Comparative study of secretion by vagotomized and isotransplanted stomachs in the rat

An acute observation of gastric secretion by syngeneic stomach transplants in Lewis male rats was compared to the gastric secretory fate of normal, pylorus-ligated, vagotomized, and combined pylorus ligation and vagotomized Lewis rats. A 5 day observation was sufficient before sympathetic fibers and vagal channels could be regenerated. A total of 36 rats were divided into five groups of which group I (ten normals), group II (five vagotomized), group III (pylorus-ligated), group IV (six vagotomized and pylorus-ligated), and group V (five syngeneic stomach-transplanted, five animals served as donors), and those stomachs were intubated to collect gastric juice by housing animals in Bollman cages. Whereas group V animals secreted a mean 24 hr gastric juice volume of 12.5 +/- 6.4 ml with free acid secretion of 0.15 +/- 0.01 mEq/24 hr, animals in groups I, II, III, and IV secreted 24.4 +/- 2.9 ml, 23.3 +/- 1.1 ml, 25.5 +/- 3.4 ml, 22.4 +/- 0.5 ml, respectively, for 24 hr periods with free acid secretions of varying rates. From these observations, the transplanted stomach mean secretory rate averaged half that of the normal stomach.     

Importance of transient receptor potential vanilloid 4 (TRPV4) in epidermal barrier function in human skin keratinocytes

The state of the skin changes drastically depending on the ambient temperature. Skin epidermal keratinocytes express thermosensitive transient receptor potential vanilloid (TRPV) cation channels, TRPV3 and TRPV4. These multimodal receptors are activated by various kinds of chemical and physical stimuli, including warm temperatures (>30°C). It has been suggested that TRPV4 is involved in cell–cell junction maturation; however, the effect of temperature fluctuations on TRPV4-dependent barrier homeostasis is unclear. In the present study, we demonstrated that activation of TRPV4 was crucial for barrier formation and recovery, both of which were critical for the prevention of excess dehydration of human skin keratinocytes. TRPV4 activation by physiological skin temperature (33°C), GSK1016790A or 4α-PDD allowed influx of Ca²⁺ from extracellular spaces which promoted cell–cell junction development. These changes resulted in augmentation of intercellular barrier integrity in vitro and ex vivo. TRPV4 disruption reduced the increase in trans-epidermal resistance and increased intercellular permeation after a Ca²⁺ switch. Furthermore, barrier recovery after the disruption of the stratum corneum was accelerated by the activation of TRPV4 either by warm temperature or a chemical activator. Our results suggest that physiological skin temperatures play important roles in cell–cell junction and skin barrier homeostasis through TRPV4 activation.     

Polycyclic aromatic hydrocarbon increases mRNA level for interleukin 1 beta in human fibroblast-like synoviocyte line via aryl hydrocarbon receptor

Rheumatoid arthritis (RA) is characterized by proliferation of synoviocytes that produce proinflammatory cytokines, which is implicated in the pathogenesis of the disease. Among the cytokines, IL-1 is the critical mediator of the disease. When human fibroblast-like synoviocytes line, MH7A, was treated with 3-methylcholanthrene (3-MC), a polycyclic aromatic hydrocarbon (PAH), mRNA of IL-1beta was up-regulated. MH7A cells express functional aryl hydrocarbon receptor (AhR) as shown by 3-MC-inducible CYP1A1 mRNA expression. The effect of 3-MC was inhibited by alpha-napthoflavone, an AhR antagonist, indicating that the effect of 3-MC is mediated via AhR. Benzo[a]pyrene (B[a]P) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) also up-regulated mRNA level of IL-1beta in the cells via AhR. As PAHs are much contained in cigarette smoke, these findings provide the possible basis for epidemiological studies indicating a strong association between heavy cigarette smoking and outcome of RA.     

Practice patterns regarding prostate cancer and benign prostatic hyperplasia in Japanese primary care practitioners

OBJECTIVE: Although primary care practitioners (PCP) take an active role in diagnosis of prostate disorders in Western countries, how PCP take part in management of prostate disease still differs worldwide by country. We investigated practice and referral patterns concerning prostate disease among Japanese PCP and compared these with reported patterns in the West. METHODS: A 26-question multiple-choice questionnaire was mailed to 935 PCP in Tokyo for anonymous completion. Most items involved prostate cancer screening or management of benign prostatic hyperplasia (BPH). RESULTS: The survey was completed by 281 non-urological practitioners, among whom digital rectal examination was performed by 43%. Prostate-specific antigen (PSA) was determined in serum by 89%. For asymptomatic men older than 50, serum PSA was determined routinely each year by only 17%. When PSA was 4.1-10.0 ng/mL, 70% of respondents immediately referred patients to urologists, while 18% did not make a referral unless PSA exceeded 10.0 ng/mL. Seventy-four percent prescribed medication for benign prostate hypertrophy; among these respondents, 87% reported common use of alpha-blockers. Although 31% of respondents were aware of the International Prostate Symptom Score (IPSS), only 2% used it. CONCLUSIONS: Although Japanese PCP were involved increasingly in diagnosis and management of prostate disease, degree and proficiency of involvement were too limited and less than in Western countries. Continuing medical education appears desirable for PCP in Japan regarding prostate disease.     

