR) 1.25; 95% confidence interval (CI) 1.07–1.46] and those in age group 25–44 years were more frequently coinfected. TB cases originating from the WHO African region had the highest proportion of coinfection (aOR 3.28 versus origin in EU/EEA; 95% CI 2.35–4.57). TB treatment was completed successfully by 57.9% of HIV-positive TB cases and 83.5% of HIV-negative cases. In 2014, 3863 cases of AIDS were reported by 29 EU/EEA countries; 691 (17.9%) of these cases presented with TB as an AIDS-defining illness. Persons who had acquired HIV through injecting drug use had higher odds of TB as an AIDS-defining illness (aOR 1.78 versus heterosexual route of transmission; 95% CI 1.37–2.32). Conclusion: TB/HIV coinfection is a substantial problem in the EU/EEA. The occurrence of TB in HIV-positive cases and the low TB treatment success rate suggest that international guidelines for prevention and treatment of TB in HIV-infected adults need to be better implemented. PMID:27755106

  14. CD4+ T-cell-independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection.

    PubMed

    Foreman, Taylor W; Mehra, Smriti; LoBato, Denae N; Malek, Adel; Alvarez, Xavier; Golden, Nadia A; Bucşan, Allison N; Didier, Peter J; Doyle-Meyers, Lara A; Russell-Lodrigue, Kasi E; Roy, Chad J; Blanchard, James; Kuroda, Marcelo J; Lackner, Andrew A; Chan, John; Khader, Shabaana A; Jacobs, William R; Kaushal, Deepak

    2016-09-20

    The synergy between Mycobacterium tuberculosis (Mtb) and HIV in coinfected patients has profoundly impacted global mortality because of tuberculosis (TB) and AIDS. HIV significantly increases rates of reactivation of latent TB infection (LTBI) to active disease, with the decline in CD4(+) T cells believed to be the major causality. In this study, nonhuman primates were coinfected with Mtb and simian immunodeficiency virus (SIV), recapitulating human coinfection. A majority of animals exhibited rapid reactivation of Mtb replication, progressing to disseminated TB and increased SIV-associated pathology. Although a severe loss of pulmonary CD4(+) T cells was observed in all coinfected macaques, a subpopulation of the animals was still able to prevent reactivation and maintain LTBI. Investigation of pulmonary immune responses and pathology in this cohort demonstrated that increased CD8(+) memory T-cell proliferation, higher granzyme B production, and expanded B-cell follicles correlated with protection from reactivation. Our findings reveal mechanisms that control SIV- and TB-associated pathology. These CD4-independent protective immune responses warrant further studies in HIV coinfected humans able to control their TB infection. Moreover, these findings will provide insight into natural immunity to Mtb and will guide development of novel vaccine strategies and immunotherapies.

  15. Mucocutaneous Leishmaniasis/HIV Coinfection Presented as a Diffuse Desquamative Rash

    PubMed Central

    da Silva, Guilherme Almeida Rosa; Sugui, Daniel; Nunes, Rafael Fernandes; de Azevedo, Karime; de Azevedo, Marcelo; Marques, Alexandre; Martins, Carlos; Ferry, Fernando Raphael de Almeida

    2014-01-01

    Leishmaniasis is an infectious disease that is endemic in tropical areas and in the Mediterranean. This condition spreads to 98 countries in four continents, surpassing 12 million infected individuals, with 350 million people at risk of infection. This disease is characterized by a wide spectrum of clinical syndromes, caused by protozoa of the genus Leishmania, with various animal reservoirs, such as rodents, dogs, wolves, foxes, and even humans. Transmission occurs through a vector, a sandfly of the genus Lutzomyia. There are three main clinical forms of leishmaniasis: visceral leishmaniasis, cutaneous leishmaniasis, and mucocutaneous leishmaniasis. The wide spectrum of nonvisceral forms includes: localized cutaneous leishmaniasis, a papular lesion that progresses to ulceration with granular base and a large framed board; diffuse cutaneous leishmaniasis; mucocutaneous leishmaniasis, which can cause disfiguring and mutilating injuries of the nasal cavity, pharynx, and larynx. Leishmaniasis/HIV coinfection is considered an emerging problem in several countries, including Brazil, where, despite the growing number of cases, a problem of late diagnosis occurs. Clinically, the cases of leishmaniasis associated with HIV infection may demonstrate unusual aspects, such as extensive and destructive lesions. This study aims to report a case of mucocutaneous leishmaniasis/HIV coinfection with atypical presentation of diffuse desquamative eruption and nasopharyngeal involvement. PMID:25548691

  16. The genetic differences with whole genome linkage disequilibrium mapping between responder and non-responder in interferon-alpha and ribavirin combined therapy for chronic hepatitis C patients.

    PubMed

    Chen, P-J; Hwang, Y; Lin, C G-J; Wu, Y-J; Wu, L S-H

    2008-04-01

    Interferon-alpha and ribavirin combined therapy has been a mainstream treatment for hepatitis C infection. The efficacy of this combined treatment is around 30% to 60%, and the factors affecting the responsiveness are still poorly defined. Our study is intended to investigate the genetic differences between responder and non-responder patients. The genome-wide linkage disequilibrium screening for loci associated with genetic difference between two patient groups was conducted by using 382 autosomal short tandem repeat (STR) markers involving 92 patients. We have identified 19 STR markers displaying different allele frequencies between the two patient groups. In addition, based on their genomic location and biological function, we selected the CD81 and IL15 genes to perform single nucleotide polymorphism genotyping. In conclusion, this study may provide a new approach for identifying the associated polymorphisms and the susceptible loci for interferon-alpha and ribavirin combined therapy in patients with chronic hepatitis C.

  17. Beneficial Metabolic Effects of Duodenal Jejunal Bypass Liner for the Treatment of Adipose Patients with Type 2 Diabetes Mellitus: Analysis of Responders and Non-Responders.

    PubMed

    Stratmann, B; Krepak, Y; Schiffer, E; Jarick, I; Hauber, M; Lee-Barkey, Y H; Fischer, M; Tschoepe, D

    2016-09-01

    Implantation of a duodenal-jejunal endoluminal bypass liner (DJBL) has shown to induce weight loss and to improve metabolic parameters. DJBL is a reversible endoduodenal sleeve mimicking duodenal bypass while lacking risks and limitations of bariatric surgery.Effects on metabolic control, body mass parameters, appetite regulation, glucose tolerance, organ health, and lipid profile were determined in 16 morbidly overweight patients with type 2 diabetes mellitus. In addition, relevant hormones (leptin, ghrelin, gastric inhibitory peptide, glucagon-like peptide, and insulin) were measured by enzyme-linked immunosorbent assay (ELISA) and chemiluminescent microparticle immunoassay (CMIA) at 0, 1, 32, and 52 weeks post-implant following a mixed meal tolerance test. Lipoprotein subclasses were analysed by proton nuclear magnetic resonance ((1)H NMR) spectrometry. DJBL provoked weight loss, a decrease in fat mass, and an improvement in insulin resistance and hepatic function in most but not all of the patients, but in the long term did not increase gut hormone fasting levels pointing to a combined effect of more than gut parameters alone. Lipidome analysis was done in 10 patients, allowing classification to responders and non-responders by reduction of sLDL-p subfraction; and to further analyse the atherogenic profile. Responders showed an overall more pronounced effect regarding improvement of HbA1c, BMI, and HOMA index.Implantation of a DJBL in obese type 2 diabetes patients does not per se lead to an improvement of the metabolic situation. Further analyses including larger cohorts have to be performed to identify responding patients, to better treat non-responders and to analyse the key effectors.

  18. T-Cell surface CCR5 density is not correlated with hepatitis severity in hepatitis C virus/HIV-coinfected individuals: implications for the therapeutic use of CCR5 antagonists.

    PubMed

    Vincent, Thierry; Portales, Pierre; Baillat, Vincent; de Boever, Corinne Merle; Le Moing, Vincent; Vidal, Michèle; Ducos, Jacques; Clot, Jacques; Reynes, Jacques; Corbeau, Pierre

    2005-03-01

    CCR5 antagonists represent promising anti-HIV agents. Yet, if the CCR5 chemokine receptor plays a positive role in hepatitis C virus (HCV) infection, CCR5 antagonists might be contraindicated in HCV/HIV-coinfected subjects. Therefore, we tested the hypothesis that the level of T-cell surface CCR5 expression, which might determine the intensity of HCV-specific T-cell recruitment into the liver, and thereby the efficiency of the anti-HCV response, could determine HCV disease evolution. For this purpose, we compared CCR5 density, measured by quantitative flow cytometry at the surface of nonactivated (human leukocyte antigen-D-related [HLA-DR]-) T cells of 51 HCV/HIV patients, with HCV load, serum aminotransferase levels, and liver histology (inflammatory activity, fibrosis, and rate of fibrosis progression). DR-CD4+ T-cell surface CCR5 density, which correlated with DR-CD8+ T-cell surface CCR5 density and was stable over time in HCV/HIV-coinfected individuals, did not correlate with any of the biologic parameters of HCV infection analyzed and was not linked to the capacity to clear the virus. In conclusion, we failed to demonstrate any impact of interindividual variability in T-cell surface CCR5 density on HCV infection, which would have argued against the use of CCR5 antagonists in HIV/HCV-coinfected subjects.

  19. Mollicutes/HIV Coinfection and the Development of AIDS: Still Far from a Definitive Response

    PubMed Central

    Lange, Leonardo

    2016-01-01

    Background. Mycoplasmas are known to cause various infections in humans, mainly in the respiratory and urogenital tracts. The different species are usually host-specific and cause diseases in well-defined sites. New species have been isolated, including those from HIV-infected persons. Summary. Its in vitro properties, combined with clinical findings, have led to the hypothesis that these microorganisms may act as cofactors of HIV in AIDS development. Even today this point of view is quite polemic among infectious disease specialists and many aspects remain to be clarified, in contrast to what happens, for instance, with HIV/Mycobacterium tuberculosis coinfection. Dozens of papers have been published covering aspects of Mollicutes/HIV coinfection, but they add little to no information about the putative contribution of Mollicutes to the evolution of AIDS. Very few researchers have devoted their efforts to trying to answer this question, which remains open. In this review, we discuss the evidences that may support this statement in the light of current knowledge in the field of mycoplasmology. PMID:27413383

  20. Insulin-like Growth Factor 1 Differentially Affects Lithium Sensitivity of Lymphoblastoid Cell Lines from Lithium Responder and Non-responder Bipolar Disorder Patients.

    PubMed

    Milanesi, Elena; Hadar, Adva; Maffioletti, Elisabetta; Werner, Haim; Shomron, Noam; Gennarelli, Massimo; Schulze, Thomas G; Costa, Marta; Del Zompo, Maria; Squassina, Alessio; Gurwitz, David

    2015-07-01

    Bipolar disorder (BD) is a chronic psychiatric illness with an unknown etiology. Lithium is considered the cornerstone in the management of BD, though about 50-60 % of patients do not respond sufficiently to chronic treatment. Insulin-like growth factor 1 (IGF1) has been identified as a candidate gene for BD susceptibility, and its low expression has been suggested as a putative biomarker for lithium unresponsiveness. In this study, we examined the in vitro effects of insulin-like growth factor 1 (IGF-1) on lithium sensitivity in lymphoblastoid cell lines (LCLs) from lithium responder (R) and non-responder (NR) bipolar patients. Moreover, we evaluated levels of microRNA let-7c, a small RNA predicted to target IGF1. We found that exogenous IGF-1 added to serum-free media increased lithium sensitivity selectively in LCLs from NR BD patients. However, no significant differences were observed when comparing let-7c expression in LCLs from R vs. NR BD patients. Our data support a key role for IGF-1 in lithium resistance/response in the treatment of bipolar disorder.

  1. St. John's Wort in patients non-responders to clopidogrel undergoing percutaneous coronary intervention: a single-center randomized open-label trial (St. John's Trial).

    PubMed

    Trana, Catalina; Toth, Gabor; Wijns, William; Barbato, Emanuele

    2013-06-01

    We assessed if St. John's Wort (SJW) improves platelet response in patients (pts) resistant to clopidogrel after percutaneous coronary intervention (PCI). Stable angina pts non-responders to 600 mg clopidogrel (P2Y12 reaction units (PRU) >240) were randomized (2:1) to SJW (n = 15) or placebo (n = 8). SJW (300 mg × 3/day) was administrated for 2 weeks after PCI. Platelet reactivity was assessed by VerifyNowTM before (BL), 2 (T1), and 4 weeks (T2) after PCI. PRU significantly changed during protocol in SJW (BL (316 ± 60) vs. T1 (170 ± 87) vs. T2 (220 ± 96), p < 0.0001) and placebo group (BL (288 ± 36) vs. T1 (236 ± 31) vs. T2 (236 ± 62), p = 0.046). Yet, PRU changes from BL were higher at T1 in SJW than in placebo group (Δ%, -47 ± 24 vs. -16 ± 15, p = 0.0033), with no differences at T2 between the groups (Δ%, -30 ± 29 vs. -17 ± 24, p = 0.30). Residual platelet reactivity improved with SJW during the first month post-PCI.

  2. Real-world effectiveness of natalizumab and fingolimod compared with self-injectable drugs in non-responders and in treatment-naïve patients with multiple sclerosis.

    PubMed

    Prosperini, Luca; Saccà, Francesco; Cordioli, Cinzia; Cortese, Antonio; Buttari, Fabio; Pontecorvo, Simona; Bianco, Assunta; Ruggieri, Serena; Haggiag, Shalom; Brescia Morra, Vincenzo; Capra, Ruggero; Centonze, Diego; Di Battista, Giancarlo; Ferraro, Elisabetta; Francia, Ada; Galgani, Simonetta; Gasperini, Claudio; Millefiorini, Enrico; Mirabella, Massimiliano; Pozzilli, Carlo

    2017-02-01

    In this independent, multicentre post-marketing study we directly compared the effectiveness of natalizumab (NTZ), fingolimod (FNG) and self-injectable drugs (INJ), in non-responders to first immunomodulating treatment and in highly active treatment-naïve patients with multiple sclerosis. As main outcome measure we considered the proportions of patients with no evidence of disease activity (NEDA-3), defined as absence of relapses, disability worsening and radiological activity. A total of 567 non-responders to interferon beta (IFNB) or glatiramer acetate (GA) [dataset A] and 216 highly active treatment-naïves [dataset B] were followed up to 24 months from the beginning of NTZ, FNG or INJ, i.e. switching from IFNB to GA or viceversa (in the case of non-responders) or starting high-dose IFNB (in the case of highly active treatment-naïves). Propensity score matching in a 1:1:1 ratio was used to select only patients with similar baseline characteristics, retaining 330 and 120 patients in dataset A and B, respectively. In dataset A, the 24-month proportion with NEDA-3 was greater in both NTZ group (67%) and FNG group (42%) than in INJ group (35%) (p ≤ 0.016); however, NTZ was superior to FNG in promoting the attainment of NEDA-3 status (p = 0.034). In dataset B, the 24-month proportion with NEDA-3 was greater in NTZ group (75%) and FNG group (67%) than in INJ group (40%), but the small cohort sizes most likely prevented the detection of any statistically significant difference. Our study provides real-world evidence that NTZ was more effective than both FNG and INJ in non-responders, while it could seem that, in highly active treatment-naïves, NTZ was as effective as FNG and both were superior to INJ.

  3. Time-Intensity Curves Obtained after Microbubble Injection Can Be Used to Differentiate Responders from Nonresponders among Patients with Clinically Active Crohn Disease after 6 Weeks of Pharmacologic Treatment.

    PubMed

    Quaia, Emilio; Sozzi, Michele; Angileri, Roberta; Gennari, Antonio Giulio; Cova, Maria Assunta

    2016-11-01

    Purpose To assess whether contrast material-enhanced ultrasonography (US) can be used to differentiate responders from nonresponders among patients with clinically active Crohn disease after 6 weeks of pharmacologic treatment. Materials and Methods This prospective study was approved by our ethics committee, and written informed consent was obtained from all patients. Fifty consecutive patients (26 men and 24 women; mean age, 34.76 years ± 9) with a proved diagnosis of active Crohn disease who were scheduled to begin therapy with biologics (infliximab or adalimumab) were included, with enrollment from June 1, 2013, to June 1, 2015. In each patient, the terminal ileal loop was imaged with contrast-enhanced US before the beginning and at the end of week 6 of pharmacologic treatment. Time-intensity curves obtained in responders (those with a decrease in the Crohn disease endoscopic index of severity score of 25-44 before treatment to 10-15 after treatment, an inflammatory score <7, and/or a decrease ≥70 in the Crohn disease activity index score compared with baseline) and nonresponders were compared with Mann-Whitney test. Results Responders (n = 31) and nonresponders (n = 19) differed (P < .05) in the percent change of peak enhancement (-40.78 ± 62.85 vs 53.21 ± 72.5; P = .0001), wash-in (-34.8 ± 67.72 vs 89.44 ± 145.32; P = .001) and washout (-5.64 ± 130.71 vs 166.83 ± 204.44; P = .002) rate, wash-in perfusion index (-42.29 ± 59.21 vs 50.96 ± 71.13; P = .001), area under the time-intensity curve (AUC; -46.17 ± 48.42 vs 41.78 ± 87.64; P = .001), AUC during wash-in (-43.93 ± 54.29 vs 39.79 ± 70.85; P = .001), and AUC during washout (-49.36 ± 47.42 vs 42.65 ± 97.09; P = .001). Responders and nonresponders did not differ in the percent change of rise time (5.09 ± 49.13 vs 6.24 ± 48.06; P = .93) and time to peak enhancement (8.82 ± 54.5 vs 10.21 ± 43.25; P = .3). Conclusion Analysis of time-intensity curves obtained after injection of microbubble

  4. The Proton Pump Inhibitor Non-Responder: A Clinical Conundrum

    PubMed Central

    Hussain, Zilla H; Henderson, Emily E; Maradey-Romerao, Carla; George, Nina; Fass, Ronnie; Lacy, Brian E

    2015-01-01

    Gastroesophageal reflux disease (GERD) is a highly prevalent chronic condition where in stomach contents reflux into the esophagus causing symptoms, esophageal injury, and subsequent complications. Proton pump inhibitors (PPI) remain the mainstay of therapy for acid suppression. Despite their efficacy, significant proportions of GERD patients are either partial or non-responders to PPI therapy. Patients should be assessed for mechanisms that can lead to PPI failure and may require further evaluation to investigate for alternative causes. This monograph will outline a diagnostic approach to the PPI non-responder, review mechanisms associated with PPI failure, and discuss therapeutic options for those who fail to respond to PPI therapy. PMID:26270485

  5. A nationwide population-based cross-sectional survey of health-related quality of life in patients with myeloproliferative neoplasms in Denmark (MPNhealthSurvey): survey design and characteristics of respondents and nonrespondents

    PubMed Central

    Brochmann, Nana; Flachs, Esben Meulengracht; Christensen, Anne Illemann; Andersen, Christen Lykkegaard; Juel, Knud; Hasselbalch, Hans Carl; Zwisler, Ann-Dorthe

    2017-01-01

    Objective The Department of Hematology, Zealand University Hospital, Denmark, and the National Institute of Public Health, University of Southern Denmark, created the first nationwide, population-based, and the most comprehensive cross-sectional health-related quality of life (HRQoL) survey of patients with myeloproliferative neoplasms (MPNs). In Denmark, all MPN patients are treated in public hospitals and treatments received are free of charge for these patients. Therefore, MPN patients receive the best available treatment to the extent of its suitability for them and if they wish to receive the treatment. The aims of this article are to describe the survey design and the characteristics of respondents and nonrespondents. Material and methods Individuals with MPN diagnoses registered in the Danish National Patient Register (NPR) were invited to participate. The registers of the Danish Civil Registration System and Statistics Denmark provided information regarding demographics. The survey contained 120 questions: validated patient-reported outcome (PRO) questionnaires and additional questions addressing lifestyle. Results A total of 4,704 individuals were registered with MPN diagnoses in the NPR of whom 4,236 were eligible for participation and 2,613 (62%) responded. Overall, the respondents covered the broad spectrum of MPN patients, but patients 70–79 years old, living with someone, of a Danish/Western ethnicity, and with a higher level of education exhibited the highest response rate. Conclusion A nationwide, population-based, and comprehensive HRQoL survey of MPN patients in Denmark was undertaken (MPNhealthSurvey). We believe that the respondents broadly represent the MPN population in Denmark. However, the differences between respondents and nonrespondents have to be taken into consideration when examining PROs from the respondents. The results of the investigation of the respondents’ HRQoL in this survey will follow in future articles. PMID:28280390

  6. [Hepatitis C treatment in special patient groups].

    PubMed

    Berenguer, Marina; Jorquera, Francisco; Ángel Serra, Miguel; Sola, Ricard; Castellano, Gregorio

    2014-07-01

    The treatment plan for chronic hepatitis C in special populations varies according to comorbidity and the current evidence on treatment. In patients with hepatitis C virus and HIV coinfection, the results of dual therapy (pegylated interferon plus ribavirin) are poor. In patients with genotype 1 infection, triple therapy (dual therapy plus boceprevir or telaprevir) has doubled the response rate, but protease inhibitors can interact with some antiretroviral drugs and provoke more adverse effects. These disadvantages are avoided by the new, second-generation, direct-acting antiviral agents. In patients who are candidates for liver transplantation or are already liver transplant recipients, the optimal therapeutic option at present is to combine the new antiviral agents, with or without ribavirin and without interferon. The treatment of patients under hemodialysis due to chronic renal disease continues to be dual therapy (often with reduced doses of pegylated interferon and ribavirin), since there is still insufficient information on triple therapy and the new antiviral agents. In mixed cryoglobulinemia, despite the scarcity of experience, triple therapy seems to be superior to dual therapy and may be used as rescue therapy in non-responders to dual therapy. However, a decision must always be made on whether antiviral treatment should be used concomitantly or after immunosuppressive therapy.

  7. Natural history and treatment of HCV/HIV coinfection: Is it time to change paradigms?

    PubMed

    Arends, Joop E; Lieveld, Faydra I; Boeijen, Lauke L; de Kanter, Clara T M M; van Erpecum, Karel J; Salmon, Dominique; Hoepelman, Andy I M; Asselah, Tarik; Ustianowski, Andrew

    2015-11-01

    Evidence over the past decades have shown that HIV/HCV coinfected patients did not respond as well to HCV therapy as HCV mono-infected patients. However, these paradigms are being recently reassessed with the improvements of care for HIV and HCV patients. This article reviews these original paradigms and how the new data is impacting upon them. Treatment efficacy now appears comparable for HIV/HCV coinfected and HCV mono-infected patients, while liver fibrosis progression is increasingly similar in optimally managed patients. Additional importance of therapy is directed to drug-drug interactions and the impact of HCV reinfection, as well as the possibility of transmitted drug resistance.

  8. Low Efficacy of Pegylated Interferon plus Ribavirin plus Nitazoxanide for HCV Genotype 4 and HIV Coinfection

    PubMed Central

    Macías, Juan; López-Cortés, Luis F.; Téllez, Francisco; Recio, Eva; Ojeda-Burgos, Guillermo; Ríos, MªJosé; Rivero-Juárez, Antonio; Delgado, Marcial; Jeremías, Rivas-; Pineda, Juan A.

    2015-01-01

    Background Nitazoxanide (NTZ) plus pegylated interferon and ribavirin (Peg-IFN/RBV) improved the sustained virological response (SVR) achieved with Peg-IFN/RBV in hepatitis C virus genotype 4 (HCV-4)-monoinfected patients. There are no data currently on the efficacy of Peg-IFN/RBV plus NTZ for human immunodeficiency virus (HIV)/HCV-4 coinfection. Therefore, the objectives of this clinical trial were to assess the efficacy and to evaluate the safety of Peg-IFN/RBV plus NTZ in HIV/HCV-4-coinfected patients. Patients and Methods This was an open-label, single arm, multicenter phase II pilot clinical trial (NCT01529073) enrolling HIV-infected individuals with HCV-4 chronic infection, naïve to HCV therapy. Patients were treated with NTZ 500 mg bid for 4 weeks, followed by NTZ 500 mg bid plus Peg-IFN alpha-2b 1.5 μg/kg/week plus weight-adjusted RBV during 48 weeks. Analyses were done by intention-to-treat (ITT, missing = failure). A historical cohort of HIV/HCV-4-infected patients treated with Peg-IFN alpha-2b and RBV at the same area was used as control. Results Two (9.5%) of 21 patients included in the trial compared with 5 (21.7%) of 23 patients included in the historical cohort achieved SVR (SVR risk difference, -12.2%; 95% confidence interval, -33.2% to 8.8%; p = 0.416). Virological failure was due to lack of response in 13 (62%) individuals recruited in the trial. Two (9.5%) patients included in the trial and two (9.5%) individuals from the historical cohort discontinued permanently due to adverse events. Conclusions No increase in SVR was observed among HIV/HCV-4-coinfected patients receiving Peg-IFN/RBV plus NTZ compared with a historical cohort treated with Peg-IFN/RBV. Interruptions due to adverse events of Peg-IFN/RBV plus NTZ were similar to those of dual therapy. Trial Registration ClinicalTrials.gov NCT01529073 PMID:26640956

  9. Fatal Pediatric Cerebral Malaria Is Associated with Intravascular Monocytes and Platelets That Are Increased with HIV Coinfection

    PubMed Central

    Hochman, Sarah E.; Madaline, Theresa F.; Wassmer, Samuel C.; Mbale, Emmie; Choi, Namjong; Seydel, Karl B.; Whitten, Richard O.; Varughese, Julie; Grau, Georges E. R.; Kamiza, Steve; Molyneux, Malcolm E.; Taylor, Terrie E.; Lee, Sunhee; Milner, Danny A.

    2015-01-01

    ABSTRACT  Cerebral malaria (CM) is a major contributor to malaria deaths, but its pathophysiology is not well understood. While sequestration of parasitized erythrocytes is thought to be critical, the roles of inflammation and coagulation are controversial. In a large series of Malawian children hospitalized with CM, HIV coinfection was more prevalent than in pediatric population estimates (15% versus 2%, P < 0.0001, chi-square test), with higher mortality than that seen in HIV-uninfected children (23% versus 17%, P = 0.0178, chi-square test). HIV-infected (HIV+) children with autopsy-confirmed CM were older than HIV-uninfected children (median age, 99 months versus 32 months, P = 0.0007, Mann-Whitney U test) and appeared to lack severe immunosuppression. Because HIV infection is associated with dysregulated inflammation and platelet activation, we performed immunohistochemistry analysis for monocytes, platelets, and neutrophils in brain tissue from HIV+ and HIV-uninfected children with fatal CM. Children with autopsy-confirmed CM had significantly (>9 times) more accumulations of intravascular monocytes and platelets, but not neutrophils, than did children with nonmalarial causes of coma. The monocyte and platelet accumulations were significantly (>2-fold) greater in HIV+ children than in HIV-uninfected children with autopsy-confirmed CM. Our findings indicate that HIV is a risk factor for CM and for death from CM, independent of traditional measures of HIV disease severity. Brain histopathology supports the hypotheses that inflammation and coagulation contribute to the pathogenesis of pediatric CM and that immune dysregulation in HIV+ children exacerbates the pathological features associated with CM. Importance  There are nearly 1 million malaria deaths yearly, primarily in sub-Saharan African children. Cerebral malaria (CM), marked by coma and sequestered malaria parasites in brain blood vessels, causes half of these deaths, although the mechanisms

  10. Absence of neurocognitive effect of hepatitis C infection in HIV-coinfected people

    PubMed Central

    Vaida, Florin; Kao, Yu-Ting; Franklin, Donald R.; Letendre, Scott L.; Collier, Ann C.; Marra, Christina M.; Gelman, Benjamin B.; McArthur, Justin C.; Morgello, Susan; Simpson, David M.; Grant, Igor; Heaton, Robert K.

    2015-01-01

    Objective: To investigate the effect of hepatitis C virus (HCV) on neurocognitive performance in chronically HIV-infected patients enrolled in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study. Methods: A total of 1,582 participants in CHARTER who were tested for HCV antibody underwent neurocognitive testing; serum HCV RNA was available for 346 seropositive patients. Neurocognitive performance was compared in 408 HCV-seropositive and 1,174 HCV-seronegative participants and in a subset of 160 seropositive and 707 seronegative participants without serious comorbid neurologic conditions that might impair neurocognitive performance, using linear regression and taking into account HIV-associated and demographic factors (including IV drug use) and liver function. Results: Neurocognitive performance characterized by global deficit scores and the proportion of individuals who were impaired were the same in the HCV-seropositive and HCV-seronegative groups. In univariable analyses in the entire sample, only verbal domain scores showed small statistically different superior performance in the HCV+ group that was not evident in multivariable analysis. In the subgroup without significant comorbidities, scores in all 7 domains of neurocognitive functioning did not differ by HCV serostatus. Among the HCV-seropositive participants, there was no association between neurocognitive performance and serum HCV RNA concentration. Conclusion: In HIV-infected patients, HCV coinfection does not contribute to neurocognitive impairment, at least in the absence of substantial HCV-associated liver damage, which was not evident in our cohort. PMID:25503616

  11. Abatacept (cytotoxic T lymphocyte antigen 4-immunoglobulin) improves B cell function and regulatory T cell inhibitory capacity in rheumatoid arthritis patients non-responding to anti-tumour necrosis factor-α agents.

    PubMed

    Picchianti Diamanti, A; Rosado, M M; Scarsella, M; Germano, V; Giorda, E; Cascioli, S; Laganà, B; D'Amelio, R; Carsetti, R

    2014-09-01

    The use of biological agents combined with methotrexate (MTX) in rheumatoid arthritis (RA) patients has strongly improved disease outcome. In this study, the effects of abatacept on the size and function of circulating B and T cells in RA patients not responding to anti-tumour necrosis factor (TNF)-α have been analysed, with the aim of identifying immunological parameters helpful to choosing suitable tailored therapies. We analysed the frequency of peripheral B and T cell subsets, B cell function and T regulatory cell (Treg ) inhibitory function in 20 moderate/severe RA patients, according to the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) criteria, primary non-responders to one TNF-α blocking agent, who received abatacept + MTX. Patients were studied before and 6 months after therapy. We found that abatacept therapy significantly reduced disease activity score on 44 joints (DAS)/erythrocyte sedimentation rate (ESR) values without causing severe side effects. The size of the circulating B and T cell compartments in RA patients was not significantly different from healthy donors, but B cell proliferation and plasma cell differentiation was impaired before therapy and restored by abatacept. While Treg cell frequency was normal, its inhibitory function was absent before therapy and was partially recovered 6 months after abatacept. B and Treg cell function is impaired in RA patients not responding to the first anti-TNF-α agent. Abatacept therapy was able to rescue immune function and led to an effective and safe clinical outcome, suggesting that RA patients, in whom anti-TNF-α failed, are immunologically prone to benefit from an agent targeting a different pathway.

  12. Pharmacokinetic interactions between telaprevir and antiretroviral drugs in HIV/HCV-coinfected patients with advanced liver fibrosis and prior HCV non-responders.

    PubMed

    Milazzo, Laura; Cattaneo, Dario; Calvi, Elisa; Gervasoni, Cristina; Mazzali, Cristina; Ronzi, Paola; Peri, Anna Maria; Ridolfo, Anna Lisa; D'Avolio, Antonio; Antinori, Spinello

    2015-05-01

    Complex drug-drug interactions have been reported with concurrent administration of telaprevir (TVR) and human immunodeficiency virus (HIV) protease inhibitors (PIs), leading to relevant limitations of the therapeutic options for patients coinfected with hepatitis C virus (HCV) and HIV. However, little is known about the pharmacokinetics and drug interactions between TVR and antiretrovirals in HIV/HCV-coinfected patients with advanced liver fibrosis. Here we report the pharmacokinetics of TVR and antiretrovirals in a cohort of HIV/HCV genotype 1-coinfected patients with advanced liver fibrosis treated with TVR-based triple anti-HCV therapy. No significant differences were observed in the pharmacokinetics of atazanavir, amprenavir or tenofovir at baseline and at Day 15 of TVR, whereas the AUC0-4h of darunavir was 36% lower in the presence of TVR (AUC0-4h 15007ngh/mL and 9563ngh/mL at baseline and at Day 15 of TVR administration, respectively). Noteworthy, the AUC0-4h, Cmin and Cmax of raltegravir were reduced by 61%, 50% and 64%, respectively. However, none of the patient's plasma levels of tenofovir, atazanavir, amprenavir or raltegravir declined below their minimum effective concentrations even in association with TVR, and no HIV treatment failure occurred. A non-significant trend for lower TVR exposure was seen in patients concomitantly given amprenavir versus those given atazanavir (AUC0-4h, 9840ngh/mL and 13345ngh/mL, respectively). In conclusion, this study highlighted the feasibility of maintaining the current antiretroviral regimen in HIV/HCV-coinfected patients, even when significant interactions with TVR are predictable, whenever a change of HIV PIs is not deemed appropriate.

  13. Incidence of and factors associated with hepatocellular carcinoma among hepatitis C virus and human immunodeficiency virus coinfected patients with decompensated cirrhosis.

    PubMed

    García-García, José A; Romero-Gómez, Manuel; Girón-González, José A; Rivera-Irigoin, Robin; Torre-Cisneros, Julián; Montero, José L; González-Serrano, Mercedes; Andrade, Raúl J; Aguilar-Guisado, Manuela; Grilo, Israel; Martín-Vivaldi, Javier; Salmerón, Javier; Caballero-Granado, Francisco J; Macías, Juan; Vergara-López, Salvador; Pineda, Juan A

    2006-12-01

    We compared the incidence of and factors associated with hepatocellular carcinoma (HCC) among hepatitis C virus (HCV)-monoinfected subjects and human immunodeficiency virus (HIV)/HCV-coinfected individuals, both with decompensated cirrhosis. In a retrospective study, a cohort of 180 individuals with HIV coinfection and 1037 HCV-monoinfected patients with decompensated HCV-related cirrhosis from eight centres in Spain were analyzed. HCC was found in 234 (23%) HCV-monoinfected subjects and in four (2%) HIV-coinfected subjects (p<0.001). At the time of the first hepatic decompensation, 188 (17%) and 4 (2%) (p<0.001) patients in the former and in the latter group, respectively, showed HCC. Fifty-four (11%) patients without HCC at baseline developed such a disease during follow-up. There were no incident cases among the HIV-coinfected population. The density of incidence (95% IC) of HCC in HIV/HCV-coinfected and HCV-monoinfected patients was 0 (0-1.70) and 3.31 (2.70-4.64) cases per 100 person-years (p<0.001), respectively. Lack of HIV infection [adjusted odds risk (AOR) (95% IC)=16.7 (3.9-71.1)] and high alanine aminotransferase levels [AOR (95% IC)=2.5 (1.1-5)] were the only two independent predictors of the emergence of HCC. In the group of patients in whom the date of HCV infection could be estimated, the time elapsed until HCC diagnosis was shorter among HIV-coinfected subjects. The incidence of HCC in patients with HCV-related cirrhosis after the first hepatic decompensation is lower in HIV-coinfected patients. This is probably due to the fact that HIV infection shortens the survival of HCV-coinfected patients with end-stage liver disease to such an extent that HCC not had a chance to emerge.

  14. Boceprevir or Telaprevir Based Triple Therapy against Chronic Hepatitis C in HIV Coinfection: Real-Life Safety and Efficacy

    PubMed Central

    Neukam, Karin; Munteanu, Daniela I.; Rivero-Juárez, Antonio; Lutz, Thomas; Fehr, Jan; Mandorfer, Mattias; Bhagani, Sanjay; López-Cortés, Luis F.; Haberl, Annette; Stoeckle, Marcel; Márquez, Manuel; Scholten, Stefan; de los Santos-Gil, Ignacio; Mauss, Stefan; Rivero, Antonio; Collado, Antonio; Delgado, Marcial; Rockstroh, Juergen K.; Pineda, Juan A.

    2015-01-01

    Background and Aims Clinical trials of therapy against chronic hepatitis C virus (HCV) infection including boceprevir (BOC) or telaprevir (TVR) plus pegylated interferon and ribavirin (PR) have reported considerably higher response rates than those achieved with PR alone. This study sought to evaluate the efficacy and safety of triple therapy including BOC or TVR in combination with PR in HIV/HCV-coinfected patients under real-life conditions. Methods In a multicentre study conducted in 24 sites throughout five European countries, all HIV/HCV-coinfected patients who initiated a combination of BOC or TVR plus PR and who had at least 60 weeks of follow-up, were analyzed. Sustained virologic response 12 weeks after the scheduled end of therapy date (SVR12) and the rate of discontinuations due to adverse events (AE) were evaluated. Results Of the 159 subjects included, 127 (79.9%) were male, 45 (34.4%) were treatment-naïve for PR and 60 (45.4%) showed cirrhosis. SVR12 was observed in 31/46 (67.4%) patients treated with BOC and 69/113 (61.1%) patients treated with TVR. Overall discontinuations due to AE rates were 8.7% for BOC and 8% for TVR. Grade 3 or 4 hematological abnormalities were frequently observed; anemia 7%, thrombocytopenia 17.2% and neutropenia 16.4%. Conclusion The efficacy and safety of triple therapy including BOC or TVR plus PR under real-life conditions of use in the HIV/HCV-coinfected population was similar to what is observed in clinical trials. Hematological side effects are frequent but manageable. PMID:25923540

  15. Brain Changes in Responders vs. Non-Responders in Chronic Migraine: Markers of Disease Reversal

    PubMed Central

    Hubbard, Catherine S.; Becerra, Lino; Smith, Jonathan H.; DeLange, Justin M.; Smith, Ryan M.; Black, David F.; Welker, Kirk M.; Burstein, Rami; Cutrer, Fred M.; Borsook, David

    2016-01-01

    The aim of this study was to identify structural and functional brain changes that accompanied the transition from chronic (CM; ≥15 headache days/month) to episodic (EM; <15 headache days/month) migraine following prophylactic treatment with onabotulinumtoxinA (BoNT-A). Specifically, we examined whether CM patients responsive to prophylaxis (responders; n = 11), as evidenced by a reversal in disease status (defined by at least a 50% reduction in migraine frequency and <15 headache days/month), compared to CM patients whose migraine frequency remained unchanged (non-responders; n = 12), showed differences in cortical thickness using surface-based morphometry. We also investigated whether areas showing group differences in cortical thickness displayed altered resting-state functional connectivity (RS-FC) using seed-to-voxel analyses. Migraine characteristics measured across groups included disease duration, pain intensity and headache frequency. Patient reports of headache frequency over the 4 weeks prior to (pre-treatment) and following (post-treatment) prophylaxis were compared (post minus pre) and this measure served as the clinical endpoint that determined group assignment. All patients were scanned within 2 weeks of the post-treatment visit. Results revealed that responders showed significant cortical thickening in the right primary somatosensory cortex (SI) and anterior insula (aINS), and left superior temporal gyrus (STG) and pars opercularis (ParsOp) compared to non-responders. In addition, disease duration was negatively correlated with cortical thickness in fronto-parietal and temporo-occipital regions in responders but not non-responders, with the exception of the primary motor cortex (MI) that showed the opposite pattern; disease duration was positively associated with MI cortical thickness in responders versus non-responders. Our seed-based RS-FC analyses revealed anti-correlations between the SI seed and lateral occipital (LOC) and dorsomedial

  16. The Effect of Nonrespondents on a Self-Administered Mail Survey.

    ERIC Educational Resources Information Center

    Krushat, W. Mark; Molnar, John I.

    1993-01-01

    After a mailed questionnaire and two follow-ups, hard-core survey nonrespondents were contacted to ask why they had not responded and what they would have answered had they responded. Results from 28 subjects indicate that efforts to pursue nonrespondents may be unnecessary, because bias resulting from nonresponse appeared minimal. (SLD)

  17. A comparison of small monetary incentives to convert survey non-respondents: a randomized control trial

    PubMed Central

    2011-01-01

    Background Maximizing response rates is critically important in order to provide the most generalizable and unbiased research results. High response rates reduce the chance of respondents being systematically different from non-respondents, and thus, reduce the risk of results not truly reflecting the study population. Monetary incentives are often used to improve response rates, but little is known about whether larger incentives improve response rates in those who previously have been unenthusiastic about participating in research. In this study we compared the response rates and cost-effectiveness of a $5 versus $2 monetary incentive accompanying a short survey mailed to patients who did not respond or refused to participate in research study with a face-to-face survey. Methods 1,328 non-responders were randomly assigned to receive $5 or $2 and a short, 10-question survey by mail. Reminder postcards were sent to everyone; those not returning the survey were sent a second survey without incentive. Overall response rates, response rates by incentive condition, and odds of responding to the larger incentive were calculated. Total costs (materials, postage, and labor) and incremental cost-effectiveness ratios were also calculated and compared by incentive condition. Results After the first mailing, the response rate within the $5 group was significantly higher (57.8% vs. 47.7%, p < .001); after the second mailing, the difference narrowed by 80%, resulting in a non-significant difference in cumulative rates between the $5 and $2 groups (67.3% vs. 65.4%, respectively, p = .47). Regardless of incentive or number of contacts, respondents were significantly more likely to be male, white, married, and 50-75 years old. Total costs were higher with the larger versus smaller incentive ($13.77 versus $9.95 per completed survey). Conclusions A $5 incentive provides a significantly higher response rate than a $2 incentive if only one survey mailing is used but not if two survey

  18. Pretreatment cognitive and neural differences between sapropterin dihydrochloride responders and non-responders with phenylketonuria.

    PubMed

    Hawks, Zoë; Shimony, Joshua; Rutlin, Jerrel; Grange, Dorothy K; Christ, Shawn E; White, Desirée A

    2017-09-01

    Sapropterin dihydrochloride (BH4) reduces phenylalanine (Phe) levels and improves white matter integrity in a subset of individuals with phenylketonuria (PKU) known as "responders." Although prior research has identified biochemical and genotypic differences between BH4 responders and non-responders, cognitive and neural differences remain largely unexplored. To this end, we compared intelligence and white matter integrity prior to treatment with BH4 in 13 subsequent BH4 responders with PKU, 16 subsequent BH4 non-responders with PKU, and 12 healthy controls. Results indicated poorer intelligence and white matter integrity in non-responders compared to responders prior to treatment. In addition, poorer white matter integrity was associated with greater variability in Phe across the lifetime in non-responders but not in responders. These results underscore the importance of considering PKU as a multi-faceted, multi-dimensional disorder and point to the need for additional research to delineate characteristics that predict response to treatment with BH4.

  19. On the nature of non-responding in discrimination learning with and without errors1

    PubMed Central

    Terrace, H. S.

    1974-01-01

    In human subjects, discrimination learning with errors results in active responding incompatible with the reinforced response. The direction of such incompatible behavior is opposite to that of the reinforced response. Responding occurs only during the stimulus correlated with extinction. The frequency of active non-responding is maximal shortly after the start of discrimination training (the time at which the frequency of errors decreases most rapidly) and approaches zero as discrimination training continues. The magnitude of behavioral contrast is not related systematically to the number of errors. Instead it is related directly to the frequency of active non-responding. Active non-responding appears to be motivated by the aversiveness of self-produced frustration, in the sense that active non-responding allows the subject to avoid the aversiveness of non-reinforced responding. ImagesFig. 1.Fig. 2. PMID:16811774

  20. HIV treatment cascade in tuberculosis patients

    PubMed Central

    Lessells, Richard J.; Swaminathan, Soumya; Godfrey-Faussett, Peter

    2015-01-01

    Purpose of review Globally, the number of deaths associated with tuberculosis (TB) and HIV coinfection remains unacceptably high. We review the evidence around the impact of strengthening the HIV treatment cascade in TB patients and explore recent findings about how best to deliver integrated TB/HIV services. Recent findings There is clear evidence that the timely provision of antiretroviral therapy (ART) reduces mortality in TB/HIV coinfected adults. Despite this, globally in 2013, only around a third of known HIV-positive TB cases were treated with ART. Although there is some recent evidence exploring the barriers to achieve high coverage of HIV testing and ART initiation in TB patients, our understanding of which factors are most important and how best to address these within different health systems remains incomplete. There are some examples of good practice in the delivery of integrated TB/HIV services to improve the HIV treatment cascade. However, evidence of the impact of such strategies is of relatively low quality for informing integrated TB/HIV programming more broadly. In most settings, there remain barriers to higher-level organizational and functional integration. Summary There remains a need for commitment to patient-centred integrated TB/HIV care in countries affected by the dual epidemic. There is a need for better quality evidence around how best to deliver integrated services to strengthen the HIV treatment cascade in TB patients, both at primary healthcare level and within community settings. PMID:26352390

  1. Hepatitis C virus NS3/4A quasispecies diversity in acute hepatitis C infection in HIV-1 co-infected patients.

    PubMed

    Nevot, M; Boesecke, C; Parera, M; Andrés, C; Franco, S; Revollo, B; Ingiliz, P; Tural, C; Clotet, B; Rockstroh, J K; Martinez, M A

    2014-06-01

    The growing number of cases of acute hepatitis C (AHC) infections among human immunodeficiency virus type 1 (HIV-1)-positive men who have sex with men (MSM) in the last 10 years has promoted the search for predictors of AHC clearance as well as for epidemiological networks of viral transmission. We characterized the diversity and catalytic efficiency of HCV NS3/4A protease quasispecies in AHC patients coinfected with HIV-1. Plasma samples obtained at HCV diagnosis from 18 MSM HIV-coinfected patients with AHC were studied. Five HCV monoinfected patient samples with AHC were also investigated. An average of 39 clones from each sample was analysed. The catalytic efficiency of the dominant quasispecies (i.e. the most abundant) from each quasispecies was also assayed for mitochondrial antiviral signalling protein (MAVS) cleavage. Phylogenetic analysis identified two clusters of patients with highly related viruses, suggesting a common source of HCV infection. None of the 18 MSM HIV-coinfected patients spontaneously cleared HCV, although 78% of the treated patients achieved a sustained virological response after early treatment with pegylated interferon (pegIFN) plus ribavirin (RBV). The synonymous-nonsynonymous (ds/dn) mutation ratio, a marker of selective pressure, was higher in AHC compared to 26 HIV-1-infected men with genotype 1a chronic hepatitis C (CHC) (P < 0.0001). NS3/4A proteases from AHC patients also exhibited higher catalytic efficiency compared to CHC patients (P < 0.0001). No differences were found when ds/dn mutation ratios and NS3/4A protease catalytic efficiencies from AHC HIV-coinfected patients were compared with AHC monoinfected patients. The presence of epidemiological networks of HCV transmission was confirmed among HIV-1-positive MSM. In addition, substantial genetic diversity was demonstrated in AHC. NS3/4A protease efficiency cleaving MAVS may be associated with virus transmission and response to pegIFN/RBV treatment.

  2. Immunogenicity and Tolerance of a 7-Valent Pneumococcal Conjugate Vaccine in Nonresponders to the 23-Valent Pneumococcal Vaccine

    PubMed Central

    Zielen, S.; Bühring, I.; Strnad, N.; Reichenbach, J.; Hofmann, D.

    2000-01-01

    There is still a lack of effective vaccination strategies for patients with a deficient antibody response to bacterial polysaccharide antigens. In an open trial, we evaluated the immunogenicity and tolerance of a new 7-valent pneumococcal conjugate vaccine in 22 infection-prone nonresponders to pneumococcal polysaccharide vaccine and 21 controls. In the patient group, nonresponsiveness was confirmed by repeated vaccination with a 23-valent pneumococcal polysaccharide vaccine. The study protocol provided two doses of the pneumococcal conjugate vaccine, given 4 to 6 weeks apart, for both groups. The antibody response was determined before each vaccination and on follow-up by an enzyme-linked immunosorbent assay and compared to the response in a functional opsonophagocytosis assay. Patients showed a significantly lower postvaccination immune response for all serotypes than did controls. The postvaccination response was serotype dependent. A median titer of >1 μg/ml in patients was recorded only for serotypes 4, 9V, 14, and 19F, which are known to be more immunogenic than serotypes 6B, 18C, and 23F. In the patient group, 70% responded to serotype 19F (Pnc 19F), 65% responded to Pnc 14 and 4, 60% responded to Pnc 9V, 55% responded to Pnc 18C, 50% responded to Pnc 23F, and 25% responded to Pnc 6B. In the control group >95% of individuals showed a titer of >1 μg/ml to every serotype. The vaccine was tolerated well, and no major side effects have been reported. The new pneumococcal conjugate vaccine is clearly more immunogenic in previous nonresponders than is the 23-valent pneumococcal vaccine. Immunization with a pneumococcal conjugate vaccine should be considered as a strategy to protect high-risk patients. PMID:10678957

  3. Factors associated with mortality and default among patients with tuberculosis attending a teaching hospital clinic in Accra, Ghana.

    PubMed

    Burton, Nicole T; Forson, Audrey; Lurie, Mark N; Kudzawu, Samuel; Kwarteng, Ernest; Kwara, Awewura

    2011-12-01

    Tuberculosis (TB) remains a major cause of mortality despite availability of effective chemotherapy. This study was performed to identify contributing factors for poor outcome during anti-tuberculosis treatment at a teaching hospital chest clinic. Medical records of registered patients treated for TB between 1 January and 31 December, 2009 were reviewed and abstracted for demographic, clinical and outcome data. Risk factors for mortality during therapy were assessed using bivariate and multivariate logistics approaches. Of 599 patients, 355 (58.9%) completed therapy and/or were cured, 192 (32.1%) died, and 39 (6.5%) defaulted. In multivariate analysis, independent risk factors for mortality included pulmonary cases for which sputum smear status was unknown (odds ratio [OR] 13.7; 95% confidence interval [CI] 6.0, 31.4), HIV coinfection (OR, 3.6; 95% CI 2.4, 5.4), disseminated TB (OR, 2.2; 95% CI 1.0, 4.9), TB meningitis (OR, 2.8; 95% CI 1.5, 5.3), not having a treatment supporter (OR, 2.0; 95% CI 1.3, 3.1), and low body weight (OR, 11.0; 95% CI 3.1, 38.6). Not having a treatment supporter (OR, 3.2; 95% CI 1.6, 6.6) and HIV coinfection (OR, 2.4; 95% CI 1.2, 5.2) were also independently associated with treatment default. Our findings suggest that enhanced measures to reduce mortality and default in TB patients with HIV coinfection, disseminated or meningeal disease and those who have no treatment supporters may help improve treatment outcomes in Ghana.

  4. Magnitude of visceral leishmaniasis and poor treatment outcome among HIV patients: meta-analysis and systematic review

    PubMed Central

    Alemayehu, Mekuriaw; Wubshet, Mamo; Mesfin, Nebiyu

    2016-01-01

    Background Visceral leishmaniasis (VL) coinfection with HIV/AIDS most often results in unfavorable responses to treatment, frequent relapses, and premature deaths. Scarce data are available, regarding the magnitude and poor treatment outcomes of VL-HIV coinfection. Objective The main objective of this systematic review was to describe the pooled prevalence of VL and poor treatment outcome among HIV patients. Review methods Electronic databases mainly PubMed were searched. Databases, such as Google and Google scholar, were searched for gray literature. Articles were selected based on their inclusion criterion, whether they included HIV-positive individuals with VL diagnosis. STATA 11 software was used to conduct a meta-analysis of pooled prevalence of VL-HIV coinfection. Results Fifteen of the 150 articles fulfilled the inclusion criteria. A majority of the study participants were males between 25 years and 41 years of age. The pooled prevalence of VL-HIV coinfection is 5.2% with 95% confidence interval of (2.45–10.99). Two studies demonstrated the impact of antiretroviral treatment on reduction in relapse rate compared with patients who did not start antiretroviral treatment. One study showed that the higher the baseline CD4+ cell count (>100 cells/mL) the lower the relapse rate. Former VL episodes were identified as risk factors for relapse in two articles. In one of the articles, an earlier bout of VL remains significant in the model adjusted to other variables. Conclusion The pooled prevalence of VL in HIV-infected patients is low and an earlier bout of VL and CD4+ count <100 cells/mL at the time of primary VL diagnosis are factors that predict poor treatment outcome. PMID:27042142

  5. Lithium response in bipolar disorder: No difference in GADL1 gene expression between cell lines from excellent-responders and non-responders.

    PubMed

    Moreira, Jeverson; Courtin, Cindie; Geoffroy, Pierre A; Curis, Emmanuel; Bellivier, Frank; Marie-Claire, Cynthia

    2017-05-01

    Previous association studies have shown mixed results between glutamic acid decarboxylase like-1 (GADL1) gene polymorphism and prophylactic lithium response in bipolar disorder (BD) patients. In the present study, GADL1 gene expression was investigated in regard to lithium response, using Alda scale, in lymphoblastoid cells (LCLs) of 36 Caucasian BD patients. No difference in GADL1 expression was observed among LCLs from excellent-responders, non-responders or controls. Furthermore, lithium did not induce significant changes in GADL1 expression levels after 4 or 8 days. These results did not support an association of GADL1 expression in the determination of a lithium response in BD patients.

  6. Understanding Faculty Survey Nonrespondents: Their Characteristics, Organizational Citizenship Behaviors, Workplace Attitudes, and Reasons for Nonparticipation

    ERIC Educational Resources Information Center

    Mathews, Kiernan Robert

    2013-01-01

    College and university administrators frequently survey their faculty to inform decisions affecting the academic workplace. Higher education researchers, too, rely heavily on survey methodologies in their scholarly work. Survey response rates, however, have been declining steadily for decades, and when nonrespondents and respondents systematically…

  7. Human cysticercosis: antigens, antibodies and non-responders.

    PubMed Central

    Flisser, A; Woodhouse, E; Larralde, C

    1980-01-01

    Immunoelectrophoresis of sera from patients with brain cysticercosis against a crude antigenic extract from Cysticercus cellulosae indicates that nearly 50% of the patients do not make sufficient antibodies to ostensively precipitate. The other 50% of the patients who do make precipitating antibodies show a very heterogeneous response in the number of antigens they recognize as well as in the type of antigen--as classified by their electrophoretic mobilities. The most favoured, called antigen B, is recognized by 84% of positive sera and corresponds to one or a limited number of antigens isoelectric at pH 8.6. Indirect immunofluorescence with monospecific anti-human immunoglobulins, performed upon the immunoelectrophoretic preparations, reveal that all cysticercus antigens induced the synthesis of antibodies in the immunoglobulin classes in the order G greater than M greater than E greater than A greater than D. Finally, antigen H (an anodic component) seems to favour IgE relative to its ability to induce IgG. Thus, although in natural infection a good proportion of cysticercotic patients do not seem to mount an energetic antibody response against the parasite, giving rise to some speculations about immunosuppression, the fact that 50% do synthesize antibodies allows for some optimistic expectations from vaccination of humans--in view of the good results of vaccination in experimental animals mediated by IgG antibodies. A likely prospect for a human vaccine would be antigen B because it is the most frequently detected by humans, although its immunizing and toxic properties remain to be properly studied. Images FIG. 1 FIG. 3 FIG. 6 PMID:7389197

  8. Bacille-Calmette-Guerin non-responders: how to manage

    PubMed Central

    von Rundstedt, Friedrich-Carl

    2015-01-01

    Intravesical immunotherapy with bacille-Calmette-Guerin (BCG) is indicated in the treatment of high-risk and intermediate-risk non-muscle invasive bladder cancer (NMIBC). Our goal is to describe the various disease states following induction and maintenance BCG and to describe contemporary treatment options and the current and projected clinical trial landscape for patients who recur following BCG therapy. PMID:26816828

  9. Care of HIV patients with chronic hepatitis B: updated recommendations from the HIV-Hepatitis B Virus International Panel.

    PubMed

    Soriano, Vincent; Puoti, Massimo; Peters, Marion; Benhamou, Yves; Sulkowski, Mark; Zoulim, Fabien; Mauss, Stefan; Rockstroh, Juergen

    2008-07-31

    Nearly 10% of the estimated 36 million people having HIV worldwide suffer from chronic hepatitis B virus (HBV) infection. The advent of new antiviral agents against HBV and the recent availability of improved molecular diagnostic tools have revolutioned the management of HIV/HBV coinfected patients. The present study represents an update of the current knowledge about HBV/HIV coinfection and an intent to provide practical advise about how to give the best care to HIV-infected persons with chronic hepatitis B.

  10. Participation in a mail survey: role of repeated mailings and characteristics of nonrespondents among recent mothers.

    PubMed

    Larroque, B; Kaminski, M; Bouvier-Colle, M H; Hollebecque, V

    1999-04-01

    This study analysed the characteristics of respondent and nonrespondent mothers at each stage of a survey procedure, from a initial questionnaire to a reminder letter and two repeated mailings. Of 938 mothers of liveborn children who, while maternity inpatients, received a questionnaire and information about a mail survey to follow 2 months later, 828 completed and returned the initial questionnaire, 708 agreed to participate in the mail survey and were sent the mail questionnaire, and 612 finally completed and returned the questionnaire at 2 months. There were differences between respondents and non-respondents for socio-demographic factors at each stage of the process. The final response rate to the mail questionnaire was higher among mothers who were younger, were breast feeding, and had more education, an occupation and fewer children. The characteristics of late respondents were intermediate between those of early to middle respondents and nonrespondents for age, educational level, breast feeding and occupation. Maternal and infant health varied only slightly according to response status. Repeated mailings increased response and diminished selection. A mail questionnaire after contact in a maternity ward is a cost-effective means of gathering data about a large sample of recent mothers and their children.

  11. Peginterferon alfa-2b and ribavirin in thalassaemia/chronic hepatitis C virus-co-infected non-responder to standard interferon-based.

    PubMed

    Hamidah, A; Thambidorai, C R; Jamal, R

    2005-10-01

    We describe a patient with HbE-beta thalassaemia and chronic hepatitis C virus infection (genotype 1a) who was treated successfully with peginterferon alfa-2b and ribavirin, following failure to respond to standard interferon and ribavirin therapy. She had sustained virological response for nearly 24 months after completing peginterferon alfa-2b and ribavirin therapy. Transfusion requirements were significantly increased during combination therapy due to ribavirin-induced haemolysis. The adverse effects of interferon were well tolerated. Combination therapy with peginterferon alfa-2b and ribavirin maybe a feasible treatment option for a subset of thalassaemia/HCV infected non-responders to standard interferon-based therapy.

  12. Comparative Proteomic Analysis of Advanced Ovarian Cancer Tissue to Identify Potential Biomarkers of Responders and Nonresponders to First-Line Chemotherapy of Carboplatin and Paclitaxel

    PubMed Central

    Sehrawat, Urmila; Pokhriyal, Ruchika; Gupta, Ashish Kumar; Hariprasad, Roopa; Khan, Mohd Imran; Gupta, Divya; Naru, Jasmine; Singh, Sundararajan Baskar; Mohanty, Ashok Kumar; Vanamail, Perumal; Kumar, Lalit; Kumar, Sunesh; Hariprasad, Gururao

    2016-01-01

    Conventional treatment for advanced ovarian cancer is an initial debulking surgery followed by chemotherapy combination of carboplatin and paclitaxel. Despite initial high response, three-fourths of these women experience disease recurrence with a dismal prognosis. Patients with advanced-stage ovarian cancer who underwent cytoreductive surgery were enrolled and tissue samples were collected. Post surgery, these patients were started on chemotherapy and followed up till the end of the cycle. Fluorescence-based differential in-gel expression coupled with mass spectrometric analysis was used for discovery phase of experiments, and real-time polymerase chain reaction, Western blotting, and pathway analysis were performed for expression and functional validation of differentially expressed proteins. While aldehyde reductase, hnRNP, cyclophilin A, heat shock protein-27, and actin are upregulated in responders, prohibitin, enoyl-coA hydratase, peroxiredoxin, and fibrin-β are upregulated in the nonresponders. The expressions of some of these proteins correlated with increased apoptotic activity in responders and decreased apoptotic activity in nonresponders. Therefore, the proteins qualify as potential biomarkers to predict chemotherapy response. PMID:26997873

  13. A comparison of physical and psychological features of responders and non-responders to cervical facet blocks in chronic whiplash

    PubMed Central

    2013-01-01

    Background Cervical facet block (FB) procedures are often used as a diagnostic precursor to radiofrequency neurotomies (RFN) in the management of chronic whiplash associated disorders (WAD). Some individuals will respond to the FB procedures and others will not respond. Such responders and non-responders provided a sample of convenience to question whether there were differences in their physical and psychological features. This information may inform future predictive studies and ultimately the clinical selection of patients for FB procedures. Methods This cross-sectional study involved 58 individuals with chronic WAD who responded to cervical FB procedures (WAD_R); 32 who did not respond (WAD_NR) and 30 Healthy Controls (HC)s. Measures included: quantitative sensory tests (pressure; thermal pain thresholds; brachial plexus provocation test); nociceptive flexion reflex (NFR); motor function (cervical range of movement (ROM); activity of the superficial neck flexors during the cranio-cervical flexion test (CCFT). Self-reported measures were gained from the following questionnaires: neuropathic pain (s-LANSS); psychological distress (General Health Questionnaire-28), post-traumatic stress (PDS) and pain catastrophization (PCS). Individuals with chronic whiplash attended the laboratory once the effects of the blocks had abated and symptoms had returned. Results Following FB procedures, both WAD groups demonstrated generalized hypersensitivity to all sensory tests, decreased neck ROM and increased superficial muscle activity with the CCFT compared to controls (p < 0.05). There were no significant differences between WAD groups (all p > 0.05). Both WAD groups demonstrated psychological distress (GHQ-28; p < 0.05), moderate post-traumatic stress symptoms and pain catastrophization. The WAD_NR group also demonstrated increased medication intake and elevated PCS scores compared to the WAD_R group (p < 0.05). Conclusions Chronic WAD responders and non-responders to FB

  14. The Auditory P3 in Antidepressant Pharmacotherapy Treatment Responders, Non-Responders and Controls

    PubMed Central

    Jaworska, Natalia; De Somma, Elisea; Blondeau, Claude; Tessier, Pierre; Norris, Sandhaya; Fusee, Wendy; Smith, Dylan; Blier, Pierre; Knott, Verner

    2013-01-01

    Event-related potentials (ERPs), derived from electroencephalographic (EEG) recordings, can index electrocortical activity related to cognitive operations. The fronto-central P3a ERP is involved in involuntary processing of novel auditory information, whereas the parietal P3b indexes controlled attention processing. The amplitude of the auditory P3b has been found to be decreased in major depressive disorder (MDD). However, few studies have examined the relationship between the P3b, the related P3a, and antidepressant treatment response. We tested 53 unmedicated individuals (25 females) with MDD as well as 43 non-depressed controls (23 females) on the novelty oddball task, wherein infrequent deviant (target) and frequent standard (non-target) tones were presented, along with infrequent novel (non-target/distractor) sounds. The P3a and P3b ERPs were assessed to the novel and target sounds, respectively, as were accompanying behavioural performance measures. Depression ratings and antidepressant response status were assessed following 12 weeks of pharmacotherapy with three different regimens. Antidepressant treatment non-responders had smaller baseline P3a/b amplitudes than responders and healthy controls. Baseline P3b amplitude also weakly predicted the extent of depression rating changes by week 12. Females exhibited larger P3a/b amplitudes than males. With respect to task performance, controls had more target hits than treatment non-responders. ERP measures correlated with clinical changes in males and with behavioural measures in females. These results suggest that greater (or control-like) baseline P3a/b amplitudes are associated with a positive antidepressant response, and that gender differences characterize the P3 and, hence, basic attentive processes. PMID:23664712

  15. [Bias due to non-responders in an epidemiological study (SAPALDIA)].

    PubMed

    Luthi, J C; Zellweger, J P; Grize, L; Leuenberger, P; Ackermann-Liebrich, U

    1997-01-01

    Within the Swiss Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) 16267 adults aged 18 to 60 years from 8 different locations in Switzerland were randomly selected for answering a questionnaire about respiratory health and have a lung function examination with allergy test. 9561 subjects agreed with the examination (59%) (= responders, R). In order to study the possible influence of the bias introduced by non-responders (NR), 221 subjects who refused to participate among the 966 first subjects selected in Payerne were contacted by phone. 142 accepted a home visit and answered a shortened questionnaire about the main respiratory symptoms and diseases and indicated furthermore the reasons for their refusal. Non-responders have a lower mean educational level and belong to lower social classes than responders. The frequency of respiratory symptoms and diseases, allergies and smoking is similar in R and NR except a higher frequency of wheezing during the last 12 month (R: 12.5%, NR: 5.6%, p = 0.03). The level of carbon monoxide in expired air is higher in NR (17.6 ppm) that in R (11.9 ppm) (p = 0.01). A similar difference exists between NR (30.7 pp) and R (24.8 ppm) among current smokers (p < 0.01). The main reasons for refusal are lack of time (27.5%), lack of interest for medical study (22.6%), fear of health professionals (18.3%) or the existence of a another disease (9.9%). Furthermore, 2.8% of the subjects consider a medical study as useless and refuse principally any participation. The role of local press and media in the decision to participate seems to be important. Globally, the differences between R and NR are minimal and should not influence the validity of the results of the SAPALDIA study.

  16. Characterization of clinical and immunological features in patients coinfected with dengue virus and HIV.

    PubMed

    Torrentes-Carvalho, Amanda; Hottz, Eugênio Damaceno; Marinho, Cintia Ferreira; da Silva, Jéssica Badolato-Corrêa; Pinto, Luzia Maria de Oliveira; Fialho, Luciana Gomes; Bozza, Fernando Augusto; Cunha, Rivaldo Venâncio; Damasco, Paulo Vieira; Kubelka, Claire Fernandes; de Azeredo, Elzinandes Leal

    2016-03-01

    The pathogenesis of dengue in subjects coinfected with HIV remains largely unknown. We investigate clinical and immunological parameters in coinfected DENV/HIV patients. According to the new dengue classification, most coinfected DENV/HIV patients presented mild clinical manifestations of dengue infection. Herein, we show that DENV/HIV coinfected patients had higher CD8 T cells percentages reflected as a lower CD4/CD8 ratio. Furthermore, CCR5 expression on CD4 T cells and CD107a expression on both T subsets were significantly higher in coinfected patients when compared with monoinfected DENV and HIV individuals respectively. Increased inflammatory response was observed in treated HAART coinfected patients despite undetectable HIV load. These data indicate that DENV infection may influence the clinical profile and immune response in individuals concomitantly infected with HIV.

  17. Adult separation anxiety in treatment nonresponders with anxiety disorders: delineation of the syndrome and exploration of attachment-based psychotherapy and biomarkers.

    PubMed

    Milrod, Barbara; Altemus, Margaret; Gross, Charles; Busch, Fredric; Silver, Gabrielle; Christos, Paul; Stieber, Joshua; Schneier, Franklin

    2016-04-01

    Clinically significant separation anxiety [SA] has been identified as being common among patients who do not respond to psychiatric interventions, regardless of intervention type (pharmacological or psychotherapeutic), across anxiety and mood disorders. An attachment formation and maintenance domain has been proposed as contributing to anxiety disorders. We therefore directly determined prevalence of SA in a population of adult treatment non-responders suffering from primary anxiety. In these separation anxious nonresponders, we pilot-tested an SA-focused, attachment-based psychotherapy for anxiety, Panic-Focused Psychodynamic Psychotherapy-eXtended Range [PFPP-XR], and assessed whether hypothesized biomarkers of attachment were engaged. We studied separation anxiety [SA] in 46 adults (ages 23-70 [mean 43.9 (14.9)]) with clinically significant anxiety symptoms (Hamilton Anxiety Rating Scale [HARS]≥15), and reporting a history of past non-response to psychotherapy and/or medication treatments. Thirty-seven (80%) had clinically significant symptoms of separation anxiety (Structured Clinical Interview for Separation Anxiety Symptoms [SCI-SAS] score≥8). Five of these subjects completed an open clinical trial of Panic Focused Psychodynamic Psychotherapy eXtended Range [PFPP-XR], a 21-24 session, 12-week manualized attachment-focused anxiolytic psychodynamic psychotherapy for anxiety. Patients improved on "adult threshold" SCI-SAS (current separation anxiety) (p=.016), HARS (p=0.002), and global severity, assessed by the Clinical Global Impression Scale (p=.0006), at treatment termination. Salivary oxytocin levels decreased 67% after treatment (p=.12). There was no significant change in high or low frequency HRV after treatment, but change in high frequency HRV inversely correlated with treatment change in oxytocin (p<.02), and change in low frequency HRV was positively associated with change in oxytocin (p<.02). SA is surprisingly prevalent among non-responders to

  18. Factors Related to Outcome in a School-Based Intensive Mental Health Program: An Examination of Nonresponders

    ERIC Educational Resources Information Center

    Jacobs, Anne K.; Roberts, Michael C.; Vernberg, Eric M.; Nyre, Joseph E.; Randall, Camille J.; Puddy, Richard W.

    2008-01-01

    We examined factors related to treatment responders (n = 35) and nonresponders (n = 16) in a group of 51 children admitted to the Intensive Mental Health Program (IMHP). Children's response to treatment was coded based on their functioning at intake and discharge using total CAFAS scores. Demographic variables, length of treatment, number of…

  19. Stopping rules for surveys with multiple waves of nonrespondent follow-up.

    PubMed

    Rao, R Sowmya; Glickman, Mark E; Glynn, Robert J

    2008-05-30

    In surveys with multiple waves of follow-up, nonrespondents to the first wave are sometimes followed intensively but this does not guarantee an increase in the response rate or an appreciable change in the estimate of interest. Most prior research has focused on stopping rules for Phase I clinical trials. To our knowledge there are no standard methods to stop follow-up in observational studies. Previous research suggests optimal stopping strategies where decisions are based on achieving a given precision for minimum cost or reducing cost for a given precision. In this paper, we propose three stopping rules that are based on assessing whether successive waves of sampling provide evidence that the parameter of interest is changing. Two of the rules rely on examining patterns of observed responses while the third rule uses missing data methods to multiply impute missing responses. We also present results from a simulation study to evaluate our proposed methods. Our simulations suggest that rules that adjust for nonresponse are preferred for decisions to discontinue follow-up since they reduce bias in the estimate of interest. The rules are not complicated and may be applied in a straightforward manner. Discontinuing follow-up would save time and possibly resources, and adjusting for the nonresponse in the analysis would reduce the impact of nonresponse bias.

  20. Constraints of nonresponding flows based on cross layers in the networks

    NASA Astrophysics Data System (ADS)

    Zhou, Zhi-Chao; Xiao, Yang; Wang, Dong

    2016-02-01

    In the active queue management (AQM) scheme, core routers cannot manage and constrain user datagram protocol (UDP) data flows by the sliding window control mechanism in the transport layer due to the nonresponsive nature of such traffic flows. However, the UDP traffics occupy a large part of the network service nowadays which brings a great challenge to the stability of the more and more complex networks. To solve the uncontrollable problem, this paper proposes a cross layers random early detection (CLRED) scheme, which can control the nonresponding UDP-like flows rate effectively when congestion occurs in the access point (AP). The CLRED makes use of the MAC frame acknowledgement (ACK) transmitting congestion information to the sources nodes and utilizes the back-off windows of the MAC layer throttling data rate. Consequently, the UDP-like flows data rate can be restrained timely by the sources nodes in order to alleviate congestion in the complex networks. The proposed CLRED can constrain the nonresponsive flows availably and make the communication expedite, so that the network can sustain stable. The simulation results of network simulator-2 (NS2) verify the proposed CLRED scheme.

  1. A Comparison of Gene Expression Profiles between Glucocorticoid Responder and Non-Responder Bovine Trabecular Meshwork Cells Using RNA Sequencing

    PubMed Central

    Bermudez, Jaclyn Y.; Webber, Hannah C.; Brown, Bartley; Braun, Terry A.; Clark, Abbot F.; Mao, Weiming

    2017-01-01

    The most common ocular side effect of glucocorticoid (GC) therapy is GC-induced ocular hypertension (OHT) and GC-induced glaucoma (GIG). GC-induced OHT occurs in about 40% of the general population, while the other 60% are resistant. This study aims to determine the genes and pathways involved in differential GC responsiveness in the trabecular meshwork (TM). Using paired bovine eyes, one eye was perfusion-cultured with 100nM dexamethasone (DEX), while the fellow eye was used to establish a bovine TM (BTM) cell strain. Based on maximum IOP change in the perfused eye, the BTM cell strain was identified as a DEX-responder or non-responder strain. Three responder and three non-responder BTM cell strains were cultured, treated with 0.1% ethanol or 100nM DEX for 7 days. RNA and proteins were extracted for RNA sequencing (RNAseq), qPCR, and Western immunoblotting (WB), respectively. Data were analyzed using the human and bovine genome databases as well as Tophat2 software. Genes were grouped and compared using Student’s t-test. We found that DEX induced fibronectin expression in responder BTM cells but not in non-responder cells using WB. RNAseq showed between 93 and 606 differentially expressed genes in different expression groups between responder and non-responder BTM cells. The data generated by RNAseq were validated using qPCR. Pathway analyses showed 35 pathways associated with differentially expressed genes. These genes and pathways may play important roles in GC-induced OHT and will help us to better understand differential ocular responsiveness to GCs. PMID:28068412

  2. Liver fibrosis progression is related to CD4 cell depletion in patients coinfected with hepatitis C virus and human immunodeficiency virus.

    PubMed

    Puoti, M; Bonacini, M; Spinetti, A; Putzolu, V; Govindarajan, S; Zaltron, S; Favret, M; Callea, F; Gargiulo, F; Donato, F; Carosi, G

    2001-01-01

    A total of 204 patients with liver biopsy-proven hepatitis C virus (HCV) infection, 84 with and 120 without human immunodeficiency virus (HIV) coinfection, were studied, to evaluate variables possibly associated with the stage of liver fibrosis. All patients were injection drugs users, with a mean age of 32 years and an estimated duration of HCV infection of 12 years. Twenty-four patients (11%) had many fibrous septa with (5%) or without (6%) cirrhosis, 56 (27%) had few fibrous septa, and 124 (60%) had no fibrous septa. In all patients, an association was found between CD4 cell counts <500 cells/mm(3)and the presence of many fibrous septa (odds ratio, 3.2; P=.037), independent of HIV infection and other factors. These results suggest that HIV infection-induced CD4 depletion is independently associated with the severity of liver fibrosis in chronic HCV infection.

  3. Low dose revaccination induces robust protective anti-HBs antibody response in the majority of healthy non-responder neonates.

    PubMed

    Jafarzadeh, A; Zarei, S; Shokri, F

    2008-01-10

    A sizeable proportion (1-10%) of healthy adults and to lesser extent neonates vaccinated with triple 10 microg hepatitis B (HB) vaccine fail to mount a protective antibody response. Revaccination with the same vaccine dose has proved to be effective in a significant number of primary non-responders. The influence of revaccination with lower vaccine doses however has not been studied adequately in non-responder neonates. This study was conducted to evaluate the influence of supplementary vaccination with a single low and standard dose of a recombinant hepatitis B (HB) vaccine in healthy Iranian non-responder neonates to primary vaccination. Iranian neonates unable to respond to primary vaccination with 10, 5 or 2.5 microg doses of recombinant HB vaccine were revaccinated with a single additional dose of the same concentration. Serum anti-HBs antibody titer was measured by sandwich ELISA. Administration of a single additional dose induced seroprotection (anti-HBs> or =10IU/L) in 10/12 (83%), 10/12 (83%) and 21/24 (87.5%) of non-responder neonates in 10, 5 and 2.5 microg vaccine recipients with geometric mean titers (and 95% confidence limits) of 1358 (258-7142), 401 (79-2038) and 164 (62-433) IU/L, respectively. The log-transformed antibody titer obtained for the 10 microg dose recipients was significantly higher than that of the 2.5 microg dose vaccinees (p=0.028). No significant differences in anti-HBs titer were observed between other groups of vaccinees. However, the total seroprotection rates obtained after administration of four low doses of 2.5 and 5 microg were significantly higher than that obtained after administration of the classical three 10 microg doses (p=0.029 and p=0.006, respectively). The total seroprotection rates were similar between all groups of vaccines receiving four doses of 2.5, 5 and 10 microg vaccine doses. These results indicate that a significant proportion of non-responder neonates can be induced to develop a protective anti

  4. Experimental systems for studying Plasmodium/HIV coinfection.

    PubMed

    Frischknecht, Friedrich; Fackler, Oliver T

    2016-07-01

    Coinfections with Human Immunodeficiency Virus (HIV) and Plasmodium, the causative agents of AIDS and malaria, respectively, are frequent and their comorbidity especially in sub-Saharan Africa is high. While clinical studies suggest an influence of the two pathogens on the outcome of the respective infections, experimental studies on the molecular and immunological impact of coinfections are rare. This reflects the limited availability of suitable model systems that reproduce key properties of both pathologies. Here, we discuss key aspects of coinfection with a focus on currently established experimental systems, their limitations for coinfection studies and potential strategies for their improvement.

  5. The cursed duet today: Tuberculosis and HIV-coinfection.

    PubMed

    Tiberi, Simon; Carvalho, Anna Cristina C; Sulis, Giorgia; Vaghela, Devan; Rendon, Adrian; Mello, Fernanda C de Q; Rahman, Ananna; Matin, Nashaba; Zumla, Ali; Pontali, Emanuele

    2017-03-01

    The tuberculosis (TB) and HIV syndemic continues to rage and are a major public health concern worldwide. This deadly association raises complexity and represent a significant barrier towards TB elimination. TB continues to be the leading cause of death amongst HIV-infected people. This paper reports the challenges that lay ahead and outlines some of the current and future strategies that may be able to address this co-epidemic efficiently. Improved diagnostics, cheaper and more effective drugs, shorter treatment regimens for both drug-sensitive and drug-resistant TB are discussed. Also, special topics on drug interactions, TB-IRIS and TB relapse are also described. Notwithstanding the defeats and meagre investments, diagnosis and management of the two diseases have seen significant and unexpected improvements of late. On the HIV side, expansion of ART coverage, development of new updated guidelines aimed at the universal treatment of those infected, and the increasing availability of newer, more efficacious and less toxic drugs are an essential element to controlling the two epidemics. On the TB side, diagnosis of MDR-TB is becoming easier and faster thanks to the new PCR-based technologies, new anti-TB drugs active against both sensitive and resistant strains (i.e. bedaquiline and delamanid) have been developed and a few more are in the pipeline, new regimens (cheaper, shorter and/or more effective) have been introduced (such as the "Bangladesh regimen") or are being tested for MDR-TB and drug-sensitive-TB. However, still more resources will be required to implement an integrated approach, install new diagnostic tests, and develop simpler and shorter treatment regimens.

  6. Total Delay Is Associated with Unfavorable Treatment Outcome among Pulmonary Tuberculosis Patients in West Gojjam Zone, Northwest Ethiopia: A Prospective Cohort Study

    PubMed Central

    Gebreegziabher, Senedu Bekele; Bjune, Gunnar Aksel; Yimer, Solomon Abebe

    2016-01-01

    Background delay in diagnosis and treatment of tuberculosis (TB) may worsen the disease, increase mortality and enhance transmission in the community. This study aimed at assessing the association between total delay and unfavorable treatment outcome among newly diagnosed pulmonary TB (PTB) patients. Methods A prospective cohort study was conducted in West Gojjam Zone, Amhara Region of Ethiopia from October 2013 to May 2015. Newly diagnosed PTB patients who were ≥15 years of age were consecutively enrolled in the study from 30 randomly selected public health facilities. Total delay (the time period from onset of TB symptoms to first start of anti-TB treatment) was measured. Median total delay was calculated. Mixed effect logistics regression was used to analyze factors associated with unfavorable treatment outcome. Results Seven hundred six patients were enrolled in the study. The median total delay was 60 days. Patients with total delay of > 60 days were more likely to have unfavorable TB treatment outcome than patients with total delay of ≤ 60 days (adjusted odds ratio [AOR], 2.33; 95% confidence interval [CI], 1.04–5.26). Human immunodeficiency virus (HIV) positive TB patients were 8.46 times more likely to experience unfavorable treatment outcome than HIV negative TB patients (AOR, 8.46; 95% CI, 3.14–22.79). Conclusions Long total delay and TB/HIV coinfection were associated with unfavorable treatment outcome. Targeted interventions that can reduce delay in diagnosis and treatment of TB, and early comprehensive management of TB/HIV coinfection are needed to reduce increased risk of unfavorable treatment outcome. PMID:27442529

  7. Parents' difficulties as co-therapists in CBT among non-responding youths with anxiety disorders: Parent and therapist experiences.

