immunologic factors

Summary

Summary: Biologically active substances whose activities affect or play a role in the functioning of the immune system.

Top Publications

  1. Vanhoutte E, Latov N, Deng C, Hanna K, Hughes R, Bril V, et al. Vigorimeter grip strength in CIDP: a responsive tool that rapidly measures the effect of IVIG--the ICE study. Eur J Neurol. 2013;20:748-55 pubmed publisher
    ..Grip strength can be considered a sensitive tool for assessing clinically relevant changes in patients with CIDP. Its use in daily practice is suggested. ..
  2. Chen G, Severo M, Sohail M, Sakhon O, Wikel S, Kotsyfakis M, et al. Ixodes scapularis saliva mitigates inflammatory cytokine secretion during Anaplasma phagocytophilum stimulation of immune cells. Parasit Vectors. 2012;5:229 pubmed publisher
    ..However, how I. scapularis saliva influences host cytokine secretion in the presence of the obligate intracellular rickettsial pathogen Anaplasma phagocytophilum remains elusive...
  3. Preston S, Majtan J, Kouremenou C, Ryśnik O, Burger L, Cabezas Cruz A, et al. Novel immunomodulators from hard ticks selectively reprogramme human dendritic cell responses. PLoS Pathog. 2013;9:e1003450 pubmed publisher
    ..Our results suggest a previously unknown mechanism for parasite-induced subversion of adaptive immunity, one which may also facilitate pathogen transmission. ..
  4. Jakopin Z. Murabutide revisited: a review of its pleiotropic biological effects. Curr Med Chem. 2013;20:2068-79 pubmed
    ..This review covers the findings of all relevant studies and focuses on the role of murabutide and its potential in the treatment of several microbial diseases. ..
  5. Weidenbusch M, Römmele C, Schröttle A, Anders H. Beyond the LUNAR trial. Efficacy of rituximab in refractory lupus nephritis. Nephrol Dial Transplant. 2013;28:106-11 pubmed publisher
    ..At present, no such trial is available for the use of RTX in refractory LN...
  6. Jokubaitis V, Li V, Kalincik T, Izquierdo G, Hodgkinson S, Alroughani R, et al. Fingolimod after natalizumab and the risk of short-term relapse. Neurology. 2014;82:1204-11 pubmed publisher
    ..This study provides Class IV evidence that RRs are not higher in patients with multiple sclerosis switching to fingolimod from natalizumab compared to those patients switching to fingolimod from other therapies. ..
  7. Giacomini E, Severa M, Rizzo F, Mechelli R, Annibali V, Ristori G, et al. IFN-? therapy modulates B-cell and monocyte crosstalk via TLR7 in multiple sclerosis patients. Eur J Immunol. 2013;43:1963-72 pubmed publisher
    ..Collectively, our data unveil a novel TLR7-regulated mechanism in in vivo IFN-?-stimulated whole leukocytes that could be exploited to define new TLR7-based strategies for the treatment of MS. ..
  8. Hotchkiss R, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis. 2013;13:260-8 pubmed publisher
    ..We hypothesise that immunoadjuvant therapy represents the next major advance in sepsis. ..
  9. Badoux X, Keating M, Wen S, Wierda W, O Brien S, Faderl S, et al. Phase II study of lenalidomide and rituximab as salvage therapy for patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2013;31:584-91 pubmed publisher
    ..The combination of lenalidomide and rituximab is active in patients with recurrent CLL and warrants further investigation. ..

More Information

Publications62

  1. Suszko A, Obminska Mrukowicz B. Influence of polysaccharide fractions isolated from Caltha palustris L. on the cellular immune response in collagen-induced arthritis (CIA) in mice. A comparison with methotrexate. J Ethnopharmacol. 2013;145:109-17 pubmed publisher
    ..These results are similar to those obtained in the case of MTX treatment. This indicates that fraction B may be a potent candidate for botanical anti-arthritic agent. ..
  2. Jander S, Turowski B, Kieseier B, Hartung H. Emerging tumefactive multiple sclerosis after switching therapy from natalizumab to fingolimod. Mult Scler. 2012;18:1650-2 pubmed publisher
    ..The possible relevance of natalizumab withdrawal vs fingolimod introduction is discussed against the background of recently published case studies. ..