Association of ITPA polymorphism with outcomes of peginterferon-α plus ribavirin combination therapy

AIM:To analyzed the association between inosine triphosphatase(ITPA)(rs1127354) genotypes and sustained virological response(SVR) rates in peginterferon(Peg-IFN)α + ribavirin(RBV) treatment.METHODS:Patients who underwent Peg-IFNα + RBV combination therapy were enrolled(n = 120) and they had no history of other IFN-based treatments.Variation in hemoglobin levels during therapy,cumulative reduction of RBV dose,frequency of treatment withdrawal,and SVR rates were investigated in each ITPA genotype.RESULTS:In patients with ITPA CC genotype,hemoglobin decline was significantly greater and the percentage of patients in whom total RBV dose was < 60% of standard and/or treatment was withdrawn was significantly higher compared with CA/AA genotype.However,SVR rates were equivalent between CC and CA/AA genotypes,and within a subset of patients with Interleukin 28B(IL28B)(rs8099917) TT genotype,SVR rates tended to be higher in patients with ITPA CC genotype,although the difference was not significant.CONCLUSION:ITPA CC genotype was a disadvantageous factor for Peg-IFNα + RBV treatment in relation to completion rates and RBV dose.However,CC genotype was not inferior to CA/AA genotype for SVR rates.When full-length treatment is accomplished,it is plausible that more SVR is achieved in patients with ITPA CC variant,especially in a background of IL28B TT genotype.     

Early decline of the HCV core antigen can predict SVR in patients with HCV treated by Pegylated interferon plus ribavirin combination therapy

OBJECTIVE: Pegylated interferon (PEG‐IFN) plus ribavirin (RBV) combination therapy is now a popular treatment for patients with chronic hepatitis C; however, the reported sustained virologic response (SVR) rate remains at nearly 50% in genotype 1b infected patients. Therefore, it is of clinical benefit to be able to predict the effect of combination therapy on individual patients earlier in the treatment. We estimated the predictive serum HCV core antigen levels for SVR in the early therapeutic stage of combination therapy. METHODS: The HCV core antigen in patients with high‐level HCV viremia, in whom standard PEG‐IFNα2b plus RBV combination therapy had been completed, was measured at baseline and at 3, 7, 14, 28 and 84 days of treatment, and their SVR was determined at 24 weeks after treatment. Sixty genotype 1b‐ and 30 genotype 2‐infected patients were included. RESULTS: Thirty (50%) genotype 1b and 27 (90%) genotype 2 patients achieved a SVR. In genotype 1b patients the decline of HCV core antigen levels was statistically different between the SVR and non‐SVR groups. When we defined a separation level at 500 fmol/L, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for SVR at day 7 was 79.4%, 88.5%, 90%, 76.7%, and 83.3%, respectively. In genotype 2 patients, there was no significant difference in the HCV core antigen values between the SVR and non‐SVR groups. CONCLUSION: In genotype 1b patients, 500 fmol/L of HCV core antigen level at day 7 was the best predictor for therapeutic response in the early stage of treatment.     

Genetic polymorphisms of OCT-1 confer susceptibility to severe progression of primary biliary cirrhosis in Japanese patients

Background

To identify the genetic factors involved in the pathogenesis of primary biliary cirrhosis (PBC), we focused on the organic cation transporter 1 (OCT1/SLC22A1), which is closely associated with phosphatidylcholine synthesis in hepatocytes.

Methods

We selected four (rs683369, rs2282143, rs622342 and rs1443844) OCT-1 single nucleotide polymorphisms (SNPs), and genotyped these SNPs using the TaqMan probe method in 275 Japanese PBC patients and 194 gender-matched, healthy volunteers as controls.

Results

The Chi-square test revealed that the rs683369 variant allele (G) was associated with insusceptibility to PBC development [P = 0.009, odds ratio (OR) 0.60, 95 % confidence interval (CI) 0.40–0.88] in an allele model, and that the rs683369 variant allele (G) was associated with jaundice-type progression in a minor allele dominant genotype model (P = 0.032, OR 3.10, 95 % CI 1.05–9.14). The OCT-1 rs2282143 variant (T) and rs622342 variant (C) were also associated with jaundice-type progression in a minor allele recessive genotype model (P = 0.0002, OR 10.58, 95 % CI 2.36–47.54, and P = 0.006, OR 7.84, 95 % CI 1.39–44.36, respectively). Furthermore, the association of OCT-1 rs683369 and rs622342 with susceptibility to jaundice-type progression was confirmed by a replication study with a distinct set of PBC patients who underwent liver transplantation.

Conclusions

The present study is the first report on the association of OCT-1 genetic polymorphisms with the overall development and jaundice-type progression of PBC.