    PubMed

    Lundkvist-Houndoumadi, Irene; Thastum, Mikael; Nielsen, Klaus

    2016-07-01

    No increased effect has been associated with parent involvement in cognitive behavioral therapy (CBT) for youths with anxiety disorders. The purpose of this study was to explore parent and therapist experiences of CBT among non-responding youths with anxiety disorders, with a primary focus on parent involvement in therapy. Interpretative phenomenological analysis was applied to 24 sets of semi-structured interviews with families and therapists of anxiety-disordered youths who had not profited from CBT with parental inclusion. From the superordinate theme parents' difficulties acting as co-therapists, which emerged from the analyses, two master themes represented the perspectives of parents (difficulty working together with the youth and feeling unqualified, with limited resources), and two represented the perspectives of therapists (family dynamics stood in the way of progress and difficulty transferring control to parents). Parent and therapist experiences complemented each other, offering two different perspectives on parent difficulties as co-therapists. However, the two groups' views on their respective roles in therapy were in conflict. Parents wished to remain being "just the parents" and for the experts to take over, while therapists wished to act as facilitators transferring the control to parents. Clinical implications are drawn for parental involvement and enhancement of treatment outcomes for likely non-responders.

  8. Upregulation of IL-21 Receptor on B Cells and IL-21 Secretion Distinguishes Novel 2009 H1N1 Vaccine Responders from Nonresponders among HIV-Infected Persons on Combination Antiretroviral Therapy

    PubMed Central

    Pallikkuth, Suresh; Kanthikeel, Sudheesh Pilakka; Silva, Sandra Y.; Fischl, Margaret; Pahwa, Rajendra; Pahwa, Savita

    2011-01-01

    Mechanisms underlying failure of novel 2009 H1N1 influenza vaccine-induced Ab responses in HIV-infected persons are poorly understood. This study prospectively evaluated 16 HIV-infected patients on combination antiretroviral therapy and eight healthy controls (HC) who received a single 15 μg dose of nonadjuvanted novel 2009 H1N1 influenza vaccine during the 2009 H1N1 epidemic. Peripheral blood was collected at baseline (T0) and at 7 d (T1) and 28 d (T2) postvaccination for evaluation of immune responses. Prevaccination hemagglutination inhibition Ab titer was <1:20 in all except one study participant. At T2, all HC and 8 out of 16 patients (50%) developed a vaccine-induced Ab titer of ≥1:40. Vaccine responder (R) and vaccine nonresponder patients were comparable at T0 in age, CD4 counts, virus load, and B cell immunophenotypic characteristics. At T2, HC and R patients developed an expansion of phenotypic and functional memory B cells and ex vivo H1N1-stimulated IgG Ab-secreting cells in an ELISPOT assay. The memory B cell response was preceded by a significant expansion of plasmablasts and spontaneous H1N1-specific Ab-secreting cells at T1. At T2, HC and R patients also exhibited significant increases in serum IL-21 levels and in the frequency and mean fluorescence intensity of IL-21R–expressing B cells, which correlated with serum H1N1 Ab titers. Vaccine nonresponder patients failed to develop the above-described vaccine-induced immunologic responses. The novel association of novel 2009 H1N1 vaccine-induced Ab responses with IL-21/IL-21R upregulation and with development of memory B cells and plasmablasts has implications for future research in vaccine design. PMID:21531891

  9. D-Cycloserine for Treatment Nonresponders with Obsessive-Compulsive Disorder: A Case Report

    ERIC Educational Resources Information Center

    Norberg, Melissa M.; Gilliam, Christina M.; Villavicencio, Anna; Pearlson, Godfrey D.; Tolin, David F.

    2012-01-01

    Despite being the most effective treatment available, as many as one third of patients who receive exposure and response prevention (ERP) for obsessive-compulsive disorder (OCD) do not initially respond to treatment. Recent research suggests that the n-methyl d-aspartate (NMDA) receptor partial agonist D-Cycloserine (DCS) may speed up the course…

  10. Visual Motor Integration as a Screener for Responders and Non-Responders in Preschool and Early School Years: Implications for Inclusive Assessment in Oman

    ERIC Educational Resources Information Center

    Emam, Mahmoud Mohamed; Kazem, Ali Mahdi

    2016-01-01

    Visual motor integration (VMI) is the ability of the eyes and hands to work together in smooth, efficient patterns. In Oman, there are few effective methods to assess VMI skills in children in inclusive settings. The current study investigated the performance of preschool and early school years responders and non-responders on a VMI test. The full…

  11. An Open Trial of Intensive Family Based Cognitive-Behavioral Therapy in Youth with Obsessive-Compulsive Disorder Who Are Medication Partial Responders or Nonresponders

    ERIC Educational Resources Information Center

    Storch, Eric A.; Lehmkuhl, Heather D.; Ricketts, Emily; Geffken, Gary R.; Marien, Wendi; Murphy, Tanya K.

    2010-01-01

    This study reports an open-trial of family-based cognitive-behavioral therapy (CBT) in children and adolescents with obsessive-compulsive disorder (OCD). Thirty primarily Caucasian youth with OCD (range = 7-19 years; 15 girls) who were partial responders or nonresponders to two or more medication trials that were delivered either serially or…

  12. Successful treatment of a cardiac resynchronization therapy nonresponder by identifying lead malpositioning

    PubMed Central

    Prasad, Karthik Venkatesh; Ferreira, Scott Wayne; Mehdirad, Ali Akbar

    2017-01-01

    This case describes some of the commonly overlooked device-related issues in patients who have reportedly failed to respond to cardiac resynchronization therapy (CRT). The case demonstrates voltage-dependent right ventricular capture instead of right atrial capture by a subtly malpositioned right atrial lead. CRT therapy failed to improve symptoms of heart failure and the diagnosis of “CRT nonresponder” was made. With a detailed fact-finding approach, the mechanism behind this nonresponse was identified, and the outcome of CRT was significantly improved with rectification of the problems.

  13. Successful Tuberculosis Treatment Outcomes among HIV/TB Coinfected Patients Down-Referred from a District Hospital to Primary Health Clinics in Rural South Africa

    PubMed Central

    Jacobson, Karen B.; Moll, Anthony P.; Friedland, Gerald H.; Shenoi, Sheela V.

    2015-01-01

    Background HIV and tuberculosis (TB) coinfection remains a major public health threat in sub-Saharan Africa. Integration and decentralization of HIV and TB treatment services are being implemented, but data on outcomes of this strategy are lacking in rural, resource-limited settings. We evaluated TB treatment outcomes in TB/HIV coinfected patients in an integrated and decentralized system in rural KwaZulu-Natal, South Africa. Methods We retrospectively studied a cohort of HIV/TB coinfected patients initiating treatment for drug-susceptible TB at a district hospital HIV clinic from January 2012-June 2013. Patients were eligible for down-referral to primary health clinics(PHCs) for TB treatment completion if they met specific clinical criteria. Records were reviewed for patients’ demographic, baseline clinical and laboratory information, past HIV and TB history, and TB treatment outcomes. Results Of 657(88.7%) patients, 322(49.0%) were female, 558(84.9%) were new TB cases, and 572(87.1%) had pulmonary TB. After TB treatment initiation, 280(42.6%) were down-referred from the district level HIV clinic to PHCs for treatment completion; 377(57.4%) remained at the district hospital. Retained patients possessed characteristics indicative of more severe disease. In total, 540(82.2%) patients experienced treatment success, 69(10.5%) died, and 46(7.0%) defaulted. Down-referred patients experienced higher treatment success, and lower mortality, but were more likely to default, primarily at the time of transfer to PHC. Conclusion Decentralization of TB treatment to the primary care level is feasible in rural South Africa. Treatment outcomes are favorable when patients are carefully chosen for down-referral. Higher mortality in retained patients reflects increased baseline disease severity while higher default among down-referred patients reflects failed linkage of care. Better linkage mechanisms are needed including improved identification of potential defaulters, increased

  14. Prevalence and genotypic variability of TTV in HIV-infected patients.

    PubMed

    Sherman, K E; Rouster, S D; Feinberg, J

    2001-11-01

    TT virus is a small, circular DNA virus, that has been associated with transfusion hepatitis. We sought to determine the prevalence of TT virus (TTV) in patients with human immunodeficiency virus (HIV) infection and to characterize the virus in terms of genotypic variability and in the relationship to CD4+, HIV viral loads, HCV/HIV coinfection, and ALT abnormalities. A cross-sectional analysis of HIV-infected patients in the United States, including 86 HIV-positive subjects and 118 HIV-negative controls was performed. TTV was detected using a seminested PCR technique. Samples underwent cloning and sequence analysis and/or RFLP to determine genotype. Thirty-eight percent of HIV-positive patients had TTV infection versus 14.4% of patients within the matching cohort (P = 0.0009). The highest rate of TTV infection was in patients with concurrent HCV/HIV infection (54% vs 30%, P = 0.038). HIV-infected subjects with TTV had lower ALT levels than those without TTV (P = 0.036). Intravenous drug use was the leading factor associated with TTV positivity among HIV-positive subjects. Mixed genotypes were more common in those with HIV. Therefore, TTV prevalence, ALT levels, and genomic heterogeneity of TTV all seem to be altered in patients with HIV.

  15. Factors Associated with Mortality among Patients on TB Treatment in the Southern Region of Zimbabwe, 2013

    PubMed Central

    Sandy, Charles; Masuka, Nyasha; Hazangwe, Patrick; Choto, Regis C.; Mutasa-Apollo, Tsitsi; Nkomo, Brilliant; Sibanda, Edwin; Mugurungi, Owen; Siziba, Nicholas

    2017-01-01

    Background. In 2013, the tuberculosis (TB) mortality rate was highest in southern Zimbabwe at 16%. We therefore sought to determine factors associated with mortality among registered TB patients in this region. Methodology. This was a retrospective record review of registered patients receiving anti-TB treatment in 2013. Results. Of 1,971 registered TB patients, 1,653 (84%) were new cases compared with 314 (16%) retreatment cases. There were 1,538 (78%) TB/human immunodeficiency virus (HIV) coinfected patients, of whom 1,399 (91%) were on antiretroviral therapy (ART) with median pre-ART CD4 count of 133 cells/uL (IQR, 46–282). Overall, 428 (22%) TB patients died. Factors associated with increased mortality included being ≥65 years old [adjusted relative risk (ARR) = 2.48 (95% CI 1.35–4.55)], a retreatment TB case [ARR = 1.34 (95% CI, 1.10–1.63)], and being HIV-positive [ARR = 1.87 (95% CI, 1.44–2.42)] whilst ART initiation was protective [ARR = 0.25 (95% CI, 0.22–0.29)]. Cumulative mortality rates were 10%, 14%, and 21% at one, two, and six months, respectively, after starting TB treatment. Conclusion. There was high mortality especially in the first two months of anti-TB treatment, with risk factors being recurrent TB and being HIV-infected, despite a high uptake of ART. PMID:28352474

  16. Brief Report: A High Rate of β7+ Gut-Homing Lymphocytes in HIV-Infected Immunological Nonresponders is Associated With Poor CD4 T-Cell Recovery During Suppressive HAART

    PubMed Central

    Girard, Alexandre; Vergnon-Miszczycha, Delphine; Depincé-Berger, Anne-Emmanuelle; Roblin, Xavier; Lutch, Frederic; Lambert, Claude; Rochereau, Nicolas; Bourlet, Thomas; Genin, Christian

    2016-01-01

    Objective: Correlation between GALT homing markers on lymphocytes and the low blood CD4 T-cell reconstitution in immunological nonresponders (INRs) has been studied. Design: Thirty-one INRs, 19 immunological responders (IRs), and 12 noninfected controls were enrolled in this study. INRs were defined by an undetectable plasma viral load RNA less than 40 copies per milliliter and CD4+ T-cell count <500 cells per cubic milliliter in at least 3 years. Methods: A complete peripheral and mucosal lymphocyte immunophenotyping was performed on these patients with a focus on the CCR9, CCR6, and α4β7 gut-homing markers. Results: A highly significant upregulation of α4β7 on INRs peripheral lymphocytes compared with that of IRs has been observed. This upregulation impacts different lymphocyte subsets namely CD4+, CD8+, and B lymphocytes. The frequency of β7+ Th17 and Treg cells are increased compared with IRs and healthy controls. The frequency of β7+ CD8+ T cells in the blood is negatively correlated with integrated proviral DNA in rectal lymphoid cells in contrast to β7+ CD4+ T cells associated with HIV integration. Conclusions: Alteration of lymphocyte homing abilities would have deleterious effects on GALT reconstitution and could participate to HIV reservoir constitution. These results emphasize the great interest to consider α4β7-targeted therapy in INR patients to block homing of lymphocytes and/or to directly impair gp120-α4β7 interactions. PMID:27306505

  17. Low Double-Negative CD3+CD4−CD8− T Cells Are Associated with Incomplete Restoration of CD4+ T Cells and Higher Immune Activation in HIV-1 Immunological Non-Responders

    PubMed Central

    Lu, Xiaofan; Su, Bin; Xia, Huan; Zhang, Xin; Liu, Zhiying; Ji, Yunxia; Yang, Zixuan; Dai, Lili; Mayr, Luzia M.; Moog, Christiane; Wu, Hao; Huang, Xiaojie; Zhang, Tong

    2016-01-01

    Failure of immune reconstitution increases the risk of AIDS or non-AIDS related morbidity and mortality in HIV-1-infected patients. CD3+CD4−CD8− T cells, which are usually described as double-negative (DN) T cells, display CD4-like helper and immunoregulatory functions. Here, we have measured the percentage of DN T cells in the immune reconstituted vs. non-immune reconstituted HIV-1-infected individuals. We observed that immunological non-responders (INRs) had a low number of DN T cells after long-term antiretroviral therapy (ART), and the number of these cells positively correlated with the CD4+ T cell count. The ART did not result in complete suppression of immune activation recorded by the percentage of CD38+HLA-DR+CD8+ T cells in INRs, and a strong inverse correlation was observed between DN T cells and immune activation. A low proportion of TGF-β1+DN T cells was found in INRs. Further mechanism study demonstrated that the level of TGF-β1-producing DN T cells and immune activation had a negative correlation after ART. Taken together, our study suggests that DN T cells control the immunological response in HIV-1-infected patients. These findings expand our understanding of the mechanism of immune reconstitution and could develop specific treatments to return the immune system to homeostasis following initiation of HIV-1 therapy. PMID:28018346

  18. Low Double-Negative CD3(+)CD4(-)CD8(-) T Cells Are Associated with Incomplete Restoration of CD4(+) T Cells and Higher Immune Activation in HIV-1 Immunological Non-Responders.

    PubMed

    Lu, Xiaofan; Su, Bin; Xia, Huan; Zhang, Xin; Liu, Zhiying; Ji, Yunxia; Yang, Zixuan; Dai, Lili; Mayr, Luzia M; Moog, Christiane; Wu, Hao; Huang, Xiaojie; Zhang, Tong

    2016-01-01

    Failure of immune reconstitution increases the risk of AIDS or non-AIDS related morbidity and mortality in HIV-1-infected patients. CD3(+)CD4(-)CD8(-) T cells, which are usually described as double-negative (DN) T cells, display CD4-like helper and immunoregulatory functions. Here, we have measured the percentage of DN T cells in the immune reconstituted vs. non-immune reconstituted HIV-1-infected individuals. We observed that immunological non-responders (INRs) had a low number of DN T cells after long-term antiretroviral therapy (ART), and the number of these cells positively correlated with the CD4(+) T cell count. The ART did not result in complete suppression of immune activation recorded by the percentage of CD38(+)HLA-DR(+)CD8(+) T cells in INRs, and a strong inverse correlation was observed between DN T cells and immune activation. A low proportion of TGF-β1(+)DN T cells was found in INRs. Further mechanism study demonstrated that the level of TGF-β1-producing DN T cells and immune activation had a negative correlation after ART. Taken together, our study suggests that DN T cells control the immunological response in HIV-1-infected patients. These findings expand our understanding of the mechanism of immune reconstitution and could develop specific treatments to return the immune system to homeostasis following initiation of HIV-1 therapy.

  19. Immunogenicity of an investigational hepatitis B vaccine (hepatitis B surface antigen co-administered with an immunostimulatory phosphorothioate oligodeoxyribonucleotide) in nonresponders to licensed hepatitis B vaccine.

    PubMed

    Halperin, Scott A; Ward, Brian J; Dionne, Marc; Langley, Joanne M; McNeil, Shelly A; Smith, Bruce; Mackinnon-Cameron, Donna; Heyward, William L; Martin, J Tyler

    2013-07-01

    An additional one to three doses of hepatitis B vaccine are recommended for nonresponders to an initial standard three-dose series. We compared the safety and immunogenicity of an investigational hepatitis B surface antigen vaccine (HBsAg-1018) with a phosphorothioate oligodeoxyribonucleotide adjuvant that targets toll-like receptor-9 to a commercially available, alum-adjuvanted hepatitis B vaccine (HBsAg-Eng) in nonresponders to three previous doses (primary study) or to four to six previous doses (substudy) of HBsAg-Eng. Both vaccines were well tolerated, although HBsAg-1018 was associated with more injection-site tenderness (63.2% vs. 18.8%, p = 0.016 in the primary study and 81.8% vs. 15.4%, p = 0.003 in the substudy). No statistically significant differences in rates of seroprotection (anti-HBs concentration ≥ 10 mIU/mL) or geometric mean antibody concentrations were found in the primary study. In the substudy, a greater proportion of HBsAg-1018 recipients achieved an anti-HBs concentration ≥ 100 mIU/mL (54.5% vs. 8.3%, p = 0.027), and those responders had higher geometric mean antibody concentrations at 4 weeks (264 vs. 46.5 mIU/mL, p = 0.021) and 52 weeks (7.0 vs. 1.2 mIU/mL, p = 0.030) than HBsAg-Eng recipients. Although this study suggests that HBsAg-1018 may have improved immunogenicity in nonresponders to hepatitis B vaccine vaccination when compared with HBsAg-Eng, larger studies are required.

  20. Hepatitis B revaccination in healthy non-responder Chinese children: five-year follow-up of immune response and immunologic memory.

    PubMed

    Zhuang, Gui-Hua; Yan, Hong; Wang, Xue-Liang; Hwang, Lu-Yu; Wu, Qian; Wang, Li-Rong; Gao, Hai-Yan

    2006-03-15

    To assess persistence of anti-HBs and immunologic memory of non-responders after revaccination, 40 healthy non-responder children were given a three-dose recombinant hepatitis B vaccine revaccination randomly by intramuscular (10 microg per dose) or intradermal (2 microg per dose) route and followed up to five years. All 17 intramuscular and 22 of 23 intradermal children developed a seroprotective antibody response (anti-HBs>or=10 mIU/mL) after revaccination. Children of intramuscular group had significantly higher seroprotection rates and anti-HBs geometric mean titers than the intradermal group. At year 5, 50% of children in intramuscular group, but only 18.2% of intradermal group still maintained seroprotection (P=0.075). By the end of follow-up, a booster dose (5 microg) was given to those who had lost seroprotection. All the eight intramuscular children developed an anamnestic response with increase of anti-HBs level by 215 times, but two of the 18 intradermal children failed to produce seroprotective level. Three-routine-dose intramuscular revaccination was significantly more effective than low-dose intradermal revaccination with the same number of injections. No child seroconverted to HBsAg, and 11 had transient infections indicated by seroconversion to anti-HBc. These results demonstrated that non-responders could benefit from three doses intramuscular revaccination not only in high proportion of anti-HBs conversion but also in long-term persistence of seroprotection, and more importantly in preservation of the immunologic memory years after loss of protective anti-HBs.

  1. Safety and efficacy of daclatasvir in the management of patients with chronic hepatitis C

    PubMed Central

    Manolakopoulos, Spilios; Zacharakis, George; Zissis, Miltiadis; Giannakopoulos, Vassilis

    2016-01-01

    Daclatasvir (Daklinza™), a new oral direct-acting antiviral, is an inhibitor of hepatitis C virus NS5A protein and has recently been approved in the United States, Europe and Japan in chronic hepatitis C. It shows potent pangenotypic activity and moderately high genetic barrier to resistance improving the sustained virological response (SVR) rates. In COMMAND phase 2 trials, daclatasvir demonstrated high SVR rates in HCV genotype 1-4 chronically infected patients treated with peginterferon-a (pegIFNα) plus ribavirin (RBV). Furthermore, it produced even higher response rates in all-oral combination with sofosbuvir, an interferon-free regimen, with or without ribavirin, in patients with advanced liver disease, HCV/HIV coinfection, liver transplantation in ALLY studies and other real-world studies. This narrative review provides information on the pharmacological properties, role, efficacy and safety of daclatasvir-containing regimens in chronic hepatitis C patients. Daclatasvir administered once-daily in combination with sofosbuvir is an effective 12-week treatment in adult patients with chronic hepatitis C and is generally safe and well tolerated. PMID:27366028

  2. Variability of platelet aggregation in patients with clopidogrel treatment and hip fracture: A retrospective case-control study on 112 patients

    PubMed Central

    Clareus, Anna; Fredriksson, Inga; Wallén, Håkan; Gordon, Max; Stark, André; Sköldenberg, Olof

    2015-01-01

    AIM: To identify the rate of non-responders to clopidogrel treatment in hip fracture patients and study how non-responders differ from controls. METHODS: In a retrospective case-control study we included 28 cases of acute proximal femoral fracture with clopidogrel treatment 2011 to 2013. Eighty-four controls from the same time period were included. Data collected included response to clopidogrel measured with multiple electrode aggregometry (MEA), intraoperative bleeding, erythrocyte transfusion, time to surgery and the incidence of adverse events up to 3 mo after surgery. RESULTS: Eight (29%) of the 28 cases were non-responders. The median intraoperative bleeding was 300 mL (range, 0-1500), and was lower for non-responders (50 mL) but did not reach statistical significance. Erythrocyte transfusions did not differ between responders, non-responders and controls. Forty-five (40%) of 112 patients had adverse events postoperatively but the rate did not differ between patients with and without clopidogrel treatment. CONCLUSION: Almost one-third of patients with clopidogrel treatment and an acute proximal femoral fracture are non-responders to antiplatelet therapy and can be operated without delay. PMID:26085986

  3. Prevalence of serotype D in Cryptococcus neoformans isolates from HIV positive and HIV negative patients in Italy.

    PubMed

    Tortorano, A M; Viviani, M A; Rigoni, A L; Cogliati, M; Roverselli, A; Pagano, A

    1997-11-01

    Cryptococcus neoformans strains isolated from 207 HIV positive and HIV negative patients hospitalized in Northern Italy were serotyped by slide agglutination. One Brazilian HIV negative woman was infected by var. gattii serotype B and all the other patients by var. neoformans, serotype D in 71%, serotype A in 24.6% and serotype AD in 3.4%. No difference was observed between subjects with serotypes A and D in HIV coinfection, exposure categories for AIDS, age, sex, and CD4 count of HIV positive patients. Meningeal and respiratory tract involvements and prostatic reservoir occurred with comparable frequency in AIDS patients infected by serotypes A and D. Skin lesions were observed only in serotype D infections, occurring in 12.6% of HIV positive and 58.3% of HIV negative patients infected by this serotype. Serotype A was found less susceptible to fluconazole than serotype D: 53.7% of serotype A strains had a MIC > or = 25 micrograms ml-1 compared to 17.7% of the serotype D isolates. On the other hand, both serotypes were highly susceptible to itraconazole.

  4. Improved cell mediated immune responses after successful re-vaccination of non-responders to the hepatitis B virus surface antigen (HBsAg) vaccine using the combined hepatitis A and B vaccine.

    PubMed

    Nyström, Jessica; Cardell, Kristina; Björnsdottir, Thora Björg; Fryden, Aril; Hultgren, Catharina; Sällberg, Matti

    2008-11-05

    We successfully re-vaccinated hepatitis B virus (HBV) vaccine non-responders using a double dose of the combined hepatitis A virus (HAV) and HBV vaccine. The hope was to improve priming of hepatitis B surface antigen (HBsAg)-specific cell mediated immune response (CMI) by an increased antigen dose and a theoretical adjuvant-effect from the local presence of a HAV-specific CMI. A few non-responders had a detectable HBsAg-specific CMI before re-vaccination. An in vitro detectable HBsAg-specific CMI was primed equally effective in non-responders (58%) as in first time vaccine recipients (68%). After the third dose a weak, albeit significant, association was observed between the magnitude of HBsAg-specific proliferation and anti-HBs levels. This regimen improves the priming of HBsAg-specific CMIs and antibodies.

  5. Cellular immune responses in multiple sclerosis patients treated with interferon-beta

    PubMed Central

    Bustamante, M. F.; Rio, J.; Castro, Z.; Sánchez, A.; Montalban, X.; Comabella, M.

    2013-01-01

    Summary We investigated cellular immune responses at baseline in peripheral blood mononuclear cells (PBMC) of patients with multiple sclerosis (MS) treated with interferon (IFN)-β and classified into responders and non-responders according to clinical response criteria. Levels for IFN-γ, interleukin (IL)-17A, IL-17F, IL-10 and IL-4 were determined in activated PBMC of 10 responders, 10 non-responders and 10 healthy controls by cytometric bead arrays. Cytokine levels in cell culture supernatants were similar between responders and non-responders, and comparable to those obtained in healthy controls. These findings do not support differential cellular immune responses in PBMC at baseline between IFN-β responders and non-responders. PMID:23379429

  6. Predominance of Hepatitis B Virus genotype A among treated HIV infected patients experiencing high HBV drug resistance in Nairobi, Kenya.

    PubMed

    Mabeya, Sepha Nyatichi; Ngugi, Caroline Wangari; Lihana, Raphael W; Khamadi, Samoel Ashimosi; Nyamache, Anthony Kebira

    2017-03-19

    HBV/HIV coinfections are becoming common with information on HBV genetic diversity and drug resistance still remaining elusive. To evaluate the HBV genetic diversity and drug resistance associated mutations among drug experienced HIV patients, the genetic analysis of the partial HBV-pol-reverse trancriptase gene was successfully sequenced from 13 samples. Analysis of the sequences showed that all (13) the sequences belonged to genotype A. Nucleos(t)ide drug resistance mutations were found in six (6) patients. Five subjects had rtV173L, rtL180M, rtM204V and one with rtL180M, rtM204V major mutations. HBV genotype A remains the most predominant genotype circulating in Nairobi city with detected high level of HBV drug resistance to Lamivudine telbivudine and emtricitabine. The detected circulating HBV genotype A in Nairobi reflects its possible spread in the population with its origin being within the country. We suggest that patients should not be on lamivudine monotherapy. These individuals should be managed on combination of tenofovir plus lamivudine or emtricitabine therapy in order to prevent the emergence of HBV drug resistant variants alongside a continuous surveillance monitoring of drug resistance and HBV genotypes.

  7. Clinical validation of sublingual formulations of Immunoxel (Dzherelo) as an adjuvant immunotherapy in treatment of TB patients.

    PubMed

    Efremenko, Yuri V; Arjanova, Olga V; Prihoda, Natalia D; Yurchenko, Larisa V; Sokolenko, Nina I; Mospan, Igor V; Pylypchuk, Volodymyr S; Rowe, John; Jirathitikal, Vichai; Bourinbaiar, Aldar S; Kutsyna, Galyna A

    2012-03-01

    Immunoxel (Dzherelo) is a water-alcohol extract of medicinal plants used in Ukraine as an adjunct immunotherapy to TB and HIV therapy. Four types of solid sublingual formulations of Immunoxel were made: sugar dragées, sugar-coated pills, gelatin pastilles and dried-honey lozenges. They were administered once-daily along with TB drugs. After 1 month, 84.1% of TB patients became sputum-negative with rates in individual groups of 89.5, 70, 76.9 and 100%, respectively. The conversion rate was independent of bodyweight, age, gender, differences in chemotherapy regimens or whether subjects had newly diagnosed TB, re-treated TB, multidrug-resistant TB or TB with HIV coinfection. Patients experienced earlier clinical improvement, faster defervescence, weight gain, a higher hemoglobin content and reduced inflammation as evidenced by lower leukocyte counts and erythrocyte sedimentation rate. By contrast, in the placebo group, only 19% of patients had converted. These findings imply that mucosal delivery of solid Immunoxel is equivalent to the original liquid formula given per os twice-daily for 2-4 months.

  8. Increased Natural Killer Cell Activation in HIV-Infected Immunologic Non-Responders Correlates with CD4+ T Cell Recovery after Antiretroviral Therapy and Viral Suppression

    PubMed Central

    Luo, Zhenwu; Li, Zhen; Martin, Lisa; Hu, Zhiliang; Wu, Hao; Wan, Zhuang; Kilby, Michael; Heath, Sonya L.; Huang, Lei; Jiang, Wei

    2017-01-01

    The role of natural killer (NK) cell function in HIV disease especially in the setting of long-term antiretroviral therapy (ART) and viral suppression is not fully understood. In the current study, we have investigated NK cell activation in healthy controls and aviremic ART-treated HIV+ subjects with different degrees of immune restoration. We performed a cross sectional study in 12 healthy controls and 24 aviremic ART-treated HIV-infected subjects including 13 HIV+ subjects with CD4+ T cells above 500 cells/μL defined as “immunologic responders” and 11 HIV+ subjects with CD4+ T cells below 350 cells/μL defined as “immunologic non-responders”. We analyzed NK cell number, subset, and activation by expression of CD107a and NKG2D and co-expression of CD38 and HLA-DR. NK cell-mediated cytotoxicity against uninfected CD4+ T cells was tested in vitro. We found that NK cell absolute number, percentage of NK cells, and percentage of NK cell subsets were similar in the three study groups. The increased NK cell activation was found predominantly in CD56dimCD16+ subset of immunologic non-responders but not immunologic responders compared to healthy controls. The activation of NK cells was inversely correlated with the peripheral CD4+ T cell count in HIV+ subjects, even after controlling for chronic T cell activation, sex, and age, potential contributors for CD4+ T cell counts in HIV disease. Interestingly, NK cells from immunologic non-responders mediated cytotoxicity against uninfected CD4+ T cells ex vivo. NK cells may play a role in blunted CD4+ T cell recovery in ART-treated HIV disease. PMID:28076376

  9. [Clinical, epidemiological and immunological study of patients coinfected with HIV and HTLV-1].

    PubMed

    Scapellato, Pablo G; Bottaro, Edgardo G; Seoane, María B; Rodriguez Brieschke, María T; Scapellato, Jose L; Dato, Adriana; Vidal, Gabriela I

    2004-01-01

    We studied the prevalence of antibodies against HTLV-1 among every HIV-infected outpatients assisted in our hospital between January 1st 2000 and June 30th 2003. We reviewed the epidemiological data, clinical findings, viral load and CD4 cells-count, comparing coinfected with non HTLV-1 coinfected. We found a prevalence of HTLV-1 infection of 8.1% (23/282); 8.5% (12/141) in men and 7.8% (11/141) in women [[OR=0.91 (0.36patients users of illicit drugs and 4.6% (7/152) among non-users [OR=2.93 (1.09patients [p=0.000006 OR=7.42 (2.71patients (96/282) had history of AIDS defining diseases (ADD). No differences in the ADD were found among coinfected and no coinfected patients. No patient developed any disease relative to HTLV-1. The mean of CD4-cells among HTLV-1 coinfected with history of ADD naïve patients (n=7) was 211 cells/ml, and 87.9 cells/ml among those not-coinfected (n=55) [t-test=2.82; p=0.006]. The viral load was similar among every investigated group of patients. We found a high prevalence of HTLV-1 infection in HIV-infected patients (higher among IDU). The CD4-cell count of patients suffering from an AIDS defining disease was higher among HTLV-1/HIV coinfected patients than in singly HIV infected, this could show a grade of missfunction of CD4-cells in coinfected patients.

  10. Human T Cell Lymphotropic Virus Type 2a Strains Among HIV Type 1-Coinfected Patients from Brazil Have Originated Mostly from Brazilian Amerindians

    PubMed Central

    Magri, Mariana Cavalheiro; Brigido, Luis Fernando de Macedo; Morimoto, Helena Kaminami

    2013-01-01

    Abstract The human T cell lymphotropic virus type 2 (HTLV-2) is found mainly in Amerindians and in intravenous drug users (IDUs) from urban areas of the United States, Europe, and Latin America. Worldwide, HTLV-2a and HTLV-2b subtypes are the most prevalent. Phylogenetic analysis of HTLV-2 isolates from Brazil showed the HTLV-2a subtype, variant -2c, which spread from Indians to the general population and IDUs. The present study searched for the types of HTLV-2 that predominate among HIV-1-coinfected patients from southern and southeastern Brazil. Molecular characterization of the LTR, env, and tax regions of 38 isolates confirmed the HTLV-2c variant in 37 patients, and one HTLV-2b in a patient from Paraguay. Phylogenetic analysis of sequences showed different clades of HTLV-2 associated with risk factors and geographic region. These clades could represent different routes of virus transmission and/or little diverse evolutionary rates of virus. Taking into account the results obtained in the present study and the lack of the prototypic North American HTLV-2a strain and HTLV-2b subtypes commonly detected among HIV-coinfected individuals worldwide, we could speculate on the introduction of Brazilian HTLV-2 strains in such populations before the introduction of HIV. PMID:23484539

  11. Rifapentine for latent tuberculosis infection treatment in the general population and human immunodeficiency virus-positive patients: summary of evidence.

    PubMed

    Vidal, Júlia Souza; Silva, Marcus Tolentino; Sanchez, Mauro Niskier

    2015-01-01

    Latent tuberculosis infection (LTBI) and human immunodeficiency virus (HIV)-coinfection are challenges in the control of tuberculosis transmission. We aimed to assess and summarize evidence available in the literature regarding the treatment of LTBI in both the general and HIV-positive population, in order to support decision making by the Brazilian Tuberculosis Control Program for LTBI chemoprophylaxis. We searched MEDLINE, Cochrane Library, Centre for Reviews and Dissemination, Embase, LILACS, SciELO, Trip database, National Guideline Clearinghouse, and the Brazilian Theses Repository to identify systematic reviews, randomized clinical trials, clinical guidelines, evidence-based synopses, reports of health technology assessment agencies, and theses that investigated rifapentine and isoniazid combination compared to isoniazid monotherapy. We assessed the quality of evidence from randomized clinical trials using the Jadad Scale and recommendations from other evidence sources using the Grading of Recommendations, Assessment, Development, and Evaluations approach. The available evidence suggests that there are no differences between rifapentine + isoniazid short-course treatment and the standard 6-month isoniazid therapy in reducing active tuberculosis incidence or death. Adherence was better with directly observed rifapentine therapy compared to self-administered isoniazid. The quality of evidence obtained was moderate, and on the basis of this evidence, rifapentine is recommended by one guideline. Available evidence assessment considering the perspective of higher adherence rates, lower costs, and local peculiarity context might support rifapentine use for LTBI in the general or HIV-positive populations. Since novel trials are ongoing, further studies should include patients on antiretroviral therapy.

  12. [The National Danish Survey of Patient Experiences has a small positive bias].

    PubMed

    Rosenstjerne Andersen, Angelo; Fuglsang, Marie; Kyed, Daisy

    2012-10-01

    The response rate in The National Danish Survey of Patient Experiences in 2009 was 54%. In order to evaluate bias due to non-responders, The Unit of Patient-perceived Quality merged survey data and data on patient background from Statistics Denmark. The relationships between the responding patients' background and their answers to six questions in the survey questionnaire are estimated with logistic regression analysis and subsequently used for predicting the answers of the non-responders. Results indicate a small positive bias in four of the questions and no bias in the remaining two.

  13. Comparing recidivism rates of treatment responders/nonresponders in a sample of 413 child molesters who had completed community-based sex offender treatment in the United kingdom.

    PubMed

    Beech, Anthony R; Mandeville-Norden, Rebecca; Goodwill, Alasdair

    2012-02-01

    Analysis of psychometric data from a sample of 413 child molesters who had completed a U.K. probation-based sex offender treatment program was carried out to assess (a) the effectiveness of therapy in the short term and (b) the longer term implications of treatment in relation to sexual recidivism. It was found that 12% (51 offenders) of the sample had recidivated within 2 to 4 years. Of these recidivists, 86% (44 offenders) had been reconvicted for a sexually related offense. One hundred thirty-five offenders (33%) demonstrated a treated profile (i.e., demonstrated no offense-specific problems and few, or no, socioaffective problems at the posttreatment stage). This group was compared with a sample of offenders deemed as not responding to treatment, matched by their levels of pretreatment risk/need. It was found that a significantly smaller proportion (n = 12, 9%) of treatment responders had recidivated, compared to the treatment nonresponders (n = 20, 15%), indicating a 40% reduction in recidivism in those who had responded to treatment (effect size = .18). Matching length of treatment to the offenders' level of pretreatment risk/need (i.e., higher risk/treatment-need offenders typically undertook longer treatment) reduced the rate of recidivism among this group to the level of recidivism observed among the lower risk/need offenders.

  14. Relationship Between HIV Coinfection, Interleukin 10 Production, and Mycobacterium tuberculosis in Human Lymph Node Granulomas

    PubMed Central

    Diedrich, Collin R.; O'Hern, Jennifer; Gutierrez, Maximiliano G.; Allie, Nafiesa; Papier, Patricia; Meintjes, Graeme; Coussens, Anna K.; Wainwright, Helen; Wilkinson, Robert J.

    2016-01-01

    Background. Human immunodeficiency virus type 1 (HIV)–infected persons are more susceptible to tuberculosis than HIV–uninfected persons. Low peripheral CD4+ T-cell count is not the sole cause of higher susceptibility, because HIV–infected persons with a high peripheral CD4+ T-cell count and those prescribed successful antiretroviral therapy (ART) remain more prone to active tuberculosis than HIV–uninfected persons. We hypothesized that the increase in susceptibility is caused by the ability of HIV to manipulate Mycobacterium tuberculosis–associated granulomas. Methods. We examined 71 excised cervical lymph nodes (LNs) from persons with HIV and M. tuberculosis coinfection, those with HIV monoinfection, and those with M. tuberculosis monoinfection with a spectrum of peripheral CD4+ T-cell counts and ART statuses. We quantified differences in M. tuberculosis levels, HIV p24 levels, cellular response, and cytokine presence within granulomas. Results. HIV increased M. tuberculosis numbers and reduced CD4+ T-cell counts within granulomas. Peripheral CD4+ T-cell depletion correlated with granulomas that contained fewer CD4+ and CD8+ T cells, less interferon γ, more neutrophils, more interleukin 10 (IL-10), and increased M. tuberculosis numbers. M. tuberculosis numbers correlated positively with IL-10 and interferon α levels and fewer CD4+ and CD8+ T cells. ART reduced IL-10 production. Conclusions. Peripheral CD4+ T-cell depletion correlated with increased M. tuberculosis presence, increased IL-10 production, and other phenotypic changes within granulomas, demonstrating the HIV infection progressively changes these granulomas. PMID:27462092

  15. Population Pharmacokinetics of Rifampin in Pregnant Women with Tuberculosis and HIV Coinfection in Soweto, South Africa.

    PubMed

    Denti, Paolo; Martinson, Neil; Cohn, Silvia; Mashabela, Fildah; Hoffmann, Jennifer; Msandiwa, Reginah; Castel, Sandra; Wiesner, Lubbe; Chaisson, Richard E; McIlleron, Helen; Dooley, Kelly E

    2015-12-07

    Effective treatment of tuberculosis during pregnancy is essential for preventing maternal and fetal mortality, but little is known about the effects of pregnancy on the disposition of antituberculosis drugs. We explored the effects of pregnancy on the pharmacokinetics of rifampin, the key sterilizing drug in tuberculosis treatment, in Tshepiso, a prospective cohort study involving pregnant HIV-infected women with or without tuberculosis in Soweto, South Africa. Participants receiving standard first-line tuberculosis treatment underwent sparse sampling for rifampin at 37 weeks' gestation or delivery and then postpartum. Cord blood was collected when possible. A population pharmacokinetic model was developed to investigate the effects of pregnancy on rifampin pharmacokinetics. Among the 48 participants, median age and weight were 28 years and 67 kg, respectively. A one-compartment model with first-order elimination, transit compartment absorption, and allometric scaling described the data well. Pregnancy reduced rifampin clearance by 14%. The median (interquartile range) model-estimated rifampin area under the concentration-time curve over 24 h (AUC0-24) during pregnancy or intrapartum was 40.8 h · mg/liter (27.1 to 54.2 h · mg/liter) compared to 37.4 h · mg/liter (26.8 to 50.3 h · mg/liter) postpartum. The maximum concentrations were similar during pregnancy and postpartum. Rifampin was detectable in 36% (8/22) of cord blood samples, and 88% (42/48) of the women had successful treatment outcomes. There was one case of perinatal tuberculosis. In conclusion, rifampin clearance is modestly reduced during the last trimester of pregnancy. Exposures are only slightly increased, so dose adjustment during pregnancy is not needed. Rifampin was detected in cord blood samples when delivery occurred soon after dosing. The consequences of exposure to this potent inducer of metabolizing enzymes among HIV-exposed infants are unclear.

  16. Population Pharmacokinetics of Rifampin in Pregnant Women with Tuberculosis and HIV Coinfection in Soweto, South Africa

    PubMed Central

    Denti, Paolo; Martinson, Neil; Cohn, Silvia; Mashabela, Fildah; Hoffmann, Jennifer; Msandiwa, Reginah; Castel, Sandra; Wiesner, Lubbe; Chaisson, Richard E.; McIlleron, Helen

    2015-01-01

    Effective treatment of tuberculosis during pregnancy is essential for preventing maternal and fetal mortality, but little is known about the effects of pregnancy on the disposition of antituberculosis drugs. We explored the effects of pregnancy on the pharmacokinetics of rifampin, the key sterilizing drug in tuberculosis treatment, in Tshepiso, a prospective cohort study involving pregnant HIV-infected women with or without tuberculosis in Soweto, South Africa. Participants receiving standard first-line tuberculosis treatment underwent sparse sampling for rifampin at 37 weeks' gestation or delivery and then postpartum. Cord blood was collected when possible. A population pharmacokinetic model was developed to investigate the effects of pregnancy on rifampin pharmacokinetics. Among the 48 participants, median age and weight were 28 years and 67 kg, respectively. A one-compartment model with first-order elimination, transit compartment absorption, and allometric scaling described the data well. Pregnancy reduced rifampin clearance by 14%. The median (interquartile range) model-estimated rifampin area under the concentration-time curve over 24 h (AUC0–24) during pregnancy or intrapartum was 40.8 h · mg/liter (27.1 to 54.2 h · mg/liter) compared to 37.4 h · mg/liter (26.8 to 50.3 h · mg/liter) postpartum. The maximum concentrations were similar during pregnancy and postpartum. Rifampin was detectable in 36% (8/22) of cord blood samples, and 88% (42/48) of the women had successful treatment outcomes. There was one case of perinatal tuberculosis. In conclusion, rifampin clearance is modestly reduced during the last trimester of pregnancy. Exposures are only slightly increased, so dose adjustment during pregnancy is not needed. Rifampin was detected in cord blood samples when delivery occurred soon after dosing. The consequences of exposure to this potent inducer of metabolizing enzymes among HIV-exposed infants are unclear. PMID:26643345

  17. Effects and prevalence of nonresponders after 12 weeks of high-intensity interval or resistance training in women with insulin resistance: a randomized trial.

    PubMed

    Álvarez, Cristian; Ramírez-Campillo, Rodrigo; Ramírez-Vélez, Robinson; Izquierdo, Mikel

    2017-04-01

    Our aim was to investigate the effects and prevalence of nonresponders (NR) to high-intensity interval training (HIIT) and resistance training (RT) in women with insulin resistance on cardiometabolic health parameters. Sedentary overweight/obese insulin-resistant women (age = 33.5 ± 6.5 yr; body mass index = 29.9 ± 3.7 kg/m(2)) were randomly assigned to a triweekly HIIT program (HIIT; n = 18) or resistance training (RT; n = 17). Anthropometry (body mass, fat mass, muscle mass, waist circumference, and skinfold thickness), cardiovascular (blood pressure), metabolic [fasting glucose, fasting insulin, and homeostatic model of insulin resistance (HOMA-IR)], as well as muscle strength, and endurance performance covariables were measured before and after 12 wk in both intervention groups. The interindividual variability to exercise training of the subjects was categorized as responders and NR using as cut points two times the typical error of measurement in mean outcomes. After intervention, significant reduction in waist circumference, skinfold thicknesses, fat mass, blood pressure, fasting glucose, insulin, and HOMA-IR (P < 0.05) were identified to HIIT and RT group, respectively. Both HIIT and RT groups exhibited a significant decrease in the endurance performance, whereas only RT exhibited increased muscle strength. Significant differences in the NR prevalence between the HIIT and RT groups were identified for a decrease in fat mass (HIIT 33.3% vs. RT 70.5%; P = 0.028), muscle mass (HIIT 100% vs. RT 52.9%; P = 0.001), and tricipital skinfold (HIIT 5.5% vs. RT 29.4%; P < 0.041). For diastolic blood pressure, significant differences were observed in the NR prevalence between the HIIT and RT groups (55.5% vs. 94.1; P = 0.009). However, there were no differences in the NR prevalence between HIIT and RT for decreasing fasting glucose. Twelve weeks of HIIT and RT have similar effects and NR prevalence to improve glucose control variables; however, there is different NR

  18. Dominant enrichment of phenotypically activated CD38(+) HLA-DR(+) CD8(+) T cells, rather than CD38(+) HLA-DR(+) CD4(+) T cells, in HIV/HCV coinfected patients on antiretroviral therapy.

    PubMed

    d'Ettorre, Gabriella; Ceccarelli, Giancarlo; Serafino, Sara; Giustini, Noemi; Cavallari, Eugenio Nelson; Bianchi, Luigi; Pavone, Paolo; Bellelli, Valeria; Turriziani, Ombretta; Antonelli, Guido; Stroffolini, Tommaso; Vullo, Vincenzo

    2016-08-01

    HIV infection may enhance immune-activation, while little is known regarding the role of HCV infection. This study investigates the impact of HCV in HIV coinfected patients with undetectable viraemia under HAART on the levels of peripheral T cell's immune-activation. We determined T lymphocytes subsets to characterize immune-activation defined as CD38 and/or HLA-DR expression in chronic monoinfected HCV, HIV, and HIV/HCV coinfected subjects. One hundred and fifty six patients were divided into three groups: (i) 77 HIV+ patients; (ii) 50 HCV+ patients; and (iii) 29 coinfected HIV/HCV patients. The level of CD4(+) was significantly higher in HCV+ than in HIV+ or in coinfected HIV/HCV subjects. The frequencies of CD4(+) CD38(+) /HLA-DR(-) , CD4(+) CD38(-) /HLA-DR(+) and CD4(+) CD38(+) /HLA-DR(+) in HIV+ patients were comparable to those measured in coinfected patients, but statistically higher than those observed in HCV+ subjects. The percentage of CD8(+) was comparable in HIV-1+ patients and coinfected HIV/HCV but the results obtained in both groups were significantly higher compared to the results obtained in HCV patients. The level of CD8(+) CD38(+) /HLA-DR(-) showed values lower in HIV+ patients than in that monoinfected HCV and coinfected HIV/HCV patients. The frequencies of CD8(+) CD38(-) /HLA-DR(+) were higher in HIV+ patients compared to HCV+ and coinfected HIV/HCV patients. HIV/HCV coinfected group showed highest levels of CD8(+) CD38(+) /HLA-DR(+) . HIV plays a pivotal role to determine the immune activation in the host. The role of HCV needs of further investigations but our data show that HCV mainly influences the immune-activation of the pool of CD8, but also probably plays a supporting additive effect on CD4 immune-activation. J. Med. Virol. 88:1347-1356, 2016. © 2016 Wiley Periodicals, Inc.

  19. Clinical Features of Human Immunodeficiency Virus-Infected Patients Presenting with Cholera in Port-au-Prince, Haiti.

    PubMed

    Sévère, Karine; Anglade, Stravinsky B; Bertil, Claudin; Duncan, Aynsley; Joseph, Patrice; Deroncenay, Alexandra; Mabou, Marie M; Ocheretina, Oksana; Reif, Lindsey; Seo, Grace; Pape, Jean W; Fitzgerald, Daniel W

    2016-11-02

    Human immunodeficiency virus (HIV) infection has been postulated to alter the natural history of cholera, including increased susceptibility to infection, severity of illness, and chronic carriage of Vibrio cholerae Haiti has a generalized HIV epidemic with an adult HIV prevalence of 1.9% and recently suffered a cholera epidemic. We conducted a prospective study at the cholera treatment center (CTC) of GHESKIO in Haiti to characterize the coinfection. Adults admitted at the CTC for acute diarrhea were invited to participate in the study. Vital signs, frequency, and volume of stools and/or vomiting were monitored, and single-dose doxycycline was administered. After counseling, participants were screened for HIV by enzyme-linked immunosorbent assay and for cholera by culture. Of 729 adults admitted to the CTC, 99 (13.6%) had HIV infection, and 457 (63%) had culture-confirmed cholera. HIV prevalence was three times higher in patients without cholera (23%, 63/272) than in those with culture-confirmed cholera (7.9%, 36/457). HIV prevalence in patients with culture-confirmed cholera (7.9%) was four times higher than the adult prevalence in Port-au-Prince (1.9%). Of the 36 HIV-infected patients with cholera, 25 (69%) had moderate/severe dehydration versus 302/421 (72%) in the HIV negative. Of 30 HIV-infected patients with weekly stool cultures performed after discharge, 29 (97%) were negative at week 1. Of 50 HIV-negative patients with weekly stool cultures, 49 (98%) were negative at week 1. In countries with endemic HIV infection, clinicians should consider screening patients presenting with suspected cholera for HIV coinfection.

  20. Risk factors for multidrug-resistant tuberculosis among tuberculosis patients: a case-control study

    PubMed Central

    Workicho, Abdulhalik; Kassahun, Wondwosen; Alemseged, Fessahaye

    2017-01-01

    Background Multidrug-resistant tuberculosis (MDR-TB) did not receive major attention until recently in sub-Saharan Africa where the tuberculosis incidence and risk factors are highest. Factors leading to development of drug resistance need to be understood to develop appropriate control strategies for national programs. The objective of this study was to identify the risk factors for MDR-TB among tuberculosis patients. Methods A case-control study was conducted to assess sociodemographic, behavioral and clinical risk factors using a structured questionnaire and clinical record reviewing. The data were entered and analyzed using SPSS windows version 16. Descriptive analysis was done to generate summary values for the variables and those significant variables in the bivariate analysis at p-value less than 0.25 were entered to multivariable logistic regression to identify independent determinants. Statistical significance was declared at p-value less than or equal to 0.05. Results A total of 90 cases and 90 controls were included in the study. Age of respondents (adjusted odds ratio [AOR] =7; 95% confidence interval [CI]: 2.6–24.5), living in a household with only one room (AOR=5; 95%CI: 1.68–15.38), history of previous treatment (AOR=21; 95% CI: 17.8–28) and being HIV infected (AOR=3.1; 95%CI: 1.02–9.4) were found to be independent predictors of MDR-TB. Conclusion In light of these findings, the strategies in controlling MDR-TB should emphasize on patients with HIV coinfection, young patients, those who have a history of previous treatment, and those living in crowded places. PMID:28331350

  1. UGT1A1∗28 relationship with abnormal total bilirubin levels in chronic hepatitis C patients

    PubMed Central

    de Souza, Marcelo Moreira Tavares; Vaisberg, Victor Van; Abreu, Rodrigo Martins; Ferreira, Aline Siqueira; daSilvaFerreira, Camila; Nasser, Paulo Dominguez; Paschoale, Helena Scavone; Carrilho, Flair José; Ono, Suzane Kioko

    2017-01-01

    Abstract Gilbert syndrome (GS) is a frequent benign clinical condition, marked by intermittent unconjugated hyperbilirubinemia, mostly due to the polymorphism uridine diphosphate-glucuronosyltransferase 1A1∗28 (UGT1A1∗28). Hyperbilirubinemia has been reported in a GS patient undergoing hepatitis C treatment, and other UGT isoforms polymorphisms have been linked to worse outcomes in viral hepatitis. Yet, little is known to GS contributions’ to the liver disease scenario. Our aim was to assess UGT1A1 genotypes’ frequency in chronic hepatitis C (CHC) patients and correlate with total bilirubin (TB). This is a case–control study in a large tertiary medical center. Cases were CHC patients confirmed by hepatitis C virus (HCV)–polymerase chain reaction. Exclusion criteria were hepatitis B virus or human immunodeficiency virus (HIV) coinfection. Control were healthy blood donors. UGT1A1 promoter region gene genotyping was performed, and bilirubin serum levels were available for HCV patients. Genotypes and alleles frequencies were similar in case (n = 585; P = 0.101) and control groups (n = 313; P = 0.795). Total bilirubin increase was noticed according to thymine–adenine repeats in genotypes (P < 0.001), and the TB greater than 1 mg/dL group had more UGT1A1∗28 subjects than in the group with TB values <1 mg/dL (18.3 vs 5.3; P < 0.001). Bilirubin levels are linked to the studied polymorphisms, and this is the first time that these findings are reported in a chronic liver disease sample. Among patients with increased TB levels, the frequency of UGT1A1∗28 is higher than those with normal TB. Personalized care should be considered to GS, regarding either abnormal bilirubin levels or drug metabolism. PMID:28296739

  2. Assessment of isoniazid preventive therapy in the reduction of tuberculosis among ART patients in Arba Minch Hospital, Ethiopia

    PubMed Central

    Abossie, Ashenafi; Yohanes, Tsegaye

    2017-01-01

    Background Tuberculosis (TB) is the most frequent life-threatening opportunistic disease among people living with HIV and remains a leading cause of mortality, even among persons receiving antiretroviral therapy (ART). Isoniazid preventive therapy (IPT) and cotrimoxazole prophylaxis have been recommended for the benefit of HIV/AIDS-infected individuals to prevent opportunistic infections. The aim of this study was to assess IPT prophylaxis in the reduction of TB among ART patients. Methods The study was a hospital-based retrospective study. A total of 271 study participants’ available information such as demographic data, the type of prophylaxis used, and TB/HIV coinfection status as well as other variables were collected from clinical laboratory and HIV care/ART follow-up clinic. Data analysis was performed using Statistical Package for the Social Sciences (SPSS) version 20.0. Results TB-infected ART patients were higher among non-IPT group (37 [27.8%]) compared to IPT group (12 [8.7%]). The finding showed that IPT prophylaxis significantly reduces acquiring TB with the relative risk =0.31 (95% confidence interval =0.122, 0.49) in ART patients of this study site where the tuberculosis prevalence is prominent. ART had significant contribution for CD4+ T-cell lymphocyte count improvement in both IPT and non-IPT groups (P<0.05) in this study. Conclusion IPT had significant contributions to reduce the burden of TB in ART patients than non-IPT group. This result highlights the use of IPT for the prevention of TB, especially for all ART patients. Other longitudinal studies are needed to observe the benefits and side effects of IPT prophylaxis in tuberculin skin test-positive individuals. PMID:28392698

  3. Efficacy of and risk of bleeding during pegylated interferon plus ribavirin treatment in HIV/HCV-coinfected patients with pretreatment thrombocytopenia.

    PubMed

    Mira, J A; Neukam, K; López-Cortés, L F; Rivero-Juárez, A; Téllez, F; Girón-González, J A; de los Santos-Gil, I; Ojeda-Burgos, G; Merino, D; Ríos-Villegas, M J; Collado, A; Torres-Cornejo, A; Macías, J; Rivero, A; Pérez-Pérez, M; Pineda, J A

    2015-09-01

    The aim of this study was to assess the efficacy of and the risk of major bleeding during pegylated interferon (peg-IFN)/ribavirin (RBV) treatment among human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients according to the pretreatment platelet count. Two hundred and seventy-four HCV/HIV-coinfected, previously naïve individuals with compensated cirrhosis enrolled in one Spanish prospective cohort who received peg-IFN/RBV were included in this study. The frequency of severe bleeding and sustained virological response (SVR) rate were compared between patients with a pretreatment platelet count ≤70,000/mm(3) and >70,000/mm(3), respectively. Sixty-one (22 %) patients had a baseline platelet count ≤70,000/mm(3). The median (Q1-Q3) pretreatment platelet count was 58,000 (49,000-65,000) cells/mm(3) in the platelet ≤70,000 group and 129,000 (102,500-166,000) cells/mm(3) in the platelet >70,000 group (p < 0.0001). Seventeen (28 %) subjects of the platelet ≤70,000 group and 71 (33 %) patients of the platelet >70,000 group achieved SVR (p = 0.4). Only 2 (3.2 %) patients in the platelet ≤70,000 group developed a severe hemorrhagic event, specifically esophageal variceal bleeding. The efficacy of therapy with peg-IFN/RBV in HIV/HCV-coinfected patients with low pretreatment platelet counts is comparable to that found in the overall subset of subjects with compensated cirrhosis. The frequency of severe hemorrhagic events related with this therapy is low in this population.

  4. Hepatitis C virus long-term persistence in peripheral blood mononuclear cells in patients with haemophilia. Detection of occult genotype 1.

    PubMed

    Parodi, C; García, G; Monzani, M C; Culasso, A; Aloisi, N; Corti, M; Campos, R; de E de Bracco, M M; Baré, P

    2015-07-01

    Peripheral blood mononuclear cells (PBMC) from chronic hepatitis C virus-infected persons can harbour viral variants that are not detected in plasma samples. We explored the presence and persistence of HCV genotypes in plasma and PBMC cultures from 25 HCV-monoinfected and 25 HIV/HCV-coinfected patients with haemophilia. Cell cultures were performed at different time points between 1993 and 2010-2011, and the HCV genome was examined in culture supernatants. Sequential plasma samples were studied during the same time period. Analysing sequential plasma samples, 21% of patients had mixed-genotype infections, while 50% had mixed infections determined from PBMC culture supernatants. HIV coinfection was significantly associated with the presence of mixed infections (OR = 4.57, P = 0.02; 95% CI = 1.38-15.1). In our previous study, genotype 1 was found in 72% of 288 patients of this cohort. Similar results were obtained with the sequential plasma samples included in this study, 69% had genotype 1. However, when taking into account plasma samples and the results from PBMC supernatants, genotype 1 was identified in 94% of the population. The PBMC-associated variants persisted for 10 years in some subjects, emphasizing their role as long-term reservoirs. The presence of genotype 1 in PBMC may be associated with therapeutic failure and should not be disregarded when treating haemophilic patients who have been infected by contaminated factor concentrates. The clinical implications of persistent lymphotropic HCV variants deserve further examination among multiple exposed groups of HCV-infected patients.

  5. Changes in CD4+ T-cells and HIV RNA resulting from combination of anti-TB therapy with Dzherelo in TB/HIV dually infected patients

    PubMed Central

    Nikolaeva, Lyudmila G; Maystat, Tatyana V; Masyuk, Lilia A; Pylypchuk, Volodymyr S; Volyanskii, Yuri L; Kutsyna, Galyna A

    2008-01-01

    The open-label, phase II clinical trial of antituberculosis therapy (ATT) with or without oral immunomodulator Dzherelo (Immunoxel) was conducted in TB/HIV coinfected, antiretroviral therapy naïve patients to evaluate the effect on CD4 T-lymphocyte counts and viral load. The arm A (n = 20) received isoniazid (H); rimfapicin (R); pyrazinamide (Z); streptomycin (S); and ethambutol (E), and arm B (n = 20) received 50 drops of Dzherelo twice per day in addition to HRZSE. After 2 months in 90% of Dzherelo patients the population of absolute CD4 T-cells expanded by an average of 71.2% (from 174 to 283 cells/μl; P = 0.00003), but declined in ATT-alone patients (182 to 174; P = 0.34). The ratio between CD4/CD8 cells deteriorated in 80% of individuals in arm A (1.213 > 0.943; P = 0.002), but improved in the same proportion of patients in arm B (1.244 > 1.536; P = 0.007). The number of total CD3+ lymphocytes rose from 728 to 921 cells in arm B (P = 0.025) whereas it fell from 650 to 585 cells in arm A (P = 0.25). The viral load, as measured by plasma RNA-PCR, decreased in 70% of Dzherelo recipients (2.174 > 1.558 copies/ml; P = 0.002), but increased in 70% of HRZSE only receivers (1.907 > 2.076 copies/ml; P = 0.03). Dzherelo has a favorable effect on the immune status and viral burden in TB/HIV patients when given as an immunomodulating adjunct to ATT. PMID:19920896

  6. Rifaximin has a Marginal Impact on Microbial Translocation, T-cell Activation and Inflammation in HIV-Positive Immune Non-responders to Antiretroviral Therapy – ACTG A5286

    PubMed Central

    Tenorio, Allan R.; Chan, Ellen S.; Bosch, Ronald J.; Macatangay, Bernard J. C.; Read, Sarah W.; Yesmin, Suria; Taiwo, Babafemi; Margolis, David M.; Jacobson, Jeffrey M.; Landay, Alan L.; Wilson, Cara C.; Mellors, John W.; Keshavarzian, Ali; Rodriguez, Benigno; Aziz, Mariam; Presti, Rachel; Deeks, Steven; Ebiasah, Ruth; Myers, Laurie; Borowski, LuAnn; Plants, Jill; Palm, David A.; Weibel, Derek; Putnam, Beverly; Lindsey, Elizabeth; Player, Amy; Albrecht, Mary; Kershaw, Andrea; Sax, Paul; Keenan, Cheryl; Walton, Patricia; Baum, Jane; Stroberg, Todd; Hughes, Valery; Coster, Laura; Kumar, Princy N.; Yin, Michael T.; Noel-Connor, Jolene; Tebas, Pablo; Thomas, Aleshia; Davis, Charles E.; Redfield, Robert R.; Sbrolla, Amy; Flynn, Teri; Davis, Traci; Whitely, Kim; Singh, Baljinder; Swaminathan, Shobha; McGregor, Donna; Palella, Frank; Aberg, Judith; Cavanagh, Karen; Santana Bagur, Jorge L.; Flores, Olga Méndez; Fritsche, Janice; Sha, Beverly; Slamowitz, Debbie; Valle, Sandra; Tashima, Karen; Patterson, Helen; Harber, Heather; Para, Michael; Eaton, Molly; Maddox, Dale; Currier, Judith; Cajahuaringa, Vanessa; Luetkemeyer, Annie; Dwyer, Jay; Fichtenbaum, Carl J.; Saemann, Michelle; Ray, Graham; Campbell, Thomas; Fischl, Margaret A.; Bolivar, Hector; Oakes, Jonathan; Chicurel-Bayard, Miriam; Tripoli, Christine; Weinman, D. Renee; Adams, Mary; Hurley, Christine; Dunaway, Shelia; Storey, Sheryl; Klebert, Michael; Royal, Michael

    2015-01-01

    Background. Rifaximin, a nonabsorbable antibiotic that decreases lipopolysaccharide (LPS) in cirrhotics, may decrease the elevated levels of microbial translocation, T-cell activation and inflammation in human immunodeficiency virus (HIV)-positive immune nonresponders to antiretroviral therapy (ART). Methods. HIV-positive adults receiving ART for ≥96 weeks with undetectable viremia for ≥48 weeks and CD4+ T-cell counts <350 cells/mm3 were randomized 2:1 to rifaximin versus no study treatment for 4 weeks. T-cell activation, LPS, and soluble CD14 were measured at baseline and at weeks 2, 4, and 8. Wilcoxon rank sum tests compared changes between arms. Results. Compared with no study treatment (n = 22), rifaximin (n = 43) use was associated with a significant difference between study arms in the change from baseline to week 4 for CD8+T-cell activation (median change, 0.0% with rifaximin vs +0.6% with no treatment; P = .03). This difference was driven by an increase in the no-study-treatment arm because there was no significant change within the rifaximin arm. Similarly, although there were significant differences between study arms in change from baseline to week 2 for LPS and soluble CD14, there were no significant changes within the rifaximin arm. Conclusions. In immune nonresponders to ART, rifaximin minimally affected microbial translocation and CD8+T-cell activation. Trial registration number. NCT01466595. PMID:25214516

  7. Immune response gene control of collagen reactivity in man: collagen unresponsiveness in HLA-DR4 negative nonresponders is due to the presence of T-dependent suppressive influences

    SciTech Connect

    Solinger, A.M.; Stobo, J.D.

    1982-11-01

    To determine whether the failure to detect collagen reactivity in nonresponders represents an absence of collagen-reactive T cells or a preponderance of suppressive influences, the peripheral blood mononuclear cells from HLA-DR4/sup -/ individuals were subjected to three procedures capable of separating suppressive influences from LIF-secreting cells; irradiation (1000 rad), discontinuous gradient fractionation, and cytolysis with the monoclonal antibody OKT 8. Each procedure resulted in the specific appearance of reactivity to collagen, which was identical to that seen in HLA-DR4/sup +/ individuals with regard to its cellular requirements and antigenic specificity. Addition of unresponsive (i.e., nonirradiated or low-density T cells) to responsive (i.e., irradiated or high-density T cells) autologous populations resulted in specific suppression of collagen reactivity. Radiation-sensitive suppressive influences could not be detected in HLA-DR4/sup +/ collagen responders.These studies indicate that the expression of T-dependent reactivity to collagen in man reflects the net influence of collage-reactive vs collagen-suppressive T cells. Moreover, it is the influence of HLA-D-linked genes on the development of suppressive influences rather than on the development of collagen-reactive, LIF-secreting T cells that serves to distinguish HLA-DR4/sup +/ collagen responders from HLA-DR4/sup -/ collagen nonresponders. (JMT)

  8. Slow CD4+ T-Cell Recovery in Human Immunodeficiency Virus/Hepatitis B Virus-Coinfected Patients Initiating Truvada-Based Combination Antiretroviral Therapy in Botswana

    PubMed Central

    Anderson, Motswedi; Gaseitsiwe, Simani; Moyo, Sikhulile; Thami, Kerapetse P.; Mohammed, Terence; Setlhare, Ditiro; Sebunya, Theresa K.; Powell, Eleanor A.; Makhema, Joseph; Blackard, Jason T.; Marlink, Richard; Essex, Max; Musonda, Rosemary M.

    2016-01-01

    Background. Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) coinfection has emerged as an important cause of morbidity and mortality. We determined the response to Truvada-based first-line combination antiretroviral therapy (cART) in HIV/HBV-coinfected verus HIV-monoinfected patients in Botswana. Methods. Hepatitis B virus surface antigen (HBsAg), HBV e antigen (HBeAg), and HBV deoxyribonucleic acid (DNA) load were determined from baseline and follow-up visits in a longitudinal cART cohort of Truvada-based regimen. We assessed predictors of HBV serostatus and viral suppression (undetectable HBV DNA) using logistic regression techniques. Results. Of 300 participants, 28 were HBsAg positive, giving an HIV/HBV prevalence of 9.3% (95% confidence interval [CI], 6.3–13.2), and 5 of these, 17.9% (95% CI, 6.1–36.9), were HBeAg positive. There was a reduced CD4+ T-cell gain in HIV/HBV-coinfected compared with HIV-monoinfected patients. Hepatitis B virus surface antigen and HBeAg loss was 38% and 60%, respectively, at 24 months post-cART initiation. The HBV DNA suppression rates increased with time on cART from 54% to 75% in 6 and 24 months, respectively. Conclusions. Human immunodeficiency virus/HBV coinfection negatively affected immunologic recovery compared with HIV-1C monoinfection. Hepatitis B virus screening before cART initiation could help improve HBV/HIV treatment outcomes and help determine treatment options when there is a need to switch regimens. PMID:27800524

  9. Influence of striatal dopamine transporter availability on the response to methylphenidate in adult patients with ADHD.

    PubMed

    Krause, Johanna; la Fougere, Christian; Krause, Klaus-Henning; Ackenheil, Manfred; Dresel, Stefan H

    2005-12-01

    In this study, we investigated whether availability of striatal dopamine transporter (DAT) may have an influence on the response of adult patients with attention deficit hyperactivity disorder (ADHD) on methylphenidate (MPH). In 18 non-smoking and non-medicated adult patients with ADHD, availability of DAT was measured with [(99m)Tc] TRODAT-1 SPECT. Then, the patients received methylphenidate (MPH), individually titrated up to 60 mg per day. Ten weeks later, clinical improvement was rated by Clinical Global Impressions scale. In all, 6 patients were classified as non-responders, and 12 responded to MPH. From the non-responders, 5 presented with a DAT availability below that of normal controls of the same age, whereas in the group of responders all patients had elevated DAT availability. There was a significant negative correlation between values for global clinical improvement and striatal DAT availability. In conclusion, ADHD patients with low DAT availability seem not to respond to therapy with MPH.

  10. Actigraphic assessment of periodic leg movements in patients with restless legs syndrome.

    PubMed

    Cippà, Maria A T; Baumann, Christian R; Siccoli, Massimiliano M; Bassetti, Claudio L; Poryazova, Rositsa; Werth, Esther

    2013-10-01

    The diagnosis of restless legs syndrome (RLS) relies upon diagnostic criteria which are based on history only, and dopaminergic treatment is not normally the first choice of treatment for all patients. It would be worthwhile to identify patients non-responsive to dopaminergic treatment beforehand, because they may suffer from a restless legs-like syndrome and may require alternative treatment. We included retrospectively 24 adult patients fulfilling the four essential criteria for restless legs and 12 age-matched healthy controls. They were investigated by ambulatory actigraphy from both legs over three nights, and patients started treatment with dopamine agonists after this diagnostic work-up. We examined 12 responders to dopaminergic treatment and 12 non-responders and studied the association between response to dopaminergic treatment and the periodic limb movement index (PLMI) as assessed with actigraphy. Demographic characteristics, excessive daytime sleepiness and fatigue at baseline were similar in all three groups. Baseline RLS severity was similar between responders and non-responders [International Restless Legs Severity Scale (IRLS): 25 ± 9 and 24 ± 8]. Group comparisons of PLMI before treatment initiation showed significant differences between the three groups. Post-hoc pairwise comparisons revealed that healthy controls had significantly lower PLMI (4.9 ± 4.5) than responders (29.3 ± 22.7) and non-responders (13.3 ± 11.2). Similarly, the PLMI in responders was lower than in non-responders. PLMI day-to-day variability did not differ between responders and non-responders and there was no correlation between treatment effect, as assessed by the decrease of the IRLS and baseline PLMI. Our retrospective study indicates that actigraphy to assess periodic limb movements may contribute to a better diagnosis of dopamine-responsive restless legs syndrome.

  11. Defective antigen presentation by monocytes in ESRD patients not responding to hepatitis B vaccination: impaired HBsAg internalization and expression of ICAM-1 and HLA-DR/Ia molecules

    PubMed Central

    Barth, C.; Pollok, M.; Michałkiewicz, J.; Madaliński, K.; Maciejewski, J.; Baldamis, C. A.

    1995-01-01

    This study was undertaken to evaluate the monocyte function of uraemic non-responders to hepatitis B vaccination. Therefore, some parameters concerning antigen processing by monocytes (Mo) as antigen presenting cells (APC) were analysed. It was found that in uraemic non-responders, (1) the internalization of HBsAg by monocytes was significantly decreasjed—HBsAg complexed with specific IgG or as immune complex isolated from patients is better internalized compared with free HBsAg; (2) during antigen presentation the expression of adhesion (ICAM-1) and accessory (HLA-DR/Ia) molecules was significantly decreased in uraemic patients, especially in non-responders; and (3) impaired internalization of HBsAg as well as a decrease in ICAM-1 and HLA-DR/Ia expression, correlated well with the blunted proliferation of CD4+ T cells stimulated by autologous monocytes induced by HBsAg. PMID:18475616

  12. Retinopathy in chronic hepatitis C patients during interferon treatment with ribavirin

    PubMed Central

    Jain, K; Lam, W; Waheeb, S; Thai, Q; Heathcote, J

    2001-01-01

    AIM—To assess the ocular effect of interferon alfa 2b prescribed with ribavirin in patients undergoing therapy for chronic hepatitis C.
METHODS—19 patients with chronic hepatitis C who satisfied the follow up criteria were assessed for ocular complications using slit lamp biomicroscopy and indirect ophthalmoscopy before, during, and after the treatment at regular intervals.
RESULTS—8/19 patients, while on treatment, developed an asymptomatic retinopathy. Among these 3/8 were relapsers and 5/9 were non-responders to interferon monotherapy. All retinal changes faded, often while the patients continued the therapy. There was no significant association in occurrence of retinopathy with haematological and/or biochemical changes.
CONCLUSION—Retinopathy was more common in interferon monotherapy non-responders than relapsers when treated with interferon alfa 2b with the addition of ribavirin. The changes were transient, disappearing while the patients were still being treated.

 PMID:11567959

  13. The induction of CD80 and apoptosis on B cells and CD40L in CD4+ T cells in response to seasonal influenza vaccination distinguishes responders versus non-responders in healthy controls and aviremic ART-treated HIV-infected individuals

    PubMed Central

    Powell, Anna M.; Luo, Zhenwu; Martin, Lisa; Wan, Zhuang; Ma, Lei; Liao, Guoyang; Song, Yuxia; Li, Xiaochun; Kilby, J. Michael; Huang, Lei; Jiang, Wei

    2016-01-01

    Background Studies have shown that HIV infection is associated with an impaired influenza vaccine response. We examined the role of cellular phenotypes and function in influenza vaccine responsiveness in healthy controls and aviremic HIV-infected subjects on antiretroviral treatment (ART). Methods 16 healthy controls and 26 ART+ aviremic HIV+ subjects were enrolled in the current study. Blood was collected at pre-vaccination (D0), and on days 7–10 (D7) and 14–21 (D14) following the 2013–2014 seasonal influenza vaccine administrations. Subjects were classified as responders if neutralizing titers against H1N1 virus increased ≥ 4-fold at D14 compared to D0. A serial analysis of B and CD4+ T cell frequencies and activation was performed on D0 and D7 by flow cytometry. Results 9 of 26 (34.6%) HIV-infected individuals and 7 of 16 (43.8%) healthy controls were classified as responders to influenza vaccines. Total B cell apoptosis (annexin V) was increased on D7 post-vaccination in non-responders but not in responders among both controls and HIV+ subjects. Surface CD80 expression on memory B cells and intracellular CD40L expression on memory CD4+ T cells were induced on D7 in responders of controls but not in non-responders. The CD80 and CD40L induction was not demonstrable in HIV-infected subjects regardless of responders and non-responders. Memory CD4+ T cell cycling tended to increase on D7 in the four study groups but did not achieve significance. All the other parameters were indistinguishable between responders and non-responders, regardless of HIV-infection status. Conclusion The perturbation of activation and apoptotic induction on B cells or CD4+ T cells after seasonal influenza vaccination in non-responders and HIV-infected subjects may help understand the mechanism of impaired vaccine responsiveness. PMID:28017428

  14. PknE, a serine/threonine protein kinase of Mycobacterium tuberculosis initiates survival crosstalk that also impacts HIV coinfection.

    PubMed

    Parandhaman, Dinesh Kumar; Hanna, Luke Elizabeth; Narayanan, Sujatha

    2014-01-01

    Serine threonine protein kinases (STPK) play a major role in the pathogenesis of Mycobacterium tuberculosis. Here, we examined the role of STPK pknE, using a deletion mutant ΔpknE in the modulation of intracellular signaling events that favor M. tuberculosis survival. Phosphorylation kinetics of MAPK (p38MAPK, Erk½ and SAPK/JNK) was defective in ΔpknE compared to wild-type infected macrophages. This defective signaling dramatically delayed and reduced the phosphorylation kinetics of transcription factors ATF-2 and c-JUN in ΔpknE infected macrophages. MAPK inhibitors instead of reducing the phosphorylation in ΔpknE infected macrophages, revealed crosstalks with Erk½ signaling influenced by SAPK/JNK and p38 pathways independently. Modulations in intra cellular signaling altered the expression of coreceptors CCR5 and CXCR4 in ΔpknE infected macrophages. In conclusion, pknE plays a role in MAPK crosstalks that enables intracellular survival of M. tuberculosis. This survival strategy also impacts HIV/TB coinfection.

  15. Review of the treatment of psoriatic arthritis with biological agents: choice of drug for initial therapy and switch therapy for non-responders.

    PubMed

    D'Angelo, Salvatore; Tramontano, Giuseppina; Gilio, Michele; Leccese, Pietro; Olivieri, Ignazio

    2017-01-01

    Psoriatic arthritis (PsA) is a heterogeneous chronic inflammatory disease with a broad clinical spectrum and variable course. It can involve musculoskeletal structures as well as skin, nails, eyes, and gut. The management of PsA has changed tremendously in the last decade, thanks to an earlier diagnosis, an advancement in pharmacological therapies, and a wider application of a multidisciplinary approach. The commercialization of tumor necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab) as well as interleukin (IL)-12/23 (ustekinumab) and IL-17 (secukinumab) inhibitors is representative of a revolution in the treatment of PsA. No evidence-based strategies are currently available for guiding the rheumatologist to prescribe biological drugs. Several international and national recommendation sets are currently available with the aim to help rheumatologists in everyday clinical practice management of PsA patients treated with biological therapy. Since no specific biological agent has been demonstrated to be more effective than others, the drug choice should be made according to the available safety data, the presence of extra-articular manifestations, the patient's preferences (e.g., administration route), and the drug price. However, future studies directly comparing different biological drugs and assessing the efficacy of treatment strategies specific for PsA are urgently needed.

  16. Baseline Gene Expression Signatures in Monocytes from Multiple Sclerosis Patients Treated with Interferon-beta

    PubMed Central

    Bustamante, Marta F.; Nurtdinov, Ramil N.; Río, Jordi; Montalban, Xavier; Comabella, Manuel

    2013-01-01

    Background A relatively large proportion of relapsing-remitting multiple sclerosis (RRMS) patients do not respond to interferon-beta (IFNb) treatment. In previous studies with peripheral blood mononuclear cells (PBMC), we identified a subgroup of IFNb non-responders that was characterized by a baseline over-expression of type I IFN inducible genes. Additional mechanistic experiments carried out in IFNb non-responders suggested a selective alteration of the type I IFN signaling pathway in the population of blood monocytes. Here, we aimed (i) to investigate whether the type I IFN signaling pathway is up-regulated in isolated monocytes from IFNb non-responders at baseline; and (ii) to search for additional biological pathways in this cell population that may be implicated in the response to IFNb treatment. Methods Twenty RRMS patients classified according to their clinical response to IFNb treatment and 10 healthy controls were included in the study. Monocytes were purified from PBMC obtained before treatment by cell sorting and the gene expression profiling was determined with oligonucleotide microarrays. Results and discussion Purified monocytes from IFNb non-responders were characterized by an over-expression of type I IFN responsive genes, which confirms the type I IFN signature in monocytes suggested from previous studies. Other relevant signaling pathways that were up-regulated in IFNb non-responders were related with the mitochondrial function and processes such as protein synthesis and antigen presentation, and together with the type I IFN signaling pathway, may also be playing roles in the response to IFNb. PMID:23637780

  17. Review of the treatment of psoriatic arthritis with biological agents: choice of drug for initial therapy and switch therapy for non-responders

    PubMed Central

    D’Angelo, Salvatore; Tramontano, Giuseppina; Gilio, Michele; Leccese, Pietro; Olivieri, Ignazio

    2017-01-01

    Psoriatic arthritis (PsA) is a heterogeneous chronic inflammatory disease with a broad clinical spectrum and variable course. It can involve musculoskeletal structures as well as skin, nails, eyes, and gut. The management of PsA has changed tremendously in the last decade, thanks to an earlier diagnosis, an advancement in pharmacological therapies, and a wider application of a multidisciplinary approach. The commercialization of tumor necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab) as well as interleukin (IL)-12/23 (ustekinumab) and IL-17 (secukinumab) inhibitors is representative of a revolution in the treatment of PsA. No evidence-based strategies are currently available for guiding the rheumatologist to prescribe biological drugs. Several international and national recommendation sets are currently available with the aim to help rheumatologists in everyday clinical practice management of PsA patients treated with biological therapy. Since no specific biological agent has been demonstrated to be more effective than others, the drug choice should be made according to the available safety data, the presence of extra-articular manifestations, the patient’s preferences (e.g., administration route), and the drug price. However, future studies directly comparing different biological drugs and assessing the efficacy of treatment strategies specific for PsA are urgently needed. PMID:28280401

  18. Fine specificity of regulatory T cells. II. Suppressor and helper T cells are induced by different regions of hen egg-white lysozyme in a genetically nonresponder mouse strain.