  3. Kouakou K, Schepetkin I, Yapi A, Kirpotina L, Jutila M, Quinn M. Immunomodulatory activity of polysaccharides isolated from Alchornea cordifolia. J Ethnopharmacol. 2013;146:232-42 pubmed publisher
    ..Our results provide a molecular basis to explain a portion of the beneficial therapeutic properties of water extracts from Alchornea cordifolia leaves in traditional folk medicine of Africa. ..
  4. Bulliard Y, Jolicoeur R, Windman M, Rue S, Ettenberg S, Knee D, et al. Activating Fc ? receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. J Exp Med. 2013;210:1685-93 pubmed publisher
    ..These findings may have broad implications for antibody engineering efforts aimed at enhancing the therapeutic activity of immunomodulatory antibodies. ..
  5. Gandhi A, Kang J, Havens C, Conklin T, Ning Y, Wu L, et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.). Br J Haematol. 2014;164:811-21 pubmed publisher
    ..In conclusion, we present a molecular model in which drug binding to cereblon results in the interaction of Ikaros and Aiolos to CRL4(CRBN) , leading to their ubiquitination, subsequent proteasomal degradation and T cell activation. ..
  6. Lopez Olivo M, Tayar J, Martinez Lopez J, Pollono E, Cueto J, Gonzales Crespo M, et al. Risk of malignancies in patients with rheumatoid arthritis treated with biologic therapy: a meta-analysis. JAMA. 2012;308:898-908 pubmed publisher
    ..The use of BRMs among patients with RA included in RCTs of at least 6 months' duration was not significantly associated with an increased risk of malignancy compared with other disease-modifying antirheumatic drugs or with placebo. ..
  7. Liu L, Yin W, Wang R, Sun D, He X, Ding Y. The prognostic role of abnormal liver function in IVIG unresponsiveness in Kawasaki disease: a meta-analysis. Inflamm Res. 2016;65:161-8 pubmed publisher
    ..In summary, our meta-analysis suggested that liver abnormality was significantly associated with IVIG unresponsiveness in KD patients. Further study from more clinical investigations is needed to confirm this finding. ..
  8. Mendis M, Leclerc E, Simsek S. Arabinoxylans, gut microbiota and immunity. Carbohydr Polym. 2016;139:159-66 pubmed publisher
    ..The existing literature indicates the role of fine structural details of AX on its potential as polysaccharides that can impact the gut associated microbial growth and immune system. ..
  9. Wendtner C, Hallek M, Fraser G, Michallet A, Hillmen P, Dürig J, et al. Safety and efficacy of different lenalidomide starting doses in patients with relapsed or refractory chronic lymphocytic leukemia: results of an international multicenter double-blinded randomized phase II trial. Leuk Lymphoma. 2016;57:1291-9 pubmed publisher
    ..Lower starting doses allowed subsequent dose escalation of lenalidomide while maintaining an acceptable tolerability profile in patients with relapsed/refractory CLL. ..
  10. Marcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, et al. Obinutuzumab for the First-Line Treatment of Follicular Lymphoma. N Engl J Med. 2017;377:1331-1344 pubmed publisher
    ..Obinutuzumab is a glycoengineered type II anti-CD20 monoclonal antibody. We compared rituximab-based chemotherapy with obinutuzumab-based chemotherapy in patients with previously untreated advanced-stage follicular lymphoma...
  11. Brandse J, Mathôt R, van der Kleij D, Rispens T, Ashruf Y, Jansen J, et al. Pharmacokinetic Features and Presence of Antidrug Antibodies Associate With Response to Infliximab Induction Therapy in Patients With Moderate to Severe Ulcerative Colitis. Clin Gastroenterol Hepatol. 2016;14:251-8.e1-2 pubmed publisher
    ..Patients with high baseline serum levels of CRP had lower serum concentrations of infliximab. NL39626.018.12. ..
  12. Furudate S, Fujimura T, Kambayashi Y, Kakizaki A, Hidaka T, Aiba S. Immunomodulatory Effect of Imiquimod Through CCL22 Produced by Tumor-associated Macrophages in B16F10 Melanomas. Anticancer Res. 2017;37:3461-3471 pubmed
    ..Our results suggest a possible mechanism for the antitumor immune response induced by IQM through tumor-associated macrophages. ..
