Twenty-four weeks of interferon alpha-2b in combination with ribavirin for Japanese hepatitis C patients: sufficient treatment period for patients with genotype 2 but not for patients with genotype 1.

BACKGROUND: Hepatitis C virus (HCV) RNA titer and HCV genotype are two major determinants of the outcome of interferon (IFN) monotherapy. To clarify the usefulness of combination therapy with IFN and ribavirin in Japanese hepatitis C patients, we treated patients with a relatively high dose of IFN in combination with ribavirin for 24 weeks and examined the effects in relation to the viral parameters. METHODS: Two hundred and ninety-five patients were enrolled in the study. The patients received either 6 or 10 million units (MU) of interferon alpha-2b every day for 2 weeks and then three times a week for 22 weeks with a daily dose of either 600 or 800 mg of ribavirin. The treatment response and safety of this treatment were examined. RESULTS: The sustained virologic response (SVR) rates were 26.8% in genotype 1 and 76.5% in genotype 2 (P < 0.001), and 36.1% with the 6 MU group and 45.8% with the 10 MU group (P = 0.09). Multivariate analysis indicated that SVR was associated with genotype 2, HCV RNA <500 kilointernational unit/ml (kIU/ml), and HCV RNA undetectability at week 8 of treatment. CONCLUSION: Our current study showed that a 24-week course of IFN plus ribavirin combination therapy was effective with respect to virologic response in Japanese hepatitis C patients, particularly in patients with HCV genotype 2.     

L-Kynurenine, an amino acid identified as a sex pheromone in the urine of ovulated female masu salmon

Many animals employ sex pheromones to find mating partners during their reproductive seasons. However, most sex pheromones of vertebrates remain to be identified. Over the past 20 years, steroids and prostaglandins have been identified as sex pheromones in several fishes. These pheromones are broadly termed "hormonal pheromones" because they or their precursors act as hormones in these fishes. Hitherto, no other type of sex pheromone has been unambiguously identified in teleost fish. Here we report the identification of a "nonhormonal pheromone" in teleost fish. The urine of the reproductively mature female masu salmon (Oncorhynchus masou) contains a male-attracting pheromone. Bioassay-guided fractionation yielded an active compound that was identical to L-kynurenine in spectral and chromatographic properties. L-Kynurenine is a major metabolite of L-tryptophan in vertebrates. This pheromone elicits a male-specific behavior at even picomolar concentrations; its electrophysiological threshold is 10(-14) M. L-Kynurenine is a reasonable substance for female masu salmon to advertise their readiness for mating.     

Tensin3 is a novel thyroid-specific gene

Thyroid-specific genes, such as thyroid peroxidase, thyroglobulin, Na+/I- symporter and thyroid-stimulating hormone receptor, play fundamental roles in thyroid function and relate to many pathological conditions. Using sequence specific-differential display, we detected three genes that showed higher expression levels in normal thyroid tissues than in thyroid tumor tissues. After subcloning and sequencing analysis, one of the genes was revealed to be tensin3. The expression level of tensin3 was examined with real-time quantitative PCR analysis. Its expression levels were more depressed in thyroid tumor tissues than in normal thyroid tissues. The decrease was even more evident in two anaplastic carcinomas. High and moderate levels of tensin3 mRNA expression were observed in the thyroid and placenta respectively. Tensin3 mRNA was expressed only in low levels in other tissues, such as the brain, heart, lung, liver, pancreas, kidney, skeletal muscle, white blood cells and prostate. These results show that tensin3 is a novel thyroid-specific gene and further investigations may reveal its relation to thyroid function or thyroid disease.     