    PubMed

    Adorini, L; Harvey, M A; Miller, A; Sercarz, E E

    1979-08-01

    We have examined the ability of two purified peptide fragments derived from hen (chicken) egg-white lysozyme (HEL); N-terminal, Co-terminal peptide (a.a. 1--17:cys 6--cys 127:120--129) and mixed disulfide LII peptide (LII) (a.a. 13--105) to induce antigen-specific suppression or help in B10 (H-2b) nonresponder and B10.A (H-2a) responder mice. An anti-HEL primary in vitro antibody response can be obtained in either strain by stimulation with HEL coupled to erythrocytes (RBC). Preimmunization with HEL-complete Freund's adjuvant-(CFA) or N-C-CFA-induced suppression of the anti-HEL PFC response to HEL-RBC in spleen cell cultures from B10 mice, whereas helper activity was demonstrated in cultures from B10.A mice similarly immunized. LII-CFA priming elicited helper cells in both C57BL/10 Sn (B10) and B10.A/SgSn (B10.A) mice. The genetic nonresponsiveness of B10 mice to HEL can therefore be attributed to the activation of suppressor T cells by a limited portion of the molecule (e.g., N-C) which prevent the potential response directed against other epitopes on the same molecule (e.g., LII). One manifestation of major histocompatibility complex gene activity appears to be the intramolecular selection of different antigenic determinants leading to activation of functionally different T-cell subpopulations.

  19. Potential determinants of efficacy of mirror therapy in stroke patients – A pilot study

    PubMed Central

    Brunetti, Maddalena; Morkisch, Nadine; Fritzsch, Claire; Mehnert, Jan; Steinbrink, Jens; Niedeggen, Michael; Dohle, Christian

    2015-01-01

    Abstract Background: Mirror therapy (MT) was found to improve motor function after stroke. However, there is high variability between patients regarding motor recovery. Objectives: The following pilot study was designed to identify potential factors determining this variability between patients with severe upper limb paresis, receiving MT. Methods: Eleven sub-acute stroke patients with severe upper limb paresis participated, receiving in-patient rehabilitation. After a set of pre-assessments (including measurement of brain activity at the primary motor cortex and precuneus during the mirror illusion, using near-infrared spectroscopy as described previously), four weeks of MT were applied, followed by a set of post-assessments. Discriminant group analysis for MT responders and non-responders was performed. Results: Six out of eleven patients were defined as responders and five as non-responders on the basis of their functional motor improvement. The initial motor function and the activity shift in both precunei (mirror index) were found to discriminate significantly between responders and non-responders. Conclusions: In line with earlier results, initial motor function was confirmed as crucial determinant of motor recovery. Additionally, activity response to the mirror illusion in both precunei was found to be a candidate for determination of the efficacy of MT. PMID:26409402

  20. Genetic Polymorphism of CYP2D6 and Clomiphene Concentrations in Infertile Patients with Ovulatory Dysfunction Treated with Clomiphene Citrate.

    PubMed

    Ji, Misuk; Kim, Kwang-Rae; Lee, Woochang; Choe, Wonho; Chun, Sail; Min, Won-Ki

    2016-02-01

    CYP2D6 is primarily responsible for the metabolism of clomiphene citrate (CC). The purpose of the present study was to investigate the relationship between CYP2D6 genotypes, concentrations of CC and its major metabolites and drug response in infertility patients. We studied 42 patients with ovulatory dysfunction treated with only CC. Patients received a dose of 100 mg/day CC on days 3-7 of the menstrual cycle. CYP2D6 genotyping and measurement of CC and the major metabolite concentrations were performed. Patients were categorized into CC responders or non-responders according to one cycle response for the ovulation. Thirty-two patients were CC responders and 10 patients were non-responders with 1 cycle treatment. The CC concentrations were highly variable within the same group, but non-responders revealed significantly lower (E)-clomiphene concentration and a trend of decreased concentrations of active metabolites compared to the responders. Nine patients with intermediate metabolizer phenotype were all responders. We confirmed that the CC and the metabolite concentrations were different according to the ovulation status. However, our results do not provide evidence for the contribution of CYP2D6 polymorphism to either drug response or CC concentrations.

  1. Factors associated with the glucose-lowering effect of vildagliptin identified from the results of the oral glucose tolerance test in Japanese patients with type 2 diabetes.

    PubMed

    Nakamura, Akinobu; Terauchi, Yasuo

    2013-01-01

    In order to investigate the factors contributing to the glucose-lowering effect of vildagliptin, we analyzed the results of the oral glucose tolerance test together with several clinical parameters in Japanese patients with type 2 diabetes before and after 24 weeks of treatment with vildagliptin. The data of the 13 patients who satisfactorily completed the follow-up examinations were included. After 24 weeks treatment with vildagliptin, the patients were classified into a responder group (69.2%) and a non-responder group (30.8%); the responders consisting of subjects whose HbA1c decreased following 24 weeks treatment with vildagliptin, and the non-responders consisting of subjects who did not show any significant decrease of HbA1c. There were no differences in baseline characteristics between the two groups before administration of vildagliptin. After 24 weeks of treatment, HbA1c was significantly reduced from 7.3 ± 0.5% to 6.7 ± 0.5% in the responder group (P = 0.0077), while it tended to rather increased from 7.1 ± 0.6% to 7.5 ± 0.7% in the non-responder group (P = 0.0679). Also, parameters reflecting the glucose-stimulated insulin secretion, such as the insulinogenic index and oral disposition index, were significantly higher in the responder group than in the non-responder group, whereas insulin sensitivity was similar between the two groups. These results suggest that the difference in the degree of improvement of the glucose tolerance between the responder group and non-responder group in this study could be associated with the effect of vildagliptin on the glucose-stimulated insulin secretion, but not on the insulin sensitivity.

  2. Determinants of Pain Treatment Response and Non-Response: Identification of TMD Patient Subgroups

    PubMed Central

    Litt, Mark D.; Porto, Felipe B.

    2013-01-01

    The purpose of the present study was to determine if we could identify a specific subtype of temporomandibular disorder (TMD) pain patients that does not respond to treatment. Patients were 101 men and women with chronic TMD pain recruited from the community and randomly assigned to one of two treatment conditions: a standard conservative care (STD) condition or a standard care plus cognitive-behavioral treatment condition (STD+CBT) in which patients received all elements of STD, but also received cognitive-behavioral coping skills training. Growth mixture modeling, incorporating a series of treatment-related predictors, was used to distinguish several distinct classes of responders or non-responders to treatment based on reported pain over a one-year follow-up period. Results indicated that treatment non-responders accounted for 16% of the sample, and did not differ from treatment responders on demographics or temporomandibular joint pathology, but that they reported more psychiatric symptoms, poorer coping, and higher levels of catastrophizing. Treatment-related predictors of membership in treatment responder groups versus the non-responder group included the addition of CBT to standard treatment, treatment attendance, and decreasing catastrophization. It was concluded that CBT may be made more efficacious for TMD patients by placing further emphasis on decreasing catastrophization and on individualizing care. PMID:24094979

  3. Impact of HIV infection on sustained virological response to treatment against hepatitis C virus with pegylated interferon plus ribavirin.

    PubMed

    Monje-Agudo, P; Castro-Iglesias, A; Rivero-Juárez, A; Martínez-Marcos, F; Ortega-González, E; Real, L M; Pernas, B; Merchante, N; Cid, P; Macías, J; Merino, M D; Rivero, A; Mena, A; Neukam, K; Pineda, J A

    2015-10-01

    It is commonly accepted that human immunodeficiency (HIV) coinfection negatively impacts on the rates of sustained virological response (SVR) to therapy with pegylated interferon plus ribavirin (PR). However, this hypothesis is derived from comparing different studies. The aim of this study was to determine the impact of HIV coinfection on SVR to PR in one single population. In a multicentric, prospective study conducted between 2000 and 2013, all previously naïve hepatitis C virus (HCV)-infected patients who started PR in five Spanish hospitals were analyzed. SVR was evaluated 24 weeks after the scheduled end of therapy. Of the 1046 patients included in this study, 413 (39%) were coinfected with HIV. Three hundred and forty-one (54%) HCV-monoinfected versus 174 (42%) HIV/HCV-coinfected patients achieved SVR (p < 0.001). The corresponding figures for undetectable HCV RNA at treatment week 4 were 86/181 (47%) versus 59/197 (30%), p < 0.001. SVR was observed in 149 (69%) HCV genotype 2/3-monoinfected subjects versus 91 (68%) HIV/HCV genotype 2/3-coinfected subjects (p = 0.785). In the HCV genotype 1/4-infected population, 188 (46%) monoinfected patients versus 82 (30%) with HIV coinfection (p < 0.001) achieved SVR. In this subgroup, absence of HIV coinfection was independently associated with higher SVR [adjusted odds ratio (95% confidence interval): 2.127 (1.135-3.988); p = 0.019] in a multivariate analysis adjusted for age, sex, baseline HCV RNA load, IL28B genotype, fibrosis stage, and type of pegylated interferon. HIV coinfection impacts on the rates of SVR to PR only in HCV genotype 1/4-infected patients, while it has no effect on SVR in the HCV genotype 2/3-infected subpopulation.

  4. Effect of infliximab on mRNA expression profiles in synovial tissue of rheumatoid arthritis patients

    PubMed Central

    Lindberg, Johan; af Klint, Erik; Catrina, Anca Irinel; Nilsson, Peter; Klareskog, Lars; Ulfgren, Ann-Kristin; Lundeberg, Joakim

    2006-01-01

    We examined the gene expression profiles in arthroscopic biopsies retrieved from 10 rheumatoid arthritis patients before and after anti-TNF treatment with infliximab to investigate whether such profiles can be used to predict responses to the therapy, and to study effects of the therapy on the profiles. Responses to treatment were assessed using European League Against Rheumatism response criteria. Three patients were found to be good responders, five patients to be moderate responders and two patients to be nonresponders. The TNF-α status of the biopsies from each of the patients before treatment was also investigated immunohistochemically, and it was detected in biopsies from four of the patients, including all three of the good responders. The gene expression data demonstrate that all patients had unique gene expression signatures, with low intrapatient variability between biopsies. The data also revealed significant differences between the good responding and nonresponding patients (279 differentially expressed genes were detected, with a false discovery rate < 0.025). Among the identified genes we found that MMP-3 was significantly upregulated in good responders (log2 fold change, 2.95) compared with nonresponders, providing further support for the potential of MMP-3 as a marker for good responses to therapy. An even more extensive list of 685 significantly differentially expressed genes was found between patients in whom TNF-α was found and nonresponders, indicating that TNF-α could be an important biomarker for successful infliximab treatment. Significant differences were also observed between biopsies taken before and after anti-TNF treatment, including 115 differentially expressed genes in the good responding group. Interestingly, the effect was even stronger in the group in which TNF-α was immunohistochemically detected before therapy. Here, 1,058 genes were differentially expressed, including many that were novel in this context (for example, CXCL3

  5. Gene mutation analysis in EGFR wild type NSCLC responsive to erlotinib: are there features to guide patient selection?

    PubMed

    Ulivi, Paola; Delmonte, Angelo; Chiadini, Elisa; Calistri, Daniele; Papi, Maximilian; Mariotti, Marita; Verlicchi, Alberto; Ragazzini, Angela; Capelli, Laura; Gamboni, Alessandro; Puccetti, Maurizio; Dubini, Alessandra; Burgio, Marco Angelo; Casanova, Claudia; Crinò, Lucio; Amadori, Dino; Dazzi, Claudio

    2014-12-31

    Tyrosine kinase inhibitors (TKIs) are very efficacious in non-small-cell lung cancer (NSCLC) patients harboring activating Epidermal Growth Factor Receptor (EGFR) mutations. However, about 10% of EGFR wild type (wt) patients respond to TKI, with unknown molecular mechanisms of sensitivity. We considered a case series of 34 EGFR wt NSCLC patients responsive to erlotinib after at least one line of therapy. Responsive patients were matched with an equal number of non-responsive EGFR wt patients. A panel of 26 genes, for a total of 214 somatic mutations, was analyzed by MassARRAY® System (Sequenom, San Diego, CA, USA). A 15% KRAS mutation was observed in both groups, with a prevalence of G12C in non-responders (80% vs. 40% in responders). NOTCH1, p53 and EGFR-resistance-related mutations were found more frequently in non-responders, whereas EGFR-sensitizing mutations and alterations in genes involved in proliferation pathways were more frequent in responders. In conclusion, our findings indicate that p53, NOTCH1 and exon 20 EGFR mutations seem to be related to TKI resistance. KRAS mutations do not appear to influence the TKI response, although G12C mutation is more frequent in non-responders. Finally, the use of highly sensitive methodologies could lead to the identification of under-represented EGFR mutations potentially associated with TKI sensitivity.

  6. Does the Degree of Hepatocellular Carcinoma Tumor Necrosis following Transarterial Chemoembolization Impact Patient Survival?

    PubMed Central

    Haywood, Nathan; Gennaro, Kyle; Obert, John; Sauer, Paul F.; Redden, David T.; Zarzour, Jessica; Smith, J. Kevin; Bolus, David; Saddekni, Souheil; Aal, Ahmed Kamel Abdel; Gray, Stephen; White, Jared; Eckhoff, Devin E.; DuBay, Derek A.

    2016-01-01

    Purpose. The association between transarterial chemoembolization- (TACE-) induced HCC tumor necrosis measured by the modified Response Evaluation Criteria In Solid Tumors (mRECIST) and patient survival is poorly defined. We hypothesize that survival will be superior in HCC patients with increased TACE-induced tumor necrosis. Materials and Methods. TACE interventions were retrospectively reviewed. Tumor response was quantified via dichotomized (responders and nonresponders) and the four defined mRECIST categories. Results. Median survival following TACE was significantly greater in responders compared to nonresponders (20.8 months versus 14.9 months, p = 0.011). Survival outcomes also significantly varied among the four mRECIST categories (p = 0.0003): complete, 21.4 months; partial, 20.8; stable, 16.8; and progressive, 7.73. Only progressive disease demonstrated significantly worse survival when compared to complete response. Multivariable analysis showed that progressive disease, increasing total tumor diameter, and non-Child-Pugh class A were independent predictors of post-TACE mortality. Conclusions. Both dichotomized (responders and nonresponders) and the four defined mRECIST responses to TACE in patients with HCC were predictive of survival. The main driver of the survival analysis was poor survival in the progressive disease group. Surprisingly, there was small nonsignificant survival benefit between complete, partial, and stable disease groups. These findings may inform HCC treatment decisions following first TACE. PMID:26949394

  7. Relationship between evaluation by quantitative fatty acid myocardial scintigraphy and response to beta-blockade therapy in patients with dilated cardiomyopathy.

    PubMed

    Ito, T; Hoshida, S; Nishino, M; Aoi, T; Egami, Y; Takeda, T; Kawabata, M; Tanouchi, J; Yamada, Y; Kamada, T

    2001-12-01

    Predicting the effect of beta-blockade therapy on the clinical outcome of patients with dilated cardiomyopathy (DCM) is difficult prior to the initiation of therapy. Myocardial fatty acid metabolism has been shown to be impaired in patients with DCM. We examined whether the extent of myocardial injury, as assessed by iodine-123 15-( p-iodophenyl)-3- R, S-methylpentadecanoic acid (BMIPP) myocardial scintigraphy, is related to the response of patients with DCM to beta-blockade therapy. Thirty-seven patients with DCM were examined using BMIPP myocardial scintigraphy before and after 6 months of treatment with metoprolol. Myocardial BMIPP uptake (%BM uptake) was estimated quantitatively as a percentage of the total injected count ratio. The left ventricular end-diastolic and end-systolic dimensions (LVDd, LVDs) and ejection fraction (LVEF) were also evaluated. The patients were divided into two groups according to their functional improvement (>10% elevation of LVEF) after 6 months of metoprolol therapy. Twenty-eight patients responded to the therapy, while nine did not. Prior to the therapy, no significant differences in LVDd, LVDs or LVEF were observed between the responders and non-responders. However, the %BM uptake was significantly lower in the non-responders than in the responders (1.0%+/-0.2% vs 2.1%+/-0.5%, P<0.001). The %BM uptake could be used to distinguish the responders from the non-responders with a sensitivity of 0.93 and a specificity of 1.00 at a threshold value of 1.4. After the metoprolol therapy, the %BM uptake improved significantly in the responders (2.5%+/-0.5%, P<0.01) but did not change in the non-responders. These results indicate that myocardial BMIPP uptake could predict the response of DCM patients to beta-blockade therapy.

  8. Surgical castration efficiently delays the time of starting a systemic chemotherapy in castration-resistant prostate cancer patients refractory to initial androgen-deprivation therapy

    PubMed Central

    Kang, Minyong; Lee, Sangchul; Oh, Jong Jin; Hong, Sung Kyu; Lee, Sang Eun; Byun, Seok-Soo

    2015-01-01

    Background The aim of this study was to investigate the effects of surgical castration, particularly delaying the time to entrance of systemic chemotherapy, in castration-resistant prostate cancer (CRPC) patients who were refractory to initial combination androgen deprivation therapy. Materials and methods We analyzed the clinical data of 14 CRPC patients diagnosed at Seoul National University Bundang Hospital (SNUBH) from November 2008 through May 2015. After exclusion of three patients, we finally analyzed the baseline characteristics of 11 CRPC patients. We also assessed the delaying time of docetaxel administration, which was defined as response duration, after surgical castration. Results After bilateral orchiectomy, the treatment response rate was 45.4% and the median duration of response was 9 months (range 4–48 mo). Responders had less aggressive biopsy Gleason scores compared to nonresponders. Notably, responders showed the reducing pattern of serum prostate specific antigen levels, while nonresponders demonstrated increasing tendency after surgical castration. Moreover, responders also presented with a reduction pattern of serum testosterone levels, whereas nonresponders showed an increasing pattern of testosterone levels after bilateral orchiectomy. Conclusions In summary, despite the limited number of cases for convincing evidence, our results shed light again on the clinical benefits of surgical castration prior to the systemic chemotherapy in some CRPC patients after initial hormone therapy. PMID:26779458

  9. Role of opsonins in clinical response to granulocyte transfusion in granulocytopenic patients

    SciTech Connect

    Keusch, G.T.; Ambinder, E.P.; Kovacs, I.; Goldberg, J.D.; Phillips, D.M.; Holland, J.F.

    1982-10-01

    Fifty febrile severely granulocytopenic patients were given four daily transfusions of 2.2 X 10(10) normal donor granulocytes. Twenty-three responded clinically, although both responders and nonresponders were similar in clinical characteristics at the outset. This study examines the relation between serum opsonic activity before initiation of granulocyte administration and clinical response. Opsonic activity to three test organisms (Escherichia coli 286 and ON 2, and Staphylococcus aureus) and to 15 blood stream isolates from 14 patients was measured as serum-dependent uptake of heat-killed /sup 14/C-labeled bacteria by normal donor leukopheresis granulocytes in an in vitro assay and compared with results obtained with a standard normal serum in each assay. At a concentration of 8 percent serum, all patient groups were equivalent to standard for the three test organisms. When rate-limiting concentrations of serum were employed, opsonic activity remained similar to standard for S. aureus in all patient groups and for the two E. coli strains in responders. In contrast, opsonins for E. coli decreased to 41 to 50 percent of standard in nonresponders. When patients with proved infection were separately analyzed, opsonin activity for E. coli was significantly greater in responders than nonresponders. Eight of 10 patients with 75 percent or greater of standard for opsonic activity against their own blood stream isolates also responded, whereas zero of four with less than 75 percent of standard had a favorable outcome. These results indicate that serum opsonic activity may be a determinant of clinical response to granulocyte transfusion in infected granulocytopenic patients. We conclude that opsonic activity should be assessed in such patients before granulocyte administration and suggest a trial of plasma infusion in opsonin-deficient patients.

  10. A comparison between augmentation with olanzapine and increased risperidone dose in acute schizophrenia patients showing early non-response to risperidone.

    PubMed

    Hatta, Kotaro; Otachi, Taro; Sudo, Yasuhiko; Kuga, Hironori; Takebayashi, Hiroshi; Hayashi, Hideaki; Ishii, Ryusuke; Kasuya, Masataka; Hayakawa, Tatsuro; Morikawa, Fumiyoshi; Hata, Kazuya; Nakamura, Mitsuru; Usui, Chie; Nakamura, Hiroyuki; Hirata, Toyoaki; Sawa, Yutaka

    2012-07-30

    We examined whether augmentation with olanzapine would be superior to increased risperidone dose among acute schizophrenia patients showing early non-response to risperidone. We performed a rater-blinded, randomized controlled trial at psychiatric emergency sites. Eligible patients were newly admitted patients with acute schizophrenia. Early response was defined as Clinical Global Impressions-Improvement Scale score ≤3 following 2 weeks of treatment. Early non-responders were allocated to receive either augmentation with olanzapine (RIS+OLZ group) or increased risperidone dose (RIS+RIS group). The 78 patients who completed 2 weeks of treatment were divided into 52 early responders to risperidone and 26 early non-responders to risperidone (RIS+OLZ group, n=13; RIS+RIS group, n=13). No difference in the achievement of ≥50% improvement in Positive and Negative Syndrome Scale total score was observed between RIS+OLZ and RIS+RIS groups. Although time to treatment discontinuation for any cause was significantly shorter in the RIS+RIS group (6.8 weeks [95% confidence interval, 5.2-8.4]) than in early responders to risperidone (8.6 weeks [7.9-9.3]; P=0.018), there was no significant difference between the RIS+OLZ group (7.9 weeks [6.3-9.5]) and early responders to risperidone. Secondary outcomes justify the inclusion of augmentation arms in additional, larger studies comparing strategies for early non-responders.

  11. Do Patient Profiles Influence the Effects of Massage? A Controlled Clinical Trial.

    PubMed

    Díaz-Rodríguez, Lourdes; Fernández-Pérez, Antonio Manuel; Galiano-Castillo, Noelia; Cantarero-Villanueva, Irene; Fernández-Lao, Carolina; Martín-Martín, L M; Arroyo-Morales, Manuel

    2016-10-01

    Considerable scientific evidence has been published on the effectiveness of massage in different conditions, but it remains unclear whether this effectiveness is modulated by the profile of patients. The aim of this study was to compare the effects of a 21-min myofascial therapy protocol on stress responders and nonresponders stressed in the laboratory with a cold pressor test. Dependent variables included heart rate variability (HRV), blood pressure, and salivary markers such as flow rate, cortisol, immunoglobulin A (IgA), and α-amylase activity. A controlled, repeated measures, single-blind trial was conducted in 30 Caucasian students with a mean (SD) age of 20.70 (4.50) years. We found no significant between-group differences in descriptive characteristics or in any preintervention outcome measure. Analysis of covariance revealed significant increases in HRV index (F = 0.18, p = .01), salivary flow rate (F = 0.16, p = .02), and salivary IgA concentration (F = 4.36, p = .04) and significant decreases in the low-frequency domain (F = 0.18, p = .04) and LF-high-frequency ratio (F = 0.18, p = .01) in the stress responder group in comparison to the nonresponder group. In conclusion, a better response to massage was observed in stress responders than in nonresponders across various HRV parameters and salivary measures.

  12. Presence of anti-HBc is associated to high rates of HBV resolved infection and low threshold for Occult HBV Infection in HIV patients with negative HBsAg in Chile.

    PubMed

    Vargas, Jose Ignacio; Jensen, Daniela; Sarmiento, Valeska; Peirano, Felipe; Acuña, Pedro; Fuster, Felipe; Soto, Sabrina; Ahumada, Rodrigo; Huilcaman, Marco; Bruna, Mario; Jensen, Werner; Fuster, Francisco

    2016-04-01

    HBV-HIV coinfection is prevalent. Frequently, anti-HBc is the only serological marker of HBV, which can be indicative of HBV resolved infection, when found together with anti-HBs reactivity; or present as "isolated anti-HBc," related to HBV occult infection with presence of detectable DNA HBV, more prevalent in HIV-positive individuals. Regional data about this condition are scarce. Anti-HBc rapid test has been used as screening, but its performance has not been described in HIV-positive patients. The aim of this study was determine prevalence of anti-HBc in HIV-positive patients, serological pattern of HBV resolved infection and isolated anti-HBc, evaluating presence of HBV occult infection. Assess anti-HBc rapid test compared to ECLIA. Methods included measurement of anti-HBc and anti-HBs in HIV-positive patients with negative HBsAg. Serum HBV DNA quantification and HBV booster vaccination to "isolated anti-HBc" individuals. Detection of anti-HBc by rapid test and ECLIA. In 192 patients, prevalence of anti-HBc was 42.7% (82/192); associated to male gender, drug use, men-sex-men, positive-VDRL, and longer time HIV diagnosis. 34.4% (66/192) had presence of anti-HBs, mean titers of 637 ui/ml. Isolated anti-HBc in 8.3% (16/192), associated to detectable HIV viral load and no-use of HAART; in them, HBV DNA was undetectable, and 60% responded to HBV vaccination booster. Anti-HBc rapid test showed low sensibility (32.9%) compared to ECLIA. These results show that prevalence of anti-HBc in HIV-positive individuals is high, in most cases accompanied with anti-HBs as HBV resolved infection. Low prevalence of "isolated anti-HBc," with undetectable HBV DNA, and most had anamnestic response to HBV vaccination; suggest low possibility of occult HBV infection. Anti-HBc rapid test cannot be recommended as screening method for anti-HBc.

  13. Effect of thymidylate synthase (TYMS) gene polymorphisms with methotrexate treatment outcome in south Indian Tamil patients with rheumatoid arthritis.

    PubMed

    Muralidharan, Niveditha; Misra, Durga P; Jain, Vikramraj K; Negi, Vir Singh

    2017-03-27

    Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease causing joint damage and significant functional impairment. Methotrexate (MTX) remains the mainstay for the treatment of RA. MTX inhibits several enzymes of the folate and nucleotide pathways. Thymidylate synthase (TYMS) is an important enzyme in the de novo pyrimidine pathway responsible for DNA replication. The two common gene polymorphisms analyzed in TYMS are 28-bp tandem repeat polymorphism and a 6-bp insertion/deletion polymorphism. The present study was carried out to find the role of these TYMS gene polymorphisms with clinical phenotype, treatment response, and MTX adverse events in 254 patients with RA of south Indian Tamil ethnicity. TYMS gene polymorphisms were analyzed by PCR. The allele frequencies of TYMS gene polymorphisms did not differ between good and non-responders. However, the TYMS 28-bp tandem repeat 3R allele was higher in non-responders than in patients undergoing remission [64 vs 51.11%, p = 0.06, OR 0.58, 95% CI (0.34-1.00)]. The TYMS 6-bp deletion allele was higher in non-responders than good responders [78.20 vs 64.92%, p = 0.06, OR 0.51 95% CI (0.27-0.98)]. TYMS 3R allele and TYMS 6-bp deletion allele may favor non-response to MTX in south Indian Tamils. TYMS gene polymorphisms did not influence MTX adverse events.

  14. Role of Right Ventricular Dysfunction and Diabetes Mellitus in N-terminal pro-B-type Natriuretic Peptide Response of Patients With Severe Mitral Regurgitation and Heart Failure After MitraClip.

    PubMed

    Kaneko, Hidehiro; Neuss, Michael; Weissenborn, Jens; Butter, Christian

    2017-04-06

    MitraClip (MC) is an alternative therapeutic option for patients with severe mitral regurgitation (MR) who are at high surgical risk. Most candidates for MC have severe heart failure (HF) with increased N-terminal pro-B-type natriuretic peptide (NT-pro BNP) levels. We sought to clarify the response of NT-pro BNP after MC and to identify the determinants of NT-pro BNP nonresponders. Among 136 consecutive patients successfully treated with MC, we excluded 20 patients due to low baseline NT-pro BNP levels and therefore examined 116 patients. NT-pro BNP responders were defined as patients whose NT-pro BNP levels decreased by > 30% at 6 months after MC. Mean NT-pro BNP levels significantly decreased from 6,117 pg/mL at baseline to 4,143 pg/mL at 6 months after MC (P < 0.001); 61 patients (53%) were responders. Diabetes mellitus (DM) (51% versus 25%; P = 0.003) and atrial fibrillation (67% versus 49%; P = 0.049) were more common in nonresponders. Baseline New York Heart Association (NYHA) class and NT-proBNP levels were higher in responders. Right ventricular systolic dysfunction (RVSD) defined as tricuspid annular plane systolic excursion (TAPSE) < 15 mm was more common in nonresponders (41% versus 18%; P = 0.008). Multivariable logistic regression analysis revealed that DM (odds ratio [OR], 2.966; P = 0.014), RVSD (OR, 3.948; P = 0.006), and baseline NT-proBNP > 5,000 pg/mL (OR, 0.204; P = 0.001) were independent determinants of nonresponders. All-cause death tended to be less common in responders to NT-pro BNP (20% versus 31%; P = 0.163). In conclusion, NT-pro BNP levels significantly decreased after MC. DM and RVSD were determinants of NT-pro BNP nonresponse after the MC procedure.

  15. Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy

    PubMed Central

    Baird, Angela C; Mallon, Dominic; Radford-Smith, Graham; Boyer, Julien; Piche, Thierry; Prescott, Susan L; Lawrance, Ian C; Tulic, Meri K

    2016-01-01

    AIM To study the innate immune function in ulcerative colitis (UC) patients who fail to respond to anti-tumor necrosis factor (TNF) therapy. METHODS Effects of anti-TNF therapy, inflammation and medications on innate immune function were assessed by measuring peripheral blood mononuclear cell (PBMC) cytokine expression from 18 inflammatory bowel disease patients pre- and 3 mo post-anti-TNF therapy. Toll-like receptor (TLR) expression and cytokine production post TLR stimulation was assessed in UC “responders” (n = 12) and “non-responders” (n = 12) and compared to healthy controls (n = 12). Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were measured in blood to assess disease severity/activity and inflammation. Pro-inflammatory (TNF, IL-1β, IL-6), immuno-regulatory (IL-10), Th1 (IL-12, IFNγ) and Th2 (IL-9, IL-13, IL-17A) cytokine expression was measured with enzyme-linked immunosorbent assay while TLR cellular composition and intracellular signalling was assessed with FACS. RESULTS Prior to anti-TNF therapy, responders and non-responders had similar level of disease severity and activity. PBMC’s ability to respond to TLR stimulation was not affected by TNF therapy, patient’s severity of the disease and inflammation or their medication use. At baseline, non-responders had elevated innate but not adaptive immune responses compared to responders (P < 0.05). Following TLR stimulation, non-responders had consistently reduced innate cytokine responses to all TLRs compared to healthy controls (P < 0.01) and diminished TNF (P < 0.001) and IL-1β (P < 0.01) production compared to responders. This innate immune dysfunction was associated with reduced number of circulating plasmacytoid dendritic cells (pDCs) (P < 0.01) but increased number of CD4+ regulatory T cells (Tregs) (P = 0.03) as well as intracellular accumulation of IRAK4 in non-responders following TLR-2, -4 and -7 activation (P < 0.001). CONCLUSION Reduced innate immunity in

  16. Different Effects of Tolvaptan in Patients with Idiopathic Membranous Nephropathy with Nephrotic Syndrome

    PubMed Central

    Tanaka, Atsushi; Nakamura, Tsukasa; Sato, Eiichi; Ueda, Yoshihiko; Node, Koichi

    2017-01-01

    This case report discusses the clinical indication for immunosuppressants in patients with idiopathic membranous nephropathy (IMN). Because this disease occasionally shows spontaneous remission, it is necessary to determine the predictive values for a therapeutic effect in order to provide appropriate treatment. Two distinct cases described herein illustrate the different effects of tolvaptan in responders and non-responders, according to the pre-treatment levels of AQP-2 immunostaining in the samples from renal biopsy and urinary levels of AQP-2 and osmolality, suggesting that these values may be useful predictors of response to tolvaptan in patients with nephrotic IMN. PMID:28090051

  17. Pharmacogenomic study in patients with multiple sclerosis

    PubMed Central

    Bustamante, Marta F.; Morcillo-Suárez, Carlos; Malhotra, Sunny; Rio, Jordi; Leyva, Laura; Fernández, Oscar; Zettl, Uwe K.; Killestein, Joep; Brassat, David; García-Merino, Juan Antonio; Sánchez, Antonio J.; Urcelay, Elena; Alvarez-Lafuente, Roberto; Villar, Lusia M.; Alvarez-Cermeño, Jose Carlos; Farré, Xavier; Lechner-Scott, Jeannette; Vandenbroeck, Koen; Rodríguez-Antigüedad, Alfredo; Drulovic, Jelena S.; Martinelli Boneschi, Filippo; Chan, Andrew; Oksenberg, Jorge; Navarro, Arcadi; Montalban, Xavier

    2015-01-01

    Objectives: We aimed to investigate the association between polymorphisms located in type I interferon (IFN)-induced genes, genes belonging to the toll-like receptor (TLR) pathway, and genes encoding neurotransmitter receptors and the response to IFN-β treatment in patients with multiple sclerosis (MS). Methods: In a first or screening phase of the study, 384 polymorphisms were genotyped in 830 patients with MS classified into IFN-β responders (n = 416) and nonresponders (n = 414) according to clinical criteria. In a second or validation phase, the most significant polymorphisms associated with IFN-β response were genotyped in an independent validation cohort of 555 patients with MS (281 IFN-β responders and 274 nonresponders). Results: Seven single nucleotide polymorphisms (SNPs) were selected from the screening phase for further validation: rs832032 (GABRR3; p = 0.0006), rs6597 (STUB1; p = 0.019), rs3747517 (IFIH1; p = 0.010), rs2277302 (PELI3; p = 0.017), rs10958713 (IKBKB; p = 0.003), rs2834202 (IFNAR1; p = 0.030), and rs4422395 (CXCL1; p = 0.017). None of these SNPs were significantly associated with IFN-β response when genotyped in an independent cohort of patients. Combined analysis of these SNPs in all patients with MS (N = 1,385) revealed 2 polymorphisms associated with IFN-β response: rs2277302 (PELI3; p = 0.008) and rs832032 (GABRR3; p = 0.006). Conclusions: These findings do not support an association between polymorphisms located in genes related to the type I IFN or TLR pathways or genes encoding neurotransmitter receptors and the clinical response to IFN-β. Nevertheless, additional genetic and functional studies of PELI3 and GABRR3 are warranted. PMID:26445728

  18. Removal of 2-arachidonylglycerol by direct hemoperfusion therapy with polymyxin B immobilized fibers benefits patients with septic shock.

    PubMed

    Kase, Yoichi; Obata, Toru; Okamoto, Yasuhisa; Iwai, Kenichi; Saito, Keita; Yokoyama, Keitaro; Takinami, Masanori; Tanifuji, Yasumasa

    2008-10-01

    Arachidonylethanolamide (AEA) and 2-arachidonylglycerol (2-AG) are endocannabinoids involved in septic shock, and 8-epi prostaglandin F2alpha (F2-isoprostane) is a biomarker of oxidative stress in biological systems. Because the antibiotic polymyxin B absorbs endocannabinoids as well as endotoxins, direct hemoperfusion therapy with polymyxin B-immobilized fibers (PMX-DHP) decreases serum levels of endocannabinoids. To investigate the features of sepsis and determine the proper use of PMX-DHP, we measured the changes in levels of endocannabinoids and F2-isoprostane in patients with septic shock. Twenty-six patients with septic shock, including those with septic shock induced by peritonitis, underwent laparotomy for drainage. Endocannabinoids absorption with PMX-DHP was examined in two groups of patients: patients whose mean arterial blood pressure (mABP) had increased more than 20 mm Hg (responder group; N = 13); and patients iwhose mABP did not increase or had increased no more than 20 mm Hg (non-responder group; N = 13). Levels of AEA did not change after PMX-DHP in either the non-responder or responder groups, whereas levels of 2-AG decreased significantly after PMX-DHP in the responder group, but not in the non-responder group. F2-isoprostane gradually increased after PMX-DHP treatment; on the other hand, levels of F2-isoprostane remained constant in the responder group. Patients with septic shock are under considerable oxidative stress, and 2-AG plays an important role in the cardiovascular status of these patients. The removal of 2-AG by PMX-DHP benefits patients with septic shock by stabilizing cardiovascular status and decreasing long-term oxidative stress.

  19. Mutations of KRAS/NRAS/BRAF predict cetuximab resistance in metastatic colorectal cancer patients

    PubMed Central

    Hsu, Hung-Chih; Thiam, Tan Kien; Lu, Yen-Jung; Yeh, Chien Yuh; Tsai, Wen-Sy; You, Jeng Fu; Hung, Hsin Yuan; Tsai, Chi-Neu; Hsu, An; Chen, Hua-Chien; Chen, Shu-Jen; Yang, Tsai-Sheng

    2016-01-01

    Approximately 45% of metastatic colorectal cancer (mCRC) patients with wild-type KRAS exon 2 are resistant to cetuximab treatment. We set out to identify additional genetic markers that might predict the response to cetuximab treatment. Fifty-three wild-type KRAS exon 2 mCRC patients were treated with cetuximab/irinotecan-based chemotherapy as a first- or third-line therapy. The mutational statuses of 10 EGFR pathway genes were analyzed in primary tumors using next-generation sequencing. BRAF, PIK3CA, KRAS (exons 3 and 4), NRAS, PTEN, and AKT1 mutations were detected in 6, 6, 5, 4, 1, and 1 patient, respectively. Four of the BRAF mutations were non-V600 variants. Four tumors harbored multiple co-existing (complex) mutations. All patients with BRAF mutations or complex mutation patterns were cetuximab non-responders. All patients but one harboring KRAS, NRAS, or BRAF mutations were non-responders. Mutations in any one of these three genes were associated with a poor response rate (7.1%) and reduced survival (PFS = 8.0 months) compared to wild-type patients (74.4% and 11.6 months). Our data suggest that KRAS, NRAS, and BRAF mutations predict response to cetuximab treatment in mCRC patients. PMID:26989027

  20. IL2/IL21 region polymorphism influences response to rituximab in systemic lupus erythematosus patients.

    PubMed

    Márquez, Ana; Dávila-Fajardo, Cristina Lucía; Robledo, Gema; Rubio, José Luis Callejas; de Ramón Garrido, Enrique; García-Hernández, Francisco J; González-León, Rocío; Ríos-Fernández, Raquel; Barrera, José Cabeza; González-Escribano, Ma Francisca; García, Ma Teresa Camps; Palma, Ma Jesús Castillo; del Mar Ayala, Ma; Ortego-Centeno, Norberto; Martín, Javier

    2013-08-01

    To determine whether the IL2/IL21 region, a general autoimmunity locus, contributes to the observed variation in response to rituximab in patients with systemic lupus erythematosus as well as to analyze its influence in a cohort including other autoimmune diseases. rs6822844 G/T polymorphism at the IL2-IL21 region was analyzed by TaqMan assay in 84 systemic lupus erythematosus (SLE) and 60 different systemic autoimmune diseases Spanish patients receiving rituximab. Six months after the first infusion patients were classified, according to the EULAR criteria, as good responders, partial responders and non-responders. A statistically significant difference was observed in GG genotype frequency between responder (total and partial response) (83.56%) and non-responder (45.45%) SLE patients (p=0.010, odds ratio (OR)=6.10 [1.28-29.06]). No association with the response was evident in the group of patients with autoimmune diseases other than lupus. Furthermore, when both groups of patients were pooled in a meta-analysis, a reduced statistical significance of the association was observed (p=0.024, OR=3.53 [1.06-11.64]). Our results show for a first time that IL2-IL21 region seems to play a role in the response to rituximab in SLE patients but not in other autoimmune diseases.

  1. Extra-pulmonary manifestations of paracoccidioidomycosis associated with acquired immunodeficiency syndrome: a case report*

    PubMed Central

    Safe, Izabella Picinin; do Valle, Fabio Francesconi; Maia, Daniela Cristina Caetano; Agonio, Bárbara; Monte, Rossicléia Lins; Araújo, José de Ribamar; Cordeiro-Santos, Marcelo

    2014-01-01

    We present a patient with Paracoccidioidomycosis/HIV coinfection which has been investigated because of chronic monoarthritis and mucocutaneous lesions. A biopsy of the synovial membrane and skin revealed structures consistent with Paracoccidioides brasiliensis. At diagnosis, the count of CD4 + T cells was 44 cells/mm3. We emphasize the importance of clinical suspicion of Paracoccidioidomycosis in patients with HIV/AIDS who live in or are from risk areas. PMID:24626662

  2. Immune reconstitution inflammatory syndrome in HIV and sporotrichosis coinfection: report of two cases and review of the literature.

    PubMed

    Lyra, Marcelo Rosandiski; Nascimento, Maria Letícia Fernandes Oliveira; Varon, Andréa Gina; Pimentel, Maria Inês Fernandes; Antonio, Liliane de Fátima; Saheki, Maurício Naoto; Bedoya-Pacheco, Sandro Javier; Valle, Antonio Carlos Francesconi do

    2014-01-01

    We report 2 cases of patients with immune reconstitution inflammatory syndrome (IRIS) associated with cutaneous disseminated sporotrichosis and human immunodeficiency virus (HIV) coinfection. The patients received specific treatment for sporotrichosis. However, after 4 and 5 weeks from the beginning of antiretroviral therapy, both patients experienced clinical exacerbation of skin lesions despite increased T CD4+ cells (T cells cluster of differentiation 4 positive) count and decreased viral load. Despite this exacerbation, subsequent mycological examination after systemic corticosteroid administration did not reveal fungal growth. Accordingly, they were diagnosed with IRIS. However, the sudden withdrawal of the corticosteroids resulted in the recurrence of IRIS symptoms. No serious adverse effects could be attributed to prednisone. We recommend corticosteroid treatment for mild-to-moderate cases of IRIS in sporotrichosis and HIV coinfection with close follow-up.

  3. Development of a pigtail macaque model of sexually transmitted infection/HIV coinfection using Chlamydia trachomatis, Trichomonas vaginalis, and SHIVSF162P3

    PubMed Central

    Henning, Tara; Fakile, Yetunde; Phillips, Christi; Sweeney, Elizabeth; Mitchell, James; Patton, Dorothy; Sturdevant, Gail; Caldwell, Harlan D.; Secor, W. Evan; Papp, John; Hendry, R. Michael; McNicholl, Janet; Kersh, Ellen

    2012-01-01

    Background Sexually transmitted infections (STIs) are associated with an increased risk of HIV infection. To model the interaction between STIs and HIV infection, we evaluated the capacity of the pigtail macaque model to sustain triple infection with Trichomonas vaginalis, Chlamydia trachomatis, and SHIVSF162P3. Methods Seven SHIVSF162P3-infected pigtail macaques were inoculated with T. vaginalis only (n = 2), C. trachomatis only (n = 1), both T. vaginalis and C. trachomatis (n = 2), or control media (no STI; n = 2). Infections were confirmed by culture and/or nucleic acid testing. Genital mucosa was visualized by colposcopy. Results Characteristic gynecologic signs were observed for both STIs, but not in control animals. Manifestations were most prominent at days 7–10 post-infection. STIs persisted between 4 and 6 weeks and were cleared with antibiotics. Conclusions These pilot studies demonstrate the first successful STI-SHIV triple infection of pigtail macaques, with clinical presentation of genital STI symptoms similar to those observed in humans. PMID:21781129

  4. [Interferon-alpha and liver fibrosis in patients with chronic damage due to hepatitis C virus].

    PubMed

    Gonzalez-Huezo, María Sarai; Gallegos-Orozco, Juan Fernando

    2003-01-01

    The present review focuses on the published information published regarding the effects of interferon alpha therapy on liver fibrosis in patients with chronic liver damage secondary to hepatitis C infection. Data reviewed included results of the in vitro effects of interferon on hepatic cell line cultures with regards to indirect markers of fibrosis, activation of hepatic stellate cells and oxidative stress response. In the clinical arena, there is current clear evidence of a favorable histological outcome in patients with sustained viral response to interferon therapy. For this reason, the current review focuses more on the histological outcomes regarding liver fibrosis in patients who have not attained viral response to therapy (non-responders) or who already have biopsy defined cirrhosis. Data in these patients were analyzed according to the results of objective testing of fibrosis through the assessment of liver biopsy and its change during time, specially because the morbidity and mortality of this disease is directly related to the complications of liver cirrhosis and not necessarily to the persistence of the hepatitis C virus. Lastly, it is concluded that the process of liver fibrosis/cirrhosis is a dynamic one and that there is some evidence to support the usefulness of interferon alpha therapy as a means to halt or retard the progression of hepatic fibrosis. The result of current clinical trials in which interferon therapy is being used to modify the progression of fibrosis in non-responders or cirrhotic patients is eagerly awaited.

  5. Clinical profile and treatment outcome of older (>75 years) patients with systemic AL amyloidosis

    PubMed Central

    Sachchithanantham, Sajitha; Offer, Mark; Venner, Christopher; Mahmood, Shameem A.; Foard, Darren; Rannigan, Lisa; Lane, Thirusha; Gillmore, Julian D.; Lachmann, Helen J.; Hawkins, Philip N.; Wechalekar, Ashutosh D.

    2015-01-01

    Systemic AL amyloidosis, a disease with improving outcomes using novel therapies, is increasingly recognized in the elderly but treatment and outcomes have not been systematically studied in this group of patients in whom comorbidities and frailty may compound morbidity and mortality. We report the outcomes of 295 patients with systemic AL amyloidosis ≥75 years seen at the UK National Amyloidosis Centre from 2005–2012. The median age was 78.5 years. The median overall survival was 20 months. Two hundred and thirty-eight patients received chemotherapy and 57 elected for supportive care only (overall survival – 24 and 8.4 months, respectively). On intention-to-treat analysis, 44% achieved a hematologic response including a very good partial response or better in 23%. The median overall survival was 6.2 years in patients achieving very good partial response or better at the 6-month landmark analysis and 1.5 years in non-responders. Factors independently indicating a poor prognosis were: cardiac involvement, performance status ≥2; systolic blood pressure <100 mmHg and, on landmark analysis, achieving less than a very good partial response. Treatment of systemic AL amyloidosis in the elderly is challenging. Deep clonal responses are associated with excellent survival and organ responses. Achieving a response to the first-line regimen appears particularly important as outcomes of non-responders are similar to those of untreated patients. Prospective trials with lower toxicity, outpatient treatment regimens are needed. PMID:26294730

  6. Inflammatory and Antioxidant Pattern Unbalance in “Clopidogrel-Resistant” Patients during Acute Coronary Syndrome

    PubMed Central

    Gori, Anna Maria; Cecchettini, Antonella; Parodi, Guido; Marcucci, Rossella; Parolini, Marina; Romagnuolo, Ilaria; Citti, Lorenzo; Abbate, Rosanna

    2015-01-01

    Background. In acute coronary syndrome (ACS), inflammation and redox response are associated with increased residual platelet reactivity (RPR) on clopidogrel therapy. We investigated whether clopidogrel interaction affects platelet function and modulates factors related to inflammation and oxidation in ACS patients differently responding to clopidogrel. Material and Methods. Platelet aggregation was measured in 29 ACS patients on dual (aspirin/clopidogrel) antiplatelet therapy. Nonresponders (NR) were defined as RPR ≥70% by ADP. Several inflammatory and redox parameters were assayed and platelet proteome was determined. Results. Eight (28%) out of 29 ACS patients resulted NR to clopidogrel. At 24 hours, the levels of Th2-type cytokines IL-4, IFNγ, and MCP-1 were higher in NR, while blood GSH (r-GSHbl) levels were lower in NR than responders (R). Proteomic analysis evidenced an upregulated level of platelet adhesion molecule, CD226, and a downregulation of the antioxidant peroxiredoxin-4. In R patients the proinflammatory cytokine IL-6 decreased, while the anti-inflammatory cytokine IL-1Ra increased. Conclusions. In patients with high RPR on clopidogrel therapy, an unbalance of inflammatory factors, platelet adhesion molecules, and circulatory and platelet antioxidant molecules was observed during the acute phase. Proinflammatory milieu persists in nonresponders for a long time after the acute event while antioxidant blood factors tend to conform to normal responsiveness. PMID:25873769

  7. Hepatitis C virus infection and risk of cancer: a population-based cohort study

    PubMed Central

    Omland, Lars Haukali; Farkas, Dora Körmendiné; Jepsen, Peter; Obel, Niels; Pedersen, Lars

    2010-01-01

    Background: Hepatitis C virus (HCV) infection is associated with an increased risk of primary liver cancer; however, 5- and 10-year risk estimates are needed. The association of HCV with non-Hodgkin lymphoma (NHL) is uncertain and the association with other cancers is unknown. Method: We conducted a nationwide, population-based cohort study of 4,349 HCV-infected patients in Denmark, computing standardized incidence ratios (SIR) of cancer incidence in HCV infected patients compared with cancer incidence of the general population. We calculated 5- and 10-year risks of developing cancer, stratifying our analyses based on the presence of HIV coinfection and cirrhosis. Results: We recorded an increased risk of primary liver cancer (SIR: 76.63 [95% CI: 51.69–109.40]), NHL (SIR: 1.89 [95% CI: 0.39–5.52]), and several smoking- and alcohol-related cancers in HCV infected patients without HIV coinfection. HCV-infected patients without HIV coinfection had a 6.3% (95% CI: 4.6%–8.7%) risk of developing cancer and 2.0% (95% CI: 1.1%–3.8%) risk of developing primary liver cancer within 10 years. Conclusion: We confirmed the association of HCV infection with primary liver cancer and NHL. We also observed an association between HCV infection and alcohol- and smoking-related cancers. PMID:20865115

  8. Symptom predictors of response to electroconvulsive therapy in older patients with treatment-resistant depression

    PubMed Central

    Tominaga, Keiichiro; Okazaki, Mioto; Higuchi, Hisashi; Utagawa, Itaru; Nakamura, Etsuko; Yamaguchi, Noboru

    2011-01-01

    Background: Electroconvulsive therapy (ECT) has been used for treatment-resistant depression. However, predictors of response to ECT have not been adequately studied using the Montgomery and Åsberg Depression Rating Scale, especially in older patients with treatment-resistant depression. Methods: This study included 18 Japanese patients who fulfilled the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition Text Revision criteria for a diagnosis of major depressive disorder or bipolar disorder with a current major depressive episode, and met the definition of treatment-resistant depression outlined by Thase and Rush, scoring ≥21 on the Montgomery and Åsberg Depression Rating Scale. The three-factor model of the Montgomery and Åsberg Depression Rating Scale was used for analysis. Factor 1 was defined by three items, factor 2 by four items, and factor 3 by three items, representing dysphoria, retardation, and vegetative symptoms, respectively. ECT was performed twice a week for a total of six sessions using a Thymatron System IV device with the brief pulse technique. Clinical responses were defined on the basis of a ≥50% decrease in total pretreatment Montgomery and Åsberg Depression Rating Scale scores. Results: The mean pretreatment factor 2 score for responders (n = 7) was significantly lower than that for nonresponders (n = 11). Furthermore, a significant difference in mean factor 3 score between responders and nonresponders was observed one week after six sessions of ECT, indicating a time lag of response. No significant differences were observed for age, number of previous episodes, and duration of the current episode between responders and nonresponders. Conclusion: This study suggests that a low pretreatment factor 2 score is a good predictor of response to ECT in older patients with major depression. PMID:21845058

  9. Normalization of compression-induced hemodynamics in patients responding to neoadjuvant chemotherapy monitored by dynamic tomographic optical breast imaging (DTOBI)

    PubMed Central

    Sajjadi, Amir Y.; Isakoff, Steven J.; Deng, Bin; Singh, Bhawana; Wanyo, Christy M.; Fang, Qianqian; Specht, Michelle C.; Schapira, Lidia; Moy, Beverly; Bardia, Aditya; Boas, David A.; Carp, Stefan A.

    2017-01-01

    We characterize novel breast cancer imaging biomarkers for monitoring neoadjuvant chemotherapy (NACT) and predicting outcome. Specifically, we recruited 30 patients for a pilot study in which NACT patients were imaged using dynamic tomographic optical breast imaging (DTOBI) to quantify the hemodynamic changes due to partial mammographic compression. DTOBI scans were obtained pre-treatment (referred to as day 0), as well as 7 and 30 days into therapy on female patients undergoing NACT. We present data for the 13 patients who participated in both day 0 and 7 measurements and had evaluable data, of which 7 also returned for day 30 measurements. We acquired optical images over 2 minutes following 4-8 lbs (18-36 N) of compression. The timecourses of tissue-volume averaged total hemoglobin (HbT), as well as hemoglobin oxygen saturation (SO2) in the tumor vs. surrounding tissues were compared. Outcome prediction metrics based on the differential behavior in tumor vs. normal areas for responders (>50% reduction in maximum diameter) vs. non-responders were analyzed for statistical significance. At baseline, all patients exhibit an initial decrease followed by delayed recovery in HbT, and SO2 in the tumor area, in contrast to almost immediate recovery in surrounding tissue. At day 7 and 30, this contrast is maintained in non-responders; however, in responders, the contrast in hemodynamic time-courses between tumor and normal tissue starts decreasing at day 7 and substantially disappears at day 30. At day 30 into NACT, responding tumors demonstrate “normalization” of compression induced hemodynamics vs. surrounding normal tissue whereas non-responding tumors did not. This data suggests that DTOBI imaging biomarkers, which are governed by the interplay between tissue biomechanics and oxygen metabolism, may be suitable for guiding NACT by offering early predictions of treatment outcome. PMID:28270967

  10. Persistent expression and function of P-glycoprotein on peripheral blood lymphocytes identifies corticosteroid resistance in patients with systemic lupus erythematosus.

    PubMed

    Kansal, Amit; Tripathi, Deepak; Rai, Mohit K; Agarwal, Vikas

    2016-02-01

    Corticosteroids (CS) are the mainstay of treatment in systemic lupus erythematosus (SLE) patients. However, some patients have poor response to CS treatment. Among the multiple mechanisms of CS resistance, overexpression of P-glycoprotein (P-gp) on peripheral blood lymphocytes (PBL) may be one of them as this result in efflux of CS from lymphocytes. Thus, we evaluated the role of P-gp protein on PBLs in patients with SLE in its response to CS therapy. SLE patients (n = 42) (fulfilling ACR revised criteria) who were naïve to CS and immunosuppressive drugs were enrolled. Disease activity was assessed using SLE disease activity index (SLEDAI) and expression, and function of P-gp was evaluated by flow cytometry at baseline and after 3 months of therapy with CS. At 3 months, patients with SLEDAI >4 and SLEDAI ≤4 were grouped as nonresponders and responders, respectively. P-gp expression was significantly increased on PBLs of SLE patients as compared to healthy controls (p < 0.001). P-gp expression and function correlated with SLEDAI (r = 0.49, p = 0.005; and r = 0.49, p = 0.001, respectively). P-gp expression and function were not different in responders and nonresponders at baseline. However, at 3 months of CS therapy, P-gp expression and function decreased in responders (p < 0.001 and p < 0.005, respectively), whereas in nonresponders, it remained unchanged. Persistent overexpression and activity of P-gp are associated with poor response to CS in CS naïve patients of SLE.

  11. Clinical predictive circulating peptides in rectal cancer patients treated with neoadjuvant chemoradiotherapy.

    PubMed

    Crotti, Sara; Enzo, Maria Vittoria; Bedin, Chiara; Pucciarelli, Salvatore; Maretto, Isacco; Del Bianco, Paola; Traldi, Pietro; Tasciotti, Ennio; Ferrari, Mauro; Rizzolio, Flavio; Toffoli, Giuseppe; Giordano, Antonio; Nitti, Donato; Agostini, Marco

    2015-08-01

    Preoperative chemoradiotherapy is worldwide accepted as a standard treatment for locally advanced rectal cancer. Current standard of treatment includes administration of ionizing radiation for 45-50.4 Gy in 25-28 fractions associated with 5-fluorouracil administration during radiation therapy. Unfortunately, 40% of patients have a poor or absent response and novel predictive biomarkers are demanding. For the first time, we apply a novel peptidomic methodology and analysis in rectal cancer patients treated with preoperative chemoradiotherapy. Circulating peptides (Molecular Weight <3 kDa) have been harvested from patients' plasma (n = 33) using nanoporous silica chip and analyzed by Matrix-Assisted Laser Desorption/Ionization-Time of Flight mass spectrometer. Peptides fingerprint has been compared between responders and non-responders. Random Forest classification selected three peptides at m/z 1082.552, 1098.537, and 1104.538 that were able to correctly discriminate between responders (n = 16) and non-responders (n = 17) before therapy (T0) providing an overall accuracy of 86% and an area under the receiver operating characteristic (ROC) curve of 0.92. In conclusion, the nanoporous silica chip coupled to mass spectrometry method was found to be a realistic method for plasma-based peptide analysis and we provide the first list of predictive circulating biomarker peptides in rectal cancer patients underwent preoperative chemoradiotherapy.

  12. Evaluations of primary lesions by endoscopy clearly distinguishes prognosis in patients with gastric cancer who receive chemotherapy

    PubMed Central

    Shibata, Tomoyuki; Okubo, Masaaki; Kawamura, Tomohiko; Horiguchi, Noriyuki; Yoshida, Dai; Ishizuka, Takamitsu; Nagasaka, Mitsuo; Nakagawa, Yoshihito; Ohmiya, Naoki

    2017-01-01

    Background Chemotherapy may improve outcomes in gastric cancer (GC), especially for the patients with advanced stage. To explore useful predictive factor for GC performing chemotherapy, we compared the tumor responses assessed using computed tomography (CT) with endoscopy based criteria. Methods 192 GC patients performing chemotherapy were retrospectively studied. CT based response assessment was performed after 2 courses of treatment. Endoscopic evaluation according to The Japanese classification of gastric carcinoma was also performed at same period. Data were correlated with overall survival (OS) and progression-free survival (PFS). Results Majority of the cases (n = 178, 93%) received S-1 based chemotherapy as the first line treatment. 55 (29%) and 91 (47%) cases were considered to be CT and endoscopic responders. Endoscopic responder was more clearly associated with better OS and PFS compared to CT based responder by the log-rank test (P<0.0001 vs. 0.01 and P<0.0001 vs. 0.008, respectively). The association was more striking among patients performing neoadjuvant chemotherapy (P<0.0001 vs. 0.15 and P<0.0001 vs. 0.1, respectively). Multivariate survival analysis using Cox's regression model revealed that endoscopic non-responder was the independent predictive factor, being more strongly associated with worse OS when compared to CT non-responder (hazard ratio: 4.60 vs. 1.77, 95% confidence interval: 2.83–7.49 vs.1.08–2.89, P<0.0001 vs. 0.02). More advanced T, N stage and cases who had peritoneal dissemination were significantly associated with endoscopic non-responder (all P values <0.01). Conclusion Endoscopy based evaluation of primary lesions are clearly associated with prognosis in patients with GC who perform chemotherapy. PMID:28288188

  13. Quantitative analysis of interferon alpha receptor subunit 1 and suppressor of cytokine signaling 1 gene transcription in blood cells of patients with chronic hepatitis C

    PubMed Central

    2010-01-01

    Background Interferon (IFN)-α receptor 1 (ifnar1) and suppressor of cytokine signaling 1 (socs1) transcription levels were quantified in peripheral blood mononuclear cells (PBMC) of 59 patients infected with hepatitis C virus (HCV) and 17 non-infected individuals. Samples were obtained from patients infected with HCV that were either untreated or treated with IFN-α2 plus ribavirin for 1 year and divided into responders and non-responders based on viral load reduction 6 months after treatment. Ifnar1 and socs1 transcription was quantified by real-time RT-PCR, and the fold difference (2-ΔΔCT) with respect to hprt housekeeping gene was calculated. Results Ifnar1 transcription increased significantly in HCV-infected patients either untreated (3.26 ± 0.31), responders (3.1 ± 0.23) and non-responders (2.18 ± 0.23) with respect to non-infected individuals (1 ± 0.34; P = 0.005). Ifnar1 transcription increased significantly (P = 0.003) in patients infected with HCV genotypes 1a (4.74 ± 0.25) and 1b (2.81 ± 0.25) but not in 1a1b (1.58 ± 0.21). No association was found of Ifnar1 transcription with disease progress, initial viral load or other clinical factors. With respect to socs1 transcription, values were similar for non-infected individuals (1 ± 0.28) and untreated patients (0.99 ± 0.41) but increased in responders (2.81 ± 0.17) and non-responder patients (1.67 ± 0.41). Difference between responder and non-responder patients was not statistically significant. Socs1 transcription increased in patients infected with HCV genotypes 1a and 1b (2.87 ± 0.45 and 2.22 ± 0.17, respectively) but not in 1a1b (1.28 ± 0.40). Socs1 transcript was absent in three patients infected with HCV genotype 1b. A weak correlation between ifnar1 and socs1 transcription was found, when Spearman's correlation coefficient was calculated. Conclusion Our results suggest that HCV infection may up-regulate ifnar1 transcription. HCV genotypes differ in their capacity to affect ifnar1 and

  14. Hepcidin-25, mean corpuscular volume, and ferritin as predictors of response to oral iron supplementation in hemodialysis patients.

    PubMed

    Takasawa, Kazuya; Takaeda, Chikako; Maeda, Teiryo; Ueda, Norishi

    2014-12-29

    The benefit of oral iron therapy (OIT) and factors predictive of OIT response are not established in hemodialysis (HD) patients with iron deficiency anemia (IDA). We examined the values of hepcidin-25, mean corpuscular volume (MCV), and ferritin as predictors of OIT response. Oral ferrous fumarate (50 mg/day, 8 weeks) was given to 51 HD patients with IDA (hemoglobin (Hb) < 12 g/dL, ferritin < 100 ng/mL) treated with an erythropoietin activator. Sixteen patients were responders (improvement of Hb (ΔHb) ≥ 2 g/dL) and 35 were non-responders (ΔHb < 2g/dL). Baseline Hb, MCV, serum hepcidin-25, ferritin, iron parameters, and C-reactive protein (CRP) before and ΔHb after OIT were compared between groups. Hepcidin-25, MCV, ferritin, and transferrin saturation were lower in the responders than in the non-responders. Hepcidin-25 positively correlated with ferritin. Hepcidin-25, MCV, and ferritin positively correlated with baseline Hb and negatively correlated with ΔHb. Despite normal CRP levels in all patients, CRP correlated positively with hepcidin-25 and ferritin. Stepwise multiple linear regression analysis and receiver operating characteristics curve analysis revealed that hepcidin-25, MCV, and ferritin could predict OIT response. We conclude that hepcidin-25, MCV, and ferritin could be useful markers of iron storage status and may help predict OIT response in HD patients.

  15. Evaluation of the response to vaccination with hepatitis B vaccine in pediatric patients diagnosed with celiac disease

    PubMed Central

    Egberg, Matthew; Nelson, Catherine; Eickoff, Jens

    2014-01-01

    Background: A gap exists in the literature on celiac disease populations and the response to hepatitis B vaccination. Objective: To identify pediatric patients with celiac disease who received the primary hepatitis B vaccination and investigate their response to vaccine. Design/Methods: Patients underwent blood draw for hepatitis B surface antibody titers. Patients with undetectable or non-protective HBsAb titers were contacted. Study outcome measures and patient characteristics variables were summarized by means, standard deviations, medians, and ranges. A two-sample t-test was used to compare normally distributed continuous variables between responders and non-responders. Results: In all, 58% of patients did not meet the threshold for “protective” antibody titers. The mean time between completion of hepatitis B vaccination and diagnosis of celiac disease was 8.1 years for responders versus 10.5 years for non-responders. In a multivariate analysis, time between completion of vaccine and diagnosis of celiac disease was statistically significant predictor of response with an adjusted odds ratio of 0.69 (95% confidence interval: 0.50–0.95; p = 0.021). Conclusion: Our celiac disease population shows a high hepatitis B vaccine failure. The time between completion of vaccine series and diagnosis of celiac disease is an independent predictor for response. PMID:26770758

  16. A phase Ib study of the effects of black raspberries on rectal polyps in patients with familial adenomatous polyposis.

    PubMed

    Wang, Li-Shu; Burke, Carol A; Hasson, Henrietta; Kuo, Chieh-Ti; Molmenti, Christine L Sardo; Seguin, Claire; Liu, Pengyuan; Huang, Tim H-M; Frankel, Wendy L; Stoner, Gary D

    2014-07-01

    Familial adenomatous polyposis (FAP) is characterized by the early onset of colonic polyposis and a high risk for colorectal cancer. FAP is treated by colectomy followed by lifelong removal of rectal polyps. This study determined whether black raspberries (BRBs) might regress rectal polyps in patients with FAP. Fourteen patients with FAP were treated with BRBs daily for 9 months. Seven patients received BRB powder orally plus two BRB suppositories inserted into the rectum at bedtime. The other 7 received an oral placebo plus the suppositories. Rectal polyp counts and polyp sizes were obtained at time zero and after 9 months of BRB treatment. Polyps and adjacent normal tissue were collected at both time points. The burden (P = 0.036) but not number (P = 0.069) of rectal polyps was significantly decreased. No benefit was noted with the addition of oral BRBs. Three patients were nonresponders. BRBs significantly decreased cellular proliferation, DNA methylation methyl transferase 1 protein expression, and p16 promoter methylation, but not promoter methylation of the Wnt pathway antagonists, SFRP2 and WIF1, in rectal polyps (adenomas) from responders but not from nonresponders. The MBD-seq assay revealed more demethylated transcription start sites (TSS), including those for miRNAs, in BRB-treated adenomas from the responders. In conclusion, BRB suppositories seem sufficient for regressing rectal polyps in patients with FAP.

  17. Response to recombinant erythropoietin alpha, without the adjunct of granulocyte-colony stimulating factor, is associated with a longer survival in patients with transfusion-dependent myelodysplastic syndromes.

    PubMed

    Musto, Pellegrino; Villani, Oreste; Martorelli, Maria Carmen; Pietrantuono, Giuseppe; Guariglia, Roberto; Mansueto, Giovanna; D'Auria, Fiorella; Grieco, Vitina; Bianchino, Gabriella; Sparano, Anna; Zonno, Antonia; Lerose, Rosa; Sanpaolo, Grazia; Falcone, Antonietta

    2010-08-01

    This was a retrospective, comparative study focused on the extended follow-up of 192 transfusion-dependent patients with myelodysplastic syndromes treated (n. 83) or not treated (n. 109) with recombinant erythropoietin alpha (r-EPO) as single agent during the course of their disease. The results supported the safety of this treatment in the long term and also showed a significant survival advantage (median 52 months vs. 31 months, p<0.0095) in responding patients as compared to non-responding ones or to subjects never treated with r-EPO. At multivariate analysis, response to r-EPO maintained an independent prognostic value on OS.

  18. Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients.

    PubMed

    Wheeler, Christopher J; Black, Keith L; Liu, Gentao; Mazer, Mia; Zhang, Xiao-xue; Pepkowitz, Samuel; Goldfinger, Dennis; Ng, Hiushan; Irvin, Dwain; Yu, John S

    2008-07-15

    Cancer vaccine trials have failed to yield robust immune-correlated clinical improvements as observed in animal models, fueling controversy over the utility of human cancer vaccines. Therapeutic vaccination represents an intriguing additional therapy for glioblastoma multiforme (GBM; grade 4 glioma), which has a dismal prognosis and treatment response, but only early phase I vaccine trial results have been reported. Immune and clinical responses from a phase II GBM vaccine trial are reported here. IFN-gamma responsiveness was quantified in peripheral blood of 32 GBM patients given therapeutic dendritic cell vaccines. Posttreatment times to tumor progression (TTP) and survival (TTS) were compared in vaccine responders and nonresponders and were correlated with immune response magnitudes. GBM patients (53%) exhibited >or=1.5-fold vaccine-enhanced cytokine responses. Endogenous antitumor responses of similar magnitude occurred in 22% of GBM patients before vaccination. Vaccine responders exhibited significantly longer TTS and TTP relative to nonresponders. Immune enhancement in vaccine responders correlated logarithmically with TTS and TTP spanning postvaccine chemotherapy, but not with initial TTP spanning vaccination alone. This is the first report of a progressive correlation between cancer clinical outcome and T-cell responsiveness after therapeutic vaccination in humans and the first tracing of such correlation to therapeutically exploitable tumor alteration. As such, our findings offer unique opportunities to identify cellular and molecular components of clinically meaningful antitumor immunity in humans.

  19. Genetic polymorphisms, their allele combinations and IFN-β treatment response in Irish multiple sclerosis patients

    PubMed Central

    O’Doherty, Catherine; Favorov, Alexander; Heggarty, Shirley; Graham, Colin; Favorova, Olga; Ochs, Michael; Hawkins, Stanley; Hutchinson, Michael; O’Rourke, Killian; Vandenbroeck, Koen

    2009-01-01

    Introduction IFN-β is widely used as first-line immunomodulatory treatment for multiple sclerosis. Response to treatment is variable (30–50% of patients are nonresponders) and requires a long treatment duration for accurate assessment to be possible. Information about genetic variations that predict responsiveness would allow appropriate treatment selection early after diagnosis, improve patient care, with time saving consequences and more efficient use of resources. Materials & methods We analyzed 61 SNPs in 34 candidate genes as possible determinants of IFN-β response in Irish multiple sclerosis patients. Particular emphasis was placed on the exploration of combinations of allelic variants associated with response to therapy by means of a Markov chain Monte Carlo-based approach (APSampler). Results The most significant allelic combinations, which differed in frequency between responders and nonresponders, included JAK2–IL10RB–GBP1–PIAS1 (permutation p-value was pperm = 0.0008), followed by JAK2–IL10–CASP3 (pperm = 0.001). Discussion The genetic mechanism of response to IFN-β is complex and as yet poorly understood. Data mining algorithms may help in uncovering hidden allele combinations involved in drug response versus nonresponse. PMID:19604093

  20. Long-term safety and efficacy of dalfampridine for walking impairment in patients with multiple sclerosis: Results of open-label extensions of two Phase 3 clinical trials

    PubMed Central

    Goodman, Andrew D; Bethoux, Francois; Brown, Theodore R; Schapiro, Randall T; Cohen, Ron; Marinucci, Lawrence N; Henney, Herbert R

    2015-01-01

    Background: In Phase 3 double-blind trials (MS-F203 and MS-F204), dalfampridine extended release tablets 10 mg twice daily (dalfampridine-ER; prolonged-release fampridine in Europe; fampridine modified or sustained release elsewhere) improved walking speed relative to placebo in patients with multiple sclerosis (MS). Objectives: Evaluation of long-term safety and efficacy of dalfampridine-ER in open-label extensions (MS-F203EXT, MS-F204EXT). Methods: Patients received dalfampridine-ER 10 mg twice daily; and had Timed 25-Foot Walk (T25FW) assessments at 2, 14 and 26 weeks, and then every 6 months. Subjects were categorized as dalfampridine-ER responders or non-responders, based on their treatment response in the double-blind parent trials that assessed T25FW. Results: We had 269 patients enter MS-F203EXT and 154 patients complete it; for a maximum exposure of 5 years. We had 214 patients enter MS-F204EXT and 146 complete it; for a maximum exposure of 3.3 years. No new safety signals emerged and dalfampridine-ER tolerability was consistent with the double-blind phase. Improvements in walking speed were lost after dalfampridine-ER was discontinued in the parent trial, but returned by the 2-week assessment after re-initiation of the drug. Throughout the extensions, mean improvement in walking speed declined, but remained improved, among the double-blind responders as compared with non-responders. Conclusions: The dalfamipridine-ER safety profile was consistent with the parent trials. Although walking speed decreased over time, dalfampridine-ER responders continued to show improved walking speed, which was sustained compared with non-responders. PMID:25583832

  1. Phenotypic differences of CD4(+) T cells in response to red blood cell immunization in transfused sickle cell disease patients.

    PubMed

    Vingert, Benoît; Tamagne, Marie; Habibi, Anoosha; Pakdaman, Sadaf; Ripa, Julie; Elayeb, Rahma; Galacteros, Frédéric; Bierling, Philippe; Ansart-Pirenne, Hélène; Bartolucci, Pablo; Noizat-Pirenne, France

    2015-06-01

    Alloimmunization against red blood cells (RBCs) is the main immunological risk associated with transfusion in patients with sickle cell disease (SCD). However, about 50-70% of SCD patients never get immunized despite frequent transfusion. In murine models, CD4(+) T cells play a key role in RBC alloimmunization. We therefore explored and compared the CD4(+) T-cell phenotypes and functions between a group of SCD patients (n = 11) who never became immunized despite a high transfusion regimen and a group of SCD patients (n = 10) who had become immunized (at least against Kidd antigen b) after a low transfusion regimen. We studied markers of CD4(+) T-cell function, including TLR, that directly control lymphocyte function, and their spontaneous cytokine production. We also tested responders for the cytokine profile in response to Kidd antigen b peptides. Low TLR2/TLR3 expression and, unexpectedly, strong expression of CD40 on CD4(+) T cells were associated with the nonresponder status, whereas spontaneous expression of IL-10 by CD4(+) T cells and weak Tbet expression were associated with the responder status. A Th17 profile was predominant in responders when stimulated by Jb(k) . These findings implicate CD4(+) T cells in alloimmunization in humans and suggest that they may be exploited to differentiate responders from nonresponders.

  2. Portal hypertension in primary biliary cirrhosis (PBC): A reversible condition? Yes, but not in all UDCA treated patients.

    PubMed

    Huet, Pierre-Michel; Vincent, Catherine; Deslauriers, Julie; Coté, Jean; Fenyves, Daphna; Matsutani, Shoichi; Boileau, Robert; Kerckvoorde, Jacline Huet-Van

    2009-10-01

    Portal hypertension is not a rare complication of PBC, but there are no useful clinical predictors of its severity. In fact, in PBC patients, the evaluation of portal hypertension needs a direct access to the portal vein in order to measure the real porto-hepatic gradient (PHG), mainly because of a possible pre-sinusoidal component. The severity of portal hypertension, as measured by the PHG using a thin needle, correlated significantly with the long-term survival of PBC patients, but the initial Mayo score remained the best predictor of survival. In addition to the well-known effects on biological parameters, ursodeoxycholic acid (UDCA) treatment has been associated with a stabilization or improvement of portal hypertension but this effect was not observed in all patients: "responders" and "non-responders" to the UDCA could be identified according to changes in PHG and aspartate aminotransferase (AST) levels observed 2 years after UDCA therapy and had significantly different long-term survivals. This notion of "responders" and "non-responders" is new and may well explain the conflicting data found in the literature concerning the effects of UDCA in PBC patients as reported in various clinical trials. These findings are of interest when considering the emerging non-invasive methods aimed at evaluating liver fibrosis, particularly elastography that may prove useful in the indirect assessment of portal hypertension in the near future, therefore avoiding the need for the invasive measurement of the PHG.

  3. Cholinesterase inhibitors are compatible with psychosocial intervention for Alzheimer disease patients suggested by neuroimaging findings.

    PubMed

    Meguro, Kenichi

    2017-01-30

    We previously reported that the frontal lobe was stimulated by psychosocial intervention for dementia patients, and that the parietal lobe was associated with logical judgment. We hypothesized that the combined therapeutic approach with symptomatic drug treatment can directly stimulate not only attention function but also judgment function indirectly to observing other participants' behaviors. Fifty-two patients with Alzheimer disease underwent the group reminiscence approach with reality orientation, as well as the donepezil treatment. The cerebral blood flow (CBF) was assessed with (99m)Tc-ECD SPECT. Two analyses were performed: Analysis 1 was to compare Responders vs. Non-responders as shown by MMSE scores, whereas Analysis 2 was to compare Good vs. Poor reminders of the intervention content. We found that the CBF in the frontal lobe was significantly higher in Responders (vs. Non-responders). The CBF in the parietal lobe, especially the left side, was significantly higher in the Good reminders (vs. Poor reminders). The donepezil stimulated the areas similar to where the psychosocial intervention was previously found to be stimulated directly, thus the drug was thought to be compatible for psychosocial intervention. The parietal lobe was stimulated indirectly, suggesting that the indirect effect of the intervention may be based on logical judgment function.

  4. Prospective analysis of the factors influencing the antibody response to hepatitis B vaccine in hemodialysis patients.

    PubMed

    Peces, R; de la Torre, M; Alcázar, R; Urra, J M

    1997-02-01

    Hepatitis B vaccine is effective in producing protection against hepatitis B virus (HBV) infection in hemodialysis (HD) patients, but the antibody response is variable. To identify those factors implicated in the vaccine response, in a prospective study over a 24-month period, we vaccinated 80 seronegative patients on HD (group A) and monitored clinical, biochemical, and immunologic parameters. The protective immunity acquired by vaccination was compared with that developed through HBV infection in 22 age-matched HD patients (group B). The anti-HBs antibody-seronegative patients followed a four-dose vaccination schedule (0, 1, 2, and 6 months) with 40 microg DNA-recombinant hepatitis B vaccine. One month after vaccination, 77.5% of the patients had seroconverted, and 72.5% achieved high antibody response, whereas 22.5% were nonresponders. Patients aged younger than 40 years seroconverted 100%; those aged 40 to 60 years, 75% (P < 0.01); and patients older than 60 years, 74% (P < 0.001). No differences between responders and nonresponders concerning sex, time on HD, HD dose, nutritional status, hemoglobin level, HD membrane, iPTH level, calcitriol treatment, or number of transfusions during vaccination were found. The presence of other factors, such as recombinant human erythropoietin (rHuEPO) therapy or hepatitis C virus (HCV) infection, did not significantly influence antibody responses to hepatitis B immunization. A greater frequency of DR3 (53.8% v 25.7%, P < 0.05), DR7 (53.8% v 18.6%, P < 0.01), and DQ2 (76.9% v 44.1%, P < 0.05), and a lesser frequency of A2 (7.7% v 37.2%, P < 0.05) were found in nonresponders compared with responders. Eighteen months after vaccination, the analysis showed similar antibody titers but lower seroconversion rates in group A as compared with group B. In conclusion, unresponsiveness to hepatitis B vaccine in HD patients was related to factors such as older age, the presence of DR3, DR7, and DQ2, and the absence of A2 alleles

  5. Per cent of patients with chronic migraine who responded per onabotulinumtoxinA treatment cycle: PREEMPT

    PubMed Central

    Silberstein, Stephen D; Dodick, David W; Aurora, Sheena K; Diener, Hans-Christoph; DeGryse, Ronald E; Lipton, Richard B; Turkel, Catherine C

    2015-01-01

    Objective The approved use of onabotulinumtoxinA for prophylaxis of headaches in patients with chronic migraine (CM) involves treatment every 12 weeks. It is currently unknown whether patients who fail to respond to the first onabotulinumtoxinA treatment cycle will respond to subsequent treatment cycles. To help inform decisions about treating non-responders, we examined the probability of treatment cycle 1 non-responders responding in cycle 2, and cycle 1 and 2 non-responders responding in cycle 3. Methods Pooled PREEMPT data (two studies: a 24-week, 2-cycle, double-blind, randomised (1:1), placebo-controlled, parallel-group phase, followed by a 32-week, 3-cycle, open-label phase) evaluated onabotulinumtoxinA (155–195 U) for prophylaxis of headaches in persons with CM (≥15 days/month with headache ≥4 h/day). End points of interest included the proportion of study patients who first achieved a ≥50% reduction in headache days, moderate/severe headache days, total cumulative hours of headache on headache days, or a ≥5-point improvement in Headache Impact Test (HIT)-6. For treatment cycle 1, all eligible participants were included. For subsequent cycles, responders in a previous cycle were no longer considered first responders. Results Among onabotulinumtoxinA-treated patients (n=688) 49.3% had a ≥50% reduction in headache-day frequency during treatment cycle 1, with 11.3% and 10.3% of patients first responding during cycles 2 and 3, respectively. 54.2%, 11.6% and 7.4% of patients first responded with a ≥50% reduction in cumulative hours of headache, and 56.3%, 14.5% and 7.7% of patients first responded with a ≥5-point improvement in total HIT-6 during treatment cycles 1, 2 and 3, respectively. Conclusions A meaningful proportion of patients with CM treated with onabotulinumtoxinA who did not respond to the first treatment cycle responded in the second and third cycles of treatment. Trial registration number NCT00156910, NCT00168428. PMID

  6. VIP (etoposide, ifosfamide, and cisplatin) in patients with previously treated soft tissue sarcoma.

    PubMed

    Moon, Ji Young; Baek, Seung-Woo; Ryu, Hyewon; Choi, Yoon-Seok; Song, Ik-Chan; Yun, Hwan-Jung; Jo, Deog-Yeon; Kim, Samyong; Lee, Hyo Jin

    2017-01-01

    We retrospectively reviewed outcomes of treatment with VIP (combination of etoposide, ifosfamide, and cisplatin) in patients with previously treated soft tissue sarcoma (STS).We analyzed the medical records of patients with advanced or relapsed STS who had undergone VIP treatment as second-line or more chemotherapy between January 2000 and December 2015. The patients were treated with a combination of etoposide (100 mg/m for 5 days), ifosfamide (2000 mg/m for 2 days), and cisplatin (20 mg/m for 5 days) once every 4 weeks. Treatment response, progression-free survival (PFS), and overall survival (OS) were analyzed in all patients and between responder and nonresponder groups (responders showed a tumor response to any prior systemic chemotherapy before VIP).Twenty-four patients with a median age of 50 years (range: 20-68 years) were treated with VIP. Eleven (45.8%) patients were male and 7 (29.2%) received 2 or more chemotherapy regimens before VIP. Median PFS was 3.7 months (95% confidence interval [CI], 1.3-6.1 months) and median OS was 10.0 months (95% CI, 6.6-13.5). The overall response rate was 37.5%, and the disease control rate was 50%. The responder group showed better PFS (7.7 months vs 3.0 months; P = 0.101) and significantly improved OS (11.0 months vs 8.8 months; P = 0.039) compared to those of nonresponders. All patients reported some grade of hematological toxicity. The most frequently encountered hematological toxicity was neutropenia (any grade, 77.7%; grade 3 or 4, 74.0%).VIP might be effective in patients with previously treated STS.