  13. Kosowicz J, Lee J, Peiffer B, Guo Z, Chen J, Liao G, et al. Drug Modulators of B Cell Signaling Pathways and Epstein-Barr Virus Lytic Activation. J Virol. 2017;91: pubmed publisher
    ..Finally, we show that BCR activation of lytic infection occurs not only in tumor cell lines but also in freshly isolated B cells from patients and that this activation can be blocked by BCR inhibitors. ..
  14. Hassan E, Matloub A, Aboutabl M, Ibrahim N, Mohamed S. Assessment of anti-inflammatory, antinociceptive, immunomodulatory, and antioxidant activities of Cajanus cajan L. seeds cultivated in Egypt and its phytochemical composition. Pharm Biol. 2016;54:1380-91 pubmed publisher
    ..Moreover, hexane extract (200 and 400 mg/kg) decreased the number of writhings by 61 and 83%, respectively. The butanol fraction showed DPPH radical scavenging (inhibitory concentration (IC50) value: 9.07 μg/ml). ..
  15. Conti F, Priori R, Alessandri C, Misasi R, Capozzi A, Pendolino M, et al. Diagnosis of catastrophic anti-phospholipid syndrome in a patient tested negative for conventional tests. Clin Exp Rheumatol. 2017;35:678-680 pubmed
    ..To our knowledge, this is the first ever reported case of CAPS diagnosed by means of thin layer chromatography immunostaining and vimentin/cardiolipin antibody ELISA test. ..
  16. Wang D, Gao Q, Wang T, Qian F, Wang Y. Theanine: the unique amino acid in the tea plant as an oral hepatoprotective agent. Asia Pac J Clin Nutr. 2017;26:384-391 pubmed publisher
    ..In this review, we summarize published results describing the potential mechanisms for these beneficial health effects and provide new insight into how theanine can be therapeutic for liver injury and chronic liver disease. ..
  17. Willis M, Fox R. Progressive Multiple Sclerosis. Continuum (Minneap Minn). 2016;22:785-98 pubmed publisher
    ..A multidisciplinary approach is needed to address the many symptoms that impact quality of life for patients with progressive MS. ..
  18. Raza A, Crothers J, McGill M, Mawe G, Teuscher C, Krementsov D. Anti-inflammatory roles of p38? MAPK in macrophages are context dependent and require IL-10. J Leukoc Biol. 2017;102:1219-1227 pubmed publisher
  19. Stuve O, Cataldi F, Pradhan V, Gorelick K. Normal intrathecal leukocyte cell number and composition do not decrease the incidence of post-lumbar puncture headache. J Neuroimmunol. 2017;310:69-71 pubmed publisher
    ..The lymphocyte composition was unaltered by PF-00547659 anti-MAdCAM-1 therapy. Our observations suggest that normal numbers and composition of intrathecal leukocytes do not decrease the incidence of PLPH. ..
  20. Chen T, Sazinsky S, Houde D, DiLillo D, Bird J, Li K, et al. Engineering Aglycosylated IgG Variants with Wild-Type or Improved Binding Affinity to Human Fc Gamma RIIA and Fc Gamma RIIIAs. J Mol Biol. 2017;429:2528-2541 pubmed publisher
    ..These aglycosylated variants have the potential to allow therapeutic antibodies to be produced in virtually any expression system and still maintain effector function. ..
  21. Cho J, Yi H, Jang E, Lee M, Lee J, Kang C, et al. Mycophenolic mofetil, an alternative antiviral and immunomodulator for the highly pathogenic avian influenza H5N1 virus infection. Biochem Biophys Res Commun. 2017;494:298-304 pubmed publisher
    ..These results indicated that MMF could represent a novel inhibitor of viral replication and a potent immunomodulator for the treatment of H5N1 virus infection...