Direct evidence for ex vivo expansion of human hematopoietic stem cells

To characterize human hematopoietic stem cells (HSCs), xenotransplantation techniques such as the severe combined immunodeficiency (SCID) mouse repopulating cell (SRC) assay have proven the most reliable methods thus far. While SRC quantification by limiting dilution analysis (LDA) is the gold standard for measuring in vitro expansion of human HSCs, LDA is a statistical method and does not directly establish that a single HSC has self-renewed in vitro. This would require a direct clonal method and has not been done. By using lentiviral gene marking and direct intra-bone marrow injection of cultured CD34+ CB cells, we demonstrate here the first direct evidence for self-renewal of individual SRC clones in vitro. Of 74 clones analyzed, 20 clones (27%) divided and repopulated in more than 2 mice after serum-free and stroma-dependent culture. Some of the clones were secondary transplantable. This indicates symmetric self-renewal divisions in vitro. On the other hand, 54 clones (73%) present in only 1 mouse may result from asymmetric divisions in vitro. Our data demonstrate that current ex vivo expansion conditions result in reliable stem cell expansion and the clonal tracking we have employed is the only reliable method that can be used in the development of clinically appropriate expansion methods.     

Alterations in basal and glucose-stimulated voltage-dependent Ca2+ channel activities in pancreatic beta cells of non-insulin-dependent diabetes mellitus GK rats.

In genetically occurring non-insulin-dependent diabetes mellitus (NIDDM) model rats (GK rats), the activities of L- and T-type Ca2+ channels in pancreatic beta cells are found to be augmented, by measuring the Ba2+ currents via these channels using whole-cell patch-clamp technique, while the patterns of the current-voltage curves are indistinguishable. The hyper-responsiveness of insulin secretion to nonglucose depolarizing stimuli observed in NIDDM beta cells could be the result, therefore, of increased voltage-dependent Ca2+ channel activity. Perforated patch-clamp recordings reveal that the augmentation of L-type Ca2+ channel activity by glucose is markedly less pronounced in GK beta cells than in control beta cells, while glucose-induced augmentation of T-type Ca2+ channel activity is observed neither in the control nor in the GK beta cells. This lack of glucose-induced augmentation of L-type Ca2+ channel activity in GK beta cells might be causatively related to the selective impairment of glucose-induced insulin secretion in NIDDM beta cells, in conjunction with an insufficient plasma membrane depolarization due to impaired closure of the ATP-sensitive K+ channels caused by the disturbed intracellular glucose metabolism in NIDDM beta cells.     

Transcutaneous iodine absorption in adult patients with thyroid cancer disinfected with povidone-iodine at operation.

Povidone-iodine is used as disinfection in patients undergoing many kinds of operations. Several cases of thyroid dysfunction induced by transcutaneous absorption of povidone-iodine have been reported in small infants. However, transcutaneous absorption was not clearly reported in adults. The aim of this study was to assess transcutaneous absorption of iodine in patients who received single topical application with povidoneiodine and serial changes of urinary iodine excretion under the condition with a simple iodine-restricted diet in Japan, an iodine-sufficient area. Sixty-eight patients with thyroid carcinoma undergoing total thyroidectomy received single skin disinfection with either povidone-iodine (group A; n = 47) or chlohexidine gluconate, a noniodine containing biguanide (group B; n = 21). In group A, urinary iodine excretion on the first day after operation increased up to 7 times that of the preoperative value. The amounts of urinary iodine correlated positively with operating time. Increased urinary iodine, however, returned to preoperative values on the third or fifth day after operation. In group B, there was no increase in urinary iodine excretion and urinary iodine excretion was ranged from 54 to 193 microg/g of creatinine on the third day of operation. In conclusion, a large amount of povidone-iodine was absorbed through healthy skin even in adults. This may possibly interfere with scintigraphy or radioactive iodine treatment, or cause thyroid disinfection in susceptible patients.     

Hyperamylasemia induced by percutaneous papillary balloon dilatation for symptomatic choledocholithiasis

