Rapid Responder Research Articles

Association of Amino Acid Substitution Pattern in Core Protein of Hepatitis C Virus Genotype 2a High Viral Load and Virological Response to Interferon-Ribavirin Combination Therapy

Background: Substitution of amino acids (aa) 70 and 91 in the core region of HCV genotype 1b is a useful pretreatment predictor of poor response to interferon + ribavirin combination therapy, but the impacts of aa substitutions in the core region of HCV genotype 2a are still not clear. Methods: 154 consecutive Japanese adults with a high viral load (≥100 kIU/ml) of genotype 2a who could complete combination therapy for 24 weeks were evaluated. To examine the differences in virological characteristics between non-sustained virological response (non-SVR) and rapid responder (SVR patients who could achieve a HCV-RNA-negative status within 8 weeks), 86 patients could be analyzed by pretreatment substitution patterns of the core region. Results: SVR was achieved in 127 of 154 patients (83%), and rapid response in 113 of 127 (90%). In all 154 patients, multivariate analysis identified younger age, lower level of viremia, and higher level of albumin as significant determinants of SVR. As significant determinants of rapid response in 86 patients, multivariate analysis identified substitution of aa 4 (non-asparagine) in addition to the significant determinants of SVR. Conclusions: Our results suggest that the aa substitution pattern of the core region in patients with a high titer of genotype 2a may partly affect the virological response to combination therapy.

Multivariate Analysis for Factors Predicting Rapid Response of Leukocytapheresis in Patients With Steroid‐resistant Ulcerative Colitis: A Multicenter Prospective Open‐label Study

Leukocytapheresis (LCAP) has been advocated as a treatment for moderate to severe active ulcerative colitis (UC) in Japan. To clarify the predictive factors for a rapid response to LCAP treatment, we conducted a multicenter prospective open-label study. A total of 105 patients with UC were analyzed. LCAP was performed using a Cellsorba EX column once a week for 5-10 sessions. The response was evaluated by the clinical activity index (CAI). When the CAI score decreased to less than half the pretreatment value or to less than 5 points within 3 weeks, the patient was considered to be a rapid responder. The average CAI significantly decreased from 11.7 to 4.2 (P < 0.01). Seventy-four percent of the patients responded to the therapy, and 53% of these patients were rapid responders. The following significant factors correlated with the rapid LCAP response: (i) steroid resistance (P < 0.05), (ii) severe disease indicated by a CAI score greater than 11 (P = 0.05), (iii) disease duration of less than 1 year (P < 0.05), and (iv) C-reactive protein levels before treatment (P < 0.01). These results suggest that the early initiation of LCAP is beneficial in patients with steroid-resistant UC.

High iodine (substrate) turnover Graves' disease: the intriguing ‘rapid responder’ variant of thyrotoxicosis

Factors determining the responsiveness to antithyroid drugs (ATDs) in Graves' disease are not fully known. Notwithstanding the typical pattern and tempo of thyroid hormone responses to thionamides, the existence of an unusual subset of Graves' disease with extraordinarily rapid thyroid hormone responses to ATDs will prove challenging even to the expert clinician. Termed 'rapid responder Graves' disease' or 'high turnover Graves' disease', the serum thyroxine (FT4) and triiodothyronine (FT3) of patients with this variant of thyrotoxicosis can decline precipitously during the initiation of ATDs and yet escalate acutely upon discontinuation of pharmacological intervention. We describe a case that presented with low serum FT4 and FT3 in association with suppressed serum thyrotropin (TSH) concentrations soon after starting carbimazole even at a low dose. The erratic clinical course comprising largely of serum FT4 nadirs and peaks is elaborated to facilitate appreciation of the difficulty in the stabilization of the thyroid with ATDs. The possible pathogenetic mechanisms for the chaotic fluctuations in thyroid hormones to minor changes in thionamide dose adjustments are discussed as well.

Immunological and mutagenic actions of ribavirin monotherapy preceding combination therapy with interferon for patients with chronic hepatitis C

We aimed to investigate the effects of ribavirin on hepatitis C virus (HCV). Immunological and virological effects were analysed in patients undergoing treatment with ribavirin monotherapy prior to the initiation of combination therapy with interferon-alpha. A total of 25 patients with chronic HCV infection were enrolled in this study. All patients received ribavirin for 4 weeks during monotherapy; subsequently, interferon-alpha2b was additionally given as combined therapy. Patients were divided into two groups according to virological response. A rapid viral responder (RVR) was defined as a patient in whom HCV RNA became undetectable within 4 weeks after combination therapy. The changes of the T-helper (Th)1/Th2 subset of peripheral blood CD4(+) T-cells, serum cytokine levels and the alignment of the interferon sensitivity-determining region (ISDR) during ribavirin monotherapy were analysed by flow cytometry, ELISAs and sequencing methods. A total of 17 patients were classed as RVR. In the RVR group, the mean +/-sd serum alanine aminotransferase levels significantly decreased (before treatment 103 +/-92 IU/l and after treatment 57 +/-46 IU/l; P<0.05) during ribavirin monotherapy. The mean +/-sd Th1/Th2 ratio significantly increased (before treatment 13.9 +/-5.1 and after treatment 16.7 +/-6.2; P<0.05), but did not change in the non-RVR group. The levels of Th2 cytokines (interleukin-10 and soluble CD30) significantly decreased, especially in the RVR group. The mean +/-sd mutation rates of ISDR at the nucleotide level increased in the RVR group (before treatment 2.6 +/-0.9 sites/clone and after treatment 3.9 +/-1.6 sites/clone; P<0.05), but did not change in the non-RVR group. Ribavirin administration might increase the efficacy of interferon therapy for patients with chronic hepatitis C by stimulating the host immune system and promoting HCV gene mutation.