  22. Mochizuki H, Kato M, Higuchi T, Koyamada R, Arai S, Okada S, et al. Overlap of IgG4-related Disease and Multicentric Castleman's Disease in a Patient with Skin Lesions. Intern Med. 2017;56:1095-1099 pubmed publisher
    ..The patient was diagnosed with IgG4-related disease (RD). Rituximab only had a slight effect. This case demonstrates that overlapping features of IgG4-RD and MCD may present in a single patient, which suggests a shared pathogenesis. ..
  23. Burgis J, Nguyen K, Park K, Cox K. Response to strict and liberalized specific carbohydrate diet in pediatric Crohn's disease. World J Gastroenterol. 2016;22:2111-7 pubmed publisher
    ..Disease control may be attainable with the SCD in pediatric CD. Further studies are needed to assess adherence, impact on mucosal healing and growth. ..
  24. Léger J, Guimarães Costa R, Muntean C. Immunotherapy in Peripheral Neuropathies. Neurotherapeutics. 2016;13:96-107 pubmed publisher
  25. Moreira T, Zhang L, Shaulov L, Harel A, Kuss S, Williams J, et al. Sec13 Regulates Expression of Specific Immune Factors Involved in Inflammation In Vivo. Sci Rep. 2015;5:17655 pubmed publisher
    ..In sum, Sec13 regulates specific expression of immune factors with key functions in inflammation. ..
  26. Tsuji T, Okuno S, Kuroda A, Hamazaki J, Chikami T, Sakurai S, et al. Therapeutic approach to mite-induced intractable dermatitis using novel immunomodulator FTY720 ointment (fingolimod) in NC/Nga mice. Allergol Int. 2016;65:172-179 pubmed publisher
    ..FTY720 ointment is a promising candidate for treatment of intractable AD. These findings also provide the first evidence that FTY720 ointment ameliorates epidermal barrier function. ..
  27. Hu T, Jiang C, Huang Q, Sun F. A comb-like branched β-D-glucan produced by a Cordyceps sinensis fungus and its protective effect against cyclophosphamide-induced immunosuppression in mice. Carbohydr Polym. 2016;142:259-67 pubmed publisher
    ..Moreover, EPS could significantly enhance immune organs and stimulate the release of major cytokines TNF-α and INF-γ, suggesting that EPS exhibited protective effect in immunocompromised mice. ..
  28. Takeshita S, Kanai T, Kawamura Y, Yoshida Y, Nonoyama S. A comparison of the predictive validity of the combination of the neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio and other risk scoring systems for intravenous immunoglobulin (ivig)-resistance in Kawasaki disease. PLoS ONE. 2017;12:e0176957 pubmed publisher
    ..83 and PLR?150, which is a simple and convenient indicator, was equal to or higher than that of the other risk scores. This suggests that the new score could be a widely available marker for predicting IVIG resistance in KD. ..
  29. Hviid M, Macklon N. Immune modulation treatments-where is the evidence?. Fertil Steril. 2017;107:1284-1293 pubmed publisher
    ..The current evidence base does not support the clinical use of immunomodulation therapies in patients undergoing IVF. However, more discerning phenotyping may identify groups who could benefit. ..
  30. Dutta A, Hewett D, Fink J, Grady J, Zannettino A. Cutting edge genomics reveal new insights into tumour development, disease progression and therapeutic impacts in multiple myeloma. Br J Haematol. 2017;178:196-208 pubmed publisher
    ..MM disease progression will illuminate possible mechanisms underlying the tumour. ..
  31. Auyeung K, Han Q, Ko J. Astragalus membranaceus: A Review of its Protection Against Inflammation and Gastrointestinal Cancers. Am J Chin Med. 2016;44:1-22 pubmed publisher
  32. Gövert F, Witt K, Erro R, Hellriegel H, Paschen S, Martinez Hernandez E, et al. Orthostatic myoclonus associated with Caspr2 antibodies. Neurology. 2016;86:1353-5 pubmed publisher
  33. Sonneveld P, Broijl A. Treatment of relapsed and refractory multiple myeloma. Haematologica. 2016;101:396-406 pubmed publisher
    ..It is becoming increasingly more important to consider the therapeutic options for the whole duration of the disease rather than take a step by step approach, and to develop a systematic approach for each individual patient. ..