  7. VIP (etoposide, ifosfamide, and cisplatin) in patients with previously treated soft tissue sarcoma

    PubMed Central

    Moon, Ji Young; Baek, Seung-Woo; Ryu, Hyewon; Choi, Yoon-Seok; Song, Ik-Chan; Yun, Hwan-Jung; Jo, Deog-Yeon; Kim, Samyong; Lee, Hyo Jin

    2017-01-01

    Abstract We retrospectively reviewed outcomes of treatment with VIP (combination of etoposide, ifosfamide, and cisplatin) in patients with previously treated soft tissue sarcoma (STS). We analyzed the medical records of patients with advanced or relapsed STS who had undergone VIP treatment as second-line or more chemotherapy between January 2000 and December 2015. The patients were treated with a combination of etoposide (100 mg/m2 for 5 days), ifosfamide (2000 mg/m2 for 2 days), and cisplatin (20 mg/m2 for 5 days) once every 4 weeks. Treatment response, progression-free survival (PFS), and overall survival (OS) were analyzed in all patients and between responder and nonresponder groups (responders showed a tumor response to any prior systemic chemotherapy before VIP). Twenty-four patients with a median age of 50 years (range: 20–68 years) were treated with VIP. Eleven (45.8%) patients were male and 7 (29.2%) received 2 or more chemotherapy regimens before VIP. Median PFS was 3.7 months (95% confidence interval [CI], 1.3–6.1 months) and median OS was 10.0 months (95% CI, 6.6–13.5). The overall response rate was 37.5%, and the disease control rate was 50%. The responder group showed better PFS (7.7 months vs 3.0 months; P = 0.101) and significantly improved OS (11.0 months vs 8.8 months; P = 0.039) compared to those of nonresponders. All patients reported some grade of hematological toxicity. The most frequently encountered hematological toxicity was neutropenia (any grade, 77.7%; grade 3 or 4, 74.0%). VIP might be effective in patients with previously treated STS. PMID:28121937

  8. Low ABCB1 and high OCT1 levels play a favorable role in the molecular response to imatinib in CML patients in the community clinical practice.

    PubMed

    da Cunha Vasconcelos, Flavia; Mauricio Scheiner, Marcos Antonio; Moellman-Coelho, Arthur; Mencalha, André Luiz; Renault, Ilana Zalcberg; Rumjanek, Vivian Mary; Maia, Raquel Ciuvalschi

    2016-12-01

    Despite the favorable clinical evolution of patients with chronic myeloid leukemia (CML), resistance or intolerance to imatinib is present in approximately 35% of patients. Sokal score is a widely used risk factor, however efflux and influx transporters are provisional risk factors implicated in imatinib resistance. This study analyzed Sokal score, ABCB1, ABCG2 and OCT1 mRNA transporter expression levels as well as P-glycoprotein expression and efflux transporters activity to seek a possible correlation between these factors and the molecular response at 12 months from imatinib start as well as 8-year overall survival (OS). Low plus intermediate Sokal score correlated to optimal imatinib responses, as well as OS at 8-years, thus confirming the established role of Sokal score as a prognostic factor in CML patients. Low ABCB1 and high OCT1 mRNA levels were associated with an optimal molecular response, while the inverse levels were associated with non-responders (warning and failure) patients. Our results suggest that ABCB1 and OCT1 mRNA expressions may present biological relevance to identify responder and non-responder patients to imatinib treatment.

  9. Analysis of potentially predictive factors of efficacy of adjunct extended-release quetiapine fumarate in patients with major depressive disorder.

    PubMed

    Bauer, Michael; Thase, Michael E; Liu, Sherry; Earley, Willie; Eriksson, Hans

    2015-05-01

    Identification of predictors of treatment response in patients with major depressive disorder (MDD) may facilitate improved disease management. Data were pooled from two 6-week, double-blind, placebo-controlled studies of extended-release quetiapine (quetiapine XR; 150 or 300 mg/day) as adjunct to ongoing antidepressant therapy. Effects of psychiatric history and baseline demographic and disease characteristics on efficacy outcomes (Week 6 Montgomery Åsberg Depression Rating Scale [MADRS] total score reduction) were evaluated in population subgroups (quetiapine XR both doses pooled, n = 616; placebo, n = 303). Baseline Clinical Global Impressions-Severity (CGI-S) score and previous depressive episodes on Week 6 MADRS total score change, and baseline MADRS individual item scores on Week 6 change in CGI-Improvement score, were also evaluated. No major differences between responders and non-responders to quetiapine XR were observed for patient characteristics or demographic and disease characteristics. No suggestion of a predictive association was found between baseline CGI-S score, number of depressive episodes, and baseline MADRS item scores and efficacy outcomes. These analyses showed no major differences between responders and non-responders, and no predictive association between the parameters assessed and efficacy outcomes for adjunct quetiapine XR in patients with MDD and an inadequate response to prior antidepressant therapy.

  10. Venlafaxine inhibits the upregulation of plasma tumor necrosis factor-alpha (TNF-α) in the Chinese patients with major depressive disorder: a prospective longitudinal study.

    PubMed

    Li, Zezhi; Qi, Dake; Chen, Jun; Zhang, Chen; Yi, Zhenghui; Yuan, Chengmei; Wang, Zuowei; Hong, Wu; Yu, Shunying; Cui, Donghong; Fang, Yiru

    2013-01-01

    Although tumor necrosis factor-alpha (TNF-α) has been recognized to be involved in the pathogenesis of major depressive disorder (MDD) for a long time, only few studies so far investigated the effects of antidepressant, venlafaxine on TNF-α and the results are inconsistent. Moreover, the association between plasma TNF-α levels and suicide accompanied with MDD is entirely unknown. To elucidate these relationships, in the present study, 64 first-episode drug-naïve MDD patients and 64 matched healthy controls were recruited. Total 61 MDD patients received 8-week venlafaxine treatment and they were divided into responders and non-responders according to the reduction rate of HRSD-17. Prior to venlafaxine treatment, both responders and non-responders shared a similar plasma TNF-α (p=0.33), which was significantly decreased following venlafaxine treatment (p<0.001, p=0.03, respectively). Compared to non-responders, the responder group had a greater reduction in TNF-α (p=0.01), which was associated with the greater reduction rate of HRSD-17 (B=1.02, p=0.01). In addition, the plasma TNF-α levels were equally higher in both suicidal and non-suicidal MDD patients (p=0.84) compared to the healthy controls on admission (p=0.001, p=0.03, respectively). Together, our data suggest that MDD per se rather than suicide is associated with the elevated plasma TNF-α, which can be inhibited with venlfaxine monotherapy. The extent of TNF-α reduction may be associated with the efficiency of venlafaxine.

  11. The effects of electroacupuncture on analgesia and peripheral sensory thresholds in patients with burn scar pain.

    PubMed

    Cuignet, Olivier; Pirlot, A; Ortiz, S; Rose, T

    2015-09-01

    The aim of this study is to observe if the effects of electro-acupuncture (EA) on analgesia and peripheral sensory thresholds are transposable from the model of heat pain in volunteers to the clinical setting of burn scar pain. After severe burns, pathological burn scars (PPBS) may occur with excruciating pain that respond poorly to treatment and prevent patients from wearing their pressure garments, thereby leading to unesthetic and function-limiting scars. EA might be of greater benefit in terms of analgesia and functional recovery, should it interrupt this vicious circle by counteracting the peripheral hyperalgesia characterizing PPBS. Therefore we enrolled 32 patients (22 males/10 females) aged of 46±11 years with clinical signs of PPBS and of neuropathic pain despite treatment. The study protocol consisted in 3 weekly 30-min sessions of standardized EA with extra individual needles in accordance to Traditional Chinese Medicine, in addition of previous treatments. We assessed VAS for pain and quantitative sensory testing (QST) twice: one week before and one after protocol. QST measured electrical thresholds for non-nociceptive A-beta fibers, nociceptive A-delta and C fibers in 2 dermatomes, respectively from the PPBS and from the contralateral pain-free areas. Based on heat pain studies, EA consisted in sessions at the extremity points of the main meridian flowing through PPBS (0.300s, 5Hz, sub noxious intensity, 15min) and at the bilateral paravertebral points corresponding to the same metameric level, 15min. VAS reduction of 3 points or below 3 on a 10 points scale was considered clinically relevant. Paired t-test compared thresholds (mean [SD]) and Wilcoxon test compared VAS (median [IQR]) pre and after treatment, significant p<0.05. The reduction of VAS for pain reached statistical but not clinical relevance (6.8 [3] vs. 4.5 [3.6]). This was due to a large subgroup of 14 non-responders whose VAS did not change after treatment (6.6 [2.7] vs. 7.2 [3

  12. New Insights in the Management of Antipsychotics in the Treatment of Schizophrenia in a Patient with Prolactinoma: A Case Report and Review of the Literature

    PubMed Central

    Santos Andrade, Elvis Henrique; Pan, Pedro Mario; da Silva, Paula F. Ramalho; Gadelha, Ary

    2010-01-01

    Prolactinomas are the commonest pituitary adenomas and the major pathological cause of hyperprolactinaemia. Symptomatic prolactinomas are treated mainly by dopamine agonists; surgery and radiotherapy are options for nonresponders. Schizophrenia treatment is based on antipsychotics, which acts mainly at serotonergic and dopaminergic systems. We report a case of a 39-year-old schizophrenic male patient that was diagnosed with a macroprolactinoma 8 years after his first psychotic episode. The association of Schizophrenia and prolactinoma represents a clinical challenge once the treatment of one disease can exacerbate the symptoms of the other. PMID:21076684

  13. A PRIM approach to predictive-signature development for patient stratification.

    PubMed

    Chen, Gong; Zhong, Hua; Belousov, Anton; Devanarayan, Viswanath

    2015-01-30

    Patients often respond differently to a treatment because of individual heterogeneity. Failures of clinical trials can be substantially reduced if, prior to an investigational treatment, patients are stratified into responders and nonresponders based on biological or demographic characteristics. These characteristics are captured by a predictive signature. In this paper, we propose a procedure to search for predictive signatures based on the approach of patient rule induction method. Specifically, we discuss selection of a proper objective function for the search, present its algorithm, and describe a resampling scheme that can enhance search performance. Through simulations, we characterize conditions under which the procedure works well. To demonstrate practical uses of the procedure, we apply it to two real-world data sets. We also compare the results with those obtained from a recent regression-based approach, Adaptive Index Models, and discuss their respective advantages. In this study, we focus on oncology applications with survival responses.

  14. Therapy of lupus nephritis: lessons learned from clinical research and daily care of patients

    PubMed Central

    2012-01-01

    Despite numerous randomized clinical trials over the last three decades for identifying the optimal treatment option for lupus nephritis, renal involvement still significantly impacts the survival and quality of life of patients with lupus and the search for the ideal immunosuppressive regimen is far from complete. The purpose of this review is to summarize the major recent achievements in the field. More specifically, the following topics will be discussed: intravenous cyclophosphamide versus mycophenolate mofetil (MMF) for induction; azathioprine versus MMF for maintenance; targeted therapies. The review will address clues for optimal global care, such as the need for complete initial evaluation, the importance of patient education, the unmasking of non-compliance to therapy, the reason for an early treatment switch in non-responding patients, the need for prolonged immunosuppression, optimal renal protection, and prevention of cardiovascular disease and other comorbidities. PMID:22293173

  15. The P3 event-related potential is a biomarker for the efficacy of vagus nerve stimulation in patients with epilepsy.

    PubMed

    De Taeye, Leen; Vonck, Kristl; van Bochove, Marlies; Boon, Paul; Van Roost, Dirk; Mollet, Lies; Meurs, Alfred; De Herdt, Veerle; Carrette, Evelien; Dauwe, Ine; Gadeyne, Stefanie; van Mierlo, Pieter; Verguts, Tom; Raedt, Robrecht

    2014-07-01

    Currently, the mechanism of action of vagus nerve stimulation (VNS) is not fully understood, and it is unclear which factors determine a patient's response to treatment. Recent preclinical experiments indicate that activation of the locus coeruleus noradrenergic system is critical for the antiepileptic effect of VNS. This study aims to evaluate the effect of VNS on noradrenergic signaling in the human brain through a noninvasive marker of locus coeruleus noradrenergic activity: the P3 component of the event-related potential. We investigated whether VNS differentially modulates the P3 component in VNS responders versus VNS nonresponders. For this purpose, we recruited 20 patients with refractory epilepsy who had been treated with VNS for at least 18 months. Patients were divided into 2 groups with regard to their reduction in mean monthly seizure frequency: 10 responders (>50 %) and 10 nonresponders (≤50 %). Two stimulation conditions were compared: VNS OFF and VNS ON. In each condition, the P3 component was measured during an auditory oddball paradigm. VNS induced a significant increase of the P3 amplitude at the parietal midline electrode, in VNS responders only. In addition, logistic regression analysis showed that the increase of P3 amplitude can be used as a noninvasive indicator for VNS responders. These results support the hypothesis that activation of the locus coeruleus noradrenergic system is associated with the antiepileptic effect of VNS. Modulation of the P3 amplitude should be further investigated as a noninvasive biomarker for the therapeutic efficacy of VNS in patients with refractory epilepsy.

  16. Usefulness of ultrasonographic measurement of the diameter of the inferior vena cava to predict responsiveness to intravascular fluid administration in patients with cancer

    PubMed Central

    Arredondo-Armenta, Juan M.; Guevara-García, Humberto; Barragán-Dessavre, Mireya; García-Guillén, Francisco J.; Sánchez-Hurtado, Luis A.; Córdova-Sánchez, Bertha; Bautista-Ocampo, Andoreni R.; Herrera-Gómez, Angel; Meneses-García, Abelardo

    2016-01-01

    We conducted an observational, longitudinal prospective study in which we measured the diameters of the inferior vena cava (IVC) of 47 patients using ultrasonography. The aim of our study was to assess the state of blood volume and to determine the percentage of patients who responded to intravascular volume expansion. Only 17 patients (36%) responded to fluid management. A higher number of responding patients had cardiovascular failure compared with nonresponders (82% vs. 50%, P = 0.03). Among the patients with cardiovascular failure, the probability of finding responders was 4.6 times higher than that of not finding responders (odds ratio, 4.66; 95% confidence interval, 1.10–19.6; P = 0.04). No significant difference was observed in the mortality rate between the two groups (11% vs. 23%, P = 0.46). In conclusion, responding to intravascular volume expansion had no impact on patient survival in the intensive care unit. PMID:27695165

  17. Dynamics of hepatitis B virus quasispecies heterogeneity and virologic response in patients receiving low-to-moderate genetic barrier nucleoside analogs.

    PubMed

    Peveling-Oberhag, J; Herrmann, E; Kronenberger, B; Farnik, H; Susser, S; Sarrazin, C; Zeuzem, S; Hofmann, W-P

    2013-04-01

    We characterized the early dynamics of hepatitis B virus (HBV) quasispecies evolution during the first weeks of antiviral therapy with low-to-moderate genetic barrier antiviral drugs and associated these data with antiviral response patterns. Fifteen chronic hepatitis B patients (men, 10; mean age, 34; HBeAg positive, 6) who received lamivudine or telbivudine for at least 52 weeks were included. HBV DNA was extracted from serum, and a 910-bp fragment covering domains A-F of the reverse transcriptase region was amplified, cloned and sequenced. Parameters of quasispecies heterogeneity, genetic diversity and complexity were calculated and were correlated with complete virologic response, defined as undetectable HBV DNA at week 52. Nine patients achieved complete virologic response during the observational period. While baseline HBV DNA levels and HBeAg status were associated with virologic response, baseline quasispecies complexity and diversity of responders showed no significant difference to those of nonresponders (P > 0.05). However, at week 4, quasispecies complexity of nonresponders was significantly higher compared with that of responders on the nucleotide level (P = 0.01) and the aa level (P = 0.04). The number of synonymous substitutions per synonymous site dropped significantly in responders at week 4 (P = 0.04), while there was no difference in nonresponders. The HBV quasispecies complexity at the early stage of antiviral therapy (week 4) with the low-to-moderate genetic barrier nucleoside analogs lamivudine or telbivudine was associated with subsequent virologic response. Further studies are needed to confirm HBV quasispecies evolution as additional predictive marker for beneficial treatment outcome.

  18. Why QRS Duration Should Be Replaced by Better Measures of Electrical Activation to Improve Patient Selection for Cardiac Resynchronization Therapy.

    PubMed

    Engels, Elien B; Mafi-Rad, Masih; van Stipdonk, Antonius M W; Vernooy, Kevin; Prinzen, Frits W

    2016-08-01

    Cardiac resynchronization therapy (CRT) is a well-known treatment modality for patients with a reduced left ventricular ejection fraction accompanied by a ventricular conduction delay. However, a large proportion of patients does not benefit from this therapy. Better patient selection may importantly reduce the number of non-responders. Here, we review the strengths and weaknesses of the electrocardiogram (ECG) markers currently being used in guidelines for patient selection, e.g., QRS duration and morphology. We shed light on the current knowledge on the underlying electrical substrate and the mechanism of action of CRT. Finally, we discuss potentially better ECG-based biomarkers for CRT candidate selection, of which the vectorcardiogram may have high potential.

  19. The role of IL-28, IFN-γ, and TNF-α in predicting response to pegylated interferon/ribavirin in chronic HCV patients.

    PubMed

    Abdou, Asmaa Gaber; Asaad, Nancy Youssef; Ehsan, Nermin; Eltahmody, Mohammad; El-Sabaawy, Maha Mohamed; Elkholy, Shimaa; Elnaidany, Nada Farag

    2015-01-01

    The primary goal of HCV therapy is to achieve a sustained virological response (SVR). Many host and viral factors influence the treatment response. Cytokines play an important role in the defense against viral infections, where successful treatment of hepatitis C depends on a complex balance between pro- and anti-inflammatory responses. In the present study, we investigated the relationship between the presence and percentage of some cytokines (IL-28, IFN-γ, and TNF-α) regarding different clinicopathological parameters including response to therapy in chronic HCV patients using immunohistochemical technique. This study was carried out on 64 chronic HCV patients (34 responders and 30 non-responders). Of cases, 54% showed IL-28 expression, which was associated with low AST (p = 0.002) and low HAI score (p = 0.006). Of cases, 67 and 45% showed IFN-γ and TNF-α expression, respectively, where the median percentage of TNF-α expression was higher in grade II spotty necrosis compared to grade I. Some inflammatory cytokines expressed by intrahepatic inflammatory cells in chronic HCV patients promote inflammation and injury (pro-inflammatory) such as TNF-α. Other cytokines aid in resolving inflammation and injury (anti-inflammatory) such as IL-28. The balance between these cytokines will determine the degree of inflammatory state. None of the investigated cytokines proved its clear cut role in affecting response to therapy, however, their levels varied between responders and non-responders for further investigations to clarify.

  20. Recovery of Adrenal Function in Patients with Glucocorticoids Induced Secondary Adrenal Insufficiency

    PubMed Central

    Baek, Jong Ha; Kim, Soo Kyoung; Jung, Jung Hwa; Hahm, Jong Ryeal

    2016-01-01

    Background The chronic use of glucocorticoids (GC) suppresses function of the hypothalamic-pituitary-adrenal axis and often results in secondary adrenal insufficiency (AI). The present study aimed to determine the recovery rate of adrenal function in patients with secondary AI within 1 to 2 years and to assess the factors predictive of adrenal function recovery. Methods This was a retrospective observational study that enrolled patients diagnosed with GC-induced secondary AI between 2007 and 2013. AI was defined by peak serum cortisol levels <18 µg/dL during a standard-dose short synacthen test (SST). A follow-up SST was performed after 1 to 2 years, and responders were defined as those with adrenocorticotropic hormone (ACTH)-stimulated peak serum cortisol levels ≥18 µg/dL. Results Of the total 34 patients diagnosed with GC-induced secondary AI at first, 20 patients (58.8%) recovered normal adrenal function by the time of the follow-up SST (median follow-up period, 16.5 months). Although the baseline serum ACTH and cortisol levels at the first SST did not differ between responders and non-responders, the incremental cortisol response during the first SST was higher in responders than that of non-responders (7.88 vs. 3.56, P<0.01). Additionally, higher cortisol increments during the first SST were an independent predictive factor of the adrenal function recovery (odds ratio, 1.58; 95% confidence interval, 1.02 to 2.46; P<0.05). Conclusion In the present study, adrenal function recovery was achieved frequently in patients with GC-induced secondary AI within 1 to 2 years. Additionally, an incremental cortisol response at the first SST may be an important predictive factor of adrenal function recovery. PMID:26676337

  1. Can hydroxyurea serve as a free radical scavenger and reduce iron overload in β-thalassemia patients?

    PubMed

    Italia, Khushnooma; Chandrakala, S; Ghosh, Kanjaksha; Colah, Roshan

    2016-09-01

    In this study, we hypothesize that hydroxyurea could provide an additional benefit as a free radical scavenger and/or iron chelator in β-thalassemia patients with iron overload. Twenty-one β-thalassemia intermedia patients who presented between 3 and 17 years but later required regular blood transfusions were enrolled for hydroxyurea therapy for a year. Fourteen patients responded to the therapy with hemoglobin levels maintained above 7.5 g/dl without transfusions. Hydroxyurea was discontinued after 6 months in seven patients who did not respond to the therapy and had to be continued on regular blood transfusions. We observed a statistically significant decrease in serum ferritin levels from 4194 ± 4850 ng/ml to 2129 ± 2380 ng/ml among the responders and from 2955 ± 2909 ng/ml to 2040 ± 2432 ng/ml among the non-responders and statistically significant decrease in labile iron pool from 18678.7 ± 10067.4 mean fluorescence intensity (MFI) to 14888.5 ± 5284.0 MFI among responders and from 17986.3 ± 9079.8 MFI to 15634.8 ± 8976.9 MFI among the non-responders after therapy. Phosphatidylserine externalization also showed a statistically significant decrease from 44.2 ± 22.2 MFI to 16.6 ± 6.7 MFI among the responders and from 46.9 ± 33.1 MFI to 39.8 ± 7.4 MFI among the non-responders along with a statistically significant decrease in the levels of reactive oxygen species from 72.8 ± 35.5 MFI to 29.0 ± 8.3 MFI among the responders and from 80.9 ± 41.4 MFI to 40.5 ± 15.8 MFI among the non-responders after therapy. A statistically significant increase in reduced glutathione levels was also observed from 430.8 ± 201.1 MFI to 715.5 ± 292.4 MFI among the responders and from 359.6 ± 165.6 MFI to 450.3 ± 279.5 MFI among the non-responders after therapy. This suggests the possible additional role of hydroxyurea as a free radical scavenger and

  2. Identification and characterization of HPA-axis reactivity endophenotypes in a cohort of female PTSD patients.

    PubMed

    Zaba, Monika; Kirmeier, Thomas; Ionescu, Irina A; Wollweber, Bastian; Buell, Dominik R; Gall-Kleebach, Dominique J; Schubert, Christine F; Novak, Bozidar; Huber, Christine; Köhler, Katharina; Holsboer, Florian; Pütz, Benno; Müller-Myhsok, Bertram; Höhne, Nina; Uhr, Manfred; Ising, Marcus; Herrmann, Leonie; Schmidt, Ulrike

    2015-05-01

    Analysis of the function of the hypothalamic-pituitary-adrenal (HPA)-axis in patients suffering from posttraumatic stress disorder (PTSD) has hitherto produced inconsistent findings, inter alia in the Trier Social Stress Test (TSST). To address these inconsistencies, we compared a sample of 23 female PTSD patients with either early life trauma (ELT) or adult trauma (AT) or combined ELT and AT to 18 age-matched non-traumatized female healthy controls in the TSST which was preceded by intensive baseline assessments. During the TSST, we determined a variety of clinical, psychological, endocrine and cardiovascular parameters as well as expression levels of four HPA-axis related genes. Using a previously reported definition of HPA-axis responsive versus non-responsive phenotypes, we identified for the first time two clinically and biologically distinct HPA-axis reactivity subgroups of PTSD. One subgroup ("non-responders") showed a blunted HPA-axis response and distinct clinical and biological characteristics such as a higher prevalence of trauma-related dissociative symptoms and of combined AT and ELT as well as alterations in the expression kinetics of the genes encoding for the mineralocorticoid receptor (MR) and for FK506 binding protein 51 (FKBP51). Interestingly, this non-responder subgroup largely drove the relatively diminished HPA axis response of the total cohort of PTSD patients. These findings are limited by the facts that the majority of patients was medicated, by the lack of traumatized controls and by the relatively small sample size. The here for the first time identified and characterized HPA-axis reactivity endophenotypes offer an explanation for the inconsistent reports on HPA-axis function in PTSD and, moreover, suggest that most likely other factors than HPA-axis reactivity play a decisive role in determination of PTSD core symptom severity.

  3. Tics Moderate Sertraline, but Not Cognitive-Behavior Therapy Response in Pediatric Obsessive-Compulsive Disorder Patients Who Do Not Respond to Cognitive-Behavior Therapy

    PubMed Central

    Compton, Scott; Thomsen, Per Hove; Weidle, Bernhard; Dahl, Kitty; Nissen, Judith Becker; Torp, Nor Christian; Hybel, Katja; Melin, Karin Holmgren; Valderhaug, Robert; Wentzel-Larsen, Tore; Ivarsson, Tord

    2015-01-01

    Abstract Objective: The purpose of this study was to investigate whether the presence of tic disorder is negatively associated with sertraline (SRT) outcomes, but not with continued cognitive-behavioral therapy (CBT), in a sample of youth who were unresponsive to an initial full course of CBT. Methods: In the Nordic Long-Term OCD Study, children and adolescents with OCD who were rated as nonresponders to 14 weeks of open-label CBT were randomized to continued CBT (n=28) or SRT treatment (n=22) for an additional 16 weeks of treatment. We investigated whether the presence or absence of comorbid tic disorder moderated treatment outcomes on the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Results: Twelve out of 50 (24.0%) participants were diagnosed with comorbid tic disorder, with 7 receiving continued CBT and 5 receiving SRT, respectively. In patients without tic disorder, results showed no significant between-group differences on average CY-BOCS scores. However, in patients with comorbid tic disorder, those who received SRT had significantly lower average CY-BOCS scores than those who received continued CBT. Conclusions: Children and adolescents with OCD and comorbid tic disorder, who are nonresponders to an initial 14 week course of CBT, may benefit more from a serotonin reuptake inhibitor (SRI) than from continued CBT. PMID:26091197

  4. NLRP3 inflammasome is associated with the response to IFN-β in patients with multiple sclerosis

    PubMed Central

    Malhotra, Sunny; Río, Jordi; Urcelay, Elena; Nurtdinov, Ramil; Bustamante, Marta F; Fernández, Oscar; Oliver, Begoña; Zettl, Uwe; Brassat, David; Killestein, Joep; Lechner-Scott, Jeannette; Drulovic, Jelena; Chan, Andrew; Martinelli-Boneschi, Filippo; García-Merino, Antonio; Montalban, Xavier

    2015-01-01

    Evidence exists for a potential modulation of inflammasome activity by interferon beta. Here, we investigated the roles of inflammasomes [absent in melanoma 2 (AIM2); NLR family, CARD domain containing 4 (NLRC4); NLR family, pyrin domain containing 1 and 3 (NLRP1 and NLRP3)] and related cytokines (IL1B, IL10, IL18) in the response to interferon beta in patients with relapsing-remitting multiple sclerosis. Ninety-seven patients treated with interferon beta were classified into responders and non-responders according to clinical criteria after 24 months and clinical-radiological criteria after 12 months of treatment. Messenger RNA expression levels of inflammasomes and cytokines were determined by real-time polymerase chain reaction in peripheral blood mononuclear cells collected before treatment with interferon beta. In a subgroup of patients, NLRP3 and IL1B expression was also determined after 3 months (n = 32) and 12 months (n = 20) of interferon beta treatment. A polymorphism located in the NLRP3 gene, rs35829419, was genotyped in 789 multiple sclerosis patients treated with interferon beta. Baseline mRNA expression levels for NLRP3 and IL1B were increased in peripheral blood mononuclear cells from non-responders compared to responders classified according to clinical criteria after 24 months (P = 0.02 and P = 0.001, respectively). No significant differences were observed for other inflammasomes and related cytokines. Differences in NLRP3 and IL1B expression remained significant following a clinical-radiological classification after 12 months (P = 0.007 and P = 0.02, respectively). After treatment with interferon beta, NLRP3 and IL1B expression was increased in responders but unchanged in non-responders. A trend for association was observed between rs35829419 and interferon beta response (pM-H = 0.08). These results point to a role of the NLRP3 inflammasome and its related cytokine IL1B in the response to interferon beta in patients with relapsing

  5. Efficacy and Factors Affecting Outcome of Gemcitabine Concurrent Chemoradiotherapy in Patients With Locally Advanced Pancreatic Cancer

    SciTech Connect

    Huang, P.-I.; Chao, Yee; Li, C.-P.; Lee, R.-C.; Chi, K.-H.; Shiau, C.-Y.; Wang, L.-W.; Yen, S.-H.

    2009-01-01

    Purpose: To evaluate the efficacy and prognostic factors of gemcitabine (GEM) concurrent chemoradiotherapy (CCRT) in patients with locally advanced pancreatic cancer. Methods and Materials: Between January 2002 and December 2005, 55 patients with locally advanced pancreatic cancer treated with GEM (400 mg/m{sup 2}/wk) concurrently with radiotherapy (median dose, 50.4 Gy; range, 26-61.2) at Taipei Veterans General Hospital were enrolled. GEM (1,000 mg/m{sup 2}) was continued after CCRT as maintenance therapy once weekly for 3 weeks and repeated every 4 weeks. The response, survival, toxicity, and prognostic factors were evaluated. Results: With a median follow-up of 10.8 months, the 1- and 2-year survival rate was 52% and 19%, respectively. The median overall survival (OS) and median time to progression (TTP) was 12.4 and 5.9 months, respectively. The response rate was 42% (2 complete responses and 21 partial responses). The major Grade 3-4 toxicities were neutropenia (22%) and anorexia (19%). The median OS and TTP was 15.8 and 9.5 months in the GEM CCRT responders compared with 7.5 and 3.5 months in the nonresponders, respectively (both p < 0.001). The responders had a better Karnofsky performance status (KPS) (86 {+-} 2 vs. 77 {+-} 2, p = 0.002) and had received a greater GEM dose intensity (347 {+-} 13 mg/m{sup 2}/wk vs. 296 {+-} 15 mg/m{sup 2}/wk, p = 0.02) than the nonresponders. KPS and serum carbohydrate antigen 19-9 were the most significant prognostic factors of OS and TTP. Conclusion: The results of our study have shown that GEM CCRT is effective and tolerable for patients with locally advanced pancreatic cancer. The KPS and GEM dose correlated with response. Also, the KPS and CA 19-9 level were the most important factors affecting OS and TTP.

  6. Molecular epidemiology, genotype-phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria.

    PubMed

    Aldámiz-Echevarría, Luis; Llarena, Marta; Bueno, María A; Dalmau, Jaime; Vitoria, Isidro; Fernández-Marmiesse, Ana; Andrade, Fernando; Blasco, Javier; Alcalde, Carlos; Gil, David; García, María C; González-Lamuño, Domingo; Ruiz, Mónica; Ruiz, María A; Peña-Quintana, Luis; González, David; Sánchez-Valverde, Felix; Desviat, Lourdes R; Pérez, Belen; Couce, María L

    2016-08-01

    Phenylketonuria (PKU), the most common inborn error of amino acid metabolism, is caused by mutations in the phenylalanine-4-hydroxylase (PAH) gene. This study aimed to assess the genotype-phenotype correlation in the PKU Spanish population and the usefulness in establishing genotype-based predictions of BH4 responsiveness in our population. It involved the molecular characterization of 411 Spanish PKU patients: mild hyperphenylalaninemia non-treated (mild HPA-NT) (34%), mild HPA (8.8%), mild-moderate (20.7%) and classic (36.5%) PKU. BH4 responsiveness was evaluated using a 6R-BH4 loading test. We assessed genotype-phenotype associations and genotype-BH4 responsiveness in our population according to literature and classification of the mutations. The mutational spectrum analysis showed 116 distinct mutations, most missense (70.7%) and located in the catalytic domain (62.9%). The most prevalent mutations were c.1066-11G>A (9.7%), p.Val388Met (6.6%) and p.Arg261Gln (6.3%). Three novel mutations (c.61-13del9, p.Ile283Val and p.Gly148Val) were reported. Although good genotype-phenotype correlation was observed, there was no exact correlation for some genotypes. Among the patients monitored for the 6R-BH4 loading test: 102 were responders (87, carried either one or two BH4-responsive alleles) and 194 non-responders (50, had two non-responsive mutations). More discrepancies were observed in non-responders. Our data reveal a great genetic heterogeneity in our population. Genotype is quite a good predictor of phenotype and BH4 responsiveness, which is relevant for patient management, treatment and follow-up.

  7. Gait Biomechanics and Patient-Reported Function as Predictors of Response to a Hip Strengthening Exercise Intervention in Patients with Knee Osteoarthritis

    PubMed Central

    Kobsar, Dylan; Osis, Sean T.; Hettinga, Blayne A.; Ferber, Reed

    2015-01-01

    Objective Muscle strengthening exercises have been shown to improve pain and function in adults with mild-to-moderate knee osteoarthritis, but individual response rates can vary greatly. Predicting individuals who respond and those who do not is important in developing a more efficient and effective model of care for knee osteoarthritis (OA). Therefore, the purpose of this study was to use pre-intervention gait kinematics and patient-reported outcome measures to predict post-intervention response to a 6-week hip strengthening exercise intervention in patients with mild-to-moderate knee OA. Methods Thirty-nine patients with mild-to-moderate knee osteoarthritis completed a 6-week hip-strengthening program and were subgrouped as Non-Responders, Low-Responders, or High-Responders following the intervention based on their change in Knee injury Osteoarthritis Outcome Score (KOOS). Predictors of responder subgroups were retrospectively determined from baseline patient-reported outcome measures and kinematic gait parameters in a discriminant analysis of principal components. A 3–4 year follow-up on 16 of the patients with knee OA was also done to examine long-term changes in these parameters. Results A unique combination of patient-reported outcome measures and kinematic factors was able to successfully subgroup patients with knee osteoarthritis with a cross-validated classification accuracy of 85.4%. Lower patient-reported function in daily living (ADL) scores and hip frontal plane kinematics during the loading response were most important in classifying High-Responders from other sub-groups, while a combination of hip, knee, ankle kinematics were used to classify Non-Responders from Low-Responders. Conclusion Patient-reported outcome measures and objective biomechanical gait data can be an effective method of predicting individual treatment success to an exercise intervention. Measuring gait kinematics, along with patient-reported outcome measures in a clinical setting

  8. Coinfection of Leishmania guyanensis and Human Immunodeficiency Virus-Acquired Immune Deficiency Syndrome: Report of a Case of Disseminated Cutaneous Leishmaniasis in Ecuador.

    PubMed

    Calvopina, Manuel; Aguirre, Cristina; Cevallos, William; Castillo, Alberto; Abbasi, Ibrahim; Warburg, Alon

    2017-02-13

    Reported herein is the first case of Leishmania-human immunodeficiency virus (HIV) coinfection in Ecuador. In Ecuador, HIV infections overlap endemic areas of leishmaniasis. Immunosuppression is a well-established risk factor for developing severe disease. This is a severe case of a 32-year-old man presenting with disseminated pleomorphic ulcers, papules, and cutaneous plaque-like lesions over his whole body. Numerous amastigotes were observed in both skin scrapings and biopsies. The sequence of the cytochrome b gene confirmed the presence of Leishmania guyanensis The patient was treated but failed to respond to meglumine antimoniate and amphotericin B. Six months later, the patient died due to bacterial septic shock.

  9. [Expert recommendations for the diagnosis and treatment of chronic hepatitis C infection in the prison setting].

    PubMed

    Saiz de la Hoya-Zamácola, Pablo; Marco-Mouriño, Andrés; Clemente-Ricote, Gerardo; Portilla-Sogorb, Joaquín; Boix-Martínez, Vicente; Núñez-Martínez, Oscar; Reus-Bañuls, Sergio; Teixidó i Pérez, Nuria

    2006-11-01

    The prevalence of HCV infection in Spanish prisons is very high (38.5%). The characteristics of the infected patients, particularly the high rate of HIV coinfection, makes it very likely that the morbidity and mortality produced by serious liver disease secondary to this infection will increase considerably in the coming years. A group of Spanish experts with experience in patients who are inmates has been invited to establish a series of recommendations for the diagnosis and treatment of chronic hepatitis C infection in Spanish prisons.

  10. Angina Relief by Ranolazine Identifies False-Negative SPECT Myocardial Perfusion Scans in Patients with Coronary Disease Demonstrated by Coronary Angiography

    PubMed Central

    Murray, Gary L.

    2014-01-01

    Normal myocardial perfusion imaging (MPI) reduces intermediate- or high-risk pretest probability patients to low- or intermediate-risk posttest probability, respectively, for coronary disease (CD). Since ranolazine (RAN) relieves only angina, anginal patients with normal MPI whose angina is relieved by RAN present a significant dilemma. The purpose of this retrospective chart review was to confirm the impression that coronary angiography (CA) is indicated in patients whose class 3 to 4 angina is relieved by RAN, but have normal myocardial single-photon emission computed tomography (SPECT) MPIs. Charts of patients with stable class 3 to 4 angina (typical and atypical) and normal MPIs (left ventricular ejection fraction [LVEF] ≥50% and segmental score = 0) were reviewed. CA was done on all the patients with complete angina relief taking RAN, as well as nonresponders whose anginal etiology could not be explained. Stenoses were considered flow-restrictive when more than 70% diameter stenosis is observed by quantitative CA, or, when 50 to 70%, fractional flow reserve (FFR) measured ≤0.80. RAN relieved angina in 36 of 54 (67%) patients. Of the known cases, 25 of these 36 (69%) had 43 stenoses ≥50% (mean = 66%): 15 (60%) had 1 vessel disease; 9 (36%) had multivessel disease; 18 (72%) had left anterior descending (LAD) disease; 1 (4%) had left main disease. Twenty one of 43 (49%) stenosis were > 70%; 22 (51%) stenoses were 50 to 70% and required FFR measurement. Twenty nine of 43 stenoses (67%) were considered flow-restrictive in 18 of these 25 (72%) patients. Eight RAN nonresponders with no explanation for angina had no CD at CA. RAN angina relief is invaluable in identifying falsely negative SPECT MPI, and 50% of these patients have flow-restrictive stenoses. PMID:25317027

  11. Rapid Decrease of Intact Parathyroid Hormone Could Be a Predictor of Better Response to Cinacalcet in Hemodialysis Patients

    PubMed Central

    Kim, Jwa-Kyung; Kwon, Young Joo; Kim, Soo Wan; Kim, Yeong-Hoon; Park, Cheol Whee; Choi, Kyu Bok; Hwang, Seung Duk

    2013-01-01

    Purpose Cinacalcet is effective for treating refractory secondary hyperparathyroidism (SHPT), but little is known about the response rates and clinical factors influencing the response. Materials and Methods A prospective, single-arm, multi-center study was performed for 24 weeks. Cinacalcet was administered to patients with intact parathyroid hormone (iPTH) level greater than 300 pg/mL. Cinacalcet was started at a dose of 25 mg daily and titrated until 100 mg to achieve a serum iPTH level <300 pg/mL (primary end point). Early response to cinacalcet was defined as a decrease of iPTH more than 50% within one month. Results Fifty-seven patients were examined. Based on the magnitude of iPTH decrease, patients were divided into responder (n=47, 82.5%) and non-responder (n=10, 17.5%) groups. Among the responders, 38 achieved the primary end point, whereas 9 patients showed a reduction in serum iPTH of 30% or more, but did not reach the primary end point. Compared to non-responders, responders were significantly older (p=0.026), female (p=0.041), and diabetics (p<0.001). Additionally, early response was observed more frequently in the responders (30/47, 63.8%), of whom the majority (27/30, 90.0%) achieved the primary end point. Multivariate analysis showed that lower baseline iPTH levels [odds ratio (OR) 0.96, 95% confidence interval (CI) 0.93-0.99], the presence of diabetes (OR 46.45, CI 1.92-1125.6) and early response (OR 21.54, CI 2.94-157.7) were significant clinical factors affecting achievement of iPTH target. Conclusion Cinacalcet was effective in most hemodialysis patients with refractory SHPT. The presence of an early response was closely associated with the achievement of target levels of iPTH. PMID:23364981

  12. D-Dimer Plasma Levels Parallel the Clinical Response to Omalizumab in Patients with Severe Chronic Spontaneous Urticaria.

    PubMed

    Asero, Riccardo; Marzano, Angelo V; Ferrucci, Silvia; Cugno, Massimo

    2017-01-01

    Omalizumab is very effective in the majority of patients with severe chronic spontaneous urticaria (CSU), but its mechanism of action is still unclear. In CSU the coagulation cascade is activated with an intensity that parallels the disease severity, and elevated plasma D-dimer levels are associated with a poor response to both antihistamines and cyclosporin. We measured D-dimer plasma levels before and after the first administration of omalizumab in 32 patients with severe CSU. A number of clinical and laboratory parameters were recorded, including the urticaria activity score, presence of angioedema, disease duration, C-reactive protein, anti-nuclear, and anti-thyroid antibodies. Baseline D-dimer levels were elevated in 19 (59%) cases. Omalizumab induced a complete response in 25 patients (78%), in most cases already after the first administration. At baseline, 14/25 responders had increased D-dimer plasma levels versus 5/7 non-responders. All responders showed a dramatic decrease of D-dimer plasma levels after the first administration of the drug (from 1,024 ± 248 [mean ± SE] to 251 ± 30 ng/mL; p = 0.003). In contrast, non-responders did not show any reduction in D-dimer levels after omalizumab administration (from 787 ± 206 to 1,230 ± 429 ng/mL; p = ns). In conclusion, plasma levels of D-dimer are frequently elevated in patients with severe CSU before omalizumab administration and decrease according to the clinical response of the disease to the drug, suggesting a possible effect of omalizumab on coagulation activation and fibrin degradation in a subset of CSU patients.

  13. Clinical Response and Outcome in Patients with Multidrug Resistant Gram-negative Infections

    PubMed Central

    Malekolkottab, Masoume; Shojaei, Lida; Khalili, Hossein; Doomanlou, Mahsa

    2017-01-01

    Objective: In this study, frequency and antimicrobial sensitivity pattern of multidrug resistant (MDR) microorganisms were evaluated in a referral teaching hospital in Iran. Methods: Patients with MDR Gram-negative pathogens were followed during the course of hospitalization. Demographic data, baseline diseases, type of biological sample, isolated microorganism, type of infection, antibiotic regimen before the availability of the culture result and change in the antibiotic regimen following receiving the antibiogram results, response to the treatment regimen, and duration of hospitalization and patient's outcome were considered variables for each recruited patient. Findings: In 71% of the patients, antibiotic regimens were changed according to the antibiogram results. A carbapenem alone or plus amikacin or ciprofloxacin were selected regimens for patients with extended-spectrum beta-lactamase (ESBL) infections. For patients with probable carbapenem-resistant Enterobacteriaceae infections, a carbapenem plus colistin was the most common antibiotic regimen. Clinical response was detected in 54.5% of the patients who were treated based on the antibiogram results. Clinical response was higher in the ESBL producers (ESBL-P) than the non-ESBL-P infections (75% vs. 52%). However, this difference was not significant (P = 0.09). Most nonresponders (80%) had sepsis due to Klebsiella species. Finally, 41.9% of the patients were discharged from the hospital and 58.2% died. Conclusion: Same as other countries, infections due MDR microorganisms is increasing in the recent years. This type of resistance caused poor clinical response and high rate mortality in the patients. PMID:28331866

  14. Iowa dentists' involvement in care for patients who are homebound.

    PubMed

    Watkins, Catherine; Ettinger, Ronald L; Cowen, Howard; Qian, Fang; Dawson, Deborah V

    2012-01-01

    This study investigated the frequency of Iowa dentists' provision of in-office and out-of-office dental care for people who are homebound, as well as comparing the practice and educational characteristics among dentists who did and did not provide care for patients who were homebound. The authors mailed a survey form to all licensed dentists on the Iowa State Health Professional license database (n = 1,168), excluding pediatric dentists and orthodontists. A second mailing was sent to all nonrespondents four months later, resulting in 638 returned forms for a 54.6% response rate. The questionnaire included two outcome responses associated with the treatment in the dentist's office or in the patient's home for patients who are homebound. About 40% of Iowa dentists reported providing care in the office to patients who are homebound, but care outside of the office was provided by fewer dentists (6%) who had more years of practice experience. These results suggest an increased sense of professional or community responsibility among these older Iowa dentists. Education efforts may increase homebound care and more involvement of younger dentists.

  15. The TNFRSF1B rs1061622 polymorphism (p.M196R) is associated with biological drug outcome in Psoriasis patients.

    PubMed

    González-Lara, Leire; Batalla, Ana; Coto, Eliecer; Gómez, Juan; Eiris, Noemí; Santos-Juanes, Jorge; Queiro, Rubén; Coto-Segura, Pablo

    2015-07-01

    Genetic factors are involved not only in the overall risk of suffering psoriasis, but also in their clinical characteristics and eventually in drug outcome. Biological therapies have dramatically improved the prognosis of Psoriasis. However, these treatments are very expensive and patients often exhibit a heterogeneous response that could be partially attributed to their genetic background. Thus, the research for genetic markers in psoriatic patients that could predict a poor response to biological therapies is an important issue. Our aim was to evaluate the effect of DNA variants at the "TNFα pathway" that could affect the risk of developing Psoriasis or the response to biological therapies among these patients. The genetic association study included a total of 518 Psoriatic patients and 480 healthy controls. Ninety of these patients received biological treatment and based on the change in the PASI score after 24 weeks were classified as good (PASI score ≥75%), intermediate (PASI 50-75), and non-responders (PASI <50). Next generation sequencing (NGS) with semiconductor-array technology was used to identify the nucleotide variants in the TNF α, TNFRSF1A and TNFRSF1B, and we only found three missense amino acid changes, all in TNFRSF1B. Interestingly, we found a significantly higher frequency of rs1061622 G carriers among CW6-positive patients (p = 0.004; OR = 1.69, 95% CI = 1.18-2.41). Allele G (p.196R) carriers were significantly more frequent in the non-responder group (56%) (p = 0.05). In conclusion, we report a significant association between the TNFRSF1B p.M196R variant and the risk for psoriasis and the response to treatment with anti-TNF or anti-Il-12/Il-23. The genotyping of this polymorphism could help to optimize the treatment by identifying patients with a likely poor response to biological drugs.

  16. Persistence of immunologic memory in long-term hemodialysis patients and healthcare workers given hepatitis B vaccine: role of a booster dose on antibody response.

    PubMed

    Peces, R; Laurés, A S

    2001-10-01

    Hepatitis B (HB) vaccine is effective in producing protection against HB virus infection, but the persistence of immunity remains largely unknown. Seventy-six hemodialysis (HD) patients (60 after primary HB vaccination and 16 with natural immunity) and 46 healthcare workers (32 after primary HB vaccination and 14 with natural immunity) were followed up for 10 years to evaluate the persistence of immunity. Ten years after vaccination, the analysis showed a lower seroconversion rate (38 vs. 75%, p < 0.001) in HD patients as compared with healthcare workers. In the follow-up period, the protective immunity developed through HB virus infection also showed a lower seroconversion rate (44 vs. 86%, p < 0.025) in HD patients as compared with healthcare workers. To assess the status of immunologic memory, we administered a booster dose of HB vaccine 3-12 years (mean 6.7 +/- 0.6 years) after primary vaccination in a selected group of 37 HD patients who presented a decline of their antibodies or were nonresponders. In another group of 12 healthcare workers who had a decline of their antibodies, we also administered a booster dose of HB vaccine 5-8 years (mean 5.8 +/- 0.3 years) after primary vaccination. Nineteen of the 37 HD patients (51%) presented an anamnestic response to the booster dose, and 15 of these (40%) were high responders. All of the healthcare workers responded to the booster dose with a high antibody response. We conclude that patients undergoing HD not only have lower rates of immunization to HB than healthy adults, but also that these are frequently transient. Booster doses after a primary course of vaccine are effective in about the half of HD patients who presented a decline of their antibodies or were nonresponders but whether they are necessary is unclear. The majority of healthcare workers continue to have high levels of protective HBs antibody for at least 10 years and routine boosters are not required.

  17. Experience of Varied Presentation of Chronic Progressive Disseminated Histoplasmosis in Immunocompetent Patients: A Diagnostic Conundrum

    PubMed Central

    Ghosh, Roumi; Mishra, Pranshu; Sen, Sumit; Maiti, Prasanta Kumar; Chatterjee, Govinda

    2016-01-01

    We report two cases of chronic progressive disseminated histoplasmosis with unusual and rare clinical picture in a patient with no underlying risk factor. One 50-year-old male, presented with hoarseness of voice, chronic cough, with a history of nonresponding anti-tubercular therapy, revealed mucocutaneous lesions on examination. Fungating vocal cord lesions were visualized on bronchoscopy, raised suspicion of carcinoma. The second case, a 22-year-old female, referred to hospital with suspected vasculitis, with complaints of “off and on” fever with decreased oral intake, arthralgia, who later developed generalized nodular skin eruptions. On investigation, human immunodeficiency virus test was found to be negative in both the cases. Histopathological findings of skin biopsy, adrenal and bone marrow aspirates raised suspicion, whereas fungal cultures confirmed Histoplasma infection. Although diagnosis was delayed, but both of them were successfully treated with amphotericin B. PMID:27688460

  18. Response as a predictor of survival in patients with recurrent glioblastoma treated with bevacizumab

    PubMed Central

    Prados, Michael; Cloughesy, Timothy; Samant, Meghna; Fang, Liang; Wen, Patrick Y.; Mikkelsen, Tom; Schiff, David; Abrey, Lauren E.; Yung, W.K. Alfred; Paleologos, Nina; Nicholas, Martin K.; Jensen, Randy; Vredenburgh, James; Das, Asha; Friedman, Henry S.

    2011-01-01

    Development of effective therapies for recurrent glioblastoma multiforme (GBM) and reliable, timely evaluation of their benefit are needed. Understanding the relationship between objective response (OR) and survival is important for determining whether OR can provide an early signal of treatment activity in clinical trials. We performed a landmark analysis to evaluate the association between OR and survival at 9, 18, and 26 weeks for 167 patients with recurrent GBM who participated in BRAIN, a phase II trial that evaluated efficacy of bevacizumab alone or in combination with irinotecan, using the Cox regression models adjusted for age, baseline Karnofsky performance score, first vs second relapse, and treatment arm. Hazard ratios (HRs) and P-values for survival between responders and nonresponders were calculated. Additional analyses were performed to test robustness, validity, fit, and accuracy of the models. The relationships between progression-free survival (PFS) and survival and between OR and PFS were also explored. There were 55 responders and 112 nonresponders across the 2 treatment arms in BRAIN. OR status at 9, 18, and 26 weeks was a statistically significant predictor of survival (HR ≤ 0.52, P < .01). PFS was also a statistically significant predictor of survival at each landmark (HR ≤ 0.25, P < .0001). The association between OR and PFS was not statistically significant, likely due to inadequate statistical power for the analysis. Clarifying the relationship of OR and survival is important for determining whether OR can be a reliable predictor of the benefit of a therapeutic agent in patients with recurrent GBM. PMID:21084434

  19. QEEG Theta Cordance in the Prediction of Treatment Outcome to Prefrontal Repetitive Transcranial Magnetic Stimulation or Venlafaxine ER in Patients With Major Depressive Disorder.

    PubMed

    Bares, Martin; Brunovsky, Martin; Novak, Tomas; Kopecek, Miloslav; Stopkova, Pavla; Sos, Peter; Höschl, Cyril

    2015-04-01

    The aims of this double-blind study were to assess and compare the efficacy of quantitative electroencephalographic (QEEG) prefrontal theta band cordance in the prediction of response to 4-week, right, prefrontal, 1-Hz repetitive transcranial magnetic stimulation (rTMS) or venlafaxine ER in patients with major depressive disorder (MDD). Prefrontal QEEG cordance values of 50 inpatients (25 subjects in each group) completing 4 weeks of the study were obtained at baseline and after 1 week of treatment. Depressive symptoms were assessed using Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline and at week 1 and 4. Treatment response was defined as a ≥50% reduction in baseline MADRS total score. All responders (n = 9) and 6 of 16 nonresponders in the rTMS group had reduced cordance at week 1 (P < .01). Reduction of theta cordance value at week 1 was detected in all responders (n = 10) to venlafaxine ER, but only in 4 of 15 nonresponders (P = .005). The comparison of the areas under the curve of cordance change for prediction of response between rTMS (0.75) and venlafaxine ER (0.89) treated groups yielded no significant difference (P = .27). Our study indicates that prefrontal QEEG cordance is a promising tool not only for predicting the response to certain antidepressants but also to rTMS treatment, with comparable predictive efficacy for both therapeutic interventions.

  20. Development and validation of a gene expression score that predicts response to fulvestrant in breast cancer patients.

    PubMed

    Knudsen, Steen; Jensen, Thomas; Hansen, Anker; Mazin, Wiktor; Lindemann, Justin; Kuter, Irene; Laing, Naomi; Anderson, Elizabeth

    2014-01-01

    Fulvestrant is a selective estrogen receptor antagonist. Based on the measured growth inhibition of 60 human cancer cell lines (NCI60) in the presence of fulvestrant, as well as the baseline gene expression of the 60 cell lines, a gene expression score that predicts response to fulvestrant was developed. The score is based on 414 genes, 103 of which show increased expression in sensitive cell lines, while 311 show increased expression in the non-responding cell lines. The sensitivity genes primarily sense signaling through estrogen receptor alpha, whereas the resistance genes modulate the PI3K signaling pathway. The latter genes suggest that resistance to fulvestrant can be overcome by drugs targeting the PI3K pathway. The level of this gene expression score and its correlation with fulvestrant response was measured in a panel of 20 breast cancer cell lines. The predicted sensitivity matched the measured sensitivity well (CC = -0.63, P = 0.003). The predictor was applied to tumor biopsies obtained from a Phase II clinical trial. The sensitivity of each patient to treatment with fulvestrant was predicted based on the RNA profile of the biopsy taken before neoadjuvant treatment and without knowledge of the subsequent response. The prediction was then compared to clinical response to show that the responders had a significantly higher sensitivity prediction than the non-responders (P = 0.01). When clinical covariates, tumor grade and estrogen receptor H-score, were included in the prediction, the difference in predicted senstivity between responders and non-responders improved (P = 0.003). Using a pre-defined cutoff to separate patients into predicted sensitive and predicted resistant yielded a positive predictive value of 88% and a negative predictive value of 100% when compared to clinical data. We conclude that pre-screening patients with the new gene expression predictor has the potential to identify those postmenopausal women with locally advanced

  1. Estimating the monetary value of the annual productivity gained in patients with early rheumatoid arthritis receiving etanercept plus methotrexate: interim results from the PRIZE study

    PubMed Central

    Zhang, Wei; Bansback, Nick; Sun, Huiying; Pedersen, Ronald; Kotak, Sameer; Anis, Aslam H

    2015-01-01

    Objective To measure and value the impact of combined etanercept (ETN) and methotrexate (MTX) therapy on work productivity in patients with early rheumatoid arthritis (RA) over 52 weeks. Methods MTX- and biological-naïve patients with RA (symptom onset ≤12 months; Disease Activity Score based on a 28-joint count (DAS28) >3.2) received open-label ETN50/MTX for 52 weeks. The Valuation of Lost Productivity (VOLP) questionnaire, measuring paid and unpaid work productivity impacts, was completed approximately every 13 weeks. Bootstrapping methods were used to test changes in VOLP outcomes over time. One-year productivity impacts were compared between responders (DAS28 ≤3.2) at week 13 and non-responders using zero-inflated models for time loss and two-part models for total costs of lost productivity. Results 196 patients were employed at baseline and had ≥1 follow-up with VOLP. Compared with baseline, at week 52, patients gained 33.4 h per 3 months in paid work and 4.2 h per week in unpaid work. Total monetary productivity gains were €1322 per 3 months. Over the 1-year period, responders gained paid (231 h) and unpaid work loss (122 h) compared with non-responders, which amounted to a gain of €3670 for responders. Conclusions This is the first clinical trial to measure and value the impact of biological treatment on all the labour input components that affect overall productivity. Combination therapy with ETN50/MTX was associated with a significant productivity gain for patients with early RA who were still observed at week 52. Over the 1-year treatment period, responders at week 13 suffered significantly less productivity loss than non-responders suggesting this gain was related to treatment response. Trial registration number ClinicalTrials.gov number NCT00913458 PMID:26535135

  2. Treatment of hepatitis C in patients with haemophilia - the Israeli National Hemophilia Center experience.

    PubMed

    Maor, Y; Schapiro, J M; Bashari, D; Lurie, Y; Safadi, R; Segol, O; Paritsky, M; Rachlis, Z; Avidan, B; Bar-Meir, S; Martinowitz, U

    2008-03-01

    Treatment with pegylated interferon (Peg-IFN) and ribavirin, now the standard of care, has been shown to achieve sustained viral response (SVR) in up to 60% of patients with hepatitis C (HCV). Studies of response to this combination in HCV-infected haemophilia patients are scarce. The aim of the study was to report the results and safety of interferon/ribavirin treatment in HCV and HCV-/HIV-infected patients at the Israeli National Hemophilia Center. A retrospective observational cohort study was conducted on haemophilia patients infected with HCV or HCV/HIV. Patients received combination of Peg-IFN and ribavirin. Few were still treated with standard interferon. The primary end-point was sustained viral response (SVR). The secondary end-point was safety, with emphasis on increased bleeding episodes. Some 18/43 (42%) HCV mono-infected haemophilia patients achieved SVR. Relapse occurred in 14 (33%), while 11 patients (25%) were non-responders. SVR was achieved among 17/37 (46%) naïve patients receiving Peg-IFN and ribavirin. Among patients with genotype-1, SVR was achieved in 12/36 (33%) and 11/30 (37%) in the whole group and Peg-IFN treated naïve patients, respectively. In HCV/HIV co-infected patients only 1 patient achieved SVR. Severe anaemia occurred in 14/50 (28%) patients, four received erythropoietin. None maintained stable haemoglobin levels. Two patients had significant bleeding episodes. In our cohort of haemophilia patients, SVR was achieved in a lower than expected rates. A relatively high relapse rate in the HCV mono-infected patients and a very high non-response rate in the HCV/HIV co-infected patients were observed as anticipated. Anaemia was a major side effect and the use of growth factors seemed unrevealing.

  3. The Role of Azacitidine in the Treatment of Elderly Patients with Acute Myeloid Leukemia: Results of a Retrospective Multicenter Study

    PubMed Central

    Tombak, Anıl; Uçar, Mehmet Ali; Akdeniz, Aydan; Tiftik, Eyüp Naci; Gören Şahin, Deniz; Akay, Olga Meltem; Yıldırım, Murat; Nevruz, Oral; Kis, Cem; Gürkan, Emel; Medeni Solmaz, Şerife; Özcan, Mehmet Ali; Yıldırım, Rahşan; Berber, İlhami; Erkurt, Mehmet Ali; Tuğlular, Tülin Fıratlı; Tarkun, Pınar; Yavaşoğlu, İrfan; Doğu, Mehmet Hilmi; Sarı, İsmail; Merter, Mustafa; Özcan, Muhit; Yıldızhan, Esra; Kaynar, Leylagül; Mehtap, Özgür; Uysal, Ayşe; Şahin, Fahri; Salim, Ozan; Sungur, Mehmet Ali

    2016-01-01

    Objective: In this study, we aimed to investigate the efficacy and safety of azacitidine (AZA) in elderly patients with acute myeloid leukemia (AML), including patients with >30% bone marrow (BM) blasts. Materials and Methods: In this retrospective multicenter study, 130 patients of ≥60 years o ld who were ineligible for intensive chemotherapy or had progressed despite conventional treatment were included. Results: The median age was 73 years and 61.5% of patients had >30% BM blasts. Patients received AZA for a median of four cycles (range: 1-21). Initial overall response [including complete remission (CR)/CR with incomplete recovery/partial remission] was 36.2%. Hematologic improvement (HI) of any kind was documented in 37.7% of all patients. HI was also documented in 27.1% of patients who were unresponsive to treatment. Median overall survival (OS) was 18 months for responders and 12 months for nonresponders (p=0.005). In the unresponsive patient group, any HI improved OS compared to patients without any HI (median OS was 14 months versus 10 months, p=0.068). Eastern Cooperative Oncology Group performance status of <2, increasing number of AZA cycles (≥5 courses), and any HI predicted better OS. Age, AML type, and BM blast percentage had no impact. Conclusion: We conclude that AZA is effective and well tolerated in elderly comorbid AML patients, irrespective of BM blast count, and HI should be considered a sufficient response to continue treatment with AZA. PMID:27095141

  4. Challenges Associated with Management of Buruli Ulcer/Human Immunodeficiency Virus Coinfection in a Treatment Center in Ghana: A Case Series Study

    PubMed Central

    Tuffour, Joseph; Owusu-Mireku, Evelyn; Ruf, Marie-Therese; Aboagye, Samuel; Kpeli, Grace; Akuoku, Victor; Pereko, Janet; Paintsil, Albert; Bonney, Kofi; Ampofo, William; Pluschke, Gerd; Yeboah-Manu, Dorothy

    2015-01-01

    The synergy between Mycobacterium tuberculosis infection and human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome is well established but not so in Buruli ulcer (BU). We screened confirmed BU cases for HIV infection and followed seven BU/HIV-coinfected patients. Management of BU/HIV was based on the World Health Organization guidelines and patient condition. The HIV positivity among BU patients (8.2%; 11/134) was higher compared with that of general patients attending the facility (4.8%; 718/14,863; P = 0.07) and that of pregnant women alone (2.5%; 279/11,125; P = 0.001). All seven BU/HIV-coinfected cases enrolled in the study presented with very large (category III) lesions with four having multiple lesions compared with 54.5% of category III lesions among HIV-negative BU patients. During the recommended BU treatment with streptomycin and rifampicin (SR) all patients developed immune infiltrates including CD4 T cells in their lesions. However, one patient who received antiretroviral therapy (ART) 1 week after beginning SR treatment developed four additional lesions during antibiotic treatment, while two out of the four who did not receive ART died. Further evidence is required to ascertain the most appropriate time to commence ART in relation to SR treatment to minimize paradoxical reactions. PMID:26055745

  5. Evidence for a central mode of action for etoricoxib (COX-2 inhibitor) in patients with painful knee osteoarthritis.

    PubMed

    Arendt-Nielsen, Lars; Egsgaard, Line Lindhardt; Petersen, Kristian Kjær

    2016-08-01

    The COX-2 inhibitor etoricoxib modulates the peripheral and central nociceptive mechanisms in animals. This interaction has not been studied in patients with pain. This randomized, double-blind, placebo-controlled, 2-way crossover, 4-week treatment study investigated the pain mechanisms modulated by etoricoxib in patients with painful knee osteoarthritis. Patients were randomized to group A (60 mg/d etoricoxib followed by placebo) or B (placebo followed by 60 mg/d etoricoxib). The quantitative, mechanistic pain biomarkers were pressure pain thresholds, temporal summation (TS), and conditioning pain modulation. Clinical readouts were Brief Pain Inventory, WOMAC, painDETECT questionnaire (PD-Q), and time and pain intensity during walking and stair climbing. Etoricoxib as compared with placebo significantly modulated the pressure pain thresholds (P = 0.012, localized sensitization) at the knee and leg (control site) (P = 0.025, spreading sensitization) and TS assessed from the knee (P = 0.038) and leg (P = 0.045). Conditioning pain modulation was not modulated. The Brief Pain Inventory (pain scores), PD-Q, WOMAC, and walking and stair climbing tests were all significantly improved by etoricoxib. Based on a minimum of 30% or 50% pain alleviation (day 0-day 28), responders and nonresponders were defined. The nonresponders showed a significant association between increased facilitation of TS and increased pain alleviation. None of the other parameters predicted the degree of pain alleviation. Generally, a responder to etoricoxib has the most facilitated TS. In conclusion, etoricoxib (1) modulated central pain modulatory mechanisms and (2) improved pain and function in painful osteoarthritis. Stronger facilitation of TS may indicate a better response to etoricoxib, supporting the central mode-of-action of the drug.

  6. Brain changes in Alzheimer's disease patients with implanted encapsulated cells releasing nerve growth factor.

    PubMed

    Ferreira, Daniel; Westman, Eric; Eyjolfsdottir, Helga; Almqvist, Per; Lind, Göran; Linderoth, Bengt; Seiger, Ake; Blennow, Kaj; Karami, Azadeh; Darreh-Shori, Taher; Wiberg, Maria; Simmons, Andrew; Wahlund, Lars-Olof; Wahlberg, Lars; Eriksdotter, Maria

    2015-01-01

    New therapies with disease-modifying effects are urgently needed for treating Alzheimer's disease (AD). Nerve growth factor (NGF) protein has demonstrated regenerative and neuroprotective effects on basal forebrain cholinergic neurons in animal studies. In addition, AD patients treated with NGF have previously shown improved cognition, EEG activity, nicotinic binding, and glucose metabolism. However, no study to date has analyzed brain atrophy in patients treated with NGF producing cells. In this study we present MRI results of the first clinical trial in patients with AD using encapsulated NGF biodelivery to the basal forebrain. Six AD patients received the treatment during twelve months. Patients were grouped as responders and non-responders according to their twelve-months change in MMSE. Normative values were created from 131 AD patients from ADNI, selecting 36 age- and MMSE-matched patients for interpreting the longitudinal changes in MMSE and brain atrophy. Results at baseline indicated that responders showed better clinical status and less pathological levels of cerebrospinal fluid (CSF) Aβ1-42. However, they showed more brain atrophy, and neuronal degeneration as evidenced by higher CSF levels of T-tau and neurofilaments. At follow-up, responders showed less brain shrinkage and better progression in the clinical variables and CSF biomarkers. Noteworthy, two responders showed less brain shrinkage than the normative ADNI group. These results together with previous evidence supports the idea that encapsulated biodelivery of NGF might have the potential to become a new treatment strategy for AD with both symptomatic and disease-modifying effects.

  7. Immunosuppressive Treatment for Lupus Nephritis: Long-Term Results in 178 Patients

    PubMed Central

    Makarova, Tatiana A.; Zvonova, Elena V.; Anilina, Alina M.; Stolyarevich, Ekaterina S.

    2016-01-01

    Lupus nephritis is one of the most severe Systemic Lupus Erythematosus features, defining treatment modality and prognosis. Our retrospective study, including 178 patients treated for lupus nephritis during 23 years with mostly cyclophosphamide-based initial regimens followed by azathioprine or mycophenolic acid, demonstrates 84.8% of renal response with 19.2% of flares, 15-year patient survival 78.7% and kidney survival 76.3%, and low damage accrual. Both patient and kidney survival significantly differ for subgroups that achieved complete or partial renal response and nonresponders: patient 15-year survival 95% versus 65% versus 35%; kidney 15-year survival 100% versus 58% versus 0%, respectively. 51% (24 out of 47) of patients evaluated at the end of the study period sustained complete renal response; however, only 9 of them had 0 disease activity according to SELENA SLEDAI scale, while 13 patients had scores 2–4 due to the serological abnormalities only. We conclude that (1) initial treatment with cyclophosphamide followed by azathioprine is effective and can be used in agreement with International Guidelines until the evidence for biological treatments benefits becomes available; (2) complete and even partial renal response have positive prognostic value, and failure to achieve renal response negatively influences kidney and patient survival; (3) the validity of complete renal response in SLE is questioned by the absence of conventional definition of SLE remission. PMID:28050564

  8. Is Response to Radiotherapy in Patients Related to the Severity of Pretreatment Pain?

    SciTech Connect

    Kirou-Mauro, Andrea; Hird, Amanda; Wong, Jennifer; Sinclair, Emily; Barnes, Elizabeth A.; Tsao, May; Danjoux, Cyril; Chow, Edward

    2008-07-15

    Purpose: The primary objective of this study was to determine whether there is a relationship between the severity of pretreatment pain and response to palliative radiotherapy (RT) for painful bone metastases. Methods and Materials: The database for patients with bone metastases seen at the Rapid Response Radiotherapy Program at the Odette Cancer Center from 1999 to 2006 was analyzed. The proportion of patients with mild (scores 1-4), moderate (scores 5-6), or severe (scores 7-10) pain at baseline who experienced a complete response, partial response, stable response, or progressive response after palliative RT was determined according to International Bone Metastases Consensus definitions. Results: During the 7-year study period 1,053 patients received palliative radiation for bone metastases. The median age was 68 years and the median Karnofsky performance status was 70. Of the patients, 53% had a complete or partial response at 1 month, 52% at 2 months, and 54% at 3 months post-RT. Conclusions: There was no significant difference in terms of the proportion of responders (patients with complete or partial response) and nonresponders in terms of painful bone metastases among patients presenting with mild, moderate, or severe pain. Patients with moderate pain should be referred for palliative RT.

  9. Safe and effective sofosbuvir-based therapy in patients with mental health disease on hepatitis C virus treatment

    PubMed Central

    Tang, Lydia Shuk Yee; Masur, Jack; Sims, Zayani; Nelson, Amy; Osinusi, Anu; Kohli, Anita; Kattakuzhy, Sarah; Polis, Michael; Kottilil, Shyam

    2016-01-01

    AIM To study impact of baseline mental health disease on hepatitis C virus (HCV) treatment; and Beck’s Depression Inventory (BDI) changes with sofosbuvir- and interferon-based therapy. METHODS This is a retrospective cohort study of participants from 5 studies enrolled from single center trials conducted at the Clinical Research Center of the National Institutes of Health, Bethesda, MD, United States. All participants were adults with chronic HCV genotype 1 infection and naïve to HCV therapy. Two of the studies included HCV mono-infected participants only (SPARE, SYNERGY-A), and 3 included human immunodeficiency virus (HIV)/HCV co-infected participants only (ERADICATE, PFINPK, and ALBIN). Patients were treated for HCV with 3 different regimens: Sofosbuvir and ribavirin in the SPARE trial, ledipasvir and sofosbuvir in SYNERGY-A and ERADICATE trials, and pegylated interferon (IFN) and ribavirin for 48 wk in the PIFNPK and ALBIN trials. Participants with baseline mental health disease (MHD) were identified (defined as either a DSM IV diagnosis of major depression, bipolar disorder, schizophrenia, generalized anxiety, and post-traumatic stress disorder or requiring anti-depressants, antipsychotics, mood stabilizers or psychotropics prescribed by a psychiatrist). For our first aim, we compared sustained virologic response (SVR) and adherence (pill counts, study visits, and in 25 patients, blood levels of the sofosbuvir metabolite, GS-331007) within each study. For our second aim, only patients with HIV coinfection were evaluated. BDI scores were obtained pre-treatment, during treatment, and post-treatment among participants treated with sofosbuvir-based therapy, and compared to scores from participants treated with interferon-based therapy. Statistical differences for both aims were analyzed by Fisher’s Exact, and t-test with significance defined as a P value less than 0.05. RESULTS Baseline characteristics did not differ significantly between all participants with

  10. Plasma Derived From Human Umbilical Cord Blood Modulates Mitogen-Induced Proliferation of Mononuclear Cells Isolated From the Peripheral Blood of ALS Patients.

    PubMed

    Eve, David J; Ehrhart, Jared; Zesiewicz, Theresa; Jahan, Israt; Kuzmin-Nichols, Nicole; Sanberg, Cyndy Davis; Gooch, Clifton; Sanberg, Paul R; Garbuzova-Davis, Svitlana

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by degeneration of motor neurons in the spinal cord and brain. This disease clinically manifests as gradual muscular weakness and atrophy leading to paralysis and death by respiratory failure. While multiple interdependent factors may contribute to the pathogenesis of ALS, increasing evidence shows the possible presence of autoimmune mechanisms that promote disease progression. The potential use of plasma derived from human umbilical cord blood (hUCB) as a therapeutic tool is currently in its infancy. The hUCB plasma is rich in cytokines and growth factors that are required for growth and survival of cells during hematopoiesis. In this study, we investigated the effects of hUCB plasma on the mitogen-induced proliferation of mononuclear cells (MNCs) isolated from the peripheral blood of ALS patients and apoptotic activity by detection of caspase 3/7 expression of the isolated MNCs in vitro. Three distinct responses to phytohemagglutinin (PHA)-induced proliferation of MNCs were observed, which were independent of age, disease duration, and the ALS rating scale: Group I responded normally to PHA, Group II showed no response to PHA, while Group III showed a hyperactive response to PHA. hUCB plasma attenuated the hyperactive response (Group III) and potentiated the normal response in Group I ALS patients, but did not alter that of the nonresponders to PHA (Group II). The elevated activity of caspase 3/7 observed in the MNCs from ALS patients was significantly reduced by hUCB plasma treatment. Thus, study results showing different cell responses to mitogen suggest alteration in lymphocyte functionality in ALS patients that may be a sign of immune deficiency in the nonresponders and autoimmunity alterations in the hyperactive responders. The ability of hUCB plasma to modulate the mitogen cell response and reduce caspase activity suggests that the use of hUCB plasma alone, or with

  11. Adrenocorticotropic hormone but not high-density lipoprotein cholesterol or salivary cortisol was a predictor of adrenal insufficiency in patients with septic shock.

    PubMed

    Festti, Josiane; Grion, Cintia Magalhães Carvalho; Festti, Luciana; Mazzuco, Tânia Longo; Lima-Valassi, Helena Pantelion; Brito, Vinícius Nahime; Barbosa, Décio Sabbatini; Carrilho, Alexandre José Faria

    2014-07-01

    Relative adrenal insufficiency in sepsis has been extensively debated on; however, accurate diagnosis and therapeutic intervention remain controversial. The authors aimed to evaluate adrenocorticotropic hormone (ACTH), salivary cortisol, total cortisol and estimated plasma-free cortisol, cholesterol, and lipoproteins as predictors of adrenal insufficiency in patients within 24 h of septic shock diagnosis. This prospective study evaluated all hospitalized patients older than 18 years who developed septic shock and were using vasoactive drugs within 24 h of diagnosis. Blood and saliva samples were drawn at baseline and 60 min (T60) after 250 μg tetracosactide intravenous injection. Patients were divided into two groups: responders (Δ [T60 minus baseline] total cortisol >9 μg/dL) and nonresponders (Δ total cortisol ≤ 9 μg/dL or baseline total cortisol <10 μg/dL). The latter group was considered to have adrenal insufficiency. A total of 7,324 hospitalized patients were monitored, and 34 subjects with septic shock were included in the analysis. Adrenal insufficiency was found in 32.4%. Total cholesterol, high-density lipoprotein cholesterol, triglycerides, and salivary cortisol did not differ between groups. Estimated plasma-free cortisol was not better than total plasma cortisol in estimating adrenal function. Baseline endogenous ACTH was higher in nonresponders than responders (55.5 pg/mL vs. 18.3 pg/mL, respectively; P = 0.01). The cutoff ACTH value that discriminated patients with adrenal insufficiency was 31.5 pg/mL. Thus, endogenous ACTH measured within 24 h of septic shock diagnosis could predict adrenal response to tetracosactide.

  12. Clinical and treatment effects on /sup 3/H-clonidine and /sup 3/H-imipramine binding in elderly depressed patients

    SciTech Connect

    Georgotas, A.; Schweitzer, J.; McCue, R.E.; Armour, M.; Friedhoff, A.J.

    1987-06-01

    /sup 3/H-clonidine and /sup 3/H-imipramine binding were measured in depressed patients, 55 years and older. There was no significant difference in either /sup 3/H-clonidine or /sup 3/H-imipramine binding between depressed patients and age- and sex-matched controls. There was no significant correlation between /sup 3/H-clonidine or /sup 3/H-imipramine binding and severity of depression before treatment. There was a significant negative correlation between the K/sub D/ of /sup 3/H-imipramine binding sites and Hamilton score over seven weeks of antidepressant treatment. There was no significant difference between receptor data of responders and nonresponders to antidepressant treatment. 19 references, 2 tables.

  13. Combination inhibition of PI3K and mTORC1 yields durable remissions in orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases

    PubMed Central

    Ni, Jing; Ramkissoon, Shakti H.; Xie, Shaozhen; Goel, Shom; Stover, Daniel G.; Guo, Hanbing; Luu, Victor; Marco, Eugenio; Ramkissoon, Lori A.; Kang, Yun Jee; Hayashi, Marika; Nguyen, Quang-De; Ligon, Azra H.; Du, Rose; Claus, Elizabeth B.; Alexander, Brian M.; Yuan, Guo-Cheng; Wang, Zhigang C.; Iglehart, J. Dirk; Krop, Ian E.; Roberts, Thomas M.; Winer, Eric P.; Lin, Nancy U.; Ligon, Keith L.; Zhao, Jean J.