BACKGROUND/AIMS: We investigated the relationship between percutaneous papillary balloon dilatation (PPBD) and hyperamylasemia after PPBD. METHODOLOGY: We studied the rate of pancreatitis and asymptomatic hyperamylasemia after PPBD for choledocholithiasis in 64 symptomatic patients. Pancreatitis was defined as epigastric pain combined with at least a 3-fold rise in serum amylase at 24 hours after PPBD. Asymptomatic hyperamylasemia was defined as a rise in serum amylase (normal range, 50 to 160 IU/L) without epigastric pain. RESULTS: The stones were successfully pushed out into the duodenum in all patients. Three patients developed post-PPBD pancreatitis, graded moderate in one and mild in two. Serum amylase values were elevated over the normal upper limit in 21 patients, 33%, over 3-fold in 10, 16% over 1000 IU/L in 6, 9%. Asymptomatic hyperamylasemia was observed in 18 patients. The amylase value after PPBD was elevated to more than 160 IU/L in 44% (17/39) of patients 80 years old or under vs. 16% (4/25) of patients older than 80 and in 23% (10/44) of patients with intrahepatic bile duct dilatation on admission vs. 55% (11/20) of patients without it, with a significant difference, respectively (p<0.05). The amylase value after PPBD was elevated to more than 1000 IU/L in 15% (6/39) of patients 80 years old or under vs. 0% (0/25) of patients older than 80 and in 29% (4/14) of patients with bile duct stones having a horizontal diameter of 8mm or smaller and 4% (2/50) of patients with stones larger than 8mm (p < 0.05 and p<0.01, respectively). CONCLUSIONS: We believe that postoperative continuous decompression of the bile duct by PPBD is reliable and that it contributed to the prevention of severe pancreatitis. We conclude that PPBD can be performed more safely in symptomatic patients older than 80 with choledocholithiasis with intrahepatic bile duct dilatation at the time of admission.     

Decreased cell-mediated immune status in colorectal cancer patients with hepatic metastasis

BACKGROUND/AIMS: Depression of cell-mediated immunity frequently accompanies solid tumor malignancy, and appears to be worsened as the disease progresses. In this study, we investigated cell-mediated immune status in colorectal cancer patients. METHODOLOGY: Interleukin-2 (IL-2) productivity by phytohemagglutinin (PHA)-stimulated non-adherent peripheral blood mononuclear cells (PBMC), and prostaglandin E2 (PGE2) productivity by LPS-stimulated adherent PBMC were investigated in colorectal cancer patients with hepatic metastasis (n=20) and without hepatic metastasis (n=20), and in non-malignant disease controls (n=20). Percentages of peripheral blood T-cell subsets and NK activity were also investigated. RESULTS: In the colorectal cancer patients with hepatic metastasis IL-2 productivity was significantly decreased, compared with the controls. However, the percentages of T-cell subsets and NK activity were not significantly different among the groups. Meanwhile, PGE2 productivity in the patients with hepatic metastasis was significantly increased, compared with the other groups, and was significantly correlated with the hepatic tumor load. CONCLUSIONS: Tumor-bearing state, especially metastasis to the liver, may influence immune status of the patient. For evaluating cellular immunity status, cytokine productivity by activated lymphocytes and monocytes may be a more sensitive marker rather than other conventional immunological parameters, and may also provide useful information for immune intervention in the treatment of patients from this point of view.     

Effect of treatment with interferon α-2b and ribavirin in patients infected with genotype 2 hepatitis C virus

Aim:  Nearly 20% of chronic hepatitis C (CHC) patients with genotype 2 hepatitis C virus (HCV) infection are not curable, even by interferon (IFN)–ribavirin combination therapy. The aim of this study is to investigate the factors that determine the efficacy of combination therapy in patients with genotype 2 HCV infection.
Methods:  Fifty patients with CHC who underwent a treatment of 6 MU IFN α-2b with ribavirin for 24 weeks were retrospectively analyzed.
Results:  All the patients showed no serum HCV-RNA within 12 weeks after starting the therapy. Forty-one of the 50 patients (82%) achieved a sustained virological response (SVR). The age, sex, genotype (2a vs. 2b) and grade/stage of the liver by histopathology and pretreatment viral load werenot different between the sustained responders and relapsers. Univariate analysis showed that an earlier viral clearance from blood and a larger number of amino acid substitutions in the interferon sensitivity determining region (ISDR) were predictors of SVR. Multivariate analysis showed that a large number of amino acid substitutions in the ISDR was a predictor of SVR.
Conclusion:  The characterization of the amino acid sequences of ISDR may be helpful for predicting a relapse after combination therapy in patients with genotype 2 HCV infection.