  34. Berenguer Ruiz L, Sempere A, Gimenez Martinez J, Gabaldón Torres L, Tahoces L, Sanchez Perez R, et al. Rescue Therapy Using Rituximab for Multiple Sclerosis. Clin Neuropharmacol. 2016;39:178-81 pubmed publisher
  35. Lang P, Aspinall R. Vitamin D Status and the Host Resistance to Infections: What It Is Currently (Not) Understood. Clin Ther. 2017;39:930-945 pubmed publisher
    ..For the most part, we are unable to identify tissue-specific applications of supplementation except for those subjects at high risk of osteomalacia and osteoporosis. ..
  36. Villani S, Zanotta N, Ambrogi F, Comar M, Franciotta D, Dolci M, et al. Multiplex array analysis of circulating cytokines and chemokines in natalizumab-treated patients with multiple sclerosis. J Neuroimmunol. 2017;310:91-96 pubmed publisher
    ..No patient developed the JCPyV-related progressive multifocal leukoencephalopathy (PML), the major risk factor of natalizumab therapy. Our data suggest that natalizumab has marginal impact on the systemic immunity. ..
  37. Matas E, Bau L, Martínez Iniesta M, Romero Pinel L, Mañé Martínez M, Martínez Yélamos S. Absence of MxA induction is related to a poor clinical response to interferon beta treatment in multiple sclerosis patients. J Neurol. 2016;263:722-9 pubmed publisher
    ..031), were predictors of poor response to interferon-β in naïve MS patients. Patients showing a lower capacity for MxA induction following 3 months of interferon-β treatment are more likely to be non-responders to this therapy. ..
  38. Papamichael K, Mantzaris G, Peyrin Biroulet L. A safety assessment of anti-tumor necrosis factor alpha therapy for treatment of Crohn's disease. Expert Opin Drug Saf. 2016;15:493-501 pubmed publisher
    ..The role of therapeutic drug monitoring in predicting and preventing SAE awaits confirmation. ..
  39. Le Cann F, Delehouze C, Leverrier Penna S, Filliol A, Comte A, Delalande O, et al. Sibiriline, a new small chemical inhibitor of receptor-interacting protein kinase 1, prevents immune-dependent hepatitis. FEBS J. 2017;284:3050-3068 pubmed publisher
    ..Finally, Sib protects mice from concanavalin A-induced hepatitis. These results reveal the small-molecule Sib as a new RIPK1 inhibitor potentially of interest for the treatment of immune-dependent hepatitis...
  40. Nakao H, Ishiguro A, Ikoma N, Nishi K, Su C, Nakadate H, et al. Acquired idiopathic thrombotic thrombocytopenic purpura successfully treated with intravenous immunoglobulin and glucocorticoid: A case report. Medicine (Baltimore). 2017;96:e6547 pubmed publisher
    ..Compared with biological agents, immunoglobulin is cost-effective, readily available, and has a proven long-term safety record, making it a possible treatment option for acquired thrombotic thrombocytopenic purpura. ..
  41. Sun X, Roudi R, Chen S, Fan B, Li H, Zhou M, et al. Immune-related adverse events associated with PD-1 and PD-L1 inhibitors for nonsmall cell lung cancer: Protocol for a systematic review and meta-analysis. Medicine (Baltimore). 2017;96:e8407 pubmed publisher
    ..Nevertheless, the immune-related adverse events (irAEs) associated with PD-1 and PD-L1 inhibitors are unique, and early recognition and treatment of these events are essential...
  42. Hsu D, Faldetta K, Pei L, Sheikh V, Utay N, Roby G, et al. A Paradoxical Treatment for a Paradoxical Condition: Infliximab Use in Three Cases of Mycobacterial IRIS. Clin Infect Dis. 2016;62:258-261 pubmed publisher
    ..Immunologic and virologic responses to antiretroviral therapy were unaffected. Tumor necrosis factor blockade may be beneficial for IRIS and warrants further study in clinical trials. ..
  43. Sotirchos E, Bhargava P, Eckstein C, Van Haren K, Baynes M, Ntranos A, et al. Safety and immunologic effects of high- vs low-dose cholecalciferol in multiple sclerosis. Neurology. 2016;86:382-90 pubmed publisher
    ..This study provides Class I evidence that cholecalciferol supplementation with 10,400 IU daily is safe and well-tolerated in patients with MS and exhibits in vivo pleiotropic immunomodulatory effects. ..
  44. Jiang L, Liu Y, Zhang L, Santoro C, Rodriguez A. Rituximab for treating inhibitors in people with inherited severe hemophilia. Cochrane Database Syst Rev. 2017;7:CD010810 pubmed publisher
    ..However, prior to the publication of any possible future randomized controlled trials, meta-analysis of case reports and case series may provide some evidence. ..
  45. Liang D, Zuo A, Zhao R, Shao H, Kaplan H, Sun D. Regulation of Adenosine Deaminase on Induced Mouse Experimental Autoimmune Uveitis. J Immunol. 2016;196:2646-54 pubmed publisher
    ..Our results demonstrated that the existing immune status strongly influences the anti- or proinflammatory effects of ADA. Our observations should help to improve the design of ADA- and adenosine receptor-targeted therapies. ..
  46. Wei W, Feng L, Bao W, Ma D, Leung C, Nie S, et al. Structure Characterization and Immunomodulating Effects of Polysaccharides Isolated from Dendrobium officinale. J Agric Food Chem. 2016;64:881-9 pubmed publisher
    ..They also induced the proliferation of lymphocytes alone and with mitogens. DOPa and DOPb are thus proven to be major, active polysaccharide markers of D. officinale...
  47. Murakami S, Eikawa S, Kaya S, Imao M, Aji T. AntiTumor and Immunoregulatory Effects of Fermented Papaya Preparation (FPP: SAIDOPS501). Asian Pac J Cancer Prev. 2016;17:3077-84 pubmed
    ..In vitro, treatment of PBMC with FPP induced IL1?, TNF? and IFN? production. Moreover, FPP suppressed proliferation of PHAstimulated Foxp3expressing Treg. These results suggest that FPP has chemotherapeutic properties. ..
  48. Yuan X, Huang H, Huang Y, Wang J, Yan J, Ding L, et al. Nuclear factor E2-related factor 2 knockdown enhances glucose uptake and alters glucose metabolism in AML12 hepatocytes. Exp Biol Med (Maywood). 2017;242:930-938 pubmed publisher
  49. Okeagu C, Baker E, Barreras N, Vaupel Z, Fortin P, Baker K. Review of Mechanical, Processing, and Immunologic Factors Associated With Outcomes of Fresh Osteochondral Allograft Transplantation of the Talus. Foot Ankle Int. 2017;38:808-819 pubmed publisher
    ..Further research is warranted to investigate the role of immunological mechanisms as an etiology of OCA failure. Level V, expert opinion. ..
  50. Li T, Ferns K, Yan Z, Yin S, Kou J, Li D, et al. Acanthopanax senticosus: Photochemistry and Anticancer Potential. Am J Chin Med. 2016;44:1543-1558 pubmed
    ..senticosus has potential to be developed as an effective anticancer drug. This paper reviews recent findings on the pharmacological properties of A. senticosus, with a focus on its anticancer effects. ..
  51. Moghimi S. Complement Propriety and Conspiracy in Nanomedicine: Perspective and a Hypothesis. Nucleic Acid Ther. 2016;26:67-72 pubmed publisher
    ..Pigs (and sheep) are often used as predictive models of nanomedicine-mediated infusion-related reactions in humans. The validity of these models in relation to human responses is questioned, and an alternative hypothesis is presented. ..
  52. Dalakas M, Rakocevic G, Dambrosia J, Alexopoulos H, McElroy B. A double-blind, placebo-controlled study of rituximab in patients with stiff person syndrome. Ann Neurol. 2017;82:271-277 pubmed publisher
    ..Ann Neurol 2017;82:271-277. ..
  53. Giamarellos Bourboulis E, Tziolos N, Routsi C, Katsenos C, Tsangaris I, Pneumatikos I, et al. Improving outcomes of severe infections by multidrug-resistant pathogens with polyclonal IgM-enriched immunoglobulins. Clin Microbiol Infect. 2016;22:499-506 pubmed publisher
    ..0001). Results favour the use of IgGAM as an adjunct to antimicrobial treatment for the management of septic shock caused by MDR Gram-negative bacteria. A prospective randomized trial is warranted. ..