    2016-01-01

    Brain metastases represent the greatest clinical challenge in treating HER2-positive breast cancer. We report the development of orthotopic patient-derived xenografts (PDXs) of HER2-expressing breast cancer brain metastases (BCBM), and their use for the identification of targeted combination therapies. Combined inhibition of PI3K and mTOR resulted in durable tumor regressions in three of five PDXs, and therapeutic response correlated with reduction of 4EBP1 phosphorylation. The two non-responding PDXs showed hypermutated genomes with enrichment of mutations in DNA repair genes, suggesting an association of genomic instability with therapeutic resistance. These findings suggest that a biomarker-driven clinical trial of PI3K inhibitor plus an mTOR inhibitor should be conducted for patients with HER2-positive BCBM. PMID:27270588

  14. Clinical Outcome of a Novel Anti-CD6 Biologic Itolizumab in Patients of Psoriasis with Comorbid Conditions

    PubMed Central

    2016-01-01

    Psoriasis is a common, chronic, immune mediated, inflammatory disease of skin characterized by red patches enclosed with white scales and affects 2-3% of people in the world. Topical therapy, phototherapy, and systemic therapy were employed for management of disease from many last decades. However, long term uses of these agents are associated with unwanted effects and toxicities. Recently, Itolizumab has been developed as world's first anti-CD6 humanized monoclonal IgG1 antibody for the management of moderate-to-severe chronic plaque psoriasis in India. Here we are presenting the response indicated by Itolizumab in 7 Indian patients having moderate-to-severe psoriasis with severe comorbidities and who were intolerant/nonresponding to conventional therapies. PMID:27885324

  15. Clinical Outcome of a Novel Anti-CD6 Biologic Itolizumab in Patients of Psoriasis with Comorbid Conditions.

    PubMed

    Singh, Vinay

    2016-01-01

    Psoriasis is a common, chronic, immune mediated, inflammatory disease of skin characterized by red patches enclosed with white scales and affects 2-3% of people in the world. Topical therapy, phototherapy, and systemic therapy were employed for management of disease from many last decades. However, long term uses of these agents are associated with unwanted effects and toxicities. Recently, Itolizumab has been developed as world's first anti-CD6 humanized monoclonal IgG1 antibody for the management of moderate-to-severe chronic plaque psoriasis in India. Here we are presenting the response indicated by Itolizumab in 7 Indian patients having moderate-to-severe psoriasis with severe comorbidities and who were intolerant/nonresponding to conventional therapies.

  16. Immunosuppressive Therapy in Patients with Aplastic Anemia: A Single-Center Retrospective Study

    PubMed Central

    Jalaeikhoo, Hasan; Khajeh-Mehrizi, Ahmad

    2015-01-01

    Background Aplastic anemia (AA) is a rare disease in which hematopoietic stem cells are severely diminished resulting in hypocellular bone marrow and pancytopenia. Etiology of AA includes auto immunity, toxins, infection, ionizing radiation, drugs and rare genetic disorders, but in the majority of cases no cause can be identified. In the present study we assessed response rate, survival, relapse and clonal evolution in patients with AA treated with immunosuppressive therapy. Methods Patients with AA who received immunosuppressive therapy between May 1998 and September 2013 were included in this study. Patients with non-severe AA (NSAA) were treated with cyclosporine (CsA) and danazol while patients with severe AA (SAA) as well as patients with NSAA who progressed to SAA after beginning of the treatment, were candidates for receiving antithymocyte globulin in addition to CsA and danazol. Results Among the 63 studied patients, 29 (46%) had NSAA and 34 (54%) had SAA. Three months after treatment, overall response was 58.6% in NSAA and 12.9% in patients with SAA. Survival of all patients at 5, 10 and 15 years were 73%, 55% and 49%, respectively. Survival rates were significantly higher in patients with NSAA compared to patients with SAA as well as in patients who responded at 6 months compared to non-responders. The relapse risk was 39.7% at 10 years. Relapse occurred in patients who discontinued the therapy more than those who continued taking CsA (p value<0.01). The risk of clonal evolution was 9.9% at 10 years and 22.8% at 15 years after treatment. Conclusion This long-term retrospective study indicated that immunosuppressive therapy should be recommended to patients with AA. Also, our experience indicated that immunosuppressive therapy should not be discontinued after response to therapy in patients with both NSAA and SAA due to high risk of relapse. Low dose of CsA should be continued indefinitely. PMID:25970182

  17. Physical function improvements and relief from fatigue and pain are associated with increased productivity at work and at home in rheumatoid arthritis patients treated with certolizumab pegol

    PubMed Central

    Taylor, Peter; Strand, Vibeke; Purcaru, Oana; Coteur, Geoffroy; Mease, Philip

    2010-01-01

    Objectives. To evaluate the association between improvements in physical function, fatigue and pain and improvements in productivity at work and at home in patients treated with certolizumab pegol (CZP) in combination with MTX. Methods. Physical function, fatigue and pain were assessed in two CZP clinical trials (Rheumatoid Arthritis PreventIon of structural Damage 1 and 2) using the HAQ-Disability Index (HAQ-DI), Fatigue Assessment Scale (FAS) and Patient Assessment of Pain, with minimal clinically important differences (MCIDs) defined as ≥0.22, ≥1 and ≥10 points, respectively. Work and home productivity were evaluated using the RA-specific Work Productivity Survey (WPS-RA). The odds of achieving an HAQ-DI, FAS or pain ‘response’ at Week 12, defined as improvements ≥MCID, were compared between CZP and control groups. Improvements in productivity at Week 12 were compared between CZP-treated HAQ-DI, FAS or pain responders and non-responders. Results. The odds of achieving improvements ≥MCID were five times higher for pain, and two to three times higher for physical function and fatigue, in patients receiving CZP vs control. Per month, responders reported significantly greater improvements in productivity at work and reduced interference of RA with their work productivity than non-responders. Responders also reported significantly greater improvements in productivity at home and participation in family, social and leisure activities. Conclusions. This study demonstrated a clear association between patient-reported improvements in physical function, fatigue and pain, and improvements in productivity both at work and home. PMID:20547658

  18. HBV quasispecies composition in Lamivudine-failed chronic hepatitis B patients and its influence on virological response to Tenofovir-based rescue therapy

    PubMed Central

    Banerjee, Priyanka; Chakraborty, Abhijit; Mondal, Rajiv Kumar; Khatun, Mousumi; Datta, Somenath; Das, Kausik; Pandit, Pratap; Mukherjee, Souvik; Banerjee, Soma; Ghosh, Saurabh; Chakrabarti, Saikat; Chowdhury, Abhijit; Datta, Simanti

    2017-01-01

    The present study sought to evaluate the structure of HBV quasispecies in Lamivudine (LMV)-failed chronic hepatitis B (CHB) patients and its impact in defining the subsequent virological responses to Tenofovir (TDF)-based rescue-therapy. By analyzing HBV clones encompassing reverse transcriptase (RT) and surface (S) region from LMV-failed and treatment-naïve CHB patients, we identified 5 classical and 12 novel substitutions in HBV/RT and 9 substitutions in immune-epitopes of HBV/S that were significantly associated with LMV failure. In silico analysis showed spatial proximity of some of the newly-identified, mutated RT residues to the RT catalytic centre while most S-substitutions caused alteration in epitope hydrophobicity. TDF administration resulted in virological response in 60% of LMV-failed patients at 24-week but non-response in 40% of patients even after 48-weeks. Significantly high frequencies of 6 S-substitutions and one novel RT-substitution, rtH124N with 6.5-fold-reduced susceptibility to TDF in vitro, were noted at baseline in TDF non-responders than responders. Follow-up studies depicted greater evolutionary drift of HBV quasispecies and significant decline in frequencies of 3 RT and 6 S-substitutions in responder-subgroup after 24-week TDF-therapy while most variants persisted in non-responders. Thus, we identified the HBV-RT/S variants that could potentially predict unfavorable response to LMV/TDF-therapy and impede immune-mediated viral clearance. PMID:28303969

  19. Analysis of a successful HCV-specific CD8+ T cell response in patients with recurrent HCV-infection after orthotopic liver transplantation.

    PubMed

    Gruener, Norbert Hubert; Jung, Maria-Christina; Ulsenheimer, Axel; Gerlach, Joern Tilman; Zachoval, Reinhart; Diepolder, Helmut Michael; Baretton, Gustavo; Schauer, Rolf; Pape, Gerd Rudolf; Schirren, Carl Albrecht

    2004-12-01

    Virus-specific CD8+ T cells play a major role in antiviral immune defenses; their significance in the transplant setting, however, is unclear. In the present study, we asked whether hepatitis C virus (HCV)-specific CD8+ T cells were detectable in the presence of an immunosuppressive treatment and whether the HCV-specific CD8+ T cell response correlates with treatment outcome in patients who receive interferon (IFN)-alpha / ribavirin therapy after orthotopic liver transplantation (OLTx). Liver- and blood-derived T cell lines of 21 patients after OLTx were studied before, at the end of, and after antiviral treatment. Virus-specific IFN-gamma production in response to a panel of previously identified HCV-specific epitopes restricted by the human leukocyte antigen (HLA) class I molecules A2, A3, B7, B35, and B44 of structural and nonstructural HCV protein was determined by enzyme-linked immunospot (ELISPOT) assay. Before treatment, only low numbers of HCV-specific CD8+ T cells were detectable. In 6 patients with a sustained virological response, a significant, multispecific, and sustained CD8+ T cell response was detectable, which was mainly found in the peripheral blood. Nonresponders and transient responders showed undetectable, weak, or transient HCV-specific CD8+ T cell responses. (Sustained responders vs. transient and nonresponders: Wilcoxon rank-signed test; P < .01). In conclusion, our data indicate that despite immunosuppression, HCV-specific CD8+ T cells are detectable in patients with recurrent HCV infection after OLTx and that a significant, multispecific, and long-lasting HCV-specific CD8+ T cell response contributes to viral elimination.

  20. HBV quasispecies composition in Lamivudine-failed chronic hepatitis B patients and its influence on virological response to Tenofovir-based rescue therapy.

    PubMed

    Banerjee, Priyanka; Chakraborty, Abhijit; Mondal, Rajiv Kumar; Khatun, Mousumi; Datta, Somenath; Das, Kausik; Pandit, Pratap; Mukherjee, Souvik; Banerjee, Soma; Ghosh, Saurabh; Chakrabarti, Saikat; Chowdhury, Abhijit; Datta, Simanti

    2017-03-17

    The present study sought to evaluate the structure of HBV quasispecies in Lamivudine (LMV)-failed chronic hepatitis B (CHB) patients and its impact in defining the subsequent virological responses to Tenofovir (TDF)-based rescue-therapy. By analyzing HBV clones encompassing reverse transcriptase (RT) and surface (S) region from LMV-failed and treatment-naïve CHB patients, we identified 5 classical and 12 novel substitutions in HBV/RT and 9 substitutions in immune-epitopes of HBV/S that were significantly associated with LMV failure. In silico analysis showed spatial proximity of some of the newly-identified, mutated RT residues to the RT catalytic centre while most S-substitutions caused alteration in epitope hydrophobicity. TDF administration resulted in virological response in 60% of LMV-failed patients at 24-week but non-response in 40% of patients even after 48-weeks. Significantly high frequencies of 6 S-substitutions and one novel RT-substitution, rtH124N with 6.5-fold-reduced susceptibility to TDF in vitro, were noted at baseline in TDF non-responders than responders. Follow-up studies depicted greater evolutionary drift of HBV quasispecies and significant decline in frequencies of 3 RT and 6 S-substitutions in responder-subgroup after 24-week TDF-therapy while most variants persisted in non-responders. Thus, we identified the HBV-RT/S variants that could potentially predict unfavorable response to LMV/TDF-therapy and impede immune-mediated viral clearance.

  1. CT venography for deep venous thrombosis: can it predict catheter-directed thrombolysis prognosis in patients with iliac vein compression syndrome?

    PubMed

    Choi, Jin Woo; Jae, Hwan Jun; Kim, Hyo-Cheol; Min, Sang-Il; Min, Seung-Kee; Lee, Whal; Chung, Jin Wook

    2015-02-01

    To evaluate the prognostic value of CT venography for catheter-directed thrombolysis (CDT) in iliac vein compression syndrome (IVCS) patients with deep venous thrombosis (DVT). The institutional review board approved this retrospective study and waived informed consent. Among the 201 consecutive patients treated in our interventional suite for DVT from January 2001 to June 2013, 48 IVCS patients (12 men, 36 women) who underwent pre-procedural CT venography, CDT with stenting, and follow-up imaging were analyzed. To identify possible determinants of 6-month patency, CT venography was evaluated with Fisher's exact test and logistic regression analyses. Based on the analyses, image-based criteria were established and compared to the current symptom duration-based approach by receiver-operating-characteristic curve analyses and the McNemar test. Recoiling of external iliac vein (EIV) diameter (<120 %) [hazard ratio (HR) 28.652, p = .007] and severe rim enhancement (HR 20.545, p = .016) were significant risk factors for venous occlusion within 6 months of CDT. The dual-parameter image-based criteria were significantly superior to the current symptom duration-based approach in terms of area under the curve value (p = .010) and predictive accuracy (p = .031). With a 2-point cut-off, the proposed criteria demonstrated a 66.7 % sensitivity, 100.0 % specificity, and 92.9 % predictive accuracy for identifying non-responders of CDT. CT venography may be useful in assessing CDT prognoses in IVCS patients, particularly to identify non-responders who demonstrate recoiling of EIV diameter and rim enhancement on CT venography.

  2. Predictors for the immediate responders to cervical manipulation in patients with neck pain.

    PubMed

    Tseng, Yuh-Liang; Wang, Wendy T J; Chen, Wen-Yin; Hou, Tsun-Jen; Chen, Tzu-Ching; Lieu, Fu-Kong

    2006-11-01

    Cervical manipulation has been considered an effective treatment for managing neck pain. However, clinical observation showed that cervical manipulation was not effective for every patient. Development of clinical prediction rules for identifying patients with neck pain who are likely to respond to cervical manipulation may improve clinical decision-making and the treatment success rate. The purpose of the study was to identify predictors for the immediate responders to cervical manipulation treatment in patients with neck pain. One hundred patients with neck pain (34 males and 66 females, mean age = 46 +/- 11 years) participated in the study. Patient's demographic data, symptom aggravating or easing factors, pain, and disability level were obtained through an initial assessment. A series of physical examinations were also administered. After receiving a single session of cervical manipulation, the patient was re-evaluated immediately to determine if a successful response to treatment was obtained. The successful response was determined by improvements seen in one of the three outcome variables that included reduction of pain intensity, significant perceived improvement, and high satisfaction level. From these judgment criteria, patients were classified into either responders or nonresponders to the cervical manipulation. Univariate analyses were used to assess if the treatment responders and nonresponders were different in their clinical presentations. The clinical factors that showed significant differences between two groups were then entered into a stepwise multiple logistic regression analysis to identify significant predictors and the prediction rule for treatment responders. Six predictors including "initial scores on Neck Disability Index < 11.50", "having bilateral involvement pattern", "not performing sedentary work > 5 h/day", "feeling better while moving the neck", "without feeling worse while extending the neck", and "the diagnosis of spondylosis

  3. Hematologic responses in patients with aplastic anemia treated with deferasirox: a post hoc analysis from the EPIC study.

    PubMed

    Lee, Jong Wook; Yoon, Sung-Soo; Shen, Zhi Xiang; Ganser, Arnold; Hsu, Hui-Chi; El-Ali, Ali; Habr, Dany; Martin, Nicolas; Porter, John B

    2013-07-01

    Reports are emerging of hematologic responses associated with iron chelation therapy; however, studies are limited in aplastic anemia patients. Deferasirox reduced iron overload in aplastic anemia patients enrolled in the EPIC (Evaluation of Patients' Iron Chelation with Exjade(®)) study (n=116). A post hoc analysis of hematologic responses was conducted on 72 patients with evaluable hematologic parameters (according to UK guideline criteria), 24 of whom received deferasirox without concomitant immunosuppressive treatment. Partial hematologic responses were observed in 11 of 24 (45.8%) patients; all became transfusion-independent. One patient had an additional platelet response and one patient had an additional platelet and hemoglobin response. Mean serum ferritin levels at end of study were significantly reduced in partial hematologic responders (n=11; -3948 ± 4998 ng/mL; baseline 6693 ± 7014 ng/mL; percentage change from baseline -45.7%; P=0.0029). In non-responders, the reduction in serum ferritin was less pronounced (n=13; -2021 ± 3242 ng/mL; baseline 4365 ± 3063 ng/mL; % change from baseline -27.6%; P=0.0171). Alongside reduction in iron overload, deferasirox may, therefore, improve hematologic parameters in a subset of aplastic anemia patients. Further investigation is required to elucidate the mechanisms involved.

  4. Pasireotide: a novel treatment for patients with acromegaly.

    PubMed

    Cuevas-Ramos, Daniel; Fleseriu, Maria

    2016-01-01

    Morbidity and mortality rates in patients with active acromegaly are higher than the general population. Adequate biochemical control restores mortality to normal rates. Now, medical therapy has an increasingly important role in the treatment of patients with acromegaly. Somatostatin receptor ligands (SRLs) are considered the standard medical therapy, either after surgery or as a first-line therapy when surgery is deemed ineffective or is contraindicated. Overall, octreotide and lanreotide are first-generation SRLs and are effective in ~20%-70% of patients. Pegvisomant, a growth hormone receptor antagonist, controls insulin-like growth factor 1 in 65%-90% of cases. Consequently, a subset of patients (nonresponders) requires other treatment options. Drug combination therapy offers the potential for more efficacious disease control. However, the development of new medical therapies remains essential. Here, emphasis is placed on new medical therapies to control acromegaly. There is a focus on pasireotide long-acting release (LAR) (Signifor LAR®), which was approved in 2014 by the US Food and Drug Administration and the European Medicine Agency for the treatment of acromegaly. Pasireotide LAR is a long-acting somatostatin multireceptor ligand. In a Phase III clinical trial in patients with acromegaly (naïve to medical therapy or uncontrolled on a maximum dose of first-generation SRLs), 40 and 60 mg of intramuscular pasireotide LAR achieved better biochemical disease control than octreotide LAR, and tumor shrinkage was noted in both pasireotide groups. Pasireotide LAR tolerability was similar to other SRLs, except for a greater frequency and degree of hyperglycemia and diabetes mellitus. Baseline glucose may predict hyperglycemia occurrence after treatment, and careful monitoring of glycemic status and appropriate treatment is required. A precise definition of patients with acromegaly who will derive the greatest therapeutic benefit from pasireotide LAR remains to be

  5. Pasireotide: a novel treatment for patients with acromegaly

    PubMed Central

    Cuevas-Ramos, Daniel; Fleseriu, Maria

    2016-01-01

    Morbidity and mortality rates in patients with active acromegaly are higher than the general population. Adequate biochemical control restores mortality to normal rates. Now, medical therapy has an increasingly important role in the treatment of patients with acromegaly. Somatostatin receptor ligands (SRLs) are considered the standard medical therapy, either after surgery or as a first-line therapy when surgery is deemed ineffective or is contraindicated. Overall, octreotide and lanreotide are first-generation SRLs and are effective in ~20%–70% of patients. Pegvisomant, a growth hormone receptor antagonist, controls insulin-like growth factor 1 in 65%–90% of cases. Consequently, a subset of patients (nonresponders) requires other treatment options. Drug combination therapy offers the potential for more efficacious disease control. However, the development of new medical therapies remains essential. Here, emphasis is placed on new medical therapies to control acromegaly. There is a focus on pasireotide long-acting release (LAR) (Signifor LAR®), which was approved in 2014 by the US Food and Drug Administration and the European Medicine Agency for the treatment of acromegaly. Pasireotide LAR is a long-acting somatostatin multireceptor ligand. In a Phase III clinical trial in patients with acromegaly (naïve to medical therapy or uncontrolled on a maximum dose of first-generation SRLs), 40 and 60 mg of intramuscular pasireotide LAR achieved better biochemical disease control than octreotide LAR, and tumor shrinkage was noted in both pasireotide groups. Pasireotide LAR tolerability was similar to other SRLs, except for a greater frequency and degree of hyperglycemia and diabetes mellitus. Baseline glucose may predict hyperglycemia occurrence after treatment, and careful monitoring of glycemic status and appropriate treatment is required. A precise definition of patients with acromegaly who will derive the greatest therapeutic benefit from pasireotide LAR remains to

  6. Pharmacokinetics and Pharmacodynamics with Extended Dosing of CC-486 in Patients with Hematologic Malignancies

    PubMed Central

    Garcia-Manero, Guillermo; Cogle, Christopher R.; Gore, Steven D.; Hetzer, Joel; Kumar, Keshava; Skikne, Barry; MacBeth, Kyle J.

    2015-01-01

    CC-486 (oral azacitidine) is an epigenetic modifier in development for patients with myelodysplastic syndromes and acute myeloid leukemia. In part 1 of this two-part study, a 7-day CC-486 dosing schedule showed clinical activity, was generally well tolerated, and reduced DNA methylation. Extending dosing of CC-486 beyond 7 days would increase duration of azacitidine exposure. We hypothesized that extended dosing would therefore provide more sustained epigenetic activity. Reported here are the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of CC-486 extended dosing schedules in patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) or acute myeloid leukemia (AML) from part 2 of this study. PK and/or PD data were available for 59 patients who were sequentially assigned to 1 of 4 extended CC-486 dosing schedules: 300mg once-daily or 200mg twice-daily for 14 or 21 days per 28-day cycle. Both 300mg once-daily schedules and the 200mg twice-daily 21-day schedule significantly (all P < .05) reduced global DNA methylation in whole blood at all measured time points (days 15, 22, and 28 of the treatment cycle), with sustained hypomethylation at cycle end compared with baseline. CC-486 exposures and reduced DNA methylation were significantly correlated. Patients who had a hematologic response had significantly greater methylation reductions than non-responding patients. These data demonstrate that extended dosing of CC-486 sustains epigenetic effects through the treatment cycle. Trial Registration ClinicalTrials.gov NCT00528983 PMID:26296092

  7. Study of IL-2 receptor expression after chemoimmunotherapy in patients treated for metastatic malignant melanoma.

    PubMed Central

    Mouawad, R; Ichen, M; Rixe, O; Benhammouda, A; Vuillemin, E; Weil, M; Khayat, D; Soubrane, C

    1994-01-01

    Using flow cytometry, cellular IL-2 receptors were studied before and following chemoimmunotherapy combination in 20 patients with metastatic malignant melanoma (MMM). Patients received cisplatin (100 mg/m2) at days 1 and 28, recombinant IL-2 by continuous infusion from days 3 to 6, 17 to 21, 31 to 34, and 45 to 49. Interferon-alpha (IFN-alpha) was given subcutaneously three times weekly. In terms of clinical response, we observed 55% objective response (complete: 15%). When pretreatment blood samples were compared with those of healthy donors, we did not observe any change in low (alpha chain) and high affinity receptor (alpha + beta) expression. In contrast, intermediate affinity p75 (beta chain) expression was decreased significantly (P < or = 0.0001) in MMM patients. During treatment, we found a dramatic increase of beta chain as well as high affinity (alpha + beta) expression in responding patients, as soon as IL-2 therapy began. Furthermore, the increase of beta chain expression was limited to natural killer (NK) cells (CD56+). In non-responding patients, on the other hand, increase of both receptors was seen only at day 31. These data suggest the involvement of beta chain expression in the mechanism of cell activation after chemoimmunotherapy. Moreover, this early beta chain expression is correlated with the clinical response to chemoimmunotherapy. PMID:8082289

  8. Clopidogrel Responsiveness in Patients Undergoing Peripheral Angioplasty

    SciTech Connect

    Pastromas, Georgios Spiliopoulos, Stavros Katsanos, Konstantinos Diamantopoulos, Athanasios Kitrou, Panagiotis Karnabatidis, Dimitrios Siablis, Dimitrios

    2013-12-15

    Purpose: To investigate the incidence and clinical significance of platelet responsiveness in patients receiving clopidogrel after peripheral angioplasty procedures. Materials and Methods: This prospective study included patients receiving antiplatelet therapy with clopidogrel 75 mg after infrainguinal angioplasty or stenting and who presented to our department during routine follow-up. Clopidogrel responsiveness was tested using the VerifyNow P2Y12 Assay. Patients with residual platelet reactivity units (PRU) {>=} 235 were considered as nonresponders (NR group NR), whereas patients with PRU < 235 were considered as normal (responders [group R]). Primary end points were incidence of resistance to clopidogrel and target limb reintervention (TLR)-free survival, whereas secondary end points included limb salvage rates and the identification of any independent predictors influencing clinical outcomes. Results: In total, 113 consecutive patients (mean age 69 {+-} 8 years) with 139 limbs were enrolled. After clopidogrel responsiveness analysis, 61 patients (53.9 %) with 73 limbs (52.5 %) were assigned to group R and 52 patients (46.1 %) with 66 limbs (47.5 %) to group NR. Mean follow-up interval was 27.7 {+-} 22.9 months (range 3-95). Diabetes mellitus, critical limb ischemia, and renal disease were associated with clopidogrel resistance (Fisher's exact test; p < 0.05). According to Kaplan-Meier analysis, TLR-free survival was significantly superior in group R compared with group NR (20.7 vs. 1.9 %, respectively, at 7-year follow-up; p = 0.001), whereas resistance to clopidogrel was identified as the only independent predictor of decreased TLR-free survival (hazard rate 0.536, 95 % confidence interval 0.31-0.90; p = 0.01). Cumulative TLR rate was significantly increased in group NR compared with group R (71.2 % [52 of 73] vs. 31.8 % [21 of 66], respectively; p < 0.001). Limb salvage was similar in both groups. Conclusion: Clopidogrel resistance was related with

  9. Hepatic compartmentalization of exhausted and regulatory cells in HIV/HCV-coinfected patients.

    PubMed

    Barrett, L; Trehanpati, N; Poonia, S; Daigh, L; Sarin, S Kumar; Masur, H; Kottilil, S

    2015-03-01

    Accelerated intrahepatic hepatitis C virus (HCV) pathogenesis is likely the result of dysregulation within both the innate and adaptive immune compartments, but the exact contribution of peripheral blood and liver lymphocyte subsets remains unclear. Prolonged activation and expansion of immunoregulatory cells have been thought to play a role. We determined immune cell subset frequency in contemporaneous liver and peripheral blood samples from chronic HCV-infected and HIV/HCV-coinfected individuals. Peripheral blood mononuclear cells (PBMC) and biopsy-derived liver-infiltrating lymphocytes from 26 HIV/HCV-coinfected, 10 chronic HCV-infected and 10 HIV-infected individuals were assessed for various subsets of T and B lymphocytes, dendritic cell, natural killer (NK) cell and NK T-cell frequency by flow cytometry. CD8(+) T cells expressing the exhaustion marker PD-1 were increased in HCV-infected individuals compared with uninfected individuals (P = 0.02), and HIV coinfection enhanced this effect (P = 0.005). In the liver, regulatory CD4(+) CD25(+) Foxp3(+) T cells, as well as CD4(+) CD25(+) PD1(+) T cells, were more frequent in HIV/HCV-coinfected than in HCV-monoinfected samples (P < 0.001). HCV was associated with increased regulatory T cells, PD-1(+) T cells and decreased memory B cells, regardless of HIV infection (P ≤ 0.005 for all). Low CD8(+) expression was observed only in PD-1(+) CD8(+) T cells from HCV-infected individuals and healthy controls (P = 0.002) and was associated with enhanced expansion of exhausted CD8(+) T cells when exposed in vitro to PHA or CMV peptides. In conclusion, in HIV/HCV coinfection, ongoing HCV replication is associated with increased regulatory and exhausted T cells in the periphery and liver that may impact control of HCV. Simultaneous characterization of liver and peripheral blood highlights the disproportionate intrahepatic compartmentalization of immunoregulatory T cells, which may contribute to establishment of chronicity and

  10. Response to hydroxychloroquine in Japanese patients with systemic lupus erythematosus using the cutaneous lupus erythematosus disease area and severity index (CLASI).

    PubMed

    Yokogawa, Naoto; Kato, Yukihiko; Sugii, Shoji; Inada, Shinichi

    2012-04-01

    We evaluated the cutaneous lupus erythematosus disease area and severity index (CLASI) in Japanese patients with systemic lupus erythematosus (SLE) in order to design a clinical trial of hydroxychloroquine (HCQ) in Japan. Our prospective cohort study consisted of seven SLE patients with active skin disease who started HCQ at Tokyo Metropolitan Tama Medical Center. The therapeutic responses were assessed at 4 months. Patients were categorized as responders (improved) or non-responders (unchanged or worsened) using the criteria of a 4-point or 20% decrease in the CLASI activity score. We also assessed joint pain determined by patient visual analog scale (VAS), malaise (VAS), patient global assessment of SLE (VAS), and constitutional and musculoskeletal symptoms according to the British Isles Lupus Assessment Group (BILAG) disease activity index. Six patients (86%) were categorized as responders. The median (range) CLASI activity score of all patients at assessment had changed from 8.0 (2-22) to 4 (2-10). All five patients with joint pain and all five patients with malaise showed improvement in patient VAS but the BILAG findings failed to capture these improvements. In conclusion, the cutaneous aspects of SLE can be measured by the CLASI. The CLASI activity score may be a reasonable primary endpoint when performing a clinical trial of HCQ.

  11. TRAIL and TRAIL receptors splice variants during long-term interferon β treatment of patients with multiple sclerosis: evaluation as biomarkers for therapeutic response

    PubMed Central

    López-Gómez, Carlos; Oliver-Martos, Begoña; Pinto-Medel, María-Jesús; Suardiaz, Margarita; Reyes-Garrido, Virginia; Urbaneja, Patricia; Fernández, Óscar; Leyva, Laura

    2016-01-01

    Objective We aimed to assess the effects of interferon β (IFNβ) treatment on the expression of the splice variants of the Tumour necrosis factor-Related Apoptosis Inducing Ligand (TRAIL) and its receptors in different cell subpopulations (CD14+, CD4+ and CD8+) from patients with multiple sclerosis (MS), and to determine whether this expression discriminated responders from non-responders to IFNβ therapy. Methods We examined mRNA expression of the TRAIL and TRAIL receptors variants in patients with MS, at baseline and after one year of IFNβ therapy, according to responsiveness to this drug. Results Long-term therapy with IFNβ increased the expression of TRAIL-α in T cell subsets exclusively from responders and decreased the expression of the isoform 2 of TRAILR-2 in monocytes from responders as well as non-responders. Lower expression of TRAIL-α, and higher expression of TRAIL-β in monocytes and T cells, was found before the onset of IFNβ therapy in patients who will subsequently become responders. Baseline expression of TRAILR-1 was also significantly higher in monocytes and CD4+ T cells from responders. Conclusions The present study shows that long-term IFNβ treatment has a direct influence on TRAIL-α and TRAILR-2 isoform 2 expression. Besides, receiver operating characteristic analysis revealed that the baseline expression of TRAIL-α in monocytes and T cells, and that of TRAILR-1 in monocytes and CD4+ T cells, showed a predictive value of the clinical response to IFNβ therapy, pointing to a role of TRAIL system in the mechanism of action of IFNβ in MS that will need further investigation. PMID:25736057

  12. The rationale for patient-reported outcomes surveillance in cancer and a reproducible method for achieving it.

    PubMed

    Smith, Tenbroeck G; Castro, Kathleen M; Troeschel, Alyssa N; Arora, Neeraj K; Lipscomb, Joseph; Jones, Shelton M; Treiman, Katherine A; Hobbs, Connie; McCabe, Ryan M; Clauser, Steven B

    2016-02-01

    Patient-reported outcomes (PROs) measure quality of life, symptoms, patient functioning, and patient perceptions of care; they are essential for gaining a full understanding of cancer care and the impact of cancer on people's lives. Repeatedly captured facility-level and/or population-level PROs (PRO surveillance) could play an important role in quality monitoring and improvement, benchmarking, advocacy, policy making, and research. This article describes the rationale for PRO surveillance and the methods of the Patient Reported Outcomes Symptoms and Side Effects Study (PROSSES), which is the first PRO study to use the American College of Surgeons Commission on Cancer's Rapid Quality Reporting System to identify patients and manage study data flow. The American Cancer Society, the National Cancer Institute, the Commission on Cancer, and RTI International collaborated on PROSSES. PROSSES was conducted at 17 cancer programs that participated in the National Cancer Institute Community Cancer Centers Program among patients diagnosed with locoregional breast or colon cancer. The methods piloted in PROSSES were successful as demonstrated by high eligibility (93%) and response (61%) rates. Differences in clinical and demographic characteristics between respondents and nonrespondents were mostly negligible, with the exception that non-white individuals were somewhat less likely to respond. These methods were consistent across cancer centers and reproducible over time. If repeated and expanded, they could provide PRO surveillance data from patients with cancer on a national scale.

  13. Serum Autotaxin is a Marker of the Severity of Liver Injury and Overall Survival in Patients with Cholestatic Liver Diseases

    PubMed Central

    Wunsch, Ewa; Krawczyk, Marcin; Milkiewicz, Malgorzata; Trottier, Jocelyn; Barbier, Olivier; Neurath, Markus F.; Lammert, Frank; Kremer, Andreas E.; Milkiewicz, Piotr

    2016-01-01

    Autotaxin (ATX) is involved in the synthesis of lysophosphatidic acid. Both have recently been linked to cholestatic pruritus and liver injury. We aimed to investigate whether ATX is an indicator of cholestatic liver injury, health-related quality of life (HRQoL) and prognosis based on a group of 233 patients, 118 with primary biliary cholangitis (PBC) and 115 with primary sclerosing cholangitis (PSC). Patients were followed for 1–60 months, cumulative survival rates were calculated. ATX activity was significantly higher in both groups than in the 103 controls, particularly in patients with cirrhosis and in patients with longer disease duration. Ursodeoxycholic acid (UDCA) non-responders with PBC exhibited increased ATX activity. ATX activity was correlated with liver biochemistry, MELD, Mayo Risk scores and was associated with worse disease-specific HRQoL aspects. In both groups, Cox model analysis indicated that ATX was a negative predictor of survival. Increased ATX levels were associated with a 4-fold higher risk of death/liver transplantation in patients with PBC and a 2.6-fold higher risk in patients with PSC. We conclude that in patients with cholestatic conditions, ATX is not only associated with pruritus but also indicates impairment of other HRQoL aspects, liver dysfunction, and can serve as a predictor of survival. PMID:27506882

  14. The tumor necrosis factor receptor superfamily member 1B polymorphisms predict response to anti-TNF therapy in patients with autoimmune disease: A meta-analysis.

    PubMed

    Chen, Wenjuan; Xu, Hui; Wang, Xiuxiu; Gu, Junying; Xiong, Huizi; Shi, Yuling

    2015-09-01

    Numerous published data on the tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) gene polymorphisms are shown to be associated with response or non-response to anti-TNF therapy in autoimmune diseases such as rheumatoid arthritis (RA), psoriasis and Crohn's Disease (CD). The aim of this study is to investigate whether the TNFRSF1B rs1061622 T/G or TNFRSF1A A/G rs767455 polymorphisms can predict the response to anti-TNF-based therapy in patients with autoimmune diseases. We conducted a meta-analysis of studies on the association between TNFRSF1B rs1061622 T/G polymorphism or TNFRSF1A A/G rs767455 polymorphism and non-responsiveness to anti-TNF therapy in autoimmune diseases. A total of 8 studies involving 929 subjects for TNFRSF1B rs1061622 and 564 subjects for TNFRSF1A rs767455 were finally considered. These studies consisted of seven studies on the TNFRSF1B polymorphism and four studies on the TNFRSF1A polymorphism. Meta-analysis showed significant association between the TNFRSF1B rs1061622 allele and non-responders to anti-TNF therapy [T/G odds ratio (OR) 0.72, 95% confidence interval (CI) 0.57-0.93, p=0.01]. Stratification by disease type indicated an association between the TNFRSF1B rs1061622 allele and non-responders to TNF antagonist in RA (T/G OR 0.69, 95% CI 0.48-0.99, p<0.05) and psoriasis (T/G OR 0.39, 95% CI 0.23-0.67, p<0.001), but not in CD (T/G OR 1.14, 95% CI 0.57-0.93, p=0.57). And there was no association between TNFRSF1A rs767455 genotype and non-responders to the anti-TNF therapy (A/G OR 0.93, 95% CI 0.70-1.23, p=0.59). This meta-analysis demonstrates that TNFRSF1B T allele carriers show a better response to anti-TNF therapy, and individuals carrying TNFRSF1A A allele have no relationship with the response to anti-TNF therapy for autoimmune diseases. The genotyping of this polymorphism could help to optimize the treatment by identifying patients with a likely poor response to biological drugs.

  15. Duration of hemodynamic effects of crystalloids in patients with circulatory shock after initial resuscitation

    PubMed Central

    2014-01-01

    Background In the later stages of circulatory shock, monitoring should help to avoid fluid overload. In this setting, volume expansion is ideally indicated only for patients in whom the cardiac index (CI) is expected to increase. Crystalloids are usually the choice for fluid replacement. As previous studies evaluating the hemodynamic effect of crystalloids have not distinguished responders from non-responders, the present study was designed to evaluate the duration of the hemodynamic effects of crystalloids according to the fluid responsiveness status. Methods This is a prospective observational study conducted after the initial resuscitation phase of circulatory shock (>6 h vasopressor use). Critically ill, sedated adult patients monitored with a pulmonary artery catheter who received a fluid challenge with crystalloids (500 mL infused over 30 min) were included. Hemodynamic variables were measured at baseline (T0) and at 30 min (T1), 60 min (T2), and 90 min (T3) after a fluid bolus, totaling 90 min of observation. The patients were analyzed according to their fluid responsiveness status (responders with CI increase >15% and non-responders ≤15% at T1). The data were analyzed by repeated measures of analysis of variance. Results Twenty patients were included, 14 of whom had septic shock. Overall, volume expansion significantly increased the CI: 3.03 ± 0.64 L/min/m2 to 3.58 ± 0.66 L/min/m2 (p < 0.05). From this period, there was a progressive decrease: 3.23 ± 0.65 L/min/m2 (p < 0.05, T2 versus T1) and 3.12 ± 0.64 L/min/m2 (p < 0.05, period T3 versus T1). Similar behavior was observed in responders (13 patients), 2.84 ± 0.61 L/min/m2 to 3.57 ± 0.65 L/min/m2 (p < 0.05) with volume expansion, followed by a decrease, 3.19 ± 0.69 L/min/m2 (p < 0.05, T2 versus T1) and 3.06 ± 0.70 L/min/m2 (p < 0.05, T3 versus T1). Blood pressure and cardiac filling pressures also decreased significantly after

  16. Aquaporin-4 antibody titration in NMO patients treated with rituximab

    PubMed Central

    Marnetto, Fabiana; Granieri, Letizia; Capobianco, Marco; Bertolotto, Antonio

    2016-01-01

    Objective: We undertook an observational retrospective study to investigate the usefulness of aquaporin-4 (AQP4) antibodies (Ab) titration in the management of patients with neuromyelitis optica (NMO) treated with rituximab (RTX) by studying (1) the correlation between AQP4-Ab titer and disease activity, (2) the influence of RTX on antibody levels, and (3) the association between AQP4-Ab levels and responsiveness to RTX. Methods: A cell-based assay was used for AQP4-Ab titration in 322 serum samples from 7 patients with NMO treated with RTX (median follow-up 65 months), according to a treatment-to-target approach. Serum samples were collected every month following standardized procedures. Results: (1) In group analysis, AQP4-Ab titers correlated with the disease activity, showing higher titers during and preceding relapses than during remission. However, in individual analysis, an increase in AQP4-Ab titers and CD19+ B cells did not always precede a relapse. (2) A reduction of AQP4-Ab titers in the short-term and long-term period was observed during RTX treatment. (3) Reduction of AQP4-Ab titers was observed in responder patients both 3 months after RTX infusion and in the long-term follow-up. In one nonresponder patient, AQP4-Ab levels never decreased during the treatment period. Conclusions: Titration of AQP4-Abs could be useful in the clinical management of patients with NMO treated with RTX: titration before each reinfusion and 3 months after each reinfusion may provide information about responsiveness to RTX. Although a relationship among AQP4-Ab levels, disease activity, and response to RTX was observed, the usefulness of AQP4-Ab titration to predict relapses is limited. PMID:28054001

  17. The Relationship between Leishmaniasis and AIDS: the Second 10 Years

    PubMed Central

    Alvar, Jorge; Aparicio, Pilar; Aseffa, Abraham; Den Boer, Margriet; Cañavate, Carmen; Dedet, Jean-Pierre; Gradoni, Luigi; Ter Horst, Rachel; López-Vélez, Rogelio; Moreno, Javier

    2008-01-01

    Summary: To date, most Leishmania and human immunodeficiency virus (HIV) coinfection cases reported to WHO come from Southern Europe. Up to the year 2001, nearly 2,000 cases of coinfection were identified, of which 90% were from Spain, Italy, France, and Portugal. However, these figures are misleading because they do not account for the large proportion of cases in many African and Asian countries that are missed due to a lack of diagnostic facilities and poor reporting systems. Most cases of coinfection in the Americas are reported in Brazil, where the incidence of leishmaniasis has spread in recent years due to overlap with major areas of HIV transmission. In some areas of Africa, the number of coinfection cases has increased dramatically due to social phenomena such as mass migration and wars. In northwest Ethiopia, up to 30% of all visceral leishmaniasis patients are also infected with HIV. In Asia, coinfections are increasingly being reported in India, which also has the highest global burden of leishmaniasis and a high rate of resistance to antimonial drugs. Based on the previous experience of 20 years of coinfection in Europe, this review focuses on the management of Leishmania-HIV-coinfected patients in low-income countries where leishmaniasis is endemic. PMID:18400800

  18. Patients with Haemoglobinopathies and Chronic Hepatitis C: A Real Difficult to Treat Population in 2016?

    PubMed Central

    Zachou, Kalliopi; Arvaniti, Pinelopi; Gatselis, Nikolaos K.; Azariadis, Kalliopi; Papadamou, Georgia; Rigopoulou, Eirini; Dalekos, George N.

    2017-01-01

    Background & objectives In the past, patients with haemoglobinopathies were at high risk of acquiring hepatitis C virus (HCV) due to multiple transfusions before HCV screening. In these patients, the coexistence of haemochromatosis and chronic hepatitis C (CHC) often leads to more severe liver disease. We assessed the HCV prevalence, clinical characteristics and outcome in this setting with particular attention to the response to treatment including therapies with the new direct acting antivirals (DAAs). Methods The medical records of 81 consecutive patients followed the last 15 years were reviewed retrospectively. Results 43/81 (53%) patients were anti-HCV positive including 31/43 (72.1%) with CHC (HCV-RNA positive; age 25±7 years; 45.2% with genotype 1b; 19.4% cirrhotics; baseline ferritin 887 ng/ml; range: 81–10.820). Thirty patients received IFN-based therapy with or without ribavirin with sustained virological response (SVR) in 14/30 (46.7%). Eleven patients (9 non-responders to IFN-based therapies, one in relapse and one naïve) received treatment with DAAs (SVR: 100%). 3/11 patients increased their transfusion needs while 1/11 reported mild arthralgias. No drug-drug interactions between DAAs and chelation agents were observed as attested by the stability of ferritin levels during treatment. Conclusions More than 1/3 of patients with haemoglobinopathies suffered from CHC. Response rates to IFN-based treatment seem to be similar to other patients with CHC, while most importantly, treatment with DAAs was excellent and safe even in difficult to treat patients (most null responders with severe fibrosis) suggesting that this group of HCV patients should no longer be regarded as a difficult to treat. PMID:28101309

  19. Tophus burden reduction with pegloticase: results from phase 3 randomized trials and open-label extension in patients with chronic gout refractory to conventional therapy

    PubMed Central

    2013-01-01

    Introduction Two replicate randomized, placebo-controlled six-month trials (RCTs) and an open-label treatment extension (OLE) comprised the pegloticase development program in patients with gout refractory to conventional therapy. In the RCTs, approximately 40% of patients treated with the approved dose saw complete response (CR) of at least one tophus. Here we describe the temporal course of tophus resolution, total tophus burden in patients with multiple tophi, tophus size at baseline, and the relationship between tophus response and urate-lowering efficacy. Methods Baseline subcutaneous tophi were analyzed quantitatively using computer-assisted digital images in patients receiving pegloticase (8 mg biweekly or monthly) or placebo in the RCTs, and pegloticase in the OLE. Tophus response, a secondary endpoint in the trials, was evaluated two ways. Overall tophus CR was the proportion of patients achieving a best response of CR (without any new/enlarging tophi) and target tophus complete response (TT-CR) was the proportion of all tophi with CR. Results Among 212 patients randomized in the RCTs, 155 (73%) had ≥1 tophus and 547 visible tophi were recorded at baseline. Overall tophus CR was recorded in 45% of patients in the biweekly group (P = 0.002 versus placebo), 26% in the monthly group, and 8% in the placebo group after six months of RCT therapy. TT-CR rates at six months were 28%, 19%, and 2% of tophi, respectively. Patients meeting the primary endpoint of sustained urate-lowering response to therapy (responders) were more likely than nonresponders to have an overall tophus CR at six months (54% vs 20%, respectively and 8% with placebo). Both overall tophus CR and TT-CRs increased with treatment duration in the OLE, reaching 70% (39/56) of patients and 55% (132/238) of target tophi after one year of treatment in patients receiving pegloticase during both the RCTs and OLE. At that time point, more tophi had resolved in responders (102/145 or 70% of tophi) than

  20. Pulse pressure variation to predict fluid responsiveness in spontaneously breathing patients: tidal vs. forced inspiratory breathing.

    PubMed

    Hong, D M; Lee, J M; Seo, J H; Min, J J; Jeon, Y; Bahk, J H

    2014-07-01

    We evaluated whether pulse pressure variation can predict fluid responsiveness in spontaneously breathing patients. Fifty-nine elective thoracic surgical patients were studied before induction of general anaesthesia. After volume expansion with hydroxyethyl starch 6 ml.kg(-1) , patients were defined as responders by a ≥ 15% increase in the cardiac index. Haemodynamic variables were measured before and after volume expansion and pulse pressure variations were calculated during tidal breathing and during forced inspiratory breathing. Median (IQR [range]) pulse pressure variation during forced inspiratory breathing was significantly higher in responders (n = 29) than in non-responders (n = 30) before volume expansion (18.2 (IQR 14.7-18.2 [9.3-31.3])% vs. 10.1 (IQR 8.3-12.6 [4.8-21.1])%, respectively, p < 0.001). The receiver-operating characteristic curve revealed that pulse pressure variation during forced inspiratory breathing could predict fluid responsiveness (area under the curve 0.910, p < 0.0001). Pulse pressure variation measured during forced inspiratory breathing can be used to guide fluid management in spontaneously breathing patients.

  1. Baroreflex sensitivity might predict responders to milrinone in patients with heart failure.

    PubMed

    Kishi, Takuya; Sunagawa, Kenji

    2010-01-01

    The phosphodiesterase III inhibitor milrinone (MIL) is considered to be effective for "wet and cold" heart failure. In some cases, however, the inotropic effects of milrinone are insufficient. A previous study suggested that baroreflex sensitivity (BRS) predicts the cases in which MIL increases left ventricular dp/dt. The aim of this study was to determine whether BRS measured using the spontaneous sequence method predicts the MIL responders. Twenty-four patients with "wet and cold" heart failure whose systolic blood pressure > 100 mmHg were enrolled. At 2 hours MIL improved dys-pnea, general fatigue, urine volume, and tricuspid regurgitant pressure gradient in 13 patients (responders; R group), whereas it failed to improve in 11 patients (nonresponders; NR group). BRS in the R group was significantly higher than that in the NR group prior to the MIL infusion. At 2 hours after the MIL infusion, BRS was further increased in the R group, but did not increase in the NR group. The sensitivity and specificity of BRS at a cut-off level of 5 ms/mmHg for the prediction of R group were 0.94 and 0.93, respectively. BRS might be useful for identifying potential responders to milrinone in patients with blood pressure-preserved "wet and cold" heart failure.

  2. Functional Connectivity Substrates for tDCS Response in Minimally Conscious State Patients

    PubMed Central

    Cavaliere, Carlo; Aiello, Marco; Di Perri, Carol; Amico, Enrico; Martial, Charlotte; Thibaut, Aurore; Laureys, Steven; Soddu, Andrea

    2016-01-01

    Transcranial direct current stimulation (tDCS) is a non-invasive technique recently employed in disorders of consciousness, and determining a transitory recovery of signs of consciousness in almost half of minimally conscious state (MCS) patients. Although the rising evidences about its possible role in the treatment of many neurological and psychiatric conditions exist, no evidences exist about brain functional connectivity substrates underlying tDCS response. We retrospectively evaluated resting state functional Magnetic Resonance Imaging (fMRI) of 16 sub-acute and chronic MCS patients (6 tDCS responders) who successively received a single left dorsolateral prefrontal cortex (DLPFC) tDCS in a double-blind randomized cross-over trial. A seed-based approach for regions of left extrinsic control network (ECN) and default-mode network (DMN) was performed. tDCS responders showed an increased left intra-network connectivity for regions co-activated with left DLPFC, and significantly with left inferior frontal gyrus. Non-responders (NR) MCS patients showed an increased connectivity between left DLPFC and midline cortical structures, including anterior cingulate cortex and precuneus. Our findings suggest that a prior high connectivity with regions belonging to ECN can facilitate transitory recovery of consciousness in a subgroup of MCS patients that underwent tDCS treatment. Therefore, resting state-fMRI could be very valuable in detecting the neuronal conditions necessary for tDCS to improve behavior in MCS. PMID:27857682

  3. Immunological response to hepatitis B vaccination in patients with AIDS and virological response to highly active antiretroviral therapy.

    PubMed

    Paitoonpong, Leilani; Suankratay, Chusana

    2008-01-01

    Previous studies showed that an immunological response to hepatitis B virus (HBV) vaccination in patients with AIDS was lower than in the normal population. However, those with virological response to highly active antiretroviral therapy (HAART) may have a normal immunological response to HBV vaccination. In our study, patients with AIDS who had a virological response to HAART and no immunity to HBV received 3 doses of HBV vaccine (20 microg of Engerix-B(R)) on d 0, 30, and 180. Anti-HBs level was measured 1 month after complete vaccination. Of 28 patients, overall response rate to vaccination was 71.4%. The responder group had a significantly higher CD4 count at 1 month after complete vaccination than the non-responder group (466.95+/-146.94 and 335+/-112.62 cells/microl, p =0.035). The patients receiving efavirenz-containing HAART had better response than those without efavirenz-containing HAART (p =0.030). The responder group had received a longer duration of HAART. In conclusion , to our knowledge, ours is the first prospective study to determine the immunological response to HBV vaccination in all patients with AIDS who had maintained the virological response after receiving HAART throughout the study period. Patients with AIDS and virological response to HAART have a good immunological response to HBV vaccination.

  4. CT versus FDG-PET/CT response evaluation in patients with metastatic colorectal cancer treated with irinotecan and cetuximab

    PubMed Central

    Skougaard, Kristin; Johannesen, Helle Hjorth; Nielsen, Dorte; Schou, Jakob Vasehus; Jensen, Benny Vittrup; Høgdall, Estrid V S; Hendel, Helle Westergren

    2014-01-01

    We compared morphologic computed tomography (CT)-based to metabolic fluoro-deoxy-glucose (FDG) positron emission tomography (PET)/CT-based response evaluation in patients with metastatic colorectal cancer and correlated the findings with survival and KRAS status. From 2006 to 2009, patients were included in a phase II trial and treated with cetuximab and irinotecan every second week. They underwent FDG-PET/CT examination at baseline and after every fourth treatment cycle. Response evaluation was performed prospectively according to Response Evaluation Criteria in Solid Tumors (RECIST 1.0) and retrospectively according to Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST). Best overall responses were registered. Sixty-one patients were eligible for response evaluation. Partial response (PR) rate was 18%, stable disease (SD) rate 64%, and progressive disease (PD) rate 18%. Partial metabolic response (PMR) rate was 56%, stable metabolic disease rate 33%, and progressive metabolic disease (PMD) rate 11%. Response agreement was poor, κ-coefficient 0.19. Hazard ratio for overall survival for responders (PR/PMR) versus nonresponders (PD/PMD) was higher for CT- than for FDG-PET/CT evaluation. Within patients with KRAS mutations, none had PR but 44% had PMR. In conclusion, morphologic and metabolic response agreement was poor primarily because a large part of the patients shifted from SD with CT evaluation to PMR when evaluated with FDG-PET/CT. Furthermore, a larger fraction of the patients with KRAS mutations had a metabolic treatment response. PMID:24941936

  5. Glycyrrhizin in patients who failed previous interferon alpha-based therapies: biochemical and histological effects after 52 weeks

    PubMed Central

    Manns, M P; Wedemeyer, H; Singer, A; Khomutjanskaja, N; Dienes, H P; Roskams, T; Goldin, R; Hehnke, U; Inoue, H

    2012-01-01

    Chronic hepatitis C patients often fail to respond to interferon-based therapies. This phase III study aimed at confirming the efficacy and safety of glycyrrhizin in interferon + ribavirin-based therapy non-responders. A randomised, double-blind, placebo-controlled, comparison of glycyrrhizin, administered intravenously 5×/or 3×/week, and 5×/week placebo for 12 weeks to 379 patients, was followed by a randomised, open comparison of glycyrrhizin i.v. 5×/versus 3×/week for 40 weeks. Primary endpoints were: (1) the proportion of patients with ≥50% ALT (alanine aminotransferase) reduction after 12 weeks double-blind phase, and (2) the proportion of patients with improvement of necro-inflammation after 52 weeks as compared with baseline. The proportion of patients with ALT reduction ≥50% after 12 weeks was significantly higher with 5×/week glycyrrhizin (28.7%, P < 0.0001) and 3×/week glycyrrhizin (29.0%, P < 0.0001) compared with placebo (7.0%). The proportion of patients with improvement in necro-inflammation after 52 weeks was 44.9% with 5×/week and 46.0% with 3×/week, respectively. Glycyrrhizin exhibited a significantly higher ALT reduction compared to placebo after 12 weeks of therapy and an improvement of necro-inflammation and fibrosis after 52-weeks treatment. Generally, glycyrrhizin treatment was well tolerated. PMID:22762137

  6. Quantitative Thermal Testing Profiles as a Predictor of Treatment Response to Topical Capsaicin in Patients with Localized Neuropathic Pain

    PubMed Central

    Veciana, M.; Caro, C.; Montero, J.; Mayoral, V.

    2017-01-01

    There are no reliable predictors of response to treatment with capsaicin. Given that capsaicin application causes heat sensation, differences in quantitative thermal testing (QTT) profiles may predict treatment response. The aim of this study was to determine whether different QTT profiles could predict treatment outcomes in patients with localized peripheral neuropathic pain (PeLNP). We obtained from medical records QTT results and treatment outcomes of 55 patients treated between 2010 and 2013. Warm sensation threshold (WST) and heat pain threshold (HPT) values were assessed at baseline at the treatment site and in the asymptomatic, contralateral area. Responders were defined as those who achieved a > 30% decrease in pain lasting > 30 days. Two distinct groups were identified based on differences in QTT profiles. Most patients (27/31; 87.1%) with a homogenous profile were nonresponders. By contrast, more than half of the patients (13/24, 54.2%) with a nonhomogenous profile were responders (p = 0.0028). A nonhomogenous QTT profile appears to be predictive of response to capsaicin. We hypothesize patients with a partial loss of cutaneous nerve fibers or receptors are more likely to respond. By contrast, when severe nerve damage or normal cutaneous sensations are present, the pain is likely due to central sensitization and thus not responsive to capsaicin. Prospective studies with larger patient samples are needed to confirm this hypothesis. PMID:28321335

  7. Common polymorphisms of the peroxisome proliferator-activated receptor-gamma (Pro12Ala) and peroxisome proliferator-activated receptor-gamma coactivator-1 (Gly482Ser) and the response to pioglitazone in Chinese patients with type 2 diabetes mellitus.

    PubMed

    Hsieh, Ming-Chia; Lin, Kun-Der; Tien, Kai-Jen; Tu, Shih-Te; Hsiao, Jeng-Yueh; Chang, Shun-Jen; Lin, Shiu-Ru; Shing, Shih-Jang; Chen, Hung-Chun

    2010-08-01

    We investigated the effects of the common polymorphisms in the peroxisome proliferator-activated receptor-gamma (PPAR-gamma; Pro12Ala) and in PPAR-gamma coactivator-1(PGC-1; Gly482Ser) genes on the response to pioglitazone in Chinese with type 2 diabetes mellitus. A total of 250 patients with type 2 diabetes mellitus were treated with pioglitazone (30 mg/d) for 24 weeks without a change in previous medications. All patients were genotyped for the PPAR-gamma Pro12Ala and PGC-1 Gly482Ser polymorphisms. The Ala12Ala and Pro12Ala genotypes (26.0% vs 13.5%, P = .025) and Ala allele (15.6% vs 7.3%, P = .008) were significantly more frequent in pioglitazone responders than in nonresponders. The distribution of PGC-1 genotypes and alleles was not significantly different between responders and nonresponders. The decrease in fasting glucose (50.4 +/- 52.2 vs 43.3 +/- 51.7 mg/dL, P < .001) and hemoglobin A(1c) (0.57% +/- 1.44% vs 0.35% +/- 1.10%, P = .004) levels was significantly greater in subjects with the Ala12 carriers (Pro12Ala and Ala12Ala) than in those without the allele (Pro12Pro). Baseline fasting glucose and triglyceride levels were related to the response of pioglitazone. Only the PPAR-gamma Pro12Ala polymorphism was found to be associated with the response of pioglitazone by multiple logistic regression analysis. The PPAR-gamma Pro12Ala gene polymorphism is associated with the response to pioglitazone in Chinese patients with type 2 diabetes mellitus. These findings may be helpful for targeted treatment of diabetes by identifying patients who are likely to respond to pioglitazone.

  8. Long-Term Outcome of Sequential Therapy with Lamivudine Followed by Interferon-β in Nucleoside-Naive, Hepatitis B e-Antigen-Positive Patients with Chronic Hepatitis B Virus Genotype C Infection.

    PubMed

    Enomoto, Masaru; Nishiguchi, Shuhei; Tamori, Akihiro; Kozuka, Ritsuzo; Hayashi, Takehiro; Kohmoto, Madoka Toyama; Jomura, Hisato; Morikawa, Hiroyasu; Murakami, Yoshiki; Shiomi, Susumu; Kawada, Norifumi

    2015-08-01

    It is unclear whether the combination of a nucleos(t)ide analog and interferon (IFN) is superior to monotherapy for treating chronic hepatitis B. In this study, we report the long-term outcomes of sequential therapy using lamivudine followed by IFN-β. This study included 24 hepatitis B e-antigen (HBeAg)-positive patients with chronic hepatitis B virus (HBV) genotype C infection who were treated with lamivudine alone for 16-32 weeks, then with both IFN-β and lamivudine for 4 weeks, and finally with IFN-β alone for 20 weeks. All patients were followed up for 7.1±2.8 years post-treatment. The rate of response, defined as transaminase normalization, HBeAg loss, and HBV DNA <10(4) copies/mL, was 5/24 (21%) at 24 weeks post-treatment. The patients with short-term responses were younger than those with no response (P=0.039). More short-term responders had undetectable HBV DNA at the start of IFN-β compared with the nonresponders (P=0.0059). Subsequently, 4 of the 5 short-term responders remained free of the need for further drug treatment for 4.2±3.5 years post-treatment; more short-term responders remained drug free than did nonresponders (P=0.035). In conclusion, the rate of response to sequential therapy was limited in HBeAg-positive patients with chronic HBV genotype C infection at 24 weeks post-treatment. In the majority of the short-term responders, however, the response was sustainable in the long term.

  9. Long-term Efficacy and Safety of Adalimumab in Pediatric Patients with Crohn's Disease

    PubMed Central

    Dubinsky, Marla; Ruemmele, Frank M.; Escher, Johanna; Rosh, Joel; Hyams, Jeffrey S.; Eichner, Samantha; Li, Yao; Reilly, Nattanan; Thakkar, Roopal B.; Robinson, Anne M.; Lazar, Andreas

    2017-01-01

    Background: IMAgINE 1 assessed 52-week efficacy and safety of adalimumab in children with moderate to severe Crohn's disease. Long-term efficacy and safety of adalimumab for patients who entered the IMAgINE 2 extension are reported. Methods: Patients who completed IMAgINE 1 could enroll in IMAgINE 2. Endpoints assessed from weeks 0 to 240 of IMAgINE 2 were Pediatric Crohn's Disease Activity Index remission (Pediatric Crohn's Disease Activity Index ≤ 10) and response (Pediatric Crohn's Disease Activity Index decrease ≥15 from IMAgINE 1 baseline) using observed analysis and hybrid nonresponder imputation (hNRI). For hNRI, discontinued patients were imputed as failures unless they transitioned to commercial adalimumab (with study site closure) or adult care, where last observation was carried forward. Corticosteroid-free remission in patients receiving corticosteroids at IMAgINE 1 baseline, discontinuation of immunomodulators (IMMs) in patients receiving IMMs at IMAgINE 2 baseline, and linear growth improvement were reported as observed. Adverse events were assessed for patients receiving ≥1 adalimumab dose in IMAgINE 1 and 2 through January 2015. Results: Of 100 patients enrolled in IMAgINE 2, 41% and 48% achieved remission and response (hNRI) at IMAgINE 2 week 240. Remission rates were maintained by 45% (30/67, hNRI) of patients who entered IMAgINE 2 in remission. At IMAgINE 2 week 240, 63% (12/19) of patients receiving corticosteroids at IMAgINE 1 baseline achieved corticosteroid-free remission and 30% (6/20) of patients receiving IMMs at IMAgINE 2 baseline discontinued IMMs. Adalimumab treatment led to growth velocity normalization. No new safety signals were identified. Conclusions: Efficacy and safety profiles of prolonged adalimumab treatment in children with Crohn's disease were consistent with IMAgINE 1 and adult Crohn's disease adalimumab trials. PMID:28129288

  10. SPLENIC VOLUME CHANGE AND THERAPUETIC RESPONSE IN PATIENTS TREATED WITH RADIOMMUNOCONJUGATES

    SciTech Connect

    Shen, S; DeNardo, G L; Yuan, A; Siantar, C H; O'Donnell, R T; DeNardo, S J

    2005-04-06

    Splenomegaly is frequently found in non-Hodgkin's lymphoma (NHL) patients. This study evaluated the implications of splenic volume change in response to radioimmunotherapy (RIT). Twenty-nine NHL patients treated with radiolabeled-Lym-1 and 9 breast cancer patients (reference group) treated with radiolabeled-ChL6, BrE-3 or m170 were analyzed using CT splenic images obtained before and after RIT. Patient-specific radiation doses to spleen were determined using actual splenic volume determined by CT and body weight. In 13 of 29 NHL patients who had splenic volume {le} 310 ml, there was no or small change (-23 to 15 mL) in splenic volume, despite splenic doses as high as 14.4 Gy. Similarly, in a reference group of 9 breast cancer patients, there was no or small change (-5 to 13 mL), despite splenic doses as high as 11.4 Gy. In contrast, 13 of 29 NHL patients who had splenic volume 380-1400 mL, splenic volume decreased by 68 to 548 mL despite splenic doses as low as 1.40 Gy. Ten of 29 NHL patients with greater than a 15% decrease in splenic volume after RIT had nodal tumor regression (5 CR, 5 PR). In the remaining 19 NHL patients with less than a 15% decrease in splenic volume after RIT, there were 7 non-responders (5 CR and 7 PR). Splenic volume changes were found in NHL patients with splenomegaly. These splenic volume changes is likely due to therapeutic effect on malignant lymphocytes associated with splenomegaly. Nodal tumor response was more likely when splenomegaly decreased after RIT.

  11. Interaction of 5-HTT and HTR1A gene polymorphisms in treatment responses to mirtazapine in patients with major depressive disorder.

    PubMed

    Chang, Hun Soo; Lee, Hwa-Young; Cha, Ji-Hyun; Won, Eun Soo; Ham, Byung-Joo; Kim, Bohye; Lee, Min-Soo

    2014-08-01

    We tested for the association of HTR1A and 5-HTT genetic polymorphisms with treatment response to mirtazapine and evaluated the interactive effect between the polymorphisms in 283 patients with major depressive disorder. Korean subjects with diagnosis of major depressive disorder using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Axis I disorders were recruited. Clinical symptoms were evaluated using the 17-item Hamilton Depression Rating (HAMD-17) Scale at baseline and after 1, 2, 4, 8, and 12 weeks of treatment with mirtazapine. The genetic association of 5-HTTLPR and HTR1A+272G>A with treatment response was analyzed. We found a significant association of the 12.12-repeat genotype of 5-HTT various number tandem repeat (VNTR) with a large percentage decline in HAMD-17 Scale score after 4, 8, and 12 weeks of treatment with mirtazapine. We also found that the frequency of the 12.12-repeat genotype was higher in responders than in nonresponders at week 8. The HTR1A+272GG genotype was significantly associated with a large percentage decline in HAMD-17 Scale score at 4, 8, and 12 weeks, although the genotypic frequencies were comparable between responders and nonresponders during the study period. Patients with the 12.12-repeat 5-HTT VNTR and GG of HTR1A+272G>A showed the highest HAMD-17 Scale percentage reduction during the study period and a better treatment response status after 4 weeks. These results suggest that the interaction between HTR1A+272G>A and 5-HTT VNTR is involved in the response to mirtazapine treatment and that a combination of these may be a useful marker for predicting treatment response to mirtazapine.

  12. Patient-reported outcome measures in arthroplasty registries

    PubMed Central

    Bohm, Eric; Franklin, Patricia; Lyman, Stephen; Denissen, Geke; Dawson, Jill; Dunn, Jennifer; Eresian Chenok, Kate; Dunbar, Michael; Overgaard, Søren; Garellick, Göran; Lübbeke, Anne

    2016-01-01

    Abstract — The International Society of Arthroplasty Registries (ISAR) Patient-Reported Outcome Measures (PROMs) Working Group have evaluated and recommended best practices in the selection, administration, and interpretation of PROMs for hip and knee arthroplasty registries. The 2 generic PROMs in common use are the Short Form health surveys (SF-36 or SF-12) and EuroQol 5-dimension (EQ-5D). The Working Group recommends that registries should choose specific PROMs that have been appropriately developed with good measurement properties for arthroplasty patients. The Working Group recommend the use of a 1-item pain question (“During the past 4 weeks, how would you describe the pain you usually have in your [right/left] [hip/knee]?”; response: none, very mild, mild, moderate, or severe) and a single-item satisfaction outcome (“How satisfied are you with your [right/left] [hip/knee] replacement?”; response: very unsatisfied, dissatisfied, neutral, satisfied, or very satisfied). Survey logistics include patient instructions, paper- and electronic-based data collection, reminders for follow-up, centralized as opposed to hospital-based follow-up, sample size, patient- or joint-specific evaluation, collection intervals, frequency of response, missing values, and factors in establishing a PROMs registry program. The Working Group recommends including age, sex, diagnosis at joint, general health status preoperatively, and joint pain and function score in case-mix adjustment models. Interpretation and statistical analysis should consider the absolute level of pain, function, and general health status as well as improvement, missing data, approaches to analysis and case-mix adjustment, minimal clinically important difference, and minimal detectable change. The Working Group recommends data collection immediately before and 1 year after surgery, a threshold of 60% for acceptable frequency of response, documentation of non-responders, and documentation of incomplete or

  13. Reduced effect of percutaneous renal denervation on blood pressure in patients with isolated systolic hypertension.

    PubMed

    Ewen, Sebastian; Ukena, Christian; Linz, Dominik; Kindermann, Ingrid; Cremers, Bodo; Laufs, Ulrich; Wagenpfeil, Stefan; Schmieder, Roland E; Böhm, Michael; Mahfoud, Felix

    2015-01-01

    Renal denervation can reduce blood pressure in certain patients with resistant hypertension. The effect in patients with isolated systolic hypertension (ISH, ≥140/<90 mm Hg) is unknown. This study investigated the effects of renal denervation in 126 patients divided into 63 patients with ISH and 63 patients with combined hypertension (CH, ≥140/≥90 mm Hg) defined as baseline office systolic blood pressure (SBP) ≥140 mm Hg despite treatment with ≥3 antihypertensive agents. Renal denervation significantly reduced office SBP and diastolic blood pressure (DBP) at 3, 6, and 12 months by 17/18/17 and 5/4/4 mm Hg in ISH and by 28/27/30 and 13/16/18 mm Hg in CH, respectively. The reduction in SBP and DBP in ISH was lower compared with patients with CH at all observed time points (P<0.05 for SBP/DBP intergroup comparison). The nonresponder rate (change in office SBP <10 mm Hg) after 6 months was 37% in ISH and 21% in CH (P<0.001). Mean 24-hour ambulatory SBP and DBP after 3, 6, and 12 months were significantly reduced by 10/13/15 and 6/6/9 mm Hg in CH, respectively. In patients with ISH the reduction in systolic ambulatory blood pressure was 4/8/7 mm Hg (P=0.032/P<0.001/P=0.009) and 3/4/2 mm Hg (P=0.08/P<0.001/P=0.130) in diastolic ambulatory blood pressure after 3, 6, and 12 months, respectively. The ambulatory blood pressure reduction was significantly lower after 3 and 12 months in SBP and after 12 months in ambulatory DBP, respectively. In conclusion, renal denervation reduces office and ambulatory blood pressure in patients with ISH. However, this reduction is less pronounced compared with patients with CH.

  14. In vitro chemosensitivity testing of leukemic cells: prediction of response to chemotherapy in patients with acute non-lymphocytic leukemia.

    PubMed

    Santini, V; Bernabei, P A; Silvestro, L; Dal Pozzo, O; Bezzini, R; Viano, I; Gattei, V; Saccardi, R; Ferrini, P R

    1989-01-01

    The in vitro chemosensitivity to daunorubicin and cytosine arabinoside of blast cells derived from 35 patients affected by acute non-lymphocytic leukemia was assessed by a semiautomated tetrazolium-based colorimetric assay, by the use of p-iodonitrotetrazolium violet. The results of the in vitro testing were then compared a posteriori to clinical outcome of patients, who followed a schedule of therapy which always included the drugs tested in vitro. Three dosages of drugs were employed to allow the determination of a dose-response curve, which was obtained for all the patients. The data collected in INT assay correlated with the clinical sensitivity of patients, evaluated in terms of achievement of complete remission. For the dosage of ARA-C 500 ng/ml it was possible to establish a significant cutoff between responders and non-responders to therapy, while an acceptable distribution of sensitivity/resistance prediction was found for DNR 500 ng/ml and 5 micrograms/ml. Present results, together with rapid and easy execution of the test, encourage the use of INT assay in screening leukemic patients' sensitivity to antiblastic drugs before treatment or, in case of resistance to classical chemotherapy, in detecting individual sensitivity to alternative drugs.

  15. Failure of mefloquine therapy in progressive multifocal leukoencephalopathy: report of two Japanese patients without human immunodeficiency virus infection.

    PubMed

    Kobayashi, Zen; Akaza, Miho; Numasawa, Yoshiyuki; Ishihara, Shoichiro; Tomimitsu, Hiroyuki; Nakamichi, Kazuo; Saijo, Masayuki; Morio, Tomohiro; Shimizu, Norio; Sanjo, Nobuo; Shintani, Shuzo; Mizusawa, Hidehiro

    2013-01-15

    Although progressive multifocal leukoencephalopathy (PML) cases showing responses to mefloquine therapy have been reported, the efficacy of mefloquine for PML remains unclear. We report on the failure of mefloquine therapy in two Japanese patients with PML unrelated to human immunodeficiency virus. One of the patients was a 47-year-old male who had been treated with chemotherapy for Waldenström macroglobulinemia, and the other was an 81-year-old male with idiopathic CD4(+) lymphocytopenia. Diagnosis of PML was established based on MRI findings and increased JC virus DNA in the cerebrospinal fluid in both patients. Mefloquine was initiated about 5 months and 2 months after the onset of PML, respectively. During mefloquine therapy, clinical and radiological progression was observed, and JC virus DNA in the cerebrospinal fluid was increased in both patients. Both patients died about 4 months and 2 months after initiation of mefloquine, respectively. Further studies are necessary to clarify the differences between mefloquine responders and non-responders in PML.

  16. Airway Inflammatory Biomarker: Could It Tailor the Right Medications for the Right Asthmatic Patient?

    PubMed

    Zedan, Magdy Mohamed; Osman, Amal Mohamed; Laimon, Wafaa Nabil; Zedan, Mohamed Magdy; Abo-Elkheir, Nermin Youssef; Zaki, Ahmed

    2016-06-01

    Asthma is a heterogeneous disease, in which asthmatic patients present with different clinical phenotypes, variable endotypes, and different response to asthma medicines. Thus, we are faced with an asthma paradox; asthma is diagnosed subjectively by clinical history and treated with biologically active drugs. To solve this paradox, we need objective airway biomarkers to tailor the proper medications to the proper patient. Biomarkers should have one or more of the following characteristics:1) A biomarker that could differentiate poor symptoms perceivers from over perceivers, 2) A biomarker that could predict disease activity and hence disease outcome, 3) A biomarker that could clarify responders from non-responders asthma phenotypes, and finally 4) A biomarker that could characterize different clinical asthma phenotypes. In conclusion, we have conducted a review of literature trying to apply those four parameters to different airway inflammatory biomarkers. We found that FeNO fulfilled the four proposed clinical parameters of airway inflammatory biomarkers whereas; serum periostin was the single best systemic biomarker of airway luminal and tissue eosinophilia in severe uncontrolled TH2 asthma phenotype. Thus, this may be considered a trial towards tailoring the proper medication to the proper patient. However, application of biomarkers in clinical practice requires easier and cheaper techniques together with standardized methods for sample collection and analysis.

  17. Metabolic response to everolimus in patient-derived triple negative breast cancer xenografts.

    PubMed

    Euceda, Leslie R; Hill, Deborah K; Stokke, Endre; Hatem, Rana; Botty, Rania El; Bièche, Ivan; Marangoni, Elisabetta; Bathen, Tone F; Moestue, Siver A

    2017-03-14

    Patients with triple negative breast cancer (TNBC) are unresponsive to endocrine and anti-HER2 pharmacotherapy, limiting their therapeutic options to chemotherapy. TNBC is frequently associated with abnormalities in the PI3K/AKT/mTOR signaling pathway; drugs targeting this pathway are currently being evaluated in these patients. However, response is variable, partly due to heterogeneity within TNBC, conferring a need to identify biomarkers predicting response and resistance to targeted therapy. In this study, we used a metabolomics approach to assess response to the mTOR inhibitor everolimus in a panel of TNBC patient-derived xenografts (PDX) (n=103 animals). Tumor metabolic profiles were acquired using high-resolution magic angle spinning magnetic resonance spectroscopy. Partial least squares-discriminant analysis on relative metabolite concentrations discriminated treated xenografts from untreated controls with an accuracy of 67% (p=0.003). Multilevel linear mixed-effects models (LMM) indicated reduced glycolytic lactate production and glutaminolysis after treatment, consistent with PI3K/AKT/mTOR pathway inhibition. Although inherent metabolic heterogeneity between different PDX models seemed to hinder prediction of treatment response, the metabolic effects following treatment were more pronounced in responding xenografts compared to non-responders. Additionally, the metabolic information predicted p53 mutation status, which may provide complimentary insight into the interplay between PI3K signaling and other drivers of disease progression.

  18. MATE1 regulates cellular uptake and sensitivity to imatinib in CML patients

    PubMed Central

    Harrach, S; Schmidt-Lauber, C; Pap, T; Pavenstädt, H; Schlatter, E; Schmidt, E; Berdel, W E; Schulze, U; Edemir, B; Jeromin, S; Haferlach, T; Ciarimboli, G; Bertrand, J

    2016-01-01

    Although imatinib is highly effective in the treatment of chronic myeloid leukemia (CML), 25–30% patients do not respond or relapse after initial response. Imatinib uptake into targeted cells is crucial for its molecular response and clinical effectiveness. The organic cation transporter 1 (OCT1) has been proposed to be responsible for this process, but its relevance has been discussed controversially in recent times. Here we found that the multidrug and toxin extrusion protein 1 (MATE1) transports imatinib with a manifold higher affinity. MATE1 mainly mediates the cellular uptake of imatinib into targeted cells and thereby controls the intracellular effectiveness of imatinib. Importantly, MATE1 but not OCT1 expression is reduced in total bone marrow cells of imatinib-non-responding CML patients compared with imatinib-responding patients, indicating that MATE1 but not OCT1 determines the therapeutic success of imatinib. We thus propose that imatinib non-responders could be identified early before starting therapy by measuring MATE1 expression levels. PMID:27635733

  19. Predictive and Prognostic Significance of Glutathione Levels and DNA Damage in Cervix Cancer Patients Undergoing Radiotherapy

    SciTech Connect

    Vidyasagar, Mamidipudi Srinivasa; Kodali, Maheedhar; Prakash Saxena, Pu

    2010-10-01

    Purpose: To assess the predictive significance of serum glutathione (GSH) and tumor tissue DNA damage in the treatment of cervical cancer patients undergoing chemoradiotherapy. Methods and Materials: This study included subjects undergoing hysterectomy (for normal cervix tissue) and cervical cancer patients who underwent conventional concurrent chemoradiotherapy (cisplatin once per week for 5 weeks with concurrent external radiotherapy of 2 Gy per fraction for 5 weeks, followed by two applications of intracavitary brachytherapy once per week after 2 weeks' rest). Blood was collected after two fractions, whereas both blood and tissues were collected after five fractions of radiotherapy in separate groups of subjects. Serum for total GSH content and tissues were processed for single-cell gel electrophoresis (SCGE) assay for DNA damage analysis. Clinical tumor radioresponse was assessed 2 months after the completion of treatment as complete responders (CR) (100% shrinkage), partial responders (PR) (>50%), and nonresponders (NR) (<50%). Results: Serum GSH content depleted significantly after a total dose of 4 Gy and 10 Gy of radiotherapy with a single dose of cisplatin, which was significantly lesser in NR than of CR patients. Similarly, Olive Tail Moment, the index of DNA damage, indicated significantly higher values in the fifth fraction of radiotherapy (5-RT) than in pretreatment. The DNA damage after 5-RT in the NR subgroup was significantly lower than that of CR. Conclusions: Serum GSH analysis and tumor tissue SCGE assay found to be useful parameters for predicting chemoradioresponse prior to and also at an early stage of treatment of cervical cancers.

  20. Range of Effective Corticosteroid Doses for Alleviating Dyspnea in Terminal Cancer Patients: A Retrospective Review.

    PubMed

    Maeda, Tsuyoshi; Hayakawa, Toru

    2017-03-01

    This study aimed to determine the range of mean cumulative corticosteroid doses that could effectively palliate dyspnea in opioid-treated patients with terminal cancer and to investigate the demographic or biochemical factors predictive of corticosteroid responsiveness. To this end, responders and nonresponders were compared with regard to corticosteroid dose and whether they had initiated opioid use before or concomitantly with corticosteroid use. A logistic regression analysis was conducted to assess the impacts of demographic and biochemical factors on corticosteroid effectiveness. The final sample comprised 20 patients who satisfied the selection criteria. The responders accounted for 70% of the total sample (n = 14) and experienced the strongest effect with regard to dyspnea palliation at a mean cumulative dose equivalent to 64.4 mg prednisolone. However, no factors predictive of response were identified. In summary, this retrospective study identified effective corticosteroid doses for dyspnea alleviation in terminal cancer patients. Although our study sample was limited in size, the results support further prospective research.

  1. Low-density lipoprotein receptor genetic polymorphism in chronic hepatitis C virus Egyptian patients affects treatment response

    PubMed Central

    Naga, Mazen; Amin, Mona; Algendy, Dina; Elbadry, Ahmed; Fawzi, May; Foda, Ayman; Esmat, Serag; Sabry, Dina; Rashed, Laila; Gabal, Samia; Kamal, Manal

    2015-01-01

    AIM: To correlate a genetic polymorphism of the low-density lipoprotein (LDL) receptor with antiviral responses in Egyptian chronic hepatitis C virus (HCV) patients. METHODS: Our study included 657 HCV-infected patients with genotype 4 who received interferon-based combination therapy. Patients were divided into two groups based on their response to therapy: 356 were responders, and 301 were non-responders. Patients were compared to 160 healthy controls. All patients and controls underwent a thorough physical examination, measurement of body mass index (BMI) and the following laboratory tests: serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin, total bilirubin, direct bilirubin, prothrombin time, prothrombin concentration, INR, complete blood count, serum creatinine, fasting blood sugar, HCV antibody, and hepatitis B surface antigen. All HCV patients were further subjected to the following laboratory tests: HCV-RNA using quantitative polymerase chain reaction (PCR), antinuclear antibodies, thyroid-stimulating hormone, an LDL receptor (LDLR) genotype study of LDLR exon8c.1171G>A and exon10c.1413G>A using real-time PCR-based assays, abdominal ultrasonography, ultrasonographic-guided liver biopsy, and histopathological examination of liver biopsies. Correlations of LDL receptor polymorphisms with HAI, METAVIR score, presence of steatosis, and BMI were performed in all cases. RESULTS: There were no statistically significant differences in response rates between the different types of interferon used or LDLR exon10c.1413G>A. However, there was a significant difference in the frequency of the LDL receptor exon8c.1171G>A genotype between cases (AA: 25.9%, GA: 22.2%, GG: 51.9%) and controls (AA: 3.8%, GA: 53.1% and GG: 43.1%) (P < 0.001). There was a statistically significant difference in the frequency of the LDLR exon 8C:1171 G>A polymorphism between responders (AA: 3.6%, GA: 15.2%, GG: 81.2%) and non-responders (AA: 52.2%, GA: 30

  2. Long-term efficacy of empirical chronic amiodarone therapy in patients with sustained ventricular tachyarrhythmia and structural heart disease.

    PubMed

    Aiba, Takeshi; Kurita, Takashi; Taguchi, Atsushi; Shimizu, Wataru; Suyama, Kazuhiro; Aihara, Naohiko; Kamakura, Shiro

    2002-04-01

    The efficacy of empirical chronic oral amiodarone therapy in 129 patients with sustained ventricular tachyarrhythmia (VTNVF) and structural heart disease is evaluated. Twenty-nine patients were treated with class I drugs and monitored by electrophysiological study (EPS) and Holter electrocardiogram (ECG) (class I). The remaining 100 non-responders to the class I drugs were treated with oral amiodarone, of whom 70 were tolerant (AMD+) and 30 were intolerant (AMD-). Patients were followed up to 36 months. The primary and secondary end-points were recurrence of VT/VF and hypothetical death, respectively; whereby, hypothetical death was defined as actual death and the event of rapid VT.VF (heart rate >240beats/min) in patients with an implantable cardioverter defibrillator. Class I and AMD+ patients showed a better prognosis than AMD- patients. The VT/VF event free at 36 months in class I (64.8%) and AMD+ (56.1%) patients were significantly higher than that in AMD- (27.2%) (p<0.01) patients. Hypothetical survival rates in class I (92.0%) and AMD+ (83.6%) patients were significantly higher than that in AMD- (57.0%) (p<0.001) patients, but there were no significant differences in the actual survival rate among the 3 patient groups. The independent clinical factors suppressing the recurrence of VT/VF (Cox hazard) were treatment with amiodarone (p=0.02, 95% confidence interval (CI) =0.19-0.86) and EPS/Holter ECG-guided Class I drugs (p=0.04, 95% CI=0.14-0.94). The results demonstrate that empirical amiodarone has a substantial long-term benefit that is comparable to EPS/Holter ECG-guided class I drugs in the treatment of high-risk patients with VT/VF and structural heart disease.

  3. Bendamustine in heavily pre-treated multiple myeloma patients: Results of a retrospective analysis from the Korean Multiple Myeloma Working Party

    PubMed Central

    Kim, Seok Jin; Bang, Soo-Mee; Choi, Yoon Seok; Jo, Deog-Yeon; Kim, Jin Seok; Lee, Hyewon; Eom, Hyeon Seok; Yoon, Dok Hyun; Suh, Cheolwon; Lee, Je-Jung; Hong, Junshik; Lee, Jae Hoon; Koh, Youngil; Kim, Kihyun

    2016-01-01

    Background Bendamustine may be a potential treatment option for patients with myeloma, but little is known about the utility of bendamustine as a salvage treatment, especially in Asian patients. Methods We performed a multicenter retrospective study of patients with relapsed or refractory myeloma who received bendamustine and prednisone. Results The records of 65 heavily pre-treated patients, who had undergone bortezomib and lenalidomide treatment (median number of previous treatments: 5), were analyzed. The median time from diagnosis to bendamustine treatment was 3.8 years, and the median patient age was 63 years (range, 38‒77 yr). The responses to the last treatment before bendamustine were refractory disease (N=52, 80%) or disease progression from partial response (N=13, 20%). Twenty-three patients responded to the treatment, with an overall response rate of 35% (23/65), and the median number of bendamustine treatment cycles was two (range, 1‒5 cycles). The median overall survival after bendamustine treatment was 5.5 months and the overall survival rate in responders to bendamustine was significantly better than that in non-responders (P=0.036). Conclusion Bendamustine may be a potential salvage treatment to extend survival in a select group of heavily pre-treated patients with relapsed or refractory myeloma. PMID:27722131

  4. Sofosbuvir plus simeprevir for the treatment of HCV genotype 4 patients with advanced fibrosis or compensated cirrhosis is highly efficacious in real life.

    PubMed

    Willemse, S B; Baak, L C; Kuiken, S D; van der Sluys Veer, A; Lettinga, K D; van der Meer, J T M; Depla, A C T M; Tuynman, H; van Nieuwkerk, C M J; Schinkel, C J; Kwa, D; Reesink, H W; van der Valk, M

    2016-12-01

    Chronic hepatitis C virus (HCV) infection is a major cause of chronic liver disease and liver-related death. Recently, multiple regimens of different direct-acting antiviral agents (DAAs) have been registered. Although treatment with sofosbuvir (SOF) and simeprevir (SMV) is registered for the treatment of genotype 4 patients in some countries, data on efficacy of this combination are lacking. We aimed to assess the efficacy of SOF and SMV with or without RBV during 12 weeks in a real-life cohort of genotype 4 HCV patients. A retrospective multicentre observational study was conducted in 4 hospitals in Amsterdam, the Netherlands, including patients with advanced liver fibrosis or liver cirrhosis treated with SOF plus SMV with or without RBV during 12 weeks for a genotype 4 chronic HCV infection from 1 January 2015 to 1 August 2015. Sustained viral response (SVR) was established at week 12 after end of treatment. A total of 53 patients with genotype 4 HCV infection, treatment naïve and experienced, were included. SVR was achieved in 49 of 53 patients (92%). The four failures all had a virological relapse and did not receive ribavirin. Three were nonresponder to earlier interferon-based treatment, and one was treatment naive. In this real-life cohort of patients with HCV genotype 4 infection and advanced liver fibrosis/cirrhosis, we show that treatment with SOF and SMV is effective. The addition of RBV could be considered in treatment-experienced patients as recommended in guidelines.

  5. [Relation of pulmonary vascular response to pressure-flow relationship during incremental exercise in patients with chronic obstructive pulmonary disease (COPD)].

    PubMed

    Yamamoto, T; Okada, O; Tanabe, N; Yasuda, J; Satou, K; Saitou, M; Yoshida, Y; Katou, K; Kuriyama, T

    1994-03-01

    Twenty-eight COPD patients underwent right heart catheterization while in clinically stable condition. Pulmonary vascular response to oxygen was evaluated by the percent change in pulmonary arteriolar resistance after 100% oxygen inhalation (% delta PAR), and its relation to the pressure-flow relationship during incremental exercise was assessed. Mean pulmonary arterial pressure (PPA) during exercise was plotted against the cardiac index (C.I.) from rest to maximal exercise in each patient. In most of the patients, the changes in PPA were nearly linear to the C.I. Therefore, a slope could be obtained from the regression equation in each patient. Patients were divided into two groups according to whether their % delta PAR was greater than 20 defined as a responder (RES), or less than five defined as a non-responder (N-RES). Seven out of 28 patients were RES, nine were N-RES, RES showed a higher %FEV1.0 level, C.I. and stroke volume index (S.I.) at maximal exercise, and a lower level of RV/TLC as well as slope. The slope correlated significantly with %DLCO (r = -0.724, p < 0.01), baseline PAR (r = 0.562, p < 0.01) and % delta PAR (r = -0.522, p < 0.01). These results suggest that the diminished pulmonary vascular bed, and the distensibility of pulmonary vessels, appear to contribute to the steepness of the slope and reduced % delta PAR in patients with COPD.

  6. Serum hepcidin levels in patients with end-stage renal disease on hemodialysis.

    PubMed

    Rubab, Zille; Amin, Huma; Abbas, Khizer; Hussain, Shabbir; Ullah, Muhammad Ikram; Mohsin, Shahida

    2015-01-01

    Patients on hemodialysis (HD) are usually anemic because of defective erythropoeisis. Hepcidin is a polypeptide that regulates iron homeostasis and could serve as an indicator of functional iron deficiency in patients with end-stage renal disease (ESRD); this may also aid in the assessment of patient's response to erythropoietin (EPO). The present study was directed to investigate serum levels of hepcidin, iron status and inflammation markers such as C-reactive protein (CRP) in patients with ESRD on maintenance HD and to observe the correlation of serum hepcidin with conventional iron and inflammatory markers. A total of 42 patients of both sexes on maintenance HD and EPO therapy were enrolled; 42 ageand sex-matched healthy subjects were included as controls. Laboratory tests including complete blood count, serum hepcidin, total iron binding capacity (TIBC), serum ferritin, serum iron and CRP were performed. Serum hepcidin levels were significantly higher in patients with ESRD than in the control group (18.2 ± 2.8 ng/mL and 8.5 ± 2.3 ng/mL, respectively P = 0.000). The hemoglobin, hematocrit, serum iron, TIBC and transferrin saturation levels in the patient group were significantly lower than in the control group. Higher hepcidin levels were found in EPO non-responders (19.6 ± 2.4 ng/mL) while lower levels (16.9 ± 2.5 ng/mL) were seen in responders (P = 0.001). A positive and significant correlation was observed between the values of serum hepcidin and CRP. Our study indicates that higher hepcidin levels are found in ESRD patients on HD and in those not responding to EPO. Our findings suggest that hepcidin might play a role in the pathophysiology of anemia associated with chronic diseases as well as EPO resistance.

  7. Antiplatelet Effect of Sequential Administration of Cilostazol in Patients with Acetylsalycilic Acid Resistance

    PubMed Central

    Cakmak, Muzaffer; Demircelik, Bora; Cetin, Mustafa; Cetin, Zehra; Isık, Serhat; Cıcekcıoglu, Hulya; Ulusoy, Feridun Vasfi; Eryonucu, Beyhan

    2016-01-01

    Background Acetylsalicylic acid (ASA) resistance in patients with coronary artery disease is an important medical problem that can affect treatment decision-making and outcomes. Cilostazol has been investigated to determine its effectiveness in patients with acetylsalicylic acid resistance. The aim of this study was to evaluate the antiplatelet efficacy of sequential administration of CLZ in patients with ASA resistance. Methods A total of 180 patients were enrolled in our study. Patients with stable coronary artery disease were first given orally ASA 100 for 10 days, followed by collagen/epinephrine induced closure time (CTCEPI) measurements. Those who were found to be resistant to orally 100 mg of ASA were given orally 300 mg of ASA for an additional 10 days after which we repeated CTCEPI measurements. Those patients with resistance to orally 300 mg ASA were then given CLZ at a daily dose of orally 200 mg for 10 days followed by a final CTCEPI measurement. Results The rate of resistance to 100 mg ASA was 81/180 (45%) compared to a rate of 35/81 (43.2%) with 300 mg ASA. Of the 35 patients found to be resistant to 300 mg ASA, 22 (62.9%) also failed to respond to CLZ treatment. Overall, sequential administration of 300 mg ASA and 200 mg CLZ resulted in a reduction in the number of non-responders from 45% to 12.2%. Conclusions Initiation of CLZ could be of benefit in some patients with ASA-resistance for whom an effective anti-aggregant effect is of clinical importance. PMID:27274173

  8. The role of HE4 for prediction of recurrence in epithelial ovarian cancer patients-results from the OVCAD study.

    PubMed

    Nassir, Mani; Guan, Jun; Luketina, Hrvoje; Siepmann, Timo; Rohr, Irena; Richter, Rolf; Castillo-Tong, Dan Cacsire; Zeillinger, Robert; Vergote, Ignace; Van Nieuwenhuysen, Els; Concin, Nicole; Marth, Christian; Hall, Christina; Mahner, Sven; Woelber, Linn; Sehouli, Jalid; Braicu, Elena Ioana

    2016-03-01

    Patients with epithelial ovarian cancer (EOC) are at high risk of tumor recurrence. Human epididymis protein 4 (HE4) has been shown to be overexpressed in EOC. The primary aim of our study was to evaluate the role of HE4 in predicting recurrence in EOC patients. Furthermore, we assessed the role of HE4 in predicting recurrence after second-line chemotherapy. We retrospectively analyzed data of 92 out of 275 primary EOC patients of the multicenter project "Ovarian Cancer: Diagnosis of a silent killer" (OVCAD). The concentrations of HE4 and CA125 were determined preoperatively and 6 months after the end of platinum-based first-line chemotherapy (FU) using ELISA and Luminex technique, respectively. The role of HE4 and CA125 for prediction of recurrence was determined using receiver operating characteristics (ROC) curves. Out of 92 patients included, 70 (76 %) were responders and 22 (23 %) non-responders in terms of response to platinum-based first-line chemotherapy. Median HE4 concentrations at follow-up (FU) differed between responders and non-responders (60.5 vs. 237.25 pM, p = 0.0001), respectively. The combined use of HE4 and CA125 at FU with cut-off values of 49.5 pM and 25 U/ml for HE4 and CA125, respectively, for predicting recurrence within 12 months after first-line chemotherapy performed better than HE4 or CA125 alone (area under the curve (AUC) 0.928, 95 % confidence intervals (CI) 0.838-1, p < 0.001). HE4 at FU could predict recurrence within 6 months after second-line chemotherapy (AUC 0.719, 95 % CI 0.553-0.885, p = 0.024). The combination of both elevated biomarkers revealed significantly worse estimated median progression-free survival (PFS; hazard ratio (HR) 8.14, 95 % CI 3.75-17.68, p < 0.001) and slightly worse PFS in those in whom only one biomarker was elevated (HR 1.46, 95 % CI 0.72-2.96, p = 0.292) compared to those patients in whom no biomarker was elevated. For the estimated median overall survival (OS), our

  9. The effectiveness of retreatment with peginterferon alfa and ribavirin in patients with chronic viral hepatitis C genotype 2 and 3: a prospective cohort study in Brazil

    PubMed Central

    2012-01-01

    Background More than 50% of patients infected with chronic hepatitis C virus (HCV) do not respond to treatment with conventional interferon (IFN) combined with ribavirin (RBV). The aim of our study was to evaluate the effectiveness of retreatment with peginterferon alfa-2a or 2b (PEG-IFN 2a or 2b) concomitantly with RBV in patients with HCV genotype 2 and 3, which were non-responders or relapsers to initial treatment with IFN / RBV and to identify possible predictors of sustained virological response (SVR). Methods From September 2003 to March 2009 a cohort of 216 patients who had previously failed therapy with a regimen of standard interferon and ribavirin, were followed in a specialized service implemented in the Brazilian Unified Health System, Rio Grande do Sul. All patients were retreated with PEG-IFN 2a or 2b per week, associated with RBV, through oral route, with doses determined according to weight (1,000 mg if weight ≤ 75 Kg and 1,250 mg if ≥ 75 Kg) per day for 48 weeks. The HCV-RNA was tested by Polymerase Chain Reaction (PCR). Virological Response (VR) within 48 weeks and SVR in the 72 weeks was considered for evaluation of treatment efficacy. Analyses were performed in patients who received at least one dose of PEG-IFN. Results The SVR rate for non-responders to previous treatment was 34.4% and for relapsers was 50% (p = 0.031). As predictive factors that contribute to improve SVR, were identified the age (p = 0.005), to be relapsers to previous treatment (p = 0.023) and present liver biopsy examination Metavir F0-F2 (p = 0.004). In assessing the safety profile, 51 patients (23.6%) discontinued treatment prematurely. Conclusions This alternative retreatment for patients who have failed prior therapies for anti-HCV, has demonstrated promising SVR rate, provided that it includes a careful selection of patients with predictors of response and adverse events monitored. PMID:23270376

  10. 25-OH vitamin D level has no impact on the efficacy of antiviral therapy in naïve genotype 1 HCV-infected patients

    PubMed Central

    Belle, Arthur; Gizard, Emmanuel; Conroy, Guillaume; Lopez, Anthony; Bouvier-Alias, Magali; Rouanet, Stéphanie; Peyrin-Biroulet, Laurent; Pawlotsky, Jean-Michel

    2016-01-01

    Background and aim The impact of 25-OH vitamin D on sustained viral response (SVR) to antiviral therapy and on fibrosis progression in hepatitis C is debated. We assessed the impact of 25-OH vitamin D concentration on the efficacy of antiviral therapy in naïve genotype 1 hepatitis C virus (HCV)-infected patients. Methods The study population consisted of treatment-naïve genotype 1 patients enrolled in a randomised controlled trial. A total of 516 patients received peginterferon α-2a 180 µg/week plus ribavirin 800 mg/day for 24 weeks. There were 349 patients with undetectable HCV RNA (<50 IU/ml) at week 24 (W24) who were randomised to continue dual therapy (n = 173) or to continue peginterferon alone (n = 176) until week 48. 25-OH vitamin D concentration was measured at baseline in frozen serum. Results A total of 461 patients could be analysed for virologic response at W24, and 285 (119 non-responders at W24 + 166 responders who continued dual therapy until W48) for the impact of SVR. There were 487 patients who could be analysed for fibrosis progression. Metavir fibrosis scores (centralised analysis) were: F1 30%, F2 34%, F3 27% and F4 9%. Median 25-OH vitamin D concentrations were similar in virologic responders (13.5 ng/ml) and in non-responders at W24 (12.6 ng/ml), as well as in patients with SVR (12.8 ng/ml) and without SVR (12.8 ng/ml, 3.99) at W72. Median 25-OH vitamin D concentrations were: F1: 14.30 ng/ml, F2: 13.50 ng/ml, F3: 13.30 ng/ml and F4: 12.80 ng/ml. Conclusion In this study, 25-OH vitamin D level has no impact on the efficacy of antiviral therapy in naïve genotype 1 HCV-infected patients.

  11. Absolute Measurements of Macrophage Migration Inhibitory Factor and Interleukin-1-β mRNA Levels Accurately Predict Treatment Response in Depressed Patients

    PubMed Central

    Ferrari, Clarissa; Uher, Rudolf; Bocchio-Chiavetto, Luisella; Riva, Marco Andrea; Pariante, Carmine M.

    2016-01-01

    Background: Increased levels of inflammation have been associated with a poorer response to antidepressants in several clinical samples, but these findings have had been limited by low reproducibility of biomarker assays across laboratories, difficulty in predicting response probability on an individual basis, and unclear molecular mechanisms. Methods: Here we measured absolute mRNA values (a reliable quantitation of number of molecules) of Macrophage Migration Inhibitory Factor and interleukin-1β in a previously published sample from a randomized controlled trial comparing escitalopram vs nortriptyline (GENDEP) as well as in an independent, naturalistic replication sample. We then used linear discriminant analysis to calculate mRNA values cutoffs that best discriminated between responders and nonresponders after 12 weeks of antidepressants. As Macrophage Migration Inhibitory Factor and interleukin-1β might be involved in different pathways, we constructed a protein-protein interaction network by the Search Tool for the Retrieval of Interacting Genes/Proteins. Results: We identified cutoff values for the absolute mRNA measures that accurately predicted response probability on an individual basis, with positive predictive values and specificity for nonresponders of 100% in both samples (negative predictive value=82% to 85%, sensitivity=52% to 61%). Using network analysis, we identified different clusters of targets for these 2 cytokines, with Macrophage Migration Inhibitory Factor interacting predominantly with pathways involved in neurogenesis, neuroplasticity, and cell proliferation, and interleukin-1β interacting predominantly with pathways involved in the inflammasome complex, oxidative stress, and neurodegeneration. Conclusion: We believe that these data provide a clinically suitable approach to the personalization of antidepressant therapy: patients who have absolute mRNA values above the suggested cutoffs could be directed toward earlier access to more

  12. Noninvasive Transcutaneous Monitoring in Long-Term Follow-Up of Patients With Thromboangiitis Obliterans Treated With Intravenous Iloprost.

    PubMed

    Melillo, Elio; Grigoratos, Chrysanthos; Sanctis, Francesco De; Spontoni, Paolo; Nuti, Marco; Dell'Omodarme, Matteo; Ferrari, Mauro; Balbarini, Alberto

    2015-07-01

    We evaluated the effectiveness of intravenous iloprost (IVI) in outpatients with thromboangiitis obliterans (TAO) and lower limb noninvasive transcutaneous monitoring (TCM) at follow-up (FU). Ten consecutive patients with TAO underwent IVI therapy. Transcutaneous oxygen (TcPo 2) and carbon dioxide (TcPco 2) determination and laser Doppler flowmetry (LDF) were performed before and after IVI at 3, 6, and 12 months of FU. Clinical response was positive in 7 patients, whereas 3 nonresponders underwent a second IVI cycle with 1 showing a late positive clinical response. After 12 months of FU, all patients were alive without amputations. Supine and dependent TcP2 levels significantly improved (P < .005). Hallux LDF values showed significant change with the maximal hyperemic test at 44°C (P < .005). Forefoot maximal hyperemic test at 44°C LDF (P < .005) and improved venous arterial reflex (P < .05) showed statistically significant time evolution. We demonstrated some degree of IVI effectiveness and evaluated TCM in patients with TAO.

  13. Prefrontal cortex activation during neuropsychological tasks might predict response to pharmacotherapy in patients with obsessive–compulsive disorder

    PubMed Central

    Takeda, Tomoya; Sumitani, Satsuki; Hamatani, Sayo; Yokose, Yosuke; Shikata, Megumi; Ohmori, Tetsuro

    2017-01-01

    Objective We investigated oxyhemoglobin change in the prefrontal cortex (PFC) of patients with obsessive–compulsive disorder (OCD) who showed different responses to pharmacotherapy during neuropsychological tasks with near-infrared spectroscopy. Subjects and methods A total of 42 patients with OCD (mean age: 35.6±9.6 years, 14 men, 28 women) and healthy control subjects (mean age: 35.4±9.7 years, 13 men, 29 women) were selected. Patients with OCD were divided into three groups (responders to selective serotonin-reuptake inhibitors (SSRIs), responders to SSRIs with antipsychotics, and nonresponders to SSRIs and SSRIs with antipsychotics) based on pharmacological response. We investigated oxyhemoglobin change in the PFC of subjects during Stroop tasks and a verbal fluency test with near-infrared spectroscopy. Results Responders to SSRIs showed smaller activation compared to control subjects during the Stroop incongruent task and verbal fluency test, but not during the Stroop congruent task. In contrast, responders to SSRIs with antipsychotics showed smaller activation compared to control subjects during all three tasks. Conclusion Our results suggest that activation of the PFC during Stroop tasks might predict responses to pharmacotherapy of patients with OCD. PMID:28260905

  14. Accelerated Intermittent Theta Burst Stimulation for Suicide Risk in Therapy-Resistant Depressed Patients: A Randomized, Sham-Controlled Trial

    PubMed Central

    Desmyter, Stefanie; Duprat, Romain; Baeken, Chris; Van Autreve, Sara; Audenaert, Kurt; van Heeringen, Kees

    2016-01-01

    Objectives: We aimed to examine the effects and safety of accelerated intermittent Theta Burst Stimulation (iTBS) on suicide risk in a group of treatment-resistant unipolar depressed patients, using an extensive suicide assessment scale. Methods: In 50 therapy-resistant, antidepressant-free depressed patients, an intensive protocol of accelerated iTBS was applied over the left dorsolateral prefrontal cortex (DLPFC) in a randomized, sham-controlled crossover design. Patients received 20 iTBS sessions over 4 days. Suicide risk was assessed using the Beck Scale of Suicide ideation (BSI). Results: The iTBS protocol was safe and well tolerated. We observed a significant decrease of the BSI score over time, unrelated to active or sham stimulation and unrelated to depression-response. No worsening of suicidal ideation was observed. The effects of accelerated iTBS on mood and depression severity are reported in Duprat et al. (2016). The decrease in suicide risk lasted up to 1 month after baseline, even in depression non-responders. Conclusions: This accelerated iTBS protocol was safe. The observed significant decrease in suicide risk was unrelated to active or sham stimulation and unrelated to depression response. Further sham-controlled research in suicidal depressed patients is necessary. (Clinicaltrials.gov identifier: NCT01832805). PMID:27729854

  15. Early response to neoadjuvant chemotherapy can help predict long-term survival in patients with cervical cancer

    PubMed Central

    Shen, Jian; Zhou, Hang; Yang, Runfeng; Wang, Lin; Liu, Jiong; Zhang, Jincheng; Sun, Haiying; Jia, Yao; Du, Xiaofang; Wang, Haoran; Deng, Song; Ding, Ting; Jiang, Jingjing; Lu, Yunping; Li, Shuang; Wang, Shixuan; Ma, Ding

    2016-01-01

    It is still controversial whether cervical cancer patients with clinical responses after neoadjuvant chemotherapy (NACT) have a better long-term survival or not. This study was designed to investigate the effect of the clinical response on the disease-free survival (DFS) of cervical cancer patients undergoing NACT. A total of 853 patients from a retrospective study were used to evaluate whether the clinical response was an indicator for the long-term response, and 493 patients from a prospective cohort study were used for further evaluation. The survival difference was detected by log-rank test, univariate and multivariate Cox regression and a pooled analysis. The log-rank test revealed that compared with non-responders, the DFS of responders was significantly higher in the retrospective data (P = 0.007). Univariate Cox regression showed that the clinical response was an indicator of long-term survival in the retrospective study (HR 1.83, 95% CI 1.18-2.85, P = 0.007). In a multivariate Cox model, the clinical response was still retained as an independent significant prognostic factor in the retrospective study (HR 1.59, 95% CI 1.01-2.50, P = 0.046). The result was also validated in the prospective data with similar results. These findings implied that the clinical response can be regarded as an independent predictor of DFS. PMID:27557523

  16. MiR-99b-5p expression and response to tyrosine kinase inhibitor treatment in clear cell renal cell carcinoma patients

    PubMed Central

    Lukamowicz-Rajska, Magdalena; Mittmann, Christiane; Prummer, Michael; Zhong, Qing; Bedke, Jens; Hennenlotter, Jörg; Stenzl, Arnulf; Mischo, Axel; Bihr, Svenja; Schmidinger, Manuela; Vogl, Ursula; Blume, Iris; Karlo, Christoph; Schraml, Peter; Moch, Holger

    2016-01-01

    A number of treatments targeting VEGF or mTOR pathways have been approved for metastatic clear cell Renal Cell Carcinoma (ccRCC), but the majority of patients show disease progression after first line therapy with a very low rate of complete or long-term responders. It has been shown that miRs may play a role in prediction of treatment response in various cancer types. The aim of our study was to identify a miR signature predictive for RCC patients' response to antiangiogenic tyrosine kinase inhibitor (TKI) treatment in the first line therapy. Sequencing of 40 paired normal/tumor formalin fixed and paraffin embedded ccRCC tissues revealed separate clustering via unsupervised dendrograms. With supervised analysis, the strongest differential expression was obtained with miR-99b-5p, which was significantly lower in patients with short progression free survival (<8 months) and TKI non-responders (progressive disease patients according to RECIST) (p<0.0001, each). Validation using RTqPCR and a second patient cohort compiled from three different hospitals (n=65) showed higher expression of miR-99b-5p in complete responders, but this trend did not reach statistical significance. It is concluded that low miR-99b-5p expression analyzed with sequencing methodology may correlate with tumor progression in TKI-treated ccRCC patients. PMID:27738339

  17. Bendamustine with or without rituximab for the treatment of heavily pretreated non-Hodgkin's lymphoma patients : A multicenter retrospective study on behalf of the Italian Lymphoma Foundation (FIL).

    PubMed

    Rigacci, Luigi; Puccini, Benedetta; Cortelazzo, Sergio; Gaidano, Gianluca; Piccin, Andrea; D'Arco, Alfonso; Freilone, Roberto; Storti, Sergio; Orciuolo, Enrico; Zinzani, Pier Luigi; Zaja, Francesco; Bongarzoni, Velia; Balzarotti, Monica; Rota-Scalabrini, Delia; Patti, Caterina; Gobbi, Marco; Carpaneto, Andrea; Liberati, Anna Marina; Bosi, Alberto; Iannitto, Emilio

    2012-07-01

    Bendamustine is an alkylating agent with a nitrogen mustard group and a purine-like benzimidazole group. The aim of this study was to collect all the Italian experiences with this drug in order to evaluate the results in term of response to therapy and toxicities. We analyzed lymphoma patients treated in 24 Italian haematological centres with bendamustine alone or in combination with anti-CD20 antibody. One hundred seventy-five relapsed or refractory lymphoma patients were enrolled. The median age was 69 years (range 26-87). Seventy-nine patients were relapsed, 35 were refractory and 61 presented a progressive disease after partial response. The diagnoses were 60 indolent non-follicular lymphomas, 34 diffuse large B-cell lymphomas, 48 follicular lymphomas, 30 mantle cell lymphomas and three peripheral T-cell lymphomas. All patients were evaluable for response: 52 (29%) with complete remission, 72 (43%) with partial response with an overall response rate of 71%, and 51 non-responders. With a median observation period of 10 months (1-43), 70% of patients are alive. In summary, this retrospective study shows that treatment with bendamustine alone or in combination with rituximab is a safe and effective regimen in a subset of multi-resistant patients.

  18. Long-term Outcome of Lupus Nephritis Class II in Argentine Patients

    PubMed Central

    Collado, Maria Victoria; Dorado, Enrique; Rausch, Silvia; Gomez, Graciela; Khoury, Marina; Zazzetti, Federico; Gargiulo, María; Suarez, Lorena; Chaparro, Rafael; Paira, Sergio; Galvan, Laura; Juarez, Vicente; Pisoni, Cecilia; Garcia, Mercedes; Martinez, Liliana; Alvarez, Analia; Alvarez, Clarisa; Barreira, Juan; Sarano, Judith

    2016-01-01

    Background There is controversy in medical literature over the outcome of patients with lupus nephritis (LN) class II. The aim of this study was to explore the risk of histological transformation (HT) and possible factors related to negative response to treatment in patients with mesangial LN class II. Methods A retrospective and multicenter study was carried out that includes patients who had received a diagnosis of LN class II on their first renal biopsy. Creatinine, urine sediment, and proteinuria were recorded at the time of the first biopsy, 6 months, and 1, 2, and 5 years after the first biopsy. Response to treatment, HT, and long-term outcome were evaluated. Results Forty-one patients were included. The manifestation at first biopsy was proteinuria greater than 0.5 g/d in 28 patients (68.29%; 8 [28.57%] of 28 patients had nephrotic syndrome), hematuria in 18 patients (43.90%), and deterioration of renal function in 3 patients (7.31%). During the follow-up (median, 8 years; range, 1–35 years), a new biopsy was performed in 18 patients (43.90%), and in 17 patients (17/18 [94.44%]), there was HT. Median time at rebiopsy was 32 months (range, 11–305 months). Of the 18 patients who had a second biopsy, 10 (55.55%) were on hydroxychloroquine versus 100% (19/19) of patients who did not undergo the procedure (P = 0.001). A year after the first renal biopsy, there are data available from 34 patients; of them, 24 patients (70.58%) had achieved response, and 10 patients (29.41%) had no response (NR) (missing data in 7). A higher 24-hour urinary protein at 6 months was predictor of worse outcome at 1 year, with statistical significance difference for the nonresponder group (median proteinuria, 2.3 g/d [range, 0–4.7 g/d]) compared with responders (median proteinuria, 0.28 g/d [range, 0–1.7 g/d]) (P = 0.0133). In the long-term follow-up (5 years), HT was the main cause of unfavorable outcome and was measured in 78.57% of patients (11/14 patients). Conclusions This

  19. Seroclearance of Hbsag in Chronic Hepatitis B Virus Patients on Lamivudine Therapy: A 10 Year Experience

    PubMed Central

    Sali, Shahnaz; Merza, Muayad A.; Saadat, Sina; Mustafa, Nazik H.; Queiky, Farzam; Yadegarynia, Davood

    2015-01-01

    Introduction: The aim of this study was to determine hepatitis B surface antigen (HBsAg) seroclearance rate among patients treated with lamivudine at a specialized tertiary care referral hospital in Tehran, Iran. Methods: All patients on lamivudine (biovudin®) therapy at a dose of 100 mg/day, who showed seroclearnace between March 2001 and September 2011 were recruited. The main evaluation parameters were duration of HBsAg seroclearance and duration of HBsAg seroconversion. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were evaluated using standard methods. HBsAg seroclearance was defined as two consecutive negative serums HBsAg at least 6 months apart, whereas HBsAg seroconversion was defined as the disappearance of serum HBsAg and the presence of anti-HBs for >6 months. Results: A total of 203 chronic HBV patients treated with lamivudine at a dose of 100 mg/day were included in the study. HBsAg seroclearance and seroconversion were observed in 11 patients after the initiation of the lamivudine therapy. Overall, in lamivudine responder patients, the mean time to HBsAg seroclearance was 26.90±10.93 months (range: 12-48 months). Furthermore, the responders showed seroconversion after a mean time of 26.90±11.08 months from the initiation of lamivudine therapy. When comparing the characteristics of those who have responded to lamivudine and those who have not responded, baseline HBV-DNA levels was significantly lower in responder than non responder patients (p<0.001). Meantime, there was no difference in age, sex, baseline ALT, AST and liver biopsy score between lamivudine responder and lamivudine non-responder patients. Conclusion: Despite introduction of tenofovir and entecavir as first line treatment for chronic HBV infection, lamivudine remains to be a low cost, safe and effective drug for HBsAg seroclearnace. PMID:26153167

  20. Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome.

    PubMed

    Loebel, Madlen; Grabowski, Patricia; Heidecke, Harald; Bauer, Sandra; Hanitsch, Leif G; Wittke, Kirsten; Meisel, Christian; Reinke, Petra; Volk, Hans-Dieter; Fluge, Øystein; Mella, Olav; Scheibenbogen, Carmen

    2016-02-01

    Infection-triggered disease onset, chronic immune activation and autonomic dysregulation in CFS point to an autoimmune disease directed against neurotransmitter receptors. Autoantibodies against G-protein coupled receptors were shown to play a pathogenic role in several autoimmune diseases. Here, serum samples from a patient cohort from Berlin (n=268) and from Bergen with pre- and post-treatment samples from 25 patients treated within the KTS-2 rituximab trial were analysed for IgG against human α and β adrenergic, muscarinic (M) 1-5 acetylcholine, dopamine, serotonin, angiotensin, and endothelin receptors by ELISA and compared to a healthy control cohort (n=108). Antibodies against β2, M3 and M4 receptors were significantly elevated in CFS patients compared to controls. In contrast, levels of antibodies against α adrenergic, dopamine, serotonin, angiotensin, and endothelin receptors were not different between patients and controls. A high correlation was found between levels of autoantibodies and elevated IgG1-3 subclasses, but not with IgG4. Further patients with high β2 antibodies had significantly more frequently activated HLA-DR+ T cells and more frequently thyreoperoxidase and anti-nuclear antibodies. In patients receiving rituximab maintenance treatment achieving prolonged B-cell depletion, elevated β2 and M4 receptor autoantibodies significantly declined in clinical responder, but not in non-responder. We provide evidence that 29.5% of patients with CFS had elevated antibodies against one or more M acetylcholine and β adrenergic receptors which are potential biomarkers for response to B-cell depleting therapy. The association of autoantibodies with immune markers suggests that they activate B and T cells expressing β adrenergic and M acetylcholine receptors. Dysregulation of acetylcholine and adrenergic signalling could also explain various clinical symptoms of CFS.

  1. Brachial artery peak velocity variation to predict fluid responsiveness in mechanically ventilated patients

    PubMed Central

    2009-01-01

    Introduction Although several parameters have been proposed to predict the hemodynamic response to fluid expansion in critically ill patients, most of them are invasive or require the use of special monitoring devices. The aim of this study is to determine whether noninvasive evaluation of respiratory variation of brachial artery peak velocity flow measured using Doppler ultrasound could predict fluid responsiveness in mechanically ventilated patients. Methods We conducted a prospective clinical research in a 17-bed multidisciplinary ICU and included 38 mechanically ventilated patients for whom fluid administration was planned due to the presence of acute circulatory failure. Volume expansion (VE) was performed with 500 mL of a synthetic colloid. Patients were classified as responders if stroke volume index (SVi) increased ≥ 15% after VE. The respiratory variation in Vpeakbrach (ΔVpeakbrach) was calculated as the difference between maximum and minimum values of Vpeakbrach over a single respiratory cycle, divided by the mean of the two values and expressed as a percentage. Radial arterial pressure variation (ΔPPrad) and stroke volume variation measured using the FloTrac/Vigileo system (ΔSVVigileo), were also calculated. Results VE increased SVi by ≥ 15% in 19 patients (responders). At baseline, ΔVpeakbrach, ΔPPrad and ΔSVVigileo were significantly higher in responder than nonresponder patients [14 vs 8%; 18 vs. 5%; 13 vs 8%; P < 0.0001, respectively). A ΔVpeakbrach value >10% predicted fluid responsiveness with a sensitivity of 74% and a specificity of 95%. A ΔPPrad value >10% and a ΔSVVigileo >11% predicted volume responsiveness with a sensitivity of 95% and 79%, and a specificity of 95% and 89%, respectively. Conclusions Respiratory variations in brachial artery peak velocity could be a feasible tool for the noninvasive assessment of fluid responsiveness in patients with mechanical ventilatory support and acute circulatory failure. Trial Registration

  2. Determinants of patient satisfaction in ambulatory oncology: a cross sectional study based on the OUT-PATSAT35 questionnaire

    PubMed Central

    2011-01-01

    Background The aim of this study was to identify factors associated with satisfaction with care in cancer patients undergoing ambulatory treatment. We investigated associations between patients' baseline clinical and socio-demographic characteristics, as well as self-reported quality of life, and satisfaction with care. Methods Patients undergoing ambulatory chemotherapy or radiotherapy in 2 centres in France were invited, at the beginning of their treatment, to complete the OUT-PATSAT35, a 35 item and 13 scale questionnaire evaluating perception of doctors, nurses and aspects of care organisation. Additionally, for each patient, socio-demographic variables, clinical characteristics and self-reported quality of life using the EORTC QLQ-C30 questionnaire were recorded. Results Among 692 patients included between January 2005 and December 2006, only 6 were non-responders. By multivariate analysis, poor perceived global health strongly predicted dissatisfaction with care (p < 0.0001). Patients treated by radiotherapy (vs patients treated by chemotherapy) reported lower levels of satisfaction with doctors' technical and interpersonal skills, information provided by caregivers, and waiting times. Patients with primary head and neck cancer (vs other localisations), and those living alone were less satisfied with information provided by doctors, and younger patients (< 55 years) were less satisfied with doctors' availability. Conclusions A number of clinical of socio-demographic factors were significantly associated with different scales of the satisfaction questionnaire. However, the main determinant was the patient's global health status, underlining the importance of measuring and adjusting for self-perceived health status when evaluating satisfaction. Further analyses are currently ongoing to determine the responsiveness of the OUT-PATSAT35 questionnaire to changes over time. PMID:22204665

  3. Anti-TNF-α Drugs Differently Affect the TNFα-sTNFR System and Monocyte Subsets in Patients with Psoriasis.

    PubMed

    Gibellini, Lara; De Biasi, Sara; Bianchini, Elena; Bartolomeo, Regina; Fabiano, Antonella; Manfredini, Marco; Ferrari, Federica; Albertini, Giuseppe; Trenti, Tommaso; Nasi, Milena; Pinti, Marcello; Iannone, Anna; Salvarani, Carlo; Cossarizza, Andrea; Pellacani, Giovanni

    2016-01-01

    TNF-α has a central role in the development and maintenance of psoriatic plaques, and its serum levels correlate with disease activity. Anti-TNF-α drugs are, however, ineffective in a relevant percentage of patients for reasons that are currently unknown. To understand whether the response to anti-TNF-α drugs is influenced by the production of anti-drug antibodies or by the modulation of the TNFα-TNFα receptor system, and to identify changes in monocyte phenotype and activity, we analysed 119 psoriatic patients who either responded or did not respond to different anti-TNF-α therapies (adalimumab, etanercept or infliximab), and measured plasma levels of TNF-α, TNF-α soluble receptors, drug and anti-drug antibodies. Moreover, we analyzed the production of TNF-α and TNF-α soluble receptors by peripheral blood mononuclear cells (PBMCs), and characterized different monocyte populations. We found that: i) the drug levels varied between responders and non-responders; ii) anti-infliximab antibodies were present in 15% of infliximab-treated patients, while anti-etanercept or anti-adalimumab antibodies were never detected; iii) plasma TNF-α levels were higher in patients treated with etanercept compared to patients treated with adalimumab or infliximab; iv) PBMCs from patients responding to adalimumab and etanercept produced more TNF-α and sTNFRII in vitro than patients responding to infliximab; v) PBMCs from patients not responding to infliximab produce higher levels of TNF-α and sTNFRII than patients responding to infliximab; vi) anti- TNF-α drugs significantly altered monocyte subsets. A complex remodelling of the TNFα-TNFα receptor system thus takes place in patients treated with anti-TNF-α drugs, that involves either the production of anti-drug antibodies or the modulation of monocyte phenotype or inflammatory activity.

  4. Anti-TNF-α Drugs Differently Affect the TNFα-sTNFR System and Monocyte Subsets in Patients with Psoriasis

    PubMed Central

    Bianchini, Elena; Bartolomeo, Regina; Fabiano, Antonella; Manfredini, Marco; Ferrari, Federica; Albertini, Giuseppe; Trenti, Tommaso; Nasi, Milena; Pinti, Marcello; Iannone, Anna; Salvarani, Carlo; Pellacani, Giovanni

    2016-01-01

    TNF-α has a central role in the development and maintenance of psoriatic plaques, and its serum levels correlate with disease activity. Anti-TNF-α drugs are, however, ineffective in a relevant percentage of patients for reasons that are currently unknown. To understand whether the response to anti-TNF-α drugs is influenced by the production of anti-drug antibodies or by the modulation of the TNFα-TNFα receptor system, and to identify changes in monocyte phenotype and activity, we analysed 119 psoriatic patients who either responded or did not respond to different anti-TNF-α therapies (adalimumab, etanercept or infliximab), and measured plasma levels of TNF-α, TNF-α soluble receptors, drug and anti-drug antibodies. Moreover, we analyzed the production of TNF-α and TNF-α soluble receptors by peripheral blood mononuclear cells (PBMCs), and characterized different monocyte populations. We found that: i) the drug levels varied between responders and non-responders; ii) anti-infliximab antibodies were present in 15% of infliximab-treated patients, while anti-etanercept or anti-adalimumab antibodies were never detected; iii) plasma TNF-α levels were higher in patients treated with etanercept compared to patients treated with adalimumab or infliximab; iv) PBMCs from patients responding to adalimumab and etanercept produced more TNF-α and sTNFRII in vitro than patients responding to infliximab; v) PBMCs from patients not responding to infliximab produce higher levels of TNF-α and sTNFRII than patients responding to infliximab; vi) anti- TNF-α drugs significantly altered monocyte subsets. A complex remodelling of the TNFα-TNFα receptor system thus takes place in patients treated with anti-TNF-α drugs, that involves either the production of anti-drug antibodies or the modulation of monocyte phenotype or inflammatory activity. PMID:27936119

  5. Reduced Activity of Double-Strand Break Repair Genes in Prostate Cancer Patients With Late Normal Tissue Radiation Toxicity

    SciTech Connect

    Oorschot, Bregje van; Hovingh, Suzanne E.; Moerland, Perry D.; Medema, Jan Paul; Stalpers, Lukas J.A.; Vrieling, Harry; Franken, Nicolaas A.P.

    2014-03-01

    Purpose: To investigate clinical parameters and DNA damage response as possible risk factors for radiation toxicity in the setting of prostate cancer. Methods and Materials: Clinical parameters of 61 prostate cancer patients, 34 with (overresponding, OR) and 27 without (non-responding, NR) severe late radiation toxicity were assembled. In addition, for a matched subset the DNA damage repair kinetics (γ-H2AX assay) and expression profiles of DNA repair genes were determined in ex vivo irradiated lymphocytes. Results: Examination of clinical data indicated none of the considered clinical parameters to be correlated with the susceptibility of patients to develop late radiation toxicity. Although frequencies of γ-H2AX foci induced immediately after irradiation were similar (P=.32), significantly higher numbers of γ-H2AX foci were found 24 hours after irradiation in OR compared with NR patients (P=.03). Patient-specific γ-H2AX foci decay ratios were significantly higher in NR patients than in OR patients (P<.0001). Consequently, NR patients seem to repair DNA double-strand breaks (DSBs) more efficiently than OR patients. Moreover, gene expression analysis indicated several genes of the homologous recombination pathway to be stronger induced in NR compared with OR patients (P<.05). A similar trend was observed in genes of the nonhomologous end-joining repair pathway (P=.09). This is congruent with more proficient repair of DNA DSBs in patients without late radiation toxicity. Conclusions: Both gene expression profiling and DNA DSB repair kinetics data imply that less-efficient repair of radiation-induced DSBs may contribute to the development of late normal tissue damage. Induction levels of DSB repair genes (eg, RAD51) may potentially be used to assess the risk for late radiation toxicity.

  6. Unresponsiveness to AmBisome in some Sudanese patients with kala-azar.

    PubMed

    Mueller, Marius; Ritmeijer, Koert; Balasegaram, Manica; Koummuki, Youssif; Santana, Muriel Ramirez; Davidson, Robert

    2007-01-01

    In Sudan, two treatments are currently registered for visceral leishmaniasis: sodium stibogluconate (SSG) as first line and liposomal amphotericin B (AmBisome) as second line. We present 64 patients (52 relapse cases to SSG, 12 new but complicated cases) treated with AmBisome in eastern Sudan. AmBisome was administered at 2.5-8.2mg/kg (15-49mg/kg in total) per dose six times (days 1, 2, 3, 5, 10, 15) as an intravenous infusion. We measured outcome according to clinical response and parasitological clearance (lymph node aspiration). Patient outcomes fell into three groups: group 1, clinical responders (cured) with a negative test of cure (n=35); group 2, clinical responders with a positive test of cure (n=19); group 3, clinical non-responders (failures) with a positive test of cure (n=10). Of the 10 failures, six were already relapse cases. All of group 3, and 15 from group 2, were also treated with additional SSG (20mg/kg intramuscularly daily for 30-50 d) with resulting clinical and parasitological improvement. Parasite persistence and clinical failure were associated with a higher parasite density on admission (P<0.002) and underlying immunosuppressive disease: tuberculosis (three cases) or HIV (two cases). Because AmBisome monotherapy may fail in Sudan, a combination of AmBisome and SSG is recommended for relapse cases.

  7. Predictive value of the efficacy of tolvaptan in liver cirrhosis patients using free water clearance

    PubMed Central

    MIYAAKI, HISAMITSU; NAKAMURA, YUTAKA; ICHIKAWA, TATSUKI; TAURA, NAOTA; MIUMA, SATOSHI; SHIBATA, HIDETAKA; HONDA, TAKUYA; NAKAO, KAZUHIKO

    2015-01-01

    Tolvaptan, an arginine vasopressin V2 antagonist, is available for patients with refractory ascites. Free water clearance was evaluated as a predictor of tolvaptan efficacy. Twenty-one patients with refractory ascites were enrolled in the present study. Liver function test, renal function test, urine volume, free water clearance and osmotic pressure were measured at baseline (day 0) and for each dose of tolvaptan (1.875, 3.75 and 7.5 mg), and compared for efficacy. Tolvaptan increased urine volume and free water clearance decreased osmotic pressure at each dose of tolvaptan, compared to pretreatment levels. Compared to baseline, an increased volume of free water clearance at 1.875 mg of tolvaptan showed a significant correlation with body weight reduction (r=0.480 and P=0.028). Any factors (age, liver function test and renal function test) at pretreatment showed no significant correlation with body weight reduction. An increased volume of urine and osmotic pressure at each dose was not significantly correlated with the tolvaptan effect. Compared to baseline, an increased volume of free water clearance at 1.875 mg of tolvaptan in responders was significantly increased, compared to non-responders (270±241 ml/day: 27±257 ml/day; P=0.042). In conclusion, an increased volume of free water clearance on day 1 was significantly associated with body weight reduction. Free water clearance could be a simple and useful marker for the prediction of tolvaptan efficacy. PMID:26623035

  8. Predictive value of the efficacy of tolvaptan in liver cirrhosis patients using free water clearance.

    PubMed

    Miyaaki, Hisamitsu; Nakamura, Yutaka; Ichikawa, Tatsuki; Taura, Naota; Miuma, Satoshi; Shibata, Hidetaka; Honda, Takuya; Nakao, Kazuhiko

    2015-11-01

    Tolvaptan, an arginine vasopressin V2 antagonist, is available for patients with refractory ascites. Free water clearance was evaluated as a predictor of tolvaptan efficacy. Twenty-one patients with refractory ascites were enrolled in the present study. Liver function test, renal function test, urine volume, free water clearance and osmotic pressure were measured at baseline (day 0) and for each dose of tolvaptan (1.875, 3.75 and 7.5 mg), and compared for efficacy. Tolvaptan increased urine volume and free water clearance decreased osmotic pressure at each dose of tolvaptan, compared to pretreatment levels. Compared to baseline, an increased volume of free water clearance at 1.875 mg of tolvaptan showed a significant correlation with body weight reduction (r=0.480 and P=0.028). Any factors (age, liver function test and renal function test) at pretreatment showed no significant correlation with body weight reduction. An increased volume of urine and osmotic pressure at each dose was not significantly correlated with the tolvaptan effect. Compared to baseline, an increased volume of free water clearance at 1.875 mg of tolvaptan in responders was significantly increased, compared to non-responders (270±241 ml/day: 27±257 ml/day; P=0.042). In conclusion, an increased volume of free water clearance on day 1 was significantly associated with body weight reduction. Free water clearance could be a simple and useful marker for the prediction of tolvaptan efficacy.

  9. Response Assessment and Prediction in Esophageal Cancer Patients via F-18 FDG PET/CT Scans

    NASA Astrophysics Data System (ADS)

    Higgins, Kyle J.

    Purpose: The purpose of this study is to utilize F-18 FDG PET/CT scans to determine an indicator for the response of esophageal cancer patients during radiation therapy. There is a need for such an indicator since local failures are quite common in esophageal cancer patients despite modern treatment techniques. If an indicator is found, a patient's treatment strategy may be altered to possibly improve the outcome. This is investigated with various standard uptake volume (SUV) metrics along with image texture features. The metrics and features showing the most promise and indicating response are used in logistic regression analysis to find an equation for the prediction of response. Materials and Methods: 28 patients underwent F-18 FDG PET/CT scans prior to the start of radiation therapy (RT). A second PET/CT scan was administered following the delivery of ~32 Gray (Gy) of dose. A physician contoured gross tumor volume (GTV) was used to delineate a PET based GTV (GTV-pre-PET) based on a threshold of >40% and >20% of the maximum SUV value in the GTV. Deformable registration was used in VelocityAI software to register the pre-treatment and intra-treatment CT scans so that the GTV-pre-PET contours could be transferred from the pre to intra scans (GTV-intra-PET). The fractional decrease in the maximum, mean, volume to the highest intensity 10%-90%, and combination SUV metrics of the significant previous SUV metrics were compared to post-treatment pathologic response for an indication of response. Next for the >40% threshold, texture features based on a neighborhood gray-tone dimension matrix (NGTDM) were analyzed. The fractional decrease in coarseness, contrast, busyness, complexity, and texture strength were compared to the pathologic response of the patients. From these previous two types of analysis, SUV and texture features, the two most significant results were used in logistic regression analysis to find an equation to predict the probability of a non-responder

  10. Effectiveness of Corticosteroid Monotherapy for Dyspnea Relief in Patients with Terminal Cancer.

    PubMed

    Maeda, Tsuyoshi; Hayakawa, Toru

    2017-03-30

    Dyspnea is a common symptom in patients with cancer, particularly those with late-stage terminal disease. It markedly affects terminal cancer patients, reducing their quality of life. Reduced quality of life also affects survival; therefore, dyspnea is a prognostic factor. However, the role of corticosteroids, which often are used to alleviate dyspnea, has not been sufficiently validated. In this study, we retrospectively investigated whether corticosteroid monotherapy was effective for dyspnea palliation. The effectiveness rate of corticosteroid therapy was 45% in nine male and two female study subjects (mean age: 74.5 years; range: 64-86 years). No significant differences were found between responders and nonresponders in the first-day corticosteroid doses (25.5 ± 10.86 vs. 36.1 ± 16.39 mg, P = .29) or doses administered on 2 days (47.7 ± 25.99 vs. 72.2 ± 32.78 mg, P = .25). The mean ± standard error assessment score changed significantly from 2.7 ± 0.14 at the beginning of corticosteroid administration to 1.5 ± 0.37 at the time of maximum effect (P = .028); however, the decrease to 2.1 ± 0.25 at the final administration was not significant (P = .068). This indicates that corticosteroid therapy relieved dyspnea and could provide an early-stage treatment option.

  11. RAGE Genetic Polymorphisms Are Associated with Risk, Chemotherapy Response and Prognosis in Patients with Advanced NSCLC

    PubMed Central

    Hua, Feng; Wang, Bin; Mao, Wei; Feng, Xueren

    2012-01-01

    Aim To explore the association between genetic polymorphisms of the receptor for advanced glycation end-products (RAGE) and susceptibility, chemotherapy response rate and prognosis of non-small cell lung cancer (NSCLC). Method This is a prospective study in which 562 patients with NSCLC and 764 healthy controls were enrolled. Three RAGE genetic polymorphisms, namely, −429T/C, −374T/A and 82G/S were genotyped. Platinum-based chemotherapy was given to 432 subjects with advanced inoperable NSCLC and their responses to chemotherapy were evaluated. Results All the polymorphic genotypes of RAGE polymorphisms were associated with susceptibility for NSCLC. Only the 82G/S polymorphisms denoted a significant difference between responders and non-responders to chemotherapy. The 82SS genotype and 82S allele distribution not only increased the NSCLC risk, but also was associated with a lower chemotherapy response rate and poor prognosis, indicated by overall survival and progression free survival. Conclusion The 82G/S genetic polymorphism of RAGE gene might be used as a genetic marker to screen for patients sensitive to thermotherapy and to predict the prognosis of NSCLC. PMID:23071492

  12. Phase II study of targeted therapy with temozolomide in acute myeloid leukaemia and high-risk myelodysplastic syndrome patients pre-screened for low O(6) -methylguanine DNA methyltransferase expression.

    PubMed

    Brandwein, Joseph M; Kassis, Jeannine; Leber, Brian; Hogge, Donna; Howson-Jan, Kang; Minden, Mark D; Galarneau, André; Pouliot, Jean-François

    2014-12-01

    Resistance to temozolomide is largely mediated by the DNA repair enzyme O(6) -methylguanine DNA methyltransferase (MGMT). We conducted a prospective multicentre study of patients with previously untreated acute myeloid leukaemia (AML) or high-risk myelodysplastic syndrome (MDS) who were not candidates for intensive therapy. Patient selection was based on MGMT expression by Western blot. Patients with MGMT:ACTB (β-actin) ratio <0·2 were eligible to receive temozolomide 200 mg/m(2) /d ×7 d. Patients achieving a complete response (CR) could receive up to 12 monthly cycles of temozolomide ×5/28 d. Of 166 patients screened, 81 (49%) demonstrated low MGMT expression; 45 of these were treated with temozolomide. The overall response rate was 53%; 36% achieved complete clearance of blasts, with 27% achieving a CR/CR with incomplete platelet recovery (CRp). Factors associated with a trend toward a higher response rate included MDS, methylated MGMT promoter and standard cytogenetic risk group. Induction and post-remission cycles were well-tolerated and most patients were treated on an outpatient basis. Patient who achieved CR/CRp had a superior overall survival compared to partial or non-responders. In conclusion, targeted therapy based on pre-selection for low MGMT expression was associated with a higher response rate to temozolomide compared to previous reports of unselected patients.

  13. Electroconvulsive therapy in catatonic patients: Efficacy and predictors of response

    PubMed Central

    Luchini, Federica; Medda, Pierpaolo; Mariani, Michela Giorgi; Mauri, Mauro; Toni, Cristina; Perugi, Giulio

    2015-01-01

    Recent evidence favors the view of catatonia as an autonomous syndrome, frequently associated with mood disorders, but also observed in neurological, neurodevelopmental, physical and toxic conditions. From our systematic literature review, electroconvulsive therapy (ECT) results effective in all forms of catatonia, even after pharmacotherapy with benzodiazepines has failed. Response rate ranges from 80% to 100% and results superior to those of any other therapy in psychiatry. ECT should be considered first-line treatment in patients with malignant catatonia, neuroleptic malignant syndrome, delirious mania or severe catatonic excitement, and in general in all catatonic patients that are refractory or partially responsive to benzodiazepines. Early intervention with ECT is encouraged to avoid undue deterioration of the patient’s medical condition. Little is known about the long-term treatment outcomes following administration of ECT for catatonia. The presence of a concomitant chronic neurologic disease or extrapyramidal deficit seems to be related to ECT non-response. On the contrary, the presence of acute, severe and psychotic mood disorder is associated with good response. Severe psychotic features in responders may be related with a prominent GABAergic mediated deficit in orbitofrontal cortex, whereas non-responders may be characterized by a prevalent dopaminergic mediated extrapyramidal deficit. These observations are consistent with the hypothesis that ECT is more effective in “top-down” variant of catatonia, in which the psychomotor syndrome may be sustained by a dysregulation of the orbitofrontal cortex, than in “bottom-up” variant, in which an extrapyramidal dysregulation may be prevalent. Future research should focus on ECT response in different subtype of catatonia and on efficacy of maintenance ECT in long-term prevention of recurrent catatonia. Further research on mechanism of action of ECT in catatonia may also contribute to the development of

  14. Quality of life and patient satisfaction after microsurgical abdominal flap versus staged expander/implant breast reconstruction: a critical study of unilateral immediate breast reconstruction using patient-reported outcomes instrument BREAST-Q.

    PubMed

    Liu, Chunjun; Zhuang, Yan; Momeni, Arash; Luan, Jie; Chung, Michael T; Wright, Eric; Lee, Gordon K

    2014-07-01

    Staged expander-implant breast reconstruction (EIBR) and microsurgical abdominal flap breast reconstruction (MAFBR) are the most common modes of breast reconstruction (BR) in the United States. Whether the mode of breast reconstruction has an impact on patient quality of life (QoL) and satisfaction remains a question. A retrospective study was conducted identifying a population of 119 patients who underwent unilateral immediate BR. Only patients who were eligible for either EIBR or MAFBR based on preoperative characteristics were included in the study. The following parameters were retrieved: demographics, mode of reconstruction, cancer, recovery, QoL, and patient satisfaction. The latter two parameters were determined using the BREAST-Q BR module questionnaire. Two-way analysis of variance with mode of reconstruction and occurrence of complication as independent variables was used to determine the effect on patient satisfaction and QoL. The association between mode of reconstruction and patient response with each item of the QoL and satisfaction survey domains was analyzed. The overall response rate was 62.2 %. Non-respondents and respondents did not significantly differ in demographics, surgery type, cancer staging, adjuvant therapy, and complication rate. Age and BMI were significantly higher in MAFBR, while level of education was higher in EIBR. MAFBR had higher scores in psychosocial and sexual wellbeing, satisfaction with outcome, breast, information, and plastic surgeon when compared with patients who underwent EIBR. For patients eligible for both MAFBR and EIBR, MAFBR is associated with higher levels of satisfaction and QoL. Comprehensive pre-operative information of pros and cons of both modes of BR is crucial for patients to make a well-informed decision, thus, resulting in higher levels of satisfaction.

  15. Iloprost infusion in diabetic patients with peripheral arterial occlusive disease and foot ulcers.

    PubMed

    Mirenda, Francesco; La Spada, Michele; Baccellieri, Domenico; Stilo, Francesco; Benedetto, Filippo; Spinelli, Francesco

    2005-01-01

    The aim of the study was to evaluate iloprost infusion as an alternative to open surgical revascularisation in diabetic patients with foot ulcers, also as a support measure in conjunction with endovascular procedures. We studied 244 patients with critical ischaemia of the lower limbs, 146 of whom (59.8%) affected by diabetes. A femoro-distal bypass was performed in 175 patients. In the 69 nonsurgical diabetic patients (47.3% of the diabetics) an iloprost infusion was started. These diabetics presented foot ulcers, a palpable or slightly hypo-sphygmic popliteal pulse and high distal arterial flow at the ankle. In 55 of these patients (79.7% of those not operated on and 37.6% of the diabetics) who were non-responders to medical therapy, an endovascular procedure was also performed. The results of the iloprost infusion (69 pts.) were evaluated after one week. In 14 responders treated only with iloprost infusion, complete healing of the lesions occurred during the 3 weeks following the end of the 4-week course of therapy. No severe ischaemia recurrences were reported in the follow-up of these 69 patients. In the 47.3% of subjects with diabetic arteriopathy presenting foot ulcers and high distal flow, it proved possible to avoid an open surgical revascularisation procedure and to resort to medical therapy with iloprost, completed in 79.7% of cases with endovascular procedures. Iloprost infusion improves limb perfusion and, in selected cases may be an important therapeutic tool for the care of ulcerative lesions of the diabetic foot, also as a support measure in conjunction with endovascular procedures.

  16. Unique Molecular Patterns Uncovered in Kawasaki Disease Patients with Elevated Serum Gamma Glutamyl Transferase Levels: Implications for Intravenous Immunoglobulin Responsiveness

    PubMed Central

    Hao, Shiying; Deng, Xiaohong; Huang, Min; Ren, Miao; Jiang, Xiyuan; Kanegaye, John T.; Ha, Kee-Soo; Lee, JungHwa; Li, Xiaofeng; Jiang, Xuejun; Yu, Yunxian; Tremoulet, Adriana H.; Burns, Jane C.; Whitin, John C.; Shin, Andrew Y.; Sylvester, Karl G.; McElhinney, Doff B.; Cohen, Harvey J.; Ling, Xuefeng B.

    2016-01-01

    Background Resistance to intravenous immunoglobulin (IVIG) occurs in 10–20% of patients with Kawasaki disease (KD). The risk of resistance is about two-fold higher in patients with elevated gamma glutamyl transferase (GGT) levels. We sought to understand the biological mechanisms underlying IVIG resistance in patients with elevated GGT levels. Method We explored the association between elevated GGT levels and IVIG-resistance with a cohort of 686 KD patients (Cohort I). Gene expression data from 130 children with acute KD (Cohort II) were analyzed using the R square statistic and false discovery analysis to identify genes that were differentially represented in patients with elevated GGT levels with regard to IVIG responsiveness. Two additional KD cohorts (Cohort III and IV) were used to test the hypothesis that sialylation and GGT may be involved in IVIG resistance through neutrophil apoptosis. Results Thirty-six genes were identified that significantly explained the variations of both GGT levels and IVIG responsiveness in KD patients. After Bonferroni correction, significant associations with IVIG resistance persisted for 12 out of 36 genes among patients with elevated GGT levels and none among patients with normal GGT levels. With the discovery of ST6GALNAC3, a sialyltransferase, as the most differentially expressed gene, we hypothesized that sialylation and GGT are involved in IVIG resistance through neutrophil apoptosis. We then confirmed that in Cohort III and IV there was significantly less reduction in neutrophil count in IVIG non-responders. Conclusions Gene expression analyses combining molecular and clinical datasets support the hypotheses that: (1) neutrophil apoptosis induced by IVIG may be a mechanism of action of IVIG in KD; (2) changes in sialylation and GGT level in KD patients may contribute synergistically to IVIG resistance through blocking IVIG-induced neutrophil apoptosis. These findings have implications for understanding the mechanism of

  17. Achieving high treatment success for multidrug-resistant TB in Africa: initiation and scale-up of MDR TB care in Ethiopia—an observational cohort study

    PubMed Central

    Meressa, Daniel; Hurtado, Rocío M; Andrews, Jason R; Diro, Ermias; Abato, Kassim; Daniel, Tewodros; Prasad, Paritosh; Prasad, Rebekah; Fekade, Bekele; Tedla, Yared; Yusuf, Hanan; Tadesse, Melaku; Tefera, Dawit; Ashenafi, Abraham; Desta, Girma; Aderaye, Getachew; Olson, Kristian; Thim, Sok; Goldfeld, Anne E

    2015-01-01

    Background In Africa, fewer than half of patients receiving therapy for multidrug-resistant TB (MDR TB) are successfully treated, with poor outcomes reported for HIV-coinfected patients. Methods A standardised second-line drug (SLD) regimen was used in a non-governmental organisation–Ministry of Health (NGO-MOH) collaborative community and hospital-based programme in Ethiopia that included intensive side effect monitoring, adherence strategies and nutritional supplementation. Clinical outcomes for patients with at least 24 months of follow-up were reviewed and predictors of treatment failure or death were evaluated by Cox proportional hazards models. Results From February 2009 to December 2014, 1044 patients were initiated on SLD. 612 patients with confirmed or presumed MDR TB had ≥24 months of follow-up, 551 (90.0%) were confirmed and 61 (10.0%) were suspected MDR TB cases. 603 (98.5%) had prior TB treatment, 133 (21.7%) were HIV coinfected and median body mass index (BMI) was 16.6. Composite treatment success was 78.6% with 396 (64.7%) cured, 85 (13.9%) who completed treatment, 10 (1.6%) who failed, 85 (13.9%) who died and 36 (5.9%) who were lost to follow-up. HIV coinfection (adjusted HR (AHR): 2.60, p<0.001), BMI (AHR 0.88/kg/m2, p=0.006) and cor pulmonale (AHR 3.61, p=0.003) and confirmed MDR TB (AHR 0.50, p=0.026) were predictive of treatment failure or death. Conclusions We report from Ethiopia the highest MDR TB treatment success outcomes so far achieved in Africa, in a setting with severe resource constraints and patients with advanced disease. Intensive treatment of adverse effects, nutritional supplementation, adherence interventions and NGO-MOH collaboration were key strategies contributing to success. We argue these approaches should be routinely incorporated into programmes. PMID:26506854

  18. Current smoking is associated with a poor visual acuity improvement after intravitreal ranibizumab therapy in patients with exudative age-related macular degeneration.

    PubMed

    Lee, Sangmoon; Song, Su Jeong; Yu, Hyeong Gon

    2013-05-01

    In this study, the risk factors that may influence visual improvement after intravitreal ranibizumab (IVR) treatment for exudative age-related macular degeneration (AMD) were examined. From 2008 to 2012, 420 patients (448 eyes) with exudative AMD were prospectively registered at Seoul National University Hospital. From this group of patients, 125 eyes were included in this study. All patients were treated with 3 consecutive IVR injections. The visual acuity (VA) was evaluated at baseline and 1 month after the third ranibizumab injection. To evaluate the risk factors associated with VA improvement after IVR, patient demographic data and systemic risk factors were analyzed. Patients were divided into a poor VA improvement group and a good VA improvement group, with reference to the median visual improvement in all eyes. Among 125 eyes, 66 eyes (52.8%) were included in the responder group and 59 eyes (47.2%) in the non-responder group. The median VA improvement after 3 monthly ranibizumab injections was -0.05 logMAR. Multivariate analyses revealed that current smoking (adjusted OR, 7.540; 95% CI, 1.732-32.823) was independently associated with poor VA improvement after IVR treatment for exudative AMD. In conclusion, cigarette smoking is an independent risk factor for lower VA gains with IVR treatment for exudative AMD.

  19. Association of the FCGR3A-158F/V gene polymorphism with the response to rituximab treatment in Spanish systemic autoimmune disease patients.

    PubMed

    Robledo, Gema; Márquez, Ana; Dávila-Fajardo, Cristina Lucía; Ortego-Centeno, Norberto; Rubio, José Luis Callejas; Garrido, Enrique de Ramón; Sánchez-Román, Julio; García-Hernández, Francisco J; Ríos-Fernández, Raquel; González-Escribano, Maria Francisca; García, Maria Teresa Camps; Palma, Maria Jesús Castillo; Ayala, Maria Del Mar; Martín, Javier

    2012-12-01

    Rituximab is being used as treatment for systemic autoimmune diseases. The objective of this study was to determine whether the genetic variant in the Fc gamma-receptor III a (FCGR3A) gene, 158F/V, contributes to the observed variation in response to rituximab in patients with systemic autoimmune diseases. DNA samples from 132 Spanish patients with different systemic autoimmune diseases receiving rituximab were genotyped for FCGR3A-158F/V (rs396991) gene polymorphism using the TaqMan(®) allelic discrimination technology. Six months after infusion with rituximab we evaluated the response to the drug: 61% of the patients showed a complete response, partial 27% and 12% did not respond to the treatment. A statistically significant difference was observed in V allele frequency between responder (38%) and nonresponder (16%) patients (p=0.01; odds ratio [OR]=3.24, 95% confidence interval [CI] 1.17-11.1). Rituximab was also more effective in V allele carriers (94%) than in homozygous FF patients (81%): p=0.02; OR=3.96, 95% CI 1.10-17.68. These results suggest that FCGR3A-158F/V (rs396991) gene polymorphism play a role in the response to rituximab in autoimmune diseases. Validation of these findings in independent cohorts is warranted.

  20. Cognitive predictors of treatment response to bupropion and cognitive effects of bupropion in patients with major depressive disorder.

    PubMed

    Herrera-Guzmán, Ixchel; Gudayol-Ferré, Esteve; Lira-Mandujano, Jennifer; Herrera-Abarca, Jorge; Herrera-Guzmán, Daniel; Montoya-Pérez, Karina; Guardia-Olmos, Joan

    2008-07-15

    Cognitive effects of antidepressants and cognitive predictors of antidepressant treatment response are recent focuses of interest in the neuropsychology of depression. We studied the cognitive predictors of treatment response to bupropion and its neuropsychological effects in patients with major depressive disorder. Twenty subjects meeting the DSM-IV criteria for major depressive disorder were assessed with the Hamilton Depression Rating Scale and a neuropsychological battery. Subjects were medicated with 150 mg/day of bupropion sustained release for 8 weeks. At the end of the trial, 12 subjects were classified as responders to treatment and 8 were non-responders. Our findings suggest that low pretreatment measures of visual memory and low levels of mental processing speed are predictive of good response to bupropion. The cognitive effects of bupropion after the treatment showed that patients improved in visual memory measures and in mental processing speed. Our results suggest that cognitive predictors of treatment response to bupropion and cognitive effects of bupropion in patients with major depressive disorder could be closely related. These findings need to be replicated due to the exploratory nature of the present work.

  1. Prolactin-induced protein as a potential therapy response marker of adjuvant chemotherapy in breast cancer patients

    PubMed Central

    Jablonska, Karolina; Grzegrzolka, Jedrzej; Podhorska-Okolow, Marzenna; Stasiolek, Mariusz; Pula, Bartosz; Olbromski, Mateusz; Gomulkiewicz, Agnieszka; Piotrowska, Aleksandra; Rys, Janusz; Ambicka, Aleksandra; Ong, Siew Hwa; Zabel, Maciej; Dziegiel, Piotr

    2016-01-01

    Many studies are dedicated to exploring the molecular mechanisms of chemotherapy-resistance in breast cancer (BC). Some of them are focused on searching for candidate genes responsible for this process. The aim of this study was typing the candidate genes associated with the response to standard chemotherapy in the case of invasive ductal carcinoma. Frozen material from 28 biopsies obtained from IDC patients with different responses to chemotherapy were examined using gene expression microarray, Real-Time PCR (RT-PCR) and Western blot (WB). Based on the microarray results, further analysis of candidate gene expression was evaluated in 120 IDC cases by RT-PCR and in 224 IDC cases by immunohistochemistry (IHC). The results were correlated with clinical outcome and molecular subtype of the BC. Gene expression microarray revealed Prolactin-Induced Peptide (PIP) as a single gene differentially expressed in BC therapy responder or non-responder patients (p <0.05). The level of PIP expression was significantly higher in the BC therapy responder group than in the non-responder group at mRNA (p=0.0092) and protein level (p=0.0256). Expression of PIP mRNA was the highest in estrogen receptor positive (ER+) BC cases (p=0.0254) and it was the lowest in triple negative breast cancer (TNBC) (p=0.0336). Higher PIP mRNA expression was characterized by significantly longer disease free survival (DFS, p=0.0093), as well as metastasis free survival (MFS, p=0.0144). Additionally, PIP mRNA and PIP protein expression levels were significantly higher in luminal A than in other molecular subtypes and TNBC. Moreover significantly higher PIP expression was observed in G1, G2 vs. G3 cases (p=0.0027 and p=0.0013, respectively). Microarray analysis characterized PIP gene as a candidate for BC standard chemotherapy response marker. Analysis of clinical data suggests that PIP may be a good prognostic and predictive marker in IDC patients. Higher levels of PIP were related to longer DFS and MFS

  2. Sequential cis-platinum and fludarabine with or without arabinosyl cytosine in patients failing prior fludarabine therapy for chronic lymphocytic leukemia: a phase II study.

    PubMed

    Giles, F J; O'Brien, S M; Santini, V; Gandhi, V; Plunkett, W; Seymour, J F; Robertson, L E; Kantarjian, H M; Keating, M J

    1999-12-01

    Patients with chronic lymphocytic leukemia (CLL) who fail fludarabine (Fluda) therapy have a poor response to subsequent salvage regimens and a poor prognosis. This study was undertaken to determine the efficacy and toxicity of a cis-platinum, (cis-p)fluda and arabinosyl cytosine (ara-C) combination in patients who were refractory to fluda or had relapsed following prior fluda therapy for CLL. Forty-one patients who had progressive CLL were treated on study. Eleven patients (27%) were sensitive to fluda and thirty (73%) refractory prior to study entry. Therapy consisted of cis-p 100 mg/m2 continuous intravenous (i.v.) infusion over 4 days, fluda 30 mg/m2 i.v. over 15 minutes on Days 3 and 4 either given alone (PF) or with ara-C 500 mg/m2 i.v. over 1 hour on Day 4 (PFA). The median number of PF or PFA courses received was two. No patient achieved a complete response. Eight patients (19%) achieved a partial response (PR), 28 were taken off study with progressive or refractory disease and 5 had induction deaths. The overall median survival was 6 months, 15 months in responding patients, and 4 months in non-responding patients. Rai stage I-II patients had a median survival of 7 months and stage III-IV patients had a median survival of 3 months. Major toxicities (myelosuppression, sepsis, renal failure and tumor lysis syndrome) were frequent. In conclusion, it can be said that the PF and PFA regimens have equivalent modest activity in patients with progressive CLL following prior fluda therapy, predominantly among patients whose disease was sensitive to fluda at last prior exposure. Ara-C did not add to the activity of the cis-p/fluda combination in this study group.

  3. Antecedent Stimulus Control: Using Orienting Cues to Facilitate First-Word Acquisition for Nonresponders with Autism

    ERIC Educational Resources Information Center

    Koegel, Robert L.; Shirotova, Larisa; Koegel, Lynn Kern

    2009-01-01

    Although considerable progress has been made in improving the acquisition of expressive verbal communication in children with autism, research has documented that a subpopulation of children still fail to acquire speech even with intensive intervention. One variable that might be important in facilitating responding for this nonverbal subgroup of…

  4. Project TALENT's Nonrespondent Follow-up Survey: The 10th Grade Special Sample. Interim Report.

    ERIC Educational Resources Information Center

    Carrel, Kathleen S.; And Others

    Described are procedures used in the location of a sample of individuals not responding to follow-up questionnaires, eleven years after they were originally interviewed in 1960 as 10th graders. The individuals in question were a subset of more than 400,000 9th, 10th, 11th and 12th grade students used in Project TALENT's longitudinal study of the…

  5. Evaluation of early weight loss thresholds for identifying nonresponders to an intensive lifestyle intervention

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objective: Weight losses in lifestyle interventions are variable, yet prediction of long-term success is difficult. The utility of using various weight loss thresholds in the first 2 months of treatment for predicting 1-year outcomes was examined. Methods: Participants included 2,327 adults with t...

  6. Evaluation of early weight loss thresholds for identifying non-responders to an intensive lifestyle intervention

    PubMed Central

    Unick, Jessica L.; Hogan, Patricia E.; Neiberg, Rebecca H.; Cheskin, Lawrence J.; Dutton, Gareth R.; Evans-Hudnall, Gina; Jeffery, Robert; Kitabchi, Abbas E.; Nelson, Julie A.; Pi-Sunyer, F. Xavier; West, Delia Smith; Wing, Rena R.

    2014-01-01

    Weight losses in lifestyle interventions are variable, yet prediction of long-term success is difficult. Objective We examined the utility of using various weight loss thresholds in the first 2 months of treatment for predicting 1-year outcomes. Design and Methods Participants included 2327 adults with type 2 diabetes (BMI:35.8±6.0) randomized to the intensive lifestyle intervention (ILI) of the Look AHEAD trial. ILI included weekly behavioral sessions designed to increase physical activity and reduce caloric intake. 1-month, 2-month, and 1-year weight changes were calculated. Results Participants failing to achieve a ≥2% weight loss at Month 1 were 5.6 (95% CI:4.5,7.0) times more likely to also not achieve a ≥10% weight loss at Year 1, compared to those losing ≥2% initially. These odds were increased to 11.6 (95% CI:8.6,15.6) when using a 3% weight loss threshold at Month 2. Only 15.2% and 8.2% of individuals failing to achieve the ≥2% and ≥3% thresholds at Months 1 and 2 respectively, go on to achieve a ≥10% weight loss at Year 1. Conclusions Given the association between initial and 1-year weight loss, the first few months of treatment may be an opportune time to identify those who are unsuccessful and utilize rescue efforts. PMID:24771618

  7. Intervention Effects for Students with Comorbid Forms of Learning Disability: Understanding the Needs of Nonresponders

    ERIC Educational Resources Information Center

    Fuchs, Lynn S.; Fuchs, Douglas; Compton, Donald L.

    2013-01-01

    In this article, we considered evidence from our intervention research programs on whether students with learning disability (LD) in reading and mathematics (comorbid LD) respond differently to intervention, compared to students with reading LD alone (RD) or to students with mathematics LD alone (MD). The goal was to gain insight into whether…

  8. Bacterial phagocytosis by macrophages from lipopolysaccharide responder and nonresponder mouse strains.

    PubMed Central

    Cuffini, A; Carlone, N A; Forni, G

    1980-01-01

    The phagocytic capacity of macrophages from C3H/H3J mice was assessed against lipopolysaccharide-producing (Escherichia coli) and -nonproducing (Staphylococcus aureus) bacteria. Despite their gene-coded unresponsiveness to lipopolysaccharide endotoxin and lymphokines and their defective tumoricidal activity, proteose peptone-induced C3H/HeJ macrophages did not display a defective phagocytic capacity, but rather displayed an enhanced phagocytosis of both bacterial strains compared with macrophages from closely related C3H/HeN mice. Unstimulated peritoneal resident C3H/HeJ macrophages, on the other hand, displayed a normal phagocytic activity toward E. coli and enhanced phagocytosis toward S. aureus. PMID:6995321

  9. Mycobacterium tuberculosis transmission in a country with low tuberculosis incidence: role of immigration and HIV infection.

    PubMed

    Fenner, Lukas; Gagneux, Sebastien; Helbling, Peter; Battegay, Manuel; Rieder, Hans L; Pfyffer, Gaby E; Zwahlen, Marcel; Furrer, Hansjakob; Siegrist, Hans H; Fehr, Jan; Dolina, Marisa; Calmy, Alexandra; Stucki, David; Jaton, Katia; Janssens, Jean-Paul; Stalder, Jesica Mazza; Bodmer, Thomas; Ninet, Beatrice; Böttger, Erik C; Egger, Matthias

    2012-02-01

    Immigrants from high-burden countries and HIV-coinfected individuals are risk groups for tuberculosis (TB) in countries with low TB incidence. Therefore, we studied their role in transmission of Mycobacterium tuberculosis in Switzerland. We included all TB patients from the Swiss HIV Cohort and a sample of patients from the national TB registry. We identified molecular clusters by spoligotyping and mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MIRU-VNTR) analysis and used weighted logistic regression adjusted for age and sex to identify risk factors for clustering, taking sampling proportions into account. In total, we analyzed 520 TB cases diagnosed between 2000 and 2008; 401 were foreign born, and 113 were HIV coinfected. The Euro-American M. tuberculosis lineage dominated throughout the study period (378 strains; 72.7%), with no evidence for another lineage, such as the Beijing genotype, emerging. We identified 35 molecular clusters with 90 patients, indicating recent transmission; 31 clusters involved foreign-born patients, and 15 involved HIV-infected patients. Birth origin was not associated with clustering (adjusted odds ratio [aOR], 1.58; 95% confidence interval [CI], 0.73 to 3.43; P = 0.25, comparing Swiss-born with foreign-born patients), but clustering was reduced in HIV-infected patients (aOR, 0.49; 95% CI, 0.26 to 0.93; P = 0.030). Cavitary disease, male sex, and younger age were all associated with molecular clustering. In conclusion, most TB patients in Switzerland were foreign born, but transmission of M. tuberculosis was not more common among immigrants and was reduced in HIV-infected patients followed up in the national HIV cohort study. Continued access to health services and clinical follow-up will be essential to control TB in this population.

  10. Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients

    PubMed Central

    Radvanyi, Laszlo G.; Bernatchez, Chantale; Zhang, Minying; Fox, Patricia S.; Miller, Priscilla; Chacon, Jessica; Wu, Richard; Lizee, Gregory; Mahoney, Sandy; Alvarado, Gladys; Glass, Michelle; Johnson, Valen E.; McMannis, John D.; Shpall, Elizabeth; Prieto, Victor; Papadopoulos, Nicholas; Kim, Kevin; Homsi, Jade; Bedikian, Agop; Hwu, Wen-Jen; Patel, Sapna; Ross, Merrick I.; Lee, Jeffrey E.; Gershenwald, Jeffrey E.; Lucci, Anthony; Royal, Richard; Cormier, Janice N.; Davies, Michael A.; Mansaray, Rahmatu; Fulbright, Orenthial J.; Toth, Christopher; Ramachandran, Renjith; Wardell, Seth; Gonzalez, Audrey; Hwu, Patrick

    2012-01-01

    Purpose Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the results of an ongoing Phase II clinical trial testing the efficacy of ACT using TIL in metastatic melanoma patients and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response. Experimental Design Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL followed by two cycles of high-dose (HD) IL-2 therapy. The effects of patient clinical features and the phenotypes of the T-cells infused on clinical response were determined. Results Overall, 15/31 (48.4%) patients had an objective clinical response using immune-related response criteria (irRC), with two patients (6.5%) having a complete response. Progression-free survival of >12 months was observed for 9/15 (60%) of the responding patients. Factors significantly associated with objective tumor regression included a higher number of TIL infused, a higher proportion of CD8+ T-cells in the infusion product, a more differentiated effector phenotype of the CD8+ population and a higher frequency of CD8+ T-cells co-expressing the negative costimulation molecule “B- and T-lymphocyte attenuator” (BTLA). No significant difference in telomere lengths of TIL between responders and non-responders was identified. Conclusion These results indicate that immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in metastatic melanoma patients and that CD8+ T-cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression. PMID:23032743

  11. Neuromuscular electrical stimulation improves exercise tolerance in chronic obstructive pulmonary disease patients with better preserved fat-free mass

    PubMed Central

    Nápolis, Lara Maris; Corso, Simone Dal; Neder, José Alberto; Malaguti, Carla; Gimenes, Ana Cristina Oliveira; Nery, Luiz Eduardo

    2011-01-01

    BACKGROUND: High-frequency neuromuscular electrical stimulation increases exercise tolerance in patients with advanced chronic obstructive pulmonary disease (COPD patients). However, it is conceivable that its benefits are more prominent in patients with better-preserved peripheral muscle function and structure. OBJECTIVE: To investigate the effects of high-frequency neuromuscular electrical stimulation in COPD patients with better-preserved peripheral muscle function. Design: Prospective and cross-over study. METHODS: Thirty COPD patients were randomly assigned to either home-based, high-frequency neuromuscular electrical stimulation or sham stimulation for six weeks. The training intensity was adjusted according to each subject's tolerance. Fat-free mass, isometric strength, six-minute walking distance and time to exercise intolerance (Tlim) were assessed. RESULTS: Thirteen (46.4%) patients responded to high-frequency neuromuscular electrical stimulation; that is, they had a post/pre ΔTlim >10% after stimulation (unimproved after sham stimulation). Responders had a higher baseline fat-free mass and six-minute walking distance than their seventeen (53.6%) non-responding counterparts. Responders trained at higher stimulation intensities; their mean amplitude of stimulation during training was significantly related to their fat-free mass (r  =  0.65; p<0.01). Logistic regression revealed that fat-free mass was the single independent predictor of Tlim improvement (odds ratio [95% CI]  =  1.15 [1.04-1.26]; p<0.05). CONCLUSIONS: We conclude that high-frequency neuromuscular electrical stimulation improved the exercise capacity of COPD patients with better-preserved fat-free mass because they tolerated higher training stimulus levels. These data suggest that early training with high-frequency neuromuscular electrical stimulation before tissue wasting begins might enhance exercise tolerance in patients with less advanced COPD. PMID:21552662

  12. Diamond-Blackfan anemia: genotype-phenotype correlations in Italian patients with RPL5 and RPL11 mutations

    PubMed Central

    Quarello, Paola; Garelli, Emanuela; Carando, Adriana; Brusco, Alfredo; Calabrese, Roberto; Dufour, Carlo; Longoni, Daniela; Misuraca, Aldo; Vinti, Luciana; Aspesi, Anna; Biondini, Laura; Loreni, Fabrizio; Dianzani, Irma; Ramenghi, Ugo

    2010-01-01

    Background Diamond-Blackfan anemia is a rare, pure red blood cell aplasia of childhood due to an intrinsic defect in erythropoietic progenitors. About 40% of patients display various malformations. Anemia is corrected by steroid treatment in more than 50% of cases; non-responders need chronic transfusions or stem cell transplantation. Defects in the RPS19 gene, encoding the ribosomal protein S19, are the main known cause of Diamond-Blackfan anemia and account for more than 25% of cases. Mutations in RPS24, RPS17, and RPL35A described in a minority of patients show that Diamond-Blackfan anemia is a disorder of ribosome biogenesis. Two new genes (RPL5, RPL11), encoding for ribosomal proteins of the large subunit, have been reported to be involved in a considerable percentage of patients. Design and Methods In this genotype-phenotype analysis we screened the coding sequence and intron-exon boundaries of RPS14, RPS16, RPS24, RPL5, RPL11, and RPL35A in 92 Italian patients with Diamond-Blackfan anemia who were negative for RPS19 mutations. Results About 20% of the patients screened had mutations in RPL5 or RPL11, and only 1.6% in RPS24. All but three mutations that we report here are new mutations. No mutations were found in RPS14, RPS16, or RPL35A. Remarkably, we observed a higher percentage of somatic malformations in patients with RPL5 and RPL11 mutations. A close association was evident between RPL5 mutations and craniofacial malformations, and between hand malformations and RPL11 mutations. Conclusions Mutations in four ribosomal proteins account for around 50% of all cases of Diamond-Blackfan anemia in Italian patients. Genotype-phenotype data suggest that mutation screening should begin with RPL5 and RPL11 in patients with Diamond-Blackfan anemia with malformations. PMID:19773262

  13. Reduction in oral corticosteroid use in patients receiving omalizumab for allergic asthma in the real-world setting

    PubMed Central

    2013-01-01

    Background Oral corticosteroids (OCS) are commonly administered in patients with severe persistent allergic asthma. Despite their efficacy, they are associated with a wide variety of adverse events. The eXpeRience registry was set up to investigate real-world outcomes among patients receiving omalizumab for the treatment of uncontrolled allergic asthma. Here, we present the effect of omalizumab treatment on OCS use. Methods eXpeRience was a 2-year, multinational, non-interventional, observational registry of patients receiving omalizumab for uncontrolled allergic asthma. OCS use (proportion of patients on maintenance OCS, mean total daily OCS dose and change in status of OCS therapy) was assessed at baseline, 16 weeks, and 8, 12, 18, and 24 months after the initiation of omalizumab. Response to omalizumab was assessed using the physician’s Global Evaluation of Treatment Effectiveness (GETE) at approximately Week 16. Safety data were also recorded. Results A total of 943 patients (mean age, 45 years; female, 64.9%) were enrolled in the registry, 263 of whom were receiving maintenance OCS at baseline. The proportion of patients taking maintenance OCS was markedly lower at Months 12 (16.1%) and 24 (14.2%) than at baseline (28.6%; intent-to-treat population). GETE status was determined in 915 patients receiving omalizumab: 64.2% were responders (excellent or good response), 30.7% were non-responders (moderate, poor or worsening response); 5.1% had no assessment. The frequency of serious adverse events was comparable to that seen in controlled trials of omalizumab. Conclusions Omalizumab use is associated with an OCS-sparing effect in patients with uncontrolled persistent allergic asthma in the real-world setting. PMID:24305549

  14. Clinical and immunological assessment in breast cancer patients receiving anticancer therapy and bovine dialyzable leukocyte extract as an adjuvant.

    PubMed

    Lara, Humberto H; Turrent, Liliana Ixtepan; Garza-Treviño, Elsa N; Tamez-Guerra, Reyes; Rodriguez-Padilla, Cristina

    2010-05-01

    Dialyzable leukocyte extract (DLE) is one of the immunological agents used as an adjuvant in cancer therapy; it has been associated with improved quality of life during cancer chemotherapy. Based on these previous findings and on the observed clinical benefits attributed to DLE in other types of cancer, we investigated its clinical and immunological effects as a therapy adjuvant on breast cancer patients who received only chemotherapy, as compared to patients administered bovine DLE (bDLE) as an adjuvant. This study included 43 breast cancer patients who were about to begin chemotherapy. This group was divided as follows: 25 received chemotherapy and bDLE as an adjuvant therapy, and 18 received only chemotherapy without the adjuvant. All patient clinical and immunological responses were monitored. Among patients in the group that received bDLE as adjuvant, 60% showed a complete response, 32% showed a partial response and 8% did not respond. By contrast, in the group without the adjuvant, 39% showed a complete response, 50% displayed a partial response and 11% were non-responders. In addition, bDLE treatment in combination with chemotherapy resulted in the enhancement of the Karnofsky performance scale during chemotherapy. Even though patients underwent several cycles of chemotherapy without bDLE, the lymphocyte population dropped to below the reference value. On the other hand, in patients with bDLE as adjuvant, the CD4(+) and CD8(+) lymphocytes and the B lymphocytes were maintained within the median range of the reference value. The number of natural killer cells also increased after chemotherapy treatment with bDLE as an adjuvant. In conclusion, bDLE treatment contributes to significant immunological recovery in patients that have undergone heavy chemotherapy, increasing the clinical response and quality of life during chemotherapy.

  15. Adalimumab induction and maintenance therapy achieve clinical remission and response in Chinese patients with Crohn's disease

    PubMed Central

    Ran, Zhi Hua; Gao, Xiang; Chen, Minhu; Zhong, Jie; Sheng, Jian-Qiu; Kamm, Michael A; Travis, Simon; Wallace, Kori; Mostafa, Nael M; Shapiro, Marisa; Li, Yao; Thakkar, Roopal B; Robinson, Anne M

    2016-01-01

    Background/Aims This was a Phase 2 study (NCT02015793) to evaluate the pharmacokinetics, safety, and efficacy of adalimumab in Chinese patients with Crohn's disease (CD). Methods Thirty, adult Chinese patients with CD (CD Activity Index [CDAI] 220–450; high-sensitivity [hs]-C-reactive protein [CRP] ≥3 mg/L) received double-blind adalimumab 160/80 mg or 80/40 mg at weeks 0/2, followed by 40 mg at weeks 4 and 6. An open-label extension period occurred from weeks 8–26; patients received 40 mg adalimumab every other week. Serum adalimumab concentration and change from baseline in fecal calprotectin (FC) were measured during the double-blind period. Clinical remission (CDAI <150), response (decrease in CDAI ≥70 points from baseline), and change from baseline in hs-CRP were assessed through week 26. Nonresponder imputation was used for missing categorical data and last observation carried forward for missing hs-CRP/FC values. No formal hypothesis was tested. Adverse events were monitored. Results Mean adalimumab serum concentrations during the induction phase were 13.9–18.1 µg/mL (160/80 mg group) and 7.5−9.5 µg/mL (80/40 mg group). During the double-blind period, higher remission/response rates and greater reductions from baseline in hs-CRP and FC were observed with adalimumab 160/80 mg compared to that with 80/40 mg. Adverse event rates were similar among all treatment groups. Conclusions Adalimumab serum concentrations in Chinese patients with CD were comparable to those observed previously in Western and Japanese patients. Clinically meaningful remission rates and improvement in inflammatory markers were achieved with both dosing regimens; changes occurred rapidly with adalimumab 160/80 mg induction therapy. No new safety signals were reported. PMID:27175116

  16. Functional Interference Clusters in Cancer Patients With Bone Metastases: A Secondary Analysis of RTOG 9714

    SciTech Connect

    Chow, Edward; James, Jennifer; Barsevick, Andrea; Hartsell, William; Ratcliffe, Sarah; Scarantino, Charles; Ivker, Robert; Roach, Mack; Suh, John; Petersen, Ivy; Konski, Andre; Demas, William; Bruner, Deborah

    2010-04-15

    Purpose: To explore the relationships (clusters) among the functional interference items in the Brief Pain Inventory (BPI) in patients with bone metastases. Methods: Patients enrolled in the Radiation Therapy Oncology Group (RTOG) 9714 bone metastases study were eligible. Patients were assessed at baseline and 4, 8, and 12 weeks after randomization for the palliative radiotherapy with the BPI, which consists of seven functional items: general activity, mood, walking ability, normal work, relations with others, sleep, and enjoyment of life. Principal component analysis with varimax rotation was used to determine the clusters between the functional items at baseline and the follow-up. Cronbach's alpha was used to determine the consistency and reliability of each cluster at baseline and follow-up. Results: There were 448 male and 461 female patients, with a median age of 67 years. There were two functional interference clusters at baseline, which accounted for 71% of the total variance. The first cluster (physical interference) included normal work and walking ability, which accounted for 58% of the total variance. The second cluster (psychosocial interference) included relations with others and sleep, which accounted for 13% of the total variance. The Cronbach's alpha statistics were 0.83 and 0.80, respectively. The functional clusters changed at week 12 in responders but persisted through week 12 in nonresponders. Conclusion: Palliative radiotherapy is effective in reducing bone pain. Functional interference component clusters exist in patients treated for bone metastases. These clusters changed over time in this study, possibly attributable to treatment. Further research is needed to examine these effects.

  17. Laparoscopic ovarian treatment in infertile patients with polycystic ovarian syndrome (PCOS): endocrine changes and clinical outcome.

    PubMed

    Liguori, G; Tolino, A; Moccia, G; Scognamiglio, G; Nappi, C

    1996-08-01

    During the years 1991-1994, 97 anovulatory infertile women with polycystic ovarian syndrome (PCOS) were treated with laparoscopic electrocautery of the ovarian surface after they had failed to ovulate under ovarian stimulation. To assess the endocrinological and clinical outcome and in an attempt to determine the mechanism of action, the serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), androstenedione, testosterone and dehydroepiandrosterone sulfate (DHEAS) were determined before and after laparoscopic ovarian cautery. Fifty regularly cycling women undergoing laparoscopy for investigation of infertility or tubal ligation served as controls. In patients with PCOS but not in controls, the reduction of androgen levels and normalization of cycle length were highly significant. In contrast, LH and FSH levels rose during the first 2 days after the operation. These results resemble those reported after ovarian wedge resection. Ovulation was obtained in 90% (81 of 90) and pregnancy in 81.1% (73 of 90) of the patients; that increased to 84.4%, including the non-responders (nine patients) treated with clomiphene citrate (CC), after electrocautery. The response to ovarian electrocautery was influenced by body weight, with an ovulation rate of 95-96% in the slim and moderately obese women, decreasing to 81-82% in the really obese ones. When ovulation was established, the pregnancy rate was independent of body weight. However, a striking relationship was detected between smoking habits and pregnancy rate subsequent to ovarian electrocautery, ranging from 24% in smokers to 92% in non-smoking couples. In 30 second-look operations, de novo adhesions were found in 23.3% of the patients (7 of 30). Therefore, ovarian electrocautery is an effective procedure to improve the intraovarian mechanism of selecting a dominant follicle for patients with PCOS in whom initial medical management fails, and it appears to be one of the possible treatments for this

  18. Development and progression of portal hypertensive gastropathy in patients with chronic hepatitis C

    PubMed Central

    Fontana, Robert J.; Sanyal, Arun J.; Ghany, Marc G.; Bonkovsky, Herbert L.; Morgan, Timothy R.; Litman, Heather J.; Reid, Andrea E.; Lee, William M.; Naishadham, Deepa

    2013-01-01

    OBJECTIVES To determine the incidence and risk factors associated with new onset and worsening portal hypertensive gastropathy (PHG) in patients with chronic hepatitis C (CHC). METHODS 831 CHC patients with bridging fibrosis or cirrhosis at entry were prospectively monitored for clinical and histological liver disease progression while receiving either low dose peginterferonα2a or no antiviral therapy in the HALT-C Trial. Upper endoscopy with grading of PHG was performed at baseline and year 4 of the study. The presence and severity of PHG were determined using the NIEC criteria and worsening PHG was defined as a score increase of > 1 point. RESULTS During a median follow-up of 3.85 years, 50% of the 514 subjects without PHG developed new onset PHG while 26% of the 317 patients with baseline PHG had worsening PHG. Independent predictors of new onset PHG included higher alkaline phosphatase and being diabetic, while predictors of worsening PHG were Caucasian race, lower albumin, and higher serum AST/ ALT ratio and HOMA levels. New onset and worsening PHG were significantly associated with clinical as well as histological progression. New onset and worsening PHG were also associated with new onset and worsening of gastroesophageal varices. CONCLUSIONS New onset and worsening PHG develops at a rate of 12.9% per year and 6.7% per year, respectively, in non-responder CHC patients with advanced fibrosis. If confirmed in other studies, endoscopic surveillance for PHG may need to be tailored to individual patient risk factors. PMID:21139575

  19. Primary Mediastinal Large B-Cell Lymphoma: Results of Intensive Chemotherapy Regimens (MACOP-B/VACOP-B) Plus Involved Field Radiotherapy on 53 Patients. A Single Institution Experience

    SciTech Connect

    Mazzarotto, Renzo . E-mail: renzo.mazzarotto@unipd.it; Boso, Caterina; Vianello, Federica; Aversa, Maria Savina; Chiarion-Sileni, Vanna; Trentin, Livio; Zambello, Renato; Muzzio, Pier Carlo; Fiore, Davide; Sotti, Guido

    2007-07-01

    Purpose: The optimal therapy for primary mediastinal large B-cell lymphoma (PMLBCL) remains undefined. The superiority of intensive chemotherapy regimens (Methotrexate, Doxorubicin, Cyclophosphamide, Vincristine, Prednisone, Bleomycin [MACOP-B]/Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Prednisone, Bleomycin [VACOP-B]) over Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP)-like chemotherapy is upheld by some authors. The role of radiotherapy is still debated. In the absence of randomized trials, we report clinical findings and treatment response in 53 consecutive patients treated with intensive chemotherapy and mediastinal involved-field radiation therapy (IFRT). Methods and Material: Fifty-three consecutive patients with PMLBCL were retrospectively analyzed. Planned treatment consisted of induction chemotherapy (I-CT; Prednisone, Methotrexate, Doxorubicin, Cyclophosphamide, Etoposide-Mechloroethamine, Vincristine, Procarbazine, Prednisone [ProMACE-MOPP] in the first 2 patients, MACOP-B in the next 11, and VACOP-B in the last 40) followed by IFRT. Planned treatment was concluded in 43 of 53 patients; in 10 patients, I-CT was not immediately followed by IFRT. Among these 10 patients, 6 received high-dose chemotherapy (HD-CT) followed by IFRT, 2 received HD-CT, and 2 received no further treatment. Results: After a median follow-up of 93.9 months (range, 6-195 months), 45 of 53 patients (84.9%) were alive without disease. Eight patients died: 7 of PMLBCL and 1 of toxicity during HD-CT. The 5-year disease-free survival (DFS) and overall survival rates were 93.42% and 86.6%, respectively. The response rates after I-CT were complete response (CR) in 20 (37.73%) and partial response (PR) in 30 (56.60%); 3 patients (5.66%) were considered nonresponders. Among patients in PR after chemotherapy, 92% obtained a CR after IFRT. Conclusions: Our report confirms the efficacy of intensive chemotherapy plus mediastinal IFRT. IFRT plays a pivotal role in

  20. Improvements in clinical response between 12 and 24 weeks in patients with rheumatoid arthritis on etanercept therapy with or without methotrexate

    PubMed Central

    Kavanaugh, A; Klareskog, L; van der Heijde, D; Li, J; Freundlich, B; Hooper, M

    2008-01-01

    Background: Whereas many patients respond quickly to treatment with tumour necrosis factor (TNF) inhibitors, some patients may experience significant but delayed responses. Objective: To evaluate the clinical response between 12 and 24 weeks in subjects with rheumatoid arthritis from the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes. Methods: Clinical response was assessed at 24 weeks in 12-week non-responders, according to American College of Rheumatology (ACR) response criteria. The proportion of subjects who successfully maintained response to 52 weeks was analysed, as were radiographic outcomes. Results: Data from 682 subjects were included in the analysis. Non and partial responders in all three groups (etanercept, methotrexate and etanercept plus methotrexate) at week 12 showed an improvement in responses at week 24. Over 80% of the week 24 ACR20/50/70 responders in the etanercept plus methotrexate arm sustained their response to 52 weeks. In the etanercept arms, a delayed clinical response was not associated with increased radiographic progression at week 52. Conclusion: A significant proportion of non and partial responders to etanercept with or without methotrexate therapy at week 12 achieved a good clinical response or improved their overall clinical response at week 24. Discontinuing TNF inhibitor therapy at 12 weeks may be premature in some rheumatoid arthritis patients. PMID:18535115

  1. [Add-on effect of dutasteride in patients with benign prostatic hyperplasia treated with alpha blocker : its effect on overactive bladder].

    PubMed

    Wada, Naoki; Hashidume, Kazumi; Tamaki, Gaku; Kita, Masafumi; Iwata, Tatsuya; Matsumoto, Seiji; Kakizaki, Hidehiro

    2012-09-01

    We investigated the add-on effect of dutasteride (0.5 mg once a day) on lower urinary tract symptoms (LUTS), prostate volume (PV), and serum prostate specific antigen (PSA) and testosterone level in 72 patients with benign prostatic hyperplasia (BPH) who had been treated with alpha-blocker monotherapy. Inclusion criteria were men with BPH who had PV ≧30 ml and international prostate symptom score (IPSS) ≧8 or quality of life (QOL) index ≧3 under alpha-blocker monotherapy for more than 3 months. At the baseline, 12 and 24 weeks after dutasteride add-on, we assessed IPSS, overactive bladder symptom score (OABSS), PV, serum PSA and testosterone. Among 47 patients (65%) with OAB diagnosed by OABSS, responders were defined as those with urgency score of OABSS <2 or total score of OABSS <3. At the 24th week, dutasteride significantly improved IPSS (-4.2) and OABSS (-1.9) and reduced PV (-29%) compared with the baseline. Furthermore, dutasteride significantly decreased serum PSA (-45%) and increased testosterone (36%). Among OAB patients, dutasteride significantly improved urgency and urgency incontinence but not nocturia. Responders had lower OABSS, urgency incontinence score and serum testosterone at the baseline than non-responders. In conclusion, dutasteride add-on therapy is beneficial in patients with BPH who do not show enough improvement with alpha-blocker monotherapy.

  2. Osteoarticular manifestations of Mycobacterium tuberculosis infection.

    PubMed

    Zychowicz, Michael E

    2010-01-01

    Mycobacterium tuberculosis has affected humans for much of our existence. The incidence of global tuberculosis infection continues to rise, especially in concert with HIV coinfection. Many disease processes, such as diabetes, increase the likelihood of tuberculosis infection. Tuberculosis bacteria can infect any bone, joint, tendon, or bursa; however, the most common musculoskeletal site for infection includes the spine and weight-bearing joints of the hip and knee. Many patients who present with osteoarticular tuberculosis infection will have a gradual onset of pain at the site of infection. Many patients who develop a musculoskeletal tuberculosis infection will have no evidence of a pulmonary tuberculosis infection on x-ray film and many will have very mild symptoms with the initial infection. Healthcare providers must remember that many patients who develop tuberculosis infection do not progress to active tuberculosis disease; however, the latent infection may become active with immune compromise.

  3. A study into the genetic basis of aspirin resistance in Pakistani patients with coronary artery disease.

    PubMed

    Mukarram, Osama; Akhtar, Naveed; Junaid, Ayesha; Mohyuddin, Aisha

    2016-07-01

    Aspirin is a key player in the management and prevention of stroke and myocardial infarction in patients with atherothrombosis. About 12% of Pakistanis suffering from coronary artery disease are resistant to aspirin's effects. Clinical, biochemical and genetic factors are known to be responsible for this phenomenon. We conducted this study to investigate whether previously studied polymorphisms in COX-1, GPIIIa, GPIa and P2RYI genes could be the cause of aspirin resistance in our population. Blood samples were collected from 29 aspirin non-responders and 60 ethnically matched responders. Aspirin response assay was performed on IMPACT-R and DNA prepared from blood using the phenol: chloroform method. Genotyping was carried out for four SNPS including COX-1 C50T (rs3842787), GPIIIA PIA1/A2 polymorphism (rs5918), GPIA C807T (rs1126643) and p2RY1 C893T (rs1065776). No statistically significant differences were observed in the allele or genotype frequencies between the aspirin non responders and responders indicating the possible involvement of different genetic determinants of aspirin resistance in our population. This study paves the way for further research into the field of aspirin resistance in Pakistan.

  4. Behavioral factors predicting response to employment-based reinforcement of cocaine abstinence in methadone patients.

    PubMed

    Holtyn, August F; Washington, Wendy Donlin; Knealing, Todd W; Wong, Conrad J; Kolodner, Ken; Silverman, Kenneth

    2016-06-01

    We sought to identify behavioral factors associated with response to an employment-based intervention, in which participants had to provide drug-free urine samples to gain access to paid employment. The present secondary analysis included data from a randomized clinical trial. The trial evaluated whether employment-based reinforcement could decrease cocaine use in community methadone patients. Participants (N=56) in the trial worked in a model workplace for 4 hr every weekday and earned about $10 per hr. After a 4-week baseline, participants were randomly assigned to an Abstinence & Work (n = 28) or Work Only (n = 28) condition and could work for an additional 26 weeks. Abstinence & Work participants had to provide cocaine-negative urine samples to work and maintain maximum pay. Work Only participants only had to work to earn pay. For Work Only participants, cocaine abstinence during baseline and the intervention period were significantly (rs = .72, p <.001) correlated. For Abstinence & Work participants, baseline opiate abstinence was significantly correlated (rs = .59, p <.001) and workplace attendance was marginally correlated (rs = .32, p = .098) with cocaine abstinence during the intervention period. Furthermore, participants who provided over 60% cocaine-negative urine samples during the intervention period (i.e., responders) had significantly higher baseline rates of opiate abstinence (p <.0001) and workplace attendance (p = .042) than non-responders. Employment-based reinforcement of cocaine abstinence may be improved by increasing opiate abstinence and workplace attendance prior to initiating the cocaine-abstinence intervention.

  5. Diagnosing and treating renal disease in cirrhotic patients.

    PubMed

    Wong, Florence

    2016-09-01

    Renal dysfunction in cirrhosis is mostly related to the development of acute kidney injury (AKI), precipitated by either an acute disturbance of hemodynamics, or acute structural damage to the kidneys. The incidence of chronic renal failure is rising, due to increasing prevalence of conditions such as diabetes, viral hepatitis, which can be associated with renal damage. AKI is defined as a rise in serum creatinine of 0.3 mg/dL in <48 hours or by 50% from baseline within the past 3 months without setting a threshold for the final serum creatinine. Stages 1, 2, and 3 of AKI are defined as 150%, 200% and 300% of baseline serum creatinine respectively, which allows for assessment of AKI progression. Chronic kidney disease (CKD) is defined as an estimated glomerular filtration rate of <60 mL/min for >3 months. Treatment of AKI consists of removal of precipitating factors and replenishment of the intravascular volume using colloids such as albumin. Frequently, AKI can be reversed using these measures alone. Non-responders to removal of precipitating factors and volume challenge can receive vasoconstrictors such as terlipressin or norepinephrine together with albumin. Midodrine is inferior in efficacy as a vasoconstrictor when compared to terlipressin. Liver transplantation is the definitive treatment for type 1 hepatorenal syndrome with liver failure. Delay in receiving a liver transplant can result in non-recovery of renal function post transplant. Treatment of CKD in cirrhosis is unsatisfactory, mostly aimed at optimizing management of comorbid conditions, or treating the underlying refractory ascites in patients with type 2 hepatorenal syndrome.

  6. Pharmacogenetic analysis of cinacalcet response in secondary hyperparathyroidism patients

    PubMed Central

    Jeong, Sohyun; Kim, In-Wha; Oh, Kook-Hwan; Han, Nayoung; Joo, Kwon Wook; Kim, Hyo Jin; Oh, Jung Mi

    2016-01-01

    Background Secondary hyperparathyroidism (SHPT) is one of the major risk factors of morbidity and mortality in end-stage renal disease. Cinacalcet effectively controls SHPT without causing hypercalcemia and hyperphosphatemia. However, there is significant inter-individual response variance to cinacalcet treatment. Therefore, we aimed to evaluate the genetic effects related with parathyroid hormone regulation as factors for cinacalcet response variance. Methods Patients with a diagnosis of SHPT based on intact parathyroid hormone (iPTH) >300 pg/mL on dialysis were included in this study. They were over 18 years and have been treated by cinacalcet for more than 3 months. Responders and nonresponders were grouped by the serum iPTH changes. Twenty-four single nucleotide polymorphisms of CASR, VDR, FGFR1, KL, ALPL, RGS14, NR4A2, and PTHLH genes were selected for the pharmacogenetic analysis. Results After adjusting for age, sex, and calcium level, CASR rs1042636 (odds ratio [OR]: 0.066, P=0.027) and rs1802757 (OR: 10.532, P=0.042) were associated with cinacalcet response. The association of haplotypes of CASR rs1042636, rs10190, and rs1802757; GCC (OR: 0.355, P=0.015); and ATT (OR: 2.769, P=0.014) with cinacalcet response was also significant. Conclusion We obtained supporting information of the associations between cinacalcet response and CASR polymorphisms. CASR single nucleotide polymorphisms (SNPs) rs1802757, rs1042636, and haplotypes of rs1042636, rs10190, and rs1802757 were significantly associated with cinacalcet response variance. PMID:27468225

  7. Long-term follow-up of myelodysplastic syndrome patients with moderate/severe anaemia receiving human recombinant erythropoietin + 13-cis-retinoic acid and dihydroxylated vitamin D3: independent positive impact of erythroid response on survival.

    PubMed

    Crisà, Elena; Foli, Cristina; Passera, Roberto; Darbesio, Antonella; Garvey, Kimberly B; Boccadoro, Mario; Ferrero, Dario

    2012-07-01

    We previously reported a 60% erythroid response rate with recombinant erythropoietin + 13-cis retinoic acid + dihydroxylated vitamin D3 in 63 elderly myelodysplastic patients (median age 75 years) with unfavourable features for response to erythropoietin alone [70% transfusion-dependent, 35% refractory anaemia with ring sideroblasts/refractory anaemia with excess of blasts type 1 (RAEB1), 70% with International Prognostic Scoring System (IPSS) Intermediate-1 or -2]. This report updates that case study at a 7-year follow-up, and compared the impact on overall survival of erythroid response to known prognostic factors. The erythroid response duration (median 17 months; 22 in non-RAEB patients, with 20% patients in response after 6 years of therapy) was longer than in most studies with erythropoietin alone. Overall survival (median 55 months in non-RAEB, 15 in RAEB1 patients) was negatively affected by RAEB1 diagnosis, IPSS and WPSS intermediate scores and transfusion-dependence. In the multivariate analysis, erythroid response maintained an independent positive impact on survival, particularly in non-RAEB patients in the first 3 years from diagnosis (90% survival compared to 50% of non-responders). In conclusion, the long-term follow-up confirmed the achievement, by our combined treatment, of fairly long-lasting erythroid response in the majority of MDS patients with unfavourable prognostic features for response to erythropoietin: this translated in a survival benefit that was independent from other prognostic features.

  8. Ofatumumab and Lenalidomide for Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia: Correlation between Responses and Immune Characteristics

    PubMed Central

    Vitale, Candida; Falchi, Lorenzo; ten Hacken, Elisa; Gao, Hui; Shaim, Hila; Van Roosbroeck, Katrien; Calin, George; O'Brien, Susan; Faderl, Stefan; Wang, Xuemei; Wierda, William G.; Rezvani, Katayoun; Reuben, James M.; Burger, Jan A.; Keating, Michael J.; Ferrajoli, Alessandra

    2016-01-01

    Purpose We evaluated efficacy and tolerability of the combination of ofatumumab and lenalidomide in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), and explored whether immune system characteristics could influence the response to treatment. Experimental Design Thirty-four patients were enrolled in this phase II study. Ofatumumab was administered at a dose of 300 mg on day 1, 1,000 mg on days 8, 15, and 22 during course 1, 1,000 mg on day 1 during courses 3–6, and once every other course during courses 7–24 (28-day courses). Oral lenalidomide (10 mg daily) was started on day 9 and continued for as long as a clinical benefit was observed. Results The overall response rate was 71%. Eight patients (24%) achieved a complete remission (CR) or CR with incomplete recovery of blood counts, including 9% with minimal residual disease-negative CR. The median progression-free survival was 16 months, and the estimated 5-year survival was 53%. The most common treatment-related toxicity was neutropenia (grade >2 in 18% of the 574 patient courses). The most frequent infectious complications were pneumonia and neutropenic fever (24% and 9% of patients, respectively). We observed that patients who achieved a CR had at baseline higher numbers and a better preserved function of T cells and natural killer cells compared with non-responders. Conclusions The combination of ofatumumab and lenalidomide is a well-tolerated regimen that induces durable responses in the majority of patients with relapsed/refractory CLL. Our correlative data suggest a role of competent immune system in supporting the efficacy of this treatment. PMID:26733610

  9. Geometrical Measures Obtained from Pretreatment Postcontrast T1 Weighted MRIs Predict Survival Benefits from Bevacizumab in Glioblastoma Patients

    PubMed Central

    Sepúlveda, Juan M.; Peralta, Sergi; Gil-Gil, Miguel J.; Reynes, Gaspar; Herrero, Ana; De Las Peñas, Ramón; Luque, Raquel; Capellades, Jaume

    2016-01-01

    Background Antiangiogenic therapies for glioblastoma (GBM) such as bevacizumab (BVZ), have been unable to extend survival in large patient cohorts. However, a subset of patients having angiogenesis-dependent tumors might benefit from these therapies. Currently, there are no biomarkers allowing to discriminate responders from non-responders before the start of the therapy. Methods 40 patients from the randomized GENOM009 study complied the inclusion criteria (quality of images, clinical data available). Of those, 23 patients received first line temozolomide (TMZ) for eight weeks and then concomitant radiotherapy and TMZ. 17 patients received BVZ+TMZ for seven weeks and then added radiotherapy to the treatment. Clinical variables were collected, tumors segmented and several geometrical measures computed including: Contrast enhancing (CE), necrotic, and total volumes; equivalent spherical CE width; several geometric measures of the CE ‘rim’ geometry and a set of image texture measures. The significance of the results was studied using Kaplan-Meier and Cox proportional hazards analysis. Correlations were assessed using Spearman correlation coefficients. Results Kaplan-Meier and Cox proportional hazards analysis showed that total, CE and inner volume (p = 0.019, HR = 4.258) and geometric heterogeneity of the CE areas (p = 0.011, HR = 3.931) were significant parameters identifying response to BVZ. The group of patients with either regular CE areas (small geometric heterogeneity, median difference survival 15.88 months, p = 0.011) or those with small necrotic volume (median survival difference 14.50 months, p = 0.047) benefited substantially from BVZ. Conclusion Imaging biomarkers related to the irregularity of contrast enhancing areas and the necrotic volume were able to discriminate GBM patients with a substantial survival benefit from BVZ. A prospective study is needed to validate our results. PMID:27557121

  10. Treatment approach in patients with hyperbilirubinemia secondary to liver metastases in gastrointestinal malignancies: a case series and review of literature

    PubMed Central

    Quidde, Julia; Azémar, Marc; Bokemeyer, Carsten; Arnold, Dirk; Stein, Alexander

    2016-01-01

    Background: Treatment of patients with severe liver dysfunction including hyperbilirubinemia secondary to liver metastases of gastrointestinal (GI) cancer is challenging. Regimen of oxaliplatin and fluoropyrimidine (FP)/folinic acid (FA) ± a monoclonal antibody (moAb), represents a feasible option considering the pharmacokinetics. Clinical data on the respective dosage and tolerability are limited and no recommendations are available. Methods: Consecutive patients with severe hyperbilirubinemia [>2 × upper limit of the normal range (ULN) and >2.4 mg/dl] due to liver metastases of GI cancer without options for drainage receiving oxaliplatin, FP/FA ± moAb were analyzed. To collect further data a review of the literature was performed. Results: A total of 12 patients were identified between 2011 and 2015. At treatment start, median bilirubin level was 6.1 mg/dl (>5 × ULN, range 2.7–13.6). The majority of patients (n = 11) received dose-reduced regimen with oxaliplatin (60–76%) and FP/FA (0–77%), rapidly escalating to full dose regimen. During treatment, bilirubin levels dropped more than 50% within 8 weeks or normalized within 12 weeks in 6 patients (responders). Median overall survival was 5.75 months (range 1.0–16.0 months) but was significantly prolonged in responders compared to nonresponders [9.7 and 3.0 months, p = 0.026 (two-sided test); 95% confidence interval (CI): 1.10–10.22]. In addition, case reports or series comprising a further 26 patients could be identified. Based on the obtained data a treatment algorithm was developed. Conclusion: Treatment with oxaliplatin, FP/FA ± moAb is feasible and may derive relevant benefits in patients with severe liver dysfunction caused by GI cancer liver metastases without further options of drainage. PMID:27239232

  11. Study of PKRBD in HCV genotype 3a infected patients in response to interferon therapy in Pakistani population

    PubMed Central

    2013-01-01

    Background Hepatitis C virus (HCV) is a major cause of liver cirrhosis and hepatocellular carcinoma and infects about 3% world population. Response to interferon therapy depends upon the genotype of the virus and factors associated with the host. Despite a good response to interferon therapy, a considerable number of genotype 3a infected patients remains unalleviated. Results In total forty-nine patients including twenty-five non-responders (non-SVR) and twenty-four responders (SVR) were recruited. Patients were tested for viral status at different intervals and the isolated RNA was sequenced for the NS5A region in both groups. The comparison of PKRBD of HCV between the SVR and non-SVR patients did not confirm any significant difference in the number of mutations. However, when the sequence downstream to the PKRBD of NS5A was compared, two important statistically significant mutations were observed; at positions 2309 (Ala to Ser) and 2326 (Gly to Ala). These mutations were then analysed for tertiary protein structure and important structural changes were observed. Statistically significant difference was also observed when age groups of patients were compared; younger patients showed better response than the older ones. Conclusions The region between PKRBD and IRRDR may be important for prediction of response to IFN therapy for genotype 3a. ISDR and PKRBD have not shown any involvement in treatment response. Further functional analyses of these findings can help in understanding the involvement of the NS5A region in interferon treatment of HCV-3a infected patients. PMID:24321105

  12. Panobinostat as part of induction and maintenance for elderly patients with newly diagnosed acute myeloid leukemia: phase Ib/II panobidara study

    PubMed Central

    Ocio, Enrique M.; Herrera, Pilar; Olave, María-Teresa; Castro, Nerea; Pérez-Simón, José A.; Brunet, Salut; Oriol, Albert; Mateo, Marta; Sanz, Miguel-Ángel; López, Javier; Montesinos, Pau; Chillón, María-Carmen; Prieto-Conde, María-Isabel; Díez-Campelo, María; González, Marcos; Vidriales, María-Belén; Mateos, María-Victoria; San Miguel, Jesús F.

    2015-01-01

    This phase Ib/II trial combined the pan-deacetylase inhibitor panobinostat with chemotherapy followed by panobinostat maintenance in elderly patients with newly diagnosed acute myeloid leukemia. Patients with prior history of myelodysplastic syndrome were excluded and 38 evaluable patients were included in the study (median age: 71 years; range: 65–83). Study patients received an induction with idarubicin (8 mg/m2 iv days 1–3) plus cytarabine (100 mg/m2 iv days 1–7) plus panobinostat po at escalating doses (days 8, 10, 12, 15, 17 and 19) that could be repeated in non-responding patients. Patients achieving complete remission received a consolidation cycle with the same schema, followed by panobinostat maintenance (40 mg po 3 days/week) every other week until progression. Thirty-one patients were treated at the maximum tolerated dose of panobinostat in the combination (10 mg) with good tolerability. Complete remission rate was 64% with a time to relapse of 17.0 months (12.8–21.1). Median overall survival for the whole series was 17 months (5.5–28.4). Moreover, in 4 of 5 patients with persistent minimal residual disease before maintenance, panobinostat monotherapy reduced its levels, with complete negativization in two of them. Maintenance phase was well tolerated. The most frequent adverse events were thrombocytopenia (25% grades 3/4), and gastrointestinal toxicity, asthenia and anorexia (mainly grades 1/2). Five patients required dose reduction during this phase, but only one discontinued therapy due to toxicity. These results suggest that panobinostat is one of the first novel agents with activity in elderly acute myeloid leukemia patients, and suggest further investigation is warranted, particularly in the context of maintenance therapy. This trial is registered at clinicaltrials.gov identifier: 00840346. PMID:26160880

  13. Panobinostat as part of induction and maintenance for elderly patients with newly diagnosed acute myeloid leukemia: phase Ib/II panobidara study.

    PubMed

    Ocio, Enrique M; Herrera, Pilar; Olave, María-Teresa; Castro, Nerea; Pérez-Simón, José A; Brunet, Salut; Oriol, Albert; Mateo, Marta; Sanz, Miguel-Ángel; López, Javier; Montesinos, Pau; Chillón, María-Carmen; Prieto-Conde, María-Isabel; Díez-Campelo, María; González, Marcos; Vidriales, María-Belén; Mateos, María-Victoria; San Miguel, Jesús F

    2015-10-01

    This phase Ib/II trial combined the pan-deacetylase inhibitor panobinostat with chemotherapy followed by panobinostat maintenance in elderly patients with newly diagnosed acute myeloid leukemia. Patients with prior history of myelodysplastic syndrome were excluded and 38 evaluable patients were included in the study (median age: 71 years; range: 65-83). Study patients received an induction with idarubicin (8 mg/m(2) iv days 1-3) plus cytarabine (100 mg/m(2) iv days 1-7) plus panobinostat po at escalating doses (days 8, 10, 12, 15, 17 and 19) that could be repeated in non-responding patients. Patients achieving complete remission received a consolidation cycle with the same schema, followed by panobinostat maintenance (40 mg po 3 days/week) every other week until progression. Thirty-one patients were treated at the maximum tolerated dose of panobinostat in the combination (10 mg) with good tolerability. Complete remission rate was 64% with a time to relapse of 17.0 months (12.8-21.1). Median overall survival for the whole series was 17 months (5.5-28.4). Moreover, in 4 of 5 patients with persistent minimal residual disease before maintenance, panobinostat monotherapy reduced its levels, with complete negativization in two of them. Maintenance phase was well tolerated. The most frequent adverse events were thrombocytopenia (25% grades 3/4), and gastrointestinal toxicity, asthenia and anorexia (mainly grades 1/2). Five patients required dose reduction during this phase, but only one discontinued therapy due to toxicity. These results suggest that panobinostat is one of the first novel agents with activity in elderly acute myeloid leukemia patients, and suggest further investigation is warranted, particularly in the context of maintenance therapy. This trial is registered at clinicaltrials.gov identifier: 00840346.

  14. Pruritus Reduction with Systemic Anti-lymphoma Treatments in Patients with Cutaneous T Cell Lymphoma: A Narrative Review.

    PubMed

    Field, Halle; Gao, Ling; Motwani, Pooja; Wong, Henry K

    2016-12-01

    Cutaneous T-cell lymphomas (CTCL) are a heterogeneous and relatively rare group of non-Hodgkin lymphomas arising from neoplastic skin-homing memory T cells. There is no known cure for CTCL, and current treatments focus on achieving and maintaining remission, controlling symptoms, limiting toxicities and maintaining or improving quality of life. Patients with CTCL often suffer from pruritus (itching), which can be debilitating and can have a significant impact on physical well-being and quality of life. Although progress has been made towards understanding the mechanisms of pruritus, the pathophysiology of CTCL-related pruritus remains unclear. Currently, there is neither a step-wise treatment algorithm for CTCL nor a standardized approach to treating pruritus in patients with CTCL. Treatments which specifically target pruritus have been reported with varying effectiveness. However, systemic treatments that target CTCL have the potential to alleviate pruritus by treating the underlying disease. Several systemic CTCL treatments have reported anti-pruritic properties, some in both objective responders and nonresponders, but the lack of a standardized method to measure and report pruritus makes it difficult to compare the effectiveness of systemic treatments. In this review, we provide an overview of approved and investigational systemic CTCL treatments that report anti-pruritic properties. For each study, the methods used to measure and report pruritus, as well as the study design are examined so that the clinical benefits of each systemic treatment can be more readily evaluated.

  15. Efficacy, Dose Reduction, and Resistance to High-dose Fluticasone in Patients with Eosinophilic Esophagitis

    PubMed Central

    Butz, Bridget K.; Wen, Ting; Gleich, Gerald J.; Furuta, Glenn T.; Spergel, Jonathan; King, Eileen; Kramer, Robert E.; Collins, Margaret H.; Stucke, Emily; Mangeot, Colleen; Jackson, W. Daniel; O’Gorman, Molly; Abonia, J. Pablo; Pentiuk, Scott; Putnam, Philip E.; Rothenberg, Marc E.

    2014-01-01

    Background & Aims We evaluated the efficacy and safety of high-dose swallowed fluticasone propionate (FP) and dose reduction in patients with eosinophilic esophagitis (EoE) and analyzed esophageal transcriptomes to identify mechanisms. Methods We conducted a randomized, multisite, double-blind, placebo-controlled trial of daily 1760 mcg FP in participants 3–30 years old with active EoE. Twenty-eight participants received FP and 14 received placebo. After 3 months, participants given FP who were in complete remission (CR) received 880 mcg FP daily, and participants in the FP or placebo groups who were not in CR continued or started, respectively, 1760 mcg FP daily for 3 additional months. The primary endpoint was histologic evidence for CR. Secondary endpoints were partial remission (PR), symptoms, compliance, esophageal gene expression, esophageal eosinophil count, and the relationship between clinical features and FP responsiveness. Results After 3 months, 65% of subjects given FP and no subjects given placebo were in CR (P=.0001); 12% of those given FP and 8% of those given placebo were in PR. In the FP group, 73% of subjects remained in CR and 20% were in PR after the daily dose was reduced by 50%. Extending FP therapy in FP-resistant participants did not induce remission. FP decreased heartburn severity (P=.041). Compliance, age, sex, atopic status, or anthropomorphic features were not associated with response to FP. Gene expression patterns in esophageal tissues of FP responders were similar to those of patients without EoE; there was evidence for heterogeneous steroid signaling in subjects that did not respond to FP. Conclusions Daily administration of a high dose of FP induces histologic remission in 65%–77% of patients with EoE after 3 months. A 50% dose reduction remained effective in 73%–93% of patients that initially responded to FP. Nonresponders had evidence of steroid resistance; histologic and molecular markers may predict resistance

  16. Serum Cytokine Profile in Asian Indian Patients with Takayasu Arteritis and its Association with Disease Activity

    PubMed Central

    Goel, Ruchika; Kabeerdoss, Jayakanthan; Ram, Babu; Prakash, John Antony Jude; Babji, Sudhir; Nair, Aswin; Jeyaseelan, Lakshmanan; Jeyaseelan, Visalakshi; Mathew, John; Balaji, Veeraraghavan; Joseph, George; Danda, Debashish

    2017-01-01

    Background: Arterial inflammation Takayasu arteritis (TA) is an outcome of balance between pro- and anti-inflammatory cytokines. Comprehensive assessment of these cytokines is important for understanding pathogenesis and assessing disease activity. Objective: To study pro- and anti-inflammatory cytokines representing different T-helper cell pathway in serum samples of Asian Indian patients with TA and to assess their association with disease activity. Methods: Consecutive Indian patients with TA were assayed for serum interferon-γ, interleukin-6, interleukin-23, interleukin-17, interleukin-10 and transforming growth factor- β levels at baseline and follow up visit. Patients were grouped into active and stable disease based on Indian Takyasu Arteritis clinical Activity Score-2010. Serum levels of these cytokines between active and stable disease and between baseline and follow up visits were compared by non-parametric tests. Results: Among 32 patients enrolled, 15 were classified as active while 17 as stable disease at baseline. IFN-γ levels were significantly higher in active disease than stable disease (p=0.0129) while other cytokines did not differ significantly between 2 groups. Serum levels of none of the cytokines changed significantly over 2 visits in both responders and non-responders. IL23 levels positively correlate with disease duration ((r=0.999; p<0.005). Modest correlation was observed between IFN-γ and IL23 levels at both baseline and follow up and between IFN-γ and IL-6 and CRP at follow up. Conclusion: IFN-γ levels are raised in active disease in TA and correlates well with other biomarkers of disease activity and proinflammatory cytokines. There is also a direct correlation between Il-23 levels and disease duration.

  17. U.S. survey of surgical capabilities and experience with surgical procedures in patients with congenital haemophilia with inhibitors.

    PubMed

    Shapiro, A; Cooper, D L

    2012-05-01

    General guidelines exist for the use of recombinant activated factor VII (rFVIIa) to maintain haemostasis during surgery in congenital haemophilia A and B patients with high responding inhibitors (CHwI). Individual surgical plans are required and based upon historical therapy response, adverse events and anticipated procedure. Surgical interventions are feasible, yet it remains unclear how many US hemophilia treatment centres (HTCs) perform procedures in this fragile population. To better understand the US HTC surgical experience in CHwI patients and the number/types of procedures performed, a 21-question survey was sent to 133 US HTCs, with follow-up for response clarification and to non-responders. 98/133 HTCs (74%) responded, with 87 currently treating CHwI patients. In the last decade, 76/85 HTCs performed 994 surgeries on CHwI patients. Sites were experienced in the following procedures: central line insertion/removal (73 HTCs), dental (58), orthopaedic (52), abdominal (23), cardiovascular (14) and otolaryngologic (11). Experience with orthopaedic surgeries included synovectomies - arthroscopic (23 HTCs), radioisotopic (22), and open (7); joint replacement (18); fracture repair (14); and arthrodesis (8). Treatment modalities included rFVIIa bolus (83 HTCs) or continuous infusions (9), plasma-derived activated prothrombin complex concentrate (pd-aPCC) (55), antifibrinolytics (51), topical haemostatic agents (29), factor VIII (16) and fibrin sealants (14). Protocols for bypassing agents were used by 31/92 (33%) HTCs. Most US HTCs surveyed care for CHwI patients (74%) and have experience in minor surgery; fewer HTCs reported complex orthopaedic surgical experience. Identification of best practices and surgical barriers is required to guide future initiatives to support these patients.

  18. Scintigraphic detection of TNF-driven inflammation by radiolabelled certolizumab pegol in patients with rheumatoid arthritis and spondyloarthritis

    PubMed Central

    Carron, Philippe; Lambert, Bieke; Van Praet, Liesbet; De Vos, Filip; Varkas, Gaëlle; Jans, Lennart; Elewaut, Dirk; Van den Bosch, Filip

    2016-01-01

    Background Biologicals are the cornerstone for many treatment algorithms in inflammatory arthritis. While tumour necrosis factor (TNF) inhibitors may achieve important responses in ∼50% of patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA), a significant fraction of patients are partial or non-responders. We hypothesised that in vivo assessment of TNF by scintigraphy with 99mTc-radiolabelled certolizumab pegol (CZP) might lead to a more ‘evidence-based biological therapy’. Objectives Our goal was to perform a proof-of-concept study of in vivo detection of TNF by immunoscintigraphy of a radiolabelled TNF inhibitor in RA and SpA, and correlate this with clinical, imaging findings and therapeutic outcome. Methods CZP was conjugated with succinimidyl-6-hydrazino-nicotinamide and subsequently radiolabelled with Tc99m. Whole body and static images of hands, feet and sacroiliac joints of 20 patients (5 RA; 15 SpA) were acquired at 3 time points. Immunoscintigraphic findings were scored semiquantitatively. Subsequently, all patients were treated with CZP. Results In peripheral joints, clinically affected joints or abnormal ultrasound findings were observed more frequently (p<0.001) in the scintigraphic-positive group. In patients with axial SpA, bone marrow edema on MRI was detected more frequently (p<0.001) in quadrants with tracer uptake. At the patient level, the odds of a joint remaining tender despite 24 weeks of CZP treatment was significantly smaller in joints with clear tracer uptake as compared with those with no uptake (OR=0.42, p=0.04). Conclusions Immunoscintigraphy with radiolabelled CZP demonstrated both axial and peripheral inflammation, and displayed good correlation with clinical features, conventional imaging and therapy response. Trial registration number NCT01590966; Results. PMID:27403334

  19. Annual biologic treatment cost for new and existing patients with moderate to severe plaque psoriasis in Greece

    PubMed Central

    Fragoulakis, Vassilis; Raptis, Efklidis; Vitsou, Elli; Maniadakis, Nikolaos

    2015-01-01

    Aim The aim of the present study was to estimate the annual per-patient cost of treatment with adalimumab, etanercept, infliximab, and ustekinumab by response status for new and existing patients with moderate to severe psoriasis in Greece. Methods An economic analysis was developed from a national health care perspective to estimate the direct cost of treatment alternatives for new and existing patients within a 1-year time horizon. The model included drug acquisition and administration costs for responders and nonresponders. Real-world treatment pattern and resource use data were extracted through nationwide field research using telephone-based interviews with a representative sample of dermatologists. Unit costs were collected from official sources in the public domain. Results The mean annual cost of treatment for new patients who responded (or did not respond) to treatment was as follows: adalimumab €10,686 (€3,821), etanercept €10,415 (€3,224), infliximab €14,738 (€7,582), and ustekinumab €17,155 (€9,806). For existing patients the mean annual cost was €9,916, €9,462, €12,949, and €17,149, respectively. Results did not change significantly under several one-way sensitivity and scenario analyses. Conclusion Under the base-case scenario, the cost of treatment with etanercept is lower than that of the other biological agents licensed for moderate to severe plaque psoriasis in Greece, for both new and existing patients, irrespective of response status. PMID:25609988

  20. Pretreatment Evaluation of Microcirculation by Dynamic Contrast-Enhanced Magnetic Resonance Imaging Predicts Survival in Primary Rectal Cancer Patients

    SciTech Connect

    DeVries, Alexander Friedrich; Piringer, Gudrun; Kremser, Christian; Judmaier, Werner; Saely, Christoph Hubert; Lukas, Peter; Öfner, Dietmar

    2014-12-01

    Purpose: To investigate the prognostic value of the perfusion index (PI), a microcirculatory parameter estimated from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), which integrates information on both flow and permeability, to predict overall survival and disease-free survival in patients with primary rectal cancer. Methods and Materials: A total of 83 patients with stage cT3 rectal cancer requiring neoadjuvant chemoradiation were investigated with DCE-MRI before start of therapy. Contrast-enhanced dynamic T{sub 1} mapping was obtained, and a simple data analysis strategy based on the calculation of the maximum slope of the tissue concentration–time curve divided by the maximum of the arterial input function was used as a measure of tumor microcirculation (PI), which integrates information on both flow and permeability. Results: In 39 patients (47.0%), T downstaging (ypT0-2) was observed. During a mean (±SD) follow-up period of 71 ± 29 months, 58 patients (69.9%) survived, and disease-free survival was achieved in 45 patients (54.2%). The mean PI (PImean) averaged over the group of nonresponders was significantly higher than for responders. Additionally, higher PImean in age- and gender-adjusted analyses was strongly predictive of therapy nonresponse. Most importantly, PImean strongly and significantly predicted disease-free survival (unadjusted hazard ratio [HR], 1.85 [ 95% confidence interval, 1.35-2.54; P<.001)]; HR adjusted for age and sex, 1.81 [1.30-2.51]; P<.001) as well as overall survival (unadjusted HR 1.42 [1.02-1.99], P=.040; HR adjusted for age and sex, 1.43 [1.03-1.98]; P=.034). Conclusions: This analysis identifies PImean as a novel biomarker that is predictive for therapy response, disease-free survival, and overall survival in patients with primary locally advanced rectal cancer.

  1. Differences in hepatitis C virus (HCV)-specific CD8 T-cell phenotype during pegylated alpha interferon and ribavirin treatment are related to response to antiviral therapy in patients chronically infected with HCV.

    PubMed

    Caetano, Joana; Martinho, António; Paiva, Artur; Pais, Beatriz; Valente, Cristina; Luxo, Cristina

    2008-08-01

    CD8 T cells play a major role in antiviral immune responses. Their importance for progression to chronic hepatitis C and response to treatment are still unclear. To address these issues, hepatitis C virus (HCV)-specific CD8 T-cell responses were monitored, at the single-cell level, using HLA class I pentamers specific for HCV core and HCV NS3 epitopes, in 23 chronically infected patients during treatment with pegylated alpha interferon and ribavirin. Patients who presented a sustained-response to therapy had stronger HCV-specific CD8 T-cell responses at all time points studied. Moreover, there were clear differences in the phenotypes of these cells during therapy: in responder patients, terminally differentiated effector cells increased more rapidly, and their frequency was always higher than in nonresponder patients. Sustained-responder patients also showed a higher frequency of HCV-specific CD8 T cells producing cytotoxic factors. Overall, a late and inefficient differentiation process of HCV-specific CD8 T cells might be associated with lack of response to treatment. A better knowledge of the mechanisms underlying this impairment may be important for the development of new therapeutic strategies to maintain, restore, or increase CD8 T-cell effectiveness in chronic HCV infection.

  2. Transcriptome Analysis of Peripheral Blood in Chronic Inflammatory Demyelinating Polyradiculoneuropathy Patients Identifies TNFR1 and TLR Pathways in the IVIg Response.

    PubMed

    Richard, Alexandra; Corvol, Jean-Christophe; Debs, Rabab; Reach, Pauline; Tahiri, Khadija; Carpentier, Wassila; Gueguen, Justine; Guillemot, Vincent; Labeyrie, Céline; Adams, David; Viala, Karine; Cohen Aubart, Fleur

    2016-05-01

    We have studied the response to intravenous immunoglobulins (IVIg) by a transcriptomic approach in 11 chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients (CIDP duration = 6 [0.83-6.5] years). RNA was extracted from cells in whole blood collected before and 3 weeks after IVIg treatment, and hybridized on Illumina chips. After RNA quality controls, gene expression was analyzed using statistical tests fitted for microarrays (R software, limma package), and a pathway analysis was performed using DAVID software. We identified 52 genes with expression that varied significantly after IVIg (fold change [FC] > 1.2, P < 0.001, false discovery rate [FDR] <0.05). Among these 52 genes, 7 were related to immunity, 3 were related to the tumor necrosis factor (TNF)-α receptor 1 (TNFR1) pathway (inhibitor of caspase-activated DNase (ICAD): FC = 1.8, P = 1.7E-7, FDR = 0.004; p21 protein-activated kinase 2 [PAK2]: FC = 1.66, P = 2.6E-5, FDR = 0.03; TNF-α-induced protein 8-like protein 1 [TNFAIP8L1]: P = 1.00E-05, FDR = 0.026), and 2 were related to Toll-like receptors (TLRs), especially TLRs 7 and 9, and were implicated in autoimmunity. These genes were UNC93B1 (FC = 1.6, P = 2E-5, FDR = 0.03), which transports TLRs 7 and 9 to the endolysosomes, and RNF216 (FC = 1.5, P = 1E-05, FDR = 0.03), which promotes TLR 9 degradation. Pathway analysis showed that the TNFR1 pathway was significantly lessened by IVIg (enrichment score = 24, Fischer exact test = 0.003). TNF-α gene expression was higher in responder patients than in nonresponders; however, it decreased after IVIg in responders (P = 0.04), but remained stable in nonresponders. Our data suggest the actions of IVIg on the TNFR1 pathway and an original mechanism involving innate immunity through TLRs in CIDP pathophysiology and the response to IVIg. We conclude that responder patients have stronger inflammatory activity that is

  3. Transcriptome Analysis of Peripheral Blood in Chronic Inflammatory Demyelinating Polyradiculoneuropathy Patients Identifies TNFR1 and TLR Pathways in the IVIg Response

    PubMed Central

    Richard, Alexandra; Corvol, Jean-Christophe; Debs, Rabab; Reach, Pauline; Tahiri, Khadija; Carpentier, Wassila; Gueguen, Justine; Guillemot, Vincent; Labeyrie, Céline; Adams, David; Viala, Karine; Cohen Aubart, Fleur

    2016-01-01

    Abstract We have studied the response to intravenous immunoglobulins (IVIg) by a transcriptomic approach in 11 chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients (CIDP duration = 6 [0.83–6.5] years). RNA was extracted from cells in whole blood collected before and 3 weeks after IVIg treatment, and hybridized on Illumina chips. After RNA quality controls, gene expression was analyzed using statistical tests fitted for microarrays (R software, limma package), and a pathway analysis was performed using DAVID software. We identified 52 genes with expression that varied significantly after IVIg (fold change [FC] > 1.2, P < 0.001, false discovery rate [FDR] <0.05). Among these 52 genes, 7 were related to immunity, 3 were related to the tumor necrosis factor (TNF)-α receptor 1 (TNFR1) pathway (inhibitor of caspase-activated DNase (ICAD): FC = 1.8, P = 1.7E-7, FDR = 0.004; p21 protein-activated kinase 2 [PAK2]: FC = 1.66, P = 2.6E-5, FDR = 0.03; TNF-α-induced protein 8-like protein 1 [TNFAIP8L1]: P = 1.00E-05, FDR = 0.026), and 2 were related to Toll-like receptors (TLRs), especially TLRs 7 and 9, and were implicated in autoimmunity. These genes were UNC93B1 (FC = 1.6, P = 2E-5, FDR = 0.03), which transports TLRs 7 and 9 to the endolysosomes, and RNF216 (FC = 1.5, P = 1E-05, FDR = 0.03), which promotes TLR 9 degradation. Pathway analysis showed that the TNFR1 pathway was significantly lessened by IVIg (enrichment score = 24, Fischer exact test = 0.003). TNF-α gene expression was higher in responder patients than in nonresponders; however, it decreased after IVIg in responders (P = 0.04), but remained stable in nonresponders. Our data suggest the actions of IVIg on the TNFR1 pathway and an original mechanism involving innate immunity through TLRs in CIDP pathophysiology and the response to IVIg. We conclude that responder patients have stronger inflammatory activity

  4. Patient Rights

    MedlinePlus

    ... have a patient bill of rights. An important patient right is informed consent. This means that if you need a treatment, your health care provider must give you the information you need to make a decision. Many hospitals have patient advocates who can help you if you have ...

  5. How can the response to volume expansion in patients with spontaneous respiratory movements be predicted?

    PubMed Central

    Heenen, Sarah; De Backer, Daniel; Vincent, Jean-Louis

    2006-01-01

    Introduction The aim of the study was to evaluate the ability of different static and dynamic measurements of preload to predict fluid responsiveness in patients with spontaneous respiratory movements. Methods The subjects were 21 critically ill patients with spontaneous breathing movements receiving mechanical ventilation with pressure support mode (n = 9) or breathing through a face mask (n = 12), and who required a fluid challenge. Complete hemodynamic measurements, including pulmonary artery occluded pressure (PAOP), right atrial pressure (RAP), pulse pressure variation (ΔPP) and inspiratory variation in RAP were obtained before and after fluid challenge. Fluid challenge consisted of boluses of either crystalloid or colloid until cardiac output reached a plateau. Receiver operating characteristics (ROC) curve analysis was used to evaluate the predictive value of the indices to the response to fluids, as defined by an increase in cardiac index of 15% or more. Results Cardiac index increased from 3.0 (2.3 to 3.5) to 3.5 (3.0 to 3.9) l minute-1 m-2 (medians and 25th and 75th centiles), p < 0.05. At baseline, ΔPP varied between 0% and 49%. There were no significant differences in ΔPP, PAOP, RAP and inspiratory variation in RAP between fluid responders and non-responders. Fluid responsiveness was predicted better with static indices (ROC curve area ± SD: 0.73 ± 0.13 for PAOP, p < 0.05 vs ΔPP and 0.69 ± 0.12 for RAP, p = 0.054 compared with ΔPP) than with dynamic indices of preload (0.40 ± 0.13 for ΔPP and 0.53 ± 0.13 for inspiratory changes in RAP, p not significant compared with ΔPP). Conclusion In patients with spontaneous respiratory movements, ΔPP and inspiratory changes in RAP failed to predict the response to volume expansion. PMID:16846530

  6. Central modulation in cluster headache patients treated with occipital nerve stimulation: an FDG-PET study

    PubMed Central

    2011-01-01

    Background Occipital nerve stimulation (ONS) has raised new hope for drug-resistant chronic cluster headache (drCCH), a devastating condition. However its mode of action remains elusive. Since the long delay to meaningful effect suggests that ONS induces slow neuromodulation, we have searched for changes in central pain-control areas using metabolic neuroimaging. Methods Ten drCCH patients underwent an 18FDG-PET scan after ONS, at delays varying between 0 and 30 months. All were scanned with ongoing ONS (ON) and with the stimulator switched OFF. Results After 6-30 months of ONS, 3 patients were pain free and 4 had a ≥ 90% reduction of attack frequency (responders). In all patients compared to controls, several areas of the pain matrix showed hypermetabolism: ipsilateral hypothalamus, midbrain and ipsilateral lower pons. All normalized after ONS, except for the hypothalamus. Switching the stimulator ON or OFF had little influence on brain glucose metabolism. The perigenual anterior cingulate cortex (PACC) was hyperactive in ONS responders compared to non-responders. Conclusions Metabolic normalization in the pain neuromatrix and lack of short-term changes induced by the stimulation might support the hypothesis that ONS acts in drCCH through slow neuromodulatory processes. Selective activation in responders of PACC, a pivotal structure in the endogenous opioid system, suggests that ONS could restore balance within dysfunctioning pain control centres. That ONS is nothing but a symptomatic treatment might be illustrated by the persistent hypothalamic hypermetabolism, which could explain why autonomic attacks may persist despite pain relief and why cluster attacks recur shortly after stimulator arrest. PET studies on larger samples are warranted to confirm these first results. PMID:21349186

  7. Towards patient stratification and treatment in the autoimmune disease lupus erythematosus using a systems pharmacology approach.

    PubMed

    Ruiz-Cerdá, M Leire; Irurzun-Arana, Itziar; González-Garcia, Ignacio; Hu, Chuanpu; Zhou, Honghui; Vermeulen, An; Trocóniz, Iñaki F; Gómez-Mantilla, José David

    2016-10-30

    Drug development in Systemic Lupus Erythematosus (SLE) has been hindered by poor translation from successful preclinical experiments to clinical efficacy. This lack of success has been attributed to the high heterogeneity of SLE patients and to the lack of understanding of disease physiopathology. Modelling approaches could be useful for supporting the identification of targets, biomarkers and patient subpopulations with differential response to drugs. However, the use of traditional quantitative models based on differential equations is not justifiable in a sparse data situation. Boolean networks models are less demanding on the required data to be implemented and can provide insights into the dynamics of biological networks. This methodology allows the integration of all the available knowledge into a single framework to evaluate the behavior of the system under different conditions and test hypotheses about unknown aspects of the disease. In this proof-of-concept study, we explored the potential of a systems pharmacology model based on Boolean networks to support drug development in SLE. We focused the analysis on the antigen presentation by the antigen presenting cells (APC) to the T-cells to evaluate the scope of this methodology in a medium size network before full implementation of the whole SLE pathway. The heterogeneity of SLE patients was replicated using this methodology simulating subjects with distinct pathway alterations. A perturbation analysis of the network coupled with clustering analysis showed potential to identify drug targets, optimal combinatorial regimens and subpopulations of responders and non-responders to drug treatment. We propose this approach as a first step towards the development of more quantitative platforms to address the current challenges in drug development for complex diseases.

  8. Health checks on patients 75 years and over in Nottinghamshire after the new GP contract.

    PubMed Central

    Brown, K.; Williams, E. I.; Groom, L.

    1992-01-01

    OBJECTIVE--To investigate annual health checks for patients of 75 years and over required by the 1990 contract for general practitioners. DESIGN--Visits to practices to collect information on how assessments were organised and carried out; completion of questionnaires for every patient who had been assessed in a sample month, using information provided by the practice records. SETTING--20 general practices in one family health services authority. SUBJECTS--Patients of 75 years and over in 20 general practices. RESULTS--Three practices (15%) had not performed checks. Thirteen practices sent a letter to invite patients to undergo a check. Of these practices, seven followed up non-responders. Two practices visited patients' homes unannounced, and two did checks on an opportunistic basis only. Sixteen practices used a checklist. Sixteen practices involved their practice nurses; at eight of these, doctors also performed checks; in six practices the nurses undertaking the checks had no training in assessing old people. Ten practices assessed more than 75% of their old people in the first year of the new contract. Practices that did not follow up patients who had not responded to the invitation for assessment completed significantly fewer checks. During the sample month, 331 patients were assessed in the 17 practices. 204 new problems were discovered in 143 patients. Significantly more problems per patient were found in inner city areas. CONCLUSIONS--The way health checks were performed varied greatly, both in their organisation and the practices' attitudes. Many old people did not respond to letters asking if they wanted an assessment but very few refused one if followed up. Forty three per cent of those assessed had some unmet need. The number of new problems found per patient may reduce over the next few years if the assessments are successful. The need for annual assessment should be kept under review and adequate resources made available for the needs uncovered

  9. Role of Brain Perfusion SPECT with 99mTc HMPAO in the Assessment of Response to Drug Therapy in Patients with Autoimmune Vasculitis: A Prospective Study

    PubMed Central

    Mauro, Liberatore; Manuela, Morreale; Valentina, Megna; Sara, Collorone; Chondrogiannis, Sotirios; Maria, Drudi Francesco; Christos, Anagnostou; Liana, Civitelli; Ada, Francia; Maffione, Anna Margherita; Marzola, Maria Cristina; Rubello, Domenico

    2015-01-01

    Background: The diagnosis of vasculitis in the brain remains a quite difficult achievement. To the best of our knowledge, there is no imaging method reported in literature which is capable of reaching to a diagnosis of vasculitis with very high sensitivity. Aim: The aim of this study was to determine whether perfusion brain single photon emission computed tomography (SPECT) can be usefully employed in monitoring the treatment of vasculitis, allowing treating only potentially responder patients and avoiding the side effects on patients who do not respond. Materials and Methods: Twenty patients (two males and 18 females) suffering from systemic lupus erythematosus (SLE; n = 5), Behcet's disease (BD; n = 5), undifferentiated vasculitis (UV; n = 5), and Sjogren's syndrome (SS; n = 5) were included in the study. All patients underwent a wide neurological anamnestic investigation, a complete objective neurological examination and SPECT of the brain with 99mTc-hexamethyl-propylene-aminoxime (HMPAO). The brain SPECT was then repeated after appropriate medical treatment. The neurological and neuropsychiatric follow-up was performed at 6 months after the start of the treatment. Results: Overall, the differences between the scintigraphic results obtained after and before the medical treatment indicated a statistically significant increase of the cerebral perfusion (CP). In 19 out of 200 regions of interest (ROI) studied, the difference between pre- and post treatment percentages had negative sign, indicating a worsening of CP. This latter event has occurred six times (five in the same patients) in the UV, 10 times (eight in the same patients) in the SLE, never in BD, and three times (two in the same patient) in the SS. Conclusion: The reported results seem to indicate the possibility of identifying, by the means of a brain SPECT, responder and nonresponder (unchanged or worsened CP) patients, affected by autoimmune vasculitis, to the therapy. PMID:25973400

  10. Lsr2 Peptides of Mycobacterium leprae Show Hierarchical Responses in Lymphoproliferative Assays, with Selective Recognition by Patients with Anergic Lepromatous Leprosy

    PubMed Central

    Chaduvula, Mehervani; Murtaza, A.; Misra, Namita; Narayan, N. P. Shankar; Ramesh, V.; Prasad, H. K.; Rani, Rajni; Chinnadurai, R. K.

    2012-01-01

    Lsr2 protein of Mycobacterium leprae was shown earlier to elicit B and T cell responses in leprosy patients (20, 28). Lymphoproliferation to M. leprae and Lsr2 antigens was observed in >70% of tuberculoid (T) patients and in 16 and 34% of lepromatous (L) patients, respectively. We focused on the M. leprae nonresponders in the lepromatous group using 22 synthetic Lsr2 peptides (end-to-end peptides A to F and overlapping peptides p1 to p16) in in vitro T cell responses. A total of 125 leprosy and 13 tuberculosis patients and 19 healthy controls from the area of endemicity (here, healthy controls, or HC) were investigated. The highest responses were observed (67 to 100%) in HC for all peptides except p1 to p3, and the lowest was observed in tuberculosis patients. Significant differences in lymphoproliferation were observed in T, L, and HC groups (analysis of variance [ANOVA], P = 0.000 to 0.015) for all end-to-end peptides except B and for p5 and p7 to p10. Hierarchical recognition between lepromatous and tuberculoid leprosy was noted for p8 (P < 0.05) and between the HC and L groups for p7 to p10, p15, and p16 (P < 0.005 to P < 0.02). Significant lymphoproliferation was observed to peptides A to F and p1 to p9, p11, p12, p15, p16 (P = 0.000 to 0.001) with 40% responding to peptides C and p16 in L patients. Lepromatous patients also showed significantly higher levels of a gamma interferon (IFN-γ) response to peptide C than to other peptides (P < 0.05). Major histocompatibility complex (MHC) class II bias for peptide recognition was not observed. These studies indicate that Lsr2 has multiple T cell epitopes that induce in vitro T cell responses in the highly infective lepromatous leprosy patients. PMID:22144494

  11. Peripheral blood Th9 cells are a possible pharmacodynamic biomarker of nivolumab treatment efficacy in metastatic melanoma patients.

    PubMed

    Nonomura, Yumi; Otsuka, Atsushi; Nakashima, Chisa; Seidel, Judith A; Kitoh, Akihiko; Dainichi, Teruki; Nakajima, Saeko; Sawada, Yu; Matsushita, Shigeto; Aoki, Megumi; Takenouchi, Tatsuya; Fujimura, Taku; Hatta, Naohito; Koreeda, Satoshi; Fukushima, Satoshi; Honda, Tetsuya; Kabashima, Kenji

    2016-01-01

    Although nivolumab is associated with a significant improvement in overall survival and progression-free survival, only 20 to 40% of patients experience long-term benefit. It is therefore of great interest to identify a predictive marker of clinical benefit for nivolumab. To address this issue, the frequencies of CD4(+) T cell subsets (Treg, Th1, Th2, Th9, Th17 and Th22), CD8(+) T cells, and serum cytokine levels (IFNγ, IL-4, IL-9, IL-10, TGF-β) were assessed in 46 patients with melanoma. Eighteen patients responded to nivolumab, and the other 28 patients did not. An early increase in Th9 cell counts during the treatment with nivolumab was associated with an improved clinical response. Before the first nivolumab infusion, the responders displayed elevated serum concentrations of TGF-β compared to non-responders. Th9 induction by IL-4 and TGF-β was enhanced by PD-1/PD-L1 blockade in vitro. The role of IL-9 in disease progression was further assessed using a murine melanoma model. In vivo IL-9 blockade promoted melanoma progression in mice using an autochthonous mouse melanoma model, and the cytotoxic ability of murine melanoma-specific CD8(+) T cells was enhanced in the presence of IL-9 in vitro. These findings suggest that Th9 cells, which produce IL-9, play an important role in the successful treatment of melanoma patients with nivolumab. Th9 cells therefore represent a valid biomarker to be further developed in the setting of anti-PD-1 therapy.

  12. Predictors of response to intra-articular steroid injections in patients with osteoarthritis of the knee joint.

    PubMed

    Fatimah, Nibah; Salim, Babur; Raja, Ejaz-Ul-Haq; Nasim, Amjad

    2016-10-01

    This study aimed to determine the factors associated with response to intra-articular steroid injection (IASI) in patients with knee joint osteoarthritis. One hundred seventy-four female patients, age ranging from 30 to 80 years, diagnosed to have osteoarthritis of the knee joint, were given IASI. Response to IASI was assessed by using WOMAC and VAS at 2 weeks, 4 weeks and 3 months. At 3 months, the subjects were categorized as responders, partial responders and non-responders to treatment by IASI. Various factors were narrowed down to see their effect on response, namely age, BMI, smoking habits, comorbidities, presence of clinical effusion, radiographic score, local knee tenderness, range of movement and socioeconomic status. One hundred twenty-four patients completed the study. 16.1 % showed 50 % or more improvement in WOMAC score at 3 months post IASI therapy, whereas 38.7 % of OA patients had more than 50 % improvement in VAS score. Out of all factors, range of movement, local knee tenderness and radiographic score of the affected joint are the three parameters which can predict the improvement in WOMAC score after 3 months of IASI therapy (P = 0.013, P = 0.045 and P = 0.000, respectively). Age of the patient can predict improvement in VAS at 3 months post IASI (P = 0.027). We conclude that age, range of movement, local knee tenderness and radiographic score of the affected joint can predict response to IASI after 3 months of IASI therapy.

  13. Hepatitis C virus (HCV) genotype, tissue HCV antigens, hepatocellular expression of HLA-A,B,C, and intercellular adhesion-1 molecules. Clues to pathogenesis of hepatocellular damage and response to interferon treatment in patients with chronic hepatitis C.

    PubMed Central

    Ballardini, G; Groff, P; Pontisso, P; Giostra, F; Francesconi, R; Lenzi, M; Zauli, D; Alberti, A; Bianchi, F B

    1995-01-01

    To obtain information on the mechanisms of hepatocellular damage and the determinants of response to interferon, hepatitis C virus (HCV) genotype, tissue HCV antigens, hepatocellular expression of HLA-A,B,C and intercellular adhesion-1 molecules, and the number of lobular T lymphocytes were studied in 38 anti-HCV-positive patients. 14 patients did not show a primary response to interferon treatment. HCV genotype 1b was detected in 11 of them. They displayed higher scores of HCV-positive hepatocytes, HLA-A,B,C, and ICAM-1 molecules expression than with the responders. HCV-infected hepatocytes maintained the capacity to express HLA-A,B,C and ICAM-1 molecules. CD8-positive T cells in contact with infected hepatocytes and Councilman-like bodies were observed. A significant correlation was found between the number of lobular CD8-positive T cells and alanine amino transferase levels. No differences were observed in clinical, biochemical, and histological features between patients with high and low number of hepatocytes containing HCV antigens. These data suggest a prominent role of T cell-mediated cytotoxicity in the genesis of hepatocellular damage. The high expression of interferon-inducible antigens like HLA-A,B,C molecules suggests the presence of strong activation of the interferon system possibly related to high HCV replication in nonresponder patients infected with genotype 1b. Images PMID:7738174

  14. Hypomethylation and up-regulation of PD-1 in T cells by azacytidine in MDS/AML patients: A rationale for combined targeting of PD-1 and DNA methylation.

    PubMed

    Ørskov, Andreas D; Treppendahl, Marianne B; Skovbo, Anni; Holm, Mette S; Friis, Lone S; Hokland, Marianne; Grønbæk, Kirsten

    2015-04-20

    The hypomethylating agents (HMAs) are standard therapy for patients with higher-risk myelodysplastic syndrome (MDS); however, the majority of the patients will lose their response to HMAs over time due to unknown mechanisms. It has recently been shown that T cell expression of the immunoinhibitory receptor PD-1 is regulated by DNA methylation. In 12 of 27 patients (44%) PD-1 promoter demethylation was observed in sorted peripheral blood T cells isolated over consecutive cycles of treatment with 5-azacytidine (5-aza). The PD-1 promoter demethylation correlated with an increase in PD-1 expression. Moreover, demethylation of the PD-1 promoter correlated with a significantly worse overall response rate (8% vs. 60%, p = 0.014), and a trend towards a shorter overall survival (p = 0.11) was observed. A significantly higher baseline methylation level of the PD-1 promoter was observed in T cells of non-responding patients compared to healthy controls (p = 0.023). Accordingly, in addition to their beneficial function, HMAs induce PD-1 expression on T cells in the MDS microenvironment, thereby likely hampering the immune response against the MDS blasts. Thus, we suggest that activation of the PD-1 checkpoint during HMA treatment can be a possible resistance mechanism, which may be overcome by combination therapy with a PD-1 pathway inhibitor.

  15. Pharmacokinetic-pharmacodynamic modeling of fostamatinib efficacy on ACR20 to support dose selection in patients with rheumatoid arthritis (RA).

    PubMed

    Maringwa, John; Kågedal, Matts; Hamrén, Ulrika Wählby; Martin, Paul; Cox, Eugène; Hamrén, Bengt

    2015-03-01

    R788 (fostamatinib) is an oral prodrug that is rapidly converted into a relatively selective spleen tyrosine kinase (SYK) inhibitor R406, evaluated for the treatment of rheumatoid arthritis (RA). This analysis aimed at developing a pharmacodynamic model for efficacy using pooled ACR20 data from two phase II studies in patients with rheumatoid arthritis (TASKi1 and TASKi2), describing the effect of fostamatinib as a function of fostamatinib exposure (dose, R406 plasma concentration) and other explanatory variables. The exposure-response relationship of fostamatinib was implemented into a continuous time Markov model describing the time course of transition probabilities between the three possible states of ACR20 non-responder, responder, and dropout at each visit. The probability of transition to the ACR20 response state was linearly (at the rate constant level) related to average R406 plasma concentrations and the onset of this drug effect was fast. Further, increases of fostamatinib dose resulted in increased dropout and subsequent loss of efficacy. This analysis provided an increased understanding of the exposure-response relationship, and provided support for fostamatinib 100 mg BID an appropriate dose regimen for further clinical evaluation.

  16. DCE-MRI Perfusion and Permeability Parameters as predictors of tumor response to CCRT in Patients with locally advanced NSCLC

    PubMed Central

    Tao, Xiuli; Wang, Lvhua; Hui, Zhouguang; Liu, Li; Ye, Feng; Song, Ying; Tang, Yu; Men, Yu; Lambrou, Tryphon; Su, Zihua; Xu, Xiao; Ouyang, Han; Wu, Ning

    2016-01-01

    In this prospective study, 36 patients with stage III non-small cell lung cancers (NSCLC), who underwent dynamic contrast-enhanced MRI (DCE-MRI) before concurrent chemo-radiotherapy (CCRT) were enrolled. Pharmacokinetic analysis was carried out after non-rigid motion registration. The perfusion parameters [including Blood Flow (BF), Blood Volume (BV), Mean Transit Time (MTT)] and permeability parameters [including endothelial transfer constant (Ktrans), reflux rate (Kep), fractional extravascular extracellular space volume (Ve), fractional plasma volume (Vp)] were calculated, and their relationship with tumor regression was evaluated. The value of these parameters on predicting responders were calculated by receiver operating characteristic (ROC) curve. Multivariate logistic regression analysis was conducted to find the independent variables. Tumor regression rate is negatively correlated with Ve and its standard variation Ve_SD and positively correlated with Ktrans and Kep. Significant differences between responders and non-responders existed in Ktrans, Kep, Ve, Ve_SD, MTT, BV_SD and MTT_SD (P < 0.05). ROC indicated that Ve < 0.24 gave the largest area under curve of 0.865 to predict responders. Multivariate logistic regression analysis also showed Ve was a significant predictor. Baseline perfusion and permeability parameters calculated from DCE-MRI were seen to be a viable tool for predicting the early treatment response after CCRT of NSCLC. PMID:27762331

  17. Early decrease of serum biomarkers of type II collagen degradation (Coll2-1) and joint inflammation (Coll2-1 NO₂ ) by hyaluronic acid intra-articular injections in patients with knee osteoarthritis: a research study part of the Biovisco study.

    PubMed

    Henrotin, Y; Chevalier, X; Deberg, M; Balblanc, J C; Richette, P; Mulleman, D; Maillet, B; Rannou, F; Piroth, C; Mathieu, P; Conrozier, T

    2013-06-01

    To measure the evolution of the serum levels of specific Osteoarthritis (OA) biomarker, Coll2-1 and Coll2-1 NO₂ in knee osteoarthritic patients after viscosupplementation (VS). Fifty-one patients with unilateral symptomatic knee were recruited for this prospective open label study. They received three intra-articular injections of 2 ml of hyaluronic acid (Hylan GF-20) and were followed for 3 months. Walking pain was evaluated and serum samples were taken at each visit. Coll2-1 and Coll2-1 NO₂ were measured in the serum using specific immunoassays. Variations over time of each parameter and predictive factor of response were studied. Forty-five patients were analyzed. The serum concentrations of Coll2-1 and Coll2-1 NO₂ were significantly higher in KL III/IV patients compared to KL I/II patients at baseline and decreased systematically over time after VS. Its effect was ever more pronounced in patients with KL III/IV. The serum concentration of Coll2-1 was significantly lower at baseline in responders than in non-responders. This study suggests a rapid slowdown of type II collagen degradation and joint inflammation after VS with Hylan G-20 and gives additional information for the validation of accurate biomarkers for OA. The serum level of Coll2-1 appeared to be a predictive factor for response to treatment.

  18. Expression and activation of intracellular receptors TLR7, TLR8 and TLR9 in peripheral blood monocytes from HIV-infected patients

    PubMed Central

    Pinzón Herrera, Francisc; Cruz López, Juan J; Vera Gamboa, Ligia del Carmen; Pavía Ruiz, Norma; Santos Rivero, Adrián; Sánchez Lugo, Saulo; Puerto, Fernando

    2013-01-01

    Introduction: TLR´s play a role in host defense in HIV infection recognizing the viral DNA or RNA. Their activation induces a signaling pathway that includes the proteins MyD88, IRAK4, TRAF6 and the transcription factor NF-kBp65. Objective: To determine the expression of TLR7, TLR8 and TLR9, and activation of its signaling pathway in monocytes from patients infected with HIV. Methods. Expression of TLR7, TLR8 and TLR9 was determined in monocytes from HIV-infected patients (n= 13) and control subjects (n= 13), which were activated with specific ligands. The expression of MyD88 and NF-kBp65 were determined by flow cytometry; IRAK4 and TRAF6 were studied by immunoblotting. Results: No statistical difference was found in the expression of TLR7, 8 and 9 in monocytes from patients compared to controls, but we observed the non-significant increased expression of TLR9 in patients. The activation showed no significant difference in the expression of MyD88 and NF-kBp65 in patients when compared to controls, but were decreased in stimulated cells over non-stimulated cells. IRAK4 and TRAF6 were not detected. Conclusions: No statistical difference was observed in the expression of intracellular TLRs, MyD88 and NFkBp65 in monocytes from patients compared to controls. This was probably due to effective antiretroviral therapy being received at the time of study entry. Additional studies are needed under controlled conditions that include infected patients with and without ARVT, responders and non-responders, and work with different cell populations. PMID:24892454

  19. Comparison between horse and rabbit antithymocyte globulin as first-line treatment for patients with severe aplastic anemia: a single-center retrospective study.

    PubMed

    Atta, Elias Hallack; Dias, Danielle Saldanha Peixoto; Marra, Vera Lúcia Neves; de Azevedo, Alexandre Mello

    2010-09-01

    The best antithymocyte globulin preparation for first-line immune suppression in patients with severe aplastic anemia is still not clear. The aim of this study was to compare hematological response and overall survival in patients submitted to horse or rabbit antithymocyte globulin as first-line treatment for severe aplastic anemia. We retrospectively compared 71 consecutive patients with severe aplastic anemia, classified according to the antithymocyte globulin preparation. Analyses included variables related to patients and to immune suppression. Forty two patients (59.1%) received horse and 29 (40.9%) rabbit antithymocyte globulin. Response rates were higher at 6 months in patients submitted to horse in comparison to rabbit antithymocyte globulin (59.5% versus 34.5% respectively, p = 0.05). Median time to response was similar between the two groups (99 versus 88.5 days, respectively, for horse and rabbit antithymocyte globulin; p = 0.98). Overall survival at 2 years was significantly higher in patients submitted to horse in comparison to rabbit antithymocyte globulin (78.4% versus 55.4%, p = 0.03). Post-treatment response was strongly associated with survival at 2 years (97% in responders versus 41.2% in non-responders, p < 0.001). Use of rabbit antithymocyte globulin was an independent predictor of death (odds ratio 2.5; 95% confidence interval 1.03-6.04; p = 0.04). Rabbit antithymocyte globulin was associated with a significant and prolonged lymphopenia in comparison with horse antithymocyte globulin. Our data suggest the superiority of horse over rabbit antithymocyte globulin as first-line treatment for severe aplastic anemia, both regarding hematological response and survival.

  20. Changes in circulating microRNA-126 during treatment with chemotherapy and bevacizumab predicts treatment response in patients with metastatic colorectal cancer

    PubMed Central

    Hansen, T F; Carlsen, A L; Heegaard, N H H; Sørensen, F B; Jakobsen, A

    2015-01-01

    Background: This study investigated the predictive value of circulating microRNA-126 (cir-miRNA-126) in patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy combined with bevacizumab. Methods: The study included 68 patients. Blood samples (plasma) were collected before the treatment initiation, at the first clinical evaluation after 3 weeks and at progression. Levels of cir-miRNA-126 were determined by qRT–PCR after purification of total RNA from plasma. Primary clinical end points were response rates evaluated according to the Response Evaluation Criteria In Solid Tumours (RECIST) and progression-free survival (PFS). Results: Changes in circulating miRNA-126 during treatment were predictive of tumour response. Non-responding patients had a median increase in cir-miRNA-126 of 0.244 (95% confidence interval (CI), 0.050–0.565) compared with a median decrease of −0.374 (95% CI, −0.472 to −0.111) in the responding patients, P=0.002. A significant positive correlation was demonstrated by comparing the changes in tumour size with the changes in cir-miRNA-126, r=0.48, P=0.0001. Grouping the patients according to the changes in cir-miRNA-126 disclosed a borderline significant separation of the groups in the PFS analysis favouring patients with decreasing miRNA-126 levels, hazard ratio (HR) 0.60 (95% CI, 0.33–1.09), P=0.07. Conclusions: The present results indicate that changes in cir-miRNA-126 during treatment are related to the response to chemotherapy and bevacizumab in patients with mCRC, thus representing a possible biomarker for the resistance to anti-angiogenic containing treatments. PMID:25584492

  1. Changes in T cell subsets identify responders to FcR non-binding anti-CD3 mAb (teplizumab) in patients with Type 1 diabetes

    PubMed Central

    Tooley, James E; Vudattu, Nalini; Choi, Jinmyung; Cotsapas, Chris; Devine, Lesley; Raddassi, Khadir; Ehlers, Mario R; McNamara, James G; Harris, Kristina M; Kanaparthi, Sai; Phippard, Deborah; Herold, Kevan C

    2016-01-01

    The mechanisms whereby immune therapies affect progression of Type 1 diabetes (T1D) are not well understood. Teplizumab, an FcR non-binding anti-CD3 mAb, has shown efficacy in multiple randomized clinical trials. We previously reported an increase in the frequency of circulating CD8+ central memory (CD8CM) T cells in clinical responders, but the generalizability of this finding and the molecular effects of teplizumab on these T cells have not been evaluated. We analyzed data from 2 randomized clinical studies of teplizumab in patients with new and recent onset T1D. At the conclusion of therapy clinical responders showed a significant reduction in circulating CD4+ effector memory (CD4EM) T cells. Afterwards, there was an increase in the frequency and absolute number of CD8CM T cells. In vitro, teplizumab expanded CD8CM T cells by proliferation and conversion of non-CM T cells. Nanostring analysis of gene expression of CD8CM T cells from responders and non-responders vs placebo-treated control subjects identified decreases in expression of genes associated with immune activation and increases in expression of genes associated with T cell differentiation and regulation. We conclude that CD8CM T cells with decreased activation and regulatory gene expression are associated with clinical responses to teplizumab in patients with T1D. PMID:26518356

  2. Changes in T-cell subsets identify responders to FcR-nonbinding anti-CD3 mAb (teplizumab) in patients with type 1 diabetes.

    PubMed

    Tooley, James E; Vudattu, Nalini; Choi, Jinmyung; Cotsapas, Chris; Devine, Lesley; Raddassi, Khadir; Ehlers, Mario R; McNamara, James G; Harris, Kristina M; Kanaparthi, Sai; Phippard, Deborah; Herold, Kevan C

    2016-01-01

    The mechanisms whereby immune therapies affect progression of type 1 diabetes (T1D) are not well understood. Teplizumab, an FcR nonbinding anti-CD3 mAb, has shown efficacy in multiple randomized clinical trials. We previously reported an increase in the frequency of circulating CD8(+) central memory (CD8CM) T cells in clinical responders, but the generalizability of this finding and the molecular effects of teplizumab on these T cells have not been evaluated. We analyzed data from two randomized clinical studies of teplizumab in patients with new- and recent-onset T1D. At the conclusion of therapy, clinical responders showed a significant reduction in circulating CD4(+) effector memory T cells. Afterward, there was an increase in the frequency and absolute number of CD8CM T cells. In vitro, teplizumab expanded CD8CM T cells by proliferation and conversion of non-CM T cells. Nanostring analysis of gene expression of CD8CM T cells from responders and nonresponders versus placebo-treated control subjects identified decreases in expression of genes associated with immune activation and increases in expression of genes associated with T-cell differentiation and regulation. We conclude that CD8CM T cells with decreased activation and regulatory gene expression are associated with clinical responses to teplizumab in patients with T1D.

  3. Comparison of modified Thrombelastograph and Plateletworks whole blood assays to optical platelet aggregation for monitoring reversal of clopidogrel inhibition in elective surgery patients.

    PubMed

    Craft, Robert M; Chavez, Jack J; Snider, Carolyn C; Muenchen, Robert A; Carroll, Roger C

    2005-06-01

    Clinically monitoring recovery from clopidogrel and nonsteroidal anti-inflammatory drug (NSAID) inhibition requires whole blood assays corresponding to a standard methodology such as platelet-rich plasma aggregation monitored optically (OPA). We compared OPA, using an ED 50 dose of adenosine diphosphate activation, with 2 whole blood assays, Plateletworks (PWA) and modified Thrombelastograph (TEG). Two sets of assays were performed on 43 surgery patients while on clopidogrel and off clopidogrel to determine the reversal of absolute and relative inhibition. The modified TEG had Spearman correlations with OPA for absolute (rho = .424; P = .006) and relative inhibition (rho = .742; P < .0001). PWA correlations with OPA gave absolute (rho = .28; P = .08) and relative inhibition (rho = .46; P = .004) values. Bland-Altman analysis indicated agreement of both tests with OPA, showing constant biases of about 18% and some dependency on mean magnitude error. Cohen effect size thresholds defined nonresponders as < 7.7% clopidogrel inhibition relative to baseline recovery of full platelet function. Apparent nonresponse to clopidogrel or lack of platelet recovery did not correlate with statin or NSAID therapies. These PWA and modified TEG whole blood assays could prove useful for monitoring the reversal of clopidogrel and NSAID inhibition before surgery. More important, these assays done at baseline and after beginning clopidogrel therapy could monitor the effectiveness for the individual patients with cardiovascular disease and help identify the need for alternative therapies.

  4. PATIENT NAVIGATION

    PubMed Central

    Wells, Kristen J.; Battaglia, Tracy A.; Dudley, Donald J.; Garcia, Roland; Greene, Amanda; Calhoun, Elizabeth; Mandelblatt, Jeanne S.; Paskett, Electra D.; Raich, Peter C.

    2008-01-01

    Background First implemented in 1990, patient navigation interventions are emerging as an approach to reduce cancer disparities. However, there is lack of consensus about how patient navigation is defined, what patient navigators do, and what their qualifications should be. Little is known about the efficacy and cost effectiveness of patient navigation. Methods We conducted a qualitative synthesis of published literature on cancer patient navigation. Using the keywords “navigator” or “navigation” and “cancer,” we identified 45 articles from Pubmed and reference searches that were published or in press through October 2007. 16 provided data on efficacy of navigation in improving timeliness and receipt of cancer screening, diagnostic follow-up care, and treatment. Patient navigation services are defined and differentiated from other outreach services. Results Overall there is evidence for some degree of efficacy for patient navigation in increasing participation in cancer screening and adherence to diagnostic follow-up care following an abnormality, with increases in screening ranging from 10.8% to 17.1% and increases in adherence to diagnostic follow-up care ranging from 21% to 29.2%, when compared to control patients. There is less evidence regarding efficacy of patient navigation in reducing either late stage cancer diagnosis or delays in initiation of cancer treatment or improving outcomes during cancer survivorship. There were methodological limitations in most studies, such as lack of control groups, small sample sizes, and contamination with other interventions. Conclusions Although cancer-related patient navigation interventions are being increasingly adopted across the U.S. and Canada, further research is necessary to evaluate their efficacy and cost-effectiveness in improving cancer care. PMID:18780320

  5. The dimeric form of HLA-G molecule is associated with the response of early rheumatoid arthritis (ERA) patients to methotrexate.

    PubMed

    Rizzo, Roberta; Farina, Ilaria; Bortolotti, Daria; Galuppi, Elisa; Padovan, Melissa; Di Luca, Dario; Govoni, Marcello

    2017-03-01

    A growing body of evidence indicates a possible involvement of HLA (human leukocyte antigen)-G antigens in rheumatoid arthritis (RA), mainly in the HLA-G dimeric isoform, the most active HLA-G form with the strongest immunosuppression, that showed an excellent anti-inflammatory effect in collagen-induced arthritis model mice. However, the relevance of HLA-G dimers in RA response to methotrexate (MTX) treatment is still unknown. We analyzed the HLA-G dimers' amount in plasma samples from early rheumatoid arthritis (ERA) patients before MTX therapy and evaluated the role of these molecules as biomarker of the different response to the treatment. Plasma sHLA-G levels were detected by ELISA, and HLA-G dimeric and monomeric forms were revealed by Western blot in 12 MTX responder (reaching DAS28 remission <2.6) and 8 MTX non-responder (DAS28 ≥5.1) patients before the therapy. The response to MTX was evaluated after 6 months of treatment. All ERA patients reaching remission showed higher plasma sHLA-G levels and the 78 kDa HLA-G dimeric form. Unresponsive ERA patients were characterized by lower plasma sHLA-G levels, and only one patient presented the 78 kDa HLA-G dimeric form (DAS28 5.1). Our preliminary results support the hypothesis that in ERA patients, sHLA-G and, in particular, the presence of the dimeric form in plasma samples before MTX therapy could be an a priori biomarker for the response to MTX treatment.

  6. Pilot study of multiple-fraction daily radiotherapy alternating with chemotherapy in patients with stage IV non-oat cell lung cancer

    SciTech Connect

    Arcangeli, G.; Righini, R.; Nervi, C.; Guerra, A.; Tirindelli, D.; Hopkins, H.; Looney, W.

    1985-01-01

    From March 1982, 31 patients with stage IV non-oat cell lung cancer have been treated. Radiotherapy was given as three 2.00-Gy fractions on Days 1 and 2, 8 and 9, 22 and 23, and 29 and 30, for a total dose of 48 Gy over a 30-32-day treatment period. A three-drug combination of cyclophosphamide (400 mg/m2), doxorubicin (17 mg/m2), and methotrexate (15 mg/m2) was given on Days 3 and 24 and repeated thereafter every 21 days. Three of 31 evaluable patients (10%) achieved objective complete response and 18 of 31 (58%) achieved partial response (ie, regression of 50%-90%), while no change or disease progression was observed in ten of 31 (32%). The overall response rate in our study was 68%, which is a response much higher than other results in extensive disease. However, controlled trials will be necessary to definitively establish the superiority of this regimen to conventional trials. There was a significant shift of performance status towards higher values after treatment: 12 of the 27 patients classified in the 70-80 Karnofsky category before treatment moved to the higher category, 13 remained in the same status, and only two shifted to the worst category, indicating that the treatment had been effective in giving patients a better quality of life during their survival. The median survival was 35 weeks for the entire group of patients and 44 and 15 weeks for the responders and nonresponders, respectively. One of the primary findings of this pilot study was the ability to give one course of 12 Gy of radiation as multiple fractions per day during each of the first 2 weeks of treatment alternated with one course of chemotherapy, with most patients having very mild or no side effects.

  7. Genetic polymorphisms of tumour necrosis factor alpha (TNF-α) promoter gene and response to TNF-α inhibitors in Spanish patients with inflammatory bowel disease.

    PubMed

    López-Hernández, R; Valdés, M; Campillo, J A; Martínez-Garcia, P; Salama, H; Salgado, G; Boix, F; Moya-Quiles, M R; Minguela, A; Sánchez-Torres, A; Miras, M; Garcia, A; Carballo, F; Álvarez-López, M R; Muro, M

    2014-02-01

    Tumour necrosis factor alpha (TNF-α) has an important role in inflammatory response. Alterations in the regulation of TNF-α have been implicated in a variety of inflammatory disorders, including Inflammatory bowel disease (IBD). Indeed, a common treatment for IBD is the use of TNF-α inhibitors. Polymorphisms in the TNF-α promoter region are known to affect the level of gene expression. Our aim was to investigate the influence of these single nucleotide polymorphisms (SNPs) in TNF-α promoter gene play in the risk of IBD in a Spanish population and their individual response to anti-TNF-α treatment. DNA samples from patients with IBD and controls were screened for TNF-α -238G/A (rs361525) and -308G/A (rs1800629) SNPs by PCR-SSOP using a microbeads luminex assay and compared with response to TNF-α inhibitors. There were not statistical differences in -238G/A and -308G/A allele and genotype frequencies between patients. However, we found an increased frequency of -308A allele and -308GA genotype in these nonresponders patients to TNF-α inhibitors with respect to responders patients (Pc < 0.05). This -308GA genotype has been classified as high producer of this cytokine. This fact could actually be interesting to explain the different response of patients with IBD with respect to TNF-α inhibitors. TNF-α promoter gene polymorphism does not seem to play a role in IBD susceptibility, but particular TNF-α genotypes may be involved in the different responses to TNF-α inhibitor treatment in Spanish patients with IBD.

  8. Immune response and long-term clinical outcome in advanced melanoma patients vaccinated with tumor-mRNA-transfected dendritic cells.

    PubMed

    Kyte, Jon Amund; Aamdal, Steinar; Dueland, Svein; Sæbøe-Larsen, Stein; Inderberg, Else Marit; Madsbu, Ulf Erik; Skovlund, Eva; Gaudernack, Gustav; Kvalheim, Gunnar

    2016-01-01

    The most effective anticancer immune responses are probably directed against patient-specific neoantigens. We have developed a melanoma vaccine targeting this individual mutanome based on dendritic cells (DCs) loaded with autologous tumor-mRNA. Here, we report a phase I/II trial evaluating toxicity, immune response and clinical outcome in 31 metastatic melanoma patients. The first cohort (n = 22) received the vaccine without any adjuvant; the next cohort (n = 9) received adjuvant IL2. Each subject received four weekly intranodal or intradermal injections, followed by optional monthly vaccines. Immune response was evaluated by delayed-type hypersensitivity (DTH), T cell proliferation and cytokine assays. Data were collected for 10 y after inclusion of the last patient. No serious adverse events were detected. In the intention-to-treat-cohort, we demonstrated significantly superior survival compared to matched controls from a benchmark meta-analysis (1 y survival 43% vs. 24%, 2 y 23% vs. 6.6%). A tumor-specific immune response was demonstrated in 16/31 patients. The response rate was higher after intradermal than intranodal vaccination (80% vs. 38%). Immune responders had improved survival compared to non-responders (median 14 mo vs. 6 mo; p = 0.030), and all eight patients surviving >20 mo were immune responders. In addition to the tumor-specific response, most patients developed a response against autologous DC antigens. The cytokine profile was polyfunctional and did not follow a Th1/Th2 dichotomy. We conclude that the favorable safety profile and evidence of a possible survival benefit warrant further studies of the RNA/DC vaccine. The vaccine appears insufficient as monotherapy, but there is a strong rationale for combination with checkpoint modulators.

  9. Patient management.

    PubMed

    Guptill, Lynn

    2015-03-01

    Hospital-associated infections, including those caused by zoonotic agents, represent an increasing concern in veterinary practice. Veterinarians and hospital staff are obligated and expected to provide education about and protection from transmission of pathogens among animal patients and between animal patients and human beings (eg, veterinary staff, volunteers, owners) who come into contact with infected animals. Patient management involves assessing risks of pathogen transmission, identification of animals either suspected of or proved to be infected with a transmissible infectious disease agent, and the implementation of measures that minimize the likelihood of transmission of the infectious agent.

  10. Association between bevacizumab-related hypertension and response to treatment in patients with metastatic colorectal cancer

    PubMed Central

    Dionísio de Sousa, Isabel José; Ferreira, Joana; Rodrigues, Joana; Bonito, Nuno; Jacinto, Paula; Marques, Mariela; Ribeiro, João; Pais, Ana; Gervásio, Helena

    2016-01-01

    Background Bevacizumab has become standard of care as first-line treatment of metastatic colorectal cancer (mCRC), after proving increased response rates and improvement in survival outcomes. Hypertension (HTN) is a common complication of the treatment with bevacizumab and, owing to its close relation with antiangiogenic mechanism, may represent a clinical biomarker to predict the efficacy of the treatment. The aim of this study was to retrospectively evaluate if HTN grades 2 to 3 were correlated with response to treatment with bevacizumab in first line, as well as with improved progression-free survival (PFS) and overall survival (OS), in a series of patients with mCRC. Methods Retrospective evaluation of clinical records of patients with histologically proven mCRC, treated with bevacizumab as first-line treatment, between January 2008 and December 2013. Results 79 patients were evaluated. 51.9% of patients developed HTN G2-G3 during chemotherapy-bevacizumab treatment. In the group of patients who developed bevacizumab-related HTN, 73.2% showed response to treatment (complete response (CR)+ partial response (PR)) and 97.6% achieved disease control (CR, PR or stable disease) compared to 18.4% of patients with response and 63.2% with disease control in the group that did not (OR 12.08; 95% CI 4.13 to 35.29; p<0.001 responders vs non-responders; OR 20.8; 95% CI 2.56 to 168.91; p 0.005 controlled vs non controlled disease). The median OS was 28 months (22.7–33.3). Significant statistical difference was obtained in PFS between the two groups (p<0.001). In the group that developed bevacizumab-related HTN, the median OS was 33 months (25.7–40.3), and in the group that did not, it was 21 months (16.5–25.5) with no significant statistical difference between the two groups (p 0.114). Conclusions In this subset of patients, HTN G2-3 was predictive of response to treatment with bevacizumab and of PFS but not of OS. PMID:27843607

  11. The Universal Patient Centeredness Questionnaire: scaling approaches to reduce positive skew

    PubMed Central

    Bjertnaes, Oyvind; Iversen, Hilde Hestad; Garratt, Andrew M

    2016-01-01

    Purpose Surveys of patients’ experiences typically show results that are indicative of positive experiences. Unbalanced response scales have reduced positive skew for responses to items within the Universal Patient Centeredness Questionnaire (UPC-Q). The objective of this study was to compare the unbalanced response scale with another unbalanced approach to scaling to assess whether the positive skew might be further reduced. Patients and methods The UPC-Q was included in a patient experience survey conducted at the ward level at six hospitals in Norway in 2015. The postal survey included two reminders to nonrespondents. For patients in the first month of inclusion, UPC-Q items had standard scaling: poor, fairly good, good, very good, and excellent. For patients in the second month, the scaling was more positive: poor, good, very good, exceptionally good, and excellent. The effect of scaling on UPC-Q scores was tested with independent samples t-tests and multilevel linear regression analysis, the latter controlling for the hierarchical structure of data and known predictors of patient-reported experiences. Results The response rate was 54.6% (n=4,970). Significantly lower scores were found for all items of the more positively worded scale: UPC-Q total score difference was 7.9 (P<0.001), on a scale from 0 to 100 where 100 is the best possible score. Differences between the four items of the UPC-Q ranged from 7.1 (P<0.001) to 10.4 (P<0.001). Multivariate multilevel regression analysis confirmed the difference between the response groups, after controlling for other background variables; UPC-Q total score difference estimate was 8.3 (P<0.001). Conclusion The more positively worded scaling significantly lowered the mean scores, potentially increasing the sensitivity of the UPC-Q to identify differences over time and between providers. However, none of the groups exhibited large positive skew and ceiling effects, implying that such effects might not be a big

  12. Patient Empowerment

    MedlinePlus

    ... Chat Social Home FAQ Start Here Learn About Kidney Cancer Guidelines for Patients Statistics and Survival Data (NIH) Cancer Term Dictionary (NCI) Surgery for Kidney Cancer Print Surgery Information Therapies for Advanced Kidney Cancer ...

  13. A functional biological network centered on XRCC3: a new possible marker of chemoradiotherapy resistance in rectal cancer patients

    PubMed Central

    Agostini, Marco; Zangrando, Andrea; Pastrello, Chiara; D'Angelo, Edoardo; Romano, Gabriele; Giovannoni, Roberto; Giordan, Marco; Maretto, Isacco; Bedin, Chiara; Zanon, Carlo; Digito, Maura; Esposito, Giovanni; Mescoli, Claudia; Lavitrano, Marialuisa; Rizzolio, Flavio; Jurisica, Igor; Giordano, Antonio; Pucciarelli, Salvatore; Nitti, Donato

    2015-01-01

    Preoperative chemoradiotherapy is widely used to improve local control of disease, sphincter preservation and to improve survival in patients with locally advanced rectal cancer. Patients enrolled in the present study underwent preoperative chemoradiotherapy, followed by surgical excision. Response to chemoradiotherapy was evaluated according to Mandard's Tumor Regression Grade (TRG). TRG 3, 4 and 5 were considered as partial or no response while TRG 1 and 2 as complete response. From pretherapeutic biopsies of 84 locally advanced rectal carcinomas available for the analysis, only 42 of them showed 70% cancer cellularity at least. By determining gene expression profiles, responders and non-responders showed significantly different expression levels for 19 genes (P < 0.001). We fitted a logistic model selected with a stepwise procedure optimizing the Akaike Information Criterion (AIC) and then validated by means of leave one out cross validation (LOOCV, accuracy = 95%). Four genes were retained in the achieved model: ZNF160, XRCC3, HFM1 and ASXL2. Real time PCR confirmed that XRCC3 is overexpressed in responders group and HFM1 and ASXL2 showed a positive trend. In vitro test on colon cancer resistant/susceptible to chemoradioterapy cells, finally prove that XRCC3 deregulation is extensively involved in the chemoresistance mechanisms. Protein-protein interactions (PPI) analysis involving the predictive classifier revealed a network of 45 interacting nodes (proteins) with TRAF6 gene playing a keystone role in the network. The present study confirmed the possibility that gene expression profiling combined with integrative computational biology is useful to predict complete responses to preoperative chemoradiotherapy in patients with advanced rectal cancer. PMID:26023803

  14. Point-of-Care, Ultraportable Echocardiography Predicts Diuretic Response in Patients Admitted with Acute Decompensated Heart Failure

    PubMed Central

    Krishnan, Dena K.; Pawlaczyk, Barbara; McCullough, Peter A.; Enright, Susan; Kunadi, Arvind; Vanhecke, Thomas E.

    2016-01-01

    BACKGROUND Routine management of patients with acute decompensated heart failure (ADHF) requires careful attentiveness to fluid status and diuretic treatment efficacy. New advances in ultrasound have made ultraportable echocardiography (UE) available to physicians for point-of-care use. The purpose of this study is to explore physiologic measures of intravascular fluid volume derived from UE and explore predictors of diuretic response in ADHF. METHODS Various echocardiography imaging measurements, particularly diameter and collapse of inferior vena cava (IVC), were collected from 77 patients admitted with a primary diagnosis of ADHF. Patients were divided into two groups based on whether or not they achieved a net negative fluid output of 3 L within 48 hours. The demographic information, serum laboratory markers, and physical characteristics of the subjects were obtained to correlate with daily ultrasound measurements. Univariate and multivariate analyses were used to compare diuretic “responders” to “nonresponders.” RESULTS A negative change in the IVC diameter at 48 hours was robust in prediction of diuretic response. For every 1 mm decrease in the IVC diameter at 48 hours, there was an odds ratio of 1.62 (95% CI: 1.20–2.19) for responding to diuretic therapy independent of other variables including baseline renal filtration function and blood B-type natriuretic peptide. CONCLUSION Assessment of central venous pressure as a proxy for passive renal congestion independently predicts initial diuretic response in ADHF. Future research is needed to further understand the individual variation in response to loop diuresis and to identify optimal treatment approaches that utilize anatomic and physiologic measures such as venous ultrasound. PMID:28008296

  15. Survival benefits of interferon-based therapy in patients with recurrent hepatitis C after orthotopic liver transplantation.

    PubMed

    Zanaga, L P; Vigani, A G; Angerami, R N; Giorgetti, A; Escanhoela, C A F; Ataíde, E C; Boin, I F S F; Stucchi, R S B

    2017-01-09

    Recurrent hepatitis C after orthotopic liver transplantation (OLT) is universal and can lead to graft failure and, consequently, reduced survival. Hepatitis C treatment can be used to prevent these detrimental outcomes. The aim of this study was to describe rates of hepatitis C recurrence and sustained virological response (SVR) to interferon-based treatment after OLT and its relationship to survival and progression of liver disease through retrospective analysis of medical records of 127 patients who underwent OLT due to cirrhosis or hepatocellular carcinoma secondary to chronic hepatitis C between January 2002 and December 2013. Fifty-six patients were diagnosed with recurrent disease, 42 started interferon-based therapy and 37 completed treatment. Demographic, treatment- and outcome-related variables were compared between SVR and non-responders (non-SVR). There was an overall 54.1% SVR rate with interferon-based therapies. SVR was associated with longer follow-up after treatment (median 66.5 vs 37 months for non-SVR, P=0.03) and after OLT (median 105 vs 72 months, P=0.074), and lower rates of disease progression (15 vs 64.7%, P=0.0028) and death (5 vs 35.3%, P=0.033). Regardless of the result of therapy (SVR or non-SVR), there was a significant difference between treated and untreated patients regarding the occurrence of death (P<0.001) and months of survival (P<0.001). Even with suboptimal interferon-based therapies (compared to the new direct-acting antivirals) there is a 54.1% SVR rate to treatment. SVR is associated with improved survival and reduced risks of clinical decompensation, loss of the liver graft and death.

  16. MicroRNAs as Predictor Markers for Response to Interferon Treatment of Chronic Hepatitis C Genotype-4 in Egyptian Patients

    PubMed Central

    Motawi, Tarek M. K.; Rizk, Sherine M.; Shaker, Olfat G.; Mokhtar, Olfat Z. H.

    2015-01-01

    Background Hepatitis C virus genotype 4 (HCV-4) infection is common in the Middle East and Africa, with an extraordinarily high prevalence in Egypt. MicroRNAs (miRNAs) play an important role in various diseases, including HCV infection. The aim of the present study was to assess serum miR-122, miR-221 and miR-21 expression profiles in HCV-4 patients prior to treatment with HCV-4 combination therapy (pegylated alpha interferon and ribavirin) and to determine whether the miRNAs were associated with the drug response. Methods RNA was extracted from pretreatment serum samples, and miR-122, miR-221 and miR-21 levels were measured by quantitative PCR. The results were compared among patients with sustained virological responses (SVR) and non-responders (NR). Results The expression levels of miR-21 and miR-122 were significantly different between the SVR and NR groups. Receiver operator characteristic (ROC) analysis revealed that the sensitivity, specificity and positive predictive values of miR-21 were 82.2%, 77.3% and 88.1%, respectively, with a cut-off value of 1.7. The sensitivity, specificity and positive predictive values of miR-122 were 68.9%, 59.1% and 77.5%, respectively, with a cut-off value of 3.5. Conclusion and Significance miR-21 and miR-122 might be useful predictors for SVR in HCV-4 patients prior to the administration of combination therapy. A higher predictive response power was obtained for miR-21 than for miR-122. These results should reduce ineffective treatments. PMID:25811198

  17. Dynamics of PBMC gene expression in hepatitis C virus genotype 1-infected patients during combined peginterferon/ribavirin therapy

    PubMed Central

    Lu, Ming-Ying; Huang, Ching-I; Hsieh, Ming-Yen; Hsieh, Tusty-Juan; Hsi, Edward; Tsai, Pei-Chien; Tsai, Yi-Shan; Lin, Ching-Chih; Hsieh, Meng-Hsuan; Liang, Po-Cheng; Lin, Yi-Hung; Hou, Nai-Jen; Yeh, Ming-Lun; Huang, Chung-Feng; Lin, Zu-Yau; Chen, Shinn-Cherng; Huang, Jee-Fu; Chuang, Wan-Long; Dai, Chia-Yen; Yu, Ming-Lung

    2016-01-01

    Hepatitis C virus (HCV) can replicate in peripheral blood mononuclear cells (PBMCs), which can produce interferon to defend against virus infection. We hypothesized that dynamic gene expression in PBMCs might impact the treatment efficacy of peginterferon/ribavirin in HCV patients. PBMCs were collected at baseline, 1st week and 4th week of treatment from 27 chronic HCV-1 patients with 48-week peginterferon/ribavirin therapy (screening dataset n = 7; validation dataset n = 20). A sustained virologic response (SVR) was defined as undetectable HCV RNA throughout the 24 weeks after end-of-treatment. A complete early virologic response (cEVR) was defined as negative HCV RNA at treatment week 12. Forty-three differentially expressed genes identified by Affymetrix microarray were validated by quantitative polymerase chain reaction. Thirteen genes at week 1 and 24 genes at week 4 were upregulated in the SVR group compared with the non-SVR group. We selected 8 target genes (RSAD2, LOC26010, HERC5, HERC6, IFI44, SERPING1, IFITM3, and DDX60) at week 1 as the major components of the predictive model. This predictive model reliably stratified the responders and non-responders at week 1 (AUC = 0.89, p = 0.007 for SVR; AUC = 0.95, p = 0.003 for cEVR), especially among patients carrying the IL28B rs8099917 TT genotype (AUC = 0.89, p = 0.02 for SVR; AUC = 1.0, p = 0.008 for cEVR). The performance of this predictive model was superior to traditional predictors, including the rapid virologic response, viral load and IL28B genotype. PMID:27542257

  18. A functional biological network centered on XRCC3: a new possible marker of chemoradiotherapy resistance in rectal cancer patients.

    PubMed

    Agostini, Marco; Zangrando, Andrea; Pastrello, Chiara; D'Angelo, Edoardo; Romano, Gabriele; Giovannoni, Roberto; Giordan, Marco; Maretto, Isacco; Bedin, Chiara; Zanon, Carlo; Digito, Maura; Esposito, Giovanni; Mescoli, Claudia; Lavitrano, Marialuisa; Rizzolio, Flavio; Jurisica, Igor; Giordano, Antonio; Pucciarelli, Salvatore; Nitti, Donato

    2015-01-01

    Preoperative chemoradiotherapy is widely used to improve local control of disease, sphincter preservation and to improve survival in patients with locally advanced rectal cancer. Patients enrolled in the present study underwent preoperative chemoradiotherapy, followed by surgical excision. Response to chemoradiotherapy was evaluated according to Mandard's Tumor Regression Grade (TRG). TRG 3, 4 and 5 were considered as partial or no response while TRG 1 and 2 as complete response. From pretherapeutic biopsies of 84 locally advanced rectal carcinomas available for the analysis, only 42 of them showed 70% cancer cellularity at least. By determining gene expression profiles, responders and non-responders showed significantly different expression levels for 19 genes (P < 0.001). We fitted a logistic model selected with a stepwise procedure optimizing the Akaike Information Criterion (AIC) and then validated by means of leave one out cross validation (LOOCV, accuracy = 95%). Four genes were retained in the achieved model: ZNF160, XRCC3, HFM1 and ASXL2. Real time PCR confirmed that XRCC3 is overexpressed in responders group and HFM1 and ASXL2 showed a positive trend. In vitro test on colon cancer resistant/susceptible to chemoradioterapy cells, finally prove that XRCC3 deregulation is extensively involved in the chemoresistance mechanisms. Protein-protein interactions (PPI) analysis involving the predictive classifier revealed a network of 45 interacting nodes (proteins) with TRAF6 gene playing a keystone role in the network. The present study confirmed the possibility that gene expression profiling combined with integrative computational biology is useful to predict complete responses to preoperative chemoradiotherapy in patients with advanced rectal cancer.

  19. Survival benefits of interferon-based therapy in patients with recurrent hepatitis C after orthotopic liver transplantation

    PubMed Central

    Zanaga, L.P.; Vigani, A.G.; Angerami, R.N.; Giorgetti, A.; Escanhoela, C.A.F.; Ataíde, E.C.; Boin, I.F.S.F.; Stucchi, R.S.B.

    2017-01-01

    Recurrent hepatitis C after orthotopic liver transplantation (OLT) is universal and can lead to graft failure and, consequently, reduced survival. Hepatitis C treatment can be used to prevent these detrimental outcomes. The aim of this study was to describe rates of hepatitis C recurrence and sustained virological response (SVR) to interferon-based treatment after OLT and its relationship to survival and progression of liver disease through retrospective analysis of medical records of 127 patients who underwent OLT due to cirrhosis or hepatocellular carcinoma secondary to chronic hepatitis C between January 2002 and December 2013. Fifty-six patients were diagnosed with recurrent disease, 42 started interferon-based therapy and 37 completed treatment. Demographic, treatment- and outcome-related variables were compared between SVR and non-responders (non-SVR). There was an overall 54.1% SVR rate with interferon-based therapies. SVR was associated with longer follow-up after treatment (median 66.5 vs 37 months for non-SVR, P=0.03) and after OLT (median 105 vs 72 months, P=0.074), and lower rates of disease progression (15 vs 64.7%, P=0.0028) and death (5 vs 35.3%, P=0.033). Regardless of the result of therapy (SVR or non-SVR), there was a significant difference between treated and untreated patients regarding the occurrence of death (P<0.001) and months of survival (P<0.001). Even with suboptimal interferon-based therapies (compared to the new direct-acting antivirals) there is a 54.1% SVR rate to treatment. SVR is associated with improved survival and reduced risks of clinical decompensation, loss of the liver graft and death. PMID:28076451

  20. The cross-reactivity of binding antibodies with different interferon beta formulations used as disease-modifying drugs in multiple sclerosis patients.

    PubMed

    Wencel-Warot, Agnieszka; Michalak, Slawomir; Warot, Marcin; Kalinowska-Lyszczarz, Alicja; Kazmierski, Radoslaw

    2016-11-01

    Interferon beta (IFNb) preparations are commonly used as first-line therapy in relapsing-remitting multiple sclerosis (RRMS). They are, however, characterized by limited efficacy, partly due to the formation of anti-IFNb antibodies in patients.In this pilot study, we assessed with the ELISA method the presence of the binding antibodies (BAbs) against interferon beta after 2 years of therapy with subcutaneous interferon beta 1a (Rebif) in 49 RRMS patients. Antibody levels were established again within 1 year after treatment withdrawal. We used 3 interferons that are commercially available for MS therapy, namely Avonex (Biogen Idec Limited), Rebif (Merck Serono), and Betaferon (Bayer Pharma AG), as antigens.BAbs reacting with Rebif were found in 24.4% to 55% of patients, depending on the units of their expression. The levels of anti-Rebif antibodies remained high in 8 patients and in 4 patients they dropped significantly. Strong correlations were obtained in all assays (anti-Rebif-anti-Avonex, anti-Rebif-anti-Betaferon, and anti-Betaferon-anti-Avonex) and the existence of cross-reactivity in the formation of antibodies against all the tested formulations of interferon beta was confirmed. The levels of BAbs remain significant in the clinical context, and their assessment is the first choice screening; however, methods of BAbs evaluation can be crucial for further decisions. More studies are needed to confirm our results; specifically it would be of interest to evaluate methods of neutralizing antibodies identification, as we only assessed the binding antibodies. Nevertheless, our results support the concept that in interferon nonresponders, that are positive for binding antibodies, switching the therapy to alternative disease-modifying agent (for example glatiramer acetate, fingolimod, or natalizumab) is justified, whereas the switch to another interferon formulation will probably be of no benefit.

  1. Factors influencing the predictive power of models for predicting mortality and/or heart failure hospitalization in patients with heart failure.

    PubMed

    Ouwerkerk, Wouter; Voors, Adriaan A; Zwinderman, Aeilko H

    2014-10-01

    The present paper systematically reviews and compares existing prediction models in order to establish the strongest variables, models, and model characteristics in patients with heart failure predicting outcome. To improve decision making accurately predicting mortality and heart-failure hospitalization in patients with heart failure can be important for selecting patients with a poorer prognosis or nonresponders to current therapy, to improve decision making. MEDLINE/PubMed was searched for papers dealing with heart failure prediction models. To identify similar models on the basis of their variables hierarchical cluster analysis was performed. Meta-analysis was used to estimate the mean predictive value of the variables and models; meta-regression was used to find characteristics that explain variation in discriminating values between models. We identified 117 models in 55 papers. These models used 249 different variables. The strongest predictors were blood urea nitrogen and sodium. Four subgroups of models were identified. Mortality was most accurately predicted by prospective registry-type studies using a large number of clinical predictor variables. Mean C-statistic of all models was 0.66 ± 0.0005, with 0.71 ± 0.001, 0.68 ± 0.001 and 0.63 ± 0.001 for models predicting mortality, heart failure hospitalization, or both, respectively. There was no significant difference in discriminating value of models between patients with chronic and acute heart failure. Prediction of mortality and in particular heart failure hospitalization in patients with heart failure remains only moderately successful. The strongest predictors were blood urea nitrogen and sodium. The highest C-statistic values were achieved in a clinical setting, predicting short-term mortality with the use of models derived from prospective cohort/registry studies with a large number of predictor variables.

  2. The cross-reactivity of binding antibodies with different interferon beta formulations used as disease-modifying drugs in multiple sclerosis patients

    PubMed Central

    Wencel-Warot, Agnieszka; Michalak, Slawomir; Warot, Marcin; Kalinowska-Lyszczarz, Alicja; Kazmierski, Radoslaw

    2016-01-01

    Abstract Interferon beta (IFNb) preparations are commonly used as first-line therapy in relapsing-remitting multiple sclerosis (RRMS). They are, however, characterized by limited efficacy, partly due to the formation of anti-IFNb antibodies in patients. In this pilot study, we assessed with the ELISA method the presence of the binding antibodies (BAbs) against interferon beta after 2 years of therapy with subcutaneous interferon beta 1a (Rebif) in 49 RRMS patients. Antibody levels were established again within 1 year after treatment withdrawal. We used 3 interferons that are commercially available for MS therapy, namely Avonex (Biogen Idec Limited), Rebif (Merck Serono), and Betaferon (Bayer Pharma AG), as antigens. BAbs reacting with Rebif were found in 24.4% to 55% of patients, depending on the units of their expression. The levels of anti-Rebif antibodies remained high in 8 patients and in 4 patients they dropped significantly. Strong correlations were obtained in all assays (anti-Rebif-anti-Avonex, anti-Rebif-anti-Betaferon, and anti-Betaferon-anti-Avonex) and the existence of cross-reactivity in the formation of antibodies against all the tested formulations of interferon beta was confirmed. The levels of BAbs remain significant in the clinical context, and their assessment is the first choice screening; however, methods of BAbs evaluation can be crucial for further decisions. More studies are needed to confirm our results; specifically it would be of interest to evaluate methods of neutralizing antibodies identification, as we only assessed the binding antibodies. Nevertheless, our results support the concept that in interferon nonresponders, that are positive for binding antibodies, switching the therapy to alternative disease-modifying agent (for example glatiramer acetate, fingolimod, or natalizumab) is justified, whereas the switch to another interferon formulation will probably be of no benefit. PMID:27828855

  3. Interleukin-28b CC genotype predicts early treatment response and CT/TT genotypes predicts non-response in patients infected with HCV genotype 3.

    PubMed

    Gupta, Abhishak Chander; Trehanpati, Nirupma; Sukriti, Sukriti; Hissar, Syed; Midha, Vandana; Sood, Ajit; Sarin, Shiv K

    2014-04-01

    Response to antiviral therapy for hepatitis C virus (HCV) depends upon the genotype and host immune response. IL28b gene mutations have been shown to modulate host antiviral immune response against genotype 1. However, the predictive value of IL28b polymorphism in genotype 3 HCV patients is largely unknown. The association of IL28b polymorphism with virological response was studied in 356 patients with genotype 3 chronic HCV undergoing treatment with peg-interferon and ribavirin and was compared with matched controls. IL28b genotyping followed by DNA sequencing was performed to identify the CC, CT, or TT genotypes. Two log reduction of HCV RNA at Day 7 (Quick Viral Response, QVR) and HCV RNA negativity at Day 28 (Rapid Viral Response, RVR) were analyzed with CC and non-CC genotypes in addition to other predictors of response. The associations of alleles with the response patterns were predicted. Sustained viral response was seen in 250 (70.2%) patients and the IL28b genotype CC/CT/TT distribution was 61.1%; 30.5%; and 8.4%, respectively. The non-CC genotypes were significantly higher in non-responders when compared to responders (67.6% vs. 38.9%, P < 0.001). Interestingly, the rapid viral response in responders was observed in 72.7% with the CC genotype and in 27.2% with the non-CC genotype (P < 0.001). Multivariate analysis showed CC genotype as an independent factor predicting the sustained viral response in patients infected with HCV genotype 3. In conclusion, the IL28b CT/TT genotype strongly correlates with treatment non-response in patients infected with HCV genotype 3 and CC genotype of IL28b is associated with higher quick viral response.

  4. Prospective cohort study to evaluate the efficacy of taxane plus platinum and CPT-11plus platinum regimes and to identify prognostic risk factors in cervical cancer patients

    PubMed Central

    Huang, Kecheng; Li, Xiong; Yang, Ru; Shen, Jian; Chen, Zhilan; Qin, Xiaomin; Wang, Shaoshuai; Jia, Yao; Tang, Fangxu; Zhou, Hang; Sun, Haiying; Zhou, Jin; Guo, Lili; Wang, Lin; Qiao, Long; Xiong, Jiaqiang; Wang, Congyi; Ma, Ding; Li, Shuang; Hu, Ting; Wang, Shixuan

    2015-01-01

    Objective: This study was designed to evaluate the response, toxicity and survival of taxanes plus platinum (TP) and CPT-11plus platinum (CP) as neoadjuvant chemotherapies with previously untreated cervical cancer, and to identify prognostic risk factors in these patients. Methods: A cohort study was performed to evaluate the result of TP and CP regimes in the treatment of cervical cancer patients. Results: The study included 567 patients with locally advanced cervical cancer (LACC) staged as FIGO IB-IIB in our clinical departments. Clinical response was found in 76.1% and 78% of patients in the TP and CP arms, respectively, and no treatment-related deaths were reported. During the follow-up period, disease-free survival (DFS) and overall survival (OS) for the TP and CP arms were not different (P = 0.384 for DFS, P = 0.800 for OS). The CP regime showed higher survival rate for endophytic growth style (P = 0.013 for DFS, P = 0.027 for OS). The CP regime also showed higher DFS and OS for G2 tumor (P = 0.027 for DFS, P = 0.032 for OS). In multivariate cox’s proportional hazards regression model, the average death rates were much greater in the non-responder group (HR, 2.68), in the older (> 44 years) group (HR, 2.51), and in the FIGO stage II b patients (HR, 2.84). Conclusions: The CP regime showed higher survival rate for endophytic growth style or G2 tumor. Clinical response, age and FIGO stage were independent prognostic risk factors in this study for both DFS and OS. PMID:26628986

  5. Milnacipran treatment and potential biomarkers in depressed patients following an initial SSRI treatment failure: a prospective, open-label, 24-week study

    PubMed Central

    Hashimoto, Tasuku; Sakurai, Daiji; Oda, Yasunori; Hasegawa, Tadashi; Kanahara, Nobuhisa; Sasaki, Tsuyoshi; Komatsu, Hideki; Takahashi, Junpei; Oiwa, Takahiro; Sekine, Yoshimoto; Watanabe, Hiroyuki; Iyo, Masaomi

    2015-01-01

    Background We assessed the effect of switching patients with major depressive disorder to milnacipran following an initial selective serotonin reuptake inhibitor treatment failure, and explored potential biomarkers in their blood. Methods We conducted a prospective, open-label, 24-week trial. Depression was assessed with the 17-item Hamilton Depression Rating Scale. Patients showing a ≥50% reduction in Hamilton Depression Rating Scale scores from baseline to final visit were considered responders. Regarding adverse effects (AEs), moderate-to-severe AEs were specifically identified as effects that required any medical treatment or that induced treatment withdrawals. We also measured blood levels of various molecules including inflammatory cytokines. Results Of the 30 participants who enrolled, 17 completed this study. The responder rate was 30% (n=10). Baseline serum levels of interleukin-6 (Z=−2.155; P=0.031) and interleukin-8 (Z=−2.616; P=0.009) were significantly higher when moderate-to-severe AEs were present (n=13 patients with moderate-to-severe AEs). Serum levels of macrophage inflammatory protein-1β showed a significant continuous decrease from the baseline level (Friedman’s test: χ2=23.9, df=4, P<0.001) only in non-responders. Conclusion These results demonstrate that serum levels of interleukin-6, interleukin-8, and macrophage inflammatory protein-1β as potential blood biomarkers could be utilized to identify the responsiveness of patients to serotonin and norepinephrine reuptake inhibitor like milnacipran, or to identify those patients who may experience AEs strong enough to warrant discontinuation of treatment. PMID:26677330

  6. Dynamic of Mixed HCV Infection in Plasma and PBMC of HIV/HCV Patients Under Treatment With Peg-IFN/Ribavirin

    PubMed Central

    Bagaglio, Sabrina; Uberti-Foppa, Caterina; Di Serio, Clelia; Trentini, Filippo; Andolina, Andrea; Hasson, Hamid; Messina, Emanuela; Merli, Marco; Porrino, Lucy; Lazzarin, Adriano; Morsica, Giulia

    2015-01-01

    Abstract The extent of mixed hepatitis C virus (HCV) genotype in different compartments (plasma and peripheral blood mononuclear cell, PBMC) and possible association with treatment efficacy in HIV/HCV coinfected patients remains to be unknown. The objective of this study was to elucidate the frequency of mixed genotype infection (MG), its profile in different compartments during anti-HCV treatment, and the possible influence of different genotypes on the response rate. The compartmentalization of HCV population was investigated by next-generation sequencing in 19 HIV/HCV coinfected patients under anti-HCV treatment with peginterferon/ribavirin (P–R). Ten individuals were nonresponder (NR) or relapser (RE) to P–R treatment and 9 had a sustained virological response (SVR). Eleven/nineteen (58%) patients had MG in plasma compartment. Ten or 12 patients infected by a difficult to treat genotype (DTG) 1 or 4 as dominant strain, had an MG, whereas only 1/7 individuals infected by easy to treat genotype (ETG) harbored a mixed genotype, P = 0.006. HCV–RNA was more frequently detected in PBMC of NR (10/10) than in those of SVR (5/9), P = 0.032. Mixed genotype infection was detected in 6/15 (40%) PBMC-positive cases and was not associated with P–R treatment response. By multivariate analysis, MG in plasma samples was the most important viral factor affecting the treatment response (P = 0.0237). Detection of MG in plasma of HIV/HCV coinfected patients seems to represent the major determinant of response to P–R treatment. This finding may have important clinical implication in light of the new therapeutic approach in HIV/HCV coinfected individuals suggesting that combination treatment with direct acting antivirals could be less effective in MG. PMID:26512601

  7. Transferrin Level Before Treatment and Genetic Polymorphism in HFE Gene as Predictive Markers for Response to Adalimumab in Crohn's Disease Patients.

    PubMed

    Repnik, Katja; Koder, Silvo; Skok, Pavel; Ferkolj, Ivan; Potočnik, Uroš

    2016-08-01

    Tumor necrosis factor α inhibitors (anti-TNF) have improved treatment of several complex diseases, including Crohn's disease (CD). However, the effect varies and approximately one-third of the patients do not respond. Since blood parameters as well as genetic factors have shown a great potential to predict response during treatment, the aim of the study was to evaluate response to anti-TNF treatment with adalimumab (ADA) between genes HFE and TF and haematological parameters in Slovenian refractory CD patients. Single nucleotide polymorphisms (SNPs) rs1799852 in gene TF and rs2071303 in gene HFE were genotyped in 68 refractory CD patients for which response has been measured using inflammatory bowel disease questionnaire (IBDQ) index. Haematological parameters and IBDQ index were determined before therapy and after 4, 12, 20 and 30 weeks. We found novel strong association between SNP rs2071303 in gene HFE and response to ADA treatment, particularly patients with G allele comparing to A allele had better response after 20 weeks (p = 0.008). Further, we found strong association between transferrin level at baseline and treatment response after 12, 20 and 30 weeks, where average transferrin level before therapy was lower in responders (2.38 g/L) compared to non-responders (2.89 g/L, p = 0.005). Association was found between transferrin level in week 30 and SNP rs1799852 (p = 0.023), and between MCHC level before treatment and SNP rs2071303 (p = 0.007). Our results suggest that SNP in gene HFE as well as haematological markers serve as promising prognostic markers of response to anti-TNF treatment in CD patients.

  8. Impact of Helicobacter pylori eradication on refractory thrombocytopenia in patients with chronic HCV awaiting antiviral therapy.

    PubMed

    Hanafy, A S; El Hawary, A T; Hamed, E F; Hassaneen, A M

    2016-07-01

    The possibility of delaying treatment of HCV due to severe thrombocytopenia is challenging. This study aimed to detect the prevalence of active helicobacter infection as a claimed cause of thrombocytopenia in a cohort of Egyptian patients with chronic active HCV awaiting combined anti-viral therapy. The study included 400 chronic HCV patients with thrombocytopenia. Laboratory investigations included liver function tests, real time quantitative PCR, reticulocytic count, ESR, ANA, bone marrow aspiration, measurement of anti-helicobacter antibodies, and helicobacter stool antigen. Positive cases for active H. pylori were given the standard triple therapy for 2 weeks. Helicobacter stool antigen was detected 4 weeks after termination of therapy and the change in platelet count was detected 1 month after eradication. A total of 248 out of 281 seropositive patients for H. pylori (88.3 %) showed positive stool antigen (p = 0.01). Eradication was achieved in 169 (68.1 %) patients with platelet mean count 114.9 ± 18.8 × 10(3)/μl with highly significant statistical difference from pretreatment value (49.7 ± 9.2 × 10(3)/μl, p = 0.000). Seventy-nine patients were resistant to conventional triple therapy and given a 7-day course of moxifloxacin-based therapy; 61 patients responded (77.1 %) with mean platelet improvement from 76.4 ± 17.4 × 10(3)/μl to 104.2 ± 15.2 × 10(3)/μl (p = 0.000). The non-responders showed no improvement in their platelet count (74.6 ± 20.5 vs. 73.6 ± 15.3 × 10(3)/ul, P = 0.5). Eradication of active H. pylori in HCV augments platelet count and enhances the early start of antiviral therapy.

  9. Characterisation of Hypertensive Patients with Improved Endothelial Function after Dark Chocolate Consumption

    PubMed Central

    d'El-Rei, Jenifer; Cunha, Ana Rosa; Burlá, Adriana; Burlá, Marcelo; Oigman, Wille

    2013-01-01

    Recent findings indicate an inverse relationship between cardiovascular disease and consumption of flavonoids. We aimed to identify clinical and vascular parameters of treated hypertensive who present beneficial effects of dark chocolate for one-week period on vascular function. Twenty-one hypertensive subjects, aged 40–65 years, were included in a prospective study with measurement of blood pressure (BP), brachial flow-mediated dilatation (FMD), peripheral arterial tonometry, and central hemodynamic parameters. These tests were repeated after seven days of eating dark chocolate 75 g/day. Patients were divided according to the response in FMD: responders (n = 12) and nonresponders (n = 9). The responder group presented lower age (54 ± 7 versus 61 ± 6 years, P = 0.037), Framingham risk score (FRS) (2.5 ± 1.8 versus 8.1 ± 5.1%, P = 0.017), values of peripheral (55 ± 9 versus 63 ± 5 mmHg, P = 0.041), and central pulse pressure (PP) (44 ± 10 versus 54 ± 6 mmHg, P = 0.021). FMD response showed negative correlation with FRS (r = −0.60, P = 0.014), baseline FMD (r = −0.54, P = 0.011), baseline reactive hyperemia index (RHI; r = −0.56, P = 0.008), and central PP (r = −0.43, P = 0.05). However, after linear regression analysis, only FRS and baseline RHI were associated with FMD response. In conclusion, one-week dark chocolate intake significantly improved endothelial function and reduced BP in younger hypertensive with impaired endothelial function in spite of lower cardiovascular risk. PMID:23533716

  10. Characterisation of hypertensive patients with improved endothelial function after dark chocolate consumption.

    PubMed

    d'El-Rei, Jenifer; Cunha, Ana Rosa; Burlá, Adriana; Burlá, Marcelo; Oigman, Wille; Neves, Mario Fritsch; Virdis, Agostino; Medeiros, Fernanda

    2013-01-01

    Recent findings indicate an inverse relationship between cardiovascular disease and consumption of flavonoids. We aimed to identify clinical and vascular parameters of treated hypertensive who present beneficial effects of dark chocolate for one-week period on vascular function. Twenty-one hypertensive subjects, aged 40-65 years, were included in a prospective study with measurement of blood pressure (BP), brachial flow-mediated dilatation (FMD), peripheral arterial tonometry, and central hemodynamic parameters. These tests were repeated after seven days of eating dark chocolate 75 g/day. Patients were divided according to the response in FMD: responders (n = 12) and nonresponders (n = 9). The responder group presented lower age (54 ± 7 versus 61 ± 6 years, P = 0.037), Framingham risk score (FRS) (2.5 ± 1.8 versus 8.1 ± 5.1%, P = 0.017), values of peripheral (55 ± 9 versus 63 ± 5 mmHg, P = 0.041), and central pulse pressure (PP) (44 ± 10 versus 54 ± 6 mmHg, P = 0.021). FMD response showed negative correlation with FRS (r = -0.60, P = 0.014), baseline FMD (r = -0.54, P = 0.011), baseline reactive hyperemia index (RHI; r = -0.56, P = 0.008), and central PP (r = -0.43, P = 0.05). However, after linear regression analysis, only FRS and baseline RHI were associated with FMD response. In conclusion, one-week dark chocolate intake significantly improved endothelial function and reduced BP in younger hypertensive with impaired endothelial function in spite of lower cardiovascular risk.

  11. Patient Monitoring

    NASA Technical Reports Server (NTRS)

    1978-01-01

    In photo above, the electrocardiogram of a hospitalized patient is being transmitted by telemetry. Widely employed in space operations, telemetry is a process wherein instrument data is converted to electrical signals and sent to a receiver where the signals are reconverted to usable information. In this instance, heart readings are picked up by the electrode attached to the patient's body and delivered by wire to the small box shown, which is a telemetry transmitter. The signals are relayed wirelessly to the console in the background, which converts them to EKG data. The data is displayed visually and recorded on a printout; at the same time, it is transmitted to a central control station (upper photo) where a nurse can monitor the condition of several patients simultaneously. The Patient Monitoring System was developed by SCI Systems, Inc., Huntsville, Alabama, in conjunction with Abbott Medical Electronics, Houston, Texas. In developing the system, SCI drew upon its extensive experience as a NASA contractor. The company applied telemetry technology developed for the Saturn launch vehicle and the Apollo spacecraft; instrumentation technology developed for heart, blood pressure and sleep monitoring of astronauts aboard NASA's Skylab long duration space station; and communications technology developed for the Space Shuttle.

  12. Association of serotonin transporter (SLC6A4) & receptor (5HTR1A, 5HTR2A) polymorphisms with response to treatment with escitalopram in patients with major depressive disorder: A preliminary study

    PubMed Central

    Basu, Aniruddha; Chadda, R.K.; Sood, Mamta; Kaur, Harpreet; Kukreti, Ritushree

    2015-01-01

    Background & objectives: Genetic factors have potential of predicting response to antidepressants in patients with major depressive disorder (MDD). In this study, an attempt was made to find an association between response to escitalopram in patients with MDD, and serotonin transporter (SLC6A4) and receptor (5HTR1A, 5HTR2A) polymorphisms. Methods: Fifty five patients diagnosed as suffering from MDD, were selected for the study. The patients were treated with escitalopram over a period of 6-8 wk. Severity of depression, response to treatment and side effects were assessed using standardised instruments. Genetic variations from HTR1A (rs6295), HTR2A (rs6311 and rs6313) and SLC6A4 (44 base-pair insertion/deletion at 5-HTTLPR) were genotyped. The genetic data of the responders and non-responders were compared to assess the role of genetic variants in therapeutic outcome. Results: Thirty six (65.5%) patients responded to treatment, and 19 (34.5%) had complete remission. No association was observed for genotype and allelic frequencies of single nucleotide polymorphisms (SNPs) among remitter/non-remitter and responder/non-responder groups, and six most common side-effects, except memory loss which was significantly associated with rs6311 (P =0.03). Interpretation & conclusions: No significant association was found between the SNPs analysed and response to escitalopram in patients with MDD though a significant association was seen between the side effect of memory loss and rs6311. Studies with larger sample are required to find out genetic basis of antidepressant response in Indian patients. PMID:26261165

  13. Final report of toxicity and efficacy of a phase II study of oral cyclophosphamide, thalidomide, and prednisone for patients with relapsed or refractory multiple myeloma: A Hoosier Oncology Group Trial, HEM01-21.

    PubMed

    Suvannasankha, Attaya; Fausel, Christopher; Juliar, Beth E; Yiannoutsos, Constantin T; Fisher, William B; Ansari, Rafat H; Wood, Lisa L; Smith, Gina G; Cripe, Larry D; Abonour, Rafat

    2007-01-01

    Thalidomide has direct antimyeloma and immunomodulatory effects. In addition, both thalidomide and metronomic chemotherapy inhibit angiogenesis. The synergy of such a combination may decrease toxicity while maintaining efficacy. The Hoosier Oncology Group conducted a phase II trial of oral cyclophosphamide (50 mg b.i.d. for 21 days), thalidomide (200 mg/day), and prednisone (50 mg q.o.d.) (CTP) per 28-day course in patients with relapsed multiple myeloma (MM). Of the 37 patients enrolled, 16 had prior stem cell transplantation. The median follow-up time was 25.3 months (95% confidence interval [CI] 23.2-27.7). Of 35 patients treated, 22 patients (62.9%) responded: 7 (20.0%) complete responses, 2 (5.7%) near-complete responses, and 13 (37.1%) partial responses. Eight patients (22.9%) had stable disease, and three (8.6%) had disease progression. Two patients withdrew from the study early due to reasons unrelated to progression or toxicity and were treated as nonresponders. The median time to best response and time to progression were 3.6 months (95% CI 2.8-10.9) and 13.2 months (95% CI 9.4-21.0), respectively. The median number of treatment cycles was seven (range 1-12 cycles). Grade III to IV toxicities included leukopenia (42.9%; febrile neutropenia, 11.4%), hyperglycemia (20%), sensory neuropathy (11.4%), thromboses (8%), and motor neuropathy (5.7%). No patient withdrew from the study due to toxicity. The efficacy and low toxicity of the CTP regimen support the future development of such an approach in MM.

  14. Effects of antihistamine on up-regulation of histamine H1 receptor mRNA in the nasal mucosa of patients with pollinosis induced by controlled cedar pollen challenge in an environmental exposure unit.

    PubMed

    Kitamura, Yoshiaki; Nakagawa, Hideyuki; Fujii, Tatsuya; Sakoda, Takema; Enomoto, Tadao; Mizuguchi, Hiroyuki; Fukui, Hiroyuki; Takeda, Noriaki

    2015-11-01

    In the present study, we examined the effects of antihistamine on the up-regulation of H1R mRNA in the nasal mucosa of patients with pollinosis induced by controlled exposure to pollen using an environmental exposure unit. Out of 20 patients, we designated 14 responders, whose levels of H1R mRNA in the nasal mucosa were increased after the first pollen exposure and excluded 6 non-responders. Accordingly, the first exposure to pollen without treatment significantly induced both nasal symptoms and the up-regulation of H1R mRNA in the nasal mucosa of the responders. Subsequently, prophylactic administration of antihistamine prior to the second pollen exposure significantly inhibited both of the above effects in the responders. Moreover, the nasal expression of H1R mRNA before the second pollen exposure in the responders pretreated with antihistamine was significantly decreased, as compared with that before the first pollen exposure without treatment. These findings suggest that antihistamines suppressed histamine-induced transcriptional activation of H1R gene in the nasal mucosa, in addition to their blocking effect against histamine on H1R, resulting in a decrease of nasal symptoms. These findings further suggest that by their inverse agonistic activity, antihistamines suppress the basal transcription of nasal H1R in the absence of histamine in responders.

  15. Response Bias in Hospice Evaluation.

    ERIC Educational Resources Information Center

    Hayslip, Bert, Jr.; And Others

    1991-01-01

    Analyzed response bias among 34 recipients of care in hospice. Found nonrespondents to have better bereavement prognoses and tended to care for patients who were younger, male, and in program for shorter time. Nonrespondents were in contact with staff less than were respondents. Data are consistent with earlier research showing significant…

  16. Syphilis presenting as retinal detachment and orchitis in a young man with HIV.

    PubMed

    Yogo, Norihiro; Nichol, Aran Cunningham; Campbell, Thomas B; Erlandson, Kristine M

    2014-02-01

    Retinal detachment and testicular lesions are 2 rare presentations of syphilis. We describe a man with bilateral retinal detachment from ocular syphilis and syphilitic orchitis as a manifestation of syphilis and HIV coinfection.

  17. Epidermal growth factor-like domain 7 predicts response to first-line chemotherapy and bevacizumab in patients with metastatic colorectal cancer.

    PubMed

    Hansen, Torben Frøstrup; Nielsen, Boye Schnack; Sørensen, Flemming Brandt; Johnsson, Anders; Jakobsen, Anders

    2014-09-01

    The number of approved antiangiogenic drugs is constantly growing and emphasizes the need for predictive biomarkers. The aim of this study was to analyze the predictive value of epidermal growth factor-like domain 7 (EGFL7) and microRNA-126 (miR126) to first-line chemotherapy combined with bevacizumab, in patients with metastatic colorectal cancer (mCRC). A total of 158 patients from two different, but comparable, cohorts were included. Analyses were performed on tumor tissue from the primary tumor either based on a whole-tumor resection or an endoscopic biopsy. EGFL7 was analyzed by immunohistochemistry (IHC) and miR126 by in situ hybridization (ISH). Both biomarkers were quantified by image-guided analyses. Endpoints were response rate (RR) and progression-free survival (PFS). The EGFL7 vessel area (VA) in tumor resections was closely related to treatment response with a median EGFL7 VA in responding patients of 4 [95% confidence interval (CI), 4-6] compared with 8.5 (95% CI, 7-11) in nonresponders, P = 0.0008. This difference translated into a borderline significant difference in PFS (P = 0.06). Furthermore, a significant relationship between high EGFL7 VA and KRAS mutation was detected (P = 0.049). The results showed no significant relationship between the miR126 VA and the clinical endpoints. Our study suggests a predictive value of EGFL7 in regard to first-line chemotherapy and bevacizumab in patients with mCRC and supports the mechanism of a dual blocking of the vascular endothelial growth factor-A and EGFL7 axis in this setting.

  18. Lower pH values of weakly acidic refluxes as determinants of heartburn perception in gastroesophageal reflux disease patients with normal esophageal acid exposure.

    PubMed

    de Bortoli, N; Martinucci, I; Savarino, E; Franchi, R; Bertani, L; Russo, S; Ceccarelli, L; Costa, F; Bellini, M; Blandizzi, C; Savarino, V; Marchi, S

    2016-01-01

    Multichannel impedance pH monitoring has shown that weakly acidic refluxes are able to generate heartburn. However, data on the role of different pH values, ranging between 4 and 7, in the generation of them are lacking. The aim of this study was to evaluate whether different pH values of weakly acidic refluxes play a differential role in provoking reflux symptoms in endoscopy-negative patients with physiological esophageal acid exposure time and positive symptom index and symptom association probability for weakly acidic refluxes. One hundred and forty-three consecutive patients with gastroesophageal reflux disease, nonresponders to proton pump inhibitors (PPIs), were allowed a washout from PPIs before undergoing: upper endoscopy, esophageal manometry, and multichannel impedance pH monitoring. In patients with both symptom index and symptom association probability positive for weakly acidic reflux, each weakly acidic reflux was evaluated considering exact pH value, extension, physical characteristics, and correlation with heartburn. Forty-five patients with normal acid exposure time and positive symptom association probability for weakly acidic reflux were identified. The number of refluxes not heartburn related was higher than those heartburn related. In all distal and proximal liquid refluxes, as well as in distal mixed refluxes, the mean pH value of reflux events associated with heartburn was significantly lower than that not associated. This condition was not confirmed for proximal mixed refluxes. Overall, a low pH of weakly acidic reflux represents a determinant factor in provoking heartburn. This observation contributes to better understand the pathophysiology of symptoms generated by weakly acidic refluxes, paving the way toward the search for different therapeutic approaches to this peculiar condition of esophageal hypersensitivity.

  19. Genotype, viral load and age as independent predictors of treatment outcome of interferon-alpha 2a treatment in patients with chronic hepatitis C. Construct group.

    PubMed

    Bell, H; Hellum, K; Harthug, S; Maeland, A; Ritland, S; Myrvang, B; von der Lippe, B; Raknerud, N; Skaug, K; Gutigard, B G; Skjaerven, R; Prescott, L E; Simmonds, P

    1997-01-01

    Patients with chronic hepatitis C respond differently when treated with interferon. We randomized 116 patients with chronic hepatitis C in order to compare two dosage regimens of recombinant interferon alpha 2a:3 MIU x 3 per week for 6 months (arm A) or 6 MIU x 3 per week for 3 months and then 3 MIU x 3 per week for 3 months (arm B). There were no significant differences concerning outcome between the two dose regimens: sustained clearance of HCV viremia 6 months after the end of treatment was obtained in 12/59 (20%) in group A compared with 18/57 (32%) in group B (p = 0.24). In patients with genotype 1a, 4/31 (13%), in genotype 1b, none of 9 (0%), 9/15 (60%) in genotype 2, and 17/58 (29%) in genotype 3, showed sustained clearance of HCV viremia 6 months after the end of treatment (p = 0.002). In a stepwise logistic regression analysis, only pretreatment viral load (p = 0.0001), genotype (p = 0.001) and age (p = 0.04) were identified as independent predictors of sustained clearance of HCV viremia. Liver histology as assessed by Knodell index was significantly improved in patients with sustained HCV RNA response 6 months after the end of treatment (5.2 +/- 2.2 vs 2.6 +/- 2.2, p < 0.001), but not in responders with relapse or in non-responders. In conclusion, stepwise logistic regression analysis showed that viral load, HCV genotype and age were the only independent predictors for sustained HCV RNA response.

  20. Four-Year Maintenance Treatment With Adalimumab in Patients with Moderately to Severely Active Ulcerative Colitis: Data from ULTRA 1, 2, and 3

    PubMed Central

    Colombel, Jean-Frederic; Sandborn, William J; Ghosh, Subrata; Wolf, Douglas C; Panaccione, Remo; Feagan, Brian; Reinisch, Walter; Robinson, Anne M; Lazar, Andreas; Kron, Martina; Huang, Bidan; Skup, Martha; Thakkar, Roopal B

    2014-01-01

    OBJECTIVES: The safety and efficacy of adalimumab for patients with moderately to severely active ulcerative colitis (UC) has been reported up to week 52 from the placebo-controlled trials ULTRA (Ulcerative Colitis Long-Term Remission and Maintenance with Adalimumab) 1 and 2. Up to 4 years of data for adalimumab-treated patients from ULTRA 1, 2, and the open-label extension ULTRA 3 are presented. METHODS: Remission per partial Mayo score, remission per Inflammatory Bowel Disease Questionnaire (IBDQ) score, and mucosal healing rates were assessed in adalimumab-randomized patients from ULTRA 1 and 2 up to week 208. Corticosteroid-free remission was assessed in adalimumab-randomized patients who used corticosteroids at lead-in study baseline. Maintenance of remission per partial Mayo score and mucosal healing was assessed in patients who entered ULTRA 3 in remission per full Mayo score and with mucosal healing, respectively. As observed, last observation carried forward (LOCF) and nonresponder imputation (NRI) were used to report efficacy. Adverse events were reported for any adalimumab-treated patient. RESULTS: A total of 600/1,094 patients enrolled in ULTRA 1 or 2 were randomized to receive adalimumab and included in the intent-to-treat analyses of the studies. Of these, 199 patients remained on adalimumab after 4 years of follow-up. Rates of remission per partial Mayo score, remission per IBDQ score, mucosal healing, and corticosteroid discontinuation at week 208 were 24.7%, 26.3%, 27.7% (NRI), and 59.2% (observed), respectively. Of the patients who were followed up in ULTRA 3 (588/1,094), a total of 360 patients remained on adalimumab 3 years later. Remission per partial Mayo score and mucosal healing after ULTRA 1 or 2 to year 3 of ULTRA 3 were maintained by 63.6% and 59.9% of patients, respectively (NRI). Adverse event rates were stable over time. CONCLUSIONS: Remission, mucosal healing, and improved quality of life were maintained in patients with moderately to

  1. Efficacy of Anakinra in Refractory Adult-Onset Still's Disease: Multicenter Study of 41 Patients and Literature Review.

    PubMed

    Ortiz-Sanjuán, Francisco; Blanco, Ricardo; Riancho-Zarrabeitia, Leyre; Castañeda, Santos; Olivé, Alejandro; Riveros, Anne; Velloso-Feijoo, María L; Narváez, Javier; Jiménez-Moleón, Inmaculada; Maiz-Alonso, Olga; Ordóñez, Carmen; Bernal, José A; Hernández, María V; Sifuentes-Giraldo, Walter A; Gómez-Arango, Catalina; Galíndez-Agirregoikoa, Eva; Blanco-Madrigal, Juan; Ortiz-Santamaria, Vera; del Blanco-Barnusell, Jordi; De Dios, Juan R; Moreno, Mireia; Fiter, Jordi; de los Riscos, Marina; Carreira, Patricia; Rodriguez-Valls, María J; González-Vela, M Carmen; Calvo-Río, Vanesa; Loricera, Javier; Palmou-Fontana, Natalia; Pina, Trinitario; Llorca, Javier; González-Gay, Miguel A

    2015-09-01

    Adult-onset Still's disease (AOSD) is often refractory to standard therapy. Anakinra (ANK), an interleukin-1 receptor antagonist, has demonstrated efficacy in single cases and small series of AOSD. We assessed the efficacy of ANK in a series of AOSD patients. Multicenter retrospective open-label study. ANK was used due to lack of efficacy to standard synthetic immunosuppressive drugs and in some cases also to at least 1 biologic agent. Forty-one patients (26 women/15 men) were recruited. They had a mean age of 34.4 ± 14 years and a median [interquartile range (IQR)] AOSD duration of 3.5 [2-6] years before ANK onset. At that time the most common clinical features were joint manifestations 87.8%, fever 78%, and cutaneous rash 58.5%. ANK yielded rapid and maintained clinical and laboratory improvement. After 1 year of therapy, the frequency of joint and cutaneous manifestations had decreased to 41.5% and to 7.3% respectively, fever from 78% to 14.6%, anemia from 56.1% to 9.8%, and lymphadenopathy from