HCV-Specific T-Cell Response in Relation to Viral Kinetics and Treatment Outcome (DITTO-HCV Project)

The second slope of viral decline induced by interferon treatment has been suggested to be influenced mainly by the hepatitis C virus (HCV)-specific T-cell response; however, this hypothesis needs to be validated by results derived from experimental studies. To address this issue, the HCV-specific T-cell response of 32 genotype-1-infected patients of the 270 patients enrolled in the dynamically individualized treatment of hepatitis C infection and correlates of viral/host dynamics phase III, open-label, randomized, multicenter trial was studied in relation to viral kinetics and treatment outcome. Greater proliferative responses by HCV-specific CD8 cells were found before treatment in patients with a fast viral decline and with a sustained viral response. However, no significant improvement of HCV-specific CD8 responses was observed in the first weeks of therapy in both rapid viral responder and non-rapid viral responder patients. A mild enhancement of proliferative T-cell responses and a partial restoration of the cytotoxic T-cell potential was expressed only late during treatment, likely favored by HCV clearance. Early restoration of an efficient T-cell response does not seem to be an essential requirement for a rapid viral decline in the first weeks of treatment. However, patients presenting a better HCV-specific CD8 cell proliferative potential at baseline are more likely to present a rapid and sustained viral response. Therefore, future treatment protocols should consider the development of strategies aimed at improving HCV-specific T-cell responses.

Protective Effect ofHeat Shock Proteins 70.1and70.3on Retinal Photic Injury after Systemic Hyperthermia

This study aimed to determine the relationship between the heat shock protein 70 from hsps70.1 and 70.3 on retinal photic injury after systemic hyperthermia. Eight-week-old female C57BU6 mice were kept at a constant temperature of 41-42 degrees C for 25-30 minutes. After dark-adaptation for 8 hours, intense light of 11000 lux was maintained for 6 hours. Histology and immunohistochemistry for the inducible heat shock protein 70 (hsp70), the constitutive heat shock protein 70 (hsc70), and westem blot analysis, reverse transcriptase-polymerase chain reaction for hsp70.1 and hsp70.3 were performed just before photic injury and after 1, 4, 7, and 14 days. Light-induced retinal degeneration was prevented by thermotolerance. After hyperthermia, hsp70 was densely expressed in the inner segment of the photoreceptor layer on the photic injury. Hsp70 expression increased for 4 days after photic injury and slowly decreased thereafter. mRNA from hsp70.3 was induced earlier than that of hsp70.1. Retinal photic injury was prevented by hyperthermia-induced hsp70. Hsp70 from hsp70.3 may be a rapid and short-lived responder, and that from hsp70.1 is a slower and more sustained responder. Hsp70 from hsp70.3 may be an initial retinal chaperone while hsp70 from hsp70.1 may be a sustained chaperone.

Activation of ET a receptors is partially responsible for the rapid increase in haematocrit induced by bacterial lipopolysaccharide in the rat

It is believed that changes in the production and release of endothelin-1 (ET-1) are mediated over prolonged periods, and, therefore, that it is unlikely that ET-1 mediates rapid responses within the circulation. Here we show that ET-1 is involved in the rapid changes produced by injection of LPS in vivo. In anaesthetised rats, a bolus of LPS induced an increase in haematocrit and a fall in blood pressure within 10 min. The increase in haematocrit was reduced by administration of antagonists selective for endothelin ET a receptors, while the accompanying decrease in MAP was potentiated. Thus, activation of ET a receptors is partially responsible for the rapid increase in haematocrit seen in this model. This clearly demonstrates that ET-1 can act as a rapid responder to acute cardiovascular challenges.

Prolactin-brain interactions in the induction of maternal behavior in rats

Most adult female mammals display an immediate onset of maternal care toward their offspring at parturition, whereas the responses of inexperienced, nulliparous females are often less intense or absent. The shift from being a slow or nonresponder in nulliparous females to a rapid responder at parturition in primiparous animals is induced in part by the endocrine changes of pregnancy. This report reviews recent evidence demonstrating a role for prolactin in the stimulation of maternal behavior in the rat. Moreover, new findings are presented that indicate that endogenous rat prolactin acts centrally to stimulate maternal behavior in steroid-primed, nulliparous rats and that the ventromedial hypothalamus in addition to the medial preoptic area are important neural substrates regulating the rapid induction of maternal behavior at parturition.

Functional correlations between mucosal mast cell activity and immunity to Trichinella spiralis in high and low responder mice

Levels of intestinal mast cell protease (IMCP) were quantified in serum, gut tissue and in intestinal fluids taken from mice infected with Trichinella spiralis during primary and secondary infections. The ability to generate a mast cell response was dependent on the response phenotype of the mouse strain used. The mast cell response in rapid responder mice (NIH) occurred sooner and was more pronounced than in either intermediate (SWR) and low responder (B1O) mice. This pattern was also reflected in the concentration of IMCP found in various tissues examined. The correlations between IMCP concentrations in blood, and worm expulsion, are